Remeron

Tetracyclic Antidepressants

Oral Administration

May be administered without regard to meals.
The preferred administration time is in the evening prior to sleep.

Oral Solid Formulations

Orally disintegrating tablets (e.g., Remeron SolTab):
The tablet should remain in the blister pack until ready to be taken.
Use dry hands to open the blister.
The tablet should not be chewed, crushed, or split.
After removal from the blister pack, immediately place the tablet on the patient's tongue and allow it to dissolve with saliva. The tablet will disintegrate in saliva so that it can be swallowed. It does not need to be administered with water.

Severe

cholecystitis / Delayed / 0.1-1.0
bronchospasm / Rapid / 0.1-1.0
bradycardia / Rapid / 0.1-1.0
myocardial infarction / Delayed / 0.1-1.0
exfoliative dermatitis / Delayed / 0.1-1.0
ocular hypertension / Delayed / 0.1-1.0
keratoconjunctivitis / Early / 0.1-1.0
hearing loss / Delayed / 0.1-1.0
muscle paralysis / Delayed / 0-0.1
seizures / Delayed / 0-0.1
dementia / Delayed / 0-0.1
GI obstruction / Delayed / 0-0.1
pancreatitis / Delayed / 0-0.1
cirrhosis / Delayed / 0-0.1
tendon rupture / Delayed / 0-0.1
bone fractures / Delayed / 0-0.1
asphyxia / Early / 0-0.1
pneumothorax / Early / 0-0.1
pulmonary embolism / Delayed / 0-0.1
heart failure / Delayed / 0-0.1
pancytopenia / Delayed / 0-0.1
serotonin syndrome / Delayed / 0-0.1
suicidal ideation / Delayed / Incidence not known
rhabdomyolysis / Delayed / Incidence not known
ventricular fibrillation / Early / Incidence not known
torsade de pointes / Rapid / Incidence not known
agranulocytosis / Delayed / Incidence not known
diabetic ketoacidosis / Delayed / Incidence not known
toxic epidermal necrolysis / Delayed / Incidence not known
Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) / Delayed / Incidence not known
erythema multiforme / Delayed / Incidence not known
Stevens-Johnson syndrome / Delayed / Incidence not known

Moderate

hypercholesterolemia / Delayed / 15.0-15.0
constipation / Delayed / 13.0-13.0
hypertriglyceridemia / Delayed / 6.0-6.0
confusion / Early / 2.0-2.0
elevated hepatic enzymes / Delayed / 0-2.0
peripheral edema / Delayed / 2.0-2.0
hyperreflexia / Delayed / 0.1-1.0
delirium / Early / 0.1-1.0
dysarthria / Delayed / 0.1-1.0
ataxia / Delayed / 0.1-1.0
migraine / Early / 0.1-1.0
mania / Early / 0.1-1.0
hostility / Early / 0.1-1.0
hallucinations / Early / 0.1-1.0
depression / Delayed / 0-1.0
euphoria / Early / 0.1-1.0
dyskinesia / Delayed / 0.1-1.0
dystonic reaction / Delayed / 0.1-1.0
stomatitis / Delayed / 0.1-1.0
colitis / Delayed / 0.1-1.0
glossitis / Early / 0.1-1.0
dyspnea / Early / 1.0-1.0
angina / Early / 0.1-1.0
hypotension / Rapid / 0.1-1.0
dehydration / Delayed / 0.1-1.0
cystitis / Delayed / 0.1-1.0
dysuria / Early / 0.1-1.0
nephrolithiasis / Delayed / 0.1-1.0
urinary retention / Early / 0.1-1.0
vaginitis / Delayed / 0.1-1.0
impotence (erectile dysfunction) / Delayed / 0.1-1.0
urinary incontinence / Early / 0.1-1.0
hematuria / Delayed / 0.1-1.0
hyperacusis / Delayed / 0.1-1.0
conjunctivitis / Delayed / 0.1-1.0
edema / Delayed / 1.0-1.0
aphasia / Delayed / 0-0.1
nystagmus / Delayed / 0-0.1
myoclonia / Delayed / 0-0.1
hypotonia / Delayed / 0-0.1
akathisia / Delayed / 0-0.1
psychosis / Early / 0-0.1
gastritis / Delayed / 0-0.1
oral ulceration / Delayed / 0-0.1
candidiasis / Delayed / 0-0.1
bone pain / Delayed / 0-0.1
phlebitis / Rapid / 0-0.1
lymphadenopathy / Delayed / 0-0.1
lymphocytosis / Delayed / 0-0.1
thrombocytopenia / Delayed / 0-0.1
leukopenia / Delayed / 0-0.1
anemia / Delayed / 0-0.1
gout / Delayed / 0-0.1
hyponatremia / Delayed / 0-0.1
diabetes mellitus / Delayed / 0-0.1
skin ulcer / Delayed / 0-0.1
ejaculation dysfunction / Delayed / 0-0.1
goiter / Delayed / 0-0.1
hypothyroidism / Delayed / 0-0.1
blepharitis / Early / 0-0.1
withdrawal / Early / 0-0.1
amnesia / Delayed / 1.0
myasthenia / Delayed / 1.0
peripheral vasodilation / Rapid / 1.0
hypertension / Early / 1.0
orthostatic hypotension / Delayed / Incidence not known
QT prolongation / Rapid / Incidence not known
neutropenia / Delayed / Incidence not known
hyperglycemia / Delayed / Incidence not known
bullous rash / Early / Incidence not known
hyperprolactinemia / Delayed / Incidence not known
galactorrhea / Delayed / Incidence not known

Mild

drowsiness / Early / 54.0-54.0
weight gain / Delayed / 7.5-49.0
xerostomia / Early / 25.0-25.0
appetite stimulation / Delayed / 17.0-17.0
asthenia / Delayed / 8.0-8.0
dizziness / Early / 7.0-7.0
influenza / Delayed / 5.0-5.0
abnormal dreams / Early / 4.0-4.0
tremor / Early / 2.0-2.0
back pain / Delayed / 2.0-2.0
myalgia / Early / 2.0-2.0
increased urinary frequency / Early / 2.0-2.0
libido increase / Delayed / 0.1-1.0
emotional lability / Early / 0.1-1.0
paranoia / Early / 0.1-1.0
eructation / Early / 0.1-1.0
weight loss / Delayed / 0.1-1.0
nausea / Early / 0.1-1.0
epistaxis / Delayed / 0.1-1.0
syncope / Early / 0.1-1.0
fever / Early / 0.1-1.0
alopecia / Delayed / 0.1-1.0
xerosis / Delayed / 0.1-1.0
acne vulgaris / Delayed / 0.1-1.0
leukorrhea / Delayed / 0.1-1.0
amenorrhea / Delayed / 0.1-1.0
dysmenorrhea / Delayed / 0.1-1.0
mastalgia / Delayed / 0.1-1.0
otalgia / Early / 0.1-1.0
ocular pain / Early / 0.1-1.0
chills / Rapid / 0.1-1.0
headache / Early / 0-0.1
diplopia / Early / 0-0.1
tongue discoloration / Delayed / 0-0.1
hypersalivation / Early / 0-0.1
laryngitis / Delayed / 0-0.1
hiccups / Early / 0-0.1
petechiae / Delayed / 0-0.1
seborrhea / Delayed / 0-0.1
urticaria / Rapid / 0-0.1
urinary urgency / Early / 0-0.1
menorrhagia / Delayed / 0-0.1
breast enlargement / Delayed / 0-0.1
polyuria / Early / 0-0.1
parosmia / Delayed / 0-0.1
dysgeusia / Early / 0-0.1
paresthesias / Delayed / 1.0
hyperkinesis / Delayed / 1.0
hypoesthesia / Delayed / 1.0
vertigo / Early / 1.0
agitation / Early / 1.0
anxiety / Delayed / 1.0
abdominal pain / Early / 1.0
vomiting / Early / 1.0
anorexia / Delayed / 1.0
arthralgia / Delayed / 1.0
sinusitis / Delayed / 1.0
cough / Delayed / 1.0
polydipsia / Early / 1.0
photosensitivity / Delayed / 1.0
pruritus / Rapid / 1.0
rash / Early / 1.0
malaise / Early / 1.0
somnambulism / Early / Incidence not known
infection / Delayed / Incidence not known
gynecomastia / Delayed / Incidence not known

Children, suicidal ideation

Mirtazapine is not FDA-approved for the treatment of depression in adolescents or children; safety and efficacy have not been established. Two manufacturer-sponsored, randomized, double-blind, placebo-controlled clinical trials in pediatric patients 7 to 18 years of age with major depressive disorder (n = 259) failed to demonstrate significant differences between mirtazapine and placebo with regard to the primary endpoint and all secondary endpoints. In October 2004, the FDA directed manufacturers of all antidepressants to add a boxed warning to their product labels detailing the risk of suicide in pediatric patients. The risk of suicidality for these drugs was identified in a pooled analysis of 24 placebo-controlled trials (n = 4,400) lasting up to 16 weeks in pediatric patients with major depressive disorder (MDD), obsessive compulsive disorder (OCD), or other psychiatric disorders. The analysis showed a greater risk of suicidality during the first few months of treatment in those receiving antidepressants. The average risk of such events on drug was 4% and 2% for placebo; however, no suicides occurred in these trials. Pooled analysis of short-term clinical trials during early phase treatment with antidepressants in young adults (18 to 24 years) also showed an increased risk of suicidal thinking and behavior. The clinical need for an antidepressant in pediatrics or young adults for any use must be weighed against the risk of increased suicidality; patients who are started on therapy should be observed closely for clinical worsening, suicidality, or unusual changes in behavior, particularly within the first few months of starting therapy or during dose changes. It is unknown if the suicidality risk in children or young adults extends to longer-term therapy. The possibility of a suicide attempt is inherent in patients with depressive symptoms, whether these occur in primary depression or in association with another primary disorder. All patients with a history of suicidal ideation or behaviors and those with a prominence of suicidal ideation prior to treatment should be closely monitored during treatment with mirtazapine. In patients who exhibit worsening of depression or suicidality, a decision should be made to change or discontinue treatment. If discontinuing, the medication should be tapered as rapidly as possible, but with recognition that abrupt discontinuation can also cause adverse symptoms. All antidepressants should be prescribed in the smallest quantity consistent with good patient management to reduce the risk of overdose.

Remeron, Remeron SolTab

Rx

Tetracyclic serotonergic and noradrenergic antidepressant unrelated to other classes of antidepressants
Used for the treatment of major depressive disorder in adults
Increased risk of suicidality during the initial stages of treatment in pediatric and young adult patients

For the treatment of major depression. Oral dosage Adults

15 mg PO once daily at bedtime, initially. May increase the dose up to 45 mg/day at intervals of at least 1 to 2 weeks if inadequate response. Max: 45 mg/day.

For the treatment of resting tremor†, benign familial tremor† (essential tremor†) or for the treatment of levodopa-induced dyskinesias†. Oral dosage Adults

Initially 15 mg PO at bedtime. Adjust dose no more than every 1 to 2 weeks; geriatric patients may need slower titration schedules. In limited reports the effective dose, after titration, was 30 mg PO at bedtime.

For the treatment of pruritus†. For the treatment of intractable pruritus†. Oral dosage Adults

Case reports suggest that 15 to 30 mg PO once daily may be effective. In a case series of 4 patients with pruritus not relieved by other antipruritic therapy, mirtazapine resulted in reduction or elimination of pruritus. All 4 patients presented with advanced cancer. In addition to the reported malignancies, 3 patients presented with other conditions known to cause pruritus including hepatic disease and renal failure.

For the treatment of nocturnal itch associated with chronic pruritus†. Oral dosage Adults

Case reports suggest 15 mg PO once daily may be effective. In 2 patients with nocturnal itch associated with chronic pruritus, mirtazapine resulted in significant improvement in nocturnal pruritic symptoms and sleep in as early as 1 day after starting therapy. Both patients experienced a return of symptoms upon withdrawal of therapy, which resolved within 1 to 2 weeks after restarting mirtazapine.

Adolescents

A single case report suggests that 15 mg PO once daily may be effective. A significant reduction in nocturnal pruritic symptoms, regression in prurigo nodules, and improved quality of life occurred in an adolescent female with severe atopic eczema following treatment with mirtazapine. Improvement in symptoms was noted 5 days after of initiation of therapy, and was maintained during 6 months of follow up.

†Indicates off-label use

Hepatic Impairment

A dose reduction may be necessary in patients with hepatic impairment due to decreased clearance of mirtazapine in these populations.

Renal Impairment

CrCl less than 40 mL/minute: A dose reduction may be necessary in patients with moderate to severe renal impairment due to decreased clearance of mirtazapine in these populations.

Acetaminophen; Aspirin; Diphenhydramine: (Moderate) Monitor for unusual drowsiness and sedation during coadministration of diphenhydramine and mirtazapine due to the risk for additive CNS depression.
Acetaminophen; Caffeine; Dihydrocodeine: (Major) Concomitant use of opioid agonists with mirtazapine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with mirtazapine 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. Avoid prescribing opioid cough medication in patients taking mirtazapine. 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.
Acetaminophen; Caffeine; Pyrilamine: (Moderate) Consistent with the CNS depressant effects of mirtazapine, additive effects may occur with other CNS depressants such as pyrilamine. Mirtazapine should be administered cautiously with such agents because the CNS effects on cognitive performance and motor skills can be additive.
Acetaminophen; Chlorpheniramine: (Moderate) Consistent with the CNS depressant effects of mirtazapine, additive effects may occur with other CNS depressants such as chlorpheniramine. Mirtazapine should be administered cautiously with such agents because the CNS effects on cognitive performance and motor skills can be additive.
Acetaminophen; Chlorpheniramine; Dextromethorphan: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering dextromethorphan with mirtazapine. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. (Moderate) Consistent with the CNS depressant effects of mirtazapine, additive effects may occur with other CNS depressants such as chlorpheniramine. Mirtazapine should be administered cautiously with such agents because the CNS effects on cognitive performance and motor skills can be additive.
Acetaminophen; Chlorpheniramine; Dextromethorphan; Phenylephrine: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering dextromethorphan with mirtazapine. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. (Moderate) Consistent with the CNS depressant effects of mirtazapine, additive effects may occur with other CNS depressants such as chlorpheniramine. Mirtazapine should be administered cautiously with such agents because the CNS effects on cognitive performance and motor skills can be additive.
Acetaminophen; Chlorpheniramine; Dextromethorphan; Pseudoephedrine: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering dextromethorphan with mirtazapine. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. (Moderate) Consistent with the CNS depressant effects of mirtazapine, additive effects may occur with other CNS depressants such as chlorpheniramine. Mirtazapine should be administered cautiously with such agents because the CNS effects on cognitive performance and motor skills can be additive.
Acetaminophen; Chlorpheniramine; Phenylephrine : (Moderate) Consistent with the CNS depressant effects of mirtazapine, additive effects may occur with other CNS depressants such as chlorpheniramine. Mirtazapine should be administered cautiously with such agents because the CNS effects on cognitive performance and motor skills can be additive.
Acetaminophen; Codeine: (Major) Concomitant use of opioid agonists with mirtazapine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with mirtazapine 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. Avoid prescribing opioid cough medication in patients taking mirtazapine. 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.
Acetaminophen; Dextromethorphan: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering dextromethorphan with mirtazapine. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
Acetaminophen; Dextromethorphan; Doxylamine: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering dextromethorphan with mirtazapine. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. (Moderate) Monitor for unusual drowsiness and sedation during coadministration of doxylamine and mirtazapine due to the risk for additive CNS depression.
Acetaminophen; Dextromethorphan; Guaifenesin; Phenylephrine: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering dextromethorphan with mirtazapine. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
Acetaminophen; Dextromethorphan; Guaifenesin; Pseudoephedrine: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering dextromethorphan with mirtazapine. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
Acetaminophen; Dextromethorphan; Phenylephrine: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering dextromethorphan with mirtazapine. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
Acetaminophen; Dextromethorphan; Pseudoephedrine: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering dextromethorphan with mirtazapine. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
Acetaminophen; Diphenhydramine: (Moderate) Monitor for unusual drowsiness and sedation during coadministration of diphenhydramine and mirtazapine due to the risk for additive CNS depression.
Acetaminophen; Hydrocodone: (Major) Concomitant use of opioid agonists with mirtazapine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with mirtazapine 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 mirtazapine.
Acetaminophen; Oxycodone: (Major) Concomitant use of opioid agonists with mirtazapine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with mirtazapine 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.
Acetaminophen; Pamabrom; Pyrilamine: (Moderate) Consistent with the CNS depressant effects of mirtazapine, additive effects may occur with other CNS depressants such as pyrilamine. Mirtazapine should be administered cautiously with such agents because the CNS effects on cognitive performance and motor skills can be additive.
Acrivastine; Pseudoephedrine: (Moderate) Consistent with the CNS depressant effects of mirtazapine, additive effects may occur with other CNS depressants such as acrivastine. Mirtazapine should be administered cautiously with such agents because the CNS effects on cognitive performance and motor skills can be additive.
Adagrasib: (Major) Avoid concomitant use of adagrasib and mirtazapine due to the potential for increased mirtazapine exposure and additive risk for QT/QTc prolongation and torsade de pointes (TdP). If use is necessary, monitor for mirtazapine-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. Mirtazapine is a CYP3A substrate, adagrasib is a strong CYP3A inhibitor, and both medications have been associated with QT interval prolongation. Coadministration with another strong CYP3A inhibitor increased the Cmax and AUC of a single dose of mirtazapine by approximately 40% and 50%, respectively.
Alfentanil: (Major) Concomitant use of opioid agonists with mirtazapine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with mirtazapine 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.
Alfuzosin: (Moderate) Concomitant use of mirtazapine 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 mirtazapine use; consider discontinuing mirtazapine if symptomatic hyponatremia occurs and institute appropriate medical intervention. Concomitant use increases the risk for developing hyponatremia.
Almotriptan: (Major) The coadministration of serotonergic antidepressants with serotonin-agonists has sometimes resulted in serotonin syndrome. Careful observation of the patient is advised, particularly during treatment initiation and dose increases. Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, and coma), autonomic instability (e.g., tachycardia, labile blood pressure, and hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination) and/or gastrointestinal symptoms (e.g., nausea, vomiting, and diarrhea). Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome, which includes hyperthermia, muscle rigidity, autonomic instability with possible rapid fluctuation of vital signs, and mental status changes. Discontinue the serotonergic agents immediately if serotonin syndrome reactions occur and initiate supportive symptomatic treatment.
Alprazolam: (Moderate) Monitor for unusual drowsiness and sedation during coadministration of benzodiazepines and mirtazapine due to the risk for additive CNS depression.
Amiloride: (Moderate) Monitor for signs and symptoms of hyponatremia during concomitant diuretic and mirtazapine use; consider discontinuing mirtazapine if symptomatic hyponatremia occurs and institute appropriate medical intervention. Concomitant use increases the risk for developing hyponatremia.
Amiloride; Hydrochlorothiazide, HCTZ: (Moderate) Monitor for signs and symptoms of hyponatremia during concomitant diuretic and mirtazapine use; consider discontinuing mirtazapine if symptomatic hyponatremia occurs and institute appropriate medical intervention. Concomitant use increases the risk for developing hyponatremia.
Amiodarone: (Major) Concomitant use of amiodarone and mirtazapine 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) Concomitant use of amisulpride and mirtazapine 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.
Amitriptyline: (Moderate) Monitor for unusual drowsiness, sedation, and serotonin syndrome during coadministration due to the risk for additive CNS depression and serotonin syndrome. If serotonin syndrome occurs, consider discontinuation of therapy.
Amlodipine; Valsartan; Hydrochlorothiazide, HCTZ: (Moderate) Monitor for signs and symptoms of hyponatremia during concomitant diuretic and mirtazapine use; consider discontinuing mirtazapine if symptomatic hyponatremia occurs and institute appropriate medical intervention. Concomitant use increases the risk for developing hyponatremia.
Amobarbital: (Major) Monitor for excessive sedation and somnolence during coadministration of mirtazapine and barbiturates. Concurrent use may result in additive CNS depression.
Amoxapine: (Major) Monitor for excessive sedation and somnolence during coadministration of amoxapine and mirtazapine. Concurrent use may result in additive CNS depression.
Amoxicillin; Clarithromycin; Omeprazole: (Major) Concomitant use of mirtazapine and clarithromycin 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.
Amphetamine; Dextroamphetamine Salts: (Moderate) Coadministration of mirtazapine with amphetamines may increase the risk of serotonin syndrome. At high doses, amphetamines can increase serotonin release and act as serotonin agonists. 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.
Anagrelide: (Major) Concomitant use of anagrelide and mirtazapine 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.
Anxiolytics; Sedatives; and Hypnotics: (Moderate) Consistent with the pharmacology of mirtazapine and the drug's side effect profile, additive effects may occur with other CNS-active agents, including anxiolytics, sedatives, and hypnotics.
Apalutamide: (Moderate) Monitor for decreased efficacy of mirtazapine if coadministration with apalutamide is necessary; a dosage adjustment of mirtazapine may be necessary. Mirtazapine is a CYP3A4 substrate and apalutamide is a strong CYP3A4 inducer. Coadministration with other strong CYP3A4 inducers increased mirtazapine clearance by approximately 2-fold, decreasing the average mirtazapine plasma concentrations by 45% to 60%.
Apomorphine: (Major) Exercise caution when administering apomorphine concomitantly with mirtazapine as concurrent use may increase the risk of QT prolongation and CNS depression. Mirtazapine has been associated with dose-dependent prolongation of the QT interval. Torsade de pointes (TdP) has been reported postmarketing, primarily in overdose or in patients with other risk factors for QT prolongation. Dose-related QTc prolongation is associated with therapeutic apomorphine exposure. Additive sedation may also occur.
Aripiprazole: (Moderate) There may be an increased risk for QT prolongation and torsade de pointes (TdP) during concurrent use of mirtazapine and aripiprazole. Coadminister with caution. QT prolongation has occurred during therapeutic use of aripiprazole and following overdose. Cases of QT prolongation, TdP, ventricular tachycardia, and sudden death have been reported during postmarketing use of mirtazapine, primarily following overdose or in patients with other risk factors for QT prolongation, including concomitant use of other medications associated with QT prolongation.
Arsenic Trioxide: (Major) Concomitant use of arsenic trioxide and mirtazapine 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.
Artemether; Lumefantrine: (Major) Artemether; lumefantrine is associated with QT prolongation and should be avoided if possible in combination with other QT prolonging drugs, such as mirtazapine. Consider ECG monitoring if other QT prolonging drugs must be used with or after artemether; lumefantrine treatment. Cases of QT prolongation, TdP, ventricular tachycardia, and sudden death have been reported during postmarketing use of mirtazapine. The majority of reports have occurred in the setting of mirtazapine overdose or in patients with other risk factors for QT prolongation, including concomitant use of other medications associated with QT prolongation. Because llumefantrine is a CYP2D6 inhibitor and mirtazapine is partially metabolized by CYP2D6, coadministration may lead to increased mirtazapine concentrations. Monitor for mirtazapine-related side effects such as dizziness, somnolence, xerostomia, and constipation. (Major) Concomitant use of mirtazapine and artemether; lumefantrine 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.
Asenapine: (Major) Concomitant use of mirtazapine and asenapine 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; Butalbital; Caffeine: (Major) Monitor for excessive sedation and somnolence during coadministration of mirtazapine and barbiturates. Concurrent use may result in additive CNS depression.
Aspirin, ASA; Caffeine; Orphenadrine: (Moderate) Skeletal muscle relaxants like orphenadrine may cause additive CNS depression if used concomitantly with other drugs with CNS depressant properties such as mirtazapine. Combination therapy may amplify sedation and dizziness, which can impair the patient's ability to perform tasks requiring mental alertness. Dosage adjustments of either or both medications may be necessary in some instances.
Aspirin, ASA; Carisoprodol: (Moderate) Skeletal muscle relaxants like carisoprodol may cause additive CNS depression if used concomitantly with other drugs with CNS depressant properties such as mirtazapine. Combination therapy may amplify sedation and dizziness, which can impair the patient's ability to perform tasks requiring mental alertness. Dosage adjustments of either or both medications may be necessary in some instances.
Aspirin, ASA; Carisoprodol; Codeine: (Major) Concomitant use of opioid agonists with mirtazapine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with mirtazapine 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. Avoid prescribing opioid cough medication in patients taking mirtazapine. 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) Skeletal muscle relaxants like carisoprodol may cause additive CNS depression if used concomitantly with other drugs with CNS depressant properties such as mirtazapine. Combination therapy may amplify sedation and dizziness, which can impair the patient's ability to perform tasks requiring mental alertness. Dosage adjustments of either or both medications may be necessary in some instances.
Aspirin, ASA; Oxycodone: (Major) Concomitant use of opioid agonists with mirtazapine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with mirtazapine 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.
Atazanavir: (Moderate) Concurrent administration of mirtazapine and atazanavir may result in elevated mirtazapine plasma concentrations. If these drugs are coadministered, monitor patients for adverse effects associated with mirtazapine, such as constipation, drowsiness, dizziness, and QT prolongation, and decrease the dose if necessary. Mirtazapine is a substrate of CYP3A4 and protease inhibitors are potent inhibitors of CYP3A4.
Atazanavir; Cobicistat: (Moderate) Concurrent administration of mirtazapine and atazanavir may result in elevated mirtazapine plasma concentrations. If these drugs are coadministered, monitor patients for adverse effects associated with mirtazapine, such as constipation, drowsiness, dizziness, and QT prolongation, and decrease the dose if necessary. Mirtazapine is a substrate of CYP3A4 and protease inhibitors are potent inhibitors of CYP3A4. (Moderate) Monitor for an increase in mirtazapine-related adverse reactions if coadministration with cobicistat is necessary. Mirtazapine is a CYP3A substrate; cobicistat is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased the Cmax and AUC of a single dose of mirtazapine by approximately 40% and 50%, respectively.
Atenolol; Chlorthalidone: (Moderate) Monitor for signs and symptoms of hyponatremia during concomitant diuretic and mirtazapine use; consider discontinuing mirtazapine if symptomatic hyponatremia occurs and institute appropriate medical intervention. Concomitant use increases the risk for developing hyponatremia.
Atomoxetine: (Moderate) Concomitant use of atomoxetine and mirtazapine 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) Monitor for unusual drowsiness and sedation during coadministration of mirtazapine and atropine due to the risk for additive CNS depression.
Atropine; Difenoxin: (Moderate) Consistent with the pharmacology of mirtazapine and the drug's side effect profile, additive effects may occur with other CNS-active agents, including diphenoxylate/difenoxin. (Moderate) Monitor for unusual drowsiness and sedation during coadministration of mirtazapine and atropine due to the risk for additive CNS depression.
Azelastine: (Moderate) Monitor for excessive sedation and somnolence during coadministration of azelastine and mirtazapine. Concurrent use may result in additive CNS depression.
Azelastine; Fluticasone: (Moderate) Monitor for excessive sedation and somnolence during coadministration of azelastine and mirtazapine. Concurrent use may result in additive CNS depression.
Azilsartan; Chlorthalidone: (Moderate) Monitor for signs and symptoms of hyponatremia during concomitant diuretic and mirtazapine use; consider discontinuing mirtazapine if symptomatic hyponatremia occurs and institute appropriate medical intervention. Concomitant use increases the risk for developing hyponatremia.
Azithromycin: (Major) Concomitant use of azithromycin and mirtazapine 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.
Baclofen: (Moderate) Monitor for unusual drowsiness and sedation during coadministration of baclofen and mirtazapine due to the risk for additive CNS depression.
Barbiturates: (Major) Monitor for excessive sedation and somnolence during coadministration of mirtazapine and barbiturates. Concurrent use may result in additive CNS depression.
Bedaquiline: (Major) Concomitant use of mirtazapine and bedaquiline 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.
Belladonna; Opium: (Major) Concomitant use of opioid agonists with mirtazapine may cause excessive sedation, somnolence, and increased risk of serotonin syndrome. Limit the use of opioid pain medications with mirtazapine 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. Educate patients about the risks and symptoms of excessive CNS depression and serotonin syndrome.
Benazepril; Hydrochlorothiazide, HCTZ: (Moderate) Monitor for signs and symptoms of hyponatremia during concomitant diuretic and mirtazapine use; consider discontinuing mirtazapine if symptomatic hyponatremia occurs and institute appropriate medical intervention. Concomitant use increases the risk for developing hyponatremia.
Benzhydrocodone; Acetaminophen: (Major) Concomitant use of opioid agonists with mirtazapine may cause excessive sedation, somnolence, and increased risk of serotonin syndrome. Limit the use of opioid pain medications with mirtazapine 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. Educate patients about the risks and symptoms of excessive CNS depression and serotonin syndrome.
Benzodiazepines: (Moderate) Monitor for unusual drowsiness and sedation during coadministration of benzodiazepines and mirtazapine due to the risk for additive CNS depression.
Benzoic Acid; Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate: (Contraindicated) According to the manufacturer of mirtazapine, treatment initiation with mirtazapine is contraindicated in patients currently receiving intravenous methylene blue due to an increased risk of serotonin syndrome. If urgent psychiatric treatment is required, interventions other than mirtazapine (e.g., alternative medication, hospitalization) should be considered. Conversely, in patients receiving mirtazapine and requiring urgent treatment with intravenous methylene blue, mirtazapine should be discontinued immediately and methylene blue therapy initiated only if acceptable alternatives are not available and the potential benefits of methylene blue outweigh the risks. The patient should be monitored for serotonin syndrome for 2 weeks or until 24 hours after the last dose of methylene blue, whichever comes first. Mirtazapine may be re-initiated 24 hours after the last dose of methylene blue Methylene blue is a thiazine dye that is also a potent, reversible inhibitor of the enzyme responsible for the catabolism of serotonin in the brain (MAO-A) and mirtazapine increases central serotonin effects. 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 parathyroid surgery, in patients receiving serotonergic agents such as selective serotonin reuptake inhibitors, serotonin/norepinephrine reuptake inhibitors, or clomipramine. It is not known if patients receiving intravenous methylene blue with other serotonergic psychiatric agents 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. Published interaction reports between intravenously administered 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/or coma. Serotonin syndrome is characterized by rapid development of various symptoms such as hyperthermia, hypertension, myoclonus, rigidity, hyperhidrosis, incoordination, diarrhea, mental status changes (e.g., confusion, delirium, or coma), and in rare cases, death.
Benzphetamine: (Moderate) Serotonin syndrome may occur during coadministration of serotonergic drugs such as amphetamines and mirtazapine. At high doses, amphetamines can increase serotonin release, as well as act as serotonin agonists. 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.
Bismuth Subcitrate Potassium; Metronidazole; Tetracycline: (Moderate) Concomitant use of metronidazole and mirtazapine 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; Metronidazole; Tetracycline: (Moderate) Concomitant use of metronidazole and mirtazapine 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.
Bisoprolol; Hydrochlorothiazide, HCTZ: (Moderate) Monitor for signs and symptoms of hyponatremia during concomitant diuretic and mirtazapine use; consider discontinuing mirtazapine if symptomatic hyponatremia occurs and institute appropriate medical intervention. Concomitant use increases the risk for developing hyponatremia.
Brexpiprazole: (Moderate) Due to the CNS effects of brexpiprazole, caution is advisable when brexpiprazole is given in combination with other centrally-acting medications including mirtazapine.
Brompheniramine: (Moderate) Consistent with the CNS depressant effects of mirtazapine, additive effects may occur with other CNS depressants such as brompheniramine. Mirtazapine should be administered cautiously with such agents because the CNS effects on cognitive performance and motor skills can be additive.
Brompheniramine; Dextromethorphan; Phenylephrine: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering dextromethorphan with mirtazapine. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. (Moderate) Consistent with the CNS depressant effects of mirtazapine, additive effects may occur with other CNS depressants such as brompheniramine. Mirtazapine should be administered cautiously with such agents because the CNS effects on cognitive performance and motor skills can be additive.
Brompheniramine; Phenylephrine: (Moderate) Consistent with the CNS depressant effects of mirtazapine, additive effects may occur with other CNS depressants such as brompheniramine. Mirtazapine should be administered cautiously with such agents because the CNS effects on cognitive performance and motor skills can be additive.
Brompheniramine; Pseudoephedrine: (Moderate) Consistent with the CNS depressant effects of mirtazapine, additive effects may occur with other CNS depressants such as brompheniramine. Mirtazapine should be administered cautiously with such agents because the CNS effects on cognitive performance and motor skills can be additive.
Brompheniramine; Pseudoephedrine; Dextromethorphan: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering dextromethorphan with mirtazapine. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. (Moderate) Consistent with the CNS depressant effects of mirtazapine, additive effects may occur with other CNS depressants such as brompheniramine. Mirtazapine should be administered cautiously with such agents because the CNS effects on cognitive performance and motor skills can be additive.
Bumetanide: (Moderate) Monitor for signs and symptoms of hyponatremia during concomitant diuretic and mirtazapine use; consider discontinuing mirtazapine if symptomatic hyponatremia occurs and institute appropriate medical intervention. Concomitant use increases the risk for developing hyponatremia.
Buprenorphine: (Major) There may be an increased risk for QT prolongation, torsade de pointes (TdP), serotonin syndrome, or CNS depression during concurrent use of mirtazapine and buprenorphine. Cases of QT prolongation, TdP, ventricular tachycardia, and sudden death have been reported during use of mirtazapine, primarily following overdose or in patients with other risk factors for QT prolongation, including concomitant use of other medications associated with QT prolongation. Buprenorphine has been associated with QT prolongation and has a possible risk of TdP. The labeling of some buprenorphine products recommends avoiding use with any drug that has the potential to prolong the QT interval. In addition, concurrent use of opioids with other drugs that modulate serotonergic function, such as mirtazapine, has resulted in 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. Patients should be carefully observed, particularly during treatment initiation and during dose adjustments; discontinue serotonergic agents if serotonin syndrome occurs. Hypotension, profound sedation, coma, respiratory depression, or death may occur during coadministration of buprenorphine and other CNS depressants. Prior to use of buprenorphine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, the patient's overall response to treatment, and potential 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.
Buprenorphine; Naloxone: (Major) There may be an increased risk for QT prolongation, torsade de pointes (TdP), serotonin syndrome, or CNS depression during concurrent use of mirtazapine and buprenorphine. Cases of QT prolongation, TdP, ventricular tachycardia, and sudden death have been reported during use of mirtazapine, primarily following overdose or in patients with other risk factors for QT prolongation, including concomitant use of other medications associated with QT prolongation. Buprenorphine has been associated with QT prolongation and has a possible risk of TdP. The labeling of some buprenorphine products recommends avoiding use with any drug that has the potential to prolong the QT interval. In addition, concurrent use of opioids with other drugs that modulate serotonergic function, such as mirtazapine, has resulted in 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. Patients should be carefully observed, particularly during treatment initiation and during dose adjustments; discontinue serotonergic agents if serotonin syndrome occurs. Hypotension, profound sedation, coma, respiratory depression, or death may occur during coadministration of buprenorphine and other CNS depressants. Prior to use of buprenorphine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, the patient's overall response to treatment, and potential 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.
Buspirone: (Moderate) The use of mirtazapine with buspirone may increase the risk for serotonin syndrome. Both medications have serotonergic effects. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome.
Butabarbital: (Major) Monitor for excessive sedation and somnolence during coadministration of mirtazapine and barbiturates. Concurrent use may result in additive CNS depression.
Butalbital; Acetaminophen: (Major) Monitor for excessive sedation and somnolence during coadministration of mirtazapine and barbiturates. Concurrent use may result in additive CNS depression.
Butalbital; Acetaminophen; Caffeine: (Major) Monitor for excessive sedation and somnolence during coadministration of mirtazapine and barbiturates. Concurrent use may result in additive CNS depression.
Butalbital; Acetaminophen; Caffeine; Codeine: (Major) Concomitant use of opioid agonists with mirtazapine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with mirtazapine 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. Avoid prescribing opioid cough medication in patients taking mirtazapine. 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) Monitor for excessive sedation and somnolence during coadministration of mirtazapine and barbiturates. Concurrent use may result in additive CNS depression.
Butalbital; Aspirin; Caffeine; Codeine: (Major) Concomitant use of opioid agonists with mirtazapine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with mirtazapine 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. Avoid prescribing opioid cough medication in patients taking mirtazapine. 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) Monitor for excessive sedation and somnolence during coadministration of mirtazapine and barbiturates. Concurrent use may result in additive CNS depression.
Butorphanol: (Moderate) Concomitant use of butorphanol with other CNS depressants can potentiate the effects of butorphanol on respiratory depression, CNS depression, and sedation. Butorphanol should be used cautiously in any patient receiving these agents, which may include mirtazapine.
Cabotegravir; Rilpivirine: (Moderate) Concomitant use of mirtazapine 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.
Candesartan; Hydrochlorothiazide, HCTZ: (Moderate) Monitor for signs and symptoms of hyponatremia during concomitant diuretic and mirtazapine use; consider discontinuing mirtazapine if symptomatic hyponatremia occurs and institute appropriate medical intervention. Concomitant use increases the risk for developing hyponatremia.
Cannabidiol: (Moderate) Monitor for excessive sedation and somnolence during coadministration of cannabidiol and mirtazapine. CNS depressants can potentiate the effects of cannabidiol.
Capsaicin; Metaxalone: (Moderate) Coadministration of mirtazapine with metaxalone may result in additive CNS-depressant effects, such as sedation, and may increase the risk for serotonin syndrome. Use with caution and monitor for the emergence of excessive sedation or serotonin syndrome. If serotonin syndrome is suspected, serotonergic agents should be discontinued and appropriate medical treatment instituted.
Captopril; Hydrochlorothiazide, HCTZ: (Moderate) Monitor for signs and symptoms of hyponatremia during concomitant diuretic and mirtazapine use; consider discontinuing mirtazapine if symptomatic hyponatremia occurs and institute appropriate medical intervention. Concomitant use increases the risk for developing hyponatremia.
Carbamazepine: (Moderate) As carbamazepine is known to induce CYP1A2 and CYP3A4, serum concentrations of mirtazapine may be decreased because of CYP enzyme induction. Increased dosages of mirtazapine may be needed.
Carbidopa; Levodopa; Entacapone: (Major) COMT inhibitors should be given cautiously with other agents that cause CNS depression, such as mirtazapine, due to the possibility of additive sedation. COMT inhibitors have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment. Patients should be advised to avoid driving or other tasks requiring mental alertness until they know how the combination affects them.
Carbinoxamine: (Moderate) Consistent with the CNS depressant effects of mirtazapine, additive effects may occur with other CNS depressants such as carbinoxamine. Mirtazapine should be administered cautiously with such agents because the CNS effects on cognitive performance and motor skills can be additive.
Cariprazine: (Moderate) Due to the CNS effects of cariprazine, caution is advisable when cariprazine is given in combination with other centrally-acting medications including mirtazapine.
Carisoprodol: (Moderate) Skeletal muscle relaxants like carisoprodol may cause additive CNS depression if used concomitantly with other drugs with CNS depressant properties such as mirtazapine. Combination therapy may amplify sedation and dizziness, which can impair the patient's ability to perform tasks requiring mental alertness. Dosage adjustments of either or both medications may be necessary in some instances.
Celecoxib; Tramadol: (Major) Concomitant use of opioid agonists with mirtazapine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with mirtazapine 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.
Cenobamate: (Moderate) Monitor for excessive sedation and somnolence during coadministration of cenobamate and mirtazapine. Concurrent use may result in additive CNS depression.
Ceritinib: (Major) Avoid coadministration of ceritinib with mirtazapine if possible due to the risk of QT prolongation; plasma concentrations of mirtazapine may also increase. 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. Mirtazapine is a CYP3A4 substrate that has been associated with dose-dependent QT prolongation; torsade de pointes (TdP) has also been reported in postmarketing experience, primarily in overdose or in patients with other risk factors for QT prolongation. Ceritinib is a strong CYP3A4 inhibitor that is also associated with concentration-dependent QT prolongation. Coadministration with another strong CYP3A4 inhibitor increased the Cmax and AUC of a single dose of mirtazapine by approximately 40% and 50%, respectively.
Cetirizine: (Moderate) Monitor for unusual drowsiness and sedation during coadministration of cetirizine and mirtazapine due to the risk for additive CNS depression.
Cetirizine; Pseudoephedrine: (Moderate) Monitor for unusual drowsiness and sedation during coadministration of cetirizine and mirtazapine due to the risk for additive CNS depression.
Chlophedianol; Dexbrompheniramine: (Moderate) Consistent with the CNS depressant effects of mirtazapine, additive effects may occur with other CNS depressants such as dexbrompheniramine. Mirtazapine should be administered cautiously with such agents because the CNS effects on cognitive performance and motor skills can be additive.
Chlophedianol; Dexchlorpheniramine; Pseudoephedrine: (Moderate) Consistent with the CNS depressant effects of mirtazapine, additive effects may occur with other CNS depressants such as dexchlorpheniramine. Mirtazapine should be administered cautiously with such agents because the CNS effects on cognitive performance and motor skills can be additive.
Chlorcyclizine: (Moderate) Consistent with the CNS depressant effects of mirtazapine, additive effects may occur with other CNS depressants such as chlorcyclizine. Mirtazapine should be administered cautiously with such agents because the CNS effects on cognitive performance and motor skills can be additive.
Chlordiazepoxide: (Moderate) Monitor for unusual drowsiness and sedation during coadministration of benzodiazepines and mirtazapine due to the risk for additive CNS depression.
Chlordiazepoxide; Amitriptyline: (Moderate) Monitor for unusual drowsiness and sedation during coadministration of benzodiazepines and mirtazapine due to the risk for additive CNS depression. (Moderate) Monitor for unusual drowsiness, sedation, and serotonin syndrome during coadministration due to the risk for additive CNS depression and serotonin syndrome. If serotonin syndrome occurs, consider discontinuation of therapy.
Chlordiazepoxide; Clidinium: (Moderate) Monitor for unusual drowsiness and sedation during coadministration of benzodiazepines and mirtazapine due to the risk for additive CNS depression.
Chloroquine: (Major) Concomitant use of chloroquine and mirtazapine 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 mirtazapine use; consider discontinuing mirtazapine if symptomatic hyponatremia occurs and institute appropriate medical intervention. Concomitant use increases the risk for developing hyponatremia.
Chlorpheniramine: (Moderate) Consistent with the CNS depressant effects of mirtazapine, additive effects may occur with other CNS depressants such as chlorpheniramine. Mirtazapine should be administered cautiously with such agents because the CNS effects on cognitive performance and motor skills can be additive.
Chlorpheniramine; Codeine: (Major) Concomitant use of opioid agonists with mirtazapine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with mirtazapine 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. Avoid prescribing opioid cough medication in patients taking mirtazapine. 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) Consistent with the CNS depressant effects of mirtazapine, additive effects may occur with other CNS depressants such as chlorpheniramine. Mirtazapine should be administered cautiously with such agents because the CNS effects on cognitive performance and motor skills can be additive.
Chlorpheniramine; Dextromethorphan: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering dextromethorphan with mirtazapine. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. (Moderate) Consistent with the CNS depressant effects of mirtazapine, additive effects may occur with other CNS depressants such as chlorpheniramine. Mirtazapine should be administered cautiously with such agents because the CNS effects on cognitive performance and motor skills can be additive.
Chlorpheniramine; Dextromethorphan; Phenylephrine: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering dextromethorphan with mirtazapine. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. (Moderate) Consistent with the CNS depressant effects of mirtazapine, additive effects may occur with other CNS depressants such as chlorpheniramine. Mirtazapine should be administered cautiously with such agents because the CNS effects on cognitive performance and motor skills can be additive.
Chlorpheniramine; Dextromethorphan; Pseudoephedrine: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering dextromethorphan with mirtazapine. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. (Moderate) Consistent with the CNS depressant effects of mirtazapine, additive effects may occur with other CNS depressants such as chlorpheniramine. Mirtazapine should be administered cautiously with such agents because the CNS effects on cognitive performance and motor skills can be additive.
Chlorpheniramine; Dihydrocodeine; Phenylephrine: (Major) Concomitant use of opioid agonists with mirtazapine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with mirtazapine 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. Avoid prescribing opioid cough medication in patients taking mirtazapine. 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) Consistent with the CNS depressant effects of mirtazapine, additive effects may occur with other CNS depressants such as chlorpheniramine. Mirtazapine should be administered cautiously with such agents because the CNS effects on cognitive performance and motor skills can be additive.
Chlorpheniramine; Hydrocodone: (Major) Concomitant use of opioid agonists with mirtazapine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with mirtazapine 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 mirtazapine. (Moderate) Consistent with the CNS depressant effects of mirtazapine, additive effects may occur with other CNS depressants such as chlorpheniramine. Mirtazapine should be administered cautiously with such agents because the CNS effects on cognitive performance and motor skills can be additive.
Chlorpheniramine; Ibuprofen; Pseudoephedrine: (Moderate) Consistent with the CNS depressant effects of mirtazapine, additive effects may occur with other CNS depressants such as chlorpheniramine. Mirtazapine should be administered cautiously with such agents because the CNS effects on cognitive performance and motor skills can be additive.
Chlorpheniramine; Phenylephrine: (Moderate) Consistent with the CNS depressant effects of mirtazapine, additive effects may occur with other CNS depressants such as chlorpheniramine. Mirtazapine should be administered cautiously with such agents because the CNS effects on cognitive performance and motor skills can be additive.
Chlorpheniramine; Pseudoephedrine: (Moderate) Consistent with the CNS depressant effects of mirtazapine, additive effects may occur with other CNS depressants such as chlorpheniramine. Mirtazapine should be administered cautiously with such agents because the CNS effects on cognitive performance and motor skills can be additive.
Chlorpromazine: (Major) Coadministration may increase the risk of QT prolongation, torsade de pointes, and CNS depression. Due to the possibility of additive effects on the QT interval, caution is advisable during concurrent use of chlorpromazine and mirtazapine. Chlorpromazine, a phenothiazine, is associated with an established risk of QT prolongation and torsade de pointes (TdP). Cases of QT prolongation, TdP, ventricular tachycardia, and sudden death have been reported during postmarketing use of mirtazapine. The majority of reports have occurred in the setting of mirtazapine overdose or in patients with other risk factors for QT prolongation, including concomitant use of other medications associated with QT prolongation. Both drugs also have CNS depressant properties, and patients should be advised to avoid engaging in activities requiring mental alertness until they are aware of the effects of the combination.
Chlorthalidone: (Moderate) Monitor for signs and symptoms of hyponatremia during concomitant diuretic and mirtazapine use; consider discontinuing mirtazapine if symptomatic hyponatremia occurs and institute appropriate medical intervention. Concomitant use increases the risk for developing hyponatremia.
Chlorthalidone; Clonidine: (Moderate) Monitor blood pressure and for unusual drowsiness or excess sedation during coadministration of clonidine and mirtazapine. Concomitant use may result in reduced hypotensive effect of clonidine and additive CNS depression. Mirtazapine and clonidine have pharmacologic actions that potentially oppose one another. Mirtazapine inhibits central alpha-2 autoreceptors (located presynaptically on noradrenergic neurons) and stimulating norepinephrine and stimulates the serotonergic system through antagonism at alpha-2 heteroreceptors. Clonidine exerts its antihypertensive effect by stimulating the central alpha-2 autor

eceptors, thereby causing a reduction in the synthesis and release of norepinephrine. (Moderate) Monitor for signs and symptoms of hyponatremia during concomitant diuretic and mirtazapine use; consider discontinuing mirtazapine if symptomatic hyponatremia occurs and institute appropriate medical intervention. Concomitant use increases the risk for developing hyponatremia.
Chlorzoxazone: (Moderate) Skeletal muscle relaxants like chlorzoxazone may cause additive CNS depression if used concomitantly with other drugs with CNS depressant properties such as mirtazapine. Combination therapy may amplify sedation and dizziness, which can impair the patient's ability to perform tasks requiring mental alertness. Dosage adjustments of either or both medications may be necessary in some instances.
Cimetidine: (Moderate) Monitor for an increase in mirtazapine-related adverse reactions if coadministration with cimetidine is necessary; reduce the mirtazapine dose if needed. Coadministration may increase mirtazapine exposure and risk for side effects. In healthy subjects (n = 12), when cimetidine 800 mg twice daily at steady-state was coadministered with mirtazapine 30 mg/day at steady-state, mirtazapine AUC increased by more than 50%. Mirtazapine is a CYP1A2, CYP2D6, and CYP3A substrate and cimetidine is a CYP1A2, CYP2D6, and CYP3A inhibitor.
Ciprofloxacin: (Moderate) Concomitant use of ciprofloxacin and mirtazapine 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) Avoid concomitant use of mirtazapine and cisapride due to an increased risk for torsade de pointes (TdP) and QT/QTc prolongation.
Citalopram: (Major) Concomitant use of mirtazapine and citalopram may increase the risk of serotonin syndrome, QT prolongation, and torsade de pointes. Citalopram causes dose-dependent QT interval prolongation. The manufacturer of citalopram recommends avoidance of other drugs that prolong the QT interval. If concurrent therapy is required, ECG monitoring is recommended. Cases of QT prolongation, TdP, ventricular tachycardia, and sudden death have been reported during use of mirtazapine, primarily after overdose or in patients with risk factors for QT prolongation (e.g., concurrent use of other medications associated with QT prolongation). Both mirtazapine and SSRIs such as citalopram have central serotonin-enhancing effects, and case reports suggest that 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.
Clarithromycin: (Major) Concomitant use of mirtazapine and clarithromycin 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.
Clemastine: (Moderate) Consistent with the CNS depressant effects of mirtazapine, additive effects may occur with other CNS depressants such as clemastine. Mirtazapine should be administered cautiously with such agents because the CNS effects on cognitive performance and motor skills can be additive.
Clofazimine: (Moderate) Concomitant use of clofazimine and mirtazapine 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) Monitor for unusual drowsiness, sedation, and serotonin syndrome during coadministration due to the risk for additive CNS depression and serotonin syndrome. If serotonin syndrome occurs, consider discontinuation of therapy.
Clonazepam: (Moderate) Monitor for unusual drowsiness and sedation during coadministration of benzodiazepines and mirtazapine due to the risk for additive CNS depression.
Clonidine: (Moderate) Monitor blood pressure and for unusual drowsiness or excess sedation during coadministration of clonidine and mirtazapine. Concomitant use may result in reduced hypotensive effect of clonidine and additive CNS depression. Mirtazapine and clonidine have pharmacologic actions that potentially oppose one another. Mirtazapine inhibits central alpha-2 autoreceptors (located presynaptically on noradrenergic neurons) and stimulating norepinephrine and stimulates the serotonergic system through antagonism at alpha-2 heteroreceptors. Clonidine exerts its antihypertensive effect by stimulating the central alpha-2 autoreceptors, thereby causing a reduction in the synthesis and release of norepinephrine.
Clorazepate: (Moderate) Monitor for unusual drowsiness and sedation during coadministration of benzodiazepines and mirtazapine due to the risk for additive CNS depression.
Clozapine: (Moderate) Concomitant use of mirtazapine and clozapine 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.
Cobicistat: (Moderate) Monitor for an increase in mirtazapine-related adverse reactions if coadministration with cobicistat is necessary. Mirtazapine is a CYP3A substrate; cobicistat is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased the Cmax and AUC of a single dose of mirtazapine by approximately 40% and 50%, respectively.
Cocaine: (Major) Although unlikely to occur with use of mirtazapine alone, there have been rare case reports of serotonin syndrome with the drug. It is likely that the activation of 5-HT1A receptors by mirtazapine, combined with coadministration of other medications that increase serotonin release, such as cocaine, could result in serotonin syndrome.
Codeine: (Major) Concomitant use of opioid agonists with mirtazapine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with mirtazapine 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. Avoid prescribing opioid cough medication in patients taking mirtazapine. 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.
Codeine; Guaifenesin: (Major) Concomitant use of opioid agonists with mirtazapine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with mirtazapine 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. Avoid prescribing opioid cough medication in patients taking mirtazapine. 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.
Codeine; Guaifenesin; Pseudoephedrine: (Major) Concomitant use of opioid agonists with mirtazapine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with mirtazapine 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. Avoid prescribing opioid cough medication in patients taking mirtazapine. 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.
Codeine; Phenylephrine; Promethazine: (Major) Concomitant use of opioid agonists with mirtazapine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with mirtazapine 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. Avoid prescribing opioid cough medication in patients taking mirtazapine. 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) There may be an increased risk for QT prolongation and torsade de pointes (TdP) during concurrent use of mirtazapine and promethazine. Coadminister with caution. Cases of QT prolongation, TdP, ventricular tachycardia, and sudden death have been reported during postmarketing use of mirtazapine, primarily following overdose or in patients with other risk factors for QT prolongation, including concomitant use of other medications associated with QT prolongation. Promethazine, a phenothiazine, is associated with a possible risk for QT prolongation. Because both mirtazapine and promethazine have CNS depressant properties, patients should be advised to avoid engaging in activities requiring mental alertness until they are aware of how the combination affects them.
Codeine; Promethazine: (Major) Concomitant use of opioid agonists with mirtazapine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with mirtazapine 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. Avoid prescribing opioid cough medication in patients taking mirtazapine. 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) There may be an increased risk for QT prolongation and torsade de pointes (TdP) during concurrent use of mirtazapine and promethazine. Coadminister with caution. Cases of QT prolongation, TdP, ventricular tachycardia, and sudden death have been reported during postmarketing use of mirtazapine, primarily following overdose or in patients with other risk factors for QT prolongation, including concomitant use of other medications associated with QT prolongation. Promethazine, a phenothiazine, is associated with a possible risk for QT prolongation. Because both mirtazapine and promethazine have CNS depressant properties, patients should be advised to avoid engaging in activities requiring mental alertness until they are aware of how the combination affects them.
COMT inhibitors: (Major) COMT inhibitors should be given cautiously with other agents that cause CNS depression, such as mirtazapine, due to the possibility of additive sedation. COMT inhibitors have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment. Patients should be advised to avoid driving or other tasks requiring mental alertness until they know how the combination affects them.
Crizotinib: (Major) Concomitant use of crizotinib and mirtazapine 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.
Cyclizine: (Moderate) Consistent with the CNS depressant effects of mirtazapine, additive effects may occur with other CNS depressants such as cyclizine. Mirtazapine should be administered cautiously with such agents because the CNS effects on cognitive performance and motor skills can be additive.
Cyclobenzaprine: (Moderate) Skeletal muscle relaxants like cyclobenzaprine may cause additive CNS depression if used concomitantly with other drugs with CNS depressant properties such as mirtazapine. Combination therapy may amplify sedation and dizziness, which can impair the patient's ability to perform tasks requiring mental alertness. Dosage adjustments of either or both medications may be necessary in some instances. In addition, anecdotal evidence from case reports suggests that cyclobenzaprine may possess serotonin augmenting effects that may be clinically relevant during administration of the drug with serotonin-enhancing medications. In theory, there is a remote possibility that serotonin syndrome may occur from concurrent administration of cyclobenzaprine and mirtazapine since mirtazapine increases central serotonin activity. In addition, cyclobenzaprine is closely related to the tricyclic antidepressants, which are known to decrease serotonin reuptake. Caution is advisable during concurrent use with mirtazapine until more information about cyclobenzaprine's effects on serotonin becomes available.
Cyproheptadine: (Moderate) Consistent with the CNS depressant effects of mirtazapine, additive effects may occur with other CNS depressants such as cyproheptadine. Mirtazapine should be administered cautiously with such agents because the CNS effects on cognitive performance and motor skills can be additive.
Dantrolene: (Moderate) Skeletal muscle relaxants like dantrolene may cause additive CNS depression if used concomitantly with other drugs with CNS depressant properties such as mirtazapine. Combination therapy may amplify sedation and dizziness, which can impair the patient's ability to perform tasks requiring mental alertness. Dosage adjustments of either or both medications may be necessary in some instances.
Darunavir: (Moderate) Concurrent administration of mirtazapine and darunavir may result in elevated mirtazapine plasma concentrations. If these drugs are coadministered, monitor patients for adverse effects associated with mirtazapine, such as constipation, drowsiness, dizziness, and QT prolongation, and decrease the dose if necessary. Mirtazapine is a substrate of CYP3A4 and protease inhibitors are potent inhibitors of CYP3A4.
Darunavir; Cobicistat: (Moderate) Concurrent administration of mirtazapine and darunavir may result in elevated mirtazapine plasma concentrations. If these drugs are coadministered, monitor patients for adverse effects associated with mirtazapine, such as constipation, drowsiness, dizziness, and QT prolongation, and decrease the dose if necessary. Mirtazapine is a substrate of CYP3A4 and protease inhibitors are potent inhibitors of CYP3A4. (Moderate) Monitor for an increase in mirtazapine-related adverse reactions if coadministration with cobicistat is necessary. Mirtazapine is a CYP3A substrate; cobicistat is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased the Cmax and AUC of a single dose of mirtazapine by approximately 40% and 50%, respectively.
Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide: (Moderate) Concurrent administration of mirtazapine and darunavir may result in elevated mirtazapine plasma concentrations. If these drugs are coadministered, monitor patients for adverse effects associated with mirtazapine, such as constipation, drowsiness, dizziness, and QT prolongation, and decrease the dose if necessary. Mirtazapine is a substrate of CYP3A4 and protease inhibitors are potent inhibitors of CYP3A4. (Moderate) Monitor for an increase in mirtazapine-related adverse reactions if coadministration with cobicistat is necessary. Mirtazapine is a CYP3A substrate; cobicistat is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased the Cmax and AUC of a single dose of mirtazapine by approximately 40% and 50%, respectively.
Dasatinib: (Moderate) Concomitant use of mirtazapine 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.
Degarelix: (Moderate) Concomitant use of mirtazapine 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: (Moderate) Monitor for an increase in mirtazapine-related adverse reactions if coadministration with delavirdine is necessary. Mirtazapine is a CYP3A substrate; delavirdine is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased the Cmax and AUC of a single dose of mirtazapine by approximately 40% and 50%, respectively.
Desflurane: (Major) Concomitant use of halogenated and mirtazapine 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) Monitor for unusual drowsiness, sedation, and serotonin syndrome during coadministration due to the risk for additive CNS depression and serotonin syndrome. If serotonin syndrome occurs, consider discontinuation of therapy.
Desvenlafaxine: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when coadministering drugs that have serotonergic properties such as mirtazapine and desvenlafaxine. Cases of serotonin syndrome have been reported between mirtazapine and other antidepressants such as selective serotonin reuptake inhibitors (SSRIs). 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, serotonergic agents should be discontinued and appropriate medical treatment should be implemented.
Deutetrabenazine: (Moderate) Use caution when using mirtazipine in combination with deutetrabenazine. Mirtazipine has been associated with dose-dependent prolongation of the QT interval. Torsade de pointes (TdP) has been reported postmarketing with mirtazipine, primarily in overdose or in patients with other risk factors for QT prolongation. 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 excessive sedation and somnolence during coadministration of mirtazapine and deutetrabenazine. Concurrent use may result in additive CNS depression.
Dexbrompheniramine: (Moderate) Consistent with the CNS depressant effects of mirtazapine, additive effects may occur with other CNS depressants such as dexbrompheniramine. Mirtazapine should be administered cautiously with such agents because the CNS effects on cognitive performance and motor skills can be additive.
Dexbrompheniramine; Pseudoephedrine: (Moderate) Consistent with the CNS depressant effects of mirtazapine, additive effects may occur with other CNS depressants such as dexbrompheniramine. Mirtazapine should be administered cautiously with such agents because the CNS effects on cognitive performance and motor skills can be additive.
Dexchlorpheniramine: (Moderate) Consistent with the CNS depressant effects of mirtazapine, additive effects may occur with other CNS depressants such as dexchlorpheniramine. Mirtazapine should be administered cautiously with such agents because the CNS effects on cognitive performance and motor skills can be additive.
Dexchlorpheniramine; Dextromethorphan; Pseudoephedrine: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering dextromethorphan with mirtazapine. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. (Moderate) Consistent with the CNS depressant effects of mirtazapine, additive effects may occur with other CNS depressants such as dexchlorpheniramine. Mirtazapine should be administered cautiously with such agents because the CNS effects on cognitive performance and motor skills can be additive.
Dexmedetomidine: (Moderate) Concomitant use of dexmedetomidine and mirtazapine 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) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering dextromethorphan with mirtazapine. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
Dextromethorphan; Bupropion: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering dextromethorphan with mirtazapine. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
Dextromethorphan; Diphenhydramine; Phenylephrine: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering dextromethorphan with mirtazapine. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. (Moderate) Monitor for unusual drowsiness and sedation during coadministration of diphenhydramine and mirtazapine due to the risk for additive CNS depression.
Dextromethorphan; Guaifenesin: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering dextromethorphan with mirtazapine. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
Dextromethorphan; Guaifenesin; Phenylephrine: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering dextromethorphan with mirtazapine. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
Dextromethorphan; Guaifenesin; Potassium Guaiacolsulfonate: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering dextromethorphan with mirtazapine. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
Dextromethorphan; Guaifenesin; Pseudoephedrine: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering dextromethorphan with mirtazapine. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
Dextromethorphan; Quinidine: (Major) Concomitant use of quinidine and mirtazapine 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) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering dextromethorphan with mirtazapine. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
Diazepam: (Moderate) Monitor for unusual drowsiness and sedation during coadministration of benzodiazepines and mirtazapine due to the risk for additive CNS depression.
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) The use of ergot alkaloids with mirtazapine might increase the risk for serotonin syndrome. Patients receiving ergot alkaloids with mirtazapine should be monitored for the emergence of serotonin syndrome. If serotonin syndrome occurs, discontinue serotonergic agents and institute appropriate medical treatment.
Dimenhydrinate: (Moderate) Monitor for unusual drowsiness and sedation during coadministration of dimenhydrinate and mirtazapine due to the risk for additive CNS depression.
Diphenhydramine: (Moderate) Monitor for unusual drowsiness and sedation during coadministration of diphenhydramine and mirtazapine due to the risk for additive CNS depression.
Diphenhydramine; Ibuprofen: (Moderate) Monitor for unusual drowsiness and sedation during coadministration of diphenhydramine and mirtazapine due to the risk for additive CNS depression.
Diphenhydramine; Naproxen: (Moderate) Monitor for unusual drowsiness and sedation during coadministration of diphenhydramine and mirtazapine due to the risk for additive CNS depression.
Diphenhydramine; Phenylephrine: (Moderate) Monitor for unusual drowsiness and sedation during coadministration of diphenhydramine and mirtazapine due to the risk for additive CNS depression.
Diphenoxylate; Atropine: (Moderate) Consistent with the pharmacology of mirtazapine and the drug's side effect profile, additive effects may occur with other CNS-active agents, including diphenoxylate/difenoxin. (Moderate) Monitor for unusual drowsiness and sedation during coadministration of mirtazapine and atropine due to the risk for additive CNS depression.
Disopyramide: (Major) Concomitant use of disopyramide and mirtazapine 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.
Dofetilide: (Major) Concomitant use of dofetilide and mirtazapine 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.
Dolasetron: (Moderate) Administer dolasetron with caution in combination with mirtazapine as concurrent use may increase the risk of QT prolongation; the risk of serotonin syndrome may also increase. Mirtazapine has been associated with dose-dependent prolongation of the QT interval. Torsade de pointes (TdP) has been reported postmarketing, primarily in overdose or in patients with other risk factors for QT prolongation. Dolasetron has been associated with a dose-dependent prolongation in the QT, PR, and QRS intervals on an electrocardiogram. If serotonin syndrome occurs, discontinue all serotonergic agents and initiate appropriate medical treatment.
Dolutegravir; Rilpivirine: (Moderate) Concomitant use of mirtazapine 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) Concomitant use of mirtazapine and donepezil 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.
Donepezil; Memantine: (Moderate) Concomitant use of mirtazapine and donepezil 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.
Doxepin: (Moderate) Monitor for unusual drowsiness, sedation, and serotonin syndrome during coadministration due to the risk for additive CNS depression and serotonin syndrome. If serotonin syndrome occurs, consider discontinuation of therapy.
Doxylamine: (Moderate) Monitor for unusual drowsiness and sedation during coadministration of doxylamine and mirtazapine due to the risk for additive CNS depression.
Doxylamine; Pyridoxine: (Moderate) Monitor for unusual drowsiness and sedation during coadministration of doxylamine and mirtazapine due to the risk for additive CNS depression.
Dronabinol: (Moderate) Consistent with the pharmacology of mirtazapine and the drug's side effect profile, additive effects may occur with other CNS-active agents, such as dronabinol.
Dronedarone: (Contraindicated) Avoid concomitant use of mirtazapine and dronedarone due to an increased risk for torsade de pointes (TdP) and QT/QTc prolongation.
Droperidol: (Major) Droperidol should not be used in combination with any drug known to have potential to prolong the QT interval, such as mirtazapine. 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 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. Cases of QT prolongation, TdP, ventricular tachycardia, and sudden death have been reported during use of mirtazapine, particularly in the setting of overdose or when other risk factors for QT prolongation are present, including concomitant use of other medications associated with QT prolongation. Central nervous system depressants, including mirtazapine and droperidol, may have additive CNS effects. Lower doses of either agent may be required.
Duloxetine: (Moderate) Coadministration of duloxetine and mirtazapine may increase the risk for serotonin syndrome. Cases of serotonin syndrome have been reported when mirtazapine has been administered with other serotonergic antidepressants. 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 treatment should be implemented.
Efavirenz: (Moderate) Concomitant use of mirtazapine 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.
Efavirenz; Emtricitabine; Tenofovir Disoproxil Fumarate: (Moderate) Concomitant use of mirtazapine 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.
Efavirenz; Lamivudine; Tenofovir Disoproxil Fumarate: (Moderate) Concomitant use of mirtazapine 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.
Elbasvir; Grazoprevir: (Moderate) Administering mirtazapine with elbasvir; grazoprevir may result in elevated mirtazapine plasma concentrations. Mirtazapine is a substrate of CYP3A; grazoprevir is a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of adverse events.
Eletriptan: (Major) The coadministration of serotonergic antidepressants with serotonin-agonists has sometimes resulted in serotonin syndrome. Careful observation of the patient is advised, particularly during treatment initiation and dose increases. Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, and coma), autonomic instability (e.g., tachycardia, labile blood pressure, and hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination) and/or gastrointestinal symptoms (e.g., nausea, vomiting, and diarrhea). Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome, which includes hyperthermia, muscle rigidity, autonomic instability with possible rapid fluctuation of vital signs, and mental status changes. Discontinue the serotonergic agents immediately if serotonin syndrome reactions occur and initiate supportive symptomatic treatment.
Eliglustat: (Major) Concomitant use of eliglustat and mirtazapine 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.
Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Alafenamide: (Moderate) Monitor for an increase in mirtazapine-related adverse reactions if coadministration with cobicistat is necessary. Mirtazapine is a CYP3A substrate; cobicistat is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased the Cmax and AUC of a single dose of mirtazapine by approximately 40% and 50%, respectively.
Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Disoproxil Fumarate: (Moderate) Monitor for an increase in mirtazapine-related adverse reactions if coadministration with cobicistat is necessary. Mirtazapine is a CYP3A substrate; cobicistat is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased the Cmax and AUC of a single dose of mirtazapine by approximately 40% and 50%, respectively.
Emtricitabine; Rilpivirine; Tenofovir alafenamide: (Moderate) Concomitant use of mirtazapine 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) Concomitant use of mirtazapine 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; Hydrochlorothiazide, HCTZ: (Moderate) Monitor for signs and symptoms of hyponatremia during concomitant diuretic and mirtazapine use; consider discontinuing mirtazapine if symptomatic hyponatremia occurs and institute appropriate medical intervention. Concomitant use increases the risk for developing hyponatremia.
Encorafenib: (Major) Concomitant use of encorafenib and mirtazapine 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.
Entacapone: (Major) COMT inhibitors should be given cautiously with other agents that cause CNS depression, such as mirtazapine, due to the possibility of additive sedation. COMT inhibitors have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment. Patients should be advised to avoid driving or other tasks requiring mental alertness until they know how the combination affects them.
Entrectinib: (Major) Concomitant use of entrectinib and mirtazapine 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.
Enzalutamide: (Moderate) Monitor for decreased efficacy of mirtazapine if coadministration with enzalutamide is necessary; a dosage adjustment of mirtazapine may be necessary. Mirtazapine is a CYP3A4 substrate and enzalutamide is a strong CYP3A4 inducer. Coadministration with other strong CYP3A4 inducers increased mirtazapine clearance by approximately 2-fold, decreasing the average mirtazapine plasma concentrations by 45% to 60%.
Eprosartan; Hydrochlorothiazide, HCTZ: (Moderate) Monitor for signs and symptoms of hyponatremia during concomitant diuretic and mirtazapine use; consider discontinuing mirtazapine if symptomatic hyponatremia occurs and institute appropriate medical intervention. Concomitant use increases the risk for developing hyponatremia.
Ergoloid Mesylates: (Moderate) The use of ergot alkaloids with mirtazapine might increase the risk for serotonin syndrome. Patients receiving ergot alkaloids with mirtazapine should be monitored for the emergence of serotonin syndrome. If serotonin syndrome occurs, discontinue serotonergic agents and institute appropriate medical treatment.
Ergot alkaloids: (Moderate) The use of ergot alkaloids with mirtazapine might increase the risk for serotonin syndrome. Patients receiving ergot alkaloids with mirtazapine should be monitored for the emergence of serotonin syndrome. If serotonin syndrome occurs, discontinue serotonergic agents and institute appropriate medical treatment.
Ergotamine: (Moderate) The use of ergot alkaloids with mirtazapine might increase the risk for serotonin syndrome. Patients receiving ergot alkaloids with mirtazapine should be monitored for the emergence of serotonin syndrome. If serotonin syndrome occurs, discontinue serotonergic agents and institute appropriate medical treatment.
Ergotamine; Caffeine: (Moderate) The use of ergot alkaloids with mirtazapine might increase the risk for serotonin syndrome. Patients receiving ergot alkaloids with mirtazapine should be monitored for the emergence of serotonin syndrome. If serotonin syndrome occurs, discontinue serotonergic agents and institute appropriate medical treatment.
Eribulin: (Major) Concomitant use of eribulin and mirtazapine 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.
Erythromycin: (Major) Concomitant use of erythromycin and mirtazapine 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: (Moderate) Concomitant use of mirtazapine and escitalopram may increase the risk of serotonin syndrome, QT prolongation, and torsade de pointes (TdP). Escitalopram has been associated with a risk of QT prolongation and TdP. Cases of QT prolongation, TdP, ventricular tachycardia, and sudden death have been reported during use of mirtazapine, primarily after overdose or in patients with risk factors for QT prolongation (e.g., concurrent use of other medications associated with QT prolongation). Both mirtazapine and SSRIs such as escitalopram have central serotonin-enhancing effects, and case reports suggest that serotonin syndrome is possible. If serotonin syndrome occurs, all serotonergic agents should be discontinued, and appropriate medical treatment should be implemented.
Esketamine: (Major) Closely monitor patients receiving esketamine and mirtazapine 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.
Estazolam: (Moderate) Monitor for unusual drowsiness and sedation during coadministration of benzodiazepines and mirtazapine due to the risk for additive CNS depression.
Ethacrynic Acid: (Moderate) Monitor for signs and symptoms of hyponatremia during concomitant diuretic and mirtazapine use; consider discontinuing mirtazapine 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.
Etomidate: (Moderate) Consistent with the pharmacology of mirtazapine and the CNS depression that may occur, additive effects may occur with other CNS depressants, including etomidate. Close monitoring is recommended in patients receiving mirtazapine and requiring an anesthetic.
Fenfluramine: (Moderate) Use fenfluramine and mirtazapine 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.
Fentanyl: (Major) Concomitant use of opioid agonists with mirtazapine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with mirtazapine 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.
Fingolimod: (Moderate) Concomitant use of mirtazapine 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.
Flecainide: (Major) Concomitant use of flecainide and mirtazapine 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.
Flibanserin: (Moderate) The concomitant use of flibanserin with CNS depressants, such as mirtazapine, may increase the risk of CNS depression (e.g., dizziness, somnolence) compared to the use of flibanserin alone. Patients should avoid activities requiring full alertness (e.g., operating machinery or driving) until at least 6 hours after each dose and until they know how flibanserin affects them.
Fluconazole: (Moderate) Concomitant use of fluconazole and mirtazapine 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.
Fluoxetine: (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.
Fluphenazine: (Moderate) Coadministration may increase the risk of QT prolongation, torsade de pointes, and CNS depression. Due to the possibility of additive effects on the QT interval, caution is advisable during concurrent use of mirtazapine and fluphenazine. Cases of QT prolongation, TdP, ventricular tachycardia, and sudden death have been reported during postmarketing use of mirtazapine. The majority of reports have occurred in the setting of mirtazapine overdose or in patients with other risk factors for QT prolongation, including concomitant use of other medications associated with QT prolongation. Fluphenazine is associated with a possible risk for QT prolongation, particularly in overdose settings. Theoretically, fluphenazine may increase the risk of QT prolongation if coadministered with other drugs that have a risk of QT prolongation. Because both mirtazapine and fluphenazine have CNS depressant properties, patients should be advised to avoid engaging in activities requiring mental alertness until they are aware of the effects of the combination.
Flurazepam: (Moderate) Monitor for unusual drowsiness and sedation during coadministration of benzodiazepines and mirtazapine due to the risk for additive CNS depression.
Fluvoxamine: (Moderate) There may be an increased risk for QT prolongation, torsade de pointes (TdP), or serotonin syndrome during concurrent use of mirtazapine and fluvoxamine. Cases of QT prolongation, TdP, ventricular tachycardia, and sudden death have been reported during postmarketing use of mirtazapine, primarily following overdose or in patients with other risk factors for QT prolongation, including concomitant use of other medications associated with QT prolongation. QT prolongation and torsade de pointes have been reported during postmarketing use of fluvoxamine. 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. Case reports suggest that serotonin syndrome is possible during concurrent use of mirtazapine and SSRIs. In addition, mirtazapine is a substrate for CYP2D6, CYP1A2, and CYP3A4. Increased mirtazapine serum concentrations (3 to 4 fold) have been reported following the addition of fluvoxamine, an inhibitor of CYP3A4, CYP1A2, and CYP2D6, to stable mirtazapine regimens. Patients receiving mirtazapine with fluvoxamine should be monitored for the emergence of serotonin syndrome, QT prolongation, or other adverse effects.
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.
Fosamprenavir: (Moderate) Concurrent administration of mirtazapine and fosamprenavir may result in elevated mirtazapine plasma concentrations. If these drugs are coadministered, monitor patients for adverse effects associated with mirtazapine, such as constipation, drowsiness, dizziness, and QT prolongation, and decrease the dose if necessary. Mirtazapine is a substrate of CYP3A4 and protease inhibitors are potent inhibitors of CYP3A4.
Foscarnet: (Major) Concomitant use of foscarnet and mirtazapine 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.
Fosinopril; Hydrochlorothiazide, HCTZ: (Moderate) Monitor for signs and symptoms of hyponatremia during concomitant diuretic and mirtazapine use; consider discontinuing mirtazapine if symptomatic hyponatremia occurs and institute appropriate medical intervention. Concomitant use increases the risk for developing hyponatremia.
Fosphenytoin: (Moderate) Monitor for decreased efficacy of mirtazapine if coadministration with fosphenytoin is necessary; an increased mirtazapine dose may be necessary. If fosphenytoin is discontinued, a decrease in mirtazapine dose may be needed. Concomitant use may decrease mirtazapine exposure. Mirtazapine is a CYP3A substrate and fosphenytoin is a strong CYP3A inducer. Coadministration with other strong CYP3A inducers increased mirtazapine clearance by approximately 2-fold, decreasing the average mirtazapine plasma concentrations by 45% to 60%.
Fostemsavir: (Moderate) Concomitant use of mirtazapine 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: (Major) The coadministration of serotonergic antidepressants with serotonin-agonists has sometimes resulted in serotonin syndrome. Careful observation of the patient is advised, particularly during treatment initiation and dose increases. Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, and coma), autonomic instability (e.g., tachycardia, labile blood pressure, and hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination) and/or gastrointestinal symptoms (e.g., nausea, vomiting, and diarrhea). Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome, which includes hyperthermia, muscle rigidity, autonomic instability with possible rapid fluctuation of vital signs, and mental status changes. Discontinue the serotonergic agents immediately if serotonin syndrome reactions occur and initiate supportive symptomatic treatment.
Furosemide: (Moderate) Monitor for signs and symptoms of hyponatremia during concomitant diuretic and mirtazapine use; consider discontinuing mirtazapine 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 mirtazapine. Concomitant use of gabapentin with mirtazapine may cause additive CNS depression. Educate patients about the risks and symptoms of excessive CNS depression.
Gemifloxacin: (Moderate) Concomitant use of mirtazapine 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.
Gemtuzumab Ozogamicin: (Moderate) Concomitant use of mirtazapine 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.
Gilteritinib: (Moderate) Concomitant use of mirtazapine and gilteritinib 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.
Glasdegib: (Major) Concomitant use of glasdegib and mirtazapine 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.
Goserelin: (Moderate) Concomitant use of mirtazapine 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 caution when using mirtazapine in combination with granistetron as concurrent use may increase the risk of QT prolongation and serotonin syndrome. If serotonin syndrome occurs, all serotonergic agents should be discontinued and appropriate medical treatment should be implemented. Mirtazapine has been associated with dose-dependent prolongation of the QT interval. Torsade de pointes (TdP) has been reported postmarketing, primarily in overdose or in patients with other risk factors for QT prolongation. Granisetron has been associated with QT prolongation.
Guaifenesin; Hydrocodone: (Major) Concomitant use of opioid agonists with mirtazapine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with mirtazapine 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 mirtazapine.
Halogenated Anesthetics: (Major) Concomitant use of halogenated and mirtazapine 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.
Haloperidol: (Moderate) Concomitant use of mirtazapine and haloperidol 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 intravenous route may carry a higher risk for haloperidol-induced QT/QTc prolongation than other routes of administration.
Histrelin: (Moderate) Concomitant use of mirtazapine 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 mirtazapine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with mirtazapine 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 mirtazapine.
Hydrochlorothiazide, HCTZ: (Moderate) Monitor for signs and symptoms of hyponatremia during concomitant diuretic and mirtazapine use; consider discontinuing mirtazapine if symptomatic hyponatremia occurs and institute appropriate medi cal intervention. Concomitant use increases the risk for developing hyponatremia.
Hydrochlorothiazide, HCTZ; Methyldopa: (Moderate) Monitor for signs and symptoms of hyponatremia during concomitant diuretic and mirtazapine use; consider discontinuing mirtazapine 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 mirtazapine use; consider discontinuing mirtazapine if symptomatic hyponatremia occurs and institute appropriate medical intervention. Concomitant use increases the risk for developing hyponatremia.
Hydrocodone: (Major) Concomitant use of opioid agonists with mirtazapine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with mirtazapine 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 mirtazapine.
Hydrocodone; Ibuprofen: (Major) Concomitant use of opioid agonists with mirtazapine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with mirtazapine 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 mirtazapine.
Hydrocodone; Pseudoephedrine: (Major) Concomitant use of opioid agonists with mirtazapine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with mirtazapine 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 mirtazapine.
Hydromorphone: (Major) Concomitant use of opioid agonists with mirtazapine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with mirtazapine 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.
Hydroxychloroquine: (Major) Concomitant use of hydroxychloroquine and mirtazapine 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) Concomitant use of hydroxyzine and mirtazapine 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; Methenamine; Methylene Blue; Phenyl Salicylate; Sodium Biphosphate: (Contraindicated) According to the manufacturer of mirtazapine, treatment initiation with mirtazapine is contraindicated in patients currently receiving intravenous methylene blue due to an increased risk of serotonin syndrome. If urgent psychiatric treatment is required, interventions other than mirtazapine (e.g., alternative medication, hospitalization) should be considered. Conversely, in patients receiving mirtazapine and requiring urgent treatment with intravenous methylene blue, mirtazapine should be discontinued immediately and methylene blue therapy initiated only if acceptable alternatives are not available and the potential benefits of methylene blue outweigh the risks. The patient should be monitored for serotonin syndrome for 2 weeks or until 24 hours after the last dose of methylene blue, whichever comes first. Mirtazapine may be re-initiated 24 hours after the last dose of methylene blue Methylene blue is a thiazine dye that is also a potent, reversible inhibitor of the enzyme responsible for the catabolism of serotonin in the brain (MAO-A) and mirtazapine increases central serotonin effects. 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 parathyroid surgery, in patients receiving serotonergic agents such as selective serotonin reuptake inhibitors, serotonin/norepinephrine reuptake inhibitors, or clomipramine. It is not known if patients receiving intravenous methylene blue with other serotonergic psychiatric agents 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. Published interaction reports between intravenously administered 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/or coma. Serotonin syndrome is characterized by rapid development of various symptoms such as hyperthermia, hypertension, myoclonus, rigidity, hyperhidrosis, incoordination, diarrhea, mental status changes (e.g., confusion, delirium, or coma), and in rare cases, death.
Ibuprofen; Oxycodone: (Major) Concomitant use of opioid agonists with mirtazapine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with mirtazapine 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.
Ibutilide: (Major) Concomitant use of ibutilide and mirtazapine 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.
Idelalisib: (Major) Avoid concomitant use of idelalisib, a strong CYP3A inhibitor, with mirtazapine, a CYP3A substrate, as mirtazapine toxicities may be significantly increased. The AUC of a sensitive CYP3A substrate was increased 5.4-fold when coadministered with idelalisib.
Iloperidone: (Major) Concomitant use of iloperidone and mirtazapine 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.
Imipramine: (Moderate) Monitor for unusual drowsiness, sedation, and serotonin syndrome during coadministration due to the risk for additive CNS depression and serotonin syndrome. If serotonin syndrome occurs, consider discontinuation of therapy.
Indinavir: (Moderate) Concurrent administration of mirtazapine and indinavir may result in elevated mirtazapine plasma concentrations. If these drugs are coadministered, monitor patients for adverse effects associated with mirtazapine, such as constipation, drowsiness, dizziness, and QT prolongation, and decrease the dose if necessary. Mirtazapine is a substrate of CYP3A4 and protease inhibitors are potent inhibitors of CYP3A4.
Inotuzumab Ozogamicin: (Major) Concomitant use of inotuzumab and mirtazapine 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.
Iobenguane I 131: (Major) Discontinue mirtazapine for at least 5 half-lives before the administration of the dosimetry dose or a therapeutic dose of iobenguane I-131. Do not restart mirtazapine until at least 7 days after each iobenguane I-131 dose. Drugs that reduce catecholamine uptake or deplete catecholamine stores, such as mirtazapine, may interfere with iobenguane I-131 uptake into cells and interfere with dosimetry calculations resulting in altered iobenguane I-131 efficacy.
Irbesartan; Hydrochlorothiazide, HCTZ: (Moderate) Monitor for signs and symptoms of hyponatremia during concomitant diuretic and mirtazapine use; consider discontinuing mirtazapine if symptomatic hyponatremia occurs and institute appropriate medical intervention. Concomitant use increases the risk for developing hyponatremia.
Isocarboxazid: (Contraindicated) Use of mirtazapine concurrently with the monoamine oxidase inhibitors (MAOIs) is contraindicated. If combined, there is a possibility of developing serious reactions such as serotonin syndrome. In patients receiving nonselective MAOIs in combination with serotoninergic agents there have been reports of serious, sometimes fatal, reactions. At least 2 weeks should elapse between stopping one agent and beginning the other. Monitor for serotonin-related side effects during therapy transitions.
Isoflurane: (Major) Concomitant use of halogenated and mirtazapine 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) Due to the risk of serotonin syndrome, concurrent use of mirtazapine and medications with MAO-like activity, such as isoniazid, INH, should be avoided if 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. In addition, mirtazapine is a substrate for 2D6, 1A2, and 3A4. Pharmacokinetic studies with some CYP3A4 inhibitors have shown that elevations in mirtazapine concentrations are possible during coadministration. Therefore, caution is advised during concurrent use of mirtazapine and inhibitors of CYP3A4 such as isoniazid, INH.
Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Major) Due to the risk of serotonin syndrome, concurrent use of mirtazapine and medications with MAO-like activity, such as isoniazid, INH, should be avoided if 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. In addition, mirtazapine is a substrate for 2D6, 1A2, and 3A4. Pharmacokinetic studies with some CYP3A4 inhibitors have shown that elevations in mirtazapine concentrations are possible during coadministration. Therefore, caution is advised during concurrent use of mirtazapine and inhibitors of CYP3A4 such as isoniazid, INH. (Moderate) Mirtazapine plasma concentrations and pharmacologic action may be decreased in patients taking rifampin. Rifampin is a potent inducer of CYP3A4, and may be a modest inducer of CYP2D6. Rifampin is also a relatively weak inducer of CYP1A2. In vitro studies have identified mirtazapine as a substrate for several CYP450 isoenzymes including 2D6, 1A2, and 3A4. Monitor for reduced effectiveness of mirtazapine during co-administration of rifampin. It may be necessary to increase the mirtazapine dosage during concurrent therapy. Conversely, if rifampin is discontinued, the dosage of mirtazapine may need to be reduced.
Isoniazid, INH; Rifampin: (Major) Due to the risk of serotonin syndrome, concurrent use of mirtazapine and medications with MAO-like activity, such as isoniazid, INH, should be avoided if 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. In addition, mirtazapine is a substrate for 2D6, 1A2, and 3A4. Pharmacokinetic studies with some CYP3A4 inhibitors have shown that elevations in mirtazapine concentrations are possible during coadministration. Therefore, caution is advised during concurrent use of mirtazapine and inhibitors of CYP3A4 such as isoniazid, INH. (Moderate) Mirtazapine plasma concentrations and pharmacologic action may be decreased in patients taking rifampin. Rifampin is a potent inducer of CYP3A4, and may be a modest inducer of CYP2D6. Rifampin is also a relatively weak inducer of CYP1A2. In vitro studies have identified mirtazapine as a substrate for several CYP450 isoenzymes including 2D6, 1A2, and 3A4. Monitor for reduced effectiveness of mirtazapine during co-administration of rifampin. It may be necessary to increase the mirtazapine dosage during concurrent therapy. Conversely, if rifampin is discontinued, the dosage of mirtazapine may need to be reduced.
Itraconazole: (Moderate) Use itraconazole with caution in combination with mirtazapine as concurrent use may increase the risk of QT prolongation; mirtazapine exposure may also increase. Itraconazole is a strong CYP3A4 inhibitor that has been associated with prolongation of the QT interval. Mirtazapine is a CYP3A4 substrate that has been associated with dose-dependent prolongation of the QT interval. Torsade de pointes (TdP) has been reported postmarketing, primarily in overdose or in patients with other risk factors for QT prolongation.
Ivosidenib: (Major) Concomitant use of ivosidenib and mirtazapine 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.
Ketamine: (Moderate) Consistent with the pharmacology of mirtazapine and the CNS depression that may occur, additive effects may occur with other CNS depressants, including ketamine. Close monitoring is recommended in patients receiving mirtazapine and requiring an anesthetic.
Ketoconazole: (Contraindicated) Avoid concomitant use of ketoconazole and mirtazapine if possible due to an increased risk for torsade de pointes (TdP) and QT/QTc prolongation. Decrease the dose of mirtazapine if needed with concomitant strong CYP3A inhibitor use. Conversely, an increase in dosage of mirtazapine may be needed if the CYP3A inhibitor is discontinued. Mirtazapine is a CYP3A substrate and ketoconazole is a strong CYP3A inhibitor. Coadministration with ketoconazole increased the AUC of mirtazapine by approximately 50%.
Lansoprazole; Amoxicillin; Clarithromycin: (Major) Concomitant use of mirtazapine and clarithromycin 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.
Lapatinib: (Moderate) Concomitant use of mirtazapine 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.
Lasmiditan: (Moderate) Monitor for excessive sedation, somnolence, and serotonin syndrome during coadministration of lasmiditan and mirtazapine. 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.
Lefamulin: (Major) Concomitant use of lefamulin and mirtazapine 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.
Lemborexant: (Moderate) Monitor for excessive sedation and somnolence during coadministration of lemborexant and mirtazapine. Dosage adjustments of lemborexant and mirtazapine 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) Concomitant use of lenvatinib and mirtazapine 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.
Letermovir: (Moderate) Monitor for mirtazapine-related adverse events if given with letermovir. In patients who are also receiving treatment with cyclosporine, the magnitude of this interaction may be amplified. Mirtazapine is a CYP3A4 substrate. Letermovir is a moderate CYP3A4 inhibitor; however, when given with cyclosporine, the combined effect on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor. In a drug interaction study, administration with another strong CYP3A4 inhibitor increased the maximum plasma concentration and exposure of mirtazapine by approximately 40% and 50%, respectively.
Leuprolide: (Moderate) Concomitant use of mirtazapine 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: (Moderate) Concomitant use of mirtazapine 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.
Levocetirizine: (Moderate) Monitor for unusual drowsiness and sedation during coadministration of cetirizine and mirtazapine due to the risk for additive CNS depression.
Levofloxacin: (Moderate) Concomitant use of levofloxacin and mirtazapine 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 mirtazapine if possible due to an increased risk for torsade de pointes (TdP) and QT/QTc prolongation. Decrease the dose of mirtazapine if needed with concomitant strong CYP3A inhibitor use. Conversely, an increase in dosage of mirtazapine may be needed if the CYP3A inhibitor is discontinued. Mirtazapine is a CYP3A substrate and ketoconazole is a strong CYP3A inhibitor. Coadministration with ketoconazole increased the AUC of mirtazapine by approximately 50%.
Levomilnacipran: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when coadministering drugs that have serotonergic properties such as mirtazapine and levomilnacipran. Cases of serotonin syndrome have been reported between mirtazapine and other antidepressants such as selective serotonin reuptake inhibitors (SSRIs). 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, serotonergic agents should be discontinued and appropriate medical treatment should be implemented.
Levorphanol: (Major) Concomitant use of opioid agonists with mirtazapine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with mirtazapine 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.
Linezolid: (Contraindicated) Concurrent use of linezolid and mirtazapine is contraindicated due to an increased risk of serotonin syndrome. Mirtazapine is a serotonergic antidepressant and linezolid is a nonselective inhibitor of monoamine oxidase which increases central serotonin levels. If urgent psychiatric treatment is required, interventions other than mirtazapine (e.g., alternative medication, hospitalization) should be considered. Conversely, in patients receiving mirtazapine and requiring urgent treatment with linezolid, mirtazapine 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 2 weeks or until 24 hours after the last dose of linezolid, whichever comes first. Mirtazapine may be resumed 24 hours after the last dose of linezolid.
Lisdexamfetamine: (Major) Initiate with lower doses and monitor for signs and symptoms of serotonin syndrome, particularly during treatment initiation or dosage increase, during concomitant lisdexamfetamine and mirtazapine use. If serotonin syndrome occurs, discontinue therapy. Concomitant use increases the risk of serotonin syndrome.
Lisinopril; Hydrochlorothiazide, HCTZ: (Moderate) Monitor for signs and symptoms of hyponatremia during concomitant diuretic and mirtazapine use; consider discontinuing mirtazapine if symptomatic hyponatremia occurs and institute appropriate medical intervention. Concomitant use increases the risk for developing hyponatremia.
Lithium: (Moderate) Concomitant use of lithium and mirtazapine 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. Monitor patients for signs and symptoms of serotonin syndrome during concomitant use, 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.
Lofexidine: (Moderate) Monitor ECG if lofexidine is coadministered with mirtazapine due to the potential for additive QT prolongation and torsade de pointes (TdP). 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 TdP. Mirtazapine has been associated with dose-dependent prolongation of the QT interval. TdP has been reported postmarketing, primarily in overdose or in patients with other risk factors for QT prolongation.
Lonafarnib: (Moderate) Monitor for an increase in mirtazapine-related adverse reactions if coadministration with lonafarnib is necessary. Mirtazapine is a CYP3A4 substrate; lonafarnib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the Cmax and AUC of a single dose of mirtazapine by approximately 40% and 50%, respectively.
Loop diuretics: (Moderate) Monitor for signs and symptoms of hyponatremia during concomitant diuretic and mirtazapine use; consider discontinuing mirtazapine if symptomatic hyponatremia occurs and institute appropriate medical intervention. Concomitant use increases the risk for developing hyponatremia.
Loperamide: (Moderate) Concomitant use of loperamide and mirtazapine 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 mirtazapine 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) Concomitant use of lopinavir and mirtazapine 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) The plasma concentrations of mirtazapine may be elevated when administered concurrently with ritonavir. Clinical monitoring for adverse effects, such as CNS or GI effects, is recommended during coadministration. Ritonavir is a strong CYP3A4 inhibitor, while mirtazapine is a CYP3A4. Coadministration with another strong CYP3A4 inhibitor increased mirtazapine exposure by approximately 50%.
Lorazepam: (Moderate) Monitor for unusual drowsiness and sedation during coadministration of benzodiazepines and mirtazapine due to the risk for additive CNS depression.
Losartan; Hydrochlorothiazide, HCTZ: (Moderate) Monitor for signs and symptoms of hyponatremia during concomitant diuretic and mirtazapine use; consider discontinuing mirtazapine if symptomatic hyponatremia occurs and institute appropriate medical intervention. Concomitant use increases the risk for developing hyponatremia.
Lumacaftor; Ivacaftor: (Moderate) Lumacaftor; ivacaftor may reduce the efficacy of mirtazapine by decreasing its systemic exposure; if used together, it may be necessary to increase the mirtazapine dose to achieve clinical efficacy. If lumacaftor; ivacaftor is subsequently discontinued, consider mirtazapine dosage reduction. Mirtazapine is a substrate of CYP3A. Lumacaftor is a strong CYP3A inducer. At steady state, carbamazepine and phenytoin, both strong inducers of CYP3A, increased mirtazapine clearance approximately 2-fold, resulting in respective decreases of 60% and 45% in average plasma mirtazapine concentrations.
Lumateperone: (Moderate) Monitor for excessive sedation and somnolence during coadministration of lumateperone and mirtazapine. Concurrent use may result in additive CNS depression.
Macimorelin: (Major) Concomitant use of macimorelin and mirtazapine 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.
Maprotiline: (Major) Concomitant use of maprotiline and mirtazapine 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.
Meclizine: (Moderate) Consistent with the CNS depressant effects of mirtazapine, additive effects may occur with other CNS depressants such as meclizine. Mirtazapine should be administered cautiously with such agents because the CNS effects on cognitive performance and motor skills can be additive.
Mefloquine: (Moderate) Concomitant use of mirtazapine and mefloquine 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.
Meperidine: (Moderate) Because of the potential risk and severity of excessive sedation, somnolence, and serotonin syndrome, caution should be observed when administering meperidine with mirtazapine. Limit the use of opiod pain medications with mirtazapine 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. Inform patients taking this combination of the possible increased risks and monitor for the emergence of excessive CNS depression and serotonin syndrome, particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
Metaxalone: (Moderate) Coadministration of mirtazapine with metaxalone may result in additive CNS-depressant effects, such as sedation, and may increase the risk for serotonin syndrome. Use with caution and monitor for the emergence of excessive sedation or serotonin syndrome. If serotonin syndrome is suspected, serotonergic agents should be discontinued and appropriate medical treatment instituted.
Methadone: (Major) Concomitant use of opioid agonists with mirtazapine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with mirtazapine 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.
Methamphetamine: (Moderate) Serotonin syndrome may occur during coadministration of serotonergic drugs such as methamphetamine and mirtazapine. At high doses, amphetamines can increase serotonin release, as well as act as serotonin agonists. 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.
Methenamine; Sodium Acid Phosphate; Methylene Blue; Hyoscyamine: (Contraindicated) According to the manufacturer of mirtazapine, treatment initiation with mirtazapine is contraindicated in patients currently receiving intravenous methylene blue due to an increased risk of serotonin syndrome. If urgent psychiatric treatment is required, interventions other than mirtazapine (e.g., alternative medication, hospitalization) should be considered. Conversely, in patients receiving mirtazapine and requiring urgent treatment with intravenous methylene blue, mirtazapine should be discontinued immediately and methylene blue therapy initiated only if acceptable alternatives are not available and the potential benefits of methylene blue outweigh the risks. The patient should be monitored for serotonin syndrome for 2 weeks or until 24 hours after the last dose of methylene blue, whichever comes first. Mirtazapine may be re-initiated 24 hours after the last dose of methylene blue Methylene blue is a thiazine dye that is also a potent, reversible inhibitor of the enzyme responsible for the catabolism of serotonin in the brain (MAO-A) and mirtazapine increases central serotonin effects. 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 parathyroid surgery, in patients receiving serotonergic agents such as selective serotonin reuptake inhibitors, serotonin/norepinephrine reuptake inhibitors, or clomipramine. It is not known if patients receiving intravenous methylene blue with other serotonergic psychiatric agents 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. Published interaction reports between intravenously administered 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/or coma. Serotonin syndrome is characterized by rapid development of various symptoms such as hyperthermia, hypertension, myoclonus, rigidity, hyperhidrosis, incoordination, diarrhea, mental status changes (e.g., confusion, delirium, or coma), and in rare cases, death.
Methohexital: (Major) Monitor for excessive sedation and somnolence during coadministration of mirtazapine and barbiturates. Concurrent use may result in additive CNS depression.
Methyclothiazide: (Moderate) Monitor for signs and symptoms of hyponatremia during concomitant diuretic and mirtazapine use; consider discontinuing mirtazapine 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 mirtazapine, treatment initiation with mirtazapine is contraindicated in patients currently receiving intravenous methylene blue due to an increased risk of serotonin syndrome. If urgent psychiatric treatment is required, interventions other than mirtazapine (e.g., alternative medication, hospitalization) should be considered. Conversely, in patients receiving mirtazapine and requiring urgent treatment with intravenous methylene blue, mirtazapine should be discontinued immediately and methylene blue therapy initiated only if acceptable alternatives are not available and the potential benefits of methylene blue outweigh the risks. The patient should be monitored for serotonin syndrome for 2 weeks or until 24 hours after the last dose of methylene blue, whichever comes first. Mirtazapine may be re-initiated 24 hours after the last dose of methylene blue Methylene blue is a thiazine dye that is also a potent, reversible inhibitor of the enzyme responsible for the catabolism of serotonin in the brain (MAO-A) and mirtazapine increases central serotonin effects. 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 parathyroid surgery, in patients receiving serotonergic agents such as selective serotonin reuptake inhibitors, serotonin/norepinephrine reuptake inhibitors, or clomipramine. It is not known if patients receiving intravenous methylene blue with other serotonergic psychiatric agents 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. Published interaction reports between intravenously administered 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/or coma. Serotonin syndrome is characterized by rapid development of various symptoms such as hyperthermia, hypertension, myoclonus, rigidity, hyperhidrosis, incoordination, diarrhea, mental status changes (e.g., confusion, delirium, or coma), and in rare cases, death.
Methylergonovine: (Moderate) The use of ergot alkaloids with mirtazapine might increase the risk for serotonin syndrome. Patients receiving ergot alkaloids with mirtazapine should be monitored for the emergence of serotonin syndrome. If serotonin syndrome occurs, discontinue serotonergic agents and institute appropriate medical treatment.
Methylphenidate Derivatives: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when coadministering drugs that have serotonergic properties such as methylphenidate derivatives and mirtazapine.
Metolazone: (Moderate) Monitor for signs and symptoms of hyponatremia during concomitant diuretic and mirtazapine use; consider discontinuing mirtazapine if symptomatic hyponatremia occurs and institute appropriate medical intervention. Concomitant use increases the risk for developing hyponatremia.
Metoprolol; Hydrochlorothiazide, HCTZ: (Moderate) Monitor for signs and symptoms of hyponatremia during concomitant diuretic and mirtazapine use; consider discontinuing mirtazapine if symptomatic hyponatremia occurs and institute appropriate medical intervention. Concomitant use increases the risk for developing hyponatremia.
Metronidazole: (Moderate) Concomitant use of metronidazole and mirtazapine 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.
Midazolam: (Moderate) Monitor for unusual drowsiness and sedation during coadministration of benzodiazepines and mirtazapine due to the risk for additive CNS depression.
Midostaurin: (Major) Concomitant use of mirtazapine and midostaurin 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.
Mifepristone: (Major) Concomitant use of mifepristone and mirtazapine 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.
Milnacipran: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when coadministering drugs that have serotonergic properties such as mirtazapine and milnacipran. Cases of serotonin syndrome have been reported between mirtazapine and other antidepressants such as selective serotonin reuptake inhibitors (SSRIs). 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, serotonergic agents should be discontinued and appropriate medical treatment should be implemented.
Mirabegron: (Moderate) Mirabegron is a moderate CYP2D6 inhibitor. Exposure of drugs partially metabolized by CYP2D6 such as mirtazapine may be increased when co-administered with mirabegron. Mirtazapine as a substrate for several CYP450 isoenzymes including 2D6, 1A2, and 3A4 in vitro. Appropriate monitoring and dose adjustment may be necessary.
Mitotane: (Major) Use caution if mitotane and mirtazapine are used concomitantly, and monitor for decreased efficacy of mirtazapine and a possible change in dosage requirements. Mitotane is a strong CYP3A4 inducer and mirtazapine is a CYP3A4 substrate; coadministration may result in decreased plasma concentrations of mirtazapine.
Mobocertinib: (Major) Concomitant use of mobocertinib and mirtazapine 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.
Molindone: (Moderate) Molindone may cause central nervous system (CNS) depression thereby having additive effects with other drugs that can cause CNS depression such as mirtazapine. Caution is advisable during concurrent use.
Monoamine oxidase inhibitors: (Contraindicated) Use of mirtazapine concurrently with the monoamine oxidase inhibitors (MAOIs) is contraindicated. If combined, there is a possibility of developing serious reactions such as serotonin syndrome. In patients receiving nonselective MAOIs in combination with serotoninergic agents there have been reports of serious, sometimes fatal, reactions. At least 2 weeks should elapse between stopping one agent and beginning the other. Monitor for serotonin-related side effects during therapy transitions.
Morphine: (Major) Concomitant use of opioid agonists with mirtazapine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with mirtazapine 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.
Morphine; Naltrexone: (Major) Concomitant use of opioid agonists with mirtazapine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with mirtazapine 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.
Moxifloxacin: (Major) Concomitant use of moxifloxacin and mirtazapine 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.
Nabilone: (Moderate) Nabilone should be combined cautiously with mirtazapine because of additive sedation or other CNS effects.
Nalbuphine: (Major) Concomitant use of opioid agonists with mirtazapine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with mirtazapine 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.
Naratriptan: (Major) The coadministration of serotonergic antidepressants with serotonin-agonists has sometimes resulted in serotonin syndrome. Careful observation of the patient is advised, particularly during treatment initiation and dose increases. Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, and coma), autonomic instability (e.g., tachycardia, labile blood pressure, and hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination) and/or gastrointestinal symptoms (e.g., nausea, vomiting, and diarrhea). Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome, which includes hyperthermia, muscle rigidity, autonomic instability with possible rapid fluctuation of vital signs, and mental status changes. Discontinue the serotonergic agents immediately if serotonin syndrome reactions occur and initiate supportive symptomatic treatment.
Nefazodone: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering mirtazapine with other drugs that have serotonergic properties such as nefazodone. 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. Additive sedative effects are also possible. Patients receiving this combination should be monitored for the emergence of serotonin syndrome. Mirtazapine should be discontinued if a patient develops a combination of symptoms suggestive of serotonin syndrome.
Nelfinavir: (Moderate) Concurrent administration of mirtazapine and nelfinavir may result in elevated mirtazapine plasma concentrations. If these drugs are coadministered, monitor patients for adverse effects associated with mirtazapine, such as constipation, drowsiness, dizziness, and QT prolongation, and decrease the dose if necessary. Mirtazapine is a substrate of CYP3A4 and protease inhibitors are potent inhibitors of CYP3A4.
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 mirtazapine. 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.
Nilotinib: (Major) Concomitant use of nilotinib and mirtazapine 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.
Nirmatrelvir; Ritonavir: (Moderate) The plasma concentrations of mirtazapine may be elevated when administered concurrently with ritonavir. Clinical monitoring for adverse effects, such as CNS or GI effects, is recommended during coadministration. Ritonavir is a strong CYP3A4 inhibitor, while mirtazapine is a CYP3A4. Coadministration with another strong CYP3A4 inhibitor increased mirtazapine exposure by approximately 50%.
Nortriptyline: (Moderate) Monitor for unusual drowsiness, sedation, and serotonin syndrome during coadministration due to the risk for additive CNS depression and serotonin syndrome. If serotonin syndrome occurs, consider discontinuation of therapy.
Ofloxacin: (Moderate) Concomitant use of ofloxacin and mirtazapine 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 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.
Olanzapine; Fluoxetine: (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.
Olanzapine; Samidorphan: (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.
Oliceridine: (Major) Concomitant use of oliceridine with mirtazapine may cause excessive sedation and somnolence. Limit the use of oliceridine with mirtazapine 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.
Olmesartan; Amlodipine; Hydrochlorothiazide, HCTZ: (Moderate) Monitor for signs and symptoms of hyponatremia during concomitant diuretic and mirtazapine use; consider discontinuing mirtazapine if symptomatic hyponatremia occurs and institute appropriate medical intervention. Concomitant use increases the risk for developing hyponatremia.
Olmesartan; Hydrochlorothiazide, HCTZ: (Moderate) Monitor for signs and symptoms of hyponatremia during concomitant diuretic and mirtazapine use; consider discontinuing mirtazapine if symptomatic hyponatremia occurs and institute appropriate medical intervention. Concomitant use increases the risk for developing hyponatremia.
Ondansetron: (Major) Due to the potential for QT prolongation, cautious use and close monitoring are advisable if concurrent use of mirtazapine 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 mirtazapine, 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: (Major) COMT inhibitors should be given cautiously with other agents that cause CNS depression, such as mirtazapine, due to the possibility of additive sedation. COMT inhibitors have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment. Patients should be advised to avoid driving or other tasks requiring mental alertness until they know how the combination affects them.
Orphenadrine: (Moderate) Skeletal muscle relaxants like orphenadrine may cause additive CNS depression if used concomitantly with other drugs with CNS depressant properties such as mirtazapine. Combination therapy may amplify sedation and dizziness, which can impair the patient's ability to perform tasks requiring mental alertness. Dosage adjustments of either or both medications may be necessary in some instances.
Osilodrostat: (Moderate) Concomitant use of mirtazapine 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.
Osimertinib: (Major) Concomitant use of osimertinib and mirtazapine 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 mirtazapine 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.
Oxazepam: (Moderate) Monitor for unusual drowsiness and sedation during coadministration of benzodiazepines and mirtazapine due to the risk for additive CNS depression.
Oxycodone: (Major) Concomitant use of opioid agonists with mirtazapine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with mirtazapine 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.
Oxymorphone: (Major) Concomitant use of opioid agonists with mirtazapine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with mirtazapine 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.
Ozanimod: (Major) In general, do not initiate ozanimod in patients taking mirtazapine due to the risk of additive bradycardia, QT prolongation, and torsade de pointes (TdP). Additionally, there is a potential for hypertensive crisis. If treatment initiation is considered, seek advice from a cardiologist and monitor for hypertension. An active metabolite of ozanimod inhibits MAO-B, which may increase the potential for hypertensive crisis. 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. Mirtazapine is a serotonergic drug that has been associated with dose-dependent prolongation of the QT interval. TdP has been reported postmarketing, primarily in overdose or in patients with other risk factors for QT prolongation.
Pacritinib: (Major) Concomitant use of pacritinib and mirtazapine 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 mirtazapine 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.
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 mirtazapine. 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) Concomitant use of panobinostat and mirtazapine 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 pro longation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Paroxetine: (Moderate) Coadministration of paroxetine and mirtazapine may increase the risk for serotonin syndrome. Cases of serotonin syndrome have been reported when mirtazapine has been administered with other selective serotonin reuptake inhibitors (SSRIs). 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 treatment should be implemented.
Pasireotide: (Moderate) Concomitant use of mirtazapine 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.
Pazopanib: (Major) Concomitant use of pazopanib and mirtazapine 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) Monitor for adverse effects associated with increased exposure to mirtazapine if peginterferon alfa-2b is coadministered. Peginterferon alfa-2b is a CYP1A2 and CYP2D6 inhibitor, while mirtazapine is a CYP1A2 and CYP2D6 substrate.
Pentamidine: (Major) Concomitant use of pentamidine and mirtazapine 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.
Pentazocine: (Major) Concomitant use of pentazocine with other CNS depressants can potentiate respiratory depression, CNS depression, and sedation. Pentazocine should be used cautiously in any patient receiving mirtazapine.
Pentazocine; Naloxone: (Major) Concomitant use of pentazocine with other CNS depressants can potentiate respiratory depression, CNS depression, and sedation. Pentazocine should be used cautiously in any patient receiving mirtazapine.
Pentobarbital: (Major) Monitor for excessive sedation and somnolence during coadministration of mirtazapine and barbiturates. Concurrent use may result in additive CNS depression.
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 mirtazapine.
Perphenazine: (Moderate) Coadministration may increase the risk of QT prolongation, torsade de pointes, and CNS depression. Due to the possibility of additive effects on the QT interval, caution is advisable during concurrent use of mirtazapine and perphenazine. Cases of QT prolongation, TdP, ventricular tachycardia, and sudden death have been reported during postmarketing use of mirtazapine. The majority of reports have occurred in the setting of mirtazapine overdose or in patients with other risk factors for QT prolongation, including concomitant use of other medications associated with QT prolongation. Perphenazine is associated with a possible risk for QT prolongation, particularly in overdose settings. Theoretically, perphenazine may increase the risk of QT prolongation if coadministered with other drugs that have a risk of QT prolongation. Because both mirtazapine and perphenazine have CNS depressant properties, patients should be advised to avoid engaging in activities requiring mental alertness until they are aware of the effects of the combination.
Perphenazine; Amitriptyline: (Moderate) Coadministration may increase the risk of QT prolongation, torsade de pointes, and CNS depression. Due to the possibility of additive effects on the QT interval, caution is advisable during concurrent use of mirtazapine and perphenazine. Cases of QT prolongation, TdP, ventricular tachycardia, and sudden death have been reported during postmarketing use of mirtazapine. The majority of reports have occurred in the setting of mirtazapine overdose or in patients with other risk factors for QT prolongation, including concomitant use of other medications associated with QT prolongation. Perphenazine is associated with a possible risk for QT prolongation, particularly in overdose settings. Theoretically, perphenazine may increase the risk of QT prolongation if coadministered with other drugs that have a risk of QT prolongation. Because both mirtazapine and perphenazine have CNS depressant properties, patients should be advised to avoid engaging in activities requiring mental alertness until they are aware of the effects of the combination. (Moderate) Monitor for unusual drowsiness, sedation, and serotonin syndrome during coadministration due to the risk for additive CNS depression and serotonin syndrome. If serotonin syndrome occurs, consider discontinuation of therapy.
Phenelzine: (Contraindicated) Use of mirtazapine concurrently with the monoamine oxidase inhibitors (MAOIs) is contraindicated. If combined, there is a possibility of developing serious reactions such as serotonin syndrome. In patients receiving nonselective MAOIs in combination with serotoninergic agents there have been reports of serious, sometimes fatal, reactions. At least 2 weeks should elapse between stopping one agent and beginning the other. Monitor for serotonin-related side effects during therapy transitions.
Phenobarbital: (Major) Monitor for excessive sedation and somnolence during coadministration of mirtazapine and barbiturates. Concurrent use may result in additive CNS depression.
Phenobarbital; Hyoscyamine; Atropine; Scopolamine: (Major) Monitor for excessive sedation and somnolence during coadministration of mirtazapine and barbiturates. Concurrent use may result in additive CNS depression. (Moderate) Monitor for unusual drowsiness and sedation during coadministration of mirtazapine and atropine due to the risk for additive CNS depression. (Moderate) Monitor for unusual drowsiness and sedation during coadministration of mirtazapine and scopolamine due to the risk for additive CNS depression.
Phentermine: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed during co-administration of mirtazapine with other drugs that have serotonergic properties. As a drug related to the amphetamines, phentermine has the potential to cause serotonin syndrome when combined with serotonergic agents. Patients receiving this combination should be monitored for the emergence of serotonin syndrome.
Phentermine; Topiramate: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed during co-administration of mirtazapine with other drugs that have serotonergic properties. As a drug related to the amphetamines, phentermine has the potential to cause serotonin syndrome when combined with serotonergic agents. Patients receiving this combination should be monitored for the emergence of serotonin syndrome.
Phenytoin: (Moderate) Monitor for decreased efficacy of mirtazapine if coadministration with phenytoin is necessary; an increased mirtazapine dose may be necessary. If phenytoin is discontinued, a decrease in mirtazapine dose may be needed. Concomitant use may decrease mirtazapine exposure. Mirtazapine is a CYP3A substrate and phenytoin is a strong CYP3A inducer. Coadministration with other strong CYP3A inducers increased mirtazapine clearance by approximately 2-fold, decreasing the average mirtazapine plasma concentrations by 45% to 60%.
Pimavanserin: (Major) Concomitant use of pimavanserin and mirtazapine 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.
Pimozide: (Contraindicated) Avoid concomitant use of pimozide and mirtazapine due to an increased risk for torsade de pointes (TdP) and QT/QTc prolongation.
Pitolisant: (Major) Avoid coadministration of pitolisant with mirtazapine as the effect of pitolisant may be decreased; concurrent use may also increase the risk of QT prolongation. Pitolisant increases histamine concentrations in the brain; therefore, H1-receptor antagonists like mirtazapine, may reduce pitolisant efficacy. Pitolisant prolongs the QT interval. Mirtazapine has been associated with dose-dependent prolongation of the QT interval. Torsade de pointes (TdP) has been reported postmarketing, primarily in overdose or in patients with other risk factors for QT prolongation.
Ponesimod: (Major) In general, do not initiate ponesimod in patients taking mirtazapine 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. Mirtazapine has been associated with dose-dependent prolongation of the QT interval; TdP has been reported postmarketing primarily in overdose or in patients with other risk factors for QT prolongation.
Posaconazole: (Contraindicated) The concurrent use of posaconazole, a potent CYP3A4 inhibitor, with drugs that are associated with QT prolongation and are CYP3A4 substrates, such as mirtazapine, is contraindicated. Posaconazole has been associated with QT prolongation and torsade de pointes (TdP). Cases of QT prolongation, TdP, ventricular tachycardia, and sudden death have been reported during postmarketing use of mirtazapine, primarily following overdose or in patients with other risk factors for QT prolongation.
Potassium-sparing diuretics: (Moderate) Monitor for signs and symptoms of hyponatremia during concomitant diuretic and mirtazapine use; consider discontinuing mirtazapine if symptomatic hyponatremia occurs and institute appropriate medical intervention. Concomitant use increases the risk for developing hyponatremia.
Pramipexole: (Moderate) Some medicines used for treatment of Parkinson's disease, like pramipexole, could potentially cause additive drowsiness when coadministered with mirtazapine.
Pregabalin: (Major) Initiate pregabalin at the lowest recommended dose and monitor patients for symptoms of sedation and somnolence during coadministration of pregabalin and mirtazapine. Concomitant use of pregabalin with mirtazapine may cause additive CNS depression. Educate patients about the risks and symptoms of excessive CNS depression.
Primaquine: (Moderate) Concomitant use of mirtazapine 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.
Primidone: (Major) Monitor for excessive sedation and somnolence during coadministration of mirtazapine and barbiturates. Concurrent use may result in additive CNS depression.
Procainamide: (Major) Concomitant use of procainamide and mirtazapine 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.
Procarbazine: (Contraindicated) Use of mirtazapine concurrently with drugs that exhibit MAO-inhibition, such as procarbazine, is contraindicated. If combined, there is a possibility of developing serious reactions such as hyperpyrexia, hypertension, or seizures. An interval of 14 days is recommended between cessation of MAOI therapy and initiation of mirtazapine therapy and vice versa.
Prochlorperazine: (Moderate) Coadministration may increase the risk of QT prolongation, torsade de pointes, and CNS depression. Due to the possibility of additive effects on the QT interval, caution is advisable during concurrent use of mirtazapine and prochlorperazine. Cases of QT prolongation, TdP, ventricular tachycardia, and sudden death have been reported during postmarketing use of mirtazapine. The majority of reports have occurred in the setting of mirtazapine overdose or in patients with other risk factors for QT prolongation, including concomitant use of other medications associated with QT prolongation. Prochlorperazine is associated with a possible risk for QT prolongation, particularly in overdose settings. Theoretically, prochlorperazine may increase the risk of QT prolongation if coadministered with other drugs that have a risk of QT prolongation. Because both mirtazapine and prochlorperazine have CNS depressant properties, patients should be advised to avoid engaging in activities requiring mental alertness until they are aware of the effects of the combination.
Promethazine: (Moderate) There may be an increased risk for QT prolongation and torsade de pointes (TdP) during concurrent use of mirtazapine and promethazine. Coadminister with caution. Cases of QT prolongation, TdP, ventricular tachycardia, and sudden death have been reported during postmarketing use of mirtazapine, primarily following overdose or in patients with other risk factors for QT prolongation, including concomitant use of other medications associated with QT prolongation. Promethazine, a phenothiazine, is associated with a possible risk for QT prolongation. Because both mirtazapine and promethazine have CNS depressant properties, patients should be advised to avoid engaging in activities requiring mental alertness until they are aware of how the combination affects them.
Promethazine; Dextromethorphan: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering dextromethorphan with mirtazapine. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. (Moderate) There may be an increased risk for QT prolongation and torsade de pointes (TdP) during concurrent use of mirtazapine and promethazine. Coadminister with caution. Cases of QT prolongation, TdP, ventricular tachycardia, and sudden death have been reported during postmarketing use of mirtazapine, primarily following overdose or in patients with other risk factors for QT prolongation, including concomitant use of other medications associated with QT prolongation. Promethazine, a phenothiazine, is associated with a possible risk for QT prolongation. Because both mirtazapine and promethazine have CNS depressant properties, patients should be advised to avoid engaging in activities requiring mental alertness until they are aware of how the combination affects them.
Promethazine; Phenylephrine: (Moderate) There may be an increased risk for QT prolongation and torsade de pointes (TdP) during concurrent use of mirtazapine and promethazine. Coadminister with caution. Cases of QT prolongation, TdP, ventricular tachycardia, and sudden death have been reported during postmarketing use of mirtazapine, primarily following overdose or in patients with other risk factors for QT prolongation, including concomitant use of other medications associated with QT prolongation. Promethazine, a phenothiazine, is associated with a possible risk for QT prolongation. Because both mirtazapine and promethazine have CNS depressant properties, patients should be advised to avoid engaging in activities requiring mental alertness until they are aware of how the combination affects them.
Propafenone: (Major) Concomitant use of propafenone and mirtazapine 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.
Propofol: (Moderate) Consistent with the pharmacology of mirtazapine and the CNS depression that may occur, additive effects may occur with other CNS depressants, including propofol. Close monitoring is recommended in patients receiving mirtazapine and requiring an anesthetic.
Propranolol; Hydrochlorothiazide, HCTZ: (Moderate) Monitor for signs and symptoms of hyponatremia during concomitant diuretic and mirtazapine use; consider discontinuing mirtazapine if symptomatic hyponatremia occurs and institute appropriate medical intervention. Concomitant use increases the risk for developing hyponatremia.
Protriptyline: (Moderate) Monitor for unusual drowsiness, sedation, and serotonin syndrome during coadministration due to the risk for additive CNS depression and serotonin syndrome. If serotonin syndrome occurs, consider discontinuation of therapy.
Pseudoephedrine; Triprolidine: (Moderate) Consistent with the CNS depressant effects of mirtazapine, additive effects may occur with other CNS depressants such as triprolidine. Mirtazapine should be administered cautiously with such agents because the CNS effects on cognitive performance and motor skills can be additive.
Pyrilamine: (Moderate) Consistent with the CNS depressant effects of mirtazapine, additive effects may occur with other CNS depressants such as pyrilamine. Mirtazapine should be administered cautiously with such agents because the CNS effects on cognitive performance and motor skills can be additive.
Quazepam: (Moderate) Monitor for unusual drowsiness and sedation during coadministration of benzodiazepines and mirtazapine due to the risk for additive CNS depression.
Quetiapine: (Major) Concomitant use of quetiapine and mirtazapine 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. Also monitor for unusual drowsiness, sedation, and serotonin syndrome during coadministration due to the risk for additive CNS depression and serotonin syndrome.
Quinapril; Hydrochlorothiazide, HCTZ: (Moderate) Monitor for signs and symptoms of hyponatremia during concomitant diuretic and mirtazapine use; consider discontinuing mirtazapine if symptomatic hyponatremia occurs and institute appropriate medical intervention. Concomitant use increases the risk for developing hyponatremia.
Quinidine: (Major) Concomitant use of quinidine and mirtazapine 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.
Quinine: (Major) Concomitant use of quinine and mirtazapine 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.
Quizartinib: (Major) Concomitant use of quizartinib and mirtazapine 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.
Ranolazine: (Moderate) Concomitant use of mirtazapine and ranolazine 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.
Rasagiline: (Major) It is recommended to avoid concurrent use of rasagiline and antidepressants, including mirtazapine. 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 mirtazapine. Conversely, when discontinuing mirtazapine, it is advisable to wait the length of 4 to 5 half-lives of the drug prior to initiation with rasagiline.
Relugolix: (Moderate) Concomitant use of mirtazapine 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) Concomitant use of mirtazapine 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.
Remifentanil: (Major) Concomitant use of opioid agonists with mirtazapine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with mirtazapine 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.
Remimazolam: (Moderate) Monitor for unusual drowsiness and sedation during coadministration of benzodiazepines and mirtazapine due to the risk for additive CNS depression.
Ribociclib: (Major) Avoid coadministration of mirtazapine with ribociclib due to the risk of QT prolongation; mirtazapine plasma concentrations may also increase. Mirtazapine is a CYP3A4 substrate that has been associated with dose-dependent QT prolongation; torsade de pointes (TdP) has also been reported in postmarketing experience, primarily in overdose cases or in patients with other risk factors. Ribociclib is a strong CYP3A4 inhibitor that has also been associated with concentration-dependent QT prolongation. Additive QT prolongation may occur. Coadministration with another strong CYP3A4 inhibitor increased mirtazapine exposure by approximately 50%.
Ribociclib; Letrozole: (Major) Avoid coadministration of mirtazapine with ribociclib due to the risk of QT prolongation; mirtazapine plasma concentrations may also increase. Mirtazapine is a CYP3A4 substrate that has been associated with dose-dependent QT prolongation; torsade de pointes (TdP) has also been reported in postmarketing experience, primarily in overdose cases or in patients with other risk factors. Ribociclib is a strong CYP3A4 inhibitor that has also been associated with concentration-dependent QT prolongation. Additive QT prolongation may occur. Coadministration with another strong CYP3A4 inhibitor increased mirtazapine exposure by approximately 50%.
Rifampin: (Moderate) Mirtazapine plasma concentrations and pharmacologic action may be decreased in patients taking rifampin. Rifampin is a potent inducer of CYP3A4, and may be a modest inducer of CYP2D6. Rifampin is also a relatively weak inducer of CYP1A2. In vitro studies have identified mirtazapine as a substrate for several CYP450 isoenzymes including 2D6, 1A2, and 3A4. Monitor for reduced effectiveness of mirtazapine during co-administration of rifampin. It may be necessary to increase the mirtazapine dosage during concurrent therapy. Conversely, if rifampin is discontinued, the dosage of mirtazapine may need to be reduced.
Rifapentine: (Moderate) Monitor for decreased efficacy of mirtazapine if coadministration with rifapentine is necessary; an increased mirtazapine dose may be necessary. If rifapentine is discontinued, a decrease in mirtazapine dose may be needed. Concomitant use may decrease mirtazapine exposure. Mirtazapine is a CYP3A4 substrate and rifapentine is a strong CYP3A4 inducer. Coadministration with other strong CYP3A4 inducers increased mirtazapine clearance by approximately 2-fold, decreasing the average mirtazapine plasma concentrations by 45% to 60%.
Rilpivirine: (Moderate) Concomitant use of mirtazapine 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) Concomitant use of mirtazapine and risperidone 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.
Ritonavir: (Moderate) The plasma concentrations of mirtazapine may be elevated when administered concurrently with ritonavir. Clinical monitoring for adverse effects, such as CNS or GI effects, is recommended during coadministration. Ritonavir is a strong CYP3A4 inhibitor, while mirtazapine is a CYP3A4. Coadministration with another strong CYP3A4 inhibitor increased mirtazapine exposure by approximately 50%.
Rizatriptan: (Major) The coadministration of serotonergic antidepressants with serotonin-agonists has sometimes resulted in serotonin syndrome. Careful observation of the patient is advised, particularly during treatment initiation and dose increases. Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, and coma), autonomic instability (e.g., tachycardia, labile blood pressure, and hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination) and/or gastrointestinal symptoms (e.g., nausea, vomiting, and diarrhea). Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome, which includes hyperthermia, muscle rigidity, autonomic instability with possible rapid fluctuation of vital signs, and mental status changes. Discontinue the serotonergic agents immediately if serotonin syndrome reactions occur and initiate supportive symptomatic treatment.
Rolapitant: (Major) Use caution if mirtazapine and rolapitant are used concurrently, and monitor for mirtazapine-related adverse effects. Mirtazapine 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 mirtazapine 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.
Ropinirole: (Moderate) Some medicines used for treatment of Parkinson's disease, like ropinirole, could potentially cause additive drowsiness when coadministered with mirtazapine.
Saquinavir: (Moderate) Concurrent administration of mirtazapine and saquinavir may result in elevated mirtazapine plasma concentrations. If these drugs are coadministered, monitor patients for adverse effects associated with mirtazapine, such as constipation, drowsiness, dizziness, and QT prolongation, and decrease the dose if necessary. Mirtazapine is a substrate of CYP3A4 and protease inhibitors are potent inhibitors of CYP3A4.
Scopolamine: (Moderate) Monitor for unusual drowsiness and sedation during coadministration of mirtazapine and scopolamine due to the risk for additive CNS depression.
Secobarbital: (Major) Monitor for excessive sedation and somnolence during coadministration of mirtazapine and barbiturates. Concurrent use may result in additive CNS depression.
Selegiline: (Contraindicated) Mirtazapine is 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 mirtazapine. After stopping treatment with mirtazapine, a time period of at least 14 days should elapse before starting therapy with selegiline. Serotonin syndrome has occurred in patients receiving selective MAO-B inhibitors and serotonergic antidepressants simultaneously.
Selpercatinib: (Major) Concomitant use of selpercatinib and mirtazapine 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.
Serotonin-Receptor Agonists: (Major) The coadministration of serotonergic antidepressants with serotonin-agonists has sometimes resulted in serotonin syndrome. Careful observation of the patient is advised, particularly during treatment initiation and dose increases. Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, and coma), autonomic instability (e.g., tachycardia, labile blood pressure, and hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination) and/or gastrointestinal symptoms (e.g., nausea, vomiting, and diarrhea). Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome, which includes hyperthermia, muscle rigidity, autonomic instability with possible rapid fluctuation of vital signs, and mental status changes. Discontinue the serotonergic agents immediately if serotonin syndrome reactions occur and initiate supportive symptomatic treatment.
Sertraline: (Moderate) Use sertraline with caution in combination with mirtazapine. Coadministration may increase the risk for QT prolongation, torsade de pointes (TdP), and serotonin syndrome. 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. However, the risk of sertraline-induced QT prolongation is generally considered to be low in clinical practice. Its effect on QTc interval is minimal (typically less than 5 msec), and the drug has been used safely in patients with cardiac disease.
Sevoflurane: (Major) Concomitant use of halogenated and mirtazapine 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.
Siponimod: (Major) Concomitant use of siponimod and mirtazapine 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.
Sodium Stibogluconate: (Moderate) Concomitant use of sodium stibogluconate and mirtazapine 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.
Solifenacin: (Moderate) There may be an increased risk for QT prolongation and torsade de pointes (TdP) during concurrent use of mirtazapine and solifenacin. Solifenacin has been associated with dose-dependent prolongation of the QT interval. TdP has been reported with postmarketing use, although causality was not determined. This should be taken into consideration when prescribing solifenacin to patients taking other drugs that are associated with QT prolongation. Cases of QT prolongation, TdP, ventricular tachycardia, and sudden death have been reported during postmarketing use of mirtazapine, primarily following overdose or in patients with other risk factors for QT prolongation, including concomitant use of other medications associated with QT prolongation. Mirtazapine exhibits weak anticholinergic activity that may be additive with the anticholinergic effects of solifenacin.
Sorafenib: (Major) Concomitant use of sorafenib and mirtazapine 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.
Sotalol: (Major) Concomitant use of sotalol and mirtazapine 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 mirtazapine use; consider discontinuing mirtazapine if symptomatic hyponatremia occurs and institute appropriate medical intervention. Concomitant use increases the risk for developing hyponatremia.
Spironolactone; Hydrochlorothiazide, HCTZ: (Moderate) Monitor for signs and symptoms of hyponatremia during concomitant diuretic and mirtazapine use; consider discontinuing mirtazapine if symptomatic hyponatremia occurs and institute appropriate medical intervention. Concomitant use increases the risk for developing hyponatremia.
St. John's Wort, Hypericum perforatum: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering mirtazapine with St. John's Wort. 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.
Stiripentol: (Moderate) Monitor for excessive sedation and somnolence during coadministration of stiripentol and mirtazapine. CNS depressants can potentiate the effects of stiripentol.
Sufentanil: (Major) Concomitant use of opioid agonists with mirtazapine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with mirtazapine 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.
Sumatriptan: (Major) The coadministration of serotonergic antidepressants with serotonin-agonists has sometimes resulted in serotonin syndrome. Careful observation of the patient is advised, particularly during treatment initiation and dose increases. Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, and coma), autonomic instability (e.g., tachycardia, labile blood pressure, and hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination) and/or gastrointestinal symptoms (e.g., nausea, vomiting, and diarrhea). Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome, which includes hyperthermia, muscle rigidity, autonomic instability with possible rapid fluctuation of vital signs, and mental status changes. Discontinue the serotonergic agents immediately if serotonin syndrome reactions occur and initiate supportive symptomatic treatment.
Sumatriptan; Naproxen: (Major) The coadministration of serotonergic antidepressants with serotonin-agonists has sometimes resulted in serotonin syndrome. Careful observation of the patient is advised, particularly during treatment initiation and dose increases. Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, and coma), autonomic instability (e.g., tachycardia, labile blood pressure, and hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination) and/or gastrointestinal symptoms (e.g., nausea, vomiting, and diarrhea). Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome, which includes hyperthermia, muscle rigidity, autonomic instability with possible rapid fluctuation of vital signs, and mental status changes. Discontinue the serotonergic agents immediately if serotonin syndrome reactions occur and initiate supportive symptomatic treatment.
Sunitinib: (Moderate) Concomitant use of mirtazapine 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.
Suvorexant: (Moderate) CNS depressant drugs may have cumulative effects when administered concurrently and they should be used cautiously with suvorexant. A reduction in dose of the CNS depressant may be needed in some cases.
Tacrolimus: (Moderate) Concomitant use of mirtazapine 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.
Tamoxifen: (Moderate) Concomitant use of tamoxifen and mirtazapine 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.
Tapentadol: (Major) Concomitant use of opioid agonists with mirtazapine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with mirtazapine 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.
Tedizolid: (Minor) Caution is warranted with the concurrent use of tedizolid and mirtazapine. Tedizolid is an antibiotic that is also a weak reversible, non-selective inhibitor of MAO. Since monoamine oxidase type A deaminates serotonin, administration of a non-selective MAO inhibitor concurrently with mirtazapine can potentially 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.
Telavancin: (Moderate) Concomitant use of mirtazapine 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.
Telmisartan; Hydrochlorothiazide, HCTZ: (Moderate) Monitor for signs and symptoms of hyponatremia during concomitant diuretic and mirtazapine use; consider discontinuing mirtazapine if symptomatic hyponatremia occurs and institute appropriate medical intervention. Concomitant use increases the risk for developing hyponatremia.
Temazepam: (Moderate) Monitor for unusual drowsiness and sedation during coadministration of benzodiazepines and mirtazapine due to the risk for additive CNS depression.
Tetrabenazine: (Major) Concomitant use of tetrabenazine and mirtazapine 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.
Thiazide diuretics: (Moderate) Monitor for signs and symptoms of hyponatremia during concomitant diuretic and mirtazapine use; consider discontinuing mirtazapine if symptomatic hyponatremia occurs and institute appropriate medical intervention. Concomitant use increases the risk for developing hyponatremia.
Thioridazine: (Contraindicated) Avoid concomitant use of thioridazine and mirtazapine due to an increased risk for torsade de pointes (TdP) and QT/QTc prolongation.
Tipranavir: (Moderate) Concurrent administration of mirtazapine and tipranavir may result in elevated mirtazapine plasma concentrations. If these drugs are coadministered, monitor patients for adverse effects associated with mirtazapine, such as constipation, drowsiness, dizziness, and QT prolongation, and decrease the dose if necessary. Mirtazapine is a substrate of CYP3A4 and protease inhibitors are potent inhibitors of CYP3A4.
Tolcapone: (Major) COMT inhibitors should be given cautiously with other agents that cause CNS depression, such as mirtazapine, due to the possibility of additive sedation. COMT inhibitors have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment. Patients should be advised to avoid driving or other tasks requiring mental alertness until they know how the combination affects them.
Tolterodine: (Moderate) There may be an increased risk for QT prolongation and torsade de pointes (TdP) during concurrent use of mirtazapine and tolterodine. Coadminister with caution. Tolterodine has been associated with dose-dependent prolongation of the QT interval, especially in poor CYP2D6 metabolizers. Cases of QT prolongation, TdP, ventricular tachycardia, and sudden death have been reported during postmarketing use of mirtazapine, primarily following overdose or in patients with other risk factors for QT prolongation, including concomitant use of other medications associated with QT prolongation. Mirtazapine exhibits weak anticholinergic activity that may be additive with the anticholinergic effects of tolterodine.
Toremifene: (Major) Concomitant use of toremifene and mirtazapine 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 mirtazapine use; consider discontinuing mirtazapine if symptomatic hyponatremia occurs and institute appropriate medical intervention. Concomitant use increases the risk for developing hyponatremia.
Tramadol: (Major) Concomitant use of opioid agonists with mirtazapine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with mirtazapine 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.
Tramadol; Acetaminophen: (Major) Concomitant use of opioid agonists with mirtazapine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with mirtazapine 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.
Tranylcypromine: (Contraindicated) Use of mirtazapine concurrently with the monoamine oxidase inhibitors (MAOIs) is contraindicated. If combined, there is a possibility of developing serious reactions such as serotonin syndrome. In patients receiving nonselective MAOIs in combination with serotoninergic agents there have been reports of serious, sometimes fatal, reactions. At least 2 weeks should elapse between stopping one agent and beginning the other. Monitor for serotonin-related side effects during therapy transitions.
Trazodone: (Major) Due to the potential for QT prolongation, cautious use and close monitoring are advisable if concurrent use of trazodone and mirtazapine is necessary. Both drugs may cause QT interval prolongation and a risk for torsade de pointes (TdP). In addition, concurrent use of trazodone with other drugs that modulate serotonergic function, such as mirtazapine, 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.
Triamterene: (Moderate) Monitor for signs and symptoms of hyponatremia during concomitant diuretic and mirtazapine use; consider discontinuing mirtazapine if symptomatic hyponatremia occurs and institute appropriate medical intervention. Concomitant use increases the risk for developing hyponatremia.
Triamterene; Hydrochlorothiazide, HCTZ: (Moderate) Monitor for signs and symptoms of hyponatremia during concomitant diuretic and mirtazapine use; consider discontinuing mirtazapine if symptomatic hyponatremia occurs and institute appropriate medical intervention. Concomitant use increases the risk for developing hyponatremia.
Triazolam: (Moderate) Monitor for unusual drowsiness and sedation during coadministration of benzodiazepines and mirtazapine due to the risk for additive CNS depression.
Triclabendazole: (Moderate) Concomitant use of triclabendazole and mirtazapine 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) Monitor for unusual drowsiness, sedation, and serotonin syndrome during coadministration due to the risk for additive CNS depression and serotonin syndrome. If serotonin syndrome occurs, consider discontinuation of therapy.
Trifluoperazine: (Moderate) Coadministration is contraindicated due to the potential for QT prolongation and torsade de pointes. Due to the possibility of additive effects on the QT interval, caution is advisable during concurrent use of mirtazapine and trifluoperazine. Cases of QT prolongation, TdP, ventricular tachycardia, and sudden death have been reported during postmarketing use of mirtazapine. The majority of reports have occurred in the setting of mirtazapine overdose or in patients with other risk factors for QT prolongation, including concomitant use of other medications associated with QT prolongation. Trifluoperazine is associated with a possible risk for QT prolongation, particularly in overdose settings. Theoretically, trifluoperazine may increase the risk of QT prolongation if coadministered with other drugs that have a risk of QT prolongation. Because both mirtazapine and trifluoperazine have CNS depressant properties, patients should be advised to avoid engaging in activities requiring mental alertness until they are aware of the effects of the combination.
Trimipramine: (Moderate) Monitor for unusual drowsiness, sedation, and serotonin syndrome during coadministration due to the risk for additive CNS depression and serotonin syndrome. If serotonin syndrome occurs, consider discontinuation of therapy.
Triprolidine: (Moderate) Consistent with the CNS depressant effects of mirtazapine, additive effects may occur with other CNS depressants such as triprolidine. Mirtazapine should be administered cautiously with such agents because the CNS effects on cognitive performance and motor skills can be additive.
Triptorelin: (Moderate) Concomitant use of mirtazapine 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) Mirtazapine exhibits weak anticholinergic activity that is not expected to be clinically significant. However, the anticholinergic effects may be additive to the antimuscarinics. 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.
Tryptophan, 5-Hydroxytryptophan: (Major) Concurrent use of tryptophan and mirtazapine is not recommended. Since tryptophan is converted to serotonin, the use of tryptophan in patients receiving mirtazapine could lead to serotonin excess, and potentially, 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. Because tryptophan is found in some herbal supplements, patients receiving mirtazapine should be instructed to talk to their doctor or pharmacist before taking any non-prescription products.
Tucatinib: (Moderate) Monitor for an increase in mirtazapine-related adverse reactions if coadministration with tucatinib is necessary. Mirtazapine is a CYP3A4 substrate and tucatinib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the Cmax and AUC of a single dose of mirtazapine by approximately 40% and 50%, respectively.
Valsartan; Hydrochlorothiazide, HCTZ: (Moderate) Monitor for signs and symptoms of hyponatremia during concomitant diuretic and mirtazapine use; consider discontinuing mirtazapine if symptomatic hyponatremia occurs and institute appropriate medical intervention. Concomitant use increases the risk for developing hyponatremia.
Vandetanib: (Major) Concomitant use of vandetanib and mirtazapine 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 mirtazapine 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.
Vemurafenib: (Major) Concomitant use of vemurafenib and mirtazapine 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.
Venlafaxine: (Major) Concomitant use of mirtazapine and venlafaxine may increase the risk of serotonin syndrome, QT prolongation, and torsade de pointes. Both medications are associated with a possible risk of QT prolongation and torsade de pointes (TdP). Cases of serotonin syndrome have been reported between mirtazapine and other serotonin-enhancing antidepressants. If serotonin syndrome occurs, all serotonergic agents should be discontinued and appropriate medical treatment should be implemented.
Vigabatrin: (Moderate) Vigabatrin may cause somnolence and fatigue. Drugs that can cause CNS depression, if used concomitantly with vigabatrin, may increase both the frequency and the intensity of adverse effects such as drowsiness, sedation, and dizziness. Caution should be used when vigabatrin is given with mirtazapine.
Vilazodone: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering vilazodone with other drugs that have serotonergic properties such as mirtazapine. 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 toxicity. Due to the CNS effects of vilazodone, caution should be used when vilazodone is given in combination with other centrally acting medications such as mirtazapine.
Voclosporin: (Moderate) Concomitant use of mirtazapine 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.
Vonoprazan; Amoxicillin; Clarithromycin: (Major) Concomitant use of mirtazapine and clarithromycin 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.
Voriconazole: (Contraindicated) The concurrent use of voriconazole with drugs that are associated with QT prolongation and are also CYP3A4 substrates, such as mirtazapine, is contraindicated. Voriconazole has been associated with QT prolongation and rare cases of torsade de pointes (TdP). Cases of QT prolongation, TdP, ventricular tachycardia, and sudden death have been reported during postmarketing use of mirtazapine, primarily following overdose or in patients with other risk factors for QT prolongation, including concomitant use of other medications associated with QT prolongation.
Vorinostat: (Moderate) Concomitant use of mirtazapine 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.
Vortioxetine: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering vortioxetine with other drugs that have serotonergic properties such as mirtazapine. 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 is suspected, vortioxetine and concurrent serotonergic agents should be discontinued.
Warfarin: (Moderate) In a study of 16 healthy subjects, concurrent use of mirtazapine (30 mg/day) and warfarin resulted in a small (0.20) but statistically significant increase in INR. The mechanism of this interaction has not been described. Until further information becomes available, it is advisable to carefully monitor the INR during concurrent use of mirtazapine and warfarin.
Ziconotide: (Moderate) Due to potentially additive effects, dosage adjustments may be necessary if ziconotide is used with a drug that has CNS depressant effects such as mirtazipine. Coadministration of CNS depressants may increase drowsiness, dizziness, and confusion that are associated with ziconotide.
Ziprasidone: (Major) Concomitant use of ziprasidone and mirtazapine 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.
Zolmitriptan: (Major) The coadministration of serotonergic antidepressants with serotonin-agonists has sometimes resulted in serotonin syndrome. Careful observation of the patient is advised, particularly during treatment initiation and dose increases. Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, and coma), au tonomic instability (e.g., tachycardia, labile blood pressure, and hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination) and/or gastrointestinal symptoms (e.g., nausea, vomiting, and diarrhea). Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome, which includes hyperthermia, muscle rigidity, autonomic instability with possible rapid fluctuation of vital signs, and mental status changes. Discontinue the serotonergic agents immediately if serotonin syndrome reactions occur and initiate supportive symptomatic treatment.

Mirtazapine/Remeron Oral Tab: 7.5mg, 15mg, 30mg, 45mg
Mirtazapine/Remeron SolTab Oral Tab Orally Dis: 15mg, 30mg, 45mg

Adults

45 mg/day PO.

Geriatric

45 mg/day PO.

Adolescents

Safety and efficacy have not been established.

Children

Safety and efficacy have not been established.

Infants

Not indicated.

Mirtazapine inhibits presynaptic serotonin (5-HT)-2 and alpha-2 adrenergic auto- and hetero-receptors, thereby increasing serotonergic and noradrenergic neurotransmission. The increased amount of 5-HT released interacts with postsynaptic 5-HT1 receptors, which may be relevant to the antidepressant effects of the drug. The affinity of mirtazapine for central alpha-2 adrenoreceptors is 10 times higher than for peripheral receptors, resulting in fewer peripheral effects related to increased blood pressure. Mirtazapine is an antagonist at postsynaptic 5-HT2A, 5-HT2C, and 5-HT3 receptors. The blockade of these receptors may result in a lower incidence of certain adverse effects (e.g., anxiety, insomnia, nausea) than occurs with antidepressants that do not antagonize these receptors. Mirtazapine significantly antagonizes histamine H1 receptors at low doses, and this activity is associated with sedation and appetite stimulation. Higher doses have a greater effect on norepinephrine release relative to antihistamine effects, which may offset the sedative potential and appetite stimulation observed at low doses. Mirtazapine has muscarinic antagonist properties, which may be associated with xerostomia, constipation, and other anticholinergic effects. Orthostatic hypotension is the result of the peripheral alpha-1 adrenergic antagonism of the drug. Mirtazapine does not have clinically significant receptor affinity for dopamine, 5-HT1A, or 5-HT1B, and has no effects on the central reuptake of either norepinephrine or serotonin.

Mirtazapine is administered orally. Plasma protein binding is approximately 85%. Mirtazapine is extensively metabolized in the liver, primarily by demethylation and hydroxylation followed by glucuronide conjugation. The isoenzymes CYP2D6 and CYP1A2 are involved in the formation of the 8-hydroxy metabolite of mirtazapine and CYP3A is responsible for the formation of the N-desmethyl and N-oxide metabolite. Several unconjugated metabolites possess pharmacological activity but levels are very low in the plasma. The half-life of mirtazapine ranges from 20 to 40 hours. Elimination occurs primarily in the urine (75%) and to a lesser extent in the feces (15%).
 
Affected cytochrome P450 isoenzymes and drug transporters: CYP3A, CYP2D6, CYP1A2
In vitro data indicate that CYP2D6 and CYP1A2 are involved in the formation of the 8-hydroxy metabolite and that CYP3A is responsible for the formation of the N-desmethyl and N-oxide metabolites. Strong CYP3A4 inhibitors and inducers altered the pharmacokinetics of mirtazapine during drug interaction studies. Dosage adjustments may be needed during coadministration of strong CYP3A4 inhibitors or inducers. During the administration of a strong CYP2D6 inhibitor to healthy subjects that were CYP2D6 extensive metabolizers, no relevant changes to the pharmacokinetics of steady-state mirtazapine were noted.

Oral Route

Following oral administration, peak plasma concentrations are reached within about 2 hours. The absolute bioavailability is about 50%. Food has minimal effects on both the rate and extent of absorption; therefore, mirtazapine can be taken without regard to meals. Steady-state plasma concentrations are reached within 5 days. The (-) enantiomer has an elimination half-life that is approximately twice as long as the (+) enantiomer and therefore achieves plasma levels that are about 3 times as high as the (+) enantiomer.

Pregnancy

Prolonged experience with mirtazapine use during pregnancy, based on published observational studies and postmarketing reports, has not reliably identified a drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. There are risks associated with untreated depression in pregnancy, including relapse of the depressive disorder. There are also a potential risk from antidepressant use during pregnancy for persistent pulmonary hypertension in the newborn (PPHN) and for neonates who are exposed in the third trimester to experience a drug discontinuation syndrome, particularly for serotonergic antidepressants, which often have better data regarding their use during pregnancy. The effects of mirtazapine during labor and delivery are unknown. There is a pregnancy exposure registry that monitors outcomes in pregnant patients exposed to mirtazapine; information about the registry can be obtained at https://womensmentalhealth.org/research/pregnancyregistry/antidepressants/ or by calling 1-866-961-2388.