Symbyax

Selective Serotonin Reuptake Inhibitor (SSRI) Antidepressant and Antidepressant Augmentation Combinations

Oral Administration

Administer orally with or without food. If stomach upset should occur, may administer with meals.

Severe

coma / Early / 0.1-1.0
peptic ulcer / Delayed / 0.1-1.0
laryngospasm / Rapid / 0-0.1
GI obstruction / Delayed / 0-0.1
pancreatitis / Delayed / 0-0.1
ileus / Delayed / 0-0.1
GI bleeding / Delayed / 0-0.1
exfoliative dermatitis / Delayed / 0-0.1
suicidal ideation / Delayed / Incidence not known
tardive dyskinesia / Delayed / Incidence not known
esophageal ulceration / Delayed / Incidence not known
renal failure / Delayed / Incidence not known
optic neuritis / Delayed / Incidence not known
bradycardia / Rapid / Incidence not known
pulmonary embolism / Delayed / Incidence not known
stroke / Early / Incidence not known
thrombosis / Delayed / Incidence not known
rhabdomyolysis / Delayed / Incidence not known
eosinophilic pneumonia / Delayed / Incidence not known
agranulocytosis / Delayed / Incidence not known
aplastic anemia / Delayed / Incidence not known
serum sickness / Delayed / Incidence not known
angioedema / Rapid / Incidence not known
toxic epidermal necrolysis / Delayed / Incidence not known
bronchospasm / Rapid / Incidence not known
anaphylactoid reactions / Rapid / Incidence not known
Stevens-Johnson syndrome / Delayed / Incidence not known
erythema multiforme / Delayed / Incidence not known
Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) / Delayed / Incidence not known
vasculitis / Delayed / Incidence not known
erythema nodosum / Delayed / Incidence not known
hepatic necrosis / Delayed / Incidence not known
hepatic failure / Delayed / Incidence not known
neuroleptic malignant syndrome / Delayed / Incidence not known
serotonin syndrome / Delayed / Incidence not known
cardiac arrest / Early / Incidence not known
atrial fibrillation / Early / Incidence not known
water intoxication / Delayed / Incidence not known
SIADH / Delayed / Incidence not known
bone fractures / Delayed / Incidence not known
persistent pulmonary hypertension of the newborn / Delayed / Incidence not known
neonatal abstinence syndrome / Early / Incidence not known
pulmonary hypertension / Delayed / Incidence not known

Moderate

hypercholesterolemia / Delayed / 2.5-36.2
hypertriglyceridemia / Delayed / 0-15.1
edema / Delayed / 15.0-15.0
elevated hepatic enzymes / Delayed / 0-9.0
blurred vision / Early / 5.0-5.0
impotence (erectile dysfunction) / Delayed / 2.0-2.0
euphoria / Early / 0.1-1.0
myoclonia / Delayed / 0.1-1.0
ataxia / Delayed / 0.1-1.0
dysarthria / Delayed / 0.1-1.0
dystonic reaction / Delayed / 0-1.0
gastritis / Delayed / 0.1-1.0
urinary retention / Early / 0.1-1.0
anemia / Delayed / 0.1-1.0
thrombocytopenia / Delayed / 0.1-1.0
withdrawal / Early / 0.1-1.0
leukopenia / Delayed / 0-0.1
hyperbilirubinemia / Delayed / 0-0.1
osteoporosis / Delayed / 0-0.1
gout / Delayed / 0-0.1
amnesia / Delayed / 1.0
urinary incontinence / Early / 1.0
sinus tachycardia / Rapid / 2.0
peripheral vasodilation / Rapid / 1.0
hyperprolactinemia / Delayed / 28.0
QT prolongation / Rapid / 1.0
depression / Delayed / Incidence not known
akathisia / Delayed / Incidence not known
memory impairment / Delayed / Incidence not known
dysphemia / Delayed / Incidence not known
mania / Early / Incidence not known
pseudoparkinsonism / Delayed / Incidence not known
constipation / Delayed / Incidence not known
dysphagia / Delayed / Incidence not known
teeth grinding (bruxism) / Delayed / Incidence not known
ejaculation dysfunction / Delayed / Incidence not known
priapism / Early / Incidence not known
dysuria / Early / Incidence not known
cataracts / Delayed / Incidence not known
orthostatic hypotension / Delayed / Incidence not known
hypotension / Rapid / Incidence not known
galactorrhea / Delayed / Incidence not known
bleeding / Early / Incidence not known
platelet dysfunction / Delayed / Incidence not known
neutropenia / Delayed / Incidence not known
cholestasis / Delayed / Incidence not known
jaundice / Delayed / Incidence not known
hepatitis / Delayed / Incidence not known
hyponatremia / Delayed / Incidence not known
osteopenia / Delayed / Incidence not known
hypoglycemia / Early / Incidence not known
hyperlipidemia / Delayed / Incidence not known

Mild

drowsiness / Early / 24.0-27.0
weight gain / Delayed / 20.0-25.0
appetite stimulation / Delayed / 17.0-20.0
xerostomia / Early / 15.0-15.0
fatigue / Early / 12.0-12.0
tremor / Early / 9.0-9.0
restlessness / Early / 3.0-4.0
arthralgia / Delayed / 4.0-4.0
flatulence / Early / 3.0-3.0
musculoskeletal pain / Early / 3.0-3.0
asthenia / Delayed / 3.0-3.0
abdominal pain / Early / 2.0-2.0
fever / Early / 2.0-2.0
sinusitis / Delayed / 2.0-2.0
emotional lability / Early / 0.1-1.0
vomiting / Early / 0.1-1.0
nausea / Early / 0.1-1.0
urinary urgency / Early / 0.1-1.0
amenorrhea / Delayed / 0.1-1.0
epistaxis / Delayed / 0.1-1.0
pruritus / Rapid / 0.1-1.0
alopecia / Delayed / 0.1-1.0
xerosis / Delayed / 0.1-1.0
yawning / Early / 0.1-1.0
libido increase / Delayed / 0-0.1
hyperkinesis / Delayed / 0-0.1
xerophthalmia / Early / 0-0.1
purpura / Delayed / 0-0.1
diarrhea / Early / 1.0
increased urinary frequency / Early / 1.0
mastalgia / Delayed / 1.0
menorrhagia / Delayed / 1.0
dysgeusia / Early / 1.0
menstrual irregularity / Delayed / 1.0
ecchymosis / Delayed / 1.0
photosensitivity / Delayed / 1.0
weight loss / Delayed / 1.0
chills / Rapid / 1.0
insomnia / Early / Incidence not known
anxiety / Delayed / Incidence not known
headache / Early / Incidence not known
dyspepsia / Early / Incidence not known
hypersalivation / Early / Incidence not known
libido decrease / Delayed / Incidence not known
dysmenorrhea / Delayed / Incidence not known
orgasm dysfunction / Delayed / Incidence not known
anosmia / Delayed / Incidence not known
syncope / Early / Incidence not known
back pain / Delayed / Incidence not known
restless legs syndrome (RLS) / Delayed / Incidence not known
gynecomastia / Delayed / Incidence not known
breast enlargement / Delayed / Incidence not known
hyperhidrosis / Delayed / Incidence not known
urticaria / Rapid / Incidence not known
maculopapular rash / Early / Incidence not known
rash / Early / Incidence not known
polydipsia / Early / Incidence not known

Children, suicidal ideation

Olanzapine; fluoxetine is indicated for use in pediatric patients 10 years and older for the treatment of bipolar depression. Safety has not been systematically studied in children less than 10 years of age, and use for depression in pediatric patients is not established. In a pooled analysis of placebo-controlled trials of antidepressants (n = 4,500 pediatrics and 77,000 adults), there was an increased risk for suicidal thoughts and behaviors in children, adolescents, and adults 24 years of age and younger receiving an antidepressant versus placebo, with considerable variation in the risk of suicidality among drugs. The difference in absolute risk of suicidal thoughts and behaviors across different indications was highest in those with major depression. The need for an antidepressant in children, adolescents, or young adults for any use must be weighed against the risk of suicidality; it is unknown if this risk extends to long-term use. All patients should be monitored for symptom worsening or suicidality, especially at treatment initiation or after dose changes. Caregivers and/or patients should immediately notify the prescriber of changes in behavior or suicidal ideation. A change to the treatment regimen or discontinuation of olanzapine; fluoxetine may be necessary in patients with emerging suicidality or worsening depression.

Dementia, geriatric, stroke

Geriatric patients may be more susceptible than younger adults to anticholinergic effects, orthostatic hypotension, movement disorders, QT prolongation, and CNS depression with olanzapine; fluoxetine. Initiate at a low dose, with longer intervals between dosage increases. Antipsychotics are not approved for the treatment of dementia-related psychosis in geriatric patients and use should be avoided if possible due to an increase in morbidity and mortality in geriatric patients with dementia receiving atypical antipsychotics. Deaths have typically resulted from heart failure, sudden death, or infections (primarily pneumonia). An increased incidence of cerebrovascular adverse events (e.g., stroke, transient ischemic attack), including fatal events, has also been reported. The Beers Criteria consider antipsychotics and selective serotonin reuptake inhibitors to be potentially inappropriate medications (PIMs) in elderly patients. The Beers panel recommends avoiding olanzapine and/or fluoxetine in geriatric patients with syncope, delirium, dementia, or Parkinson's disease, and in geriatric men with lower urinary tract symptoms/benign prostatic hyperplasia. If the use of olanzapine; fluoxetine is necessary in geriatric patients with a history of falls or fractures, consider reducing the use of other CNS depressants and implement other fall risk strategies. Due to the potential for drug-induced hyponatremia and SIADH, sodium concentrations should be closely monitored when olanzapine; fluoxetine is initiated and after dose changes. The federal Omnibus Budget Reconciliation Act (OBRA) regulates the use of antidepressants and antipsychotics in long-term care facilities; treatment duration and indication for use should follow pertinent literature and clinical practice guidelines. The rationale for use must be documented in the individual patient record. Monitor closely for worsening of moods and behaviors, depression, and suicidal behavior or thinking, especially during initiation of therapy and during dose changes. Some side effects can increase the risk of falls. When used to manage behavior, stabilize mood, or treat a psychiatric disorder, the facility should attempt to taper psychotropics as outlined in the OBRA guidelines, unless a taper is clinically contraindicated. Refer to the OBRA guidelines for complete information.

Symbyax

Rx

Atypical antipsychotic and SSRI combination
Used for treatment-resistant depression in adults, and also for depressive episodes of bipolar I disorder in adults and pediatric patients 10 years and older
Boxed warning related to an increased risk of suicidality in children, adolescents, and young adults, as well as regarding increased mortality risk in elderly patients treated for dementia-related psychosis

For acute and maintenance treatment of treatment-resistant depression. Oral dosage Adults

Initially, 6 mg olanzapine/25 mg fluoxetine PO once daily in the evening. Dosage adjustments, if indicated, can be made according to efficacy and tolerability. PATIENTS PREDISPOSED TO HYPOTENSIVE REACTIONS, OR WITH THE POTENTIAL FOR REDUCED METABOLISM OF OLANZAPINE OR FLUOXETINE (e.g., FEMALE, NON-SMOKER), OR PHARMACODYNAMICALLY SENSITIVE TO OLANZAPINE: Initially, olanzapine 3 mg/fluoxetine 25 mg to olanzapine 6 mg/fluoxetine 25 mg PO once daily in the evening, with cautious dose escalation. USUAL DOSE RANGE: Antidepressant efficacy was demonstrated in a range of olanzapine 6 to 18 mg and fluoxetine 25 to 50 mg once daily in those with treatment-resistant depression. Max: olanzapine/fluoxetine 18 mg/75 mg PO per day. In one maintenance trial, approximately 16% of patients receiving olanzapine; fluoxetine and 32% of patients receiving fluoxetine alone experienced relapse. The relapse rate and time to relapse over 27 weeks was statistically significant in favor of the olanzapine; fluoxetine combination. Periodically re-evaluate the benefits and risks of continued treatment.

Geriatric Adults

Initially, olanzapine 3 mg/fluoxetine 25 mg to olanzapine 6 mg/fluoxetine 25 mg PO once daily in the evening. Titrate with caution. USUAL ADULT DOSE RANGE: olanzapine 6 to 18 mg and fluoxetine 25 to 50 mg once daily. Adult Max: olanzapine/fluoxetine 18 mg/75 mg PO per day. Periodically re-evaluate the benefits and risks of continued treatment. Geriatric patients have not been sufficiently formally studied to determine whether they respond differently from younger patients; however, other reported clinical experience has not identified differences in responses.

For the acute treatment of bipolar depression associated with bipolar I disorder. Oral dosage Adults

6 mg olanzapine/25 mg fluoxetine PO once daily, initially. May adjust dose based on clinical response and tolerability. Usual dose: 6 to 12 mg/day olanzapine/25 to 50 mg/day fluoxetine. Max: 18 mg/day olanzapine/75 mg/day fluoxetine.

Older Adults

3 mg olanzapine/25 mg fluoxetine or 6 mg olanzapine/25 mg fluoxetine PO once daily, initially. May adjust dose slowly based on clinical response and tolerability. Usual dose: 6 to 12 mg/day olanzapine/25 to 50 mg/day fluoxetine. Max: 18 mg/day olanzapine/75 mg/day fluoxetine.

Children and Adolescents 10 to 17 years

3 mg olanzapine/25 mg fluoxetine PO once daily, initially. May adjust dose based on clinical response and tolerability. Usual dose: 6 to 12 mg/day olanzapine/25 to 50 mg/day fluoxetine. Max: 12 mg/day olanzapine/50 mg/day fluoxetine.

Hepatic Impairment

Initially, 3 mg/25 mg to 6 mg/25 mg PO once daily in the evening in adults. Dosage may need modification depending on clinical response and degree of hepatic impairment, but no quantitative recommendations are available. Titrate with caution.

Renal Impairment

No dosage adjustments are required. Higher concentrations of the metabolites of fluoxetine (e.g., norfluoxetine) may be present in patients with severe renal impairment (e.g., renal failure); however, use of a lower or less frequent dose is not routinely necessary in renally impaired patients.

Abarelix: (Major) Since abarelix can cause QT prolongation, abarelix should be avoided in combination with other drugs that are associated with QT prolongation, such as olanzapine. Drugs that cause hyperprolactinemia, such as olanzapine, may antagonize some of the actions of gonadotropin-releasing hormone medications.
Abciximab: (Moderate) Platelet aggregation may be impaired by selective serotonin reuptake inhibitors (SSRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication in patients receiving abciximab. Monitor closely for signs and symptoms of bleeding.
Abemaciclib: (Moderate) Monitor for an increase in abemaciclib-related adverse reactions if coadministration with fluoxetine is necessary; consider reducing the dose of abemaciclib in 50-mg decrements if toxicities occur. Discontinue abemaciclib for patients unable to tolerate 50 mg twice daily. Abemaciclib is a CYP3A4 substrate. Fluoxetine is a weak CYP3A4 inhibitor, but its metabolite, norfluoxetine, is a moderate CYP3A4 inhibitor. Coadministration with other moderate CYP3A4 inhibitors is predicted to increase the relative potency adjusted unbound AUC of abemaciclib plus its active metabolites (M2, M18, and M20) by approximately 1.6- to 2.4-fold.
Abrocitinib: (Major) Do not exceed an initial abrocitinib dose of 50 mg PO once daily or a maximum dose of 100 mg PO once daily if coadministered with fluoxetine. Concurrent use may increase the combined exposure of abrocitinib and its 2 active metabolites; monitor closely for adverse reactions. Abrocitinib is a CYP2C19 substrate and fluoxetine is a strong CYP2C19 inhibitor.
Acarbose: (Moderate) Atypical antipsychotic therapy may aggravate diabetes mellitus and cause metabolic changes such as hyperglycemia. Monitor patients on antidiabetic agents for worsening glycemic control. The atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Aggravation of diabetes mellitus has been reported. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition. (Moderate) In patients with diabetes mellitus, fluoxetine may alter glycemic control. Hypoglycemia has occurred during fluoxetine therapy. Hyperglycemia has developed in patients with diabetes mellitus following discontinuation of the drug. The dosage of insulin and/or other antidiabetic agents may need to be adjusted when therapy with fluoxetine is instituted or discontinued.
Acebutolol: (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.
Acetaminophen; Aspirin, ASA; Caffeine: (Moderate) The combined use of selective serotonin reuptake inhibitors and aspirin, ASA may elevate the risk for an upper GI bleed. SSRIs may inhibit serotonin uptake by platelets, augmenting the antiplatelet effects of aspirin. Additionally, aspirin impairs the gastric mucosa defenses by inhibiting prostaglandin formation.
Acetaminophen; Aspirin: (Moderate) The combined use of selective serotonin reuptake inhibitors and aspirin, ASA may elevate the risk for an upper GI bleed. SSRIs may inhibit serotonin uptake by platelets, augmenting the antiplatelet effects of aspirin. Additionally, aspirin impairs the gastric mucosa defenses by inhibiting prostaglandin formation.
Acetaminophen; Aspirin; Diphenhydramine: (Moderate) Olanzapine exhibits anticholinergic effects that may be clinically significant. Clinicians should keep this in mind when using antimuscarinics and other medications with anticholinergic activity in combination with olanzapine. Some medications exhibit additive anticholinergic effects include sedating H1-blockers. Olanzapine may also cause additive sedation with many of these drugs. (Moderate) The combined use of selective serotonin reuptake inhibitors and aspirin, ASA may elevate the risk for an upper GI bleed. SSRIs may inhibit serotonin uptake by platelets, augmenting the antiplatelet effects of aspirin. Additionally, aspirin impairs the gastric mucosa defenses by inhibiting prostaglandin formation.
Acetaminophen; Caffeine; Dihydrocodeine: (Major) Concomitant use of opioid agonists with olanzapine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with olanzapine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Also monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. Avoid prescribing opioid cough medication in patients taking olanzapine. (Moderate) Careful monitoring, particularly during treatment initiation and dose adjustment, is recommended during coadministration of dihydrocodeine and fluoxetine because of the potential risk of serotonin syndrome, reduced dihydrocodeine efficacy, and potential for opioid withdrawal symptoms. Discontinue dihydrocodeine if serotonin syndrome is suspected. Concomitant use may increase dihydrocodeine plasma concentrations, but decrease the plasma concentration of the active metabolite, dihydromorphine, resulting in reduced efficacy or symptoms of opioid withdrawal. Monitor patients closely at frequent intervals and consider a dosage increase of dihydrocodeine until stable drug effects are achieved. Discontinuation of fluoxetine could decrease dihydrocodeine plasma concentrations and increase dihydromorphine plasma concentrations resulting in prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If fluoxetine is discontinued, monitor the patient carefully and consider reducing the opioid dosage if appropriate. Dihydrocodeine is primarily metabolized by CYP2D6 to dihydromorphine, and by CYP3A4. Fluoxetine is a strong inhibitor of CYP2D6.
Acetaminophen; Chlorpheniramine: (Moderate) Olanzapine exhibits anticholinergic effects that may be clinically significant. Clinicians should keep this in mind when using antimuscarinics and other medications with anticholinergic activity in combination with olanzapine. Some medications exhibit additive anticholinergic effects include sedating H1-blockers. Olanzapine may also cause additive sedation with many of these drugs.
Acetaminophen; Chlorpheniramine; Dextromethorphan: (Moderate) Monitor for dextromethorphan-related side effects, such as dizziness or drowsiness, if concomitant use of fluoxetine is necessary. For patients receiving combination dextromethorphan; bupropion, do not exceed a maximum dose of 45 mg dextromethorphan; 105 mg bupropion once daily. Additionally, monitor patients for signs and symptoms of serotonin syndrome. Concomitant use may increase dextromethorphan exposure and the risk for serotonin syndrome. Dextromethorphan is a CYP2D6 substrate and fluoxetine is a strong CYP2D6 inhibitor. Concomitant use with another strong CYP2D6 inhibitor increased dextromethorphan overall exposure by 2.69-fold. (Moderate) Olanzapine exhibits anticholinergic effects that may be clinically significant. Clinicians should keep this in mind when using antimuscarinics and other medications with anticholinergic activity in combination with olanzapine. Some medications exhibit additive anticholinergic effects include sedating H1-blockers. Olanzapine may also cause additive sedation with many of these drugs.
Acetaminophen; Chlorpheniramine; Dextromethorphan; Phenylephrine: (Moderate) Monitor for dextromethorphan-related side effects, such as dizziness or drowsiness, if concomitant use of fluoxetine is necessary. For patients receiving combination dextromethorphan; bupropion, do not exceed a maximum dose of 45 mg dextromethorphan; 105 mg bupropion once daily. Additionally, monitor patients for signs and symptoms of serotonin syndrome. Concomitant use may increase dextromethorphan exposure and the risk for serotonin syndrome. Dextromethorphan is a CYP2D6 substrate and fluoxetine is a strong CYP2D6 inhibitor. Concomitant use with another strong CYP2D6 inhibitor increased dextromethorphan overall exposure by 2.69-fold. (Moderate) Olanzapine exhibits anticholinergic effects that may be clinically significant. Clinicians should keep this in mind when using antimuscarinics and other medications with anticholinergic activity in combination with olanzapine. Some medications exhibit additive anticholinergic effects include sedating H1-blockers. Olanzapine may also cause additive sedation with many of these drugs.
Acetaminophen; Chlorpheniramine; Dextromethorphan; Pseudoephedrine: (Moderate) Monitor for dextromethorphan-related side effects, such as dizziness or drowsiness, if concomitant use of fluoxetine is necessary. For patients receiving combination dextromethorphan; bupropion, do not exceed a maximum dose of 45 mg dextromethorphan; 105 mg bupropion once daily. Additionally, monitor patients for signs and symptoms of serotonin syndrome. Concomitant use may increase dextromethorphan exposure and the risk for serotonin syndrome. Dextromethorphan is a CYP2D6 substrate and fluoxetine is a strong CYP2D6 inhibitor. Concomitant use with another strong CYP2D6 inhibitor increased dextromethorphan overall exposure by 2.69-fold. (Moderate) Olanzapine exhibits anticholinergic effects that may be clinically significant. Clinicians should keep this in mind when using antimuscarinics and other medications with anticholinergic activity in combination with olanzapine. Some medications exhibit additive anticholinergic effects include sedating H1-blockers. Olanzapine may also cause additive sedation with many of these drugs.
Acetaminophen; Chlorpheniramine; Phenylephrine : (Moderate) Olanzapine exhibits anticholinergic effects that may be clinically significant. Clinicians should keep this in mind when using antimuscarinics and other medications with anticholinergic activity in combination with olanzapine. Some medications exhibit additive anticholinergic effects include sedating H1-blockers. Olanzapine may also cause additive sedation with many of these drugs.
Acetaminophen; Codeine: (Major) Concomitant use of opioid agonists with olanzapine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with olanzapine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Also monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. Avoid prescribing opioid cough medication in patients taking olanzapine. (Moderate) Careful monitoring, particularly during treatment initiation and dose adjustment, is recommended during coadministration of codeine and fluoxetine because of the potential risk of serotonin syndrome, reduced codeine efficacy, and potential for opioid withdrawal symptoms. Discontinue codeine if serotonin syndrome is suspected. It is recommended to avoid this combination when codeine is being used for cough. Concomitant use may increase codeine plasma concentrations, but decrease the plasma concentration of the active metabolite, morphine, resulting in reduced efficacy or symptoms of opioid withdrawal. Monitor patients closely at frequent intervals and consider a dosage increase of codeine until stable drug effects are achieved. Discontinuation of fluoxetine could decrease codeine plasma concentrations and increase morphine plasma concentrations resulting in prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If fluoxetine is discontinued, monitor the patient carefully and consider reducing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Fluoxetine is a strong inhibitor of CYP2D6.
Acetaminophen; Dextromethorphan: (Moderate) Monitor for dextromethorphan-related side effects, such as dizziness or drowsiness, if concomitant use of fluoxetine is necessary. For patients receiving combination dextromethorphan; bupropion, do not exceed a maximum dose of 45 mg dextromethorphan; 105 mg bupropion once daily. Additionally, monitor patients for signs and symptoms of serotonin syndrome. Concomitant use may increase dextromethorphan exposure and the risk for serotonin syndrome. Dextromethorphan is a CYP2D6 substrate and fluoxetine is a strong CYP2D6 inhibitor. Concomitant use with another strong CYP2D6 inhibitor increased dextromethorphan overall exposure by 2.69-fold.
Acetaminophen; Dextromethorphan; Doxylamine: (Moderate) Monitor for dextromethorphan-related side effects, such as dizziness or drowsiness, if concomitant use of fluoxetine is necessary. For patients receiving combination dextromethorphan; bupropion, do not exceed a maximum dose of 45 mg dextromethorphan; 105 mg bupropion once daily. Additionally, monitor patients for signs and symptoms of serotonin syndrome. Concomitant use may increase dextromethorphan exposure and the risk for serotonin syndrome. Dextromethorphan is a CYP2D6 substrate and fluoxetine is a strong CYP2D6 inhibitor. Concomitant use with another strong CYP2D6 inhibitor increased dextromethorphan overall exposure by 2.69-fold. (Moderate) Olanzapine exhibits anticholinergic effects that may be clinically significant. Clinicians should keep this in mind when using antimuscarinics and other medications with anticholinergic activity in combination with olanzapine. Some medications exhibit additive anticholinergic effects include sedating H1-blockers. Olanzapine may also cause additive sedation with many of these drugs.
Acetaminophen; Dextromethorphan; Guaifenesin; Phenylephrine: (Moderate) Monitor for dextromethorphan-related side effects, such as dizziness or drowsiness, if concomitant use of fluoxetine is necessary. For patients receiving combination dextromethorphan; bupropion, do not exceed a maximum dose of 45 mg dextromethorphan; 105 mg bupropion once daily. Additionally, monitor patients for signs and symptoms of serotonin syndrome. Concomitant use may increase dextromethorphan exposure and the risk for serotonin syndrome. Dextromethorphan is a CYP2D6 substrate and fluoxetine is a strong CYP2D6 inhibitor. Concomitant use with another strong CYP2D6 inhibitor increased dextromethorphan overall exposure by 2.69-fold.
Acetaminophen; Dextromethorphan; Guaifenesin; Pseudoephedrine: (Moderate) Monitor for dextromethorphan-related side effects, such as dizziness or drowsiness, if concomitant use of fluoxetine is necessary. For patients receiving combination dextromethorphan; bupropion, do not exceed a maximum dose of 45 mg dextromethorphan; 105 mg bupropion once daily. Additionally, monitor patients for signs and symptoms of serotonin syndrome. Concomitant use may increase dextromethorphan exposure and the risk for serotonin syndrome. Dextromethorphan is a CYP2D6 substrate and fluoxetine is a strong CYP2D6 inhibitor. Concomitant use with another strong CYP2D6 inhibitor increased dextromethorphan overall exposure by 2.69-fold.
Acetaminophen; Dextromethorphan; Phenylephrine: (Moderate) Monitor for dextromethorphan-related side effects, such as dizziness or drowsiness, if concomitant use of fluoxetine is necessary. For patients receiving combination dextromethorphan; bupropion, do not exceed a maximum dose of 45 mg dextromethorphan; 105 mg bupropion once daily. Additionally, monitor patients for signs and symptoms of serotonin syndrome. Concomitant use may increase dextromethorphan exposure and the risk for serotonin syndrome. Dextromethorphan is a CYP2D6 substrate and fluoxetine is a strong CYP2D6 inhibitor. Concomitant use with another strong CYP2D6 inhibitor increased dextromethorphan overall exposure by 2.69-fold.
Acetaminophen; Dextromethorphan; Pseudoephedrine: (Moderate) Monitor for dextromethorphan-related side effects, such as dizziness or drowsiness, if concomitant use of fluoxetine is necessary. For patients receiving combination dextromethorphan; bupropion, do not exceed a maximum dose of 45 mg dextromethorphan; 105 mg bupropion once daily. Additionally, monitor patients for signs and symptoms of serotonin syndrome. Concomitant use may increase dextromethorphan exposure and the risk for serotonin syndrome. Dextromethorphan is a CYP2D6 substrate and fluoxetine is a strong CYP2D6 inhibitor. Concomitant use with another strong CYP2D6 inhibitor increased dextromethorphan overall exposure by 2.69-fold.
Acetaminophen; Dichloralphenazone; Isometheptene: (Moderate) Drugs that can cause CNS depression, including dichloralphenazone, can increase both the frequency and the intensity of adverse effects such as drowsiness, sedation, and dizziness if used concomitantly with atypical antipsychotics.
Acetaminophen; Diphenhydramine: (Moderate) Olanzapine exhibits anticholinergic effects that may be clinically significant. Clinicians should keep this in mind when using antimuscarinics and other medications with anticholinergic activity in combination with olanzapine. Some medications exhibit additive anticholinergic effects include sedating H1-blockers. Olanzapine may also cause additive sedation with many of these drugs.
Acetaminophen; Hydrocodone: (Major) Concomitant use of opioid agonists with olanzapine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with olanzapine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Also monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. Avoid prescribing opioid cough medication in patients taking olanzapine. (Moderate) Careful monitoring, particularly during treatment initiation and dose adjustment, is recommended during coadministration of hydrocodone and fluoxetine because of the potential risk of serotonin syndrome and prolonged opioid adverse reactions. Discontinue hydrocodone if serotonin syndrome is suspected. It is recommended to avoid this combination when hydrocodone is being used for cough. Concomitant use of hydrocodone with fluoxetine may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. Monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of fluoxetine could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If fluoxetine is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP2D6. Fluoxetine is a strong inhibitor of CYP2D6.
Acetaminophen; Oxycodone: (Major) Concomitant use of opioid agonists with olanzapine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with olanzapine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Also monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. (Moderate) If concomitant use of oxycodone and fluoxetine is warranted, monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
Adagrasib: (Major) Avoid concomitant use of adagrasib and fluoxetine due to the potential for increased fluoxetine exposure and additive risk for QT/QTc prolongation and torsade de pointes (TdP). If use is necessary, monitor for fluoxetine-related adverse effects and consider taking additional steps to minimize the risk for QT prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring. Fluoxetine is a CYP2D6 substrate, adagrasib is a moderate CYP2D6 inhibitor, and both medications have been associated with QT interval prolongation. (Major) Concomitant use of adagrasib and olanzapine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Aldesleukin, IL-2: (Moderate) Both aldesleukin, IL 2 and olanzapine can cause significant CNS depression. Use with caution and monitor patients for additive CNS depression.
Alfentanil: (Major) Concomitant use of opioid agonists with olanzapine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with olanzapine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Also monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. (Moderate) Alfentanil is metabolized by the cytochrome P450 3A4 isoenzyme present in the liver. Inhibitors of CYP3A4, such as fluoxetine, may decrease systemic clearance of alfentanil leading to increased or prolonged effects. Close monitoring for oversedation and respiratory depression is warranted if a CYP3A4 inhibitor is used with alfentanil.
Alfuzosin: (Moderate) Caution is advised when administering olanzapine with alfuzosin as concurrent use may increase the risk of QT prolongation. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval. Alfuzosin may also prolong the QT interval in a dose-dependent manner. (Moderate) Concomitant use of fluoxetine and alfuzosin may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP.
Aliskiren; Hydrochlorothiazide, HCTZ: (Moderate) Monitor for signs and symptoms of hyponatremia during concomitant diuretic and fluoxetine use; consider discontinuing fluoxetine if symptomatic hyponatremia occurs and institute appropriate medical intervention. Concomitant use increases the risk for developing hyponatremia.
Almotriptan: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering almotriptan with fluoxetine. Serotonin syndrome has been reported during concurrent use of serotonin-receptor agonists and selective serotonin reuptake inhibitors (SSRIs). Some patients had used the combination previously without incident when serotonin syndrome occurred. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly after a dose increase of the SSRI or the addition of other serotonergic medications to an existing SSRI regimen. Discontinue fluoxetine and almotriptan and initiate symptomatic treatment if serotonin syndrome occurs.
Alogliptin: (Moderate) Monitor blood glucose during concomitant atypical antipsychotic and dipeptidyl peptidase-4 (DPP-4) inhibitor use. Atypical antipsychotic therapy may aggravate diabetes mellitus. Atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition. (Moderate) Monitor blood glucose during concomitant dipeptidyl peptidase-4 (DPP-4) inhibitor and fluoxetine use; a DPP-4 inhibitor dose adjustment may be necessary. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
Alogliptin; Metformin: (Moderate) Monitor blood glucose during concomitant atypical antipsychotic and dipeptidyl peptidase-4 (DPP-4) inhibitor use. Atypical antipsychotic therapy may aggravate diabetes mellitus. Atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition. (Moderate) Monitor blood glucose during concomitant atypical antipsychotic and metformin use. Atypical antipsychotic therapy may aggravate diabetes mellitus. Atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition. (Moderate) Monitor blood glucose during concomitant dipeptidyl peptidase-4 (DPP-4) inhibitor and fluoxetine use; a DPP-4 inhibitor dose adjustment may be necessary. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia. (Moderate) Monitor blood glucose during concomitant metformin and fluoxetine use; a metformin dose adjustment may be necessary. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
Alogliptin; Pioglitazone: (Moderate) Atypical antipsychotic therapy may aggravate diabetes mellitus and cause metabolic changes such as hyperglycemia. Monitor patients on antidiabetic agents for worsening glycemic control. Atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Aggravation of diabetes mellitus has been reported. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition. (Moderate) Monitor blood glucose during concomitant atypical antipsychotic and dipeptidyl peptidase-4 (DPP-4) inhibitor use. Atypical antipsychotic therapy may aggravate diabetes mellitus. Atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition. (Moderate) Monitor blood glucose during concomitant dipeptidyl peptidase-4 (DPP-4) inhibitor and fluoxetine use; a DPP-4 inhibitor dose adjustment may be necessary. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
Alosetron: (Moderate) Constipation is the most frequently reported adverse effect with alosetron. Alosetron, if used with drugs that have anticholinergic effects such as olanzapine, may seriously worsen constipation, leading to events such as GI obstruction/impaction or paralytic ileus. Although specific recommendations are not available from the manufacturer, it would be prudent to avoid these drugs in patients taking alosetron.
Alpha-glucosidase Inhibitors: (Moderate) Atypical antipsychotic therapy may aggravate diabetes mellitus and cause metabolic changes such as hyperglycemia. Monitor patients on antidiabetic agents for worsening glycemic control. The atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Aggravation of diabetes mellitus has been reported. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition. (Moderate) In patients with diabetes mellitus, fluoxetine may alter glycemic control. Hypoglycemia has occurred during fluoxetine therapy. Hyperglycemia has developed in patients with diabetes mellitus following discontinuation of the drug. The dosage of insulin and/or other antidiabetic agents may need to be adjusted when therapy with fluoxetine is instituted or discontinued.
Alprazolam: (Major) Avoid coadministration of alprazolam and fluoxetine due to the potential for elevated alprazolam concentrations, which may cause prolonged sedation and respiratory depression. Coadministration of alprazolam and fluoxetine has resulted in increased alprazolam plasma concentrations and in further psychomotor performance decrement due to increased alprazolam levels. If coadministration is necessary, consider reducing the dose of alprazolam as clinically appropriate and monitor for an increase in alprazolam-related adverse reactions. Lorazepam, oxazepam, or temazepam may be safer alternatives if a benzodiazepine must be administered in combination with fluoxetine, as these benzodiazepines are not oxidatively metabolized. Alprazolam is a CYP3A4 substrate and fluoxetine is a weak CYP3A4 inhibitor. Norfluoxetine, the active metabolite of fluoxetine, is a moderate CYP3A4 inhibitor. Coadministration with fluoxetine increased alprazolam maximum concentration by 46%, decreased clearance by 21%, increased half-life by 17%, and decreased measured psychomotor performance. (Moderate) Although oral formulations of olanzapine and benzodiazepines may be used together, additive effects on respiratory depression and/or CNS depression are possible. Drugs that can cause CNS depression, if used concomitantly with olanzapine, can increase both the frequency and the intensity of adverse effects such as drowsiness, sedation, dizziness, and orthostatic hypotension. Besides ethanol, clinicians should use other anxiolytics, sedatives, and hypnotics cautiously with olanzapine.
Alteplase: (Moderate) Platelet aggregation may be impaired by selective serotonin reuptake inhibitors (SSRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication in patients receiving thrombolytic agents. Patients should be closely monitored for signs and symptoms of bleeding when a thrombolytic agent is administered with an SSRI.
Amantadine: (Moderate) Amantadine may exhibit anticholinergic activity. Medications with significant anticholinergic activity, such as olanzapine, may potentiate the anticholinergic effects of amantadine, and may increase the risk of antimuscarinic-related side effects. Clinicians should note that antimuscarinic effects might be seen not only on GI smooth muscle, but also on bladder function, the eye, neurologic function, and temperature regulation.
Amifampridine: (Major) Carefully consider the need for concomitant treatment with atypical antipsychotics and amifampridine, as coadministration may increase the risk of seizures. If coadministration occurs, closely monitor patients for seizure activity. Seizures have been observed in patients without a history of seizures taking amifampridine at recommended doses. Atypical antipsychotics may increase the risk of seizures.
Amiloride: (Moderate) Monitor for signs and symptoms of hyponatremia during concomitant diuretic and fluoxetine use; consider discontinuing fluoxetine if symptomatic hyponatremia occurs and institute appropriate medical intervention. Concomitant use increases the risk for developing hyponatremia. (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.
Amiloride; Hydrochlorothiazide, HCTZ: (Moderate) Monitor for signs and symptoms of hyponatremia during concomitant diuretic and fluoxetine use; consider discontinuing fluoxetine if symptomatic hyponatremia occurs and institute appropriate medical intervention. Concomitant use increases the risk for developing hyponatremia. (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.
Amiodarone: (Major) Concomitant use of amiodarone and fluoxetine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after drug discontinuation. (Major) Concomitant use of olanzapine and amiodarone increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after drug discontinuation.
Amisulpride: (Major) Monitor ECGs for QT prolongation when amisulpride is administered with fluoxetine. Amisulpride causes dose- and concentration- dependent QT prolongation. QT prolongation and TdP have been reported in patients treated with fluoxetine. (Major) Monitor ECGs for QT prolongation when amisulpride is administered with olanzapine. Amisulpride causes dose- and concentration- dependent QT prolongation. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval.
Amitriptyline: (Moderate) Monitor for signs and symptoms of serotonin syndrome, particularly during treatment initiation and dosage increase, during concomitant amitriptyline and fluoxetine use. If serotonin syndrome occurs, discontinue therapy. Concomitant use increases the risk for serotonin syndrome.
Amlodipine; Benazepril: (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.
Amlodipine; Olmesartan: (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.
Amlodipine; Valsartan: (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.
Amlodipine; Valsartan; Hydrochlorothiazide, HCTZ: (Moderate) Monitor for signs and symptoms of hyponatremia during concomitant diuretic and fluoxetine use; consider discontinuing fluoxetine if symptomatic hyponatremia occurs and institute appropriate medical intervention. Concomitant use increases the risk for developing hyponatremia. (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.
Amobarbital: (Moderate) Olanzapine is metabolized by the CYP1A2 hepatic microsomal isoenzyme, and inducers of this enzyme such as barbiturates, may increase olanzapine clearance. The clinical effect of this interaction is thought to be minimal; however, the clinician should be alert for reduced olanzapine effect if the drugs are coadministered. Additive effects are possible when olanzapine is combined with other drugs which cause respiratory depression and/or CNS depression. Barbiturates can cause CNS depression, and if used concomitantly with olanzapine, can increase both the frequency and the intensity of adverse effects such as drowsiness, sedation, dizziness, and orthostatic hypotension.
Amoxapine: (Moderate) Fluoxetine, a potent CYP2D6 inhibitor, may increase the plasma concentrations of the tetracyclic antidepressant amoxapine, which is partially metabolized by CYP2D6. In several cases, symptoms of toxicity, including seizures, have been reported when tricyclic antidepressants were coadministered with an SSRI, including fluoxetine. At least one case report exists of a death thought to be due to impaired clearance of the tricyclic antidepressant amitriptyline by fluoxetine. Also, this combination may represent duplicative therapy. Patients receiving amoxapine should be monitored closely for toxicity if fluoxetine is added. Monitoring should be continued for several weeks following the discontinuation of fluoxetine due to the long half-life of norfluoxetine, the active metabolite of fluoxetine which has a half-life of 7 to 9 days and is a CYP2D6 inhibitor. (Moderate) Use caution during coadministration of amoxapine and olanzapine. Amoxapine exhibits some antipsychotic activity and may increase the risk of tardive dyskinesia or neuroleptic malignant syndrome (NMS) when antipsychotics are given concurrently. CNS effects, orthostatic hypotension, anticholinergic effects, and lowering of seizure threshold are potential problems with the combined use of amoxapine and olanzapine.
Amoxicillin; Clarithromycin; Omeprazole: (Major) Concomitant use of clarithromycin and fluoxetine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. (Major) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering clarithromycin with olanzapine. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval in rare instances. Additionally, clarithromycin is associated with an established risk for QT prolongation and TdP.
Amphetamines: (Moderate) Monitor for signs and symptoms of serotonin syndrome, particularly during treatment initiation and dosage increase, during concomitant amphetamine and fluoxetine use. If serotonin syndrome occurs, discontinue therapy. Concomitant use increases the risk for serotonin syndrome.
Anagrelide: (Major) Coadministration may increase the risk for QT prolongation and torsade de pointes (TdP). TdP and ventricular tachycardia have been reported with anagrelide. In addition, dose-related increases in mean QTc and heart rate were observed in healthy subjects. A cardiovascular examination, including an ECG, should be obtained in all patients prior to initiating anagrelide therapy. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval. Monitor patients for cardiovascular effects during concurrent use. In addition, anagrelide has been shown to inhibit CYP1A2. Olanzapine is a CYP1A2 substrate. In theory, coadministration could lead to increases in the serum concentration of olanzapine and thus, adverse effects. (Major) Do not use anagrelide with other drugs that prolong the QT interval, such as fluoxetine. Torsade de pointes (TdP) and ventricular tachycardia have been reported with anagrelide; dose-related increases in mean QTc and heart rate were observed in healthy subjects. QT prolongation and TdP have been reported in patients treated with fluoxetine. In addition, platelet aggregation may be impaired by SSRIs due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication in patients receiving platelet inhibitors.
Angiotensin II receptor antagonists: (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.
Angiotensin-converting enzyme inhibitors: (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.
Anticholinergics: (Moderate) Additive anticholinergic effects may be seen when olanzapine and anticholinergics are used concomitantly; use with caution. Use of olanzapine and other drugs with anticholinergic activity can increase the risk for severe gastrointestinal adverse reactions related to hypomotility. Olanzapine exhibits anticholinergic activity. Adverse effects may be seen not only on GI smooth muscle, but also on bladder function, the CNS, the eye, and temperature regulation. Additive drowsiness may also occur, depending on the anticholinergic agent used.
Antithrombin III: (Moderate) Advise patients of the increased bleeding risk associated with the concomitant use of selective serotonin reuptake inhibitors (SSRIs) and anticoagulants like antithrombin III. Case reports and epidemiological studies have demonstrated an association between use of drugs that interfere with serotonin reuptake and gastrointestinal bleeding.
Apixaban: (Moderate) Advise patients of the increased bleeding risk associated with the concomitant use of selective serotonin reuptake inhibitors (SSRIs) and anticoagulants like apixaban. Case reports and epidemiological studies have demonstrated an association between use of drugs that interfere with serotonin reuptake and gastrointestinal bleeding.
Apomorphine: (Moderate) Coadministration of apomorphine and olanzapine may increase the risk for QT prolongation or sedation. Apomorphine and olanzapine may decrease the effectiveness of each other due to opposing effects on dopamine. Additive CNS effects are also possible. Dose-related QTc prolongation is associated with therapeutic apomorphine exposure. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval in rare instances. In general, atypical antipsychotics are less likely to interfere with Parkinson's disease treatments than traditional antipsychotics. Monitor for movement disorders, unusual changes in moods or behavior, sedation, fast, irregular heartbeat, and diminished effectiveness of either agent during coadministration. (Moderate) Concomitant use of fluoxetine and apomorphine may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP.
Aprepitant, Fosaprepitant: (Moderate) Use caution if fluoxetine and aprepitant are used concurrently and monitor for an increase in fluoxetine-related adverse effects for several days after administration of a multi-day aprepitant regimen. After administration, fosaprepitant is rapidly converted to aprepitant and shares the same drug interactions. Fluoxetine is a CYP3A4 substrate. Aprepitant, when administered as a 3-day oral regimen (125 mg/80 mg/80 mg), is a moderate CYP3A4 inhibitor and inducer; substitution of fosaprepitant 115 mg IV on day 1 of the 3-day regimen may lessen the inhibitory effects of CYP3A4. The AUC of a single dose of another CYP3A4 substrate, midazolam, increased by 2.3-fold and 3.3-fold on days 1 and 5, respectively, when coadministered with a 5-day oral aprepitant regimen. After a 3-day oral aprepitant regimen, the AUC of midazolam increased by 25% on day 4, and decreased by 19% and 4% on days 8 and 15, respectively, when given on days 1, 4, 8, and 15. As a single 40-mg oral dose, the inhibitory effect of aprepitant on CYP3A4 is weak, with the AUC of midazolam increased by 1.2-fold; the midazolam AUC increased by 1.5-fold after a single 125-mg dose of oral aprepitant. After single doses of IV fosaprepitant, the midazolam AUC increased by 1.8-fold (150 mg) and 1.6-fold (100 mg); less than a 2-fold increase in the midazolam AUC is not considered clinically important. Fluoxetine is also a weak CYP3A4 inhibitor and aprepitant is a CYP3A4 substrate. Coadministration of daily oral aprepitant (230 mg, or 1.8 times the recommended single dose) with a moderate CYP3A4 inhibitor, diltiazem, increased the aprepitant AUC 2-fold with a concomitant 1.7-fold increase in the diltiazem AUC; clinically meaningful changes in ECG, heart rate, or blood pressure beyond those induced by diltiazem alone did not occur. Information is not available regarding the use of aprepitant with weak CYP3A4 inhibitors.
Aripiprazole: (Major) Reduce the oral aripiprazole dosage by one-half of the usual dose in patients receiving strong CYP2D6 inhibitors such as fluoxetine. Reduce the oral aripiprazole dosage to one-quarter (25%) of the usual dose with subsequent adjustments based upon clinical response in patients also receiving a CYP3A4 inhibitor, as aripiprazole is also metabolized by CYP3A4. Addtionally, aripiprazole and fluoxetine are both associated with prolongation of the QT interval; caution and close monitoring are recommended. Avoid concurrent use of Aristada Initio and fluoxetine because the dose of Aristada Initio cannot be modified. For other long-active aripiprazole injectables (e.g., Ability Maintena, Aristada), dose adjustments are recommended with strong CYP2D6 inhibitors and combined strong CYP2D6/CYP3A4 inhibitors; the recommendations are dependent on the aripiprazole IM depot dosage, the product given, and the duration of the concomitant inhibitors as specified in the product labels. (Moderate) Coadministration may result in additive effects on the QT interval. Both aripiprazole and olanzapine have been associated with QT prolongation. In addition, the risk of drowsiness, dizziness, hypotension, extrapyramidal symptoms, anticholinergic effects, neuroleptic malignant syndrome, tardive dyskinesia, or seizures may be increased during combined use; therefore, it may be advisable to initiate treatment with lower dosages if combination therapy is deemed necessary.
Armodafinil: (Moderate) Armodafinil is partially metabolized by CYP3A4/5 isoenzymes. Interactions with potent inhibitors of CYP3A4 such as fluoxetine are possible. However, because armodafinil is itself an inducer of the CYP3A4 isoenzyme, drug interactions due to CYP3A4 inhibition by other medications may be complex and difficult to predict. Observation of the patient for increased effects from armodafinil may be needed.
Arsenic Trioxide: (Major) Avoid coadministration of fluoxetine and arsenic trioxide. QT prolongation and torsade de pointes (TdP) have been reported in patients treated with fluoxetine. If possible, drugs that are known to prolong the QT interval should be discontinued prior to initiating arsenic trioxide therapy. If concomitant drug use is unavoidable, frequently monitor electrocardiograms. QT prolongation should be expected with the administration of arsenic trioxide. (Major) If possible, drugs that are known to prolong the QT interval should be discontinued prior to initiating arsenic trioxide therapy. QT prolongation should be expected with the administration of arsenic trioxide. Torsade de pointes (TdP) and complete atrioventricular block have been reported. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously with arsenic trioxide include olanzapine. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval in rare instances.
Artemether; Lumefantrine: (Major) Artemether; lumefantrine is an inhibitor and olanzapine is a substrate of the CYP2D6 isoenzyme; therefore, coadministration may lead to increased olanzapine concentrations. Furthermore, although there are no studies examining the effects of artemether; lumefantrine in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation. Concomitant use of artemether; lumefantrine with drugs that may prolong the QT interval such as olanzapine should be avoided. Consider ECG monitoring if olanzapine must be used with or after artemether; lumefantrine treatment. (Major) Avoid coadministration of fluoxetine and artemether; lumefantrine due to the potential for additive QT prolongation. QT prolongation and torsade de pointes (TdP) have been reported in patients treated with fluoxetine. Artemether; lumefantrine is also associated with QT interval prolongation. (Moderate) Lumefantrine is an inhibitor and fluoxetine is a substrate/inhibitor of the CYP2D6 isoenzyme; therefore, coadministration may lead to increased fluoxetine concentrations. Additionally, lumefantrine is a substrate and fluoxetine is an inhibitor of the CYP3A4 isoenzyme; therefore, concomitant use may lead to increased lumefantrine concentrations. Concomitant use warrants caution due to the potential for increased side effects.
Articaine; Epinephrine: (Moderate) Olanzapine may induce significant alpha-adrenergic blockade in overdose, leading to profound hypotension. Do not use epinephrine, dopamine, or other sympathomimetics with beta-agonist activity since the beta-stimulation may worsen hypotension in the setting of olanzapine overdose.
Asenapine: (Major) Asenapine has been associated with QT prolongation. According to the manufacturer, asenapine should be avoided in combination with other agents also known to have this effect (e.g., olanzapine). Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval in rare instances. In addition, co-administration of olanzapine with asenapine may increase the risk of adverse effects such as drowsiness, dizziness, orthostatic hypotension, anticholinergic effects, extrapyramidal symptoms, neuroleptic malignant syndrome, or seizures. The likelihood of these pharmacodynamic interactions varies based upon the individual properties of the co-administered antipsychotic agent. Although the incidence of tardive dyskinesia from combination antipsychotic therapy has not been established and data are very limited, the risk appears to be increased during use of a conventional and atypical antipsychotic versus use of a conventional antipsychotic alone. (Major) Concomitant use of asenapine and fluoxetine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Aspirin, ASA: (Moderate) The combined use of selective serotonin reuptake inhibitors and aspirin, ASA may elevate the risk for an upper GI bleed. SSRIs may inhibit serotonin uptake by platelets, augmenting the antiplatelet effects of aspirin. Additionally, aspirin impairs the gastric mucosa defenses by inhibiting prostaglandin formation.
Aspirin, ASA; Butalbital; Caffeine: (Moderate) Olanzapine is metabolized by the CYP1A2 hepatic microsomal isoenzyme, and inducers of this enzyme such as barbiturates, may increase olanzapine clearance. The clinical effect of this interaction is thought to be minimal; however, the clinician should be alert for reduced olanzapine effect if the drugs are coadministered. Additive effects are possible when olanzapine is combined with other drugs which cause respiratory depression and/or CNS depression. Barbiturates can cause CNS depression, and if used concomitantly with olanzapine, can increase both the frequency and the intensity of adverse effects such as drowsiness, sedation, dizziness, and orthostatic hypotension. (Moderate) The combined use of selective serotonin reuptake inhibitors and aspirin, ASA may elevate the risk for an upper GI bleed. SSRIs may inhibit serotonin uptake by platelets, augmenting the antiplatelet effects of aspirin. Additionally, aspirin impairs the gastric mucosa defenses by inhibiting prostaglandin formation.
Aspirin, ASA; Caffeine: (Moderate) The combined use of selective serotonin reuptake inhibitors and aspirin, ASA may elevate the risk for an upper GI bleed. SSRIs may inhibit serotonin uptake by platelets, augmenting the antiplatelet effects of aspirin. Additionally, aspirin impairs the gastric mucosa defenses by inhibiting prostaglandin formation.
Aspirin, ASA; Caffeine; Orphenadrine: (Moderate) Additive anticholinergic effects may be seen when drugs with anticholinergic properties, like olanzapine and orphenadrine, are used concomitantly. Adverse effects may be seen not only on GI smooth muscle, but also on bladder function, the CNS, the eye, and temperature regulation. Additive drowsiness may also occur. (Moderate) The combined use of selective serotonin reuptake inhibitors and aspirin, ASA may elevate the risk for an upper GI bleed. SSRIs may inhibit serotonin uptake by platelets, augmenting the antiplatelet effects of aspirin. Additionally, aspirin impairs the gastric mucosa defenses by inhibiting prostaglandin formation.
Aspirin, ASA; Carisoprodol: (Moderate) The combined use of selective serotonin reuptake inhibitors and aspirin, ASA may elevate the risk for an upper GI bleed. SSRIs may inhibit serotonin uptake by platelets, augmenting the antiplatelet effects of aspirin. Additionally, aspirin impairs the gastric mucosa defenses by inhibiting prostaglandin formation. (Minor) Carisoprodol is extensively metabolized and is a significant substrate of CYP2C19 isoenzymes. Theoretically, CY2C19 inhibitors, such as fluoxetine, could increase carisoprodol plasma levels, with potential for enhanced CNS depressant effects.
Aspirin, ASA; Carisoprodol; Codeine: (Major) Concomitant use of opioid agonists with olanzapine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with olanzapine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Also monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. Avoid prescribing opioid cough medication in patients taking olanzapine. (Moderate) Careful monitoring, particularly during treatment initiation and dose adjustment, is recommended during coadministration of codeine and fluoxetine because of the potential risk of serotonin syndrome, reduced codeine efficacy, and potential for opioid withdrawal symptoms. Discontinue codeine if serotonin syndrome is suspected. It is recommended to avoid this combination when codeine is being used for cough. Concomitant use may increase codeine plasma concentrations, but decrease the plasma concentration of the active metabolite, morphine, resulting in reduced efficacy or symptoms of opioid withdrawal. Monitor patients closely at frequent intervals and consider a dosage increase of codeine until stable drug effects are achieved. Discontinuation of fluoxetine could decrease codeine plasma concentrations and increase morphine plasma concentrations resulting in prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If fluoxetine is discontinued, monitor the patient carefully and consider reducing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Fluoxetine is a strong inhibitor of CYP2D6. (Moderate) The combined use of selective serotonin reuptake inhibitors and aspirin, ASA may elevate the risk for an upper GI bleed. SSRIs may inhibit serotonin uptake by platelets, augmenting the antiplatelet effects of aspirin. Additionally, aspirin impairs the gastric mucosa defenses by inhibiting prostaglandin formation. (Minor) Carisoprodol is extensively metabolized and is a significant substrate of CYP2C19 isoenzymes. Theoretically, CY2C19 inhibitors, such as fluoxetine, could increase carisoprodol plasma levels, with potential for enhanced CNS depressant effects.
Aspirin, ASA; Citric Acid; Sodium Bicarbonate: (Moderate) The combined use of selective serotonin reuptake inhibitors and aspirin, ASA may elevate the risk for an upper GI bleed. SSRIs may inhibit serotonin uptake by platelets, augmenting the antiplatelet effects of aspirin. Additionally, aspirin impairs the gastric mucosa defenses by inhibiting prostaglandin formation.
Aspirin, ASA; Dipyridamole: (Moderate) Platelet aggregation may be impaired by SSRIs due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication in patients receiving platelet inhibitors. Monitor for signs and symptoms of bleeding. (Moderate) The combined use of selective serotonin reuptake inhibitors and aspirin, ASA may elevate the risk for an upper GI bleed. SSRIs may inhibit serotonin uptake by platelets, augmenting the antiplatelet effects of aspirin. Additionally, aspirin impairs the gastric mucosa defenses by inhibiting prostaglandin formation.
Aspirin, ASA; Omeprazole: (Moderate) The combined use of selective serotonin reuptake inhibitors and aspirin, ASA may elevate the risk for an upper GI bleed. SSRIs may inhibit serotonin uptake by platelets, augmenting the antiplatelet effects of aspirin. Additionally, aspirin impairs the gastric mucosa defenses by inhibiting prostaglandin formation.
Aspirin, ASA; Oxycodone: (Major) Concomitant use of opioid agonists with olanzapine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with olanzapine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Also monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. (Moderate) If concomitant use of oxycodone and fluoxetine is warranted, monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. (Moderate) The combined use of selective serotonin reuptake inhibitors and aspirin, ASA may elevate the risk for an upper GI bleed. SSRIs may inhibit serotonin uptake by platelets, augmenting the antiplatelet effects of aspirin. Additionally, aspirin impairs the gastric mucosa defenses by inhibiting prostaglandin formation.
Atazanavir: (Moderate) Caution is warranted when atazanavir is administered with olanzapine as there is a potential for elevated olanzapine concentrations. Olanzapine is a substrate of uridine glucoronyltransferase (UGT). Atazanavir is an inhibitor of UGT1A1.
Atazanavir; Cobicistat: (Moderate) Caution is warranted when atazanavir is administered with olanzapine as there is a potential for elevated olanzapine concentrations. Olanzapine is a substrate of uridine glucoronyltransferase (UGT). Atazanavir is an inhibitor of UGT1A1. (Moderate) Caution is warranted when cobicistat is administered with olanzapine as there is a potential for elevated olanzapine concentrations. Olanzapine is a substrate of CYP2D6. Cobicistat is an inhibitor of CYP2D6. (Moderate) Close monitoring for antidepressant response and careful dose titrations of the antidepressant therapy is recommended during coadministration of selective serotonin reuptake inhibitors (SSRIs) and cobicistat. Concurrent use may result in elevated SSRI plasma concentrations. Predictions regarding this interaction can be made based on the metabolic pathways of these drugs. All SSRIs are substrates for the hepatic isoenzyme CYP2D6, while citalopram, escitalopram, and sertraline are also substrates for CYP3A4; cobicistat is an inhibitor of both CYP2D6 and CYP3A4.
Atenolol: (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.
Atenolol; Chlorthalidone: (Moderate) Monitor for signs and symptoms of hyponatremia during concomitant diuretic and fluoxetine use; consider discontinuing fluoxetine if symptomatic hyponatremia occurs and institute appropriate medical intervention. Concomitant use increases the risk for developing hyponatremia. (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.
Atomoxetine: (Major) Monitor for evidence of QT prolongation and increased atomoxetine-related adverse effects during coadministration with fluoxetine. Dosage reduction of atomoxetine is recommended in patients receiving fluoxetine due to the potential for increased atomoxetine exposure and related adverse effects. In children and adolescents up to 70 kg receiving fluoxetine, atomoxetine should be initiated at 0.5 mg/kg/day and only increased to the usual target dose of 1.2 mg/kg/day if symptoms fail to improve after 4 weeks and the initial dose is well-tolerated. In children and adolescents over 70 kg and adults receiving fluoxetine, atomoxetine should be initiated at 40 mg/day and only increased to the usual target dose of 80 mg/day if symptoms fail to improve after 4 weeks and the initial dose is well-tolerated. Fluoxetine is a strong CYP2D6 inhibitor; atomoxetine is a CYP2D6 substrate. Coadministration of a strong C

YP2D6 inhibitor and atomoxetine in extensive metabolizers of CYP2D6, increased atomoxetine steady-state plasma concentrations by approximately 6 to 8-fold. This increase is similar to exposures observed in poor metabolizers. Concurrent use of a strong CYP2D6 inhibitor with atomoxetine in poor metabolizers is not expected to increase atomoxetine exposure. (Moderate) Concomitant use of atomoxetine and olanzapine may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP.
Atropine: (Moderate) Additive anticholinergic effects may be seen when olanzapine and anticholinergics are used concomitantly; use with caution. Use of olanzapine and other drugs with anticholinergic activity can increase the risk for severe gastrointestinal adverse reactions related to hypomotility. Olanzapine exhibits anticholinergic activity. Adverse effects may be seen not only on GI smooth muscle, but also on bladder function, the CNS, the eye, and temperature regulation. Additive drowsiness may also occur, depending on the anticholinergic agent used.
Atropine; Difenoxin: (Moderate) Additive anticholinergic effects may be seen when olanzapine and anticholinergics are used concomitantly; use with caution. Use of olanzapine and other drugs with anticholinergic activity can increase the risk for severe gastrointestinal adverse reactions related to hypomotility. Olanzapine exhibits anticholinergic activity. Adverse effects may be seen not only on GI smooth muscle, but also on bladder function, the CNS, the eye, and temperature regulation. Additive drowsiness may also occur, depending on the anticholinergic agent used. (Moderate) Concurrent administration of diphenoxylate/difenoxin with fluoxetine can potentiate the CNS-depressant effects of diphenoxylate/difenoxin. Use caution during coadministration. (Moderate) Drugs that decrease GI motility, such as olanzapine, may produce additive effects with antidiarrheals, such as diphenoxylate/difenoxin, if used concomitantly.
Azilsartan: (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.
Azilsartan; Chlorthalidone: (Moderate) Monitor for signs and symptoms of hyponatremia during concomitant diuretic and fluoxetine use; consider discontinuing fluoxetine if symptomatic hyponatremia occurs and institute appropriate medical intervention. Concomitant use increases the risk for developing hyponatremia. (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.
Azithromycin: (Major) Concomitant use of azithromycin and fluoxetine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. (Major) Concomitant use of olanzapine and azithromycin increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Barbiturates: (Moderate) Olanzapine is metabolized by the CYP1A2 hepatic microsomal isoenzyme, and inducers of this enzyme such as barbiturates, may increase olanzapine clearance. The clinical effect of this interaction is thought to be minimal; however, the clinician should be alert for reduced olanzapine effect if the drugs are coadministered. Additive effects are possible when olanzapine is combined with other drugs which cause respiratory depression and/or CNS depression. Barbiturates can cause CNS depression, and if used concomitantly with olanzapine, can increase both the frequency and the intensity of adverse effects such as drowsiness, sedation, dizziness, and orthostatic hypotension.
Bedaquiline: (Major) Bedaquiline has been reported to prolong the QT interval. Prior to initiating bedaquiline, obtain serum electrolyte concentrations and a baseline ECG. An ECG should also be performed at least 2, 12, and 24 weeks after starting bedaquiline therapy. Coadministration with other QT prolonging drugs may result in additive or synergistic prolongation of the QT interval. Drugs with a possible risk for QT prolongation and torsade de pointes (TdP) that should be used cautiously and with close monitoring with bedaquiline include fluoxetine. (Major) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering bedaquiline with olanzapine. Bedaquiline has been reported to prolong the QT interval. Prior to initiating bedaquiline, obtain serum electrolyte concentrations and a baseline ECG. An ECG should also be performed at least 2, 12, and 24 weeks after starting bedaquiline therapy. Limited data, including some case reports, suggest that olanzapine may also be associated with a significant prolongation of the QTc interval in rare instances.
Belladonna; Opium: (Major) Fluoxetine may inhibit the metabolism of opium. Clinicians should be alert for an exaggerated opiate response if opium is given with fluoxetine. (Moderate) Additive anticholinergic effects may be seen when olanzapine and anticholinergics are used concomitantly; use with caution. Use of olanzapine and other drugs with anticholinergic activity can increase the risk for severe gastrointestinal adverse reactions related to hypomotility. Olanzapine exhibits anticholinergic activity. Adverse effects may be seen not only on GI smooth muscle, but also on bladder function, the CNS, the eye, and temperature regulation. Additive drowsiness may also occur, depending on the anticholinergic agent used.
Belzutifan: (Moderate) Monitor for anemia and hypoxia if concomitant use of fluoxetine with belzutifan is necessary due to increased plasma exposure of belzutifan which may increase the incidence and severity of adverse reactions. Reduce the dose of belzutifan as recommended if anemia or hypoxia occur. Belzutifan is a CYP2C19 substrate and fluoxetine is a CYP2C19 inhibitor.
Benazepril: (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.
Benazepril; Hydrochlorothiazide, HCTZ: (Moderate) Monitor for signs and symptoms of hyponatremia during concomitant diuretic and fluoxetine use; consider discontinuing fluoxetine if symptomatic hyponatremia occurs and institute appropriate medical intervention. Concomitant use increases the risk for developing hyponatremia. (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.
Benzhydrocodone; Acetaminophen: (Major) Concomitant use of opioid agonists with olanzapine may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid pain medications with olanzapine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If benzhydrocodone is initiated in a patient taking olanzapine, reduce initial dosage and titrate to clinical response. If olanzapine is initiated a patient taking an opioid agonist, use a lower initial dose of olanzapine and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation. (Moderate) Concurrent use of benzhydrocodone with fluoxetine may increase the risk of increased opioid-related adverse reactions, such as fatal respiratory depression. Consider a dose reduction of benzhydrocodone until stable drug effects are achieved. Monitor patients for respiratory depression and sedation at frequent intervals. Discontinuation of fluoxetine in a patient taking benzhydrocodone may decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to opioid agonists. If fluoxetine is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Benzhydrocodone is a prodrug for hydrocodone. Hydrocodone is a substrate for CYP3A4 and CYP2D6. Fluoxetine is a strong inhibitor of CYP2D6 and a weak inhibitor of CYP3A4. Careful monitoring, particularly during treatment initiation and dose adjustment, is recommended during coadministration of benzhydrocodone and fluoxetine because of the potential risk of serotonin syndrome. Discontinue benzhydrocodone if serotonin syndrome is suspected. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome.
Benzoic Acid; Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate: (Contraindicated) According to the manufacturer of fluoxetine, treatment initiation with fluoxetine is contraindicated in patients currently receiving intravenous (IV) methylene blue due to an increased risk of serotonin syndrome. If urgent psychiatric treatment is required, interventions other than fluoxetine (e.g., alternative medication, hospitalization) should be considered. Conversely, in patients receiving fluoxetine and requiring urgent treatment with IV methylene blue, fluoxetine should be discontinued immediately and methylene blue therapy initiated only if acceptable alternatives are not available and the potential benefits outweigh the risks. The patient should be monitored for serotonin syndrome for 5 weeks or until 24 hours after the last dose of methylene blue, whichever comes first. Fluoxetine may be re-initiated 24 hours after the last dose of methylene blue. Results from an in vitro study indicate that methylene blue is a potent, reversible inhibitor of the monoamine oxidase type A enzyme (MAO-A). MAO-A is responsible for the metabolism of serotonin; therefore, concurrent use of an MAO-A inhibitor with a serotonergic agent may result in a clinically significant interaction. Cases of serotonin syndrome have been reported, primarily following administration of standard infusions of methylene blue (1 to 8 mg/kg) as a visualizing agent, in patients receiving SSRIs, serotonin/norepinephrine reuptake inhibitors, or clomipramine. It is not known if patients receiving other serotonergic psychiatric agents with IV methylene blue are at a comparable risk or if methylene blue administered by other routes (e.g., orally, local injection) or in doses less than 1 mg/kg IV can produce a similar outcome. One case describes a patient receiving citalopram who experienced agitation, restlessness, pupil dilation with sluggish response to light, myoclonic movements of the lower limbs, and brisk reflexes following an infusion of methylene blue, while another patient receiving paroxetine developed tachycardia, agitation, dystonia and abnormal eye movements. During a retrospective study of 193 surgical patients who had received a methylene blue injection, it was found that all 12 of the patients who experienced postoperative neurological sequelae had been taking a serotonin reuptake inhibitor preoperatively. One of the 12 patients experienced cardiopulmonary arrest and died. Of the remaining 181 patients who did not experience neurological sequelae, 8.8% were taking a serotonin reuptake inhibitor. Published interaction reports between IV methylene blue and serotonergic psychiatric agents have documented symptoms including lethargy, confusion, delirium, agitation, aggression, obtundation, myoclonus, expressive aphasia, hypertonia, pyrexia, elevated blood pressure, seizures, and coma. Signs and symptoms of serotonin syndrome include fever, diaphoresis, shivering, myoclonus, tremor, tachycardia, diarrhea, nausea, headache, incoordination, mental status changes (e.g., agitation, confusion), hyperreflexia, seizures, and coma. (Moderate) Additive anticholinergic effects may be seen when olanzapine and anticholinergics are used concomitantly; use with caution. Use of olanzapine and other drugs with anticholinergic activity can increase the risk for severe gastrointestinal adverse reactions related to hypomotility. Olanzapine exhibits anticholinergic activity. Adverse effects may be seen not only on GI smooth muscle, but also on bladder function, the CNS, the eye, and temperature regulation. Additive drowsiness may also occur, depending on the anticholinergic agent used. (Moderate) The combined use of selective serotonin reuptake inhibitors (SSRIs) and aspirin, ASA or other salicylates which affect hemostasis may elevate the risk for an upper GI bleed. SSRIs may inhibit serotonin uptake by platelets, augmenting the antiplatelet effects of aspirin.
Benztropine: (Moderate) Additive anticholinergic effects may be seen when olanzapine and anticholinergics are used concomitantly; use with caution. Use of olanzapine and other drugs with anticholinergic activity can increase the risk for severe gastrointestinal adverse reactions related to hypomotility. Olanzapine exhibits anticholinergic activity. Adverse effects may be seen not only on GI smooth muscle, but also on bladder function, the CNS, the eye, and temperature regulation. Additive drowsiness may also occur, depending on the anticholinergic agent used.
Berotralstat: (Moderate) Monitor for increased fluoxetine-related adverse effects if coadministered with berotralstat. Concurrent use may result in increased fluoxetine exposure. Fluoxetine is a CYP2D6 substrate and berotralstat is a moderate CYP2D6 inhibitor.
Beta-adrenergic blockers: (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.
Betaxolol: (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.
Bethanechol: (Moderate) Drugs that possess antimuscarinic properties, such as olanzapine, are pharmacologic opposites of bethanechol (a direct agonist at muscarinic cholinergic receptors). These agents should not be used with bethanechol except when the specific intent is to counteract excessive actions of one or the other.
Betrixaban: (Moderate) Advise patients of the increased bleeding risk associated with the concomitant use of selective serotonin reuptake inhibitors (SSRIs) and anticoagulants like betrixaban. Case reports and epidemiological studies have demonstrated an association between use of drugs that interfere with serotonin reuptake and gastrointestinal bleeding.
Bismuth Subcitrate Potassium; Metronidazole; Tetracycline: (Moderate) Concomitant use of metronidazole and fluoxetine may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP. (Moderate) Concomitant use of metronidazole and olanzapine may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP.
Bismuth Subsalicylate: (Moderate) Antidiarrheals decrease GI motility. Agents that inhibit intestinal motility or prolong intestinal transit time have been reported to induce toxic megacolon. The concomitant administration of olanzapine may produce additive effects. (Moderate) The combined use of selective serotonin reuptake inhibitors (SSRIs) and aspirin, ASA or other salicylates which affect hemostasis may elevate the risk for an upper GI bleed. SSRIs may inhibit serotonin uptake by platelets, augmenting the antiplatelet effects of aspirin.
Bismuth Subsalicylate; Metronidazole; Tetracycline: (Moderate) Antidiarrheals decrease GI motility. Agents that inhibit intestinal motility or prolong intestinal transit time have been reported to induce toxic megacolon. The concomitant administration of olanzapine may produce additive effects. (Moderate) Concomitant use of metronidazole and fluoxetine may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP. (Moderate) Concomitant use of metronidazole and olanzapine may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP. (Moderate) The combined use of selective serotonin reuptake inhibitors (SSRIs) and aspirin, ASA or other salicylates which affect hemostasis may elevate the risk for an upper GI bleed. SSRIs may inhibit serotonin uptake by platelets, augmenting the antiplatelet effects of aspirin.
Bisoprolol: (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.
Bisoprolol; Hydrochlorothiazide, HCTZ: (Moderate) Monitor for signs and symptoms of hyponatremia during concomitant diuretic and fluoxetine use; consider discontinuing fluoxetine if symptomatic hyponatremia occurs and institute appropriate medical intervention. Concomitant use increases the risk for developing hyponatremia. (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.
Bortezomib: (Minor) Agents that inhibit cytochrome P450 3A4 may increase the exposure to bortezomib and increase the risk for toxicity; however, bortezomib is also metabolized by other CYP isoenzymes. Therefore, the clinical significance of concurrent administration of bortezomib with fluoxetine is not known.
Bosentan: (Moderate) Bosentan is metabolized by CYP2C9 and CYP3A4. Fluoxetine may inhibit both of these isoenzymes and thereby increase the plasma concentrations of bosentan. It is prudent to monitor for potential adverse effects of bosentan during coadministration with fluoxetine; excessive dosage may result in hypotension or elevated hepatic enzymes.
Brexpiprazole: (Major) Because brexpiprazole is primarily metabolized by CYP3A4 and CYP2D6, the manufacturer recommends that the brexpiprazole dose be reduced to one-half of the usual dose in patients receiving a strong CYP2D6 inhibitor and one-quarter (25%) of the usual dose in patients receiving a moderate to strong inhibitor of CYP3A4 in combination with a moderate to strong inhibitor of CYP2D6. Fluoxetine is a strong inhibitor of CYP2D6. If these agents are used in combination, the patient should be carefully monitored for brexpiprazole-related adverse reactions. It should be noted that no dosage adjustment is needed in patients taking a strong CYP2D6 inhibitor who are receiving brexpiprazole as adjunct treatment for major depressive disorder because CYP2D6 considerations are already factored into general dosing recommendations. (Major) Caution is advisable during concurrent use of brexpiprazole with other antipsychotics such as olanzapine. The risk of drowsiness, dizziness, hypotension, extrapyramidal symptoms, anticholinergic effects, neuroleptic malignant syndrome, or seizures may be increased during combined use; therefore, it may be advisable to initiate treatment with lower dosages if combination therapy is deemed necessary.
Brimonidine; Timolol: (Moderate) Monitor for signs of bradycardia or heart block if coadministration of timolol with fluoxetine is necessary. Concomitant use may enhance the beta-blocking properties of timolol resulting in further slowing of the heart rate or cardiac conduction. Timolol is a CYP2D6 substrate and fluoxetine is a strong CYP2D6 inhibitor. (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.
Bromocriptine: (Moderate) The effectiveness of bromocriptine may be reduced by most of the atypical antipsychotics, via their action as dopamine antagonists. Monitor the patient for reduced response to bromocriptine. The atypical antipsychotics elevate prolactin to various degrees. Atypical antipsychotics may also aggravate diabetes mellitus and cause metabolic changes including hyperglycemia; use caution if bromocriptine is taken for diabetes. If bromocriptine is taken for diabetes, monitor for worsening glycemic control.
Brompheniramine: (Moderate) Olanzapine exhibits anticholinergic effects that may be clinically significant. Clinicians should keep this in mind when using antimuscarinics and other medications with anticholinergic activity in combination with olanzapine. Some medications exhibit additive anticholinergic effects include sedating H1-blockers. Olanzapine may also cause additive sedation with many of these drugs.
Brompheniramine; Dextromethorphan; Phenylephrine: (Moderate) Monitor for dextromethorphan-related side effects, such as dizziness or drowsiness, if concomitant use of fluoxetine is necessary. For patients receiving combination dextromethorphan; bupropion, do not exceed a maximum dose of 45 mg dextromethorphan; 105 mg bupropion once daily. Additionally, monitor patients for signs and symptoms of serotonin syndrome. Concomitant use may increase dextromethorphan exposure and the risk for serotonin syndrome. Dextromethorphan is a CYP2D6 substrate and fluoxetine is a strong CYP2D6 inhibitor. Concomitant use with another strong CYP2D6 inhibitor increased dextromethorphan overall exposure by 2.69-fold. (Moderate) Olanzapine exhibits anticholinergic effects that may be clinically significant. Clinicians should keep this in mind when using antimuscarinics and other medications with anticholinergic activity in combination with olanzapine. Some medications exhibit additive anticholinergic effects include sedating H1-blockers. Olanzapine may also cause additive sedation with many of these drugs.
Brompheniramine; Phenylephrine: (Moderate) Olanzapine exhibits anticholinergic effects that may be clinically significant. Clinicians should keep this in mind when using antimuscarinics and other medications with anticholinergic activity in combination with olanzapine. Some medications exhibit additive anticholinergic effects include sedating H1-blockers. Olanzapine may also cause additive sedation with many of these drugs.
Brompheniramine; Pseudoephedrine: (Moderate) Olanzapine exhibits anticholinergic effects that may be clinically significant. Clinicians should keep this in mind when using antimuscarinics and other medications with anticholinergic activity in combination with olanzapine. Some medications exhibit additive anticholinergic effects include sedating H1-blockers. Olanzapine may also cause additive sedation with many of these drugs.
Brompheniramine; Pseudoephedrine; Dextromethorphan: (Moderate) Monitor for dextromethorphan-related side effects, such as dizziness or drowsiness, if concomitant use of fluoxetine is necessary. For patients receiving combination dextromethorphan; bupropion, do not exceed a maximum dose of 45 mg dextromethorphan; 105 mg bupropion once daily. Additionally, monitor patients for signs and symptoms of serotonin syndrome. Concomitant use may increase dextromethorphan exposure and the risk for serotonin syndrome. Dextromethorphan is a CYP2D6 substrate and fluoxetine is a strong CYP2D6 inhibitor. Concomitant use with another strong CYP2D6 inhibitor increased dextromethorphan overall exposure by 2.69-fold. (Moderate) Olanzapine exhibits anticholinergic effects that may be clinically significant. Clinicians should keep this in mind when using antimuscarinics and other medications with anticholinergic activity in combination with olanzapine. Some medications exhibit additive anticholinergic effects include sedating H1-blockers. Olanzapine may also cause additive sedation with many of these drugs.
Budesonide; Glycopyrrolate; Formoterol: (Moderate) Additive anticholinergic effects may be seen when olanzapine and anticholinergics are used concomitantly; use with caution. Use of olanzapine and other drugs with anticholinergic activity can increase the risk for severe gastrointestinal adverse reactions related to hypomotility. Olanzapine exhibits anticholinergic activity. Adverse effects may be seen not only on GI smooth muscle, but also on bladder function, the CNS, the eye, and temperature regulation. Additive drowsiness may also occur, depending on the anticholinergic agent used.
Bumetanide: (Moderate) Monitor for signs and symptoms of hyponatremia during concomitant diuretic and fluoxetine use; consider discontinuing fluoxetine if symptomatic hyponatremia occurs and institute appropriate medical intervention. Concomitant use increases the risk for developing hyponatremia.
Bupivacaine Liposomal: (Minor) Bupivacaine is metabolized by CYP3A4 isoenzymes. Known inhibitors of CYP3A4, such as fluoxetine, may result in increased systemic levels of bupivacaine when given concurrently, with potential for toxicity.
Bupivacaine: (Minor) Bupivacaine is metabolized by CYP3A4 isoenzymes. Known inhibitors of CYP3A4, such as fluoxetine, may result in increased systemic levels of bupivacaine when given concurrently, with potential for toxicity.
Bupivacaine; Epinephrine: (Moderate) Olanzapine may induce significant alpha-adrenergic blockade in overdose, leading to profound hypotension. Do not use epinephrine, dopamine, or other sympathomimetics with beta-agonist activity since the beta-stimulation may worsen hypotension in the setting of olanzapine overdose. (Minor) Bupivacaine is metabolized by CYP3A4 isoenzymes. Known inhibitors of CYP3A4, such as fluoxetine, may result in increased systemic levels of bupivacaine when given concurrently, with potential for toxicity.
Bupivacaine; Lidocaine: (Moderate) Concomitant use of systemic lidocaine and fluoxetine may increase lidocaine plasma concentrations by decreasing lidocaine clearance and therefore prolonging the elimination half-life. Monitor for lidocaine toxicity if used together. Lidocaine is a CYP3A4 and CYP1A2 substrate; fluoxetine inhibits CYP3A4. (Minor) Bupivacaine is metabolized by CYP3A4 isoenzymes. Known inhibitors of CYP3A4, such as fluoxetine, may result in increased systemic levels of bupivacaine when given concurrently, with potential for toxicity.
Bupivacaine; Meloxicam: (Minor) Bupivacaine is metabolized by CYP3A4 isoenzymes. Known inhibitors of CYP3A4, such as fluoxetine, may result in increased systemic levels of bupivacaine when given concurrently, with potential for toxicity.
Buprenorphine: (Major) Due to the potential for QT prolongation and additive CNS depressant effects, cautious use and close monitoring are advisable if concurrent use of olanzapine and buprenorphine is necessary. Buprenorphine has been associated with QT prolongation and has a possible risk of torsade de pointes (TdP). Olanzapine has a possible risk for QT prolongation and TdP. FDA-approved labeling for some buprenorphine products recommend avoiding use with Class 1A and Class III antiarrhythmic medications while other labels recommend avoiding use with any drug that has the potential to prolong the QT interval. If concurrent use of olanzapine and buprenorphine is necessary, consider a dose reduction of one or both drugs. Hypotension, profound sedation, coma, respiratory depression, or death may occur during co-administration of buprenorphine and other CNS depressants. Prior to concurrent use of buprenorphine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Evaluate the patient's use of alcohol or illicit drugs. It is recommended that the injectable buprenorphine dose be halved for patients who receive other drugs with CNS depressant effects; for the buprenorphine transdermal patch, start with the 5 mcg/hour patch. Monitor patients for sedation or respiratory depression. (Major) Due to the potential for QT prolongation, cautious use and close monitoring are advisable if concurrent use of fluoxetine and buprenorphine is necessary. Fluoxetine may cause QT interval prolongation and a risk for torsade de pointes (TdP); buprenorphine caused QT prolongation in some patients during clinical trials. In addition, concurrent use of opioids with other drugs that modulate serotonergic function, such as SSRIs, has resulted in serotonin syndrome in some cases. Patients should be carefully observed, particularly during treatment initiation and during dose adjustments. Discontinue the serotonergic medications if serotonin syndrome is suspected.
Buprenorphine; Naloxone: (Major) Due to the potential for QT prolongation and additive CNS depressant effects, cautious use and close monitoring are advisable if concurrent use of olanzapine and buprenorphine is necessary. Buprenorphine has been associated with QT prolongation and has a possible risk of torsade de pointes (TdP). Olanzapine has a possible risk for QT prolongation and TdP. FDA-approved labeling for some buprenorphine products recommend avoiding use with Class 1A and Class III antiarrhythmic medications while other labels recommend avoiding use with any drug that has the potential to prolong the QT interval. If concurrent use of olanzapine and buprenorphine is necessary, consider a dose reduction of one or both drugs. Hypotension, profound sedation, coma, respiratory depression, or death may occur during co-administration of buprenorphine and other CNS depressants. Prior to concurrent use of buprenorphine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Evaluate the patient's use of alcohol or illicit drugs. It is recommended that the injectable buprenorphine dose be halved for patients who receive other drugs with CNS depressant effects; for the buprenorphine transdermal patch, start with the 5 mcg/hour patch. Monitor patients for sedation or respiratory depression. (Major) Due to the potential for QT prolongation, cautious use and close monitoring are advisable if concurrent use of fluoxetine and buprenorphine is necessary. Fluoxetine may cause QT interval prolongation and a risk for torsade de pointes (TdP); buprenorphine caused QT prolongation in some patients during clinical trials. In addition, concurrent use of opioids with other drugs that modulate serotonergic function, such as SSRIs, has resulted in serotonin syndrome in some cases. Patients should be carefully observed, particularly during treatment initiation and during dose adjustments. Discontinue the serotonergic medications if serotonin syndrome is suspected.
Bupropion: (Major) Bupropion is associated with a dose-related risk of seizures. Extreme caution is recommended during concurrent use of other drugs that may lower the seizure threshold such as antipsychotics. The manufacturer of bupropion recommends low initial dosing and slow dosage titration if this combination must be used; the patient should be closely monitored. (Moderate) Monitor for increased fluoxetine-related adverse effects if coadministered with bupropion. Concomitant use may increase fluoxetine exposure. Fluoxetine is a CYP2D6 substrate and bupropion is a strong CYP2D6 inhibitor.
Bupropion; Naltrexone: (Major) Bupropion is associated with a dose-related risk of seizures. Extreme caution is recommended during concurrent use of other drugs that may lower the seizure threshold such as antipsychotics. The manufacturer of bupropion recommends low initial dosing and slow dosage titration if this combination must be used; the patient should be closely monitored. (Moderate) Monitor for increased fluoxetine-related adverse effects if coadministered with bupropion. Concomitant use may increase fluoxetine exposure. Fluoxetine is a CYP2D6 substrate and bupropion is a strong CYP2D6 inhibitor.
Buspirone: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when coadministering buspirone and fluoxetine. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome, particularly during treatment initiation and dose increases. If serotonin syndrome occurs, serotonergic drugs should be discontinued and appropriate medical treatment should be initiated. (Moderate) Monitor for signs and symptoms of serotonin syndrome, particularly during treatment initiation and dosage increase, during concomitant atypical antipsychotic and buspirone use. If serotonin syndrome occurs, discontinue therapy. Concomitant use increases the risk for serotonin syndrome.
Butabarbital: (Moderate) Olanzapine is metabolized by the CYP1A2 hepatic microsomal isoenzyme, and inducers of this enzyme such as barbiturates, may increase olanzapine clearance. The clinical effect of this interaction is thought to be minimal; however, the clinician should be alert for reduced olanzapine effect if the drugs are coadministered. Additive effects are possible when olanzapine is combined with other drugs which cause respiratory depression and/or CNS depression. Barbiturates can cause CNS depression, and if used concomitantly with olanzapine, can increase both the frequency and the intensity of adverse effects such as drowsiness, sedation, dizziness, and orthostatic hypotension.
Butalbital; Acetaminophen: (Moderate) Olanzapine is metabolized by the CYP1A2 hepatic microsomal isoenzyme, and inducers of this enzyme such as barbiturates, may increase olanzapine clearance. The clinical effect of this interaction is thought to be minimal; however, the clinician should be alert for reduced olanzapine effect if the drugs are coadministered. Additive effects are possible when olanzapine is combined with other drugs which cause respiratory depression and/or CNS depression. Barbiturates can cause CNS depression, and if used concomitantly with olanzapine, can increase both the frequency and the intensity of adverse effects such as drowsiness, sedation, dizziness, and orthostatic hypotension.
Butalbital; Acetaminophen; Caffeine: (Moderate) Olanzapine is metabolized by the CYP1A2 hepatic microsomal isoenzyme, and inducers of this enzyme such as barbiturates, may increase olanzapine clearance. The clinical effect of this interaction is thought to be minimal; however, the clinician should be alert for reduced olanzapine effect if the drugs are coadministered. Additive effects are possible when olanzapine is combined with other drugs which cause respiratory depression and/or CNS depression. Barbiturates can cause CNS depression, and if used concomitantly with olanzapine, can increase both the frequency and the intensity of adverse effects such as drowsiness, sedation, dizziness, and orthostatic hypotension.
Butalbital; Acetaminophen; Caffeine; Codeine: (Major) Concomitant use of opioid agonists with olanzapine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with olanzapine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Also monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. Avoid prescribing opioid cough medication in patients taking olanzapine. (Moderate) Careful monitoring, particularly during treatment initiation and dose adjustment, is recommended during coadministration of codeine and fluoxetine because of the potential risk of serotonin syndrome, reduced codeine efficacy, and potential for opioid withdrawal symptoms. Discontinue codeine if serotonin syndrome is suspected. It is recommended to avoid this combination when codeine is being used for cough. Concomitant use may increase codeine plasma concentrations, but decrease the plasma concentration of the active metabolite, morphine, resulting in reduced efficacy or symptoms of opioid withdrawal. Monitor patients closely at frequent intervals and consider a dosage increase of codeine until stable drug effects are achieved. Discontinuation of fluoxetine could decrease codeine plasma concentrations and increase morphine plasma concentrations resulting in prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If fluoxetine is discontinued, monitor the patient carefully and consider reducing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Fluoxetine is a strong inhibitor of CYP2D6. (Moderate) Olanzapine is metabolized by the CYP1A2 hepatic microsomal isoenzyme, and inducers of this enzyme such as barbiturates, may increase olanzapine clearance. The clinical effect of this interaction is thought to be minimal; however, the clinician should be alert for reduced olanzapine effect if the drugs are coadministered. Additive effects are possible when olanzapine is combined with other drugs which cause respiratory depression and/or CNS depression. Barbiturates can cause CNS depression, and if used concomitantly with olanzapine, can increase both the frequency and the intensity of adverse effects such as drowsiness, sedation, dizziness, and orthostatic hypotension.
Butalbital; Aspirin; Caffeine; Codeine: (Major) Concomitant use of opioid agonists with olanzapine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with olanzapine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Also monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. Avoid prescribing opioid cough medication in patients taking olanzapine. (Moderate) Careful monitoring, particularly during treatment initiation and dose adjustment, is recommended during coadministration of codeine and fluoxetine because of the potential risk of serotonin syndrome, reduced codeine efficacy, and potential for opioid withdrawal symptoms. Discontinue codeine if serotonin syndrome is suspected. It is recommended to avoid this combination when codeine is being used for cough. Concomitant use may increase codeine plasma concentrations, but decrease the plasma concentration of the active metabolite, morphine, resulting in reduced efficacy or symptoms of opioid withdrawal. Monitor patients closely at frequent intervals and consider a dosage increase of codeine until stable drug effects are achieved. Discontinuation of fluoxetine could decrease codeine plasma concentrations and increase morphine plasma concentrations resulting in prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If fluoxetine is discontinued, monitor the patient carefully and consider reducing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Fluoxetine is a strong inhibitor of CYP2D6. (Moderate) Olanzapine is metabolized by the CYP1A2 hepatic microsomal isoenzyme, and inducers of this enzyme such as barbiturates, may increase olanzapine clearance. The clinical effect of this interaction is thought to be minimal; however, the clinician should be alert for reduced olanzapine effect if the drugs are coadministered. Additive effects are possible when olanzapine is combined with other drugs which cause respiratory depression and/or CNS depression. Barbiturates can cause CNS depression, and if used concomitantly with olanzapine, can increase both the frequency and the intensity of adverse effects such as drowsiness, sedation, dizziness, and orthostatic hypotension. (Moderate) The combined use of selective serotonin reuptake inhibitors and aspirin, ASA may elevate the risk for an upper GI bleed. SSRIs may inhibit serotonin uptake by platelets, augmenting the antiplatelet effects of aspirin. Additionally, aspirin impairs the gastric mucosa defenses by inhibiting prostaglandin formation.
Butorphanol: (Moderate) Other drugs that can cause CNS depression, such as butorphanol, if used concomitantly with olanzapine, can increase both the frequency and the intensity of adverse effects such as drowsiness, sedation, dizziness, and orthostatic hypotension.
Cabergoline: (Moderate) Cabergoline should not be coadministered with olanzapine due to mutually antagonistic effects on dopaminergic function. The dopamine antagonist action of olanzapine may diminish the prolactin-lowering ability of cabergoline while the dopamine agonist effects of cabergoline may exacerbate a psychotic disorder, reducing the effectiveness of antipsychotics such as olanzapine.
Cabotegravir; Rilpivirine: (Moderate) Caution is advised when administering rilpivirine with olanzapine as concurrent use may increase the risk of QT prolongation. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. Limited data, including some case reports, suggest that olanzapine may also be associated with a significant prolongation of the QTc interval. (Moderate) Concomitant use of fluoxetine and rilpivirine may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP. The degree of QT prolongation associated with rilpivirine is not clinically significant when administered within the recommended dosage range; QT prolongation has been described at 3 times the maximum recommended dose.
Calcium-channel blockers: (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.
Canagliflozin: (Moderate) Monitor blood glucose during concomitant atypical antipsychotic and SGLT2 inhibitor use. Atypical antipsychotic therapy may aggravate diabetes mellitus. Atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition. (Moderate) Monitor blood glucose during concomitant SGLT2 inhibitor and fluoxetine use; a SGLT2 inhibitor dose adjustment may be necessary. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
Canagliflozin; Metformin: (Moderate) Monitor blood glucose during concomitant atypical antipsychotic and metformin use. Atypical antipsychotic therapy may aggravate diabetes mellitus. Atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition. (Moderate) Monitor blood glucose during concomitant atypical antipsychotic and SGLT2 inhibitor use. Atypical antipsychotic therapy may aggravate diabetes mellitus. Atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition. (Moderate) Monitor blood glucose during concomitant metformin and fluoxetine use; a metformin dose adjustment may be necessary. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia. (Moderate) Monitor blood glucose during concomitant SGLT2 inhibitor and fluoxetine use; a SGLT2 inhibitor dose adjustment may be necessary. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
Candesartan: (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.
Candesartan; Hydrochlorothiazide, HCTZ: (Moderate) Monitor for signs and symptoms of hyponatremia during concomitant diuretic and fluoxetine use; consider discontinuing fluoxetine if symptomatic hyponatremia occurs and institute appropriate medical intervention. Concomitant use increases the risk for developing hyponatremia. (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.
Cangrelor: (Moderate) Platelet aggregation may be impaired by selective serotonin reuptake inhibitors (SSRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymosis, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving platelet inhibitors (e.g., cangrelor). Patients should be instructed to monitor for signs and symptoms of bleeding while taking an SSRI concurrently with an antiplatelet medication and to promptly report any bleeding events to the practitioner.
Cannabidiol: (Moderate) Monitor for excessive sedation and somnolence during coadministration of cannabidiol and olanzapine. Concurrent use may result in additive CNS depression.
Capsaicin; Metaxalone: (Moderate) Concomitant use of selective serotonin reuptake inhibitors (SSRIs) and metaxalone may increase the risk for serotonin syndrome. Monitor patients for serotonin syndrome if concomitant use is necessary.
Captopril: (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.
Captopril; Hydrochlorothiazide, HCTZ: (Moderate) Monitor for signs and symptoms of hyponatremia during concomitant diuretic and fluoxetine use; consider discontinuing fluoxetine if symptomatic hyponatremia occurs and institute appropriate medical intervention. Concomitant use increases the risk for developing hyponatremia. (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.
Carbamazepine: (Moderate) Monitor for reduced olanzapine efficacy; dosage adjustments might be necessary in some patients for whom carbamazepine treatment is medically necessary. Carbamazepine (200 mg BID) increases olanzapine clearance by approximately 50% via potent induction of CYP1A2. Higher daily doses of carbamazepine may cause an even greater increase in olanzapine clearance. In addition, additive CNS effects (e.g., sedation) may occur, and antipsychotic therapy may also reduce the seizure threshold in some patients.
Carbidopa; Levodopa: (Moderate) Monitor for movement disorders, unusual changes in moods or behavior, and diminished effectiveness of the atypical antipsychotic or levodopa during coadministration. Due to mutually opposing effects on dopamine, atypical antipsychotics and levodopa may interfere with the effectiveness of each other. In general, atypical antipsychotics are less likely to interfere with levodopa and other antiparkinson's treatments than traditional antipsychotics.
Carbidopa; Levodopa; Entacapone: (Moderate) Monitor for movement disorders, unusual changes in moods or behavior, and diminished effectiveness of the atypical antipsychotic or COMT inhibitor during coadministration. Due to mutually opposing effects on dopamine, atypical antipsychotics and COMT inhibitors may interfere with the effectiveness of each other. In general, atypical antipsychotics are less likely to interfere with COMT inhibitors and other Parkinson's treatments than traditional antipsychotics. The Beers Criteria recognize quetiapine and clozapine as exceptions to the general recommendation to avoid all antipsychotics in older adults with Parkinson's disease. (Moderate) Monitor for movement disorders, unusual changes in moods or behavior, and diminished effectiveness of the atypical antipsychotic or levodopa during coadministration. Due to mutually opposing effects on dopamine, atypical antipsychotics and levodopa may interfere with the effectiveness of each other. In general, atypical antipsychotics are less likely to interfere with levodopa and other antiparkinson's treatments than traditional antipsychotics.
Carbinoxamine: (Moderate) Olanzapine exhibits anticholinergic effects that may be clinically significant. Clinicians should keep this in mind when using antimuscarinics and other medications with anticholinergic activity in combination with olanzapine. Some medications exhibit additive anticholinergic effects include sedating H1-blockers. Olanzapine may also cause additive sedation with many of these drugs.
Cariprazine: (Moderate) The risk of adverse effects may be increased during concurrent use of cariprazine with other antipsychotics, such as olanzapine. Similar to other antipsychotics, cariprazine administration has been associated with drowsiness, dizziness, orthostatic hypotension, extrapyramidal symptoms, neuroleptic malignant syndrome, and seizures. The likelihood of these pharmacodynamic interactions varies based upon the individual properties of the co-administered antipsychotic agent. The incidence of tardive dyskinesia from combination antipsychotic therapy has not been established and data are very limited, but the risk appears to be increased.
Carisoprodol: (Minor) Carisoprodol is extensively metabolized and is a significant substrate of CYP2C19 isoenzymes. Theoretically, CY2C19 inhibitors, such as fluoxetine, could increase carisoprodol plasma levels, with potential for enhanced CNS depressant effects.
Carteolol: (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.
Carvedilol: (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents. (Minor) Inhibitors of the hepatic CYP450 isozyme CYP 2D6, such as fluoxetine, may inhibit the hepatic oxidative metabolism of carvedilol.
Celecoxib; Tramadol: (Moderate) If concomitant use of tramadol and olanzapine is warranted, monitor patients for seizures, excessive sedation and/or somnolence, and the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. Concomitant use of tramadol and olanzapine may increase seizure risk and cause additive CNS depression. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. (Moderate) Monitor for reduced efficacy of tramadol, signs of opioid withdrawal, seizures, or serotonin syndrome if coadministration with fluoxetine is necessary. If fluoxetine is discontinued, consider a dose reduction of tramadol and frequently monitor for signs of respiratory depression and sedation. Tramadol is a CYP2D6 substrate and fluoxetine is a CYP2D6 inhibitor. Concomitant use of tramadol with CYP2D6 inhibitors can increase the plasma concentration of tramadol and decrease the plasma concentration of the active metabolite M1. Since M1 is a more potent mu-opioid agonist, decreased M1 exposure could result in decreased therapeutic effects, and may result in signs and symptoms of opioid withdrawal in patients who have developed physical dependence to tramadol. Increased tramadol exposure can result in increased or prolonged therapeutic effects and increased risk for serious adverse events including seizures and serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
Cenobamate: (Moderate) Monitor for excessive sedation and somnolence during coadministration of cenobamate and olanzapine. Concurrent use may result in additive CNS depression.
Central-acting adrenergic agents: (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.
Ceritinib: (Major) Avoid coadministration of ceritinib with fluoxetine if possible due to the risk of QT prolongation. If concomitant use is unavoidable, periodically monitor ECGs and electrolytes; an interruption of ceritinib therapy, dose reduction, or discontinuation of therapy may be necessary if QT prolongation occurs. Ceritinib causes concentration-dependent prolongation of the QT interval. QT prolongation and torsade de pointes (TdP) have also been reported in patients treated with fluoxetine. (Major) Avoid coadministration of ceritinib with olanzapine if possible due to the risk of QT prolongation. If concomitant use is unavoidable, periodically monitor ECGs and electrolytes; an interruption of ceritinib therapy, dose reduction, or discontinuation of therapy may be necessary if QT prolongation occurs. Ceritinib causes concentration-dependent prolongation of the QT interval. Limited data, including some case reports, suggest that olanzapine may also be associated with a significant prolongation of the QTc interval.
Cetirizine: (Moderate) Monitor for unusual drowsiness and sedation during coadministration of atypical antipsychotics and cetirizine due to the risk for additive CNS depression.
Cetirizine; Pseudoephedrine: (Moderate) Monitor for unusual drowsiness and sedation during coadministration of atypical antipsychotics and cetirizine due to the risk for additive CNS depression.
Cetrorelix: (Moderate) Antipsychotic-induced hyperprolactinemia results in down-regulation of the number of pituitary GnRH receptors and may interfere with the response to any of the gonadotropin-releasing hormone (GnRH) analogs including cetrorelix.
Cevimeline: (Moderate) Monitor for an increase in cevimeline-related adverse effects if concomitant use of fluoxetine is necessary. Concomitant use may increase cevimeline exposure. Cevimeline is a CYP2D6 substrate; fluoxetine is a strong CYP2D6 inhibitor.
Charcoal: (Major) Concomitant administration of olanzapine and activated charcoal is not recommended and is not expected to occur under normal clinical use. The Cmax and AUC of olanzapine were reduced by 60% when co-administered with activated charcoal. Co-administration with activated charcoal may be appropriate in an olanzapine overdose situation, especially since peak olanzapine levels do not occur until 6 hours after an oral ingestion. However, patients should avoid dietary supplements containing activated charcoal.
Chlophedianol; Dexchlorpheniramine; Pseudoephedrine: (Moderate) Olanzapine exhibits anticholinergic effects that may be clinically significant. Clinicians should keep this in mind when using antimuscarinics and other medications with anticholinergic activity in combination with olanzapine. Some medications exhibit additive anticholinergic effects include sedating H1-blockers. Olanzapine may also cause additive sedation with many of these drugs.
Chlorcyclizine: (Moderate) Olanzapine exhibits anticholinergic effects that may be clinically significant. Clinicians should keep this in mind when using antimuscarinics and other medications with anticholinergic activity in combination with olanzapine. Some medications exhibit additive anticholinergic effects include sedating H1-blockers. Olanzapine may also cause additive sedation with many of these drugs.
Chlordiazepoxide: (Major) Concurrent use of intramuscular olanzapine and parenteral benzodiazepines is not recommended due to the potential for adverse effects from the combination, including excess sedation and/or cardiopulmonary depression. Although oral formulations of olanzapine and benzodiazepines may be used together, additive effects on respiratory depression and/or CNS depression are possible. Drugs that can cause CNS depression, if used concomitantly with olanzapine, can increase both the frequency and severity of adverse effects such as drowsiness, sedation, dizziness, and orthostatic hypotension. (Moderate) Fluoxetine could theoretically inhibit CYP3A4 metabolism of oxidized benzodiazepines, including chlordiazepoxide. Patients should be monitored for clinical response, and adjust benzodiazepine dosage if needed.
Chlordiazepoxide; Amitriptyline: (Major) Concurrent use of intramuscular olanzapine and parenteral benzodiazepines is not recommended due to the potential for adverse effects from the combination, including excess sedation and/or cardiopulmonary depression. Although oral formulations of olanzapine and benzodiazepines may be used together, additive effects on respiratory depression and/or CNS depression are possible. Drugs that can cause CNS depression, if used concomitantly with olanzapine, can increase both the frequency and severity of adverse effects such as drowsiness, sedation, dizziness, and orthostatic hypotension. (Moderate) Fluoxetine could theoretically inhibit CYP3A4 metabolism of oxidized benzodiazepines, including chlordiazepoxide. Patients should be monitored for clinical response, and adjust benzodiazepine dosage if needed. (Moderate) Monitor for signs and symptoms of serotonin syndrome, particularly during treatment initiation and dosage increase, during concomitant amitriptyline and fluoxetine use. If serotonin syndrome occurs, discontinue therapy. Concomitant use increases the risk for serotonin syndrome.
Chlordiazepoxide; Clidinium: (Major) Concurrent use of intramuscular olanzapine and parenteral benzodiazepines is not recommended due to the potential for adverse effects from the combination, including excess sedation and/or cardiopulmonary depression. Although oral formulations of olanzapine and benzodiazepines may be used together, additive effects on respiratory depression and/or CNS depression are possible. Drugs that can cause CNS depression, if used concomitantly with olanzapine, can increase both the frequency and severity of adverse effects such as drowsiness, sedation, dizziness, and orthostatic hypotension. (Moderate) Additive anticholinergic effects may be seen when olanzapine and anticholinergics are used concomitantly; use with caution. Use of olanzapine and other drugs with anticholinergic activity can increase the risk for severe gastrointestinal adverse reactions related to hypomotility. Olanzapine exhibits anticholinergic activity. Adverse effects may be seen not only on GI smooth muscle, but also on bladder function, the CNS, the eye, and temperature regulation. Additive drowsiness may also occur, depending on the anticholinergic agent used. (Moderate) Fluoxetine could theoretically inhibit CYP3A4 metabolism of oxidized benzodiazepines, including chlordiazepoxide. Patients should be monitored for clinical response, and adjust benzodiazepine dosage if needed.
Chloroquine: (Major) Avoid coadministration of chloroquine with olanzapine due to the increased risk of QT prolongation. If use together is necessary, obtain an ECG at baseline to assess initial QT interval and determine frequency of subsequent ECG monitoring, avoid any non-essential QT prolonging drugs, and correct electrolyte imbalances. Chloroquine is associated with an increased risk of QT prolongation and torsade de pointes (TdP); the risk of QT prolongation is increased with higher chloroquine doses. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval. (Major) Concomitant use of chloroquine and fluoxetine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Chlorothiazide: (Moderate) Monitor for signs and symptoms of hyponatremia during concomitant diuretic and fluoxetine use; consider discontinuing fluoxetine if symptomatic hyponatremia occurs and institute appropriate medical intervention. Concomitant use increases the risk for developing hyponatremia.
Chlorpheniramine: (Moderate) Olanzapine exhibits anticholinergic effects that may be clinically significant. Clinicians should keep this in mind when using antimuscarinics and other medications with anticholinergic activity in combination with olanzapine. Some medications exhibit additive anticholinergic effects include sedating H1-blockers. Olanzapine may also cause additive sedation with many of these drugs.
Chlorpheniramine; Codeine: (Major) Concomitant use of opioid agonists with olanzapine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with olanzapine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Also monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. Avoid prescribing opioid cough medication in patients taking olanzapine. (Moderate) Careful monitoring, particularly during trea tment initiation and dose adjustment, is recommended during coadministration of codeine and fluoxetine because of the potential risk of serotonin syndrome, reduced codeine efficacy, and potential for opioid withdrawal symptoms. Discontinue codeine if serotonin syndrome is suspected. It is recommended to avoid this combination when codeine is being used for cough. Concomitant use may increase codeine plasma concentrations, but decrease the plasma concentration of the active metabolite, morphine, resulting in reduced efficacy or symptoms of opioid withdrawal. Monitor patients closely at frequent intervals and consider a dosage increase of codeine until stable drug effects are achieved. Discontinuation of fluoxetine could decrease codeine plasma concentrations and increase morphine plasma concentrations resulting in prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If fluoxetine is discontinued, monitor the patient carefully and consider reducing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Fluoxetine is a strong inhibitor of CYP2D6. (Moderate) Olanzapine exhibits anticholinergic effects that may be clinically significant. Clinicians should keep this in mind when using antimuscarinics and other medications with anticholinergic activity in combination with olanzapine. Some medications exhibit additive anticholinergic effects include sedating H1-blockers. Olanzapine may also cause additive sedation with many of these drugs.
Chlorpheniramine; Dextromethorphan: (Moderate) Monitor for dextromethorphan-related side effects, such as dizziness or drowsiness, if concomitant use of fluoxetine is necessary. For patients receiving combination dextromethorphan; bupropion, do not exceed a maximum dose of 45 mg dextromethorphan; 105 mg bupropion once daily. Additionally, monitor patients for signs and symptoms of serotonin syndrome. Concomitant use may increase dextromethorphan exposure and the risk for serotonin syndrome. Dextromethorphan is a CYP2D6 substrate and fluoxetine is a strong CYP2D6 inhibitor. Concomitant use with another strong CYP2D6 inhibitor increased dextromethorphan overall exposure by 2.69-fold. (Moderate) Olanzapine exhibits anticholinergic effects that may be clinically significant. Clinicians should keep this in mind when using antimuscarinics and other medications with anticholinergic activity in combination with olanzapine. Some medications exhibit additive anticholinergic effects include sedating H1-blockers. Olanzapine may also cause additive sedation with many of these drugs.
Chlorpheniramine; Dextromethorphan; Phenylephrine: (Moderate) Monitor for dextromethorphan-related side effects, such as dizziness or drowsiness, if concomitant use of fluoxetine is necessary. For patients receiving combination dextromethorphan; bupropion, do not exceed a maximum dose of 45 mg dextromethorphan; 105 mg bupropion once daily. Additionally, monitor patients for signs and symptoms of serotonin syndrome. Concomitant use may increase dextromethorphan exposure and the risk for serotonin syndrome. Dextromethorphan is a CYP2D6 substrate and fluoxetine is a strong CYP2D6 inhibitor. Concomitant use with another strong CYP2D6 inhibitor increased dextromethorphan overall exposure by 2.69-fold. (Moderate) Olanzapine exhibits anticholinergic effects that may be clinically significant. Clinicians should keep this in mind when using antimuscarinics and other medications with anticholinergic activity in combination with olanzapine. Some medications exhibit additive anticholinergic effects include sedating H1-blockers. Olanzapine may also cause additive sedation with many of these drugs.
Chlorpheniramine; Dextromethorphan; Pseudoephedrine: (Moderate) Monitor for dextromethorphan-related side effects, such as dizziness or drowsiness, if concomitant use of fluoxetine is necessary. For patients receiving combination dextromethorphan; bupropion, do not exceed a maximum dose of 45 mg dextromethorphan; 105 mg bupropion once daily. Additionally, monitor patients for signs and symptoms of serotonin syndrome. Concomitant use may increase dextromethorphan exposure and the risk for serotonin syndrome. Dextromethorphan is a CYP2D6 substrate and fluoxetine is a strong CYP2D6 inhibitor. Concomitant use with another strong CYP2D6 inhibitor increased dextromethorphan overall exposure by 2.69-fold. (Moderate) Olanzapine exhibits anticholinergic effects that may be clinically significant. Clinicians should keep this in mind when using antimuscarinics and other medications with anticholinergic activity in combination with olanzapine. Some medications exhibit additive anticholinergic effects include sedating H1-blockers. Olanzapine may also cause additive sedation with many of these drugs.
Chlorpheniramine; Dihydrocodeine; Phenylephrine: (Major) Concomitant use of opioid agonists with olanzapine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with olanzapine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Also monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. Avoid prescribing opioid cough medication in patients taking olanzapine. (Moderate) Careful monitoring, particularly during treatment initiation and dose adjustment, is recommended during coadministration of dihydrocodeine and fluoxetine because of the potential risk of serotonin syndrome, reduced dihydrocodeine efficacy, and potential for opioid withdrawal symptoms. Discontinue dihydrocodeine if serotonin syndrome is suspected. Concomitant use may increase dihydrocodeine plasma concentrations, but decrease the plasma concentration of the active metabolite, dihydromorphine, resulting in reduced efficacy or symptoms of opioid withdrawal. Monitor patients closely at frequent intervals and consider a dosage increase of dihydrocodeine until stable drug effects are achieved. Discontinuation of fluoxetine could decrease dihydrocodeine plasma concentrations and increase dihydromorphine plasma concentrations resulting in prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If fluoxetine is discontinued, monitor the patient carefully and consider reducing the opioid dosage if appropriate. Dihydrocodeine is primarily metabolized by CYP2D6 to dihydromorphine, and by CYP3A4. Fluoxetine is a strong inhibitor of CYP2D6. (Moderate) Olanzapine exhibits anticholinergic effects that may be clinically significant. Clinicians should keep this in mind when using antimuscarinics and other medications with anticholinergic activity in combination with olanzapine. Some medications exhibit additive anticholinergic effects include sedating H1-blockers. Olanzapine may also cause additive sedation with many of these drugs.
Chlorpheniramine; Hydrocodone: (Major) Concomitant use of opioid agonists with olanzapine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with olanzapine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Also monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. Avoid prescribing opioid cough medication in patients taking olanzapine. (Moderate) Careful monitoring, particularly during treatment initiation and dose adjustment, is recommended during coadministration of hydrocodone and fluoxetine because of the potential risk of serotonin syndrome and prolonged opioid adverse reactions. Discontinue hydrocodone if serotonin syndrome is suspected. It is recommended to avoid this combination when hydrocodone is being used for cough. Concomitant use of hydrocodone with fluoxetine may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. Monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of fluoxetine could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If fluoxetine is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP2D6. Fluoxetine is a strong inhibitor of CYP2D6. (Moderate) Olanzapine exhibits anticholinergic effects that may be clinically significant. Clinicians should keep this in mind when using antimuscarinics and other medications with anticholinergic activity in combination with olanzapine. Some medications exhibit additive anticholinergic effects include sedating H1-blockers. Olanzapine may also cause additive sedation with many of these drugs.
Chlorpheniramine; Ibuprofen; Pseudoephedrine: (Moderate) Olanzapine exhibits anticholinergic effects that may be clinically significant. Clinicians should keep this in mind when using antimuscarinics and other medications with anticholinergic activity in combination with olanzapine. Some medications exhibit additive anticholinergic effects include sedating H1-blockers. Olanzapine may also cause additive sedation with many of these drugs.
Chlorpheniramine; Phenylephrine: (Moderate) Olanzapine exhibits anticholinergic effects that may be clinically significant. Clinicians should keep this in mind when using antimuscarinics and other medications with anticholinergic activity in combination with olanzapine. Some medications exhibit additive anticholinergic effects include sedating H1-blockers. Olanzapine may also cause additive sedation with many of these drugs.
Chlorpheniramine; Pseudoephedrine: (Moderate) Olanzapine exhibits anticholinergic effects that may be clinically significant. Clinicians should keep this in mind when using antimuscarinics and other medications with anticholinergic activity in combination with olanzapine. Some medications exhibit additive anticholinergic effects include sedating H1-blockers. Olanzapine may also cause additive sedation with many of these drugs.
Chlorpromazine: (Major) Concurrent use of olanzapine and chlorpromazine should be avoided due to an increased risk for QT prolongation and torsade de pointes (TdP). Chlorpromazine, a phenothiazine, is associated with an established risk of QT prolongation and TdP. Limited data, including some case reports, suggest that olanzapine may also be associated with a significant prolongation of the QTc interval in rare instances. In addition, coadministration may increase the risk of drowsiness, dizziness, orthostatic hypotension, anticholinergic effects, extrapyramidal symptoms, neuroleptic malignant syndrome, tardive dyskinesia, or seizures. Although the incidence of tardive dyskinesia from combination antipsychotic therapy has not been established and data are very limited, the risk appears to be increased during use of a conventional and atypical antipsychotic versus use of a conventional antipsychotic alone. (Major) Fluoxetine is associated with a possible risk of QT prolongation and torsade de pointes (TdP) and chlorpromazine also has an established risk of QT prolongation and TdP. Combination therapy with these agents should be avoided if possible. Fluoxetine is a potent inhibitor of CYP2D6 and may result in increases in serum phenothiazine concentrations, which may lead to phenothiazine-related side effects such as cardiac side effects, hypotension, CNS sedation, or extrapyramidal symptoms. The effects of fluoxetine on hepatic metabolism of interacting drugs may persist for a time after discontinuation of fluoxetine because of its long elimination half-life.
Chlorthalidone: (Moderate) Monitor for signs and symptoms of hyponatremia during concomitant diuretic and fluoxetine use; consider discontinuing fluoxetine if symptomatic hyponatremia occurs and institute appropriate medical intervention. Concomitant use increases the risk for developing hyponatremia.
Chlorthalidone; Clonidine: (Moderate) Monitor for signs and symptoms of hyponatremia during concomitant diuretic and fluoxetine use; consider discontinuing fluoxetine if symptomatic hyponatremia occurs and institute appropriate medical intervention. Concomitant use increases the risk for developing hyponatremia.
Chlorzoxazone: (Moderate) Additive CNS depression is possible if chlorzoxazone is used concomitantly with other CNS depressants, such as olanzapine. Dosage adjustments of one or both medications may be necessary.
Choline Salicylate; Magnesium Salicylate: (Moderate) Monitor for signs and symptoms of bleeding during concomitant magnesium salicylate and selective serotonin reuptake inhibitor (SSRI) use due to increased risk for bleeding. Serotonin release by platelets plays an important role in hemostasis. Epidemiological studies have demonstrated an association between use of psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper gastrointestinal bleeding. (Moderate) The combined use of selective serotonin reuptake inhibitors (SSRIs) and aspirin, ASA or other salicylates which affect hemostasis may elevate the risk for an upper GI bleed. SSRIs may inhibit serotonin uptake by platelets, augmenting the antiplatelet effects of aspirin. Additionally, aspirin impairs the gastric mucosa defenses by inhibiting prostaglandin formation. A cohort study in > 26,000 patients found that SSRI use alone increased the risk for serious GI bleed by 3.6-fold; when an SSRI was combined with aspirin the risk was increased by > 5-fold. The absolute risk of GI bleed from concomitant therapy with aspirin and a SSRI was low (20/2640 patients) in this cohort study and the clinician may determine that the combined use of these drugs is appropriate.
Cilostazol: (Major) Cilostazol is extensively metabolized by the CYP3A4 hepatic isoenzyme and appears to have pharmacokinetic interactions with many medications that are potent inhibitors of CYP3A4, including fluoxetine. These agents have been shown to increase both cilostazol AUC and Cmax when administered concurrently. When significant CYP3A4 inhibitors, such as fluoxetine, are administered concomitantly with cilostazol, the manufacturer recommends that the cilostazol dosage be reduced by 50%.
Cimetidine: (Moderate) Monitor for increased fluoxetine-related adverse effects if coadministered with cimetidine. Concomitant use may increase fluoxetine exposure. Fluoxetine is a CYP2D6 substrate and cimetidine is a weak CYP2D6 inhibitor. (Minor) Inhibitors of CYP1A2, such as cimetidine, could potentially decrease the elimination of olanzapine.
Cinacalcet: (Moderate) Monitor for increased fluoxetine-related adverse effects if coadministered with cinacalcet. Concomitant use may increase fluoxetine exposure. Fluoxetine is a CYP2D6 substrate and cinacalcet is a moderate CYP2D6 inhibitor.
Ciprofloxacin: (Major) Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval in rare instances. Therefore, caution is advised when administering olanzapine with drugs having an established causal association with QT prolongation and torsade de pointes (TdP) including ciprofloxacin. Additionally, ciprofloxacin inhibits the activity of CYP1A2. Inhibitors of CYP1A2 could potentially reduce the elimination of olanzapine. However, since multiple enzyme pathways metabolize olanzapine, inhibition of only one isoenzyme may not appreciably decrease olanzapine clearance. One case study reported elevated olanzapine plasma concentrations during ciprofloxacin coadministration, possibly due to CYP1A2 inhibition of olanzapine metabolism. Ciprofloxacin inhibits the activity of CYP1A2. Inhibitors of CYP1A2 could potentially reduce the elimination of olanzapine. However, since multiple enzyme pathways metabolize olanzapine, inhibition of only one isoenzyme may not appreciably decrease olanzapine clearance. One case study reported elevated olanzapine plasma concentrations during ciprofloxacin coadministration, possibly due to CYP1A2 inhibition of olanzapine metabolism. (Moderate) Concomitant use of ciprofloxacin and fluoxetine may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP.
Cisapride: (Contraindicated) Cisapride is metabolized by CYP3A4 isozyme, a pathway that fluoxetine is known to inhibit, and may inhibit the clearance of and potentiate the toxicity of cisapride. QT prolongation and ventricular arrhythmias, including torsade de pointes and death, have been reported when inhibitors of CYP3A4 are coadministered with cisapride. Due to the serious nature of cisapride toxicity, fluoxetine should be avoided in these patients. (Contraindicated) Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval in rare instances. Because of the potential for torsade de pointes (TdP), use of cisapride with olanzapine is contraindicated.
Citalopram: (Contraindicated) Due to the similarity in pharmacology of fluoxetine and citalopram and the potential for serious adverse reactions, including serotonin syndrome, these selective serotonin reuptake inhibitors (SSRIs) should not be administered together. Also, both fluoxetine and citalopram have been associated with QT prolongation and torsade de pointes (TdP). It is advisable to monitor for signs and symptoms of serotonin syndrome during an overlapping transition from one SSRI to another SSRI. (Major) Concomitant use of olanzapine and citalopram increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Clarithromycin: (Major) Concomitant use of clarithromycin and fluoxetine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. (Major) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering clarithromycin with olanzapine. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval in rare instances. Additionally, clarithromycin is associated with an established risk for QT prolongation and TdP.
Clemastine: (Moderate) Olanzapine exhibits anticholinergic effects that may be clinically significant. Clinicians should keep this in mind when using antimuscarinics and other medications with anticholinergic activity in combination with olanzapine. Some medications exhibit additive anticholinergic effects include sedating H1-blockers. Olanzapine may also cause additive sedation with many of these drugs.
Clobazam: (Moderate) A dosage reduction of clobazam and/or fluoxetine may be necessary during co-administration of clobazam and fluoxetine. Metabolism of N-desmethylclobazam, the active metabolite of clobazam, occurs primarily through CYP2C19 and fluoxetine is an inhibitor of CYP2C19. Extrapolation from pharmacogenomic data indicates that concurrent use of clobazam with moderate or potent inhibitors of CYP2C19 may result in up to a 5-fold increase in exposure to N-desmethylclobazam. Adverse effects, such as sedation, lethargy, ataxia, or insomnia may be potentiated. In addition, fluoxetine is a substrate of CYP2D6 and limited in vivo data suggest that clobazam is an inhibitor of CYP2D6. A dosage reduction of CYP2D6 substrates may be necessary during co-administration of clobazam. It should be noted that because fluoxetine is metabolized by multiple enzyme systems, inhibition of one pathway may not appreciably decrease its clearance. (Moderate) Clobazam, a benzodiazepine, should be combined cautiously with atypical antipsychotics because of the potential for additive CNS depressant effects. Antipsychotics may also lower the seizure threshold, which might effect the efficacy of clobazam to treat seizures. Clobazam is a weak inducer of CYP3A4 and may reduce the efficacy of atypical antipsychotics that are significantly metabolized by CYP3A4; consult the atypical antipsychotic product labeling for clinical relevance.
Clofazimine: (Moderate) Concomitant use of clofazimine and fluoxetine may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP. (Moderate) Concomitant use of clofazimine and olanzapine may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP.
Clomipramine: (Moderate) Coadministration of fluoxetine and clomipramine may increase the risk for QT prolongation, torsade de pointes (TdP), and serotonin syndrome. If serotonin syndrome is suspected, discontinue fluoxetine and concurrent serotonergic agents and initiate appropriate medical treatment. QT prolongation and TdP have been reported in patients treated with fluoxetine. Tricyclics, particularly at elevated concentrations, are associated with a possible risk of QT prolongation and TdP.
Clonazepam: (Moderate) Although oral formulations of olanzapine and benzodiazepines may be used together, additive effects on respiratory depression and/or CNS depression are possible. Drugs that can cause CNS depression, if used concomitantly with olanzapine, can increase both the frequency and the intensity of adverse effects such as drowsiness, sedation, dizziness, and orthostatic hypotension. Besides ethanol, clinicians should use other anxiolytics, sedatives, and hypnotics cautiously with olanzapine.
Clopidogrel: (Moderate) Monitor for bleeding and reduced clopidogrel efficacy during concomitant use of fluoxetine. Since selective serotonin reuptake inhibitors (SSRIs) affect platelet activation, the concomitant administration of SSRIs with clopidogrel may increase the risk of bleeding. Clopidogrel is primarily metabolized to its active metabolite by CYP2C19; fluoxetine is a CYP2C19 inhibitor.
Clorazepate: (Moderate) Although oral formulations of olanzapine and benzodiazepines may be used together, additive effects on respiratory depression and/or CNS depression are possible. Drugs that can cause CNS depression, if used concomitantly with olanzapine, can increase both the frequency and the intensity of adverse effects such as drowsiness, sedation, dizziness, and orthostatic hypotension. Besides ethanol, clinicians should use other anxiolytics, sedatives, and hypnotics cautiously with olanzapine. (Moderate) Fluoxetine could theoretically inhibit CYP3A4 metabolism of oxidized benzodiazepines, including clorazepate. Patients should be monitored for clinical response, and adjust benzodiazepine dosage if needed.
Clozapine: (Major) Concurrent use of olanzapine and clozapine should be avoided due to an increased risk for QT prolongation and torsade de pointes (TdP). Treatment with clozapine has been associated with QT prolongation, TdP, cardiac arrest, and sudden death. Limited data, including some case reports, suggest that olanzapine may also be associated with a significant prolongation of the QTc interval in rare instances. In addition, coadministration may increase the risk of drowsiness, dizziness, orthostatic hypotension, anticholinergic effects, extrapyramidal symptoms, neuroleptic malignant syndrome, tardive dyskinesia, or seizures. Some case reports describe the re-induction of bone-marrow suppression by olanzapine when the patient is known to have a history of clozapine-induced blood dyscrasias. When olanzapine therapy follows clozapine therapy in such patients, monitoring of complete blood counts is recommended. (Moderate) Consider a clozapine dose reduction if coadministered with fluoxetine and monitor for adverse reactions including QT prolongation. If fluoxetine is discontinued, monitor for lack of clozapine effect and increase dose if necessary. Modest (less than 2-fold) elevations in concentrations of clozapine and its metabolites have been reported during concurrent use of fluoxetine. Clozapine is a CYP2D6 substrate that has been associated with QT prolongation, torsade de pointes (TdP), cardiac arrest, and sudden death. Fluoxetine is a strong CYP2D6 inhibitor; QT prolongation and torsade de pointes (TdP) have been reported in patients treated with fluoxetine.
Cobicistat: (Moderate) Caution is warranted when cobicistat is administered with olanzapine as there is a potential for elevated olanzapine concentrations. Olanzapine is a substrate of CYP2D6. Cobicistat is an inhibitor of CYP2D6. (Moderate) Close monitoring for antidepressant response and careful dose titrations of the antidepressant therapy is recommended during coadministration of selective serotonin reuptake inhibitors (SSRIs) and cobicistat. Concurrent use may result in elevated SSRI plasma concentrations. Predictions regarding this interaction can be made based on the metabolic pathways of these drugs. All SSRIs are substrates for the hepatic isoenzyme CYP2D6, while citalopram, escitalopram, and sertraline are also substrates for CYP3A4; cobicistat is an inhibitor of both CYP2D6 and CYP3A4.
Cobimetinib: (Major) If concurrent use of cobimetinib and fluoxetine is necessary, use caution and monitor for increased cobimetinib-related adverse effects. Cobimetinib is a CYP3A substrate in vitro, and fluoxetine is a weak inhibitor of CYP3A. In healthy subjects (n = 15), coadministration of a single 10 mg dose of cobimetinib with itraconazole (200 mg once daily for 14 days), a strong CYP3A4 inhibitor, increased the mean cobimetinib AUC by 6.7-fold (90% CI, 5.6 to 8) and the mean Cmax by 3.2-fold (90% CI, 2.7 to 3.7). Simulations showed that predicted steady-state concentrations of cobimetinib at a reduced dose of 20 mg administered concurrently with short-term (less than 14 days) treatment of a moderate CYP3A inhibitor were similar to observed steady-state concentrations of cobimetinib 60 mg alone. The manufacturer of cobimetinib recommends avoiding coadministration with moderate to strong CYP3A inhibitors, and significantly reducing the dose of cobimetinib if coadministration with moderate CYP3A inhibitors cannot be avoided. Guidance is not available regarding concomitant use of cobimetinib with weak CYP3A inhibitors.
Cocaine: (Major) Concomitant use of cocaine with drugs that have CNS serotonergic properties, such as SSRIs, could potentiate serotonin neurotransmission, and result in the serotonin syndrome. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. Patients receiving this combination should be monitored for the emergence of serotonin syndrome or neuroleptic malignant syndrome-like reactions. Additionally, citalopram causes dose-dependent QT interval prolongation. Local anesthetics (e.g., cocaine) are associated with a possible risk for QT prolongation and according to the manufacturer of citalopram, concurrent use of citalopram with other drugs that prolong the QT interval is not recommended. If concurrent therapy is considered essential, ECG monitoring is recommended.
Codeine: (Major) Concomitant use of opioid agonists with olanzapine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with olanzapine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Also monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. Avoid prescribing opioid cough medication in patients taking olanzapine. (Moderate) Careful monitoring, particularly during treatment initiation and dose adjustment, is recommended during coadministration of codeine and fluoxetine because of the potential risk of serotonin syndrome, reduced codeine efficacy, and potential for opioid withdrawal symptoms. Discontinue codeine if serotonin syndrome is suspected. It is recommended to avoid this combination when codeine is being used for cough. Concomitant use may increase codeine plasma concentrations, but decrease the plasma concentration of the active metabolite, morphine, resulting in reduced efficacy or symptoms of opioid withdrawal. Monitor patients closely at frequent intervals and consider a dosage increase of codeine until stable drug effects are achieved. Discontinuation of fluoxetine could decrease codeine plasma concentrations and increase morphine plasma concentrations resulting in prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If fluoxetine is discontinued, monitor the patient carefully and consider reducing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Fluoxetine is a strong inhibitor of CYP2D6.
Codeine; Guaifenesin: (Major) Concomitant use of opioid agonists with olanzapine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with olanzapine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Also monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. Avoid prescribing opioid cough medication in patients taking olanzapine. (Moderate) Careful monitoring, particularly during treatment initiation and dose adjustment, is recommended during coadministration of codeine and fluoxetine because of the potential risk of serotonin syndrome, reduced codeine efficacy, and potential for opioid withdrawal symptoms. Discontinue codeine if serotonin syndrome is suspected. It is recommended to avoid this combination when codeine is being used for cough. Concomitant use may increase codeine plasma concentrations, but decrease the plasma concentration of the active metabolite, morphine, resulting in reduced efficacy or symptoms of opioid withdrawal. Monitor patients closely at frequent intervals and consider a dosage increase of codeine until stable drug effects are achieved. Discontinuation of fluoxetine could decrease codeine plasma concentrations and increase morphine plasma concentrations resulting in prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If fluoxetine is discontinued, monitor the patient carefully and consider reducing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Fluoxetine is a strong inhibitor of CYP2D6.
Codeine; Guaifenesin; Pseudoephedrine: (Major) Concomitant use of opioid agonists with olanzapine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with olanzapine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Also monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. Avoid prescribing opioid cough medication in patients taking olanzapine. (Moderate) Careful monitoring, particularly during treatment initiation and dose adjustment, is recommended during coadministration of codeine and fluoxetine because of the potential risk of serotonin syndrome, reduced codeine efficacy, and potential for opioid withdrawal symptoms. Discontinue codeine if serotonin syndrome is suspected. It is recommended to avoid this combination when codeine is being used for cough. Concomitant use may increase codeine plasma concentrations, but decrease the plasma concentration of the active metabolite, morphine, resulting in reduced efficacy or symptoms of opioid withdrawal. Monitor patients closely at frequent intervals and consider a dosage increase of codeine until stable drug effects are achieved. Discontinuation of fluoxetine could decrease codeine plasma concentrations and increase morphine plasma concentrations resulting in prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If fluoxetine is discontinued, monitor the patient carefully and consider reducing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Fluoxetine is a strong inhibitor of CYP2D6.
Codeine; Phenylephrine; Promethazine: (Major) Concomitant use of opioid agonists with olanzapine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with olanzapine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Also monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. Avoid prescribing opioid cough medication in patients taking olanzapine. (Moderate) Careful monitoring, particularly during treatment initiation and dose adjustment, is recommended during coadministration of codeine and fluoxetine because of the potential risk of serotonin syndrome, reduced codeine efficacy, and potential for opioid withdrawal symptoms. Discontinue codeine if serotonin syndrome is suspected. It is recommended to avoid this combination when codeine is being used for cough. Concomitant use may increase codeine plasma concentrations, but decrease the plasma concentration of the active metabolite, morphine, resulting in reduced efficacy or symptoms of opioid withdrawal. Monitor patients closely at frequent intervals and consider a dosage increase of codeine until stable drug effects are achieved. Discontinuation of fluoxetine could decrease codeine plasma concentrations and increase morphine plasma concentrations resulting in prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If fluoxetine is discontinued, monitor the patient carefully and consider reducing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Fluoxetine is a strong inhibitor of CYP2D6. (Moderate) Concomitant use of promethazine and fluoxetine may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP. (Moderate) The use of promethazine, a phenothiazine antiemetic, with atypical antipsychotics such as olanzapine should be avoided when possible. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval in rare instances. Promethazine has also been reported to cause QT prolongation. Coadministration of promethazine and antipsychotics may also increase the risk of adverse effects such as drowsiness, dizziness, orthostatic hypotension, anticholinergic effects, extrapyramidal symptoms, neuroleptic malignant syndrome, tardive dyskinesia, or seizures. Although the incidence of tardive dyskinesia from these combinations has not been established and data are very limited, the risk may be increased during combined use versus use of an antipsychotic alone.
Codeine; Promethazine: (Major) Concomitant use of opioid agonists with olanzapine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with olanzapine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Also monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. Avoid prescribing opioid cough medication in patients taking olanzapine. (Moderate) Careful monitoring, particularly during treatment initiation and dose adjustment, is recommended during coadministration of codeine and fluoxetine because of the potential risk of serotonin syndrome, reduced codeine efficacy, and potential for opioid withdrawal symptoms. Discontinue codeine if serotonin syndrome is suspected. It is recommended to avoid this combination when codeine is being used for cough. Concomitant use may increase codeine plasma concentrations, but decrease the plasma concentration of the active metabolite, morphine, resulting in reduced efficacy or symptoms of opioid withdrawal. Monitor patients closely at frequent intervals and consider a dosage increase of codeine until stable drug effects are achieved. Discontinuation of fluoxetine could decrease codeine plasma concentrations and increase morphine plasma concentrations resulting in prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If fluoxetine is discontinued, monitor the patient carefully and consider reducing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Fluoxetine is a strong inhibitor of CYP2D6. (Moderate) Concomitant use of promethazine and fluoxetine may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP. (Moderate) The use of promethazine, a phenothiazine antiemetic, with atypical antipsychotics such as olanzapine should be avoided when possible. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval in rare instances. Promethazine has also been reported to cause QT prolongation. Coadministration of promethazine and antipsychotics may also increase the risk of adverse effects such as drowsiness, dizziness, orthostatic hypotension, anticholinergic effects, extrapyramidal symptoms, neuroleptic malignant syndrome, tardive dyskinesia, or seizures. Although the incidence of tardive dyskinesia from these combinations has not been established and data are very limited, the risk may be increased during combined use versus use of an antipsychotic alone.
COMT inhibitors: (Moderate) Monitor for movement disorders, unusual changes in moods or behavior, and diminished effectiveness of the atypical antipsychotic or COMT inhibitor during coadministration. Due to mutually opposing effects on dopamine, atypical antipsychotics and COMT inhibitors may interfere with the effectiveness of each other. In general, atypical antipsychotics are less likely to interfere with COMT inhibitors and other Parkinson's treatments than traditional antipsychotics. The Beers Criteria recognize quetiapine and clozapine as exceptions to the general recommendation to avoid all antipsychotics in older adults with Parkinson's disease.
Conjugated Estrogens: (Moderate) Estrogens are partially metabolized by CYP3A4. Drugs that inhibit CYP3A4 such as fluoxetine may increase plasma concentrations of estrogens and cause estrogen-related side effects such as nausea and breast tenderness. Patients receiving estrogens should be monitored for an increase in adverse events.
Conjugated Estrogens; Bazedoxifene: (Moderate) Estrogens are partially metabolized by CYP3A4. Drugs that inhibit CYP3A4 such as fluoxetine may increase plasma concentrations of estrogens and cause estrogen-related side effects such as nausea and breast tenderness. Patients receiving estrogens should be monitored for an increase in adverse events.
Conjugated Estrogens; Medroxyprogesterone: (Moderate) Estrogens are partially metabolized by CYP3A4. Drugs that inhibit CYP3A4 such as fluoxetine may increase plasma concentrations of estrogens and cause estrogen-related side effects such as nausea and breast tenderness. Patients receiving estrogens should be monitored for an increase in adverse events.
Crizotinib: (Major) Avoid coadministration of crizotinib with fluoxetine due to the risk of QT prolongation. If concomitant use is unavoidable, monitor ECGs for QT prolongation and monitor electrolytes. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib if QT prolongation occurs. Crizotinib has been associated with concentration-dependent QT prolongation. Prolongation of the QT interval and torsade de pointes (TdP) have also been reported in patients treated with fluoxetine. (Major) Avoid coadministration of crizotinib with olanzapine due to the risk of QT prolongation. If concomitant use is unavoidable, monitor ECGs for QT prolongation and monitor electrolytes. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib if QT prolongation occurs. Crizotinib has been associated with concentration-dependent QT prolongation. Limited data, including some case reports, suggest that olanzapine may also be associated with a significant prolongation of the QTc interval.
Cyclobenzaprine: (Major) Because of the potential risk and severity of serotonin syndrome, concurrent use of cyclobenzaprine with other drugs that have serotonergic properties, such as the selective serotonin reuptake inhibitors (SSRIs), should generally be avoided. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. If serotonin syndrome is suspected, milnacipran and concurrent serotonergic agents should be discontinued. (Moderate) When cyclobenzaprine and olanzapine are used concurrently, an increase in anticholinergic side effects may occur. Cyclobenzaprine possesses antimuscarinic properties, which can cause dry mouth, urinary difficulties and slowing of gastrointestinal motility. If used with other drugs with antimuscarinic properties, such as olanzapine, anticholinergic side effects can be additive. Particular attention should be paid to GI problems because of the possible development of paralytic ileus.
Cyclosporine: (Moderate) Fluoxetine is a CYP3A4 inhibitor and may decrease the clearance of cyclosporine, with the potential to cause cyclosporine toxicity, including nephrotoxicity or seizures, or require the downward dosage adjustment of cyclosporine.
Cyproheptadine: (Moderate) Cyproheptadine is a serotonin antagonist in the CNS and can oppose the pharmacologic actions of selective serotonin reuptake inhibitors (SSRIs) such as fluoxetine. Cyproheptadine has been used for the management of orgasm dysfunction caused by the SSRIs and for the adjunctive treatment of SSRI overdose (i.e., serotonin syndrome) in emergency situations; however, a reversal of antidepressant effects may occur when cyproheptadine is given in a routine manner along with the SSRIs due to the serotonin antagonistic effects of cyproheptadine. Cyproheptadine reportedly has interfered with the antidepressant and anti-bulimia actions of fluoxetine but more data are needed to confirm a direct drug-drug interaction. (Moderate) Olanzapine exhibits anticholinergic effects that may be clinically significant. Clinicians should keep this in mind when using antimuscarinics and other medications with anticholinergic activity in combination with olanzapine. Some medications exhibit additive anticholinergic effects include sedating H1-blockers. Olanzapine may also cause additive sedation with many of these drugs.
Dabigatran: (Moderate) Advise patients of the increased bleeding risk associated with the concomitant use of selective serotonin reuptake inhibitors (SSRIs) and anticoagulants like dabigatran. Case reports and epidemiological studies have demonstrated an association between use of drugs that interfere with serotonin reuptake and gastrointestinal bleeding.
Dalteparin: (Moderate) Monitor for signs and symptoms of bleeding during concomitant low molecular weight heparin and selective serotonin reuptake inhibitor (SSRI) use due to increased risk for bleeding. Serotonin release by platelets plays an important role in hemostasis. Epidemiological studies have demonstrated an association between use of psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper gastrointestinal bleeding. Altered anticoagulant effects, including increased bleeding, have been reported when SSRIs are coadministered with another anticoagulant.
Dantrolene: (Moderate) Simultaneous use of skeletal muscle relaxants and other CNS depressants, such as antipsychotics, can increase CNS depression.
Dapagliflozin: (Moderate) Monitor blood glucose during concomitant atypical antipsychotic and SGLT2 inhibitor use. Atypical antipsychotic therapy may aggravate diabetes mellitus. Atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition. (Moderate) Monitor blood glucose during concomitant SGLT2 inhibitor and fluoxetine use; a SGLT2 inhibitor dose adjustment may be necessary. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
Dapagliflozin; Metformin: (Moderate) Monitor blood glucose during concomitant atypical antipsychotic and metformin use. Atypical antipsychotic therapy may aggravate diabetes mellitus. Atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition. (Moderate) Monitor blood glucose during concomitant atypical antipsychotic and SGLT2 inhibitor use. Atypical antipsychotic therapy may aggravate diabetes mellitus. Atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition. (Moderate) Monitor blood glucose during concomitant metformin and fluoxetine use; a metformin dose adjustment may be necessary. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia. (Moderate) Monitor blood glucose during concomitant SGLT2 inhibitor and fluoxetine use; a SGLT2 inhibitor dose adjustment may be necessary. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
Dapagliflozin; Saxagliptin: (Moderate) Monitor blood glucose during concomitant atypical antipsychotic and dipeptidyl peptidase-4 (DPP-4) inhibitor use. Atypical antipsychotic therapy may aggravate diabetes mellitus. Atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition. (Moderate) Monitor blood glucose during concomitant atypical antipsychotic and SGLT2 inhibitor use. Atypical antipsychotic therapy may aggravate diabetes mellitus. Atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition. (Moderate) Monitor blood glucose during concomitant dipeptidyl peptidase-4 (DPP-4) inhibitor and fluoxetine use; a DPP-4 inhibitor dose adjustment may be necessary. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia. (Moderate) Monitor blood glucose during concomitant SGLT2 inhibitor and fluoxetine use; a SGLT2 inhibitor dose adjustment may be necessary. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
Darifenacin: (Moderate) Fluoxetine inhibits CYP2D6 and CYP3A4. Serum concentrations of darifenacin, a CYP2D6 and CYP3A4 substrate, may increase when used in combination with fluoxetine. Patients should be monitored for increased anticholinergic effects if these drugs are coadministered. (Moderate) Olanzapine exhibits anticholinergic effects that may be enhanced when combined with other drugs with anticholinergic activity like darifenacin. Clinicians should note that additive antimuscarinic effects may be seen not only on GI smooth muscle, but also on bladder function, the CNS, the eye, and temperature regulation. Additive drowsiness may also occur.
Darunavir; Cobicistat: (Moderate) Caution is warranted when cobicistat is administered with olanzapine as there is a potential for elevated olanzapine concentrations. Olanzapine is a substrate of CYP2D6. Cobicistat is an inhibitor of CYP2D6. (Moderate) Close monitoring for antidepressant response and careful dose titrations of the antidepressant therapy is recommended during coadministration of selective serotonin reuptake inhibitors (SSRIs) and cobicistat. Concurrent use may result in elevated SSRI plasma concentrations. Predictions regarding this interaction can be made based on the metabolic pathways of these drugs. All SSRIs are substrates for the hepatic isoenzyme CYP2D6, while citalopram, escitalopram, and sertraline are also substrates for CYP3A4; cobicistat is an inhibitor of both CYP2D6 and CYP3A4.
Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide: (Moderate) Caution is warranted when cobicistat is administered with olanzapine as there is a potential for elevated olanzapine concentrations. Olanzapine is a substrate of CYP2D6. Cobicistat is an inhibitor of CYP2D6. (Moderate) Close monitoring for antidepressant response and careful dose titrations of the antidepressant therapy is recommended during coadministration of selective serotonin reuptake inhibitors (SSRIs) and cobicistat. Concurrent use may result in elevated SSRI plasma concentrations. Predictions regarding this interaction can be made based on the metabolic pathways of these drugs. All SSRIs are substrates for the hepatic isoenzyme CYP2D6, while citalopram, escitalopram, and sertraline are also substrates for CYP3A4; cobicistat is an inhibitor of both CYP2D6 and CYP3A4.
Dasatinib: (Moderate) Concomitant use of fluoxetine and dasatinib may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP. (Moderate) Due to a possible risk for QT prolongation and torsade de pointes (TdP), dasatinib and olanzapine should be used together cautiously. In vitro studies have shown that dasatinib has the potential to prolong cardiac ventricular repolarization (prolong QT interval). Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval.
Degarelix: (Major) Avoid coadministration of degarelix with olanzapine due to the risk of reduced efficacy of degarelix; QT prolongation may also occur. Olanzapine can cause hyperprolactinemia, which reduces the number of pituitary gonadotropin releasing hormone (GnRH) receptors; degarelix is a GnRH analog. Additionally, androgen deprivation therapy (i.e., degarelix) may prolong the QT/QTc interval. Limited data, including some case reports, suggest that olanzapine may also be associated with a significant prolongation of the QTc interval. (Moderate) Concomitant use of fluoxetine and androgen deprivation therapy (i.e., degarelix) may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP.
Delavirdine: (Minor) Delavirdine is metabolized by CYP2D6 and CYP3A4. Fluoxetine impairs both of these pathways at therapeutic doses. This interaction can result in substantial increases in the trough levels of delavirdine, up to a 50% increase.
Desflurane: (Major) Concomitant use of halogenated anesthetics and fluoxetine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Desipramine: (Moderate) Coadministration of fluoxetine and desipramine may increase the risk for QT prolongation, torsade de pointes (TdP), and serotonin syndrome. If serotonin syndrome is suspected, discontinue fluoxetine and concurrent serotonergic agents and initiate appropriate medical treatment. QT prolongation and TdP have been reported in patients treated with fluoxetine. Tricyclics, particularly at elevated concentrations, are associated with a possible risk of QT prolongation and TdP.
Desmopressin: (Minor) Additive hyponatremic effects may be seen in patients treated with desmopressin and drugs associated with water intoxication, hyponatremia, or SIADH including SSRIs. Use combination with caution, and monitor patients for signs and symptoms of hyponatremia, which may include monitoring serum sodium or electrolytes periodically. Ensure the patient is compliant with fluid restrictions and intake.
Desvenlafaxine: (Major) Due to similarity of pharmacology and the potential for additive adverse effects, including serotonin syndrome, selective serotonin reuptake inhibitors (SSRIs) should generally not be administered with serotonin norepinephrine reuptake inhibitors like desvenlafaxine. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Discontinuation symptoms have been reported when switching from other antidepressants to desvenlafaxine. It may be advisable to taper the previous antidepressant to minimize discontinuation symptoms. If serotonin syndrome is suspected, desvenlafaxine and concurrent serotonergic agents should be discontinued. Dosage adjustments of fluoxetine may be necessary during concurrent use of desvenlafaxine; the dose of CYP2D6 substrates should be reduced by up to one-half if co-administered with desvenlafaxine 400 mg/day.
Deutetrabenazine: (Moderate) Caution is advised when administering olanzapine with deutetrabenazine. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval. Deutetrabenazine may prolong the QT interval, but the degree of QT prolongation is not clinically significant when deutetrabenazine is administered within the recommended dosage range. Monitor for signs and symptoms of neuroleptic malignant syndrome (NMS), restlessness, and agitation. If NMS is diagnosed, immediately discontinue deutetrabenazine, and provide intensive symptomatic treatment and medical monitoring. Recurrence of NMS has been reported with resumption of drug therapy. If akathisia or parkinsonism develops during treatment, the deutetrabenazine dose should be reduced; discontinuation may be required. Deutetrabenazine is a reversible, dopamine depleting drug and olanzapine is a dopamine antagonist. The risk for parkinsonism, NMS, or akathisia may be increased with concomitant administration. Monitor for excessive sedation and somnolence during coadministration of olanzapine and deutetrabenazine. Concurrent use may result in additive CNS depression. (Moderate) Do not exceed 18 mg/dose or 36 mg/day of deutetrabenazine if must use concurrently with a strong CYP2D6 inhibitor, such as fluoxetine. Fluoxetine is a strong CYP2D6 inhibitor, and the metabolites of deutetrabenazine, alpha- and beta-HTBZ, are CYP2D6 substrates. The systemic exposure of alpha- and beta-HTBZ may be increased resulting in an increase in deutetrabenazine-related adverse reactions, like QT prolongation and drowsiness. QT prolongation and torsade de pointes (TdP) have been reported in patients treated with fluoxetine. Deutetrabenazine may prolong the QT interval, but the degree of QT prolongation is not clinically significant when deutetrabenazine is administered within the recommended dosage range.
Dexchlorpheniramine: (Moderate) Olanzapine exhibits anticholinergic effects that may be clinically significant. Clinicians should keep this in mind when using antimuscarinics and other medications with anticholinergic activity in combination with olanzapine. Some medications exhibit additive anticholinergic effects include sedating H1-blockers. Olanzapine may also cause additive sedation with many of these drugs.
Dexchlorpheniramine; Dextromethorphan; Pseudoephedrine: (Moderate) Monitor for dextromethorphan-related side effects, such as dizziness or drowsiness, if concomitant use of fluoxetine is necessary. For patients receiving combination dextromethorphan; bupropion, do not exceed a maximum dose of 45 mg dextromethorphan; 105 mg bupropion once daily. Additionally, monitor patients for signs and symptoms of serotonin syndrome. Concomitant use may increase dextromethorphan exposure and the risk for serotonin syndrome. Dextromethorphan is a CYP2D6 substrate and fluoxetine is a strong CYP2D6 inhibitor. Concomitant use with another strong CYP2D6 inhibitor increased dextromethorphan overall exposure by 2.69-fold. (Moderate) Olanzapine exhibits anticholinergic effects that may be clinically significant. Clinicians should keep this in mind when using antimuscarinics and other medications with anticholinergic activity in combination with olanzapine. Some medications exhibit additive anticholinergic effects include sedating H1-blockers. Olanzapine may also cause additive sedation with many of these drugs.
Dexmedetomidine: (Moderate) Concomitant use of dexmedetomidine and fluoxetine may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP. (Moderate) Concomitant use of dexmedetomidine and olanzapine may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP.
Dextromethorphan: (Moderate) Monitor for dextromethorphan-related side effects, such as dizziness or drowsiness, if concomitant use of fluoxetine is necessary. For patients receiving combination dextromethorphan; bupropion, do not exceed a maximum dose of 45 mg dextromethorphan; 105 mg bupropion once daily. Additionally, monitor patients for signs and symptoms of serotonin syndrome. Concomitant use may inc rease dextromethorphan exposure and the risk for serotonin syndrome. Dextromethorphan is a CYP2D6 substrate and fluoxetine is a strong CYP2D6 inhibitor. Concomitant use with another strong CYP2D6 inhibitor increased dextromethorphan overall exposure by 2.69-fold.
Dextromethorphan; Bupropion: (Major) Bupropion is associated with a dose-related risk of seizures. Extreme caution is recommended during concurrent use of other drugs that may lower the seizure threshold such as antipsychotics. The manufacturer of bupropion recommends low initial dosing and slow dosage titration if this combination must be used; the patient should be closely monitored. (Moderate) Monitor for dextromethorphan-related side effects, such as dizziness or drowsiness, if concomitant use of fluoxetine is necessary. For patients receiving combination dextromethorphan; bupropion, do not exceed a maximum dose of 45 mg dextromethorphan; 105 mg bupropion once daily. Additionally, monitor patients for signs and symptoms of serotonin syndrome. Concomitant use may increase dextromethorphan exposure and the risk for serotonin syndrome. Dextromethorphan is a CYP2D6 substrate and fluoxetine is a strong CYP2D6 inhibitor. Concomitant use with another strong CYP2D6 inhibitor increased dextromethorphan overall exposure by 2.69-fold. (Moderate) Monitor for increased fluoxetine-related adverse effects if coadministered with bupropion. Concomitant use may increase fluoxetine exposure. Fluoxetine is a CYP2D6 substrate and bupropion is a strong CYP2D6 inhibitor.
Dextromethorphan; Diphenhydramine; Phenylephrine: (Moderate) Monitor for dextromethorphan-related side effects, such as dizziness or drowsiness, if concomitant use of fluoxetine is necessary. For patients receiving combination dextromethorphan; bupropion, do not exceed a maximum dose of 45 mg dextromethorphan; 105 mg bupropion once daily. Additionally, monitor patients for signs and symptoms of serotonin syndrome. Concomitant use may increase dextromethorphan exposure and the risk for serotonin syndrome. Dextromethorphan is a CYP2D6 substrate and fluoxetine is a strong CYP2D6 inhibitor. Concomitant use with another strong CYP2D6 inhibitor increased dextromethorphan overall exposure by 2.69-fold. (Moderate) Olanzapine exhibits anticholinergic effects that may be clinically significant. Clinicians should keep this in mind when using antimuscarinics and other medications with anticholinergic activity in combination with olanzapine. Some medications exhibit additive anticholinergic effects include sedating H1-blockers. Olanzapine may also cause additive sedation with many of these drugs.
Dextromethorphan; Guaifenesin: (Moderate) Monitor for dextromethorphan-related side effects, such as dizziness or drowsiness, if concomitant use of fluoxetine is necessary. For patients receiving combination dextromethorphan; bupropion, do not exceed a maximum dose of 45 mg dextromethorphan; 105 mg bupropion once daily. Additionally, monitor patients for signs and symptoms of serotonin syndrome. Concomitant use may increase dextromethorphan exposure and the risk for serotonin syndrome. Dextromethorphan is a CYP2D6 substrate and fluoxetine is a strong CYP2D6 inhibitor. Concomitant use with another strong CYP2D6 inhibitor increased dextromethorphan overall exposure by 2.69-fold.
Dextromethorphan; Guaifenesin; Phenylephrine: (Moderate) Monitor for dextromethorphan-related side effects, such as dizziness or drowsiness, if concomitant use of fluoxetine is necessary. For patients receiving combination dextromethorphan; bupropion, do not exceed a maximum dose of 45 mg dextromethorphan; 105 mg bupropion once daily. Additionally, monitor patients for signs and symptoms of serotonin syndrome. Concomitant use may increase dextromethorphan exposure and the risk for serotonin syndrome. Dextromethorphan is a CYP2D6 substrate and fluoxetine is a strong CYP2D6 inhibitor. Concomitant use with another strong CYP2D6 inhibitor increased dextromethorphan overall exposure by 2.69-fold.
Dextromethorphan; Guaifenesin; Potassium Guaiacolsulfonate: (Moderate) Monitor for dextromethorphan-related side effects, such as dizziness or drowsiness, if concomitant use of fluoxetine is necessary. For patients receiving combination dextromethorphan; bupropion, do not exceed a maximum dose of 45 mg dextromethorphan; 105 mg bupropion once daily. Additionally, monitor patients for signs and symptoms of serotonin syndrome. Concomitant use may increase dextromethorphan exposure and the risk for serotonin syndrome. Dextromethorphan is a CYP2D6 substrate and fluoxetine is a strong CYP2D6 inhibitor. Concomitant use with another strong CYP2D6 inhibitor increased dextromethorphan overall exposure by 2.69-fold.
Dextromethorphan; Guaifenesin; Pseudoephedrine: (Moderate) Monitor for dextromethorphan-related side effects, such as dizziness or drowsiness, if concomitant use of fluoxetine is necessary. For patients receiving combination dextromethorphan; bupropion, do not exceed a maximum dose of 45 mg dextromethorphan; 105 mg bupropion once daily. Additionally, monitor patients for signs and symptoms of serotonin syndrome. Concomitant use may increase dextromethorphan exposure and the risk for serotonin syndrome. Dextromethorphan is a CYP2D6 substrate and fluoxetine is a strong CYP2D6 inhibitor. Concomitant use with another strong CYP2D6 inhibitor increased dextromethorphan overall exposure by 2.69-fold.
Dextromethorphan; Quinidine: (Contraindicated) Concurrent use of either quinidine or dextromethorphan; quinidine and fluoxetine is considered a contraindication. Quinidine and dextromethorphan; quinidine are contraindicated for use in patients taking drugs that prolong the QT interval and are metabolized by CYP2D6. Fluoxetine is a primary substrate of CYP2D6, and is associated with a risk of QT prolongation and torsade de pointes (TdP). (Major) Quinidine and dextromethorphan; quinidine cause dose-dependent QT prolongation. These drugs should be avoided in patients receiving drugs that may prolong the QT interval and are metabolized by CYP2D6, such as olanzapine. The manufacturer recommends an ECG in patients taking these drugs together. (Moderate) Monitor for dextromethorphan-related side effects, such as dizziness or drowsiness, if concomitant use of fluoxetine is necessary. For patients receiving combination dextromethorphan; bupropion, do not exceed a maximum dose of 45 mg dextromethorphan; 105 mg bupropion once daily. Additionally, monitor patients for signs and symptoms of serotonin syndrome. Concomitant use may increase dextromethorphan exposure and the risk for serotonin syndrome. Dextromethorphan is a CYP2D6 substrate and fluoxetine is a strong CYP2D6 inhibitor. Concomitant use with another strong CYP2D6 inhibitor increased dextromethorphan overall exposure by 2.69-fold.
Diazepam: (Major) Concurrent use of intramuscular olanzapine and parenteral benzodiazepines is not recommended due to the potential for adverse effects from the combination including excess sedation and/or cardiorespiratory depression. Although oral formulations of olanzapine and benzodiazepines may be used together, additive effects on respiratory depression and/or CNS depression are possible. Drugs that can cause CNS depression, if used concomitantly with olanzapine, can increase both the frequency and the intensity of adverse effects such as drowsiness, sedation, dizziness, and orthostatic hypotension. Besides ethanol, clinicians should use other anxiolytics, sedatives, and hypnotics cautiously with olanzapine. (Moderate) Monitor for an increase in diazepam-related adverse reactions, including sedation and respiratory depression, if coadministration with fluoxetine is necessary. Concurrent use may increase diazepam exposure. Diazepam is a CYP2C19 substrate and fluoxetine is a CYP2C19 inhibitor.
Dicyclomine: (Moderate) Additive anticholinergic effects may be seen when olanzapine and anticholinergics are used concomitantly; use with caution. Use of olanzapine and other drugs with anticholinergic activity can increase the risk for severe gastrointestinal adverse reactions related to hypomotility. Olanzapine exhibits anticholinergic activity. Adverse effects may be seen not only on GI smooth muscle, but also on bladder function, the CNS, the eye, and temperature regulation. Additive drowsiness may also occur, depending on the anticholinergic agent used.
Dienogest; Estradiol valerate: (Minor) As fluoxetine inhibits CYP3A4 activity, serum estrogen concentrations and estrogenic-related side effects (e.g., nausea, breast tenderness) may potentially increase when coadministered with either estrogens or combined hormonal contraceptives.
Diethylpropion: (Major) Phentermine and diethylpropion have a similar mechanism of action. When phentermine was given with fluoxetine, adrenergic excess and dyskinesia were observed. Thus, diethylpropion may interact with fluoxetine similarly. It is unclear, however, if all SSRIs would be affected as fluoxetine has the longest half-life of the group.
Difelikefalin: (Moderate) Monitor for dizziness, somnolence, mental status changes, and gait disturbances if concomitant use of difelikefalin with CNS depressants is necessary. Concomitant use may increase the risk for these adverse reactions.
Dihydroergotamine: (Moderate) Use fluoxetine and ergot alkaloids together with caution due to a potential for serotonin syndrome. Weakness, hyperreflexia, and incoordination have been reported rarely when ergot alkaloids or other serotonin agonists have been coadministered with SSRIs, which may be indicative of serotonin excess. If serotonin syndrome occurs, discontinue the offending agents and institute appropriate treatment.
Dimenhydrinate: (Moderate) Olanzapine exhibits anticholinergic effects that may be clinically significant. Clinicians should keep this in mind when using antimuscarinics and other medications with anticholinergic activity in combination with olanzapine. Some medications exhibit additive anticholinergic effects include sedating H1-blockers. Olanzapine may also cause additive sedation with many of these drugs.
Dipeptidyl Peptidase-4 Inhibitors: (Moderate) Monitor blood glucose during concomitant atypical antipsychotic and dipeptidyl peptidase-4 (DPP-4) inhibitor use. Atypical antipsychotic therapy may aggravate diabetes mellitus. Atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition. (Moderate) Monitor blood glucose during concomitant dipeptidyl peptidase-4 (DPP-4) inhibitor and fluoxetine use; a DPP-4 inhibitor dose adjustment may be necessary. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
Diphenhydramine: (Moderate) Olanzapine exhibits anticholinergic effects that may be clinically significant. Clinicians should keep this in mind when using antimuscarinics and other medications with anticholinergic activity in combination with olanzapine. Some medications exhibit additive anticholinergic effects include sedating H1-blockers. Olanzapine may also cause additive sedation with many of these drugs.
Diphenhydramine; Ibuprofen: (Moderate) Olanzapine exhibits anticholinergic effects that may be clinically significant. Clinicians should keep this in mind when using antimuscarinics and other medications with anticholinergic activity in combination with olanzapine. Some medications exhibit additive anticholinergic effects include sedating H1-blockers. Olanzapine may also cause additive sedation with many of these drugs.
Diphenhydramine; Naproxen: (Moderate) Olanzapine exhibits anticholinergic effects that may be clinically significant. Clinicians should keep this in mind when using antimuscarinics and other medications with anticholinergic activity in combination with olanzapine. Some medications exhibit additive anticholinergic effects include sedating H1-blockers. Olanzapine may also cause additive sedation with many of these drugs.
Diphenhydramine; Phenylephrine: (Moderate) Olanzapine exhibits anticholinergic effects that may be clinically significant. Clinicians should keep this in mind when using antimuscarinics and other medications with anticholinergic activity in combination with olanzapine. Some medications exhibit additive anticholinergic effects include sedating H1-blockers. Olanzapine may also cause additive sedation with many of these drugs.
Diphenoxylate; Atropine: (Moderate) Additive anticholinergic effects may be seen when olanzapine and anticholinergics are used concomitantly; use with caution. Use of olanzapine and other drugs with anticholinergic activity can increase the risk for severe gastrointestinal adverse reactions related to hypomotility. Olanzapine exhibits anticholinergic activity. Adverse effects may be seen not only on GI smooth muscle, but also on bladder function, the CNS, the eye, and temperature regulation. Additive drowsiness may also occur, depending on the anticholinergic agent used. (Moderate) Concurrent administration of diphenoxylate/difenoxin with fluoxetine can potentiate the CNS-depressant effects of diphenoxylate/difenoxin. Use caution during coadministration. (Moderate) Drugs that decrease GI motility, such as olanzapine, may produce additive effects with antidiarrheals, such as diphenoxylate/difenoxin, if used concomitantly.
Dipyridamole: (Moderate) Platelet aggregation may be impaired by SSRIs due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication in patients receiving platelet inhibitors. Monitor for signs and symptoms of bleeding.
Disopyramide: (Major) Because QT prolongation and torsade de pointes (TdP) have been reported in patients treated with fluoxetine, the manufacturer recommends caution when using fluoxetine with other drugs that prolong the QT interval, including disopyramide. In addition, CYP3A4 inhibitors, such as fluoxetine may increase serum plasma concentrations of disopyramide, a CYP3A4 substrate. Monitor clinical response and serum disopyramide concentrations. (Major) Olanzapine should be used cautiously and with close monitoring with disopyramide. Disopyramide administration is associated with QT prolongation and torsade de pointes (TdP). Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval in rare instances. Therefore, caution is advised when administering olanzapine with drugs having an established causal association with QT prolongation and torsade de pointes (TdP). Additive anticholinergic effects are also possible; both drugs exhibit significant anticholinergic activity.
Diuretics: (Moderate) Monitor for signs and symptoms of hyponatremia during concomitant diuretic and fluoxetine use; consider discontinuing fluoxetine if symptomatic hyponatremia occurs and institute appropriate medical intervention. Concomitant use increases the risk for developing hyponatremia.
Docetaxel: (Minor) Docetaxel is metabolized by cytochrome P450 3A enzymes. Drugs that inhibit the CYP3A enzymes, such as fluoxetine, can significantly reduce the metabolism of docetaxel.
Dofetilide: (Major) Coadministration of dofetilide and fluoxetine is not recommended as concurrent use may increase the risk of QT prolongation and torsade de pointes (TdP). QT prolongation and TdP have been reported in patients treated with fluoxetine. Dofetilide, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and TdP. The use of dofetilide with other drugs that prolong the QT interval has not been studied and is not recommended. (Major) Coadministration of dofetilide and olanzapine is not recommended as concurrent use may increase the risk of QT prolongation. Dofetilide, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and torsade de pointes (TdP). Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval.
Dolasetron: (Moderate) Administer dolasetron with caution in combination with olanzapine as concurrent use may increase the risk of QT prolongation. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval. Dolasetron has been associated with a dose-dependent prolongation in the QT, PR, and QRS intervals on an electrocardiogram. (Moderate) Concomitant use of fluoxetine and dolasetron may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP.
Dolutegravir; Rilpivirine: (Moderate) Caution is advised when administering rilpivirine with olanzapine as concurrent use may increase the risk of QT prolongation. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. Limited data, including some case reports, suggest that olanzapine may also be associated with a significant prolongation of the QTc interval. (Moderate) Concomitant use of fluoxetine and rilpivirine may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP. The degree of QT prolongation associated with rilpivirine is not clinically significant when administered within the recommended dosage range; QT prolongation has been described at 3 times the maximum recommended dose.
Donepezil: (Moderate) Consider the use of an antipsychotic with less prominent anticholinergic effects than olanzapine in patients receiving donepezil as concurrent use may decrease donepezil efficacy; additive QT prolongation may also occur. Olanzapine exhibits moderate anticholinergic activity, and is more likely than most other atypical antipsychotics to diminish the therapeutic action of donepezil. Donepezil inhibits acetylcholinesterase, the enzyme responsible for the degradation of acetylcholine, and exerts its therapeutic effect by improving the availability of acetylcholine. Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval. (Moderate) Monitor for evidence of QT prolongation and increased cholinergic effects if coadministration of donepezil and fluoxetine is necessary. Both donepezil and fluoxetine have been associated with QT prolongation and torsade de pointes (TdP). Additive effects on the QT interval are possible with concurrent use. Additionally, fluoxetine is a potent inhibitor of CYP2D6 and its metabolite is a moderate inhibitor of CYP3A4; donepezil is metabolized by CYPY2D6 and CYP3A4. Concurrent use may lead to increased plasma levels of donepezil. An increased incidence of cholinergic-related side effects may occur.
Donepezil; Memantine: (Moderate) Consider the use of an antipsychotic with less prominent anticholinergic effects than olanzapine in patients receiving donepezil as concurrent use may decrease donepezil efficacy; additive QT prolongation may also occur. Olanzapine exhibits moderate anticholinergic activity, and is more likely than most other atypical antipsychotics to diminish the therapeutic action of donepezil. Donepezil inhibits acetylcholinesterase, the enzyme responsible for the degradation of acetylcholine, and exerts its therapeutic effect by improving the availability of acetylcholine. Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval. (Moderate) Monitor for evidence of QT prolongation and increased cholinergic effects if coadministration of donepezil and fluoxetine is necessary. Both donepezil and fluoxetine have been associated with QT prolongation and torsade de pointes (TdP). Additive effects on the QT interval are possible with concurrent use. Additionally, fluoxetine is a potent inhibitor of CYP2D6 and its metabolite is a moderate inhibitor of CYP3A4; donepezil is metabolized by CYPY2D6 and CYP3A4. Concurrent use may lead to increased plasma levels of donepezil. An increased incidence of cholinergic-related side effects may occur.
Dorzolamide; Timolol: (Moderate) Monitor for signs of bradycardia or heart block if coadministration of timolol with fluoxetine is necessary. Concomitant use may enhance the beta-blocking properties of timolol resulting in further slowing of the heart rate or cardiac conduction. Timolol is a CYP2D6 substrate and fluoxetine is a strong CYP2D6 inhibitor. (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.
Doxazosin: (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.
Doxepin: (Moderate) Monitor for signs and symptoms of serotonin syndrome, particularly during treatment initiation and dosage increase, during concomitant doxepin and fluoxetine use. If serotonin syndrome occurs, discontinue therapy. Concomitant use increases the risk for serotonin syndrome.
Doxercalciferol: (Moderate) Doxercalciferol is converted in the liver to 1,25-dihydroxyergocalciferol, the major active metabolite, and 1-alpha, 24-dihydroxyvitamin D2, a minor metabolite. Although not specifically studied, cytochrome P450 enzyme inhibitors, including selective serotonin reuptake inhibitors (SSRIs), may inhibit the 25-hydroxylation of doxercalciferol, thereby decreasing the formation of the active metabolite and thus, decreasing efficacy. Patients should be monitored for a decrease in efficacy if SSRIs are coadministered with doxercalciferol.
Doxylamine: (Moderate) Olanzapine exhibits anticholinergic effects that may be clinically significant. Clinicians should keep this in mind when using antimuscarinics and other medications with anticholinergic activity in combination with olanzapine. Some medications exhibit additive anticholinergic effects include sedating H1-blockers. Olanzapine may also cause additive sedation with many of these drugs.
Doxylamine; Pyridoxine: (Moderate) Olanzapine exhibits anticholinergic effects that may be clinically significant. Clinicians should keep this in mind when using antimuscarinics and other medications with anticholinergic activity in combination with olanzapine. Some medications exhibit additive anticholinergic effects include sedating H1-blockers. Olanzapine may also cause additive sedation with many of these drugs.
Dronabinol: (Moderate) Drugs that can cause CNS depression such as dronabinol, if used concomitantly with atypical antipsychotics, can increase both the frequency and the intensity of adverse effects such as drowsiness, sedation, and dizziness. (Moderate) Use caution if coadministration of dronabinol with fluoxetine is necessary, and monitor for an increase in dronabinol-related adverse reactions (e.g., feeling high, dizziness, confusion, somnolence). Dronabinol is a CYP2C9 and 3A4 substrate; fluoxetine is a weak inhibitor of CYP2C9 and 3A4. Concomitant use may result in elevated plasma concentrations of dronabinol. A hypomanic episode was reported in a 21 year old female with depression and bulimia receiving fluoxetine 20 mg per day for 4 weeks after smoking marijuana. Her symptoms resolved in 4 days. Because dronabinol, THC is a synthetic analog of a naturally occurring substance found in marijuana, interactions with fluoxetine may also occur with dronabinol.
Dronedarone: (Contraindicated) Avoid concomitant use of fluoxetine and dronedarone due to an increased risk for torsade de pointes (TdP) and QT/QTc prolongation. (Contraindicated) Concomitant use of dronedarone and olanzapine is contraindicated. Dronedarone is an inhibitor of CYP2D6. Olanzapine is a substrate for CYP2D6. Coadministration of dronedarone and olanzapine may result in elevated plasma concentrations of olanzapine. In addition, olanzapine has been established to have a possible risk of QT prolongation and Torsade de Pointes (TdP). Dronedarone administration is associated with a dose-related increase in the QTc interval. The increase in QTc is approximately 10 milliseconds at doses of 400 mg twice daily (the FDA-approved dose) and up to 25 milliseconds at doses of 1600 mg twice daily. Although there are no studies examining the effects of dronedarone in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation.
Droperidol: (Major) Droperidol should be administered with extreme caution to patients receiving other agents that may prolong the QT interval. Droperidol administration is associated with an established risk for QT prolongation and torsades de pointes (TdP). Any drug known to have potential to prolong the QT interval should not be coadministered with droperidol. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously with droperidol include olanzapine. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval in rare instances. (Major) Droperidol should not be used in combination with any drug known to have potential to prolong the QT interval, such as fluoxetine. If coadministration cannot be avoided, use extreme caution; initiate droperidol at a low dose and increase the dose as needed to achieve the desired effect. Droperidol administration is associated with an established risk for QT prolongation and torsade de pointes (TdP). Some cases have occurred in patients with no known risk factors for QT prolongation and some cases have been fatal. QT prolongation and TdP have been reported in patients treated with fluoxetine.
Drospirenone; Estradiol: (Minor) As fluoxetine inhibits CYP3A4 activity, serum estrogen concentrations and estrogenic-related side effects (e.g., nausea, breast tenderness) may potentially increase when coadministered with either estrogens or combined hormonal contraceptives.
Drospirenone; Ethinyl Estradiol; Levomefolate: (Minor) Levomefolate and fluoxetine should be used together cautiously. Fluoxetine is a noncompetitive inhibitor of levomefolate active transport in the intestines. Monitor patients for decreased efficacy of levomefolate if these agents are used together.
Dulaglutide: (Moderate) Monitor blood glucose during concomitant atypical antipsychotic and incretin mimetic use. Atypical antipsychotic therapy may aggravate diabetes mellitus. Atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition. (Moderate) Monitor blood glucose during concomitant incretin mimetic and fluoxetine use; an incretin mimetic dose adjustment may be necessary. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
Duloxetine: (Major) Due to similarity of pharmacology and the potential for additive adverse effects, including serotonin syndrome, selective serotonin reuptake inhibitors (SSRIs) such as fluoxetine should generally not be administered with serotonin norepinephrine reuptake inhibitors (SNRIs) such as duloxetine. (Moderate) Duloxetine is an inhibitor of CYP1A2 and CYP2D6 and should be used cautiously with atypical antipsychotics metabolized by CYP1A2 and CYP2D6 such as olanzapine. Plasma concentrations of atypical antipsychotics primarily metabolized via CYP1A2, such as olanzapine, may increase substantially during concurrent use. Decreased metabolism of olanzapine may lead to clinically important adverse reactions, such as orthostatic hypotension, sedation, or extrapyramidal symptoms. In addition, olanzapine is associated with a possible risk of QT prolongation and should be used cautiously with CYP1A2 and CYP2D6 inhibitors such as duloxetine.
Dutasteride; Tamsulosin: (Moderate) Use caution if coadministration of fluoxetine with tamsulosin is necessary, especially at a tamsulosin dose higher than 0.4 mg, as the systemic exposure of tamsulosin may be increased resulting in increased treatment-related adverse reactions including hypotension, dizziness, and vertigo. Tamsulosin is a CYP2D6 substrate and fluoxetine is a strong CYP2D6 inhibitor. Concomitant treatment with another strong CYP2D6 inhibitor increased the Cmax and AUC of tamsulosin by a factor of 1.3 and 1.6, respectively.
Edoxaban: (Moderate) Advise patients of the increased bleeding risk associated with the concomitant use of selective serotonin reuptake inhibitors (SSRIs) and anticoagulants like edoxaban. Case reports and epidemiological studies have demonstrated an association between use of drugs that interfere with serotonin reuptake and gastrointestinal bleeding.
Efavirenz: (Moderate) Concomitant use of fluoxetine and efavirenz may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP. (Moderate) Consider alternatives to efavirenz when coadministering with efavirenz as concurrent use may increase the risk of QT prolongation. QTc prolongation has been observed with the use of efavirenz. Limited data, including some case reports, suggest that olanzapine may also be associated with a significant prolongation of the QTc interval.
Efavirenz; Emtricitabine; Tenofovir Disoproxil Fumarate: (Moderate) Concomitant use of fluoxetine and efavirenz may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP. (Moderate) Consider alternatives to efavirenz when coadministering with efavirenz as concurrent use may increase the risk of QT prolongation. QTc prolongation has been observed with the use of efavirenz. Limited data, including some case reports, suggest that olanzapine may also be associated with a significant prolongation of the QTc interval.
Efavirenz; Lamivudine; Tenofovir Disoproxil Fumarate: (Moderate) Concomitant use of fluoxetine and efavirenz may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP. (Moderate) Consider alternatives to efavirenz when coadministering with efavirenz as concurrent use may increase the risk of QT prolongation. QTc prolongation has been observed with the use of efavirenz. Limited data, including some case reports, suggest that olanzapine may also be associated with a significant prolongation of the QTc interval.
Elagolix; Estradiol; Norethindrone acetate: (Minor) As fluoxetine inhibits CYP3A4 activity, serum estrogen concentrations and estrogenic-related side effects (e.g., nausea, breast tenderness) may potentially increase when coadministered with either estrogens or combined hormonal contraceptives.
Elbasvir; Grazoprevir: (Moderate) Administering elbasvir; grazoprevir with fluoxetine may cause the plasma concentrations of elbasvir and grazoprevir to increase; thereby increasing the potential for adverse effects (i.e., elevated ALT concentrations and hepatotoxicity). Fluoxetine is a mild inhibitor of CYP3A; both elbasvir and grazoprevir are metabolized by CYP3A. If these drugs are used together, closely monitor for signs of hepatotoxicity.
Eletriptan: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering eletriptan with fluoxetine. Serotonin syndrome has been reported during concurrent use of serotonin-receptor agonists and selective serotonin reuptake inhibitors (SSRIs). Some patients had used the combination previously without incident when serotonin syndrome occurred. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly after a dose increase of the SSRI or the addition of other serotonergic medications to an existing SSRI regimen. Discontinue fluoxetine and eletriptan and initiate symptomatic treatment if serotonin syndrome occurs.
Elexacaftor; tezacaftor; ivacaftor: (Minor) Although an interaction between ivacaftor and fluoxetine is possible, the clinical impact of this interaction has not yet been determined. Increased monitoring is recommended if ivacaftor is administered concurrently with CYP2C9 substrates. Fluoxetine is partially metabolized by CYP2C9, but it is also a substrate for at least 2 other enzymes. In vitro studies showed ivacaftor to be a weak inhibitor of CYP2C9. Co-administration may possibly lead to increased exposure to fluoxetine; however, because fluoxetine has multiple metabolic pathways, the clinical impact of this inhibition is not clear. In addition, ivacaftor is a CYP3A substrate, and fluoxetine is a mild CYP3A inhibitor. Co-administration may lead to increased ivacaftor exposure.
Eliglustat: (Major) Coadminister olanzapine and eliglustat cautiously and with close monitoring; there may be an increased risk of QT prolongation and/or olanzapine-associated adverse effects. If coadministration is necessary, olanzapine dosage reduction may be considered but is not routinely recommended. Eliglustat is CYP2D6 inhibitor that is predicted to cause PR, QRS, and/or QT prolongation at significantly elevated plasma concentrations. Olanzapine is a minor substrate of CYP2D6 in vivo. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval in rare instances. Coadministration of olanzapine and eliglustat may result in additive effects on the QT interval and, potentially, increased plasma concentrations of olanzapine, further increasing the risk of serious adverse events (e.g., QT prolongation and cardiac arrhythmias). (Major) In poor CYP2D6 metabolizers (PMs), coadministration of fluoxetine and eliglustat is not recommended. In extensive or intermediate CYP2D6 metabolizers (EMs or IMs), concurrent use of these agents requires dosage reduction of eliglustat to 84 mg PO once daily; monitor patients closely and consider reducing the dosage of fluoxetine and titrating to clinical effect. Coadministration of eliglustat with both fluoxetine and a strong or moderate CYP3A inhibitor is contraindicated in all patients. Fluoxetine is a substrate and strong inhibitor of CYP2D6 and a weak inhibitor of CYP3A that is independently associated with QT prolongation and torsade de pointes (TdP). Eliglustat is a substrate and inhibitor of CYP2D6 and a CYP3A substrate that is predicted to cause PR, QRS, and/or QT prolongation at significantly elevated plasma concentrations. Coadministration of fluoxetine and eliglustat may result in additive effects on the QT interval and, potentially, increased plasma concentrations of one or both drugs, further increasing the risk of serious adverse events (e.g., QT prolongation and cardiac arrhythmias). Because CYP3A plays a significant role in the metabolism of eliglustat in CYP2D6 PMs, coadministration with even weak CYP3A inhibitors, such as fluoxetine, in this population may significantly increase eliglustat exposure and, hence, concurrent use is not recommended.
Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Alafenamide: (Moderate) Caution is warranted when cobicistat is administered with olanzapine as there is a potential for elevated olanzapine concentrations. Olanzapine is a substrate of CYP2D6. Cobicistat is an inhibitor of CYP2D6. (Moderate) Close monitoring for antidepressant response and careful dose titrations of the antidepressant therapy is recommended during coadministration of selective serotonin reuptake inhibitors (SSRIs) and cobicistat. Concurrent use may result in elevated SSRI plasma concentrations. Predictions regarding this interaction can be made based on the metabolic pathways of these drugs. All SSRIs are substrates for the hepatic isoenzyme CYP2D6, while citalopram, escitalopram, and sertraline are also substrates for CYP3A4; cobicistat is an inhibitor of both CYP2D6 and CYP3A4.
Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Disoproxil Fumarate: (Moderate) Caution is warranted when cobicistat is administered with olanzapine as there is a potential for elevated olanzapine concentrations. Olanzapine is a substrate of CYP2D6. Cobicistat is an inhibitor of CYP2D6. (Moderate) Close monitoring for antidepressant response and careful dose titrations of the antidepressant therapy is recommended during coadministration of selective serotonin reuptake inhibitors (SSRIs) and cobicistat. Concurrent use may result in elevated SSRI plasma concentrations. Predictions regarding this interaction can be made based on the metabolic pathways of these drugs. All SSRIs are substrates for the hepatic isoenzyme CYP2D6, while citalopram, escitalopram, and sertraline are also substrates for CYP3A4; cobicistat is an inhibitor of both CYP2D6 and CYP3A4.
Empagliflozin: (Moderate) Monitor blood glucose during concomitant atypical antipsychotic and SGLT2 inhibitor use. Atypical antipsychotic therapy may aggravate diabetes mellitus. Atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition. (Moderate) Monitor blood glucose during concomitant SGLT2 inhibitor and fluoxetine use; a SGLT2 inhibitor dose adjustment may be necessary. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
Empagliflozin; Linagliptin: (Moderate) Monitor blood glucose during concomitant atypical antipsychotic and dipeptidyl peptidase-4 (DPP-4) inhibitor use. Atypical antipsychotic therapy may aggravate diabetes mellitus. Atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition. (Moderate) Monitor blood glucose during concomitant atypical antipsychotic and SGLT2 inhibitor use. Atypical antipsychotic therapy may aggravate diabetes mellitus. Atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition. (Moderate) Monitor blood glucose during concomitant dipeptidyl peptidase-4 (DPP-4) inhibitor and fluoxetine use; a DPP-4 inhibitor dose adjustment may be necessary. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia. (Moderate) Monitor blood glucose during concomitant SGLT2 inhibitor and fluoxetine use; a SGLT2 inhibitor dose adjustment may be necessary. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
Empagliflozin; Linagliptin; Metformin: (Moderate) Monitor blood glucose during concomitant atypical antipsychotic and dipeptidyl peptidase-4 (DPP-4) inhibitor use. Atypical antipsychotic therapy may aggravate diabetes mellitus. Atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition. (Moderate) Monitor blood glucose during concomitant atypical antipsychotic and metformin use. Atypical antipsychotic therapy may aggravate diabetes mellitus. Atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition. (Moderate) Monitor blood glucose during concomitant atypical antipsychotic and SGLT2 inhibitor use. Atypical antipsychotic therapy may aggravate diabetes mellitus. Atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition. (Moderate) Monitor blood glucose during concomitant dipeptidyl peptidase-4 (DPP-4) inhibitor and fluoxetine use; a DPP-4 inhibitor dose adjustment may be necessary. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia. (Moderate) Monitor blood glucose during concomitant metformin and fluoxetine use; a metformin dose adjustment may be necessary. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia. (Moderate) Monitor blood glucose during concomitant SGLT2 inhibitor and fluoxetine use; a SGLT2 inhibitor dose adjustment may be necessary. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
Empagliflozin; Metformin: (Moderate) Monitor blood glucose during concomitant atypical antipsychotic and metformin use. Atypical antipsychotic therapy may aggravate diabetes mellitus. Atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition. (Moderate) Monitor blood glucose during concomitant atypical antipsychotic and SGLT2 inhibitor use. Atypical antipsychotic therapy may aggravate diabetes mellitus. Atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition. (Moderate) Monitor blood glucose during concomitant metformin and fluoxetine use; a metformin dose adjustment may be necessary. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia. (Moderate) Monitor blood glucose during concomitant SGLT2 inhibitor and fluoxetine use; a SGLT2 inhibitor dose adjustment may be necessary. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
Emtricitabine; Rilpivirine; Tenofovir alafenamide: (Moderate) Caution is advised when administering rilpivirine with olanzapine as concurrent use may increase the risk of QT prolongation. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. Limited data, including some case reports, suggest that olanzapine may also be associated with a significant prolongation of the QTc interval. (Moderate) Concomitant use of fluoxetine and rilpivirine may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP. The degree of QT prolongation associated with rilpivirine is not clinically significant when administered within the recommended dosage range; QT prolongation has been described at 3 times the maximum recommended dose.
Emtricitabine; Rilpivirine; Tenofovir Disoproxil Fumarate: (Moderate) Caution is advised when administering rilpivirine with olanzapine as concurrent use may increase the risk of QT prolongation. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. Limited data, including some case reports, suggest that olanzapine may also be associated with a significant prolongation of the QTc interval. (Moderate) Concomitant use of fluoxetine and rilpivirine may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP. The degree of QT prolongation associated with rilpivirine is not clinically significant when administered within the recommended dosage range; QT prolongation has been described at 3 times the maximum recommended dose.
Enalapril, Enalaprilat: (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.
Enalapril; Hydrochlorothiazide, HCTZ: (Moderate) Monitor for signs and symptoms of hyponatremia during concomitant diuretic and fluoxetine use; consider discontinuing fluoxetine if symptomatic hyponatremia occurs and institute appropriate medical intervention. Concomitant use increases the risk for developing hyponatremia. (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.
Encorafenib: (Major) Avoid coadministration of encorafenib and fluoxetine due to increased encorafenib exposure and QT prolongation. If concurrent use cannot be avoided, reduce the encorafenib dose to one-half of the dose used prior to the addition of fluoxetine. Monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. If fluoxetine is discontinued, the original encorafenib dose may be resumed after 3 to 5 elimination half-lives of fluoxetine. Encorafenib is a CYP3A4 substrate that has been associated with dose-dependent QT prolongation. Fluoxetine is a weak CYP3A4 inhibitor, but the norfluoxetine metabolite is a moderate CYP3A4 inhibitor; QT prolongation and torsade de pointes (TdP) have been reported in patients treated with fluoxetine. Coadministration of a moderate CYP3A4 inhibitor with a single 50 mg dose of encorafenib (0.1 times the recommended dose) increased the encorafenib AUC and Cmax by 2-fold and 45%, respectively. (Major) Avoid coadministration of encorafenib and olanzapine due to the potential for additive QT prolongation. If concurrent use cannot be avoided, monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. Encorafenib is associated with dose-dependent prolongation of the QT interval. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval.
Enoxaparin: (Moderate) Monitor for signs and symptoms of bleeding during concomitant low molecular weight heparin and selective serotonin reuptake inhibitor (SSRI) use due to increased risk for bleeding. Serotonin release by platelets plays an important role in hemostasis. Epidemiological studies have demonstrated an association between use of psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper gastrointestinal bleeding. Altered anticoagulant effects, including increased bleeding, have been reported when SSRIs are coadministered with another anticoagulant.
Entacapone: (Moderate) Monitor for movement disorders, unusual changes in moods or behavior, and diminished effectiveness of the atypical antipsychotic or COMT inhibitor during coadministration. Due to mutually opposing effects on dopamine, atypical antipsychotics and COMT inhibitors may interfere with the effectiveness of each other. In general, atypical antipsychotics are less likely to interfere with COMT inhibitors and other Parkinson's treatments than traditional antipsychotics. The Beers Criteria recognize quetiapine and clozapine as exceptions to the general recommendation to avoid all antipsychotics in older adults with Parkinson's disease.
Entrectinib: (Major) Avoid coadministration of entrectinib with olanzapine due to the risk of QT prolongation. Entrectinib has been associated with QT prolongation. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval. (Major) Concomitant use of entrectinib and fluoxetine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Epinephrine: (Moderate) Olanzapine may induce significant alpha-adrenergic blockade in overdose, leading to profound hypotension. Do not use epinephrine, dopamine, or other sympathomimetics with beta-agonist activity since the beta-stimulation may worsen hypotension in the setting of olanzapine overdose.
Eplerenone: (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.
Epoprostenol: (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.
Eprosartan: (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.
Eprosartan; Hydrochlorothiazide, HCTZ: (Moderate) Monitor for signs and symptoms of hyponatremia during concomitant diuretic and fluoxetine use; consider discontinuing fluoxetine if symptomatic hyponatremia occurs and institute appropriate medical intervention. Concomitant use increases the risk for developing hyponatremia. (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.
Eptifibatide: (Moderate) Platelet aggregation may be impaired by SSRIs due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication in patients receiving platelet inhibitors. Monitor for signs and symptoms of bleeding.
Ergoloid Mesylates: (Moderate) Use fluoxetine and ergot alkaloids together with caution due to a potential for serotonin syndrome. Weakness, hyperreflexia, and incoordination have been reported rarely when ergot alkaloids or other serotonin agonists have been coadministered with SSRIs, which may be indicative of serotonin excess. If serotonin syndrome occurs, discontinue the offending agents and institute appropriate treatment.
Ergot alkaloids: (Moderate) Use fluoxetine and ergot alkaloids together with caution due to a potential for serotonin syndrome. Weakness, hyperreflexia, and incoordination have been reported rarely when ergot alkaloids or other serotonin agonists have been coadministered with SSRIs, which may be indicative of serotonin excess. If serotonin syndrome occurs, discontinue the offending agents and institute appropriate treatment.
Ergotamine: (Moderate) Use fluoxetine and ergot alkaloids together with caution due to a potential for serotonin syndrome. Weakness, hyperreflexia, and incoordination have been reported rarely when ergot alkaloids or other serotonin agonists have been coadministered with SSRIs, which may be indicative of serotonin excess. If serotonin syndrome occurs, discontinue the offending agents and institute appropriate treatment.
Ergotamine; Caffeine: (Moderate) Use fluoxetine and ergot alkaloids together with caution due to a potential for serotonin syndrome. Weakness, hyperreflexia, and incoordination have been reported rarely when ergot alkaloids or other serotonin agonists have been coadministered with SSRIs, which may be indicative of serotonin excess. If serotonin syndrome occurs, discontinue the offending agents and institute appropriate treatment.
Eribulin: (Major) Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval in rare instances. Therefore, caution is advised when administering olanzapine with drugs having an established causal association with QT prolongation and torsade de pointes (TdP). Drugs with a possible risk for QT prolongation and TdP that should be used cautiously with olanzapine include eribulin. ECG monitoring is recommended; closely monitor the patient for QT interval prolongation. (Moderate) Concomitant use of fluoxetine and eribulin may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP.
Ertugliflozin: (Moderate) Monitor blood glucose during concomitant atypical antipsychotic and SGLT2 inhibitor use. Atypical antipsychotic therapy may aggravate diabetes mellitus. Atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition. (Moderate) Monitor blood glucose during concomitant SGLT2 inhibitor and fluoxetine use; a SGLT2 inhibitor dose adjustment may be necessary. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
Ertugliflozin; Metformin: (Moderate) Monitor blood glucose during concomitant atypical antipsychotic and metformin use. Atypical antipsychotic therapy may aggravate diabetes mellitus. Atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition. (Moderate) Monitor blood glucose during concomitant atypical antipsychotic and SGLT2 inhibitor use. Atypical antipsychotic therapy may aggravate diabetes mellitus. Atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition. (Moderate) Monitor blood glucose during concomitant metformin and fluoxetine use; a metformin dose adjustment may be necessary. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia. (Moderate) Monitor blood glucose during concomitant SGLT2 inhibitor and fluoxetine use; a SGLT2 inhibitor dose adjustment may be necessary. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
Ertugliflozin; Sitagliptin: (Moderate) Monitor blood glucose during concomitant atypical antipsychotic and dipeptidyl peptidase-4 (DPP-4) inhibitor use. Atypical antipsychotic therapy may aggravate diabetes mellitus. Atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition. (Moderate) Monitor blood glucose during concomitant atypical antipsychotic and SGLT2 inhibitor use. Atypical antipsychotic therapy may aggravate diabetes mellitus. Atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition. (Moderate) Monitor blood glucose during concomitant dipeptidyl peptidase-4 (DPP-4) inhibitor and fluoxetine use; a DPP-4 inhibitor dose adjustment may be necessary. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia. (Moderate) Monitor blood glucose during concomitant SGLT2 inhibitor and fluoxetine use; a SGLT2 inhibitor dose adjustment may be necessary. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
Erythromycin: (Major) Concomitant use of erythromycin and fluoxetine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. (Major) Concomitant use of olanzapine and erythromycin increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Escitalopram: (Major) Due to the similarity in pharmacology of fluoxetine and escitalopram and the potential for serious adverse reactions, including serotonin syndrome, these selective serotonin reuptake inhibitors (SSRIs) should not be administered together. Also, both fluoxetine and escitalopram have been associated with QT prolongation and torsade de pointes (TdP), which could theoretically result in additive effects on the QT interval. It is advisable to monitor for signs and symptoms of serotonin syndrome during an overlapping transition from one SSRI to another SSRI. (Moderate) Concomitant use of escitalopram and olanzapine may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP.
Esketamine: (Major) Closely monitor patients receiving esketamine and olanzapine for sedation and other CNS depressant effects. Instruct patients who receive a dose of esketamine not to drive or engage in other activities requiring alertness until the next day after a restful sleep.
Esmolol: (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.
Esomeprazole: (Minor) Fluoxetine may inhibit the CYP2C19 isoenzyme, leading to increased plasma levels of drugs that are substrates for the CYP2C19 isoenzyme, such as esomeprazole.
Estazolam: (Moderate) Although oral formulations of olanzapine and benzodiazepines may be used together, additive effects on respiratory depression and/or CNS depression are possible. Drugs that can cause CNS depression, if used concomitantly with olanzapine, can increase both the frequency and the intensity of adverse effects such as drowsiness, sedation, dizziness, and orthostatic hypotension. Besides ethanol, clinicians should use other anxiolytics, sedatives, and hypnotics cautiously with olanzapine.
Esterified Estrogens: (Minor) Estrogens are partially metabolized by CYP3A4. Drugs that inhibit CYP3A4 such as fluoxetine may increase plasma concentrations of estrogens and cause estrogen-related side effects such as nausea and breast tenderness. Patients receiving estrogens should be monitored for an increase in adverse events.
Esterified Estrogens; Methyltestosterone: (Minor) Estrogens are partially metabolized by CYP3A4. Drugs that inhibit CYP3A4 such as fluoxetine may increase plasma concentrations of estrogens and cause estrogen-related side effects such as nausea and breast tenderness. Patients receiving estrogens should be monitored for an increase in adverse events.
Estradiol: (Minor) As fluoxetine inhibits CYP3A4 activity, serum estrogen concentrations and estrogenic-related side effects (e.g., nausea, breast tenderness) may potentially increase when coadministered with either estrogens or combined hormonal contraceptives.
Estradiol; Levonorgestrel: (Minor) As fluoxetine inhibits CYP3A4 activity, serum estrogen concentrations and estrogenic-related side effects (e.g., nausea, breast tenderness) may potentially increase when coadministered with either estrogens or combined hormonal contraceptives.
Estradiol; Norethindrone: (Minor) As fluoxetine inhibits CYP3A4 activity, serum estrogen concentrations and estrogenic-related side effects (e.g., nausea, breast tenderness) may potentially increase when coadministered with either estrogens or combined hormonal contraceptives.
Estradiol; Norgestimate: (Minor) As fluoxetine inhibits CYP3A4 activity, serum estrogen concentrations and estrogenic-related side effects (e.g., nausea, breast tenderness) may potentially increase when coadministered with either estrogens or combined hormonal contraceptives.
Estradiol; Progesterone: (Minor) As fluoxetine inhibits CYP3A4 activity, serum estrogen concentrations and estrogenic-related side effects (e.g., nausea, breast tenderness) may potentially increase when coadministered with either estrogens or combined hormonal contraceptives.
Estropipate: (Minor) Estrogens are partially metabolized by CYP3A4. Drugs that inhibit CYP3A4 such as fluoxetine may increase plasma concentrations of estrogens and cause estrogen-related side effects such as nausea and breast tenderness. Patients receiving estrogens should be monitored for an increase in adverse events.
Eszopiclone: (Moderate) A reduction in the dose of eszopiclone should be considered during co-administration of other CNS depressants, such as antipsychotics, to minimize additive sedative effects. In addition, the risk of next-day psychomotor impairment is increased during co-administration of eszopiclone and other CNS depressants, which may decrease the ability to perform tasks requiring full mental alertness such as driving. Antipsychotics with a higher incidence of sedation, such as olanzapine, clozapine, quetiapine, lurasidone, chlorpromazine, and thioridazine, are more likely to interact with eszopiclone. In one evaluation, concurrent use of eszopiclone and olanzapine reduced psychomotor function as measured by the Digit Symbol Substitution Test (DSST).
Ethacrynic Acid: (Moderate) Monitor for signs and symptoms of hyponatremia during concomitant diuretic and fluoxetine use; consider discontinuing fluoxetine if symptomatic hyponatremia occurs and institute appropriate medical intervention. Concomitant use increases the risk for developing hyponatremia.
Ethanol: (Major) Advise patients to avoid alcohol consumption while taking CNS depressants. Alcohol consumption may result in additive CNS depression.
Ethotoin: (Major) Olanzapine is metabolized by the CYP1A2 hepatic microsomal isoenzyme, and inducers of this enzyme, such as hydantoins, may increase olanzapine clearance. Clinicians should monitor for reduced effectiveness of the antipsychotic agent if hydantoin therapy is added.
Everolimus: (Moderate) Monitor everolimus whole blood trough concentrations as appropriate and watch for everolimus-related adverse reactions if coadministration with fluoxetine is necessary. The dose of everolimus may need to be reduced. Everolimus is a sensitive CYP3A4 substrate and a P-glycoprotein (P-gp) substrate. Norfluoxetine, the active metabolite of fluoxetine, is a moderate CYP3A4 inhibitor. Coadministration with moderate CYP3A4/P-gp inhibitors increased the AUC of everolimus by 3.5 to 4.4-fold.
Exenatide: (Moderate) Monitor blood glucose during concomitant atypical antipsychotic and incretin mimetic use. Atypical antipsychotic therapy may aggravate diabetes mellitus. Atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition. (Moderate) Monitor blood glucose during concomitant incretin mimetic and fluoxetine use; an incretin mimetic dose adjustment may be necessary. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
Fedratinib: (Major) Avoid coadministration of fedratinib with fluoxetine as concurrent use may increase fedratinib exposure; fluoxetine exposure may also increase. Fedratinib is a substrate of both CYP3A4 and CYP2C19 and a moderate CYP2D6 inhibitor; fluoxetine is an inhibitor of both CYP3A4 and CYP2C19 and a CYP2D6 substrate. The coadministration of fedratinib with agents that are both a CYP3A4 and CYP2C19 inhibitor has not been evaluated.
Felodipine: (Moderate) Fluoxetine may decrease the clearance of calcium-channel blockers, including felodipine, via inhibition of CYP3A4 metabolism.
Fenfluramine: (Major) Concomitant use of fenfluramine and fluoxetine may increase fenfluramine plasma concentrations and the risk of adverse reactions, including serotonin syndrome. Avoid concomitant use if possible and monitor for serotonin syndrome if use is necessary. If concomitant use is unavoidable, do not exceed a maximum dose of fenfluramine 20 mg/day PO if coadministered with fluoxetine and 17 mg/day PO if patient is also receiving stiripentol plus clobazam. Fenfluramine is a CYP2D6 substrate and fluoxetine is a strong CYP2D6 inhibitor. Coadministration with another strong CYP2D6 inhibitor increased fenfluramine overall exposure by 81% and decreased norfenfluramine overall exposure by 13%. (Moderate) Use fenfluramine and olanzapine with caution due to an increased risk of serotonin syndrome and additive CNS depression. Monitor for excessive sedation, somnolence, and serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
Fenofibric Acid: (Minor) As fenofibric acid is a mild-to-moderate inhibitor of CYP2C9 and CYP2C19; while fluoxetine is a substrate of both. Although not formally studied, co-administration may lead to increased fluoxetine plasma concentrations and toxicity. Monitor the therapeutic effect of fluoxetine during coadministration with fenofibric acid. (Minor) At therapeutic concentrations, fenofibric acid is a weak inhibitor of CYP2C19. Concomitant use of fenofibric acid with CYP2C19 substrates, such as olanzapine, has not been formally studied. Fenofibric acid may theoretically increase plasma concentrations of CYP2C19 substrates and could lead to toxicity for drugs that have a narrow therapeutic range. Monitor the therapeutic effect of olanzapine during coadministration with fenofibric acid.
Fentanyl: (Major) Concomitant use of opioid agonists with olanzapine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with olanzapine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Also monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. (Moderate) If concomitant use of fentanyl and fluoxetine is warranted, monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
Fesoterodine: (Moderate) Coadministration of fesoterodine and other drugs with moderate to significant anticholinergic effects such as olanzapine may increase the frequency and/or severity of anticholinergic effects such as blurred vision, constipation, xerostomia, and urinary retention. Additive effects may be seen on GI smooth muscle, bladder function, the CNS, the eye, and temperature regulation.
Fingolimod: (Moderate) Concomitant use of fluoxetine and fingolimod may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP. (Moderate) Exercise caution when administering fingolimod concomitantly with olanzapine as concurrent use may increase the risk of QT prolongation. Fingolimod initiation results in decreased heart rate and may prolong the QT interval. Fingolimod has not been studied in patients treated with drugs that prolong the QT interval, but drugs that prolong the QT interval have been associated with cases of TdP in patients with bradycardia. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval.
Flavoxate: (Moderate) Additive anticholinergic effects may be seen when olanzapine and anticholinergics are used concomitantly; use with caution. Use of olanzapine and other drugs with anticholinergic activity can increase the risk for severe gastrointestinal adverse reactions related to hypomotility. Olanzapine exhibits anticholinergic activity. Adverse effects may be seen not only on GI smooth muscle, but also on bladder function, the CNS, the eye, and temperature regulation. Additive drowsiness may also occur, depending on the anticholinergic agent used.
Flecainide: (Major) Concomitant use of flecainide and fluoxetine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Concomitant use may also increase the exposure of flecainide, further increasing the risk of adverse effects. Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. Flecainide is a CYP2D6 substrate and fluoxetine is a strong CYP2D6 inhibitor. (Moderate) Concomitant use of flecainide and olanzapine may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP.
Flibanserin: (Major) The concomitant use of flibanserin and a strong CYP2C19 inhibitor or multiple weak CYP3A4 inhibitors, including fluoxetine, may increase flibanserin concentrations, which may increase the risk of flibanserin-induced adverse reactions. Therefore, patients should be monitored for hypotension, syncope, somnolence, or other adverse reactions, and the risks of combination therapy with multiple weak CYP3A4 inhibitors and flibanserin should be discussed with the patient.
Fluconazole: (Moderate) Concomitant use of fluconazole and fluoxetine may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP. (Moderate) Concomitant use of fluconazole and olanzapine may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP.
Fluphenazine: (Moderate) Concurrent use of olanzapine and fluphenazine should be avoided due to an increased risk for QT prolongation and torsade de pointes (TdP). Fluphenazine, a phenothiazine, is associated with a possible risk for QT prolongation. Limited data, including some case reports, suggest that olanzapine may also be associated with a significant prolongation of the QTc interval in rare instances. In addition, co-administration of olanzapine with phenothiazines may increase the risk of adverse effects such as drowsiness, dizziness, orthostatic hypotension, anticholinergic effects, extrapyramidal symptoms, neuroleptic malignant syndrome, or seizures. The likelihood of pharmacodynamic interactions varies based upon the individual properties of the co-administered antipsychotic agent. Although the incidence of tardive dyskinesia from combination antipsychotic therapy has not been established and data are very limited, the risk appears to be increased during use of a conventional and atypical antipsychotic versus use of a conventional antipsychotic alone. (Moderate) Use fluoxetine with caution in combination with fluphenazine. Coadministration may increase the risk for QT prolongation and torsade de pointes (TdP). Additionally, fluoxetine is a potent inhibitor of CYP2D6 and may result in increases in serum fluphenazine concentrations, leading to side effects. QT prolongation and TdP have been reported in patients treated with fluoxetine. Fluphenazine is associated with a possible risk for QT prolongation.
Flurazepam: (Moderate) Although oral formulations of olanzapine and benzodiazepines may be used together, additive effects on respiratory depression and/or CNS depression are possible. Drugs that can cause CNS depression, if used concomitantly with olanzapine, can increase both the frequency and the intensity of adverse effects such as drowsiness, sedation, dizziness, and orthostatic hypotension. Besides ethanol, clinicians should use other anxiolytics, sedatives, and hypnotics cautiously with olanzapine. (Moderate) Fluoxetine could theoretically inhibit CYP3A4 metabolism of oxidized benzodiazepines, including flurazepam. Patients should be monitored for clinical response, and adjust benzodiazepine dosage if needed.
Fluvastatin: (Moderate) In theory, concurrent use CYP2C9 inhibitors, such as fluoxetine, and fluvastatin, a CYP2C9 substrate, may result in reduced metabolism of fluvastatin and potential for toxicity including myopathy and rhabdomyolysis.
Fluvoxamine: (Major) Due to the similarity in pharmacology of fluoxetine and fluvoxamine and the potential for serious adverse reactions, including serotonin syndrome, these selective serotonin reuptake inhibitors (SSRIs) should not be administered together. Also, both fluoxetine and fluvoxamine have been associated with QT prolongation and torsade de pointes (TdP), which could theoretically result in additive effects on the QT interval. It is advisable to monitor for signs and symptoms of serotonin syndrome during an overlapping transition from one SSRI to another SSRI. (Major) There may be an increased risk for QT prolongation, torsade de pointes (TdP), and elevated olanzapine concentrations during concurrent use of fluvoxamine and olanzapine. Caution is advisable. The manufacturer of olanzapine suggests that lower doses of olanzapine be considered in patients receiving fluvoxamine. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval. Cases of QT prolongation and TdP have been reported during postmarketing use of fluvoxamine. In addition, fluvoxamine is a potent inhibitor of CYP1A2, which may result in decreased clearance of CYP1A2 substrates including olanzapine. Decreased metabolism of olanzapine may lead to excessive sedation, extrapyramidal symptoms, orthostatic hypotension, or QT prolongation. Fluvoxamine increases the mean olanzapine peak concentration by 54% in female nonsmokers and 77% in male smokers. The mean increase in olanzapine AUC is 52% and 108%, respectively.
Fondaparinux: (Moderate) Advise patients of the increased bleeding risk associated with the concomitant use of selective serotonin reuptake inhibitors (SSRIs) and anticoagulants like fondaparinux. Case reports and epidemiological studies have demonstrated an association between use of drugs that interfere with serotonin reuptake and gastrointestinal bleeding.
Food: (Major) Advise patients to avoid cannabis use while taking CNS depressants due to the risk for additive CNS depression and potential for other cognitive adverse reactions. (Major) Advise patients to avoid cannabis use with fluoxetine. The incidence of cannabis associated adverse effects may change following coadministration with fluoxetine. Fluoxetine is an inhibitor of CYP2C9 and CYP3A4, two isoenzymes responsible for the metabolism of cannabis's most psychoactive compound, delta-9-tetrahydrocannabinol (Delta-9-THC). When given concurrently with fluoxetine the amount of Delta-9-THC converted to the active metabolite 11-hydroxy-delta-9-tetrahydrocannabinol (11-OH-THC) may be reduced. These changes in Delta-9-THC and 11-OH-THC plasma concentrations may result in an altered cannabis adverse event profile.
Foscarnet: (Major) Concomitant use of fluoxetine and foscarnet increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. (Major) When possible, avoid concurrent use of foscarnet with other drugs known to prolong the QT interval, such as olanzapine. Foscarnet has been associated with postmarketing reports of both QT prolongation and torsade de pointes (TdP). Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval. If these drugs are administered together, obtain an electrocardiogram and electrolyte concentrations before and periodically during treatment.
Fosinopril: (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.
Fosinopril; Hydrochlorothiazide, HCTZ: (Moderate) Monitor for signs and symptoms of hyponatremia during concomitant diuretic and fluoxetine use; consider discontinuing fluoxetine if symptomatic hyponatremia occurs and institute appropriate medical intervention. Concomitant use increases the risk for developing hyponatremia. (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.
Fosphenytoin: (Major) Olanzapine is metabolized by the CYP1A2 hepatic microsomal isoenzyme, and inducers of this enzyme, such as hydantoins, may increase olanzapine clearance. Clinicians should monitor for reduced effectiveness of the antipsychotic agent if hydantoin therapy is added. (Moderate) Monitor phenytoin concentrations during concomitant therapy with fosphenytoin and fluoxetine due to risk for phenytoin toxicity. Concomitant use may increase phenytoin concentrations. Phenytoin is a CYP2C9 and CYP2C19 substrate and fluoxetine is a CYP2C9 and CYP2C19 inhibitor.
Fostemsavir: (Moderate) Caution is advised when administering olanzapine with fostemsavir due to the potential for QT prolongation. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval. Supratherapeutic doses of fostemsavir (2,400 mg twice daily, four times the recommended daily dose) have been shown to cause QT prolongation. Fostemsavir causes dose-dependent QT prolongation. (Moderate) Concomitant use of fluoxetine and fostemsavir may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP. The degree of QT prolongation associated with fostemsavir is not clinically significant when administered within the recommended dosage range; QT prolongation has been described at 4 times the recommended daily dose.
Frovatriptan: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering frovatriptan with selective serotonin reuptake inhibitors (SSRIs). Serotonin syndrome has been reported during concurrent use of serotonin-receptor agonists and SSRIs. Some patients had used the combination previously without incident when serotonin syndrome occurred. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly after a dose increase of the SSRI or the addition of other serotonergic medications to an existing SSRI regimen. Discontinue the SSRI and frovatriptan and initiate symptomatic treatment if serotonin syndrome occurs.
Furosemide: (Moderate) Monitor for signs and symptoms of hyponatremia during concomitant diuretic and fluoxetine use; consider discontinuing fluoxetine if symptomatic hyponatremia occurs and institute appropriate medical intervention. Concomitant use increases the risk for developing hyponatremia.
Gabapentin: (Major) Initiate gabapentin at the lowest recommended dose and monitor patients for symptoms of sedation and somnolence during coadministration of gabapentin and olanzapine. Concomitant use of gabapentin with olanzapine may cause additive CNS depression. Educate patients about the risks and symptoms of excessive CNS depression.
Galantamine: (Moderate) Atypical antipsychotics with significant anticholinergic effects, such olanzapine, are more likely than other atypical antipsychotics to diminish the therapeutic action of galantamine in treating dementia. Use of an alternative antipsychotic should be considered. Galantamine inhibits acetylcholinesterase, the enzyme responsible for the degradation of acetylcholine, and exerts its therapeutic effect by improving the availability of acetylcholine. Consider the use of an antipsychotic with less prominent anticholinergic effects. Monitor for decreased clinical efficacy of galantamine if olanzapine must be used concurrently.
Ganirelix: (Moderate) Antipsychotic-induced hyperprolactinemia results in down-regulation of the number of pituitary GnRH receptors and may interfere with the response to ganirelix, a gonadotropin-releasing hormone (GnRH) analog.
Gefitinib: (Moderate) Monitor for an increase in gefitinib-related adverse reactions if coadministration with fluoxetine is necessary; the risk is increased in CYP2D6 poor metabolizers. Based on in vitro data, gefitinib is metabolized to O-desmethyl gefitinib by CYP2D6 and fluoxetine is a CYP2D6 inhibitor. In healthy CYP2D6 poor metabolizers, the concentration of O-desmethyl gefitinib was not measurable and mean exposure to gefitinib was 2-fold higher compared to extensive metabolizers. The impact of CYP2D6 inhibitors on gefitinib pharmacokinetics has not been evaluated; however, the manufacturer recommends precautions based on exposure in patients with poor CYP2D6 metabolism.
Gemifloxacin: (Moderate) Concomitant use of fluoxetine and gemifloxacin may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP. (Moderate) Due to an increased risk for QT prolongation and torsade de pointes (TdP), caution is advised when administering olanzapine with gemifloxacin. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval in rare instances. Gemifloxacin may also prolong the QT interval in some patients, with the maximal change in the QTc interval occurring approximately 5 to 10 hours following oral administration. The likelihood of QTc prolongation may increase with increasing dose of gemifloxacin; therefore, the recommended dose should not be exceeded especially in patients with renal or hepatic impairment where the Cmax and AUC are slightly higher.
Gemtuzumab Ozogamicin: (Moderate) Concomitant use of fluoxetine and gemtuzumab ozogamicin may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP. (Moderate) Use gemtuzumab ozogamicin and olanzapine together with caution due to the potential for additive QT interval prolongation and risk of torsade de pointes (TdP). If these agents are used together, obtain an ECG and serum electrolytes prior to the start of gemtuzumab and as needed during treatment. Although QT interval prolongation has not been reported with gemtuzumab, it has been reported with other drugs that contain calicheamicin. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval.
Gilteritinib: (Major) Avoid coadministration of fluoxetine with gilteritinib if possible due to the potential for additive QT prolongation and decreased response to fluoxetine. Gilteritinib has been associated with QT prolongation. QT prolongation and torsade de pointes (TdP) have been reported in patients treated with fluoxetine. Coadministration has the potential for additive cardiotoxicity. Additionally, gilteritinib inhibits human 5HT2B receptor or sigma nonspecific receptors, which may reduce the effects of drugs like fluoxetine that target these receptors. (Moderate) Use caution and monitor for additive QT prolongation if concurrent use of gilteritinib and olanzapine is necessary. Gilteritinib has been associated with QT prolongation. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval.
Glasdegib: (Major) Avoid coadministration of glasdegib with fluoxetine due to the potential for additive QT prolongation. If coadministration cannot be avoided, monitor patients for increased risk of QT prolongation with increased frequency of ECG monitoring. Glasdegib therapy may result in QT prolongation and ventricular arrhythmias including ventricular fibrillation and ventricular tachycardia. QT prolongation and torsade de pointes (TdP) have been reported in patients treated with fluoxetine. (Major) Avoid coadministration of glasdegib with olanzapine due to the potential for additive QT prolongation. If coadministration cannot be avoided, monitor patients for increased risk of QT prolongation with increased frequency of ECG monitoring. Glasdegib therapy may result in QT prolongation and ventricular arrhythmias including ventricular fibrillation and ventricular tachycardia. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval.
Glipizide; Metformin: (Moderate) Monitor blood glucose during concomitant atypical antipsychotic and metformin use. Atypical antipsychotic therapy may aggravate diabetes mellitus. Atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition. (Moderate) Monitor blood glucose during concomitant metformin and fluoxetine use; a metformin dose adjustment may be necessary. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
Glyburide; Metformin: (Moderate) Monitor blood glucose during concomitant atypical antipsychotic and metformin use. Atypical antipsychotic therapy may aggravate diabetes mellitus. Atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition. (Moderate) Monitor blood glucose during concomitant metformin and fluoxetine use; a metformin dose adjustment may be necessary. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
Glycopyrrolate: (Moderate) Additive anticholinergic effects may be seen when olanzapine and anticholinergics are used concomitantly; use with caution. Use of olanzapine and other drugs with anticholinergic activity can increase the risk for severe gastrointestinal adverse reactions related to hypomotility. Olanzapine exhibits anticholinergic activity. Adverse effects may be seen not only on GI smooth muscle, but also on bladder function, the CNS, the eye, and temperature regulation. Additive drowsiness may also occur, depending on the anticholinergic agent used.
Glycopyrrolate; Formoterol: (Moderate) Additive anticholinergic effects may be seen when olanzapine and anticholinergics are used concomitantly; use with caution. Use of olanzapine and other drugs with anticholinergic activity can increase the risk for severe gastrointestinal adverse reactions related to hypomotility. Olanzapine exhibits anticholinergic activity. Adverse effects may be seen not only on GI smooth muscle, but also on bladder function, the CNS, the eye, and temperature regulation. Additive drowsiness may also occur, depending on the anticholinergic agent used.
Goserelin: (Major) Avoid coadministration of goserelin with olanzapine due to the risk of reduced efficacy of goserelin; QT prolongation may also occur. Olanzapine can cause hyperprolactinemia, which reduces the number of pituitary gonadotropin releasing hormone (GnRH) receptors; goserelin is a GnRH analog. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval. Androgen deprivation therapy (i.e., goserelin) may also prolong the QT/QTc interval. (Moderate) Concomitant use of fluoxetine and androgen deprivation therapy (i.e., goserelin) may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP.
Granisetron: (Moderate) Use fluoxetine with caution in combination with granisteron as there is an increased risk for QT prolongation, torsade de pointes (TdP), and serotonin syndrome. If serotonin syndrome is suspected, discontinue granisetron and concurrent serotonergic agents and initiate appropriate medical treatment. QT prolongation and TdP have been reported in patients treated with fluoxetine. Granisetron has also been associated with QT prolongation. (Moderate) Use granisetron with caution in combination with olanzapine due to increased risk for QT prolongation and torsade de pointes (TdP). Granisetron has been associated with QT prolongation. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval in rare instances.
Guaifenesin; Hydrocodone: (Major) Concomitant use of opioid agonists with olanzapine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with olanzapine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Also monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. Avoid prescribing opioid cough medication in patients taking olanzapine. (Moderate) Careful monitoring, particularly during treatment initiation and dose adjustment, is recommended during coadministration of hydrocodone and fluoxetine because of the potential risk of serotonin syndrome and prolonged opioid adverse reactions. Discontinue hydrocodone if serotonin syndrome is suspected. It is recommended to avoid this combination when hydrocodone is being used for cough. Concomitant use of hydrocodone with fluoxetine may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. Monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of fluoxetine could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If fluoxetine is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP2D6. Fluoxetine is a strong inhibitor of CYP2D6.
Halogenated Anesthetics: (Major) Concomitant use of halogenated anesthetics and fluoxetine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. (Major) Halogenated anesthetics should be used cautiously and with close monitoring with olanzapine. Halogenated anesthetics can prolong the QT interval. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval in rare instances. Therefore, caution is advised when administering olanzapine with drugs having an established causal association with QT prolongation and torsade de pointes (TdP).
Haloperidol: (Moderate) Caution is advised when administering olanzapine with haloperidol as concurrent use may increase the risk of QT prolongation; additive antipsychotic-related adverse effects (e.g., drowsiness, dizziness, orthostatic hypotension, anticholinergic effects, extrapyramidal symptoms, neuroleptic malignant syndrome, or seizures) may also occur. QT prolongation and torsade de pointes (TdP) have been observed during haloperidol treatment. Excessive doses (particularly in the overdose setting) or IV administration of haloperidol may be associated with a higher risk of QT prolongation. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval. The likelihood of additive pharmacodynamic interactions varies based upon the individual properties of the coadministered antipsychotic agent. Although the incidence of tardive dyskinesia from combination antipsychotic therapy has not been established and data are very limited, the risk appears to be increased during use of a conventional and atypical antipsychotic versus use of a conventional antipsychotic alone. (Moderate) Use fluoxetine with caution in combination with haloperidol as concurrent use may increase the risk of QT prolongation and haloperidol-related adverse effects. Fluoxetine is a strong CYP2D6 inhibitor that has been associated with a risk of QT prolongation and torsade de pointes (TdP). Haloperidol is a CYP2D6 substrate; QT prolongation and torsade de pointes (TdP) have been observed during haloperidol treatment. Excessive doses (particularly in the overdose setting) or IV administration of haloperidol may be associated with a higher risk of QT prolongation. Mild to moderately increased haloperidol concentrations have been reported when haloperidol was given concomitantly with CYP2D6 inhibitors.
Heparin: (Moderate) Advise patients of the increased bleeding risk associated with the concomitant use of selective serotonin reuptake inhibitors (SSRIs) and anticoagulants like heparin. Case reports and epidemiological studies have demonstrated an association between use of drugs that interfere with serotonin reuptake and gastrointestinal bleeding.
Histrelin: (Major) Avoid coadministration of histrelin with olanzapine due to the risk of reduced efficacy of histrelin; QT prolongation may also occur. Olanzapine can cause hyperprolactinemia, which reduces the number of pituitary gonadotropin releasing hormone (GnRH) receptors; histrelin is a GnRH analog. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval. Androgen deprivation therapy (i.e., histrelin) may also prolong the QT/QTc interval. (Moderate) Concomitant use of fluoxetine and androgen deprivation therapy (i.e., histrelin) may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP.
Homatropine; Hydrocodone: (Major) Concomitant use of opioid agonists with olanzapine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with olanzapine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Also monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. Avoid prescribing opioid cough medication in patients taking olanzapine. (Moderate) Additive anticholinergic effects may be seen when olanzapine and anticholinergics are used concomitantly; use with caution. Use of olanzapine and other drugs with anticholinergic activity can increase the risk for severe gastrointestinal adverse reactions related to hypomotility. Olanzapine exhibits anticholinergic activity. Adverse effects may be seen not only on GI smooth muscle, but also on bladder function, the CNS, the eye, and temperature regulation. Additive drowsiness may also occur, depending on the anticholinergic agent used. (Moderate) Careful monitoring, particularly during treatment initiation and dose adjustment, is recommended during coadministration of hydrocodone and fluoxetine because of the potential risk of serotonin syndrome and prolonged opioid adverse reactions. Discontinue hydrocodone if serotonin syndrome is suspected. It is recommended to avoid this combination when hydrocodone is being used for cough. Concomitant use of hydrocodone with fluoxetine may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. Monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of fluoxetine could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If fluoxetine is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP2D6. Fluoxetine is a strong inhibitor of CYP2D6.
Hydantoins: (Major) Olanzapine is metabolized by the CYP1A2 hepatic microsomal isoenzyme, and inducers of this enzyme, such as hydantoins, may increase olanzapine clearance. Clinicians should monitor for reduced effectiveness of the antipsychotic agent if hydantoin therapy is added.
Hydrochlorothiazide, HCTZ: (Moderate) Monitor for signs and symptoms of hyponatremia during concomitant diuretic and fluoxetine use; consider discontinuing fluoxetine if symptomatic hyponatremia occurs and institute appropriate medical intervention. Concomitant use increases the risk for developing hyponatremia.
Hydrochlorothiazide, HCTZ; Methyldopa: (Moderate) Monitor for signs and symptoms of hyponatremia during concomitant diuretic and fluoxetine use; consider discontinuing fluoxetine if symptomatic hyponatremia occurs and institute appropriate medical intervention. Concomitant use increases the risk for developing hyponatremia.
Hydrochlorothiazide, HCTZ; Moexipril: (Moderate) Monitor for signs and symptoms of hyponatremia during concomitant diuretic and fluoxetine use; consider discontinuing fluoxetine if symptomatic hyponatremia occurs and institute appropriate medical intervention. Concomitant use increases the risk for developing hyponatremia. (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.
Hydrocodone: (Major) Concomitant use of opioid agonists with olanzapine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with olanzapine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Also monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. Avoid prescribing opioid cough medication in patients taking olanzapine. (Moderate) Careful monitoring, particularly during treatment initiation and dose adjustment, is recommended during coadministration of hydrocodone and fluoxetine because of the potential risk of serotonin syndrome and prolonged opioid adverse reactions. Discontinue hydrocodone if serotonin syndrome is suspected. It is recommended to avoid this combination when hydrocodone is being used for cough. Concomitant use of hydrocodone with fluoxetine may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. Monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of fluoxetine could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If fluoxetine is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP2D6. Fluoxetine is a strong inhibitor of CYP2D6.
Hydrocodone; Ibuprofen: (Major) Concomitant use of opioid agonists with olanzapine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with olanzapine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Also monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. Avoid prescribing opioid cough medication in patients taking olanzapine. (Moderate) Careful monitoring, particularly during treatment initiation and dose adjustment, is recommended during coadministration of hydrocodone and fluoxetine because of the potential risk of serotonin syndrome and prolonged opioid adverse reactions. Discontinue hydrocodone if serotonin syndrome is suspected. It is recommended to avoid this combination when hydrocodone is being used for cough. Concomitant use of hydrocodone with fluoxetine may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. Monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of fluoxetine could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If fluoxetine is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP2D6. Fluoxetine is a strong inhibitor of CYP2D6.
Hydrocodone; Pseudoephedrine: (Major) Concomitant use of opioid agonists with olanzapine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with olanzapine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Also monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. Avoid prescribing opioid cough medication in patients taking olanzapine. (Moderate) Careful monitoring, particularly during treatment initiation and dose adjustment, is recommended during coadministration of hydrocodone and fluoxetine because of the potential risk of serotonin syndrome and prolonged opioid adverse reactions. Discontinue hydrocodone if serotonin syndrome is suspected. It is recommended to avoid this combination when hydrocodone is being used for cough. Concomitant use of hydrocodone with fluoxetine may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. Monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of fluoxetine could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If fluoxetine is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP2D6. Fluoxetine is a strong inhibitor of CYP2D6.
Hydromorphone: (Major) Concomitant use of opioid agonists with olanzapine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with olanzapine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Also monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. (Major) Fluoxetine may inhibit the metabolism of hydromorphone. Clinicians should be alert for an exaggerated opiate response if hydromorphone is given with fluoxetine.
Hydroxychloroquine: (Major) Concomitant use of hydroxychloroquine and fluoxetine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. (Major) Concomitant use of olanzapine and hydroxychloroquine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Hydroxyzine: (Moderate) Caution is recommended if hydroxyzine is administered with olanzapine due to the potential for additive QT prolongation and risk of torsade de pointes (TdP). In addition, because hydroxyzine causes pronounced sedation, an enhanced CNS depressant effect may occur when it is combined with other CNS depressants including olanzapine. Postmarketing data indicate that hydroxyzine causes QT prolongation and TdP. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval. (Moderate) Concomitant use of hydroxyzine and fluoxetine may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP.
Hyoscyamine: (Moderate) Additive anticholinergic effects may be seen when olanzapine and anticholinergics are used concomitantly; use with caution. Use of olanzapine and other drugs with anticholinergic activity can increase the risk for severe gastrointestinal adverse reactions related to hypomotility. Olanzapine exhibits anticholinergic activity. Adverse effects may be seen not only on GI smooth muscle, but also on bladder function, the CNS, the eye, and temperature regulation. Additive drowsiness may also occur, depending on the anticholinergic agent used.
Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate; Sodium Biphosphate: (Contraindicated) According to the manufacturer of fluoxetine, treatment initiation with fluoxetine is contraindicated in patients currently receiving intravenous (IV) methylene blue due to an increased risk of serotonin syndrome. If urgent psychiatric treatment is required, interventions other than fluoxetine (e.g., alternative medication, hospitalization) should be considered. Conversely, in patients receiving fluoxetine and requiring urgent treatment with IV methylene blue, fluoxetine should be discontinued immediately and methylene blue therapy initiated only if acceptable alternatives are not available and the potential benefits outweigh the risks. The patient should be monitored for serotonin syndrome for 5 weeks or until 24 hours after the last dose of methylene blue, whichever comes first. Fluoxetine may be re-initiated 24 hours after the last dose of methylene blue. Results from an in vitro study indicate that methylene blue is a potent, reversible inhibitor of the monoamine oxidase type A enzyme (MAO-A). MAO-A is responsible for the metabolism of serotonin; therefore, concurrent use of an MAO-A inhibitor with a serotonergic agent may result in a clinically significant interaction. Cases of serotonin syndrome have been reported, primarily following administration of standard infusions of methylene blue (1 to 8 mg/kg) as a visualizing agent, in patients receiving SSRIs, serotonin/norepinephrine reuptake inhibitors, or clomipramine. It is not known if patients receiving other serotonergic psychiatric agents with IV methylene blue are at a comparable risk or if methylene blue administered by other routes (e.g., orally, local injection) or in doses less than 1 mg/kg IV can produce a similar outcome. One case describes a patient receiving citalopram who experienced agitation, restlessness, pupil dilation with sluggish response to light, myoclonic movements of the lower limbs, and brisk reflexes following an infusion of methylene blue, while another patient receiving paroxetine developed tachycardia, agitation, dystonia and abnormal eye movements. During a retrospective study of 193 surgical patients who had received a methylene blue injection, it was found that all 12 of the patients who experienced postoperative neurological sequelae had been taking a serotonin reuptake inhibitor preoperatively. One of the 12 patients experienced cardiopulmonary arrest and died. Of the remaining 181 patients who did not experience neurological sequelae, 8.8% were taking a serotonin reuptake inhibitor. Published interaction reports between IV methylene blue and serotonergic psychiatric agents have documented symptoms including lethargy, confusion, delirium, agitation, aggression, obtundation, myoclonus, expressive aphasia, hypertonia, pyrexia, elevated blood pressure, seizures, and coma. Signs and symptoms of serotonin syndrome include fever, diaphoresis, shivering, myoclonus, tremor, tachycardia, diarrhea, nausea, headache, incoordination, mental status changes (e.g., agitation, confusion), hyperreflexia, seizures, and coma. (Moderate) Additive anticholinergic effects may be seen when olanzapine and anticholinergics are used concomitantly; use with caution. Use of olanzapine and other drugs with anticholinergic activity can increase the risk for severe gastrointestinal adverse reactions related to hypomotility. Olanzapine exhibits anticholinergic activity. Adverse effects may be seen not only on GI smooth muscle, but also on bladder function, the CNS, the eye, and temperature regulation. Additive drowsiness may also occur, depending on the anticholinergic agent used. (Moderate) The combined use of selective serotonin reuptake inhibitors (SSRIs) and aspirin, ASA or other salicylates which affect hemostasis may elevate the risk for an upper GI bleed. SSRIs may inhibit serotonin uptake by platelets, augmenting the antiplatelet effects of aspirin.
Ibuprofen; Oxycodone: (Major) Concomitant use of opioid agonists with olanzapine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with olanzapine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Also monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. (Moderate) If concomitant use of oxycodone and fluoxetine is warranted, monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
Ibutilide: (Major) Concomitant use of ibutilide and fluoxetine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. (Major) Ibutilide administration can cause QT prolongation and torsades de pointes (TdP); proarrhythmic events should be anticipated. The potential for proarrhythmic events with ibutilide increases with the coadministration of other drugs that prolong the QT interval, such as olanzapine. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval in rare instances.
Ifosfamide: (Moderate) Monitor for a decrease in the efficacy of ifosfamide if coadministration with fluoxetine is necessary. Ifosfamide is metabolized by CYP3A4 to its active alkylating metabolites. Fluoxetine is a weak CYP3A4 inhibitor, but its metabolite norfluoxetine is a moderate inhibitor of CYP3A4. Coadministration may decrease plasma concentrations of these active metabolites, decreasing the effectiveness of ifosfamide treatment.
Iloperidone: (Major) Avoid coadministration of fluoxetine and iloperidone due to the potential for additive QT prolongation and risk of torsade de pointes (TdP); iloperidone levels may also be increased. If concomitant use is necessary, reduce the iloperidone dose by one-half. If fluoxetine is discontinued, increase the iloperidone dose to the previous level. Iloperidone is a CYP2D6 substrate that has been associated with QT prolongation. Fluoxetine is a strong inhibitor of CYP2D6; QT prolongation and TdP have been reported in patients treated with fluoxetine. Coadministration of fluoxetine increased the AUC of iloperidone and its metabolite P88, by about 2- to 3-fold, and decreased the AUC of its metabolite P95 by one-half. (Major) Iloperidone has been associated with QT prolongation; however, torsade de pointes (TdP) has not been reported. According to the manufacturer, since iloperidone may prolong the QT interval, it should be avoided in combination with other agents also known to have this effect, such as olanzapine. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval in rare instances. In addition, coadministration may increase the risk of adverse effects such as drowsiness, dizziness, orthostatic hypotension, anticholinergic effects, extrapyramidal symptoms, neuroleptic malignant syndrome, or seizures. The likelihood of these pharmacodynamic interactions varies based upon the individual properties of the co-administered antipsychotic agent. Although the incidence of tardive dyskinesia from combination antipsychotic therapy has not been established and data are very limited, the risk appears to be increased during use of a conventional and atypical antipsychotic versus use of a conventional antipsychotic alone.
Iloprost: (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.
Imatinib: (Moderate) Agents that inhibit cytochrome P450 3A4, such as fluoxetine, may decrease imatinib, STI-571 metabolism and increase concentrations leading to toxicity.
Imipramine: (Moderate) Coadministration of fluoxetine and imipramine may increase the risk for QT prolongation, torsade de pointes (TdP), and serotonin syndrome. If serotonin syndrome is suspected, discontinue fluoxetine and concurrent serotonergic agents and initiate appropriate medical treatment. QT prolongation and TdP have been reported in patients treated with fluoxetine. Tricyclics, particularly at elevated concentrations, are associated with a possible risk of QT prolongation and TdP.
Incretin Mimetics: (Moderate) Monitor blood glucose during concomitant atypical antipsychotic and incretin mimetic use. Atypical antipsychotic therapy may aggravate diabetes mellitus. Atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition. (Moderate) Monitor blood glucose during concomitant incretin mimetic and fluoxetine use; an incretin mimetic dose adjustment may be necessary. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
Indacaterol; Glycopyrrolate: (Moderate) Additive anticholinergic effects may be seen when olanzapine and anticholinergics are used concomitantly; use with caution. Use of olanzapine and other drugs with anticholinergic activity can increase the risk for severe gastrointestinal adverse reactions related to hypomotility. Olanzapine exhibits anticholinergic activity. Adverse effects may be seen not only on GI smooth muscle, but also on bladder function, the CNS, the eye, and temperature regulation. Additive drowsiness may also occur, depending on the anticholinergic agent used.
Indapamide: (Moderate) Monitor for signs and symptoms of hyponatremia during concomitant diuretic and fluoxetine use; consider discontinuing fluoxetine if symptomatic hyponatremia occurs and institute appropriate medical intervention. Concomitant use increases the risk for developing hyponatremia.
Inotuzumab Ozogamicin: (Major) Avoid coadministration of inotuzumab ozogamicin with fluoxetine due to the potential for additive QT interval prolongation and risk of torsade de pointes (TdP). If coadministration is unavoidable, obtain an ECG and serum electrolytes prior to the start of treatment, after treatment initiation, and periodically during treatment. Inotuzumab has been associated with QT interval prolongation. QT prolongation and TdP have been reported in patients treated with fluoxetine. (Major) Avoid coadministration of inotuzumab ozogamicin with olanzapine due to the potential for additive QT prolongation and risk of torsade de pointes (TdP). If coadministration is unavoidable, obtain an ECG and serum electrolytes prior to the start of treatment, after treatment initiation, and periodically during treatment. Inotuzumab has been associated with QT interval prolongation. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval.
Insulin Degludec; Liraglutide: (Moderate) Monitor blood glucose during concomitant atypical antipsychotic and incretin mimetic use. Atypical antipsychotic therapy may aggravate diabetes mellitus. Atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition. (Moderate) Monitor blood glucose during concomitant incretin mimetic and fluoxetine use; an incretin mimetic dose adjustment may be necessary. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
Insulin Glargine; Lixisenatide: (Moderate) Monitor blood glucose during concomitant atypical antipsychotic and incretin mimetic use. Atypical antipsychotic therapy may aggravate diabetes mellitus. Atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition. (Moderate) Monitor blood glucose during concomitant incretin mimetic and fluoxetine use; an incretin mimetic dose adjustment may be necessary. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
Insulins: (Moderate) Monitor blood glucose during concomitant atypical antipsychotic and insulin use. Atypical antipsychotic therapy may aggravate diabetes mellitus. Atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition. (Moderate) Monitor blood glucose during concomitant insulin and fluoxetine use; an insulin dose adjustment may be necessary. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
Iobenguane I 123: (Major) Discontinue medications that decrease norepinephrine uptake, s uch as selective serotonin reuptake inhibitors (SSRIs), for at least 5 biological half-lives prior to iobenguane I 123 administration. Consider medication tapering or additional supportive therapy as appropriate to minimize the risk for precipitating SSRI withdrawal symptoms. Medications that decrease the uptake of norepinephrine can cause false negative imaging results. Increasing the dose of iobenguane I 123 will not overcome any potential uptake limiting effect of this medication.
Irbesartan: (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.
Irbesartan; Hydrochlorothiazide, HCTZ: (Moderate) Monitor for signs and symptoms of hyponatremia during concomitant diuretic and fluoxetine use; consider discontinuing fluoxetine if symptomatic hyponatremia occurs and institute appropriate medical intervention. Concomitant use increases the risk for developing hyponatremia. (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.
Isavuconazonium: (Moderate) Concomitant use of isavuconazonium with fluoxetine may result in increased serum concentrations of isavuconazonium. Isavuconazole, the active moiety of isavuconazonium, is a sensitive substrate of the hepatic isoenzyme CYP3A4; fluoxetine is an inhibitor of this enzyme. Caution and close monitoring are advised if these drugs are used together.
Isocarboxazid: (Contraindicated) Due to the risk of serotonin syndrome, monoamine oxidase inhibitors (MAOIs) intended to treat psychiatric disorders are contraindicated for use with selective serotonin reuptake inhibitors (SSRIs). MAOIs should not be used within 5 weeks of discontinuing treatment with fluoxetine or within 14 days of discontinuing treatment with other SSRIs. Conversely, SSRIs should not be initiated within 14 days of stopping an MAOI. Monitor the patient for serotonin-related effects during therapy transitions.
Isoflurane: (Major) Concomitant use of halogenated anesthetics and fluoxetine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Isoniazid, INH: (Major) Concurrent use of isoniazid and selective serotonin reuptake inhibitors (SSRIs) should be avoided if possible. Isoniazid is chemically related to iproniazid, a drug that was known to possess MAO inhibiting activity. Although isoniazid does not inhibit mitochondrial MAO, it does appear to inhibit plasma MAO. Isoniazid may possess enough MAO inhibiting activity to produce clinical symptoms consistent with serotonergic excess when combined with SSRIs. Concurrent use of SSRIs and MAOIs may lead to serious reactions including serotonin syndrome or neuroleptic malignant syndrome-like reactions. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. If combination therapy is necessary, patients should be monitored for the emergence of serotonin syndrome or neuroleptic malignant syndrome-like reactions.
Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Major) Concurrent use of isoniazid and selective serotonin reuptake inhibitors (SSRIs) should be avoided if possible. Isoniazid is chemically related to iproniazid, a drug that was known to possess MAO inhibiting activity. Although isoniazid does not inhibit mitochondrial MAO, it does appear to inhibit plasma MAO. Isoniazid may possess enough MAO inhibiting activity to produce clinical symptoms consistent with serotonergic excess when combined with SSRIs. Concurrent use of SSRIs and MAOIs may lead to serious reactions including serotonin syndrome or neuroleptic malignant syndrome-like reactions. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. If combination therapy is necessary, patients should be monitored for the emergence of serotonin syndrome or neuroleptic malignant syndrome-like reactions. (Moderate) Monitor for reduced olanzapine efficacy if rifampin coadministration is medically necessary; in some patients, dosage adjustments may be needed. Olanzapine is metabolized by the CYP1A2 hepatic microsomal isoenzyme, and potent inducers of this enzyme increase olanzapine clearance. While rifampin is a CYP3A inducer, it is likely its induction of CYP1A2 is responsible for the increased olanzapine clearance, and roughly 48% decrease in olanzapine AUC (exposure) seen when rifampin is used with olanzapine.
Isoniazid, INH; Rifampin: (Major) Concurrent use of isoniazid and selective serotonin reuptake inhibitors (SSRIs) should be avoided if possible. Isoniazid is chemically related to iproniazid, a drug that was known to possess MAO inhibiting activity. Although isoniazid does not inhibit mitochondrial MAO, it does appear to inhibit plasma MAO. Isoniazid may possess enough MAO inhibiting activity to produce clinical symptoms consistent with serotonergic excess when combined with SSRIs. Concurrent use of SSRIs and MAOIs may lead to serious reactions including serotonin syndrome or neuroleptic malignant syndrome-like reactions. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. If combination therapy is necessary, patients should be monitored for the emergence of serotonin syndrome or neuroleptic malignant syndrome-like reactions. (Moderate) Monitor for reduced olanzapine efficacy if rifampin coadministration is medically necessary; in some patients, dosage adjustments may be needed. Olanzapine is metabolized by the CYP1A2 hepatic microsomal isoenzyme, and potent inducers of this enzyme increase olanzapine clearance. While rifampin is a CYP3A inducer, it is likely its induction of CYP1A2 is responsible for the increased olanzapine clearance, and roughly 48% decrease in olanzapine AUC (exposure) seen when rifampin is used with olanzapine.
Isradipine: (Moderate) Fluoxetine may decrease the clearance of calcium-channel blockers, including isradipine, via inhibition of CYP3A4 metabolism.
Itraconazole: (Moderate) Concomitant use of fluoxetine and itraconazole may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP. (Moderate) Use itraconazole with caution in combination with olanzapine as concurrent use may increase the risk of QT prolongation. Itraconazole has been associated with prolongation of the QT interval. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval.
Ivacaftor: (Minor) Although an interaction between ivacaftor and fluoxetine is possible, the clinical impact of this interaction has not yet been determined. Increased monitoring is recommended if ivacaftor is administered concurrently with CYP2C9 substrates. Fluoxetine is partially metabolized by CYP2C9, but it is also a substrate for at least 2 other enzymes. In vitro studies showed ivacaftor to be a weak inhibitor of CYP2C9. Co-administration may possibly lead to increased exposure to fluoxetine; however, because fluoxetine has multiple metabolic pathways, the clinical impact of this inhibition is not clear. In addition, ivacaftor is a CYP3A substrate, and fluoxetine is a mild CYP3A inhibitor. Co-administration may lead to increased ivacaftor exposure.
Ivosidenib: (Major) Avoid coadministration of ivosidenib with fluoxetine due to an increased risk of QT prolongation. If concomitant use is unavoidable, monitor ECGs for QTc prolongation and monitor electrolytes; correct any electrolyte abnormalities as clinically appropriate. An interruption of therapy and dose reduction of ivosidenib may be necessary if QT prolongation occurs. Prolongation of the QTc interval and ventricular arrhythmias have been reported in patients treated with ivosidenib. QT prolongation and torsade de pointes (TdP) have been reported in patients treated with fluoxetine. (Major) Avoid coadministration of ivosidenib with olanzapine due to an increased risk of QT prolongation. If concomitant use is unavoidable, monitor ECGs for QTc prolongation and monitor electrolytes; correct any electrolyte abnormalities as clinically appropriate. An interruption of therapy and dose reduction of ivosidenib may be necessary if QT prolongation occurs. Prolongation of the QTc interval and ventricular arrhythmias have been reported in patients treated with ivosidenib. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval.
Ketoconazole: (Contraindicated) Avoid concomitant use of ketoconazole and fluoextine due to an increased risk for torsade de pointes (TdP) and QT/QTc prolongation. Ketoconazole has a known risk for QT prolongation and torsade de pointes (TdP). Postmarketing cases of QT interval prolongation and ventricular arrhythmia including TdP have been reported in patients treated with fluoxetine. (Contraindicated) Avoid concomitant use of ketoconazole and olanzapine due to an increased risk for torsade de pointes (TdP) and QT/QTc prolongation.
Labetalol: (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.
Lansoprazole; Amoxicillin; Clarithromycin: (Major) Concomitant use of clarithromycin and fluoxetine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. (Major) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering clarithromycin with olanzapine. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval in rare instances. Additionally, clarithromycin is associated with an established risk for QT prolongation and TdP.
Lapatinib: (Moderate) Concomitant use of fluoxetine and lapatinib may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP. (Moderate) Monitor for evidence of QT prolongation if lapatinib is administered with olanzapine. Lapatinib has been associated with concentration-dependent QT prolongation; ventricular arrhythmias and torsade de pointes (TdP) have been reported in postmarketing experience with lapatinib. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval.
Lasmiditan: (Moderate) Monitor for excessive sedation, somnolence, and serotonin syndrome during coadministration of lasmiditan and olanzapine. Inform patients taking this combination of the risks and symptoms of excessive CNS depression and serotonin syndrome, particularly after a dose increase or the addition of other serotonergic medications to an existing regimen. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. (Moderate) Serotonin syndrome may occur during coadministration of lasmiditan and selective serotonin reuptake inhibitors. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome, particularly after a dose increase or the addition of other serotonergic medications to an existing regimen. Discontinue all serotonergic agents if serotonin syndrome occurs and implement appropriate medical management.
Lefamulin: (Major) Avoid coadministration of lefamulin with fluoxetine as concurrent use may increase the risk of QT prolongation. If coadministration cannot be avoided, monitor ECG during treatment. Lefamulin has a concentration dependent QTc prolongation effect. The pharmacodynamic interaction potential to prolong the QT interval of the electrocardiogram between lefamulin and other drugs that effect cardiac conduction is unknown. QT prolongation and torsade de pointes (TdP) have been reported in patients treated with fluoxetine. (Major) Avoid coadministration of lefamulin with olanzapine as concurrent use may increase the risk of QT prolongation. If coadministration cannot be avoided, monitor ECG during treatment. Lefamulin has a concentration dependent QTc prolongation effect. The pharmacodynamic interaction potential to prolong the QT interval of the electrocardiogram between lefamulin and other drugs that effect cardiac conduction is unknown. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval.
Lemborexant: (Major) Limit the dose of lemborexant to a maximum of 5 mg PO once daily if coadministered with fluoxetine as concurrent use may increase lemborexant exposure and the risk of adverse effects. Lemborexant is a CYP3A4 substrate; fluoxetine is a weak CYP3A4 inhibitor and one metabolite, norfluoxetine, is a moderate CYP3A4 inhibitor. Coadministration of lemborexant with a weak CYP3A4 inhibitor is predicted to increase lemborexant exposure by less than 2-fold. (Moderate) Monitor for excessive sedation and somnolence during coadministration of lemborexant and atypical antipsyhotics. Dosage adjustments of lemborexant and the atypical antipsychotic may be necessary when administered together because of potentially additive CNS effects. The risk of next-day impairment, including impaired driving, is increased if lemborexant is taken with other CNS depressants.
Lenvatinib: (Major) Avoid coadministration of lenvatinib with olanzapine due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval. (Major) Concomitant use of lenvatinib and fluoxetine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Lesinurad: (Moderate) Use lesinurad and fluoxetine together with caution; fluoxetine may increase the systemic exposure of lesinurad. Fluoxetine is a mild inhibitor of CYP2C9, and lesinurad is a CYP2C9 substrate.
Lesinurad; Allopurinol: (Moderate) Use lesinurad and fluoxetine together with caution; fluoxetine may increase the systemic exposure of lesinurad. Fluoxetine is a mild inhibitor of CYP2C9, and lesinurad is a CYP2C9 substrate.
Leuprolide: (Major) Avoid coadministration of leuprolide with olanzapine due to the risk of reduced efficacy of leuprolide; QT prolongation may also occur. Olanzapine can cause hyperprolactinemia, which reduces the number of pituitary gonadotropin releasing hormone (GnRH) receptors; leuprolide is a GnRH analog. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval. Androgen deprivation therapy (i.e., leuprolide) may also prolong the QT/QTc interval. (Moderate) Concomitant use of fluoxetine and androgen deprivation therapy (i.e., leuprolide) may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP.
Leuprolide; Norethindrone: (Major) Avoid coadministration of leuprolide with olanzapine due to the risk of reduced efficacy of leuprolide; QT prolongation may also occur. Olanzapine can cause hyperprolactinemia, which reduces the number of pituitary gonadotropin releasing hormone (GnRH) receptors; leuprolide is a GnRH analog. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval. Androgen deprivation therapy (i.e., leuprolide) may also prolong the QT/QTc interval. (Moderate) Concomitant use of fluoxetine and androgen deprivation therapy (i.e., leuprolide) may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP.
Levobunolol: (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.
Levocetirizine: (Moderate) Monitor for unusual drowsiness and sedation during coadministration of atypical antipsychotics and cetirizine due to the risk for additive CNS depression.
Levodopa: (Moderate) Monitor for movement disorders, unusual changes in moods or behavior, and diminished effectiveness of the atypical antipsychotic or levodopa during coadministration. Due to mutually opposing effects on dopamine, atypical antipsychotics and levodopa may interfere with the effectiveness of each other. In general, atypical antipsychotics are less likely to interfere with levodopa and other antiparkinson's treatments than traditional antipsychotics.
Levofloxacin: (Moderate) Concomitant use of levofloxacin and fluoxetine may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP. (Moderate) Concomitant use of levofloxacin and olanzapine may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP.
Levoketoconazole: (Contraindicated) Avoid concomitant use of ketoconazole and fluoextine due to an increased risk for torsade de pointes (TdP) and QT/QTc prolongation. Ketoconazole has a known risk for QT prolongation and torsade de pointes (TdP). Postmarketing cases of QT interval prolongation and ventricular arrhythmia including TdP have been reported in patients treated with fluoxetine. (Contraindicated) Avoid concomitant use of ketoconazole and olanzapine due to an increased risk for torsade de pointes (TdP) and QT/QTc prolongation.
Levomefolate: (Minor) Levomefolate and fluoxetine should be used together cautiously. Fluoxetine is a noncompetitive inhibitor of levomefolate active transport in the intestines. Monitor patients for decreased efficacy of levomefolate if these agents are used together.
Levomilnacipran: (Major) Because of the potential risk and severity of serotonin syndrome, concurrent use of levomilnacipran with other drugs that have serotonergic properties, such as selective serotonin reuptake inhibitors (SSRIs), should generally be avoided. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. If serotonin syndrome is suspected, levomilnacipran and concurrent serotonergic agents should be discontinued.
Levorphanol: (Major) Concomitant use of opioid agonists with olanzapine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with olanzapine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Reduce the initial dose of levorphanol by approximately 50% or more. Also monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. (Major) Fluoxetine may inhibit the metabolism of levorphanol. Clinicians should be alert for an exaggerated opiate response if levorphanol is given with fluoxetine.
Lidocaine: (Moderate) Concomitant use of systemic lidocaine and fluoxetine may increase lidocaine plasma concentrations by decreasing lidocaine clearance and therefore prolonging the elimination half-life. Monitor for lidocaine toxicity if used together. Lidocaine is a CYP3A4 and CYP1A2 substrate; fluoxetine inhibits CYP3A4.
Lidocaine; Epinephrine: (Moderate) Concomitant use of systemic lidocaine and fluoxetine may increase lidocaine plasma concentrations by decreasing lidocaine clearance and therefore prolonging the elimination half-life. Monitor for lidocaine toxicity if used together. Lidocaine is a CYP3A4 and CYP1A2 substrate; fluoxetine inhibits CYP3A4. (Moderate) Olanzapine may induce significant alpha-adrenergic blockade in overdose, leading to profound hypotension. Do not use epinephrine, dopamine, or other sympathomimetics with beta-agonist activity since the beta-stimulation may worsen hypotension in the setting of olanzapine overdose.
Lidocaine; Prilocaine: (Moderate) Concomitant use of systemic lidocaine and fluoxetine may increase lidocaine plasma concentrations by decreasing lidocaine clearance and therefore prolonging the elimination half-life. Monitor for lidocaine toxicity if used together. Lidocaine is a CYP3A4 and CYP1A2 substrate; fluoxetine inhibits CYP3A4.
Linagliptin: (Moderate) Monitor blood glucose during concomitant atypical antipsychotic and dipeptidyl peptidase-4 (DPP-4) inhibitor use. Atypical antipsychotic therapy may aggravate diabetes mellitus. Atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition. (Moderate) Monitor blood glucose during concomitant dipeptidyl peptidase-4 (DPP-4) inhibitor and fluoxetine use; a DPP-4 inhibitor dose adjustment may be necessary. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
Linagliptin; Metformin: (Moderate) Monitor blood glucose during concomitant atypical antipsychotic and dipeptidyl peptidase-4 (DPP-4) inhibitor use. Atypical antipsychotic therapy may aggravate diabetes mellitus. Atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition. (Moderate) Monitor blood glucose during concomitant atypical antipsychotic and metformin use. Atypical antipsychotic therapy may aggravate diabetes mellitus. Atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition. (Moderate) Monitor blood glucose during concomitant dipeptidyl peptidase-4 (DPP-4) inhibitor and fluoxetine use; a DPP-4 inhibitor dose adjustment may be necessary. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia. (Moderate) Monitor blood glucose during concomitant metformin and fluoxetine use; a metformin dose adjustment may be necessary. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
Linezolid: (Contraindicated) According to the manufacturer of fluoxetine, treatment initiation with fluoxetine is contraindicated in patients currently receiving linezolid due to an increased risk of serotonin syndrome. If urgent psychiatric treatment is required, interventions other than fluoxetine (e.g., alternative medication, hospitalization) should be considered. Conversely, in patients receiving fluoxetine and requiring urgent treatment with linezolid, fluoxetine should be discontinued immediately and linezolid therapy initiated only if acceptable alternatives are not available and the potential benefits of linezolid outweigh the risks. The patient should be monitored for serotonin syndrome for five weeks or until 24 hours after the last dose of linezolid, whichever comes first. Fluoxetine may be re-initiated 24 hours after the last dose of linezolid. Linezolid is an antibiotic that is also a non-selective monoamine oxidase (MAO) inhibitor. Since monoamine oxidase type A deaminates serotonin, administration of a non-selective MAO inhibitor concurrently with fluoxetine can lead to serious reactions including serotonin syndrome or neuroleptic malignant syndrome-like reactions. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. Serotonin syndrome has been reported in patients receiving either citalopram, escitalopram, fluoxetine, or paroxetine in combination with linezolid.
Liraglutide: (Moderate) Monitor blood glucose during concomitant atypical antipsychotic and incretin mimetic use. Atypical antipsychotic therapy may aggravate diabetes mellitus. Atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition. (Moderate) Monitor blood glucose during concomitant incretin mimetic and fluoxetine use; an incretin mimetic dose adjustment may be necessary. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
Lisinopril: (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.
Lisinopril; Hydrochlorothiazide, HCTZ: (Moderate) Monitor for signs and symptoms of hyponatremia during concomitant diuretic and fluoxetine use; consider discontinuing fluoxetine if symptomatic hyponatremia occurs and institute appropriate medical intervention. Concomitant use increases the risk for developing hyponatremia. (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.
Lithium: (Moderate) Coadministration of fluoxetine and lithium may increase the risk for QT prolongation and serotonin syndrome. Concurrent use of fluoxetine with lithium has also resulted in both increased and decreased serum lithium concentrations; patients should be monitored closely. QT prolongation has been reported in patients treated with fluoxetine and lithium has also been associated with QT prolongation. Lithium is an effective augmenting agent to antidepressants in treatment-resistant depression; however, lithium has central serotonin-enhancing effects and may increase the risk of serotonin syndrome when combined with selective serotonin reuptake inhibitors (SSRIs) such as fluoxetine. Inform patients of the possible increased risk and monitor for serotonin syndrome, particularly during treatment initiation and dosage increases. If serotonin syndrome occurs, serotonergic agents should be discontinued and symptomatic treatment should be initiated. (Moderate) Olanzapine and lithium are associated with QT prolongation. Coadministration may increase the risk of QT prolongation; therefore, olanzapine and lithium should be coadministered with caution and close monitoring. Some atypical antipsychotics, including olanzapine, are indicated as adjunctive therapy to mood stabilizers such as lithium. However, it is advisable to monitor patients for neurotoxicity during co-administration. Neuroleptic malignant syndrome (NMS) has been observed occasionally during concurrent use of lithium and either atypical or conventional antipsychotics. Additive extrapyramidal effects have also been noted. Early case reports described an encephalopathic syndrome consisting of delirium, tremulousness, dyskinesia, seizures, leukocytosis, weakness, hyperpyrexia, confusion, extrapyramidal symptoms, elevations in laboratory values (e.g., liver function tests, blood urea nitrogen, fasting blood sugar) and, in some cases, irreversible brain damage, during use of lithium and conventional antipsychotics, particularly haloperidol. Subsequent rare reports of NMS or NMS-like reactions have been described during co-administration of lithium and atypical antipsychotics (e.g., risperidone, olanzapine, clozapine). Following resolution of NMS, there are isolated instances of re-emergence of symptoms following re-initiation of lithium as monotherapy. Lithium may be a risk factor for antipsychotic-induced NMS; however, this hypothesis has not been confirmed. In many reported cases, confounding factors have been present (e.g., previous history of NMS, high dose therapy). The ability of antipsychotics alone to precipitate NMS and the rarity of the condition further complicate assessment of lithium as a risk factor. Olanzapine does not influence the pharmacokinetics of lithium.
Lixisenatide: (Moderate) Monitor blood glucose during concomitant atypical antipsychotic and incretin mimetic use. Atypical antipsychotic therapy may aggravate diabetes mellitus. Atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition. (Moderate) Monitor blood glucose during concomitant incretin mimetic and fluoxetine use; an incretin mimetic dose adjustment may be necessary. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
Lofexidine: (Major) Monitor ECG for QT prolongation and monitor for orthostatic hypotension and bradycardia during concurrent use of lofexidine and fluoxetine. Coadministration may increase lofexidine exposure. Lofexidine is a CYP2D6 substrate that prolongs the QT interval. In addition, there are postmarketing reports of TdP. Fluoxetine is a CYP2D6 inhibitor associated with an established risk of QT prolongation and TdP. Coadministration with a strong CYP2D6 inhibitor increased the lofexidine AUC by 28%. (Moderate) Monitor ECG if lofexidine is coadministered with olanzapine due to the potential for additive QT prolongation. Additionally, monitor for excessive hypotension and sedation during coadministration as lofexidine can potentiate the effects of CNS depressants. Lofexidine prolongs the QT interval. In addition, there are postmarketing reports of torsade de pointes. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval.
Lomitapide: (Major) Concomitant use of lomitapide and fluoxetine may significantly increase the serum concentration of lomitapide. Therefore, the lomitapide dose should not exceed 30 mg/day PO during concurrent use. Fluoxetine is a weak CYP3A4 inhibitor; the exposure to lomitapide is increased by approximately 2-fold in the presence of weak CYP3A4 inhibitors.
Lonafarnib: (Major) Avoid coadministration of lonafarnib and fluoxetine; concurrent use may increase the exposure of lonafarnib and the risk of adverse effects. If coadministration is unavoidable, reduce to or continue lonafarnib at a dosage of 115 mg/m2 and closely monitor patients for lonafarnib-related adverse reactions. Resume previous lonafarnib dosage 14 days after discontinuing fluoxetine. Lonafarnib is a sensitive CYP3A4 and CYP2C9 substrate and fluoxetine is a weak CYP3A4 and CYP2C9 inhibitor.
Loop diuretics: (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.
Loperamide: (Moderate) Concomitant use of loperamide and fluoxetine may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP. (Moderate) Concomitant use of loperamide and olanzapine may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP.
Loperamide; Simethicone: (Moderate) Concomitant use of loperamide and fluoxetine may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP. (Moderate) Concomitant use of loperamide and olanzapine may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP.
Lopinavir; Ritonavir: (Major) Avoid coadministration of lopinavir with olanzapine due to the potential for additive QT prolongation. If use together is necessary, obtain a baseline ECG to assess initial QT interval and determine frequency of subsequent ECG monitoring, avoid any non-essential QT prolonging drugs, and correct electrolyte imbalances. Lopinavir is associated with QT prolongation. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval. (Major) Concomitant use of lopinavir and fluoxetine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. (Moderate) Monitor for increased fluoxetine-related adverse effects if coadministered with ritonavir. Concurrent use may result in increased fluoxetine exposure. Fluoxetine is a CYP2D6 substrate and ritonavir is a weak CYP2D6 inhibitor. (Moderate) Ritonavir may reduce olanzapine serum concentrations by approximately 50%; how this affects olanzapine efficacy, however, is not known. Ritonavir appears to induce olanzapine's metabolism by either CYP1A2 or glucuronide conjugation. If ritonavir and olanzapine are used concurrently, monitor for reduced olanzapine effect and adjust olanzapine dose as needed.
Lorazepam: (Major) Concurrent use of intramuscular olanzapine and parenteral benzodiazepines is not recommended due to the potential for adverse effects from the combination including excess sedation and/or cardiorespiratory depression. Although oral formulations of olanzapine and benzodiazepines may be used together, additive effects on respiratory depression and/or CNS depression are possible. Drugs that can cause CNS depression, if used concomitantly with olanzapine, can increase both the frequency and the intensity of adverse effects such as drowsiness, sedation, dizziness, and orthostatic hypotension. Besides ethanol, clinicians should use other anxiolytics, sedatives, and hypnotics cautiously with olanzapine.
Lorcaserin: (Major) Based on the mechanism of action of lorcaserin and the theoretical potential for serotonin syndrome, use with extreme caution in combination with other drugs that may affect the serotonergic neurotransmitter systems, including, selective serotonin reuptake inhibitors (SSRIs). Patients receiving this combination should be monitored for the emergence of serotonin syndrome or Neuroleptic Malignant Syndrome (NMS) like signs and symptoms.
Losartan: (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents. (Minor) Inhibitors of the hepatic CYP2C9 isoenzyme, such as fluoxetine, have potential to inhibit the conversion of losartan to its active metabolite. Monitor therapeutic response to individualize losartan dosage.
Losartan; Hydrochlorothiazide, HCTZ: (Moderate) Monitor for signs and symptoms of hyponatremia during concomitant diuretic and fluoxetine use; consider discontinuing fluoxetine if symptomatic hyponatremia occurs and institute appropriate medical intervention. Concomitant use increases the risk for developing hyponatremia. (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents. (Minor) Inhibitors of the hepatic CYP2C9 isoenzyme, such as fluoxetine, have potential to inhibit the conversion of losartan to its active metabolite. Monitor therapeutic response to individualize losartan dosage.
Low Molecular Weight Heparins: (Moderate) Monitor for signs and symptoms of bleeding during concomitant low molecular weight heparin and selective serotonin reuptake inhibitor (SSRI) use due to increased risk for bleeding. Serotonin release by platelets plays an important role in hemostasis. Epidemiological studies have demonstrated an association between use of psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper gastrointestinal bleeding. Altered anticoagulant effects, including increased bleeding, have been reported when SSRIs are coadministered with another anticoagulant.
Loxapine: (Moderate) Caution is advisable during concurrent use of antipsychotics, including loxapine and olanzapine. Coadministration may increase the risk of drowsiness, dizziness, orthostatic hypotension, anticholinergic effects, extrapyramidal symptoms, neuroleptic malignant syndrome, tardive dyskinesia, and seizures. Although the incidence of tardive dyskinesia from combination antipsychotic therapy has not been established and data are very limited, the risk appears to be increased during use of a conventional and atypical antipsychotic versus use of a conventional antipsychotic alone.
Lumacaftor; Ivacaftor: (Minor) Although an interaction between ivacaftor and fluoxetine is possible, the clinical impact of this interaction has not yet been determined. Increased monitoring is recommended if ivacaftor is administered concurrently with CYP2C9 substrates. Fluoxetine is partially metabolized by CYP2C9, but it is also a substrate for at least 2 other enzymes. In vitro studies showed ivacaftor to be a weak inhibitor of CYP2C9. Co-administration may possibly lead to increased exposure to fluoxetine; however, because fluoxetine has multiple metabolic pathways, the clinical impact of this inhibition is not clear. In addition, ivacaftor is a CYP3A substrate, and fluoxetine is a mild CYP3A inhibitor. Co-administration may lead to increased ivacaftor exposure.
Lumacaftor; Ivacaftor: (Minor) Concomitant use of fluoxetine and lumacaftor; ivacaftor may alter fluoxetine exposure; caution and close monitoring are advised if these drugs are used together. Fluoxetine is a substrate of CYP2C9 and CYP2C19. In vitro data suggest that lumacaftor; ivacaftor may induce CYP2C19 and induce and/or inhibit CYP2C9. Although induction of fluoxetine through the CYP2C19 pathway could potentially lead to decreased drug efficacy, the net effect of lumacaftor; ivacaftor on CYP2C9-mediated metabolism is not clear. Monitor the patient for decreased fluoxetine efficacy or increased or prolonged therapeutic effects and adverse events. Of note, norfluoxetine, the active metabolite of fluoxetine, is a moderate CYP3A inhibitor. Although lumacaftor; ivacaftor is a primary substrate of CYP3A, lumacaftor; ivacaftor dosage adjustment is not required.
Lumateperone: (Moderate) Coadministration of antipsychotics, such as lumateperone and olanzapine, may increase the risk of adverse effects such as drowsiness, dizziness, orthostatic hypotension, anticholinergic effects, extrapyramidal symptoms, neuroleptic malignant syndrome, or seizures. Although the incidence of tardive dyskinesia from antipsychotic combinations has not been established and data are very limited, the risk may be increased during combined use versus use of an antipsychotic alone.
Lurasidone: (Major) Similar to other antipsychotics, lurasidone administration has been associated with drowsiness, dizziness, orthostatic hypotension, extrapyramidal symptoms, neuroleptic malignant syndrome, and seizures. The risk of these adverse effects may be increased during concurrent use of lurasidone with other antipsychotics. The likelihood of these pharmacodynamic interactions varies based upon the individual properties of the co-administered antipsychotic agent. Although the incidence of tardive dyskinesia from combination antipsychotic therapy has not been established and data are very limited, the risk appears to be increased during use of a conventional and atypical antipsychotic versus use of a conventional antipsychotic alone. (Major) The metabolite of fluoxetine is a moderate CYP3A4 inhibitor and may decrease the clearance of CYP3A4 substrates such as lurasidone. Decreased metabolism of lurasidone may lead to clinically important adverse reactions that are associated with antipsychotic use, such as extrapyramidal symptoms. If a moderate inhibitor of CYP3A4 is being prescribed and lurasidone is added in an adult patient, the recommended starting dose of lurasidone is 20 mg/day and the maximum recommended daily dose of lurasidone is 80 mg/day. If a moderate CYP3A4 inhibitor is added to an existing lurasidone regimen, reduce the lurasidone dose to one-half of the original dose. Patients should be monitored for efficacy and toxicity. The effects of fluoxetine on the metabolism of interacting drugs may persist for several weeks after discontinuation of fluoxetine because of its long elimination half-life.
Macimorelin: (Major) Avoid concurrent administration of macimorelin with drugs that prolong the QT interval, such as fluoxetine. Use of these drugs together may increase the risk of developing torsade de pointes-type ventricular tachycardia. Sufficient washout time of drugs that are known to prolong the QT interval prior to administration of macimorelin is recommended. Treatment with macimorelin has been associated with an increase in the corrected QT (QTc) interval. QT prolongation and torsade de pointes (TdP) have been reported in patients treated with fluoxetine. (Major) Avoid concurrent administration of macimorelin with drugs that prolong the QT interval, such as olanzapine. Use of these drugs together may increase the risk of developing torsade de pointes-type ventricular tachycardia. Sufficient washout time of drugs that are known to prolong the QT interval prior to administration of macimorelin is recommended. Treatment with macimorelin has been associated with an increase in the corrected QT (QTc) interval. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval.
Magnesium Salicylate: (Moderate) Monitor for signs and symptoms of bleeding during concomitant magnesium salicylate and selective serotonin reuptake inhibitor (SSRI) use due to increased risk for bleeding. Serotonin release by platelets plays an important role in hemostasis. Epidemiological studies have demonstrated an association between use of psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper gastrointestinal bleeding.
Maprotiline: (Major) Coadministration may result in additive effects on the QT interval. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval. Maprotiline has also been reported to prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). Cases of long QT syndrome and torsade de pointes (TdP) tachycardia have been described with maprotiline use, but rarely occur when the drug is used alone in normal prescribed doses and in the absence of other known risk factors for QT prolongation. In addition, additive anticholinergic effects may be seen with coadministration. Clinicians should note that antimuscarinic effects might be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation. (Moderate) Concomitant use of fluoxetine and maprotiline may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP.
Maraviroc: (Minor) Use caution if coadministration of maraviroc with fluoxetine is necessary, due to a possible increase in maraviroc exposure. Maraviroc is a CYP3A substrate and fluoxetine is a weak CYP3A4 inhibitor. Monitor for an increase in adverse effects with concomitant use.
Mavacamten: (Contraindicated) Mavacamten is contraindicated for use with fluoxetine due to risk of heart failure due to systolic dysfunction. Concomitant use increases mavacamten exposure. Mavacamten is a CYP2C19 substrate and fluoxetine is a strong CYP2C19 inhibitor.
Mecamylamine: (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.
Meclizine: (Moderate) Meclizine is metabolized by CYP2D6, fluoxetine is a CYP2D6 inhibitor. Concomitant use may increase meclizine plasma concentrations which may intensify its sedative and anticholinergic effects. (Moderate) Olanzapine exhibits anticholinergic effects that may be clinically significant. Clinicians should keep this in mind when using antimuscarinics and other medications with anticholinergic activity in combination with olanzapine. Some medications exhibit additive anticholinergic effects include sedating H1-blockers. Olanzapine may also cause additive sedation with many of these drugs.
Mefloquine: (Moderate) Mefloquine should be used with caution in patients receiving olanzapine as concurrent use may increase the risk of QT prolongation. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval in rare instances. There is also evidence that the use of halofantrine after mefloquine causes significant lengthening of the QTc interval. Mefloquine alone has not been reported to cause QT prolongation. (Moderate) Use fluoxetine with caution in combination with mefloquine. Coadministration may increase the risk for QT prolongation and torsade de pointes (TdP). Additionally, fluoxetine may increase the systemic exposure of mefloquine due to CYP3A4 inhibition and increase the potential for mefloquine-related adverse reactions. QT prolongation and TdP have been reported in patients treated with fluoxetine. There is evidence that the use of halofantrine after mefloquine causes a significant lengthening of the QTc interval. Mefloquine alone has not been reported to cause QT prolongation. However, due to the lack of clinical data, mefloquine should be used with caution in patients receiving drugs that prolong the QT interval.
Meglitinides: (Moderate) Atypical antipsychotic therapy may aggravate diabetes mellitus and cause metabolic changes such as hyperglycemia. Monitor patients on antidiabetic agents for worsening glycemic control. The atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Aggravation of diabetes mellitus has been reported. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition. (Moderate) In patients with diabetes mellitus, fluoxetine may alter glycemic control. Hypoglycemia has occurred during fluoxetine therapy. Hyperglycemia has developed in patients with diabetes mellitus following discontinuation of the drug. The dosage of insulin and/or other antidiabetic agents may need to be adjusted when therapy with fluoxetine is instituted or discontinued.
Meperidine: (Major) Concomitant use of opioid agonists with olanzapine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with olanzapine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Also monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. (Moderate) Consider a reduced dose of meperidine with frequent monitoring for respiratory depression and sedation if concurrent use of fluoxetine is necessary; if fluoxetine is discontinued, meperidine plasma concentrations can decrease resulting in reduced efficacy and potential withdrawal syndrome in a patient who has developed physical dependence to meperidine. Meperidine is a substrate of CYP3A4, and fluoxetine and its metabolite, norfluoxetine, are weak and moderate CYP3A4 inhibitors, respectively. Concomitant use with fluoxetine can increase meperidine exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of meperidine. Also monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
Meprobamate: (Moderate) The CNS-depressant effects of meprobamate can be potentiated with concomitant administration of other drugs known to cause CNS depression including antipsychotics.
Metaxalone: (Moderate) Concomitant use of selective serotonin reuptake inhibitors (SSRIs) and metaxalone may increase the risk for serotonin syndrome. Monitor patients for serotonin syndrome if concomitant use is necessary.
Metformin: (Moderate) Monitor blood glucose during concomitant atypical antipsychotic and metformin use. Atypical antipsychotic therapy may aggravate diabetes mellitus. Atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition. (Moderate) Monitor blood glucose during concomitant metformin and fluoxetine use; a metformin dose adjustment may be necessary. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
Metformin; Repaglinide: (Moderate) Atypical antipsychotic therapy may aggravate diabetes mellitus and cause metabolic changes such as hyperglycemia. Monitor patients on antidiabetic agents for worsening glycemic control. The atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Aggravation of diabetes mellitus has been reported. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition. (Moderate) Monitor blood glucose during concomitant atypical antipsychotic and metformin use. Atypical antipsychotic therapy may aggravate diabetes mellitus. Atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition. (Moderate) Monitor blood glucose during concomitant metformin and fluoxetine use; a metformin dose adjustment may be necessary. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
Metformin; Rosiglitazone: (Moderate) Atypical antipsychotic therapy may aggravate diabetes mellitus and cause metabolic changes such as hyperglycemia. Monitor patients on antidiabetic agents for worsening glycemic control. Atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Aggravation of diabetes mellitus has been reported. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition. (Moderate) Monitor blood glucose during concomitant atypical antipsychotic and metformin use. Atypical antipsychotic therapy may aggravate diabetes mellitus. Atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition. (Moderate) Monitor blood glucose during concomitant metformin and fluoxetine use; a metformin dose adjustment may be necessary. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
Metformin; Saxagliptin: (Moderate) Monitor blood glucose during concomitant atypical antipsychotic and dipeptidyl peptidase-4 (DPP-4) inhibitor use. Atypical antipsychotic therapy may aggravate diabetes mellitus. Atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition. (Moderate) Monitor blood glucose during concomitant atypical antipsychotic and metformin use. Atypical antipsychotic therapy may aggravate diabetes mellitus. Atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition. (Moderate) Monitor blood glucose during concomitant dipeptidyl peptidase-4 (DPP-4) inhibitor and fluoxetine use; a DPP-4 inhibitor dose adjustment may be necessary. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia. (Moderate) Monitor blood glucose during concomitant metformin and fluoxetine use; a metformin dose adjustment may be necessary. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
Metformin; Sitagliptin: (Moderate) Monitor blood glucose during concomitant atypical antipsychotic and dipeptidyl peptidase-4 (DPP-4) inhibitor use. Atypical antipsychotic therapy may aggravate diabetes mellitus. Atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition. (Moderate) Monitor blood glucose during concomitant atypical antipsychotic and metformin use. Atypical antipsychotic therapy may aggravate diabetes mellitus. Atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition. (Moderate) Monitor blood glucose during concomitant dipeptidyl peptidase-4 (DPP-4) inhibitor and fluoxetine use; a DPP-4 inhibitor dose adjustment may be necessary. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia. (Moderate) Monitor blood glucose during concomitant metformin and fluoxetine use; a metformin dose adjustment may be necessary. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
Methadone: (Major) Coadministration may increase the risk of serotonin syndrome, QT prolongation, torsade de pointes (TdP), or opioid-related side effects. QT prolongation and TdP have been reported in patients treated with fluoxetine and the manufacturer recommends caution when using fluoxetine with other drugs that prolong the QT interval. Methadone is associated with an increased risk for QT prolongation and TdP, especially at higher doses (greater than 200 mg/day but averaging approximately 400 mg/day in adult patients). Most cases involve patients being treated for pain with large, multiple daily doses of methadone, although cases have been reported in patients receiving doses commonly used for maintenance treatment of opioid addiction. In addition, both fluoxetine and methadone have central serotonergic properties and serotonin syndrome is possible. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. If serotonin syndrome occurs, all serotonergic agents should be discontinued and appropriate medical treatment should be implemented. Lastly, fluoxetine may inhibit the metabolism of methadone via CYP3A4 or CYP2D6. In patients treated with methadone and fluoxetine, the plasma concentration of methadone increased. Interestingly in patients treated with methadone, the R-enantiomer (the active moiety) was increased by the addition of fluoxetine. Patients may experience increases in CNS depressive effects or respiratory depression. Thus, methadone-treated patients receiving fluoxetine should be carefully monitored and dosage adjustments may be warranted. (Major) The need to coadminister methadone with drugs known to prolong the QT interval, such as olanzapine, should be done with extreme caution and a careful assessment of treatment risks versus benefits. Methadone is considered to be associated with an increased risk for QT prolongation and torsades de pointes (TdP), especially at higher doses (> 200 mg/day but averaging approximately 400 mg/day in adult patients). In addition, concomitant use of methadone with another CNS depressant, such as olanzapine, can lead to additive respiratory depression, hypotension, profound sedation, or coma. Prior to concurrent use of methadone in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. Methadone should be used with caution and in reduced dosages if used concurrently with a CNS depressant; also consider a using a lower dose of the CNS depressant. Monitor patients for sedation and respiratory depression.
Methenamine; Sodium Acid Phosphate; Methylene Blue; Hyoscyamine: (Contraindicated) According to the manufacturer of fluoxetine, treatment initiation with fluoxetine is contraindicated in patients currently receiving intravenous (IV) methylene blue due to an increased risk of serotonin syndrome. If urgent psychiatric treatment is required, interventions other than fluoxetine (e.g., alternative medication, hospitalization) should be considered. Conversely, in patients receiving fluoxetine and requiring urgent treatment with IV methylene blue, fluoxetine should be discontinued immediately and methylene blue therapy initiated only if acceptable alternatives are not available and the potential benefits outweigh the risks. The patient should be monitored for serotonin syndrome for 5 weeks or until 24 hours after the last dose of methylene blue, whichever comes first. Fluoxetine may be re-initiated 24 hours after the last dose of methylene blue. Results from an in vitro study indicate that methylene blue is a potent, reversible inhibitor of the monoamine oxidase type A enzyme (MAO-A). MAO-A is responsible for the metabolism of serotonin; therefore, concurrent use of an MAO-A inhibitor with a serotonergic agent may result in a clinically significant interaction. Cases of serotonin syndrome have been reported, primarily following administration of standard infusions of methylene blue (1 to 8 mg/kg) as a visualizing agent, in patients receiving SSRIs, serotonin/norepinephrine reuptake inhibitors, or clomipramine. It is not known if patients receiving other serotonergic psychiatric agents with IV methylene blue are at a comparable risk or if methylene blue administered by other routes (e.g., orally, local injection) or in doses less than 1 mg/kg IV can produce a similar outcome. One case describes a patient receiving citalopram who experienced agitation, restlessness, pupil dilation with sluggish response to light, myoclonic movements of the lower limbs, and brisk reflexes following an infusion of methylene blue, while another patient receiving paroxetine developed tachycardia, agitation, dystonia and abnormal eye movements. During a retrospective study of 193 surgical patients who had received a methylene blue injection, it was found that all 12 of the patients who experienced postoperative neurological sequelae had been taking a serotonin reuptake inhibitor preoperatively. One of the 12 patients experienced cardiopulmonary arrest and died. Of the remaining 181 patients who did not experience neurological sequelae, 8.8% were taking a serotonin reuptake inhibitor. Published interaction reports between IV methylene blue and serotonergic psychiatric agents have documented symptoms including lethargy, confusion, delirium, agitation, aggression, obtundation, myoclonus, expressive aphasia, hypertonia, pyrexia, elevated blood pressure, seizures, and coma. Signs and symptoms of serotonin syndrome include fever, diaphoresis, shivering, myoclonus, tremor, tachycardia, diarrhea, nausea, headache, incoordination, mental status changes (e.g., agitation, confusion), hyperreflexia, seizures, and coma. (Moderate) Additive anticholinergic effects may be seen when olanzapine and anticholinergics are used concomitantly; use with caution. Use of olanzapine and other drugs with anticholinergic activity can increase the risk for severe gastrointestinal adverse reactions related to hypomotility. Olanzapine exhibits anticholinergic activity. Adverse effects may be seen not only on GI smooth muscle, but also on bladder function, the CNS, the eye, and temperature regulation. Additive drowsiness may also occur, depending on the anticholinergic agent used.
Methohexital: (Moderate) Olanzapine is metabolized by the CYP1A2 hepatic microsomal isoenzyme, and inducers of this enzyme such as barbiturates, may increase olanzapine clearance. The clinical effect of this interaction is thought to be minimal; however, the clinician should be alert for reduced olanzapine effect if the drugs are coadministered. Additive effects are possible when olanzapine is combined with other drugs which cause respiratory depression and/or CNS depression. Barbiturates can cause CNS depression, and if used concomitantly with olanzapine, can increase both the frequency and the intensity of adverse effects such as drowsiness, sedation, dizziness, and orthostatic hypotension.
Methscopolamine: (Moderate) Additive anticholinergic effects may be seen when olanzapine and anticholinergics are used concomitantly; use with caution. Use of olanzapine and other drugs with anticholinergic activity can increase the risk for severe gastrointestinal adverse reactions related to hypomotility. Olanzapine exhibits anticholinergic activity. Adverse effects may be seen not only on GI smooth muscle, but also on bladder function, the CNS, the eye, and temperature regulation. Additive drowsiness may also occur, depending on the anticholinergic agent used.
Methyclothiazide: (Moderate) Monitor for signs and symptoms of hyponatremia during concomitant diuretic and fluoxetine use; consider discontinuing fluoxetine if symptomatic hyponatremia occurs and institute appropriate medical intervention. Concomitant use increases the risk for developing hyponatremia.
Methylene Blue: (Contraindicated) According to the manufacturer of fluoxetine, treatment initiation with fluoxetine is contraindicated in patients currently receiving intravenous (IV) methylene blue due to an increased risk of serotonin syndrome. If urgent psychiatric treatment is required, interventions other than fluoxetine (e.g., alternative medication, hospitalization) should be considered. Conversely, in patients receiving fluoxetine and requiring urgent treatment with IV methylene blue, fluoxetine should be discontinued immediately and methylene blue therapy initiated only if acceptable alternatives are not available and the potential benefits outweigh the risks. The patient should be monitored for serotonin syndrome for 5 weeks or until 24 hours after the last dose of methylene blue, whichever comes first. Fluoxetine may be re-initiated 24 hours after the last dose of methylene blue. Results from an in vitro study indicate that methylene blue is a potent, reversible inhibitor of the monoamine oxidase type A enzyme (MAO-A). MAO-A is responsible for the metabolism of serotonin; therefore, concurrent use of an MAO-A inhibitor with a serotonergic agent may result in a clinically significant interaction. Cases of serotonin syndrome have been reported, primarily following administration of standard infusions of methylene blue (1 to 8 mg/kg) as a visualizing agent, in patients receiving SSRIs, serotonin/norepinephrine reuptake inhibitors, or clomipramine. It is not known if patients receiving other serotonergic psychiatric agents with IV methylene blue are at a comparable risk or if methylene blue administered by other routes (e.g., orally, local injection) or in doses less than 1 mg/kg IV can produce a similar outcome. One case describes a patient receiving citalopram who experienced agitation, restlessness, pupil dilation with sluggish response to light, myoclonic movements of the lower limbs, and brisk reflexes following an infusion of methylene blue, while another patient receiving paroxetine developed tachycardia, agitation, dystonia and abnormal eye movements. During a retrospective study of 193 surgical patients who had received a methylene blue injection, it was found that all 12 of the patients who experienced postoperative neurological sequelae had been taking a serotonin reuptake inhibitor preoperatively. One of the 12 patients experienced cardiopulmonary arrest and died. Of the remaining 181 patients who did not experience neurological sequelae, 8.8% were taking a serotonin reuptake inhibitor. Published interaction reports between IV methylene blue and serotonergic psychiatric agents have documented symptoms including lethargy, confusion, delirium, agitation, aggression, obtundation, myoclonus, expressive aphasia, hypertonia, pyrexia, elevated blood pressure, seizures, and coma. Signs and symptoms of serotonin syndrome include fever, diaphoresis, shivering, myoclonus, tremor, tachycardia, diarrhea, nausea, headache, incoordination, mental status changes (e.g., agitation, confusion), hyperreflexia, seizures, and coma.
Methylergonovine: (Moderate) Use fluoxetine and ergot alkaloids together with caution due to a potential for serotonin syndrome. Weakness, hyperreflexia, and incoordination have been reported rarely when ergot alkaloids or other serotonin agonists have been coadministered with SSRIs, which may be indicative of serotonin excess. If serotonin syndrome occurs, discontinue the offending agents and institute appropriate treatment.
Methylphenidate Derivatives: (Moderate) Caution should be observed when coadministering methylphenidate derivatives and the selective serotonin reuptake inhibitors (SSRIs). There are postmarketing reports of serotonin syndrome during concurrent use of methylphenidate derivatives with other serotonergic medications. Human pharmacologic studies have shown that methylphenidate may inhibit the metabolism of some SSRIs and downward dose adjustment of the SSRI may be required in some patients. Inform patients of the possible increased risk and monitor for the emergence of serotonin syndrome. If serotonin syndrome occurs, serotonergic agents should be discontinued and appropriate medical management should be implemented.
Metoclopramide: (Contraindicated) Avoid metoclopramide in patients receiving atypical antipsychotics. There is a potential for additive effects, including increased frequency and severity of tardive dyskinesia (TD), other extrapyramidal symptoms (EPS), and neuroleptic malignant syndrome (NMS). Some manufacturer labels for metoclopramide contraindicate the use of these drugs together, while others state avoidance is necessary. If these agents must be used together, monitor closely for movement disorders and additive CNS effects. There also may be additive sedation. Discontinue these medications at the first signs of dyskinesia. (Major) When metoclopramide is used with a potent CYP2D6 inhibitor for the treatment of gastroesophageal reflux (GERD), dosage reductions of oral metoclopramide are required, with maximum oral dosage not to exceed 30 mg/day (e.g., 5 mg 4 times daily or 10 mg 3 times daily). There is a known increase in metoclopramide exposure and an increased risk for extrapyramidal adverse reactions. Metoclopramide is a substrate of CYP2D6 and fluoxetine is a strong CYP2D6 inhibitor. The manufacturer recommends avoidance of fluoxetine and consideration of alternative SSRI antidepressants when oral metoclopramide is used in patients with diabetic gastroparesis. Healthy patients given 20 mg of metoclopramide and 60 mg of fluoxetine for 8 days had a 40% and 90% increase in metoclopramide Cmax and AUC, respectively, compared to patients who received metoclopramide alone. Additionally, concomitant use of metoclopramide and SSRIs such as fluoxetine may increase the risk for serotonin syndrome. In rare cases postmarketing, NMS-like symptoms, which may overlap with serotonin syndrome symptoms, have been reported with metoclopramide when used with serotonergic agents.
Metolazone: (Moderate) Monitor for signs and symptoms of hyponatremia during concomitant diuretic and fluoxetine use; consider discontinuing fluoxetine if symptomatic hyponatremia occurs and institute appropriate medical intervention. Concomitant use increases the risk for developing hyponatremia.
Metoprolol: (Moderate) Monitor for metoprolol-related adverse reactions, including bradycardia and hypotension, during coadministration with fluoxetine. Concomitant use may increase metoprolol serum concentrations which would decrease the cardioselectivity of metoprolol. Metoprolol is a CYP2D6 substrate and fluoxetine is a CYP2D6 inhibitor. (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.
Metoprolol; Hydrochlorothiazide, HCTZ: (Moderate) Monitor for metoprolol-related adverse reactions, including bradycardia and hypotension, during coadministration with fluoxetine. Concomitant use may increase metoprolol serum concentrations which would decrease the cardioselectivity of metoprolol. Metoprolol is a CYP2D6 substrate and fluoxetine is a CYP2D6 inhibitor. (Moderate) Monitor for signs and symptoms of hyponatremia during concomitant diuretic and fluoxetine use; consider discontinuing fluoxetine if symptomatic hyponatremia occurs and institute appropriate medical intervention. Concomitant use increases the risk for developing hyponatremia. (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.
Metronidazole: (Moderate) Concomitant use of metronidazole and fluoxetine may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP. (Moderate) Concomitant use of metronidazole and olanzapine may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP.
Mexiletine: (Moderate) Fluoxetine is a potent inhibitor of the hepatic CYP2D6 isoenzyme. Inhibition of CYP2D6 can result in increased concentrations of antiarrhythmic drugs metabolized via the same pathway, including mexiletine. Increased plasma concentrations may increase the risk of proarrhythmias. (Minor) Olanzapine is partially metabolized by CYP1A2. Mexiletine may inhibit CYP1A2 and may decrease the metabolism of olanzapine resulting in potential drug accumulation. Coadministration of olanzapine with mexiletine has not been studied.
Midazolam: (Major) Concurrent use of intramuscular olanzapine and parenteral benzodiazepines is not recommended due to the potential for adverse effects from the combination including excess sedation and/or cardiorespiratory depression. Although oral formulations of olanzapine and benzodiazepines may be used together, additive effects on respiratory depression and/or CNS depression are possible. Drugs that can cause CNS depression, if used concomitantly with olanzapine, can increase both the frequency and the intensity of adverse effects such as drowsiness, sedation, dizziness, and orthostatic hypotension. Besides ethanol, clinicians should use other anxiolytics, sedatives, and hypnotics cautiously with olanzapine. (Moderate) Fluoxetine could theoretically inhibit CYP3A4 metabolism of oxidized benzodiazepines, including midazolam. Patients should be monitored for clinical response, and adjust benzodiazepine dosage if needed.
Midostaurin: (Major) Concomitant use of midostaurin and fluoxetine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. (Major) The concomitant use of midostaurin and olanzapine may lead to additive QT interval prolongation. If these drugs are used together, consider electrocardiogram monitoring. In clinical trials, QT prolongation has been reported in patients who received midostaurin as single-agent therapy or in combination with cytarabine and daunorubicin. There have been case reports of significant QT prolongation occurring with olanzapine therapy.
Mifepristone: (Major) Concomitant use of mifepristone and fluoxetine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. (Moderate) Concomitant use of mifepristone and olanzapine may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP.
Miglitol: (Moderate) Atypical antipsychotic therapy may aggravate diabetes mellitus and cause metabolic changes such as hyperglycemia. Monitor patients on antidiabetic agents for worsening glycemic control. The atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Aggravation of diabetes mellitus has been reported. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition. (Moderate) In patients with diabetes mellitus, fluoxetine may alter glycemic control. Hypoglycemia has occurred during fluoxetine therapy. Hyperglycemia has developed in patients with diabetes mellitus following discontinuation of the drug. The dosage of insulin and/or other antidiabetic agents may need to be adjusted when therapy with fluoxetine is instituted or discontinued.
Milnacipran: (Major) Because of the potential risk and severity of serotonin syndrome, concurrent use of milnacipran with other drugs that have serotonergic properties, such as the selective serotonin reuptake inhibitors (SSRIs), should generally be avoided. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. If serotonin syndrome is suspected, milnacipran and concurrent serotonergic agents should be discontinued.
Mirabegron: (Moderate) Mirabegron is a moderate CYP2D6 inhibitor. Exposure of drugs metabolized by CYP2D6 isoenzymes such as fluoxetine may be increased when co-administered with mirabegron. Fluoxetine is primarily metabolized by CYP2D6. Therefore, appropriate monitoring and dose adjustment may be necessary. (Moderate) Mirabegron is a moderate CYP2D6 inhibitor. Exposure of drugs metabolized by CYP2D6 such as olanzapine may be increased when co-administered with mirabegron. Therefore, appropriate monitoring and dose adjustment may be necessary.
Mirtazapine: (Moderate) Concomitant use of mirtazapine and olanzapine may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP. (Moderate) Use fluoxetine with caution in combination with mirtazapine. Coadministration may increase the risk for QT prolongation, torsade de pointes (TdP), and serotonin syndrome. Case reports of serotonin syndrome have been reported with this combination. If serotonin syndrome occurs, all serotonergic agents should be discontinued and appropriate medical treatment should be implemented. Both drugs have been reported to cause QT prolongation and TdP.
Mobocertinib: (Major) Concomitant use of mobocertinib and fluoxetine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. (Major) Concomitant use of mobocertinib and olanzapine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Modafinil: (Moderate) Although no clinical data are available, fluoxetine may inhibit the clearance and potentiate the actions of modafinil. Modafinil is metabolized by CYP3A4 isozyme, a pathway that fluoxetine is known to inhibit.
Moexipril: (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.
Molindone: (Major) Close monitoring is advisable during concurrent use of molindone with other antipsychotics. Because molindone shares certain pharmacological properties with other antipsychotics, additive cardiac effects (e.g., hypotension), CNS effects (e.g., drowsiness), anticholinergic effects (e.g., constipation, xerostomia), extrapyramidal effects, neuroleptic malignant syndrome, or seizures may occur. The likelihood of these pharmacodynamic interactions varies based upon the individual properties of the co-administered antipsychotic agent. Although the incidence of tardive dyskinesia from combination antipsychotic therapy has not been established and data are very limited, the risk appears to be increased during use of a conventional and atypical antipsychotic versus use of a conventional antipsychotic alone.
Monoamine oxidase inhibitors: (Contraindicated) Due to the risk of serotonin syndrome, monoamine oxidase inhibitors (MAOIs) intended to treat psychiatric disorders are contraindicated for use with selective serotonin reuptake inhibitors (SSRIs). MAOIs should not be used within 5 weeks of discontinuing treatment with fluoxetine or within 14 days of discontinuing treatment with other SSRIs. Conversely, SSRIs should not be initiated within 14 days of stopping an MAOI. Monitor the patient for serotonin-related effects during therapy transitions. (Major) Avoid concomitant use, or use in rapid succession, of monoamine oxidase inhibitors (MAOIs) and olanzapine. If concomitant use is necessary, monitor for signs and symptoms of serotonin syndrome, blood pressure, and for unusual drowsiness and sedation. Concomitant use increases the risk for serotonin syndrome and additive hypotension and CNS depression. If serotonin syndrome occurs, discontinue therapy.
Morphine: (Major) Concomitant use of opioid agonists with olanzapine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with olanzapine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. For extended-release morphine tablets (MS Contin and Morphabond), start with 15 mg every 12 hours. Morphine; naltrexone should be initiated at one-third to one-half the recommended starting dosage. Also monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. (Moderate) Serotonin syndrome can occur during concomitant use of opiate agonists like morphine with serotonergic drugs, such as fluoxetine. Symptoms may occur hours to days after concomitant use, particularly after dose increases. Serotonin syndrome may occur within recommended dose ranges. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
Morphine; Naltrexone: (Major) Concomitant use of opioid agonists with olanzapine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with olanzapine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. For extended-release morphine tablets (MS Contin and Morphabond), start with 15 mg every 12 hours. Morphine; naltrexone should be initiated at one-third to one-half the recommended starting dosage. Also monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. (Moderate) Serotonin syndrome can occur during concomitant use of opiate agonists like morphine with serotonergic drugs, such as fluoxetine. Symptoms may occur hours to days after concomitant use, particularly after dose increases. Serotonin syndrome may occur within recommended dose ranges. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
Moxifloxacin: (Major) Concomitant use of moxifloxacin and fluoxetine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. (Major) Concurrent use of olanzapine and moxifloxacin should be avoided due to an increased risk for QT prolongation and torsade de pointes (TdP). Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval in rare instances. Moxifloxacin has also been associated with prolongation of the QT interval. Additionally, post-marketing surveillance has identified very rare cases of ventricular arrhythmias including TdP, usually in patients with severe underlying proarrhythmic conditions. The likelihood of QT prolongation may increase with increasing concentrations of moxifloxacin, therefore the recommended dose or infusion rate should not be exceeded.
Nabilone: (Moderate) Drugs that can cause CNS depression, if used concomitantly with atypical antipsychotics, can increase both the frequency and the intensity of adverse effects such as drowsiness, sedation, and dizziness. (Minor) A hypomanic episode was reported in a 21-year-old female with depression and bulimia receiving fluoxetine 20 mg/day for 4 weeks after smoking cannabis; symptoms resolved after 4 days. This interaction may also occur with nabilone which is a synthetic analog of a naturally occurring substance found in cannabis.
Nadolol: (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.
Nafarelin: (Moderate) Antipsychotics may cause hyperprolactinemia and should not be administered concomitantly with nafarelin since hyperprolactinemia down-regulates the number of pituitary GnRH receptors.
Nalbuphine: (Moderate) Monitor for excessive sedation and somnolence during coadministration of lumateperone and nalbuphine. Concurrent use may result in additive CNS depression.
Nanoparticle Albumin-Bound Paclitaxel: (Moderate) Monitor for an increase in paclitaxel-related adverse reactions if coadministration of nab-paclitaxel with fluoxetine is necessary due to the risk of increased plasma concentrations of paclitaxel. Nab-paclitaxel is a CYP3A4 substrate; fluoxetine is a weak inhibitor of CYP3A4, but its metabolite norfluoxetine is a moderate CYP3A4 inhibitor. In vitro, coadministration with both strong and moderate CYP3A4 inhibitors increased paclitaxel exposure; however, the concentrations used exceeded those found in vivo following normal therapeutic doses. The pharmacokinetics of paclitaxel may also be altered in vivo as a result of interactions with CYP3A4 inhibitors.
Naproxen; Esomeprazole: (Minor) Fluoxetine may inhibit the CYP2C19 isoenzyme, leading to increased plasma levels of drugs that are substrates for the CYP2C19 isoenzyme, such as esomeprazole.
Naratriptan: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering naratriptan with selective serotonin reuptake inhibitors (SSRIs). Serotonin syndrome has been reported during concurrent use of serotonin-receptor agonists ("triptans") and SSRIs. Inform patients of the possible increased risk and monitor for the emergence of serotonin syndrome, particularly after initiation of SSRI treatment or any dose increases. Discontinue serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
Nateglinide: (Moderate) Atypical antipsychotic therapy may aggravate diabetes mellitus and cause metabolic changes such as hyperglycemia. Monitor patients on antidiabetic agents for worsening glycemic control. The atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Aggravation of diabetes mellitus has been reported. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.
Nebivolol: (Major) Avoid the concomitant use of nebivolol and fluoxetine. Concomitant use may increase the exposure of nebivolol and the risk of adverse effects. Nebivolol is a CYP2D6 substrate and fluoxetine is a strong CYP2D6 inhibitor. Coadministration with fluoxetine caused an 8-fold increase in the AUC of d-nebivolol. (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.
Nebivolol; Valsartan: (Major) Avoid the concomitant use of nebivolol and fluoxetine. Concomitant use may increase the exposure of nebivolol and the risk of adverse effects. Nebivolol is a CYP2D6 substrate and fluoxetine is a strong CYP2D6 inhibitor. Coadministration with fluoxetine caused an 8-fold increase in the AUC of d-nebivolol. (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.
Nefazodone: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when coadministering drugs that have serotonergic properties such as nefazodone and fluoxetine. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. At least one case report of serotonin syndrome from the concurrent use of nefazodone and a selective serotonin reuptake inhibitor (i.e., paroxetine) has been published. Additionally, when a 200 mg dose of nefazodone was administered to subjects who had been receiving fluoxetine for 1 week, there was an increased incidence of transient serotonin-related adverse events. If serotonin syndrome occurs, all serotonergic agents should be discontinued and appropriate medical treatment should be implemented.
Neostigmine; Glycopyrrolate: (Moderate) Additive anticholinergic effects may be seen when olanzapine and anticholinergics are used concomitantly; use with caution. Use of olanzapine and other drugs with anticholinergic activity can increase the risk for severe gastrointestinal adverse reactions related to hypomotility. Olanzapine exhibits anticholinergic activity. Adverse effects may be seen not only on GI smooth muscle, but also on bladder function, the CNS, the eye, and temperature regulation. Additive drowsiness may also occur, depending on the anticholinergic agent used.
Netupitant, Fosnetupitant; Palonosetron: (Major) Because of the potential risk and severity of serotonin syndrome, use caution when administering palonosetron with other drugs that have serotonergic properties such as fluoxetine. If serotonin syndrome is suspected, discontinue palonosetron and concurrent serotonergic agents and initiate appropriate medical treatment. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death.
Nicardipine: (Moderate) Fluoxetine may decrease the clearance of calcium-channel blockers, including nicardipine, via inhibition of CYP3A4 metabolism.
Nifedipine: (Moderate) Fluoxetine may decrease the clearance of calcium-channel blockers, including nifedipine, via inhibition of CYP3A4 metabolism.
Nilotinib: (Major) Concomitant use of nilotinib and fluoxetine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Nimodipine: (Moderate) Fluoxetine may decrease the clearance of calcium-channel blockers, including nimodipine, via inhibition of CYP3A4 metabolism.
Nirmatrelvir; Ritonavir: (Moderate) Monitor for increased fluoxetine-related adverse effects if coadministered with ritonavir. Concurrent use may result in increased fluoxetine exposure. Fluoxetine is a CYP2D6 substrate and ritonavir is a weak CYP2D6 inhibitor. (Moderate) Ritonavir may reduce olanzapine serum concentrations by approximately 50%; how this affects olanzapine efficacy, however, is not known. Ritonavir appears to induce olanzapine's metabolism by either CYP1A2 or glucuronide conjugation. If ritonavir and olanzapine are used concurrently, monitor for reduced olanzapine effect and adjust olanzapine dose as needed.
Nisoldipine: (Major) Avoid coadministration of nisoldipine with fluoxetine due to increased plasma concentrations of nisoldipine. If coadministration is unavoidable, monitor blood pressure closely during concurrent use of these medications. Nisoldipine is a CYP3A4 substrate and fluoxetine is a CYP3A4 inhibitor.
Nitroglycerin: (Minor) Nitroglycerin can cause hypotension. This action may be additive with other agents that can cause hypotension such as antidepressants. Patients should be monitored more closely for hypotension if nitroglycerin is used concurrently with antidepressants.
Non-Ionic Contrast Media: (Major) Atypical antipsychotics may lower the seizure threshold and should be discontinued at least 48 hours before myelography and should not be resumed for at least 24 hours postprocedure.
Nonsteroidal antiinflammatory drugs: (Moderate) Monitor for signs and symptoms of bleeding during concomitant selective serotonin reuptake inhibitor (SSRI) and nonsteroidal antiinflammatory drug (NSAID) use due to increased risk for bleeding. Serotonin release by platelets plays an important role in hemostasis. Epidemiological studies have demonstrated an association between use of psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper gastrointestinal bleeding.
Nortriptyline: (Moderate) Coadministration of fluoxetine and nortriptyline may increase the risk for QT prolongation, torsade de pointes (TdP), and serotonin syndrome. If serotonin syndrome is suspected, discontinue fluoxetine and concurrent serotonergic agents and initiate appropriate medical treatment. QT prolongation and TdP have been reported in patients treated with fluoxetine. Tricyclics, particularly at elevated concentrations, are associated with a possible risk of QT prolongation and TdP.
Ofloxacin: (Moderate) Concomitant use of ofloxacin and fluoxetine may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP. (Moderate) Concomitant use of ofloxacin and olanzapine may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP.
Olanzapine: (Moderate) Concomitant use of fluoxetine and olanzapine may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP.
Olanzapine; Samidorphan: (Moderate) Concomitant use of fluoxetine and olanzapine may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP.
Oliceridine: (Major) Concomitant use of oliceridine with olanzapine may cause excessive sedation and somnolence. Limit the use of oliceridine with olanzapine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Also monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. (Moderate) Monitor patients closely for respiratory depression and sedation at frequent intervals and base subsequent doses on the patient's severity of pain and response to treatment if concomitant administration of oliceridine and fluoxetine is necessary; less frequent dosing of oliceridine may be required. Concomitant use of oliceridine and fluoxetine may increase the plasma concentration of oliceridine, resulting in increased or prolonged opioid effects; these effects may be more pronounced with fluoxetine as it can inhibit multiple CYP enzymes. If fluoxetine is discontinued, consider increasing the oliceridine dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Oliceridine is a CYP3A4 and CYP2D6 substrate and fluoxetine and its metabolite, norfluoxetine, are a strong CYP2D6 inhibitor and moderate CYP3A4 inhibitor, respectively. Also monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
Olmesartan: (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.
Olmesartan; Amlodipine; Hydrochlorothiazide, HCTZ: (Moderate) Monitor for signs and symptoms of hyponatremia during concomitant diuretic and fluoxetine use; consider discontinuing fluoxetine if symptomatic hyponatremia occurs and institute appropriate medical intervention. Concomitant use increases the risk for developing hyponatremia. (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.
Olmesartan; Hydrochlorothiazide, HCTZ: (Moderate) Monitor for signs and symptoms of hyponatremia during concomitant diuretic and fluoxetine use; consider discontinuing fluoxetine if symptomatic hyponatremia occurs and institute appropriate medical intervention. Concomitant use increases the risk for developing hyponatremia. (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.
Ondansetron: (Major) Concomitant use of ondansetron and olanzapine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. Do not exceed 16 mg of IV ondansetron in a single dose; the degree of QT prolongation associated with ondansetron significantly increases above this dose. (Major) Due to the potential for QT prolongation, cautious use and close monitoring are advisable if concurrent use of fluoxetine and ondansetron is necessary. Both medications may cause QT interval prolongation and a risk for torsade de pointes (TdP). ECG monitoring has been recommended for at-risk patients. In addition, concurrent use of ondansetron with other drugs that modulate serotonergic function, such as fluoxetine, has resulted in serotonin syndrome in some cases. Patients should be carefully observed, particularly during treatment initiation and during dose adjustments. Discontinue the serotonergic medications if serotonin syndrome is suspected.
Opicapone: (Moderate) Monitor for movement disorders, unusual changes in moods or behavior, and diminished effectiveness of the atypical antipsychotic or COMT inhibitor during coadministration. Due to mutually opposing effects on dopamine, atypical antipsychotics and COMT inhibitors may interfere with the effectiveness of each other. In general, atypical antipsychotics are less likely to interfere with COMT inhibitors and other Parkinson's treatments than traditional antipsychotics. The Beers Criteria recognize quetiapine and clozapine as exceptions to the general recommendation to avoid all antipsychotics in older adults with Parkinson's disease.
Oritavancin: (Moderate) Fluoxetine is metabolized by CYP2C9, CYP2C19 and CYP2D6; oritavancin is a weak inducer of CYP2D6 and a weak CYP2C9 and CYP2C19 inhibitor. Coadministration may result in altered fluoxetine plasma concentrations. If these drugs are administered concurrently, monitor for fluoxetine toxicity, such as nausea, vomiting, diarrhea, headache, or insomnia, or decreased effectiveness. (Moderate) Olanzapine is metabolized by CYP2D6; oritavancin is a weak CYP2D6 inducer. Plasma concentrations and efficacy of olanzapine may be reduced if these drugs are administered concurrently.
Orphenadrine: (Moderate) Additive anticholinergic effects may be seen when drugs with anticholinergic properties, like olanzapine and orphenadrine, are used concomitantly. Adverse effects may be seen not only on GI smooth muscle, but also on bladder function, the CNS, the eye, and temperature regulation. Additive drowsiness may also occur.
Osilodrostat: (Moderate) Concomitant use of fluoxetine and osilodrostat may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP. (Moderate) Monitor ECGs in patients receiving osilodrostat with olanzapine. Osilodrostat is associated with dose-dependent QT prolongation. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval.
Osimertinib: (Major) Avoid coadministration of olanzapine with osimertinib if possible due to the risk of QT prolongation and torsade de pointes (TdP). If concomitant use is unavoidable, periodically monitor ECGs for QT prolongation and monitor electrolytes; an interruption of osimertinib therapy with dose reduction or discontinuation of therapy may be necessary if QT prolongation occurs. Concentration-dependent QTc prolongation occurred during clinical trials of osimertinib. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval. (Major) Concomitant use of osimertinib and fluoxetine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Oxaliplatin: (Major) Concomitant use of oxaliplatin and fluoxetine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. (Major) Monitor electrolytes and ECGs for QT prolongation if coadministration of olanzapine with oxaliplatin is necessary; correct electrolyte abnormalities prior to administration of oxaliplatin. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval. QT prolongation and ventricular arrhythmias including fatal torsade de pointes have also been reported with oxaliplatin use in postmarketing experience.
Oxazepam: (Moderate) Although oral formulations of olanzapine and benzodiazepines may be used together, additive effects on respiratory depression and/or CNS depression are possible. Drugs that can cause CNS depression, if used concomitantly with olanzapine, can increase both the frequency and the intensity of adverse effects such as drowsiness, sedation, dizziness, and orthostatic hypotension. Besides ethanol, clinicians should use other anxiolytics, sedatives, and hypnotics cautiously with olanzapine.
Oxybutynin: (Moderate) Additive anticholinergic effects may be seen when olanzapine and anticholinergics are used concomitantly; use with caution. Use of olanzapine and other drugs with anticholinergic activity can increase the risk for severe gastrointestinal adverse reactions related to hypomotility. Olanzapine exhibits anticholinergic activity. Adverse effects may be seen not only on GI smooth muscle, but also on bladder function, the CNS, the eye, and temperature regulation. Additive drowsiness may also occur, depending on the anticholinergic agent used.
Oxycodone: (Major) Concomitant use of opioid agonists with olanzapine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with olanzapine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Also monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. (Moderate) If concomitant use of oxycodone and fluoxetine is warranted, monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
Oxymorphone: (Major) Concomitant use of opioid agonists with olanzapine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with olanzapine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Reduce the initial oxymorphone dosage by one-third to one-half. Also monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. (Major) Fluoxetine may inhibit the metabolism of oxymorphone. Clinicians should be alert for an exaggerated opiate response if oxymorphone is given with fluoxetine.
Ozanimod: (Major) In general, do not initiate ozanimod in patients taking fluoxetine due to the risk of additive bradycardia, QT prolongation, and torsade de pointes (TdP). Additionally, there is a potential for hypertensive crisis and serotonin syndrome. If treatment initiation is considered, seek advice from a cardiologist and monitor for hypertension and serotonergic effects. Ozanimod is a monoamine oxidase inhibitor that may result in a transient decrease in heart rate and atrioventricular conduction delays. Ozanimod has not been studied in patients taking concurrent QT prolonging drugs; however, QT prolonging drugs have been associated with TdP in patients with bradycardia. Fluoxetine is a serotonergic drug that is associated with QT prolongation and TdP. (Major) In general, do not initiate ozanimod in patients taking olanzapine due to the risk of additive bradycardia, QT prolongation, and torsade de pointes (TdP). Additionally, there is a potential for hypertensive crisis or serotonin syndrome. If treatment initiation is considered, seek advice from a cardiologist and monitor for hypertension and serotonergic effects. An active metabolite of ozanimod inhibits MAO-B, which may increase the potential for hypertensive crisis or serotonergic effects. Olanzapine has also been associated with serotonin syndrome reports postmarketing, but the mechanism is not clear. Ozanimod may also result in a transient decrease in heart rate and atrioventricular conduction delays. Ozanimod has not been studied in patients taking concurrent QT prolonging drugs; however, QT prolonging drugs have been associated with TdP in patients with bradycardia. Olanzapine has been associated with a significant prolongation of the QTc interval.
Paclitaxel: (Minor) Paciltaxel is metabolized by cytochrome P450 3A enzymes. Drugs that inhibit the CYP3A enzymes, such as fluoxetine, can significantly reduce the metabolism of paclitaxel.
Pacritinib: (Major) Concomitant use of pacritinib and fluoxetine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. (Major) Concomitant use of pacritinib and olanzapine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Paliperidone: (Major) Concomitant use of paliperidone and fluoxetine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. (Major) Paliperidone has been associated with QT prolongation; torsade de pointes (TdP) and ventricular fibrillation have been reported in the setting of overdose. According to the manufacturer, since paliperidone may prolong the QT interval, it should be avoided in combination with other agents also known to have this effect, such as olanzapine. In addition, coadministration of antipsychotics may increase the risk of adverse effects such as drowsiness, dizziness, orthostatic hypotension, anticholinergic effects, extrapyramidal symptoms, neuroleptic malignant syndrome, tardive dyskinesia, or seizures. If coadministration is considered necessary and the patient has known risk factors for cardiac disease or arrhythmias, close monitoring is essential.
Palonosetron: (Major) Because of the potential risk and severity of serotonin syndrome, use caution when administering palonosetron with other drugs that have serotonergic properties such as fluoxetine. If serotonin syndrome is suspected, discontinue palonosetron and concurrent serotonergic agents and initiate appropriate medical treatment. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death.
Panobinostat: (Major) The co-administration of panobinostat with fluoxetine is not recommended; QT prolongation has been reported with both agents. Additionally, levels of both drugs may be increased. Although an initial panobinostat dose reduction is recommended in patients taking concomitant strong CYP3A4 inhibitors, no dose recommendations with mild or moderate CYP3A4 inhibitors are provided by the manufacturer. If concomitant use of fluoxetine and panobinostat cannot be avoided, closely monitor electrocardiograms and for signs and symptoms of fluoxetine and/or panobinostat toxicity including QT prolongation and cardiac arrhythmias. Hold panobinostat if the QTcF increases to >= 480 milliseconds during therapy; permanently discontinue if QT prolongation does not resolve. Fluoxetine is a CYP3A4 inhibitor and a CYP2D6 substrate and panobinostat is a CYP3A4 substrate and CYP2D6 inhibitor. The panobinostat Cmax and AUC (0-48hr) values were increased by 62% and 73%, respectively, in patients with advanced cancer who received a single 20 mg-dose of panobinostat after taking 14 days of a strong CYP3A4 inhibitor. When a single-dose of a CYP2D6-sensitive substrate was administered after 3 doses of panobinostat (20 mg given on days 3, 5, and 8), the CYP2D6 substrate Cmax increased by 20% to 200% and the AUC value increased by 20% to 130% in 14 patients with advanced cancer; exposure was highly variable (coefficient of variance > 150%). (Major) The co-administration of panobinostat with olanzapine is not recommended; QT prolongation has been reported with both drugs. Additionally, levels of olanzapine may be increased. If concomitant use of olanzapine and panobinostat cannot be avoided, closely monitor electrocardiograms and for signs and symptoms of olanzapine toxicity including QT prolongation and cardiac arrhythmias. Hold panobinostat if the QTcF increases to >= 480 milliseconds during therapy; permanently discontinue if QT prolongation does not resolve. Olanzapine is a CYP2D6 substrate, and panobinostat is a CYP2D6 inhibitor. When a single-dose of a CYP2D6-sensitive substrate was administered after 3 doses of panobinostat (20 mg given on days 3, 5, and 8), the CYP2D6 substrate Cmax increased by 20% to 200% and the AUC value increased by 20% to 130% in 14 patients with advanced cancer; exposure was highly variable (coefficient of variance > 150%).
Paricalcitol: (Moderate) Care should be taken when dosing paricalcitol with strong CYP3A4 inhibitors, such as fluoxetine. Dose adjustments of paricalcitol may be required. Monitor plasma PTH and serum calcium and phosphorous concentrations if a patient initiates or discontinues therapy with this combination.
Paroxetine: (Major) Concurrent use of paroxetine and olanzapine may result in additive anticholinergic effects, such as urinary retention, constipation, blurred vision, and xerostomia. In addition, paroxetine is a potent inhibitor of CYP2D6, which is a minor isoenzyme pathway for the metabolism of olanzapine. Adverse effects of olanzapine that may become evident include fatigue, dizziness, weight gain, prolactin elevation, orthostatic hypotension, sedation, or extrapyramidal symptoms. In addition, olanzapine is associated with a possible risk of QT prolongation and should be used cautiously with strong CYP2D6 inhibitors such as paroxetine. (Moderate) Monitor patients for an increase in adverse reactions and signs and symptoms of serotonin syndrome during concomitant use of paroxetine and fluoxetine, particularly during treatment initiation and dosage increases. If serotonin syndrome occurs, consider discontinuation of therapy. The concomitant use of serotonergic drugs increases the risk of serotonin syndrome. Concomitant use may increase paroxetine and/or fluoxetine exposure. Paroxetine is a substrate and strong inhibitor of CYP2D6 and fluoxetine is a substrate and strong inhibitor of CYP2D6.
Pasireotide: (Moderate) Concomitant use of fluoxetine and pasireotide may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP. (Moderate) Use caution when using pasireotide in combination with olanzapine as concurrent use may increase the risk of QT prolongation. QT prolongation has occurred with pasireotide at therapeutic and supra-therapeutic doses. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval.
Pazopanib: (Major) Coadministration of pazopanib and other drugs that prolong the QT interval is not advised; pazopanib has been reported to prolong the QT interval. If pazopanib and the other drug must be continued, closely monitor the patient for QT interval prolongation. Drugs with a possible risk for QT prolongation and TdP that should be avoided with pazopanib include olanzapine. (Major) Concomitant use of pazopanib and fluoxetine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Peginterferon Alfa-2b: (Moderate) Caution is warranted with the use of fluoxetine and peginterferon alfa-2b. Fluoxetine is a substrate of CYP2D6, while peginterferon alfa-2b inhibits this enzyme. The pharmacologic effects of CYP2D6 substrates may be increased when administered with peginterferon alfa-2b. (Minor) Monitor for adverse effects associated with increased exposure to olanzapine, such as extrapyramidal symptoms, sedation, and orthostatic hypotension, if peginterferon alfa-2b is coadministered. Peginterferon alfa-2b is a CYP1A2 inhibitor, while olanzapine is a CYP1A2 substrate.
Pentamidine: (Major) Concomitant use of pentamidine and fluoxetine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. (Major) Pentamidine has been associated with QT prolongation. Drugs with a possible risk for QT prolongation and torsades de pointes (TdP) that should be used cautiously with pentamidine include olanzapine. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval in rare instances.
Pentazocine: (Major) Because of the potential risk and severity of serotonin syndrome reactions, caution should be observed when administering selective serotonin reuptake inhibitors (SSRIs) with other drugs that have serotonergic properties such as pentazocine. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. If serotonin syndrome occurs, discontinue the offending agent(s) and institute appropriate therapy. (Moderate) Coadministration of pentazocine with atypical antipsychotics may result in additive respiratory and CNS depression and anticholinergic effects, such as urinary retention and constipation. Use pentazocine with caution in any patient receiving medication with CNS depressant and/or anticholinergic activity.
Pentazocine; Naloxone: (Major) Because of the potential risk and severity of serotonin syndrome reactions, caution should be observed when administering selective serotonin reuptake inhibitors (SSRIs) with other drugs that have serotonergic properties such as pentazocine. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. If serotonin syndrome occurs, discontinue the offending agent(s) and institute appropriate therapy. (Moderate) Coadministration of pentazocine with atypical antipsychotics may result in additive respiratory and CNS depression and anticholinergic effects, such as urinary retention and constipation. Use pentazocine with caution in any patient receiving medication with CNS depressant and/or anticholinergic activity.
Pentobarbital: (Moderate) Olanzapine is metabolized by the CYP1A2 hepatic microsomal isoenzyme, and inducers of this enzyme such as barbiturates, may increase olanzapine clearance. The clinical effect of this interaction is thought to be minimal; however, the clinician should be alert for reduced olanzapine effect if the drugs are coadministered. Additive effects are possible when olanzapine is combined with other drugs which cause respiratory depression and/or CNS depression. Barbiturates can cause CNS depression, and if used concomitantly with olanzapine, can increase both the frequency and the intensity of adverse effects such as drowsiness, sedation, dizziness, and orthostatic hypotension.
Pentosan: (Moderate) Advise patients of the increased bleeding risk associated with the concomitant use of selective serotonin reuptake inhibitors (SSRIs) and pentosan, which has weak anticoagulant properties. Case reports and epidemiological studies have demonstrated an association between use of drugs that interfere with serotonin reuptake and gastrointestinal bleeding.
Perampanel: (Moderate) Co-administration of perampanel with CNS depressants, including ethanol, may increase CNS depression. The combination of perampanel (particularly at high doses) with ethanol has led to decreased mental alertness and ability to perform complex tasks (such as driving), as well as increased levels of anger, confusion, and depression; similar reactions should be expected with concomitant use of other CNS depressants, such as olanzapine.
Perindopril: (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.
Perindopril; Amlodipine: (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.
Perphenazine: (Moderate) Perphenazine, a phenothiazine, is associated with a possible risk for QT prolongation. Theoretically, perphenazine may increase the risk of QT prolongation if coadministered with drugs with a possible risk for QT prolongation, such as olanzapine. Coadministration may also increase the risk of drowsiness, dizziness, orthostatic hypotension, anticholinergic effects, extrapyramidal symptoms, neuroleptic malignant syndr ome, tardive dyskinesia, or seizures. Although the incidence of tardive dyskinesia from combination antipsychotic therapy has not been established and data are very limited, the risk appears to be increased during use of a conventional and atypical antipsychotic versus use of a conventional antipsychotic alone. (Moderate) Use fluoxetine with caution in combination with perphenazine. Coadministration may increase the risk for QT prolongation and torsade de pointes (TdP). Additionally, fluoxetine is a potent inhibitor of CYP2D6 and may result in increases in serum perphenazine concentrations, leading to side effects. QT prolongation and TdP have been reported in patients treated with fluoxetine. Perphenazine is associated with a possible risk for QT prolongation.
Perphenazine; Amitriptyline: (Moderate) Monitor for signs and symptoms of serotonin syndrome, particularly during treatment initiation and dosage increase, during concomitant amitriptyline and fluoxetine use. If serotonin syndrome occurs, discontinue therapy. Concomitant use increases the risk for serotonin syndrome. (Moderate) Perphenazine, a phenothiazine, is associated with a possible risk for QT prolongation. Theoretically, perphenazine may increase the risk of QT prolongation if coadministered with drugs with a possible risk for QT prolongation, such as olanzapine. Coadministration may also increase the risk of drowsiness, dizziness, orthostatic hypotension, anticholinergic effects, extrapyramidal symptoms, neuroleptic malignant syndrome, tardive dyskinesia, or seizures. Although the incidence of tardive dyskinesia from combination antipsychotic therapy has not been established and data are very limited, the risk appears to be increased during use of a conventional and atypical antipsychotic versus use of a conventional antipsychotic alone. (Moderate) Use fluoxetine with caution in combination with perphenazine. Coadministration may increase the risk for QT prolongation and torsade de pointes (TdP). Additionally, fluoxetine is a potent inhibitor of CYP2D6 and may result in increases in serum perphenazine concentrations, leading to side effects. QT prolongation and TdP have been reported in patients treated with fluoxetine. Perphenazine is associated with a possible risk for QT prolongation.
Phenelzine: (Contraindicated) Due to the risk of serotonin syndrome, monoamine oxidase inhibitors (MAOIs) intended to treat psychiatric disorders are contraindicated for use with selective serotonin reuptake inhibitors (SSRIs). MAOIs should not be used within 5 weeks of discontinuing treatment with fluoxetine or within 14 days of discontinuing treatment with other SSRIs. Conversely, SSRIs should not be initiated within 14 days of stopping an MAOI. Monitor the patient for serotonin-related effects during therapy transitions.
Phenobarbital: (Moderate) Olanzapine is metabolized by the CYP1A2 hepatic microsomal isoenzyme, and inducers of this enzyme such as barbiturates, may increase olanzapine clearance. The clinical effect of this interaction is thought to be minimal; however, the clinician should be alert for reduced olanzapine effect if the drugs are coadministered. Additive effects are possible when olanzapine is combined with other drugs which cause respiratory depression and/or CNS depression. Barbiturates can cause CNS depression, and if used concomitantly with olanzapine, can increase both the frequency and the intensity of adverse effects such as drowsiness, sedation, dizziness, and orthostatic hypotension.
Phenobarbital; Hyoscyamine; Atropine; Scopolamine: (Moderate) Additive anticholinergic effects may be seen when olanzapine and anticholinergics are used concomitantly; use with caution. Use of olanzapine and other drugs with anticholinergic activity can increase the risk for severe gastrointestinal adverse reactions related to hypomotility. Olanzapine exhibits anticholinergic activity. Adverse effects may be seen not only on GI smooth muscle, but also on bladder function, the CNS, the eye, and temperature regulation. Additive drowsiness may also occur, depending on the anticholinergic agent used. (Moderate) Olanzapine is metabolized by the CYP1A2 hepatic microsomal isoenzyme, and inducers of this enzyme such as barbiturates, may increase olanzapine clearance. The clinical effect of this interaction is thought to be minimal; however, the clinician should be alert for reduced olanzapine effect if the drugs are coadministered. Additive effects are possible when olanzapine is combined with other drugs which cause respiratory depression and/or CNS depression. Barbiturates can cause CNS depression, and if used concomitantly with olanzapine, can increase both the frequency and the intensity of adverse effects such as drowsiness, sedation, dizziness, and orthostatic hypotension.
Phenoxybenzamine: (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.
Phentermine: (Moderate) Use phentermine and selective serotonin reuptake inhibitors (SSRIs) together with caution due to a potential for serotonin syndrome. Monitor weight, cardiovascular status, and for potential serotonergic adverse effects. Phentermine is related to the amphetamines, and there has been historical concern that phentermine might exhibit potential to cause serotonin syndrome when combined with serotonergic agents. However, recent data suggest that phentermine's effect on MAO inhibition and serotonin augmentation is minimal at therapeutic doses and some large controlled clinical studies have allowed patients to start phentermine-based therapy for obesity along with their SSRI as long as the antidepressant dose had been stable for at least 3 months prior. Such therapy was generally well-tolerated, especially at lower phentermine doses. Because depression and obesity often coexist, the study data may be important to providing optimal co-therapies.
Phentermine; Topiramate: (Moderate) Use phentermine and selective serotonin reuptake inhibitors (SSRIs) together with caution due to a potential for serotonin syndrome. Monitor weight, cardiovascular status, and for potential serotonergic adverse effects. Phentermine is related to the amphetamines, and there has been historical concern that phentermine might exhibit potential to cause serotonin syndrome when combined with serotonergic agents. However, recent data suggest that phentermine's effect on MAO inhibition and serotonin augmentation is minimal at therapeutic doses and some large controlled clinical studies have allowed patients to start phentermine-based therapy for obesity along with their SSRI as long as the antidepressant dose had been stable for at least 3 months prior. Such therapy was generally well-tolerated, especially at lower phentermine doses. Because depression and obesity often coexist, the study data may be important to providing optimal co-therapies.
Phenytoin: (Major) Olanzapine is metabolized by the CYP1A2 hepatic microsomal isoenzyme, and inducers of this enzyme, such as hydantoins, may increase olanzapine clearance. Clinicians should monitor for reduced effectiveness of the antipsychotic agent if hydantoin therapy is added. (Moderate) Monitor phenytoin concentrations during concomitant therapy with fluoxetine due to risk for phenytoin toxicity. Concomitant use may increase phenytoin concentrations. Phenytoin is a CYP2C9 and CYP2C19 substrate and fluoxetine is a CYP2C9 and CYP2C19 inhibitor.
Pimavanserin: (Major) Concomitant use of pimavanserin and fluoxetine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. (Major) Pimavanserin may cause QT prolongation and should generally be avoided in patients receiving other medications known to prolong the QT interval, such as olanzapine. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval in rare instances. Coadministration may increase the risk for QT prolongation.
Pimozide: (Contraindicated) Olanzapine has a risk of QT prolongation and is contraindicated with pimozide. Concurrent use of pimozide with atypical agents may increase the risk of adverse effects such as drowsiness, sedation, dizziness, orthostatic hypotension, extrapyramidal symptoms, neuroleptic malignant syndrome, or seizures. The likelihood of these pharmacodynamic interactions varies based upon the individual properties of the co-administered antipsychotic agent. Although the incidence of tardive dyskinesia from combination antipsychotic therapy has not been established and data are very limited, the risk appears to be increased during use of a conventional and atypical antipsychotic versus use of a conventional antipsychotic alone. (Contraindicated) Pimozide is contraindicated for use with selective serotonin reuptake inhibitors (SSRIs) due to an increased risk of QT prolongation and torsade de pointes (TdP). Pimozide is thought to be primarily metabolized through CYP3A4, and to a lesser extent, CYP1A2 and CYP2D6. Elevated plasma concentrations of pimozide occurring through inhibition of one or more of these isoenzymes by SSRIs can lead to QT prolongation, ventricular arrhythmias, and sudden death. Additionally, most SSRIs are also associated with QT prolongation, further increasing the risk of additive QT prolongation.
Pindolol: (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.
Pioglitazone: (Moderate) Atypical antipsychotic therapy may aggravate diabetes mellitus and cause metabolic changes such as hyperglycemia. Monitor patients on antidiabetic agents for worsening glycemic control. Atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Aggravation of diabetes mellitus has been reported. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.
Pioglitazone; Glimepiride: (Moderate) Atypical antipsychotic therapy may aggravate diabetes mellitus and cause metabolic changes such as hyperglycemia. Monitor patients on antidiabetic agents for worsening glycemic control. Atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Aggravation of diabetes mellitus has been reported. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.
Pioglitazone; Metformin: (Moderate) Atypical antipsychotic therapy may aggravate diabetes mellitus and cause metabolic changes such as hyperglycemia. Monitor patients on antidiabetic agents for worsening glycemic control. Atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Aggravation of diabetes mellitus has been reported. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition. (Moderate) Monitor blood glucose during concomitant atypical antipsychotic and metformin use. Atypical antipsychotic therapy may aggravate diabetes mellitus. Atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition. (Moderate) Monitor blood glucose during concomitant metformin and fluoxetine use; a metformin dose adjustment may be necessary. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
Pitolisant: (Major) Avoid coadministration of pitolisant and fluoxetine as concurrent use may increase the risk of QT prolongation. If concurrent use is unavoidable, initiate pitolisant at 8.9 mg once daily; increase pitolisant after 7 days to a maximum dosage of 17.8 mg once daily. If fluoxetine is initiated in a patient on a stable dose of pitolisant, reduce the pitolisant dose by half. Pitolisant is a CYP2D6 substrate that prolongs the QT interval; fluoxetine is a strong CYP2D6 inhibitor that has been associated with QT prolongation and torsade de pointes. Coadministration of strong CYP2D6 inhibitors increases pitolisant exposure by 2.2-fold. (Major) Avoid coadministration of pitolisant with olanzapine as concurrent use may increase the risk of QT prolongation. Pitolisant prolongs the QT interval. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval.
Ponesimod: (Major) In general, do not initiate ponesimod in patients taking fluoxetine due to the risk of additive bradycardia, QT prolongation, and torsade de pointes (TdP). If treatment initiation is considered, seek advice from a cardiologist. Ponesimod initiation may result in a transient decrease in heart rate and atrioventricular conduction delays. Ponesimod has not been studied in patients taking concurrent QT prolonging drugs; however, QT prolonging drugs have been associated with TdP in patients with bradycardia. Fluoxetine is associated with QT prolongation and TdP. (Major) In general, do not initiate ponesimod in patients taking olanzapine due to the risk of additive bradycardia, QT prolongation, and torsade de pointes (TdP). If treatment initiation is considered, seek advice from a cardiologist. Ponesimod initiation may result in a transient decrease in heart rate and atrioventricular conduction delays. Ponesimod has not been studied in patients taking concurrent QT prolonging drugs; however, QT prolonging drugs have been associated with TdP in patients with bradycardia. Limited date, including some case reports suggest that olanzapine may be associated with a significant prolongation of the QTc interval.
Posaconazole: (Moderate) Concomitant use of fluoxetine and posaconazole may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP. (Moderate) Use posaconazole with caution in combination with olanzapine as concurrent use may increase the risk of QT prolongation. Posaconazole has been associated with prolongation of the QT interval as well as rare cases of torsade de pointes. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval.
Potassium-sparing diuretics: (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.
Pramipexole: (Moderate) Monitor for movement disorders, unusual changes in moods or behavior, and diminished effectiveness of the atypical antipsychotic or pramipexole during coadministration. Due to mutually opposing effects on dopamine, atypical antipsychotics and pramipexole may interfere with the effectiveness of each other. Additive CNS depressant effects are also possible. In general, atypical antipsychotics are less likely to interfere with pramipexole than traditional antipsychotics. The Beers Criteria recognize quetiapine and clozapine as exceptions to the general recommendation to avoid all antipsychotics in older adults with Parkinson's disease.
Pramlintide: (Moderate) Atypical antipsychotic therapy may aggravate diabetes mellitus and cause metabolic changes such as hyperglycemia. Monitor patients on antidiabetic agents for worsening glycemic control. The atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Aggravation of diabetes mellitus has been reported. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition. (Moderate) In patients with diabetes mellitus, fluoxetine may alter glycemic control. Hypoglycemia has occurred during fluoxetine therapy. Hyperglycemia has developed in patients with diabetes mellitus following discontinuation of the drug. The dosage of insulin and/or other antidiabetic agents may need to be adjusted when therapy with fluoxetine is instituted or discontinued.
Prasugrel: (Moderate) Platelet aggregation may be impaired by selective serotonin reuptake inhibitors (SSRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication in patients receiving prasugrel. Patients should be instructed to monitor for signs and symptoms of bleeding while taking an SSRI concurrently with an antiplatelet medication and to promptly report any bleeding events to the practitioner.
Pregabalin: (Moderate) Initiate pregabalin at the lowest recommended dose and monitor patients for symptoms of sedation and somnolence during coadministration of pregabalin and olanzapine. Concomitant use of pregabalin with olanzapine may cause additive CNS depression. Educate patients about the risks and symptoms of excessive CNS depression.
Prilocaine; Epinephrine: (Moderate) Olanzapine may induce significant alpha-adrenergic blockade in overdose, leading to profound hypotension. Do not use epinephrine, dopamine, or other sympathomimetics with beta-agonist activity since the beta-stimulation may worsen hypotension in the setting of olanzapine overdose.
Primaquine: (Moderate) Concomitant use of fluoxetine and primaquine may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP. (Moderate) Exercise caution when administering primaquine in combination with olanzapine as concurrent use may increase the risk of QT prolongation. Primaquine is associated with QT prolongation. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval.
Primidone: (Moderate) Olanzapine is metabolized by the CYP1A2 hepatic microsomal isoenzyme, and inducers of this enzyme such as barbiturates, may increase olanzapine clearance. The clinical effect of this interaction is thought to be minimal; however, the clinician should be alert for reduced olanzapine effect if the drugs are coadministered. Additive effects are possible when olanzapine is combined with other drugs which cause respiratory depression and/or CNS depression. Barbiturates can cause CNS depression, and if used concomitantly with olanzapine, can increase both the frequency and the intensity of adverse effects such as drowsiness, sedation, dizziness, and orthostatic hypotension.
Procainamide: (Major) Concomitant use of procainamide and fluoxetine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. (Major) Olanzapine should be used cautiously and with close monitoring with procainamide. Procainamide administration is associated with QT prolongation and torsades de pointes (TdP). Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval in rare instances. Therefore, caution is advised when administering olanzapine with drugs having an established causal association with QT prolongation and torsade de pointes (TdP).
Procarbazine: (Major) Procarbazine is a weak monoamine oxidase inhibitor (MAOI). Although procarbazine appears to be less likely than other MAOIs to produce serious drug interactions, clinicians should avoid the use of selective serotonin reuptake inhibitors (SSRIs) in patients receiving MAOIs. Fatalities have been reported when fluoxetine was administered to patients receiving MAOIs. Confusion, seizures, severe hypertension, and other, less severe symptoms have also been reported with this drug combination. Non-selective MAOIs inhibit both MAO types A and B. Since serotonin is metabolized by MAO type A, it is thought that this drug interaction may lead to serotonin syndrome or neuroleptic malignant syndrome-like reactions. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. At least 2 weeks should elapse between the discontinuation of MAOI therapy and the start of therapy with an SSRI except fluoxetine. At least 5 weeks should elapse between the discontinuation of fluoxetine therapy and commencement of MAOI therapy. This 5-week period is needed because of the long half-lives of fluoxetine and its principle metabolite norfluoxetine.
Prochlorperazine: (Moderate) Both prochlorperazine and olanzapine are associated with a possible risk for QT prolongation; this risk may be increased during concurrent use. Coadministration of antipsychotics may also increase the risk of drowsiness, dizziness, orthostatic hypotension, anticholinergic effects, extrapyramidal symptoms, neuroleptic malignant syndrome, or seizures. Although the incidence of tardive dyskinesia from combination antipsychotic therapy has not been established and data are very limited, the risk appears to be increased during use of a conventional and atypical antipsychotic versus use of a conventional antipsychotic alone. (Moderate) Use fluoxetine with caution in combination with prochlorperazine. Coadministration may increase the risk for QT prolongation and torsade de pointes (TdP). Additionally, fluoxetine is a potent inhibitor of CYP2D6 and may result in increases in serum prochlorperazine concentrations, leading to side effects. QT prolongation and TdP have been reported in patients treated with fluoxetine. Prochlorperazine is associated with a possible risk for QT prolongation.
Promethazine: (Moderate) Concomitant use of promethazine and fluoxetine may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP. (Moderate) The use of promethazine, a phenothiazine antiemetic, with atypical antipsychotics such as olanzapine should be avoided when possible. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval in rare instances. Promethazine has also been reported to cause QT prolongation. Coadministration of promethazine and antipsychotics may also increase the risk of adverse effects such as drowsiness, dizziness, orthostatic hypotension, anticholinergic effects, extrapyramidal symptoms, neuroleptic malignant syndrome, tardive dyskinesia, or seizures. Although the incidence of tardive dyskinesia from these combinations has not been established and data are very limited, the risk may be increased during combined use versus use of an antipsychotic alone.
Promethazine; Dextromethorphan: (Moderate) Concomitant use of promethazine and fluoxetine may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP. (Moderate) Monitor for dextromethorphan-related side effects, such as dizziness or drowsiness, if concomitant use of fluoxetine is necessary. For patients receiving combination dextromethorphan; bupropion, do not exceed a maximum dose of 45 mg dextromethorphan; 105 mg bupropion once daily. Additionally, monitor patients for signs and symptoms of serotonin syndrome. Concomitant use may increase dextromethorphan exposure and the risk for serotonin syndrome. Dextromethorphan is a CYP2D6 substrate and fluoxetine is a strong CYP2D6 inhibitor. Concomitant use with another strong CYP2D6 inhibitor increased dextromethorphan overall exposure by 2.69-fold. (Moderate) The use of promethazine, a phenothiazine antiemetic, with atypical antipsychotics such as olanzapine should be avoided when possible. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval in rare instances. Promethazine has also been reported to cause QT prolongation. Coadministration of promethazine and antipsychotics may also increase the risk of adverse effects such as drowsiness, dizziness, orthostatic hypotension, anticholinergic effects, extrapyramidal symptoms, neuroleptic malignant syndrome, tardive dyskinesia, or seizures. Although the incidence of tardive dyskinesia from these combinations has not been established and data are very limited, the risk may be increased during combined use versus use of an antipsychotic alone.
Promethazine; Phenylephrine: (Moderate) Concomitant use of promethazine and fluoxetine may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP. (Moderate) The use of promethazine, a phenothiazine antiemetic, with atypical antipsychotics such as olanzapine should be avoided when possible. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval in rare instances. Promethazine has also been reported to cause QT prolongation. Coadministration of promethazine and antipsychotics may also increase the risk of adverse effects such as drowsiness, dizziness, orthostatic hypotension, anticholinergic effects, extrapyramidal symptoms, neuroleptic malignant syndrome, tardive dyskinesia, or seizures. Although the incidence of tardive dyskinesia from these combinations has not been established and data are very limited, the risk may be increased during combined use versus use of an antipsychotic alone.
Propafenone: (Major) Concomitant use of fluoxetine and propafenone increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Concomitant use may also increase the exposure of propafenone, further increasing the risk of proarrhythmias. Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. Propafenone is a CYP2D6 substrate and fluoxetine is a strong CYP2D6 inhibitor. Concomitant administration of propafenone and fluoxetine in extensive metabolizers increases the S-propafenone Cmax and AUC by 39% and 50%, and the R-propafenone Cmax and AUC by 71% and 50%. (Major) Concomitant use of propafenone and olanzapine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Propantheline: (Moderate) Additive anticholinergic effects may be seen when olanzapine and anticholinergics are used concomitantly; use with caution. Use of olanzapine and other drugs with anticholinergic activity can increase the risk for severe gastrointestinal adverse reactions related to hypomotility. Olanzapine exhibits anticholinergic activity. Adverse effects may be seen not only on GI smooth muscle, but also on bladder function, the CNS, the eye, and temperature regulation. Additive drowsiness may also occur, depending on the anticholinergic agent used.
Propranolol: (Moderate) Monitor for increased propranolol adverse reactions, including bradycardia and hypotension, during coadministration of fluoxetine as concurrent use may increase propranolol exposure. Propranolol is a CYP2D6 substrate and fluoxetine is a moderate CYP2D6 inhibitor. (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.
Propranolol; Hydrochlorothiazide, HCTZ: (Moderate) Monitor for increased propranolol adverse reactions, including bradycardia and hypotension, during coadministration of fluoxetine as concurrent use may increase propranolol exposure. Propranolol is a CYP2D6 substrate and fluoxetine is a moderate CYP2D6 inhibitor. (Moderate) Monitor for signs and symptoms of hyponatremia during concomitant diuretic and fluoxetine use; consider discontinuing fluoxetine if symptomatic hyponatremia occurs and institute appropriate medical intervention. Concomitant use increases the risk for developing hyponatremia. (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.
Protriptyline: (Moderate) Coadministration of fluoxetine and protriptyline may increase the risk for QT prolongation, torsade de pointes (TdP), and serotonin syndrome. If serotonin syndrome is suspected, discontinue fluoxetine and concurrent serotonergic agents and initiate appropriate medical treatment. QT prolongation and TdP have been reported in patients treated with fluoxetine. Tricyclics, particularly at elevated concentrations, are associated with a possible risk of QT prolongation and TdP.
Pseudoephedrine; Triprolidine: (Moderate) Olanzapine exhibits anticholinergic effects that may be clinically significant. Clinicians should keep this in mind when using antimuscarinics and other medications with anticholinergic activity in combination with olanzapine. Some medications exhibit additive anticholinergic effects include sedating H1-blockers. Olanzapine may also cause additive sedation with many of these drugs.
Quazepam: (Moderate) Although oral formulations of olanzapine and benzodiazepines may be used together, additive effects on respiratory depression and/or CNS depression are possible. Drugs that can cause CNS depression, if used concomitantly with olanzapine, can increase both the frequency and the intensity of adverse effects such as drowsiness, sedation, dizziness, and orthostatic hypotension. Besides ethanol, clinicians should use other anxiolytics, sedatives, and hypnotics cautiously with olanzapine. (Moderate) Fluoxetine could theoretically inhibit CYP3A4 metabolism of oxidized benzodiazepines, including quazepam. Patients should be monitored for clinical response, and adjust benzodiazepine dosage if needed.
Quetiapine: (Major) Avoid use together if possible. Coadministration may increase the risk for QT prolongation and torsade de pointes. Caution is also advised since both drugs act on the CNS. If use together is necessary, consider using lower initial doses of the concomitantly administered drugs, using conservative titration schedules, and monitoring of clinical status. According to the manufacturer of quetiapine, other drugs having an association with QT prolongation should not be used with quetiapine. QT prolongation and torsade de pointes (TdP) have been reported during postmarketing use of fluoxetine. The manufacturer of fluoxetine recommends caution with combined use. The effects of fluoxetine on interacting drugs may persist for several weeks after discontinuation of fluoxetine because of its long elimination half-life. In a study conducted by the manufacturer, concurrent use of 60 mg/day of fluoxetine and 300 mg twice daily of quetiapine did not alter the pharmacokinetics of quetiapine. (Major) Concurrent use of quetiapine and olanzapine should be avoided due to an increased risk for QT prolongation and torsade de pointes (TdP). Limited data, including some case reports, suggest that both olanzapine and quetiapine may be associated with a significant prolongation of the QTc interval in rare instances. In addition, co-administration of quetiapine with olanzapine may increase the risk of adverse effects such as drowsiness, dizziness, orthostatic hypotension, anticholinergic effects, extrapyramidal symptoms, neuroleptic malignant syndrome, or seizures. The likelihood of pharmacodynamic interactions varies based upon the individual properties of the co-administered antipsychotic agent. Although the incidence of tardive dyskinesia from combination antipsychotic therapy has not been established and data are very limited, the risk appears to be increased during use of a conventional and atypical antipsychotic versus use of a conventional antipsychotic alone.
Quinapril: (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.
Quinapril; Hydrochlorothiazide, HCTZ: (Moderate) Monitor for signs and symptoms of hyponatremia during concomitant diuretic and fluoxetine use; consider discontinuing fluoxetine if symptomatic hyponatremia occurs and institute appropriate medical intervention. Concomitant use increases the risk for developing hyponatremia. (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.
Quinidine: (Contraindicated) Concurrent use of either quinidine or dextromethorphan; quinidine and fluoxetine is considered a contraindication. Quinidine and dextromethorphan; quinidine are contraindicated for use in patients taking drugs that prolong the QT interval and are metabolized by CYP2D6. Fluoxetine is a primary substrate of CYP2D6, and is associated with a risk of QT prolongation and torsade de pointes (TdP). (Major) Quinidine and dextromethorphan; quinidine cause dose-dependent QT prolongation. These drugs should be avoided in patients receiving drugs that may prolong the QT interval and are metabolized by CYP2D6, such as olanzapine. The manufacturer recommends an ECG in patients taking these drugs together.
Quinine: (Major) Concomitant use of quinine and fluoxetine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. (Major) Concurrent use of quinine and olanzapine should be avoided due to an increased risk for QT prolongation and torsade de pointes (TdP). Quinine has been associated with prolongation of the QT interval and rare cases of TdP. Limited data, including some case reports, suggest that olanzapine may also be associated with a significant prolongation of the QTc interval in rare instances. In addition, concentrations of olanzapine may be increased with concomitant use of quinine. Olanzapine is a CYP2D6 substrate and quinine is a CYP2D6 inhibitor.
Quizartinib: (Major) Concomitant use of quizartinib and fluoxetine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. (Major) Concomitant use of quizartinib and olanzapine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Ramelteon: (Moderate) Additive effects are possible when olanzapine is combined with other drugs which cause respiratory depression and/or CNS depression including ramelteon.
Ramipril: (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.
Ranolazine: (Major) Ranolazine is associated with dose- and plasma concentration-related increases in the QTc interval. The mean increase in QTc is about 6 milliseconds, measured at the tmax of the maximum dosage (1000 mg PO twice daily). However, in 5% of the population studied, increases in the QTc of at least 15 milliseconds have been reported. Although there are no studies examining the effects of ranolazine in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation. In addition, ranolazine and/or metabolites are moderate inhibitors of CYP2D6 isoenzymes. Based on drug interaction studies with metoprolol, a CYP2D6 substrate, ranolazine may theoretically increase plasma concentrations of CYP2D6 substrates and could lead to toxicity for drugs that have a narrow therapeutic range. The manufacturer for ranolazine suggests that lower doses of CYP2D6 substrates may be required during ranolazine treatment. Drugs that are CYP2D6 substrates that also have a possible risk for QT prolongation and TdP that should be used cautiously with ranolazine include olanzapine. (Major) Use fluoxetine with caution in combination with ranolazine. Coadministration may increase the risk for QT prolongation and torsade de pointes (TdP). Additionally, monitor for adverse effects of fluoxetine during coadministration as ranolazine may increase the concentrations of fluoxetine. QT prolongation and TdP have been reported in patients treated with fluoxetine. Ranolazine is associated with dose- and plasma concentration-related increases in the QTc interval. Fluoxetine is a substrate of CYP2D6; ranolazine is a moderate inhibitor of CYP2D6.
Rasagiline: (Major) It is recommended to avoid concurrent use of rasagiline and selective serotonin reuptake inhibitors (SSRIs). Severe CNS toxicity with hyperpyrexia has been reported during concurrent use of antidepressants and selective or non-selective MAOIs. During postmarketing use of rasagiline, non-fatal cases of serotonin syndrome have been reported during concomitant antidepressant administration. At least 2 weeks should elapse between stopping rasagiline treatment and beginning therapy with any SSRI. Conversely, when discontinuing an SSRI, it is advisable to wait the length of 4 to 5 half-lives of the individual agent being discontinued prior to initiation with rasagiline. At least 5 weeks should elapse between the discontinuation of fluoxetine therapy and initiation of rasagiline. If coadministration of rasagiline and fluvoxamine is required, do not exceed a rasagiline dose of 0.5 mg once daily. Rasagiline is primarily metabolized by CYP1A2; fluvoxamine is a strong CYP1A2 inhibitor. When rasagiline was administered with another strong CYP1A2 inhibitor, the AUC of rasagiline increased by 83%. (Moderate) Monitor for movement disorders, unusual changes in moods or behavior, and diminished effectiveness of the atypical antipsychotic or rasagiline during coadministration. Due to mutually opposing effects on dopamine, atypical antipsychotics and rasagiline may interfere with the effectiveness of each other. In general, atypical antipsychotics are less likely to interfere with rasagiline than traditional antipsychotics. The Beers Criteria recognize quetiapine and clozapine as exceptions to the general recommendation to avoid all antipsychotics in older adults with Parkinson's disease.
Relugolix: (Moderate) Caution is advised when administering olanzapine with relugolix. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval. Androgen deprivation therapy (i.e., relugolix) may also prolong the QT/QTc interval. (Moderate) Concomitant use of fluoxetine and androgen deprivation therapy (i.e., relugolix) may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP.
Relugolix; Estradiol; Norethindrone acetate: (Moderate) Caution is advised when administering olanzapine with relugolix. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval. Androgen deprivation therapy (i.e., relugolix) may also prolong the QT/QTc interval. (Moderate) Concomitant use of fluoxetine and androgen deprivation therapy (i.e., relugolix) may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP. (Minor) As fluoxetine inhibits CYP3A4 activity, serum estrogen concentrations and estrogenic-related side effects (e.g., nausea, breast tenderness) may potentially increase when coadministered with either estrogens or combined hormonal contraceptives.
Remifentanil: (Major) Concomitant use of opioid agonists with olanzapine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with olanzapine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Also monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. (Moderate) If concomitant use of remifentanil and selective serotonin reuptake inhibitors (SSRIs) is warranted, monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
Repaglinide: (Moderate) Atypical antipsychotic therapy may aggravate diabetes mellitus and cause metabolic changes such as hyperglycemia. Monitor patients on antidiabetic agents for worsening glycemic control. The atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Aggravation of diabetes mellitus has been reported. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.
Reteplase, r-PA: (Moderate) Platelet aggregation may be impaired by selective serotonin reuptake inhibitors (SSRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication in patients receiving thrombolytic agents. Patients should be closely monitored for signs and symptoms of bleeding when a thrombolytic agent is administered with an SSRI.
Ribociclib: (Major) Avoid coadministration of ribociclib with fluoxetine due to an increased risk for QT prolongation and torsade de pointes (TdP). Additionally, the systemic exposure of ribociclib may be increased resulting in an increase in treatment-related adverse reactions (e.g., neutropenia, QT prolongation). Ribociclib is a CYP3A4 substrate that has been shown to prolong the QT interval in a concentration-dependent manner. Prolongation of the QT interval and TdP have been reported in patients treated with fluoxetine. While fluoxetine is a weak inhibitor of CYP3A4, its metabolite norfluoxetine is a moderate CYP3A4 inhibitor. (Major) Avoid coadministration of ribociclib with olanzapine due to an increased risk for QT prolongation. Ribociclib has been shown to prolong the QT interval in a concentration-dependent manner. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval. Concomitant use may increase the risk for QT prolongation.
Ribociclib; Letrozole: (Major) Avoid coadministration of ribociclib with fluoxetine due to an increased risk for QT prolongation and torsade de pointes (TdP). Additionally, the systemic exposure of ribociclib may be increased resulting in an increase in treatment-related adverse reactions (e.g., neutropenia, QT prolongation). Ribociclib is a CYP3A4 substrate that has been shown to prolong the QT interval in a concentration-dependent manner. Prolongation of the QT interval and TdP have been reported in patients treated with fluoxetine. While fluoxetine is a weak inhibitor of CYP3A4, its metabolite norfluoxetine is a moderate CYP3A4 inhibitor. (Major) Avoid coadministration of ribociclib with olanzapine due to an increased risk for QT prolongation. Ribociclib has been shown to prolong the QT interval in a concentration-dependent manner. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval. Concomitant use may increase the risk for QT prolongation.
Rifampin: (Moderate) Monitor for reduced olanzapine efficacy if rifampin coadministration is medically necessary; in some patients, dosage adjustments may be needed. Olanzapine is metabolized by the CYP1A2 hepatic microsomal isoenzyme, and potent inducers of this enzyme increase olanzapine clearance. While rifampin is a CYP3A inducer, it is likely its induction of CYP1A2 is responsible for the increased olanzapine clearance, and roughly 48% decrease in olanzapine AUC (exposure) seen when rifampin is used with olanzapine.
Rilpivirine: (Moderate) Caution is advised when administering rilpivirine with olanzapine as concurrent use may increase the risk of QT prolongation. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. Limited data, including some case reports, suggest that olanzapine may also be associated with a significant prolongation of the QTc interval. (Moderate) Concomitant use of fluoxetine and rilpivirine may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP. The degree of QT prolongation associated with rilpivirine is not clinically significant when administered within the recommended dosage range; QT prolongation has been described at 3 times the maximum recommended dose.
Risperidone: (Moderate) Monitor for an increase in risperidone-related adverse effects if concomitant use with fluoxetine is necessary and reduce risperidone dosage as appropriate based on response. For patients receiving long-acting risperidone dosage forms, an anticipatory dosage decrease may be considered prior to initiation of fluoxetine. Concomitant use may increase risperidone exposure. Additionally, concomitant use may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP. Risperidone is a CYP2D6 substrate and fluoxetine is a strong CYP2D6 inhibitor. Concomitant use has been observed to increase risperidone overall exposure by 2.5- to 2.8-fold. (Moderate) Use risperidone and olanzapine together with caution due to the potential for additive QT prolongation and risk of torsade de pointes (TdP). In addition, coadministration may increase the risk of adverse effects such as drowsiness, dizziness, orthostatic hypotension, anticholinergic effects, extrapyramidal symptoms, neuroleptic malignant syndrome, or seizures. Risperidone has been associated with a possible risk for QT prolongation and/or TdP, primarily in the overdose setting. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval.
Ritonavir: (Moderate) Monitor for increased fluoxetine-related adverse effects if coadministered with ritonavir. Concurrent use may result in increased fluoxetine exposure. Fluoxetine is a CYP2D6 substrate and ritonavir is a weak CYP2D6 inhibitor. (Moderate) Ritonavir may reduce olanzapine serum concentrations by approximately 50%; how this affects olanzapine efficacy, however, is not known. Ritonavir appears to induce olanzapine's metabolism by either CYP1A2 or glucuronide conjugation. If ritonavir and olanzapine are used concurrently, monitor for reduced olanzapine effect and adjust olanzapine dose as needed.
Rivaroxaban: (Moderate) Advise patients of the increased bleeding risk associated with the concomitant use of selective serotonin reuptake inhibitors (SSRIs) and anticoagulants like rivaroxaban. Case reports and epidemiological studies have demonstrated an association between use of drugs that interfere with serotonin reuptake and gastrointestinal bleeding.
Rivastigmine: (Moderate) Olanzapine exhibits moderate anticholinergic activity, and is more likely than most other atypical antipsychotics to diminish the therapeutic action of rivastigmine. Consider the use of an antipsychotic with less prominent anticholinergic effects. Rivastigmine inhibits acetylcholinesterase, the enzyme responsible for the degradation of acetylcholine, and exerts its therapeutic effect by improving the availability of acetylcholine.
Rizatriptan: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering rizatriptan with selective serotonin reuptake inhibitors (SSRIs). Serotonin syndrome has been reported during concurrent use of serotonin-receptor agonists ("triptans") and SSRIs. Some patients had used the combination previously without incident when serotonin syndrome occurred. Inform patients of the possible increased risk and monitor for the emergence of serotonin syndrome, particularly after the initiation of the SSRI or dose increases. Discontinue serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
Rolapitant: (Major) Monitor for olanzapine-related adverse effects, including QT prolongation, if coadministered with rolapitant. Increased exposure to olanzapine may occur. Olanzapine is a CYP2D6 substrate that is individually dose-titrated, and rolapitant is a moderate CYP2D6 inhibitor; the inhibitory effect of rolapitant is expected to persist beyond 28 days for an unknown duration. Exposure to another CYP2D6 substrate, following a single dose of rolapitant increased about 3-fold on Days 8 and Day 22. The inhibition of CYP2D6 persisted on Day 28 with a 2.3-fold increase in the CYP2D6 substrate concentrations, the last time point measured. (Major) Use caution if fluoxetine and rolapitant are used concurrently, and monitor for fluoxetine-related adverse effects. Fluoxetine is a CYP2D6 substrate and rolapitant is a moderate CYP2D6 inhibitor; the inhibitory effect of rolapitant is expected to persist beyond 28 days for an unknown duration. Exposure to another CYP2D6 substrate, following a single dose of rolapitant increased about 3-fold on Days 8 and Day 22. The inhibition of CYP2D6 persisted on Day 28 with a 2.3-fold increase in the CYP2D6 substrate concentrations, the last time point measured.
Romidepsin: (Moderate) Concomitant use of fluoxetine and romidepsin may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP. (Moderate) Consider monitoring electrolytes and ECGs at baseline and periodically during treatment if romidepsin is administered with olanzapine as concurrent use may increase the risk of QT prolongation. Romidepsin has been reported to prolong the QT interval. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval.
Ropinirole: (Moderate) Monitor for movement disorders, unusual changes in moods or behavior, and diminished effectiveness of the atypical antipsychotic or ropinirole during coadministration. Due to mutually opposing effects on dopamine, atypical antipsychotics and ropinirole may interfere with the effectiveness of each other. In general, atypical antipsychotics are less likely to interfere with ropinirole than traditional antipsychotics. The Beers Criteria recognize quetiapine and clozapine as exceptions to the general recommendation to avoid all antipsychotics in older adults with Parkinson's disease.
Rosiglitazone: (Moderate) Atypical antipsychotic therapy may aggravate diabetes mellitus and cause metabolic changes such as hyperglycemia. Monitor patients on antidiabetic agents for worsening glycemic control. Atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Aggravation of diabetes mellitus has been reported. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.
Rotigotine: (Moderate) Monitor for movement disorders, unusual changes in moods or behavior, excess sedation, and diminished effectiveness of the atypical antipsychotic or rotigotine during coadministration. Due to mutually opposing effects on dopamine, atypical antipsychotics and rotigotine may interfere with the effectiveness of each other. Additive CNS depressant effects are also possible. In general, atypical antipsychotics are less likely to interfere with rotigotine than traditional antipsychotics. The Beers Criteria recognize quetiapine and clozapine as exceptions to the general recommendation to avoid all antipsychotics in older adults with Parkinson's disease.
Rucaparib: (Moderate) Monitor for increased fluoxetine-related adverse effects if coadministered with rucaparib. Concurrent use may result in increased fluoxetine exposure. Fluoxetine is a CYP2D6 substrate and rucaparib is a weak CYP2D6 inhibitor.
Ruxolitinib: (Moderate) Ruxolitinib is a CYP3A4 substrate. When used with drugs that are mild or moderate inhibitors of CYP3A4 such as fluoxetine, a dose adjustment is not necessary, but monitoring patients for toxicity may be prudent. There was an 8% and 27% increase in the Cmax and AUC of a single dose of ruxolitinib 10 mg, respectively, when the dose was given after a short course of erythromycin 500 mg PO twice daily for 4 days. The change in the pharmacodynamic marker pSTAT3 inhibition was consistent with the increase in exposure.
Sacubitril; Valsartan: (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.
Safinamide: (Major) The concurrent use of selective serotonin reuptake inhibitors (SSRIs) and monoamine oxidase inhibitors (MAOIs) is generally avoided; however, the manufacturer of safinamide recommends monitoring for serotonin syndrome and using the lowest effective dose of the SSRI during concurrent use. During clinical trial evaluation of safinamide, 1 case of serotonin syndrome occurred during co-administration with an SSRI. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. (Moderate) Monitor for movement disorders, unusual changes in moods or behavior, and diminished effectiveness of the atypical antipsychotic or safinamide during coadministration. Due to mutually opposing effects on dopamine, atypical antipsychotics and safinamide may interfere with the effectiveness of each other. In general, atypical antipsychotics are less likely to interfere with safinamide than traditional antipsychotics. The Beers Criteria recognize quetiapine and clozapine as exceptions to the general recommendation to avoid all antipsychotics in older adults with Parkinson's disease.
Salsalate: (Moderate) The combined use of selective serotonin reuptake inhibitors (SSRIs) and aspirin, ASA or other salicylates which affect hemostasis may elevate the risk for an upper GI bleed. SSRIs may inhibit serotonin uptake by platelets, augmenting the antiplatelet effects of aspirin. Additionally, aspirin impairs the gastric mucosa defenses by inhibiting prostaglandin formation. A cohort study in > 26,000 patients found that SSRI use alone increased the risk for serious GI bleed by 3.6-fold; when an SSRI was combined with aspirin the risk was increased by > 5-fold. The absolute risk of GI bleed from concomitant therapy with aspirin and a SSRI was low (20/2640 patients) in this cohort study and the clinician may determine that the combined use of these drugs is appropriate.
Saquinavir: (Major) Avoid coadministration of fluoxetine with saquinavir boosted with ritonavir due to an increased risk for QT prolongation and torsade de pointes (TdP). If no acceptable alternative therapy is available, perform a baseline ECG prior to initiation of concomitant therapy and carefully follow monitoring recommendations. QT prolongation and TdP have been reported in patients treated with fluoxetine. Saquinavir boosted with ritonavir increases the QT interval in a dose-dependent fashion, which may increase the risk for serious arrhythmias such as TdP. (Major) Concurrent use of olanzapine and saquinavir should be avoided due to an increased risk for QT prolongation and torsade de pointes (TdP). If no acceptable alternative therapy is available, perform a baseline ECG prior to initiation of concomitant therapy and carefully follow monitoring recommendations. Saquinavir boosted with ritonavir increases the QT interval in a dose-dependent fashion, which may increase the risk for serious arrhythmias such as TdP. Limited data, including some case reports, suggest that olanzapine may also be associated with a significant prolongation of the QTc interval in rare instances.
Saxagliptin: (Moderate) Monitor blood glucose during concomitant atypical antipsychotic and dipeptidyl peptidase-4 (DPP-4) inhibitor use. Atypical antipsychotic therapy may aggravate diabetes mellitus. Atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition. (Moderate) Monitor blood glucose during concomitant dipeptidyl peptidase-4 (DPP-4) inhibitor and fluoxetine use; a DPP-4 inhibitor dose adjustment may be necessary. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
Scopolamine: (Moderate) Additive anticholinergic effects may be seen when olanzapine and anticholinergics are used concomitantly; use with caution. Use of olanzapine and other drugs with anticholinergic activity can increase the risk for severe gastrointestinal adverse reactions related to hypomotility. Olanzapine exhibits anticholinergic activity. Adverse effects may be seen not only on GI smooth muscle, but also on bladder function, the CNS, the eye, and temperature regulation. Additive drowsiness may also occur, depending on the anticholinergic agent used.
Secobarbital: (Moderate) Olanzapine is metabolized by the CYP1A2 hepatic microsomal isoenzyme, and inducers of this enzyme such as barbiturates, may increase olanzapine clearance. The clinical effect of this interaction is thought to be minimal; however, the clinician should be alert for reduced olanzapine effect if the drugs are coadministered. Additive effects are possible when olanzapine is combined with other drugs which cause respiratory depression and/or CNS depression. Barbiturates can cause CNS depression, and if used concomitantly with olanzapine, can increase both the frequency and the intensity of adverse effects such as drowsiness, sedation, dizziness, and orthostatic hypotension.
Selegiline: (Contraindicated) Selective serotonin reuptake inhibitors (SSRIs) are contraindicated for use with selegiline, a selective monoamine oxidase type B inhibitor (MAO-B inhibitor). At least 14 days should elapse between discontinuation of selegiline and initiation of treatment with an SSRI. With the exception of fluoxetine, a time period equal to 4 to 5 half-lives of the SSRI or any active metabolite should elapse after discontinuing treatment with the SSRI and before starting therapy with selegiline. Because of the long half-life of fluoxetine and its active metabolite, at least 5 weeks should elapse between discontinuation of fluoxetine and initiation of treatment with selegiline. Serotonin syndrome has occurred in patients receiving selective MAO-B inhibitors and serotonin-augmenting antidepressants simultaneously. Monitor for serotonergic side effects during therapy transitions. (Moderate) Monitor for loss of selegiline efficacy, signs and symptoms of serotonin syndrome, particularly during treatment initiation and dosage increase, and unusual drowsiness and sedation during concomitant atypical antipsychotic and selegiline use. Dopamine antagonists, such as atypical antipsychotics, may diminish the effectiveness of selegiline. Concomitant use may increase the risk for serotonin syndrome or additive CNS depression. If serotonin syndrome occurs, discontinue therapy.
Selpercatinib: (Major) Concomitant u se of selpercatinib and fluoxetine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. (Major) Monitor ECGs more frequently for QT prolongation if coadministration of selpercatinib with olanzapine is necessary due to the risk of additive QT prolongation. Concentration-dependent QT prolongation has been observed with selpercatinib therapy. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval.
Semaglutide: (Moderate) Monitor blood glucose during concomitant atypical antipsychotic and incretin mimetic use. Atypical antipsychotic therapy may aggravate diabetes mellitus. Atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition. (Moderate) Monitor blood glucose during concomitant incretin mimetic and fluoxetine use; an incretin mimetic dose adjustment may be necessary. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
Sertraline: (Major) Due to the similarity in pharmacology of fluoxetine and sertraline and the potential for serious adverse reactions, including serotonin syndrome, these selective serotonin reuptake inhibitors (SSRIs) should not be administered together. Also, both fluoxetine and sertraline have been associated with QT prolongation, which could theoretically result in additive effects on the QT interval. It is advisable to monitor for signs and symptoms of serotonin syndrome during an overlapping transition from one SSRI to another SSRI. (Moderate) Concomitant use of sertraline and olanzapine may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP. The degree of QT prolongation associated with sertraline is not clinically significant when administered within the recommended dosage range; QT prolongation has been described at 2 times the maximum recommended dose.
Sevoflurane: (Major) Concomitant use of halogenated anesthetics and fluoxetine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
SGLT2 Inhibitors: (Moderate) Monitor blood glucose during concomitant atypical antipsychotic and SGLT2 inhibitor use. Atypical antipsychotic therapy may aggravate diabetes mellitus. Atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition. (Moderate) Monitor blood glucose during concomitant SGLT2 inhibitor and fluoxetine use; a SGLT2 inhibitor dose adjustment may be necessary. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
Siponimod: (Major) Concomitant use of siponimod and fluoxetine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. (Major) In general, do not initiate treatment with siponimod in patients receiving olanzapine due to the potential for QT prolongation. Consult a cardiologist regarding appropriate monitoring if siponimod use is required. Siponimod therapy prolonged the QT interval at recommended doses in a clinical study. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval.
Sitagliptin: (Moderate) Monitor blood glucose during concomitant atypical antipsychotic and dipeptidyl peptidase-4 (DPP-4) inhibitor use. Atypical antipsychotic therapy may aggravate diabetes mellitus. Atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition. (Moderate) Monitor blood glucose during concomitant dipeptidyl peptidase-4 (DPP-4) inhibitor and fluoxetine use; a DPP-4 inhibitor dose adjustment may be necessary. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
Sodium Stibogluconate: (Moderate) Concomitant use of sodium stibogluconate and fluoxetine may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP. (Moderate) Concomitant use of sodium stibogluconate and olanzapine may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP.
Sofosbuvir; Velpatasvir: (Moderate) Use caution when administering velpatasvir with fluoxetine. Taking these drugs together may increase velpatasvir plasma concentrations, potentially resulting in adverse events. Fluoxetine is a weak CYP3A4 inhibitor; velpatasvir is a substrate of CYP3A4.
Sofosbuvir; Velpatasvir; Voxilaprevir: (Moderate) Use caution when administering velpatasvir with fluoxetine. Taking these drugs together may increase velpatasvir plasma concentrations, potentially resulting in adverse events. Fluoxetine is a weak CYP3A4 inhibitor; velpatasvir is a substrate of CYP3A4.
Solifenacin: (Moderate) Concomitant use of fluoxetine and solifenacin may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP. (Moderate) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering solifenacin with olanzapine. Solifenacin has been associated dose-dependent prolongation of the QT interval. TdP has been reported with post-marketing use, although causality was not determined. Limited data, including some case reports, suggest that olanzapine may also be associated with a significant prolongation of the QTc interval in rare instances.
Sorafenib: (Major) Avoid coadministration of sorafenib with olanzapine due to the risk of additive QT prolongation. If concomitant use is unavoidable, monitor electrocardiograms and correct electrolyte abnormalities. An interruption or discontinuation of sorafenib therapy may be necessary if QT prolongation occurs. Sorafenib is associated with QTc prolongation. Limited data, including some case reports, suggest that olanzapine may also be associated with a significant prolongation of the QTc interval. (Major) Concomitant use of sorafenib and fluoxetine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Sotagliflozin: (Moderate) Monitor blood glucose during concomitant atypical antipsychotic and SGLT2 inhibitor use. Atypical antipsychotic therapy may aggravate diabetes mellitus. Atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition. (Moderate) Monitor blood glucose during concomitant SGLT2 inhibitor and fluoxetine use; a SGLT2 inhibitor dose adjustment may be necessary. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
Sotalol: (Major) Concomitant use of fluoxetine and sotalol increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. (Major) Concomitant use of sotalol and olanzapine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Spironolactone: (Moderate) Monitor for signs and symptoms of hyponatremia during concomitant diuretic and fluoxetine use; consider discontinuing fluoxetine if symptomatic hyponatremia occurs and institute appropriate medical intervention. Concomitant use increases the risk for developing hyponatremia. (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.
Spironolactone; Hydrochlorothiazide, HCTZ: (Moderate) Monitor for signs and symptoms of hyponatremia during concomitant diuretic and fluoxetine use; consider discontinuing fluoxetine if symptomatic hyponatremia occurs and institute appropriate medical intervention. Concomitant use increases the risk for developing hyponatremia. (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.
St. John's Wort, Hypericum perforatum: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when coadministering fluoxetine and St. John's Wort. Inform patients of the possible increased risk and monitor for the emergence of serotonin syndrome, particularly during treatment initiation and dose increases. If serotonin syndrome occurs, serotonergic drugs should be discontinued and appropriate medical treatment should be initiated. (Moderate) St. John's Wort appears to induce several isoenzymes of the hepatic cytochrome P450 enzyme system and could decrease the efficacy of some medications metabolized by these enzymes including olanzapine.
Stiripentol: (Moderate) Monitor for excessive sedation and somnolence during coadministration of stiripentol and olanzapine. CNS depressants can potentiate the effects of stiripentol.
Sufentanil: (Major) Because the dose of the sufentanil sublingual tablets cannot be titrated, consider an alternate opiate if fluoxetine must be administered. Consider a reduced dose of sufentanil injection with frequent monitoring for respiratory depression, sedation, and serotonin syndrome if concurrent use of fluoxetine is necessary. If fluoxetine is discontinued, consider increasing the sufentanil injection dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system like fluoxetine has resulted in serotonin syndrome. In addition, sufentanil is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like fluoxetine can increase sufentanil exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of sufentanil. If fluoxetine is discontinued, sufentanil plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to sufentanil. (Major) Concomitant use of opioid agonists with olanzapine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with olanzapine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Also monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
Sulfonylureas: (Moderate) Monitor blood glucose during concomitant atypical antipsychotic and sulfonylurea use. Atypical antipsychotic therapy may aggravate diabetes mellitus. Atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition. (Moderate) Monitor blood glucose during concomitant sulfonylurea and fluoxetine use; a sulfonylurea dose adjustment may be necessary. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
Sumatriptan: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering sumatriptan with selective serotonin reuptake inhibitors (SSRIs). Serotonin syndrome has been reported during concurrent use of serotonin-receptor agonists ("triptans") and SSRIs. Inform patients of the possible increased risk and monitor for the emergence of serotonin syndrome, particularly after initiation of SSRI treatment or any dose increases. Discontinue serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
Sumatriptan; Naproxen: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering sumatriptan with selective serotonin reuptake inhibitors (SSRIs). Serotonin syndrome has been reported during concurrent use of serotonin-receptor agonists ("triptans") and SSRIs. Inform patients of the possible increased risk and monitor for the emergence of serotonin syndrome, particularly after initiation of SSRI treatment or any dose increases. Discontinue serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
Sunitinib: (Moderate) Concomitant use of fluoxetine and sunitinib may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP. (Moderate) Monitor for evidence of QT prolongation if sunitinib is administered with olanzapine. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval. Sunitinib can prolong the QT interval.
Suvorexant: (Moderate) Monitor for excessive sedation and somnolence during coadministration of suvorexant and atypical antipsyhotics. Dosage adjustments of suvorexant and the atypical antipsychotic may be necessary when administered together because of potentially additive CNS effects. The risk of next-day impairment, including impaired driving, is increased if suvorexant is taken with other CNS depressants.
Tacrolimus: (Moderate) Concomitant use of fluoxetine and tacrolimus may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP. (Moderate) Consider ECG and electrolyte monitoring periodically during treatment if tacrolimus is administered with olanzapine. Tacrolimus may prolong the QT interval and cause torsade de pointes (TdP). Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval.
Tamoxifen: (Moderate) Concomitant use of tamoxifen and olanzapine may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP. (Moderate) Monitor for QT prolongation and decreased efficacy of tamoxifen if coadministration with fluoxetine is necessary. Concomitant use may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP. Tamoxifen is metabolized by CYP2D6 to endoxifen and 4-hydroxytamoxifen, both of which are minor metabolites but have 100-fold greater affinity for the estrogen receptor and 30- to 100-fold greater potency in suppressing estrogen-dependent cell proliferation than tamoxifen. XXX is a strong CYP2D6 inhibitor. In one study, the mean steady-state endoxifen plasma concentration was significantly reduced in patients taking CYP2D6 inhibitors compared to those not taking concomitant CYP2D6 inhibitors. In another study, the mean steady-state plasma concentration of endoxifen in CYP2D6 normal metabolizers who were not receiving CYP2D6 inhibitors were 3.6-fold higher compared to normal metabolizers who were receiving strong CYP2D6 inhibitors; plasma concentrations in CYP2D6 normal metabolizers receiving strong CYP2D6 inhibitors were similar to concentrations observed in CYP2D6 poor metabolizers taking no CYP2D6 inhibitors. Some studies have shown that the efficacy of tamoxifen may be reduced when concomitant drugs decrease the concentrations of potent active metabolites; however, others have failed to demonstrate such an effect. The clinical significance is not well established.
Tamsulosin: (Moderate) Use caution if coadministration of fluoxetine with tamsulosin is necessary, especially at a tamsulosin dose higher than 0.4 mg, as the systemic exposure of tamsulosin may be increased resulting in increased treatment-related adverse reactions including hypotension, dizziness, and vertigo. Tamsulosin is a CYP2D6 substrate and fluoxetine is a strong CYP2D6 inhibitor. Concomitant treatment with another strong CYP2D6 inhibitor increased the Cmax and AUC of tamsulosin by a factor of 1.3 and 1.6, respectively.
Tapentadol: (Major) Concomitant use of opioid agonists with olanzapine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with olanzapine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Also monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. (Moderate) If concomitant use of tapentadol and selective serotonin reuptake inhibitors (SSRIs) is warranted, monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
Tedizolid: (Minor) Caution is warranted with the concurrent use of tedizolid and selective serotonin reuptake inhibitors (SSRIs) due to the theoretical risk of serotonin syndrome. Animal studies did not predict serotonergic effects; however, patients on concurrent SSRIs were excluded from clinical trials. Addtionally, tedizolid is an antibiotic that is also a weak reversible, non-selective MAO inhibitor and monoamine oxidase type A deaminates serotonin; therefore, coadministration theoretically could lead to serious reactions including serotonin syndrome. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome has been reported in patients receiving either citalopram, escitalopram, fluoxetine, or paroxetine in combination with linezolid, which is structurally similar to tedizolid.
Telavancin: (Moderate) Concomitant use of fluoxetine and telavancin may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP. (Moderate) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering telavancin with olanzapine. Telavancin has been associated with QT prolongation. Limited data, including some case reports, suggest that olanzapine also may be associated with a significant prolongation of the QTc interval in rare instances.
Telmisartan: (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.
Telmisartan; Amlodipine: (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.
Telmisartan; Hydrochlorothiazide, HCTZ: (Moderate) Monitor for signs and symptoms of hyponatremia during concomitant diuretic and fluoxetine use; consider discontinuing fluoxetine if symptomatic hyponatremia occurs and institute appropriate medical intervention. Concomitant use increases the risk for developing hyponatremia. (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.
Temazepam: (Moderate) Although oral formulations of olanzapine and benzodiazepines may be used together, additive effects on respiratory depression and/or CNS depression are possible. Drugs that can cause CNS depression, if used concomitantly with olanzapine, can increase both the frequency and the intensity of adverse effects such as drowsiness, sedation, dizziness, and orthostatic hypotension. Besides ethanol, clinicians should use other anxiolytics, sedatives, and hypnotics cautiously with olanzapine.
Tenecteplase: (Moderate) Platelet aggregation may be impaired by selective serotonin reuptake inhibitors (SSRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication in patients receiving thrombolytic agents. Patients should be closely monitored for signs and symptoms of bleeding when a thrombolytic agent is administered with an SSRI.
Terazosin: (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.
Terbinafine: (Moderate) Systemic terbinafine inhibits hepatic isoenzyme CYP2D6, and thus may inhibit the clearance of drugs metabolized by this isoenzyme, such as selective serotonin reuptake inhibitors (SSRIs). The clinical relevance of the interaction is not known. Topical forms of terbinafine do not interact.
Tetrabenazine: (Major) Concomitant use of tetrabenazine and fluoxetine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. (Major) Tetrabenazine causes a small increase in the corrected QT interval (QTc). The manufacturer recommends avoiding concurrent use of tetrabenazine with other drugs known to prolong QTc such as olanzapine. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval in rare instances. In addition, concurrent use of olanzapine and tetrabenazine should generally be avoided since the risk of adverse effects such as drowsiness, sedation, dizziness, orthostatic hypotension, neuroleptic malignant syndrome, or extrapyramidal symptoms may be increased.
Tezacaftor; Ivacaftor: (Minor) Although an interaction between ivacaftor and fluoxetine is possible, the clinical impact of this interaction has not yet been determined. Increased monitoring is recommended if ivacaftor is administered concurrently with CYP2C9 substrates. Fluoxetine is partially metabolized by CYP2C9, but it is also a substrate for at least 2 other enzymes. In vitro studies showed ivacaftor to be a weak inhibitor of CYP2C9. Co-administration may possibly lead to increased exposure to fluoxetine; however, because fluoxetine has multiple metabolic pathways, the clinical impact of this inhibition is not clear. In addition, ivacaftor is a CYP3A substrate, and fluoxetine is a mild CYP3A inhibitor. Co-administration may lead to increased ivacaftor exposure.
Thiazide diuretics: (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.
Thiazolidinediones: (Moderate) Monitor blood glucose during concomitant thiazolidinedione and fluoxetine use; a thiazolidinedione dose adjustment may be necessary. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
Thioridazine: (Contraindicated) Fluoxetine is contraindicated for use with some phenothiazine antipsychotics including thioridazine. Thioridazine has an established risk of QT prolongation and torsade de pointes (TdP), and post-marketing reports suggest a possible risk of QT prolongation and TdP with fluoxetine. In addition, the metabolism of thioridazine may be decreased during use of CYP2D6 inhibitors such as fluoxetine. Due to the long half-life of fluoxetine and its active metabolite, thioridazine should not be initiated within 5 weeks after discontinuing fluoxetine. Decreased metabolism of this CYP2D6 substrates by fluoxetine may also lead to arrhythmias or other clinically important adverse reactions such as extrapyramidal symptoms. (Contraindicated) Thioridazine is associated with a well-established risk of QT prolongation and torsade de pointes and is contraindicated with other drugs that prolong the QTc interval. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval in rare instances. In addition, coadministration may increase the risk of drowsiness, dizziness, orthostatic hypotension, anticholinergic effects, extrapyramidal symptoms, neuroleptic malignant syndrome, tardive dyskinesia, or seizures. Although the incidence of tardive dyskinesia from combination antipsychotic therapy has not been established and data are very limited, the risk appears to be increased during use of a conventional and atypical antipsychotic versus use of a conventional antipsychotic alone.
Thiothixene: (Major) Caution is advisable during concurrent use of thiothixene and other antipsychotics. Thiothixene use may be associated with adverse events such as drowsiness, dizziness, hypotension, anticholinergic effects, extrapyramidal symptoms, neuroleptic malignant syndrome, and seizures. These effects may be potentiated during concurrent use of thiothixene and other antipsychotics. The likelihood of these pharmacodynamic interactions varies based upon the individual properties of the co-administered antipsychotic agent. Although the incidence of tardive dyskinesia from combination antipsychotic therapy has not been established and data are very limited, the risk appears to be increased during use of a conventional and atypical antipsychotic versus use of a conventional antipsychotic alone.
Thrombin Inhibitors: (Moderate) Advise patients of the increased bleeding risk associated with the concomitant use of selective serotonin reuptake inhibitors (SSRIs) and other drugs that affect coagulation like thrombin inhibitors. Case reports and epidemiological studies have demonstrated an association between use of drugs that interfere with serotonin reuptake and gastrointestinal bleeding.
Thrombolytic Agents: (Moderate) Platelet aggregation may be impaired by selective serotonin reuptake inhibitors (SSRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication in patients receiving thrombolytic agents. Patients should be closely monitored for signs and symptoms of bleeding when a thrombolytic agent is administered with an SSRI.
Ticagrelor: (Moderate) Platelet aggregation may be impaired by selective serotonin reuptake inhibitors (SSRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication in patients receiving ticagrelor. Patients should be instructed to monitor for signs and symptoms of bleeding while taking an SSRI concurrently with an antiplatelet medication and to promptly report any bleeding events to the practitioner.
Ticlopidine: (Moderate) Platelet aggregation may be impaired by selective serotonin reuptake inhibitors (SSRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymosis, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving platelet inhibitors (e.g., ticlopidine). Patients should be instructed to monitor for signs and symptoms of bleeding while taking an SSRI concurrently with an antiplatelet medication and to promptly report any bleeding events to the practitioner.
Timolol: (Moderate) Monitor for signs of bradycardia or heart block if coadministration of timolol with fluoxetine is necessary. Concomitant use may enhance the beta-blocking properties of timolol resulting in further slowing of the heart rate or cardiac conduction. Timolol is a CYP2D6 substrate and fluoxetine is a strong CYP2D6 inhibitor. (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.
Tipranavir: (Moderate) Use caution when coadministering tipranavir and ritonavir with selective serotonin reuptake inhibitors, as increased SSRI concentrations may be seen. Patients should be monitored for increased SSRI adverse effects and the SSRI dose should be adjusted if necessary.
Tirofiban: (Moderate) Platelet aggregation may be impaired by SSRIs due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication in patients receiving platelet inhibitors. Monitor for signs and symptoms of bleeding.
Tirzepatide: (Moderate) Monitor blood glucose during concomitant atypical antipsychotic and incretin mimetic use. Atypical antipsychotic therapy may aggravate diabetes mellitus. Atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition. (Moderate) Monitor blood glucose during concomitant incretin mimetic and fluoxetine use; an incretin mimetic dose adjustment may be necessary. Concomitant use may cause an increased blood glucose-lowering effect with risk of hypoglycemia.
Tobacco: (Major) Advise patients to avoid smoking tobacco while taking olanzapine. Smoking tobacco has been observed to increase olanzapine clearance by 40% to 98% and may decrease efficacy.
Tofacitinib: (Moderate) A reduction in tofacitinib dose may be necessary if tofacitinib is coadministered with fluoxetine (a strong CYP2C19 inhibitor) and a medication that is a moderate CYP3A4 inhibitor. Tofacitinib exposure is increased when coadministered with both a strong CYP2C19 and a moderate CYP3A4 inhibitor. Review the patient's other medications for this potential drug interaction and the possible need for tofacitinib dose reduction. Tofacitinib is a CYP3A4 and CYP2C19 substrate. Coadministration of tofacitinib with both a strong CYP2C19 and a moderate CYP3A4 inhibitor increased tofacitinib exposure by 1.75-fold.
Tolcapone: (Moderate) Monitor for movement disorders, unusual changes in moods or behavior, and diminished effectiveness of the atypical antipsychotic or COMT inhibitor during coadministration. Due to mutually opposing effects on dopamine, atypical antipsychotics and COMT inhibitors may interfere with the effectiveness of each other. In general, atypical antipsychotics are less likely to interfere with COMT inhibitors and other Parkinson's treatments than traditional antipsychotics. The Beers Criteria recognize quetiapine and clozapine as exceptions to the general recommendation to avoid all antipsychotics in older adults with Parkinson's disease.
Tolterodine: (Moderate) Coadministration of fluoxetine and tolterodine may increase the risk for QT prolongation and torsade de pointes (TdP). QT prolongation and TdP have been reported in patients treated with fluoxetine. Tolterodine has been associated with dose-dependent prolongation of the QT interval, especially in poor CYP2D6 metabolizers. (Moderate) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering tolterodine with olanzapine. Tolterodine is associated with dose-dependent prolongation of the QT interval, especially in poor metabolizers of CYP2D6. Limited data, including some case reports, suggest that olanzapine may also be associated with a significant prolongation of the QTc interval in rare instances. In addition, olanzapine exhibits anticholinergic effects that may be clinically significant; additive anticholinergic effects may be seen when drugs with antimuscarinic properties like tolterodine are used concomitantly. Clinicians should note that additive antimuscarinic effects may be seen not only on GI smooth muscle, but also on bladder function, the CNS, the eye, and temperature regulation. Additive drowsiness may also occur, depending on the interacting agent.
Toremifene: (Major) Avoid coadministration of olanzapine with toremifene if possible due to the risk of additive QT prolongation. If concomitant use is unavoidable, closely monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia or hypomagnesemia prior to administration of toremifene. Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner. Limited data, including some case reports, suggest that olanzapine may also be associated with a significant prolongation of the QTc interval. (Major) Concomitant use of toremifene and fluoxetine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Torsemide: (Moderate) Monitor for signs and symptoms of hyponatremia during concomitant diuretic and fluoxetine use; consider discontinuing fluoxetine if symptomatic hyponatremia occurs and institute appropriate medical intervention. Concomitant use increases the risk for developing hyponatremia.
Tramadol: (Moderate) If concomitant use of tramadol and olanzapine is warranted, monitor patients for seizures, excessive sedation and/or somnolence, and the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. Concomitant use of tramadol and olanzapine may increase seizure risk and cause additive CNS depression. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. (Moderate) Monitor for reduced efficacy of tramadol, signs of opioid withdrawal, seizures, or serotonin syndrome if coadministration with fluoxetine is necessary. If fluoxetine is discontinued, consider a dose reduction of tramadol and frequently monitor for signs of respiratory depression and sedation. Tramadol is a CYP2D6 substrate and fluoxetine is a CYP2D6 inhibitor. Concomitant use of tramadol with CYP2D6 inhibitors can increase the plasma concentration of tramadol and decrease the plasma concentration of the active metabolite M1. Since M1 is a more potent mu-opioid agonist, decreased M1 exposure could result in decreased therapeutic effects, and may result in signs and symptoms of opioid withdrawal in patients who have developed physical dependence to tramadol. Increased tramadol exposure can result in increased or prolonged therapeutic effects and increased risk for serious adverse events including seizures and serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
Tramadol; Acetaminophen: (Moderate) If concomitant use of tramadol and olanzapine is warranted, monitor patients for seizures, excessive sedation and/or somnolence, and the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. Concomitant use of tramadol and olanzapine may increase seizure risk and cause additive CNS depression. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. (Moderate) Monitor for reduced efficacy of tramadol, signs of opioid withdrawal, seizures, or serotonin syndrome if coadministration with fluoxetine is necessary. If fluoxetine is discontinued, consider a dose reduction of tramadol and frequently monitor for signs of respiratory depression and sedation. Tramadol is a CYP2D6 substrate and fluoxetine is a CYP2D6 inhibitor. Concomitant use of tramadol with CYP2D6 inhibitors can increase the plasma concentration of tramadol and decrease the plasma concentration of the active metabolite M1. Since M1 is a more potent mu-opioid agonist, decreased M1 exposure could result in decreased therapeutic effects, and may result in signs and symptoms of opioid withdrawal in patients who have developed physical dependence to tramadol. Increased tramadol exposure can result in increased or prolonged therapeutic effects and increased risk for serious adverse events including seizures and serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
Trandolapril: (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.
Trandolapril; Verapamil: (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.
Tranylcypromine: (Contraindicated) Due to the risk of serotonin syndrome, monoamine oxidase inhibitors (MAOIs) intended to treat psychiatric disorders are contraindicated for use with selective serotonin reuptake inhibitors (SSRIs). MAOIs should not be used within 5 weeks of discontinuing treatment with fluoxetine or within 14 days of discontinuing treatment with other SSRIs. Conversely, SSRIs should not be initiated within 14 days of stopping an MAOI. Monitor the patient for serotonin-related effects during therapy transitions.
Trazodone: (Major) Concomitant use of trazodone and olanzapine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. (Major) Trazodone and fluoxetine may both cause QT prolongation. Concurrent use may also increase the risk of serotonin syndrome. Serotonin syndrome has been reported with both drugs when taken alone, but especially when coadministered with other serotonergic agents. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate appropriate treatment if serotonin syndrome occurs.
Treprostinil: (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.
Triamterene: (Moderate) Monitor for signs and symptoms of hyponatremia during concomitant diuretic and fluoxetine use; consider discontinuing fluoxetine if symptomatic hyponatremia occurs and institute appropriate medical intervention. Concomitant use increases the risk for developing hyponatremia. (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.
Triamterene; Hydrochlorothiazide, HCTZ: (Moderate) Monitor for signs and symptoms of hyponatremia during concomitant diuretic and fluoxetine use; consider discontinuing fluoxetine if symptomatic hyponatremia occurs and institute appropriate medical intervention. Concomitant use increases the risk for developing hyponatremia. (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.
Triazolam: (Moderate) Although oral formulations of olanzapine and benzodiazepines may be used together, additive effects on respiratory depression and/or CNS depression are possible. Drugs that can cause CNS depression, if used concomitantly with olanzapine, can increase both the frequency and the intensity of adverse effects such as drowsiness, sedation, dizziness, and orthostatic hypotension. Besides ethanol, clinicians should use other anxiolytics, sedatives, and hypnotics cautiously with olanzapine. (Moderate) Fluoxetine could theoretically inhibit CYP3A4 metabolism of oxidized benzodiazepines, including triazolam. Patients should be monitored for clinical response, and adjust benzodiazepine dosage if needed.
Triclabendazole: (Moderate) Concomitant use of triclabendazole and fluoxetine may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP. (Moderate) Concomitant use of triclabendazole and olanzapine may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP.
Tricyclic antidepressants: (Moderate) Olanzapine or tricyclic antidepressants, at elevated serum concentrations, may prolong the QTc interval. In addition, anticholinergic effects and sedation may be seen when tricyclic antidepressants are used with olanzapine.
Trifluoperazine: (Moderate) Coadministration of fluoxetine and trifluoperazine may increase the risk for QT prolongation and torsade de pointes (TdP). Additonally, fluoxetine is a potent inhibitor of CYP2D6 and may result in increases in serum trifluoperazine concentrations, leading to side effects. QT prolongation and TdP have been reported in patients treated with fluoxetine. Trifluoperazine is associated with a possible risk for QT prolongation. (Moderate) Trifluoperazine, a phenothiazine, is associated with a possible risk for QT prolongation. Trifluoperazine may increase the risk of QT prolongation if coadministered with drugs with a possible risk for QT prolongation, such as olanzapine. Coadministration may also increase the risk of drowsiness, dizziness, orthostatic hypotension, anticholinergic effects, extrapyramidal symptoms, neuroleptic malignant syndrome, or seizures. Although the incidence of tardive dyskinesia from combination antipsychotic therapy has not been established and data are very limited, the risk appears to be increased during use of a conventional and atypical antipsychotic versus use of a conventional antipsychotic alone.
Trihexyphenidyl: (Moderate) Additive anticholinergic effects may be seen when olanzapine and anticholinergics are used concomitantly; use with caution. Use of olanzapine and other drugs with anticholinergic activity can increase the risk for severe gastrointestinal adverse reactions related to hypomotility. Olanzapine exhibits anticholinergic activity. Adverse effects may be seen not only on GI smooth muscle, but also on bladder function, the CNS, the eye, and temperature regulation. Additive drowsiness may also occur, depending on the anticholinergic agent used.
Trimipramine: (Moderate) Coadministration of fluoxetine and trimipramine may increase the risk for QT prolongation, torsade de pointes (TdP), and serotonin syndrome. If serotonin syndrome is suspected, discontinue fluoxetine and concurrent serotonergic agents and initiate appropriate medical treatment. QT prolongation and TdP have been reported in patients treated with fluoxetine. Tricyclics, particularly at elevated concentrations, are associated with a possible risk of QT prolongation and TdP.
Triprolidine: (Moderate) Olanzapine exhibits anticholinergic effects that may be clinically significant. Clinicians should keep this in mind when using antimuscarinics and other medications with anticholinergic activity in combination with olanzapine. Some medications exhibit additive anticholinergic effects include sedating H1-blockers. Olanzapine may also cause additive sedation with many of these drugs.
Triptorelin: (Major) Avoid coadministration of triptorelin with olanzapine due to the risk of reduced efficacy of triptorelin; QT prolongation may also occur. Olanzapine can cause hyperprolactinemia, which reduces the number of pituitary gonadotropin releasing hormone (GnRH) receptors; triptorelin is a GnRH analog. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval. Androgen deprivation therapy (i.e., triptorelin) may also prolong the QT/QTc interval. (Moderate) Concomitant use of fluoxetine and androgen deprivation therapy (i.e., triptorelin) may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP.
Trospium: (Moderate) Additive anticholinergic effects may be seen when drugs with antimuscarinic properties like trospium and olanzapine are used concomitantly. Clinicians should note that additive antimuscarinic effects may be seen not only on GI smooth muscle, but also on bladder function and temperature regulation. While CNS-related side effects such as drowsiness and blurred vision are not typically noted with trospium, they may occur in some patients.
Tryptophan, 5-Hydroxytryptophan: (Major) Concurrent use of tryptophan and a selective serotonin reuptake inhibitor (SSRI) is not recommended. Since tryptophan is converted to serotonin, the use of tryptophan in patients receiving SSRIs could lead to serotonin excess and, potentially, serotonin syndrome. Discontinuation of tryptophan usually resolves symptoms.
Ubrogepant: (Major) Limit the initial and second dose of ubrogepant to 50 mg if coadministered with fluoxetine. Concurrent use may increase ubrogepant exposure and the risk of adverse effects. Ubrogepant is a CYP3A4 substrate; fluoxetine is a weak CYP3A4 inhibitor.
Valbenazine: (Major) Consider reducing the dose of valbenazine, based on tolerability, during co-administration with a strong CYP2D6 inhibitor, such as fluoxetine. QT prolongation is not clinically significant at valbenazine concentrations expected with recommended dosing; however, concentrations of the active metabolite of valbenazine may be higher in patients taking a strong CYP2D6 inhibitor and QT prolongation may become clinically significant. Additionally, cases of QT prolongation and ventricular arrhythmias, including torsade de pointes (TdP), have been reported during post-marketing use of fluoxetine.
Valerian, Valeriana officinalis: (Moderate) Substances that act on the CNS, including psychoactive drugs, may theoretically interact with valerian, Valeriana officinalis. These interactions are probably pharmacodynamic in nature, or result from additive mechanisms of action. Persons taking medications such as SSRIs should discuss the use of herbal supplements with their health care professional prior to consuming these herbs. Patients should not abruptly stop taking their prescribed psychoactive medication.
Valsartan: (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.
Valsartan; Hydrochlorothiazide, HCTZ: (Moderate) Monitor for signs and symptoms of hyponatremia during concomitant diuretic and fluoxetine use; consider discontinuing fluoxetine if symptomatic hyponatremia occurs and institute appropriate medical intervention. Concomitant use increases the risk for developing hyponatremia. (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.
Vandetanib: (Major) Avoid coadministration of vandetanib with olanzapine due to an increased risk of QT prolongation and torsade de pointes (TdP). If concomitant use is unavoidable, monitor ECGs for QT prolongation and monitor electrolytes; correct hypocalcemia, hypomagnesemia, and/or hypomagnesemia prior to vandetanib administration. An interruption of vandetanib therapy or dose reduction may be necessary for QT prolongation. Vandetanib can prolong the QT interval in a concentration-dependent manner; TdP and sudden death have been reported in patients receiving vandetanib. Limited data, including some case reports, suggest that olanzapine may also be associated with a significant prolongation of the QTc interval. (Major) Concomitant use of vandetanib and fluoxetine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Vardenafil: (Moderate) Concomitant use of vardenafil and fluoxetine may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP. (Moderate) Concomitant use of vardenafil and olanzapine may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP.
Vasodilators: (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.
Vasopressin, ADH: (Moderate) Monitor hemodynamics and adjust the dose of vasopressin as needed when used concomitantly with drugs suspected of causing syndrome of inappropriate antidiuretic hormone (SIADH), such as selective serotonin reuptake inhibitors. Use together may increase the pressor and antidiuretic effects of vasopressin.
Vemurafenib: (Major) Vemurafenib has been associated with QT prolongation. If vemurafenib and another drug that is associated with a possible risk for QT prolongation and torsade de pointes (TdP) must be coadministered, ECG monitoring is recommended; closely monitor the patient for QT interval prolongation. QT prolongation and torsade de pointes (TdP) have been reported in patients treated with fluoxetine. In addition, concomitant use of vemurafenib and fluoxetine may result in increased concentrations of fluoxetine and vemurafenib. Vemurafenib is a substrate of CYP3A4 and an inhibitor of CYP2C9 and CYP2D6. Fluoxetine is an inhibitor of CYP3A4 and a substrate of CYP2C9 and CYP2D6. Use caution and monitor patients for toxicity and efficacy. (Major) Vemurafenib has been associated with QT prolongation. If vemurafenib and another drug, such as olanzapine, that is associated with a possible risk for QT prolongation and torsade de pointes (TdP) must be coadministered, ECG monitoring is recommended; closely monitor the patient for QT interval prolongation. Also, olanzapine is a substrate of CYP1A2 and 2D6, while vemurafenib is an inhibitor of both of these enzymes. Therefore, concentrations of olanzapine could be increased with concomitant use. Monitor the patient for increase side effects.
Venetoclax: (Major) Reduce the dose of venetoclax by at least 50% and monitor for venetoclax toxicity (e.g., hematologic toxicity, GI toxicity, and tumor lysis syndrome) if coadministered with fluoxetine due to the potential for increased venetoclax exposure. Resume the original venetoclax dose 2 to 3 days after discontinuation of fluoxetine. Venetoclax is a CYP3A4 substrate; norfluoxetine, the active metabolite of fluoxetine, is a moderate CYP3A4 inhibitor.
Venlafaxine: (Major) Due to similarity of pharmacology and the potential for additive adverse effects, including serotonin syndrome, selective serotonin reuptake inhibitors (SSRIs) should generally not be administered with serotonin norepinephrine reuptake inhibitors like venlafaxine. If serotonin syndrome is suspected, all serotonergic agents should be discontinued. Also, both fluoxetine and venlafaxine have been associated with QT prolongation and torsade de pointes (TdP), which could theoretically result in additive effects on the QT interval. (Moderate) Venlafaxine is associated with a possible risk of QT prolongation. Atypical antipsychotics associated with a risk for QT prolongation and TdP that should be used cautiously with venlafaxine include olanzapine. In addition, venlafaxine is a weak inhibitor of CYP2D6. Atypical antipsychotics with partial metabolism via CYP2D6 include olanzapine. Monitor patients for potential adverse effects if these drugs are co-prescribed.
Vilazodone: (Major) Due to possible additive effects on serotonin concentrations, it is advisable to avoid combining selective serotonin reuptake inhibitors (SSRIs) with vilazodone. Interactions between vilazodone and serotonergic agents can lead to serious reactions including serotonin syndrome. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Patients receiving this combination should be monitored closely for toxicity.
Viloxazine: (Moderate) Monitor for increased fluoxetine-related adverse effects if coadministered with viloxazine. Concomitant use may increase fluoxetine exposure. Fluoxetine is a CYP2D6 substrate and viloxazine is a weak CYP2D6 inhibitor. (Moderate) Monitor for olanzapine-related adverse effects, including sedation, anticholinergic effects, hypotension, and QT prolongation, if concomitant use of viloxazine is necessary. A dose reduction of olanzapine may be necessary. Concomitant use may increase olanzapine exposure. Direct glucuronidation and CYP metabolism via CYP2D6 and CYP1A2 are the primary metabolic pathways for olanzapine. Viloxazine is a strong CYP1A2 inhibitor and weak CYP2D6.
Vinblastine: (Moderate) Monitor for an earlier onset and/or increased severity of vinblastine-related adverse reactions, including myelosuppression, constipation, and peripheral neuropathy, if coadministration with fluoxetine is necessary. Vinblastine is a CYP3A4 substrate and norfluoxetine, the active metabolite of fluoxetine, is a moderate CYP3A4 inhibitor. Enhanced vinblastine toxicity was reported with coadministration of another moderate CYP3A4 inhibitor.
Vinorelbine: (Moderate) Monitor for an earlier onset and/or increased severity of vinorelbine-related adverse reactions, including constipation and peripheral neuropathy, if coadministration with fluoxetine is necessary. Vinorelbine is a CYP3A4 substrate. Fluoxetine is a weak CYP3A4 inhibitor, but its active metabolite, norfluoxetine, is a moderate inhibitor of CYP3A4.
Voclosporin: (Moderate) Concomitant use of fluoxetine and voclosporin may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP. The degree of QT prolongation associated with voclosporin is not clinically significant when administered within the recommended dosage range; QT prolongation has been described at 3 times the maximum recommended dose. (Moderate) Concomitant use of voclosporin and olanzapine may increase the risk of QT prolongation. Consider interventions to minimize the risk of progression to torsades de pointes (TdP), such as ECG monitoring and correcting electrolyte abnormalities, particularly in patients with additional risk factors for TdP. Voclosporin has been associated with QT prolongation at supratherapeutic doses. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval.
Vonoprazan; Amoxicillin; Clarithromycin: (Major) Concomitant use of clarithromycin and fluoxetine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. (Major) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering clarithromycin with olanzapine. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval in rare instances. Additionally, clarithromycin is associated with an established risk for QT prolongation and TdP.
Vorapaxar: (Moderate) Because vorapaxar inhibits platelet aggregation, a potential additive risk for bleeding exists if vorapaxar is given in combination with other agents that affect hemostasis such as selective serotonin reuptake inhibitors (SSRIs). Platelet aggregation may be impaired by SSRIs due to platelet serotonin depletion. In addition, fluoxetine and fluvoxamine are CYP3A4 inhibitors and coadministration with vorapaxar, a CYP3A4 substrate, may result in increased serum concentrations of vorapaxar. Increased exposure to vorapaxar may increase the risk of bleeding complications. Patients should be instructed to monitor for signs and symptoms of bleeding while taking a SSRI with vorapaxar and to promptly report any bleeding events.
Voriconazole: (Moderate) Caution is advised when administering voriconazole with olanzapine as concurrent use may increase the risk of QT prolongation. Voriconazole has been associated with QT prolongation and rare cases of torsade de pointes. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval. (Moderate) Concomitant use of fluoxetine and voriconazole may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP.
Vorinostat: (Moderate) Concomitant use of fluoxetine and vorinostat may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP. (Moderate) Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval in rare instances. Therefore, caution is advised when administering olanzapine with drugs having an established causal association with QT prolongation and torsade de pointes (TdP). Vorinostat therapy is associated with a risk of QT prolongation and should be used cautiously with olanzapine.
Vortioxetine: (Major) Due to similarity of pharmacology and the potential for a

Olanzapine, Fluoxetine/Olanzapine, Fluoxetine Hydrochloride/Symbyax Oral Cap: 12-25mg, 12-50mg, 3-25mg, 6-25mg, 6-50mg

Adults

Olanzapine 18 mg/day PO with fluoxetine 75 mg/day PO for combination therapy.

Geriatric

Olanzapine 18 mg/day PO with fluoxetine 75 mg/day PO for combination therapy; however, lower dosages may be required in elderly patients.

Adolescents

Olanzapine 12 mg/day PO with fluoxetine 50 mg/day PO for combination therapy.

Children

10 years and older: Olanzapine 12 mg/day PO with fluoxetine 50 mg/day PO for combination therapy.
Less than 10 years: Safety and efficacy have not been established.

The addition of an SSRI to olanzapine therapy in bipolar disorder allows for the treatment of depressive symptoms with a lower incidence of antidepressant-induced mania. The combination of fluoxetine and olanzapine has been shown to lead to synergistic increases in neurotransmitter release; therefore, olanzapine may augment the actions of the SSRIs for resistant mood and mental disorders. When both drugs are given, norepinephrine and dopamine levels increase to 269% and 349% of baseline values, respectively, suggesting a neurochemical basis for the synergistic effect.
tuberoinfundibular
Olanzapine: Olanzapine is an antagonist at several different receptor types. In vitro, olanzapine is a potent antagonist of types 1-4 dopamine receptors (Ki = 11 to 31 nM), 5-HT receptor types 2A and 2C (Ki = 4 and 11 nM, respectively), 5HT6 (Ki = 5 nM), alpha1-receptors (Ki = 19nM), and histamine H1-receptors (Ki = 7 nM). Olanzapine is an antagonist of moderate affinity for muscarinic receptors 1-5 (Ki = 73, 96, 132, 32, and 48 nM, respectively) and 5HT3 (Ki = 57 nM). In vivo, olanzapine exerts a potent antipsychotic effect, which is thought to be the result of antagonism at dopamine and serotonin type 2 receptors. Olanzapine is about twice as active at serotonin 5-HT2 receptors than at dopamine type-2 (D2)receptors; this may account for the relative lack of olanzapine-associated extrapyramidal effects. Some evidence suggests that drugs that have a higher affinity for serotonin 5-HT2 receptors than for D2 receptors (e.g., olanzapine and setoperone) are more effective for negative symptoms of schizophrenia. Olanzapine appears to relatively spare dopamine blockade within the tuberoinfundibular tract; it thus causes less hyperprolactinemia than typical antipsychotic agents or risperidone. Antagonism at muscarinic receptors, histamine H1-receptors, and alpha1-receptors may explain the various side effects of olanzapine, including anticholinergic actions, somnolence, and orthostatic hypotension, respectively. Olanzapine binds weakly to GABAA, benzodiazepine and beta-adrenergic receptors (Ki more than 10 micro-M).
Fluoxetine: The precise action of SSRIs is not fully understood, but it is believed that the most important effect is the enhancement of the actions of serotonin due to highly specific serotonin reuptake blockade (inhibition of the serotonin transporter) at the neuronal membrane. Fluoxetine also weakly inhibits the dopamine transporter. SSRIs have less sedative, anticholinergic, and cardiovascular effects than do the tricyclic antidepressant drugs due to dramatically decreased binding to receptors of histamine, acetylcholine, and norepinephrine. Monoamine oxidase is not inhibited by any of the SSRIs. Anticholinergic activity is virtually absent. Fluoxetine is metabolized to norfluoxetine which is also active. Fluoxetine exhibits the longest half-life of all the SSRIs. The long half-life becomes clinically important when assessing drug interactions, adverse reactions and initiation of alternate therapy, should it be required.

Olanzapine; fluoxetine is administered orally. Small decreases in the clearance of olanzapine (due to fluoxetine inhibition of CYP2D6) do not appear to be clinically significant. In general, the pharmacokinetic parameters of the individual components, including time to reach steady-state, are expected to reasonably characterize the overall pharmacokinetics of the combination product.
Olanzapine: Protein binding is about 93%, primarily to albumin and alpha1-acid glycoprotein. Olanzapine is primarily metabolized by glucuronidation and cytochrome P450 (CYP) oxidation. Oxidation appears to be via the CYP1A2, CYP2D6, and the flavin-containing monooxygenase system. Oxidation via CYP2D6 seems to be a minor metabolic pathway in vivo; clearance is not decreased in adults with a deficiency of this enzyme. The major circulating metabolites do not have pharmacological activity. About 57 and 30% of a dose is recovered in the urine and feces, respectively. The elimination half-life averages 30 hours (range of 21 to 54 hours).
Fluoxetine: Both fluoxetine and the active metabolite exist as enantiomers. In-vitro, S-norfluoxetine has been shown to have activity equivalent to S- or R-fluoxetine; however, R-norfluoxetine is a much less potent inhibitor of serotonin reuptake. Fluoxetine is highly protein bound (94.5%), predominantly to alpha1-acid glycoprotein. It is well distributed, and it readily crosses the blood-brain barrier and presumably the placenta; it is distributed into breast milk. Fluoxetine is extensively demethylated in the liver to several metabolites. The only known active metabolite is norfluoxetine (via the CYP2D6 pathway), which appears to be as effective as its parent in the blockade of serotonin reuptake. Fluoxetine has the slowest elimination of the SSRIs. The half-life of fluoxetine is 2 to 3 days and norfluoxetine is 7 to 9 days. There is considerable individual variation, which may be associated with variance in the rates of N-demethylation and hydroxylation. About 60% of an oral dose is excreted in urine within 35 days, and about 12% of the dose is excreted in the feces within 28 days.

Oral Route

Both olanzapine and fluoxetine have good absorption from the GI tract. When administered as single entity ingredients, food has no effect on absorption; the effect of food on the combination product has not been evaluated, although none is expected.
Olanzapine: Peak serum concentrations are reached in approximately 4 to 6 hours. There is extensive first-pass metabolism with about 40% of the dose being metabolized before reaching the systemic circulation. Steady-state concentrations are reached in approximately 1 week of continuous dosing.
Fluoxetine: Peak plasma concentrations occur in 6 to 8 hours. Steady-state plasma concentrations of fluoxetine and its principal active metabolite norfluoxetine are achieved in 2 to 4 weeks.

Pregnancy

Available data from published epidemiologic studies and postmarketing reports for olanzapine or fluoxetine have not established an increased risk of major birth defects or miscarriage. There are risks to the mother associated with untreated mental health conditions and a potential risk of persistent pulmonary hypertension of the newborn (PPHN) from SSRI use. Several publications reported an increased incidence of cardiovascular malformations in children with in utero exposure to fluoxetine. However, a causal relationship has not been established due to methodologic limitations of the studies, including possible exposure and outcome misclassification, lack of adequate controls, adjustment for confounders and confirmatory studies. Some neonates exposed to SSRIs late in the third trimester have experienced poor neonatal adaptation resulting in complications requiring prolonged hospitalization, respiratory support, and tube feeding upon delivery. Symptoms have included respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding difficulty, vomiting, hypoglycemia, hypotonia, hypertonia, hyperreflexia, tremor, jitteriness, irritability, and constant crying. These features are consistent with direct SSRI toxicity, serotonin syndrome, or a drug discontinuation syndrome. Data from published observational studies have reported that exposure to SSRIs, particularly in the month before obstetric delivery, has been associated with a less than 2-fold increase in the risk of postpartum hemorrhage. Adverse effects such as extrapyramidal effects, agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, and feeding disorder, ranging from self-limited to intensive care unit stays and prolonged hospitalization, have been reported after delivery in neonates exposed to antipsychotics during the third trimester. Neonates exposed to antipsychotic drugs during the third trimester, including olanzapine, are at risk for extrapyramidal and/or withdrawal symptoms following delivery. The National Pregnancy Registry for Psychiatric Medications evaluates pregnancy outcomes from psychiatric medications taken by women during pregnancy. Health care providers are encouraged to register patients by contacting the registry at https://womensmentalhealth.org/research/pregnancyregistry/ or by phone 1-866-961-2388.