Brisdelle

Selective Serotonin Reuptake Inhibitor Antidepressants, SSRIs

Hazardous Drugs Classification
NIOSH 2016 List: Group 3
NIOSH (Draft) 2020 List: Table 2
Observe and exercise appropriate precautions for handling, preparation, administration, and disposal of hazardous drugs.
Use gloves to handle. Cutting, crushing, or otherwise manipulating tablets/capsules will increase exposure and require additional protective equipment. Oral liquid drugs require double chemotherapy gloves and protective gown. Eye/face and respiratory protection may be needed during preparation and administration.

Oral Administration

Administer as a single dose, usually in the morning. May be administered without regard to meals, however, food may minimize GI adverse effects.

Oral Solid Formulations

Controlled-release tablets: Patients should swallow tablets whole. Do not cut, chew, or crush. Do not administer concomitantly with antacids; the tablets are enteric-coated.

Oral Liquid Formulations

Oral suspension: Shake well before each use. To ensure accurate dosing, measure dosage with a calibrated measuring device.

Severe

visual impairment / Early / 1.0-5.0
muscle paralysis / Delayed / 0.1-1.0
seizures / Delayed / 0.1-1.0
bradycardia / Rapid / 0.1-1.0
angioedema / Rapid / 0.1-1.0
anaphylactoid reactions / Rapid / 0.1-1.0
bronchospasm / Rapid / 0.1-1.0
keratoconjunctivitis / Early / 0.1-1.0
pancreatitis / Delayed / 0.1-1.0
proteinuria / Delayed / 0.1-1.0
peptic ulcer / Delayed / 0-0.1
hematemesis / Delayed / 0-0.1
GI obstruction / Delayed / 0-0.1
ileus / Delayed / 0-0.1
akinesia / Delayed / 0-0.1
torticollis / Delayed / 0-0.1
coma / Early / 0-0.1
myelitis / Delayed / 0-0.1
myocardial infarction / Delayed / 0-0.1
stroke / Early / 0-0.1
atrial fibrillation / Early / 0-0.1
heart failure / Delayed / 0-0.1
pulmonary embolism / Delayed / 0-0.1
thrombosis / Delayed / 0-0.1
erythema nodosum / Delayed / 0-0.1
erythema multiforme / Delayed / 0-0.1
exfoliative dermatitis / Delayed / 0-0.1
pulmonary edema / Early / 0-0.1
pulmonary fibrosis / Delayed / 0-0.1
hearing loss / Delayed / 0-0.1
retinal hemorrhage / Delayed / 0-0.1
ocular hypertension / Delayed / 0-0.1
ocular hemorrhage / Delayed / 0-0.1
oliguria / Early / 0-0.1
epididymitis / Delayed / 0-0.1
hyperkalemia / Delayed / 0-0.1
laryngospasm / Rapid / Incidence not known
Guillain-Barre syndrome / Delayed / Incidence not known
SIADH / Delayed / Incidence not known
vasculitis / Delayed / Incidence not known
agranulocytosis / Delayed / Incidence not known
aplastic anemia / Delayed / Incidence not known
GI bleeding / Delayed / Incidence not known
pancytopenia / Delayed / Incidence not known
hemolytic anemia / Delayed / Incidence not known
ventricular fibrillation / Early / Incidence not known
torsade de pointes / Rapid / Incidence not known
ventricular tachycardia / Early / Incidence not known
pulmonary hypertension / Delayed / Incidence not known
toxic epidermal necrolysis / Delayed / Incidence not known
Stevens-Johnson syndrome / Delayed / Incidence not known
Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) / Delayed / Incidence not known
optic neuritis / Delayed / Incidence not known
hepatic necrosis / Delayed / Incidence not known
porphyria / Delayed / Incidence not known
renal failure (unspecified) / Delayed / Incidence not known
serotonin syndrome / Delayed / Incidence not known
bone fractures / Delayed / Incidence not known
teratogenesis / Delayed / Incidence not known
neonatal abstinence syndrome / Early / Incidence not known
persistent pulmonary hypertension of the newborn / Delayed / Incidence not known

Moderate

ejaculation dysfunction / Delayed / 13.0-28.0
constipation / Delayed / 5.0-16.0
impotence (erectile dysfunction) / Delayed / 4.0-10.0
peripheral vasodilation / Rapid / 2.0-4.0
blurred vision / Early / 2.0-4.0
hypertonia / Delayed / 0.1-3.0
myoclonia / Delayed / 1.0-3.0
chest pain (unspecified) / Early / 1.0-3.0
palpitations / Early / 2.0-3.0
dysuria / Early / 0.1-3.0
memory impairment / Delayed / 2.0-2.0
amnesia / Delayed / 0.1-2.0
hypertension / Early / 1.0-2.0
sinus tachycardia / Rapid / 1.0-2.0
myopathy / Delayed / 0-2.0
teeth grinding (bruxism) / Delayed / 0.1-1.0
stomatitis / Delayed / 0.1-1.0
colitis / Delayed / 0-1.0
dysphagia / Delayed / 0.1-1.0
melena / Delayed / 0-1.0
gastritis / Delayed / 0.1-1.0
hemorrhoids / Delayed / 0.1-1.0
dyskinesia / Delayed / 0.1-1.0
dystonic reaction / Delayed / 0.1-1.0
nystagmus / Delayed / 0-1.0
confusion / Early / 1.0-1.0
migraine / Early / 0.1-1.0
ataxia / Delayed / 0-1.0
neuropathic pain / Delayed / 0-1.0
lymphadenopathy / Delayed / 0.1-1.0
anemia / Delayed / 0.1-1.0
leukopenia / Delayed / 1.0-1.0
eosinophilia / Delayed / 0.1-1.0
hematoma / Early / 0.1-1.0
orthostatic hypotension / Delayed / 0.1-1.0
hypotension / Rapid / 0.1-1.0
supraventricular tachycardia (SVT) / Early / 0.1-1.0
angina / Early / 0-1.0
edema / Delayed / 0.1-1.0
contact dermatitis / Delayed / 0.1-1.0
atopic dermatitis / Delayed / 1.0-1.0
dyspnea / Early / 0.1-1.0
conjunctivitis / Delayed / 0.1-1.0
elevated hepatic enzymes / Delayed / 0.1-1.0
vaginitis / Delayed / 0.1-1.0
urinary retention / Early / 0.1-1.0
pyuria / Delayed / 0.1-1.0
urinary incontinence / Early / 0.1-1.0
cystitis / Delayed / 0.1-1.0
myasthenia / Delayed / 0-1.0
peripheral edema / Delayed / 0.1-1.0
oral ulceration / Delayed / 0-0.1
sialadenitis / Delayed / 0-0.1
gingival hyperplasia / Delayed / 0-0.1
glossitis / Early / 0-0.1
cholelithiasis / Delayed / 0-0.1
fecal incontinence / Early / 0-0.1
esophagitis / Delayed / 0-0.1
choreoathetosis / Delayed / 0-0.1
dysarthria / Delayed / 0-0.1
trismus / Delayed / 0-0.1
meningitis / Delayed / 0-0.1
hyperreflexia / Delayed / 0-0.1
aphasia / Delayed / 0-0.1
hyperalgesia / Delayed / 0-0.1
neuritis / Delayed / 0-0.1
hyponatremia / Delayed / 0-0.1
thrombocytopenia / Delayed / 0-0.1
lymphopenia / Delayed / 0-0.1
prolonged bleeding time / Delayed / 0-0.1
lymphocytosis / Delayed / 0-0.1
bundle-branch block / Early / 0-0.1
phlebitis / Rapid / 0-0.1
candidiasis / Delayed / 0-0.1
furunculosis / Delayed / 0-0.1
skin ulcer / Delayed / 0-0.1
bullous rash / Early / 0-0.1
dysphonia / Delayed / 0-0.1
hemoptysis / Delayed / 0-0.1
amblyopia / Delayed / 0-0.1
blepharitis / Early / 0-0.1
hyperacusis / Delayed / 0-0.1
cataracts / Delayed / 0-0.1
exophthalmos / Delayed / 0-0.1
photophobia / Early / 0-0.1
hyperbilirubinemia / Delayed / 0-0.1
jaundice / Delayed / 0-0.1
hepatitis / Delayed / 0-0.1
vaginal bleeding / Delayed / 0-0.1
prostatitis / Delayed / 0-0.1
nephrolithiasis / Delayed / 0-0.1
flank pain / Delayed / 0-0.1
tetany / Early / 0-0.1
hypothyroidism / Delayed / 0-0.1
hyperthyroidism / Delayed / 0-0.1
diabetes mellitus / Delayed / 0-0.1
goiter / Delayed / 0-0.1
hyperglycemia / Delayed / 0-0.1
hypoglycemia / Early / 0-0.1
hypercalcemia / Delayed / 0-0.1
hypokalemia / Delayed / 0-0.1
hypercholesterolemia / Delayed / 0-0.1
hypocalcemia / Delayed / 0-0.1
gout / Delayed / 0-0.1
dehydration / Delayed / 0-0.1
hyperphosphatemia / Delayed / 0-0.1
osteoporosis / Delayed / 0-0.1
withdrawal / Early / 0-0.1
akathisia / Delayed / Incidence not known
bleeding / Early / Incidence not known
platelet dysfunction / Delayed / Incidence not known
pneumonitis / Delayed / Incidence not known
hepatomegaly / Delayed / Incidence not known
hyperprolactinemia / Delayed / Incidence not known
priapism / Early / Incidence not known
galactorrhea / Delayed / Incidence not known
hematuria / Delayed / Incidence not known
osteopenia / Delayed / Incidence not known
growth inhibition / Delayed / Incidence not known

Mild

headache / Early / 6.3-27.0
nausea / Early / 4.3-26.0
drowsiness / Early / 9.0-24.0
insomnia / Early / 8.0-24.0
asthenia / Delayed / 12.0-22.0
diarrhea / Early / 6.0-18.0
xerostomia / Early / 3.0-18.0
dizziness / Early / 6.0-14.0
libido decrease / Delayed / 3.0-12.0
tremor / Early / 4.0-11.0
hyperhidrosis / Delayed / 6.0-11.0
anorexia / Delayed / 1.0-9.0
orgasm dysfunction / Delayed / 2.0-9.0
infection / Delayed / 5.0-8.0
sinusitis / Delayed / 4.0-8.0
abdominal pain / Early / 3.0-7.0
flatulence / Early / 4.0-6.0
dyspepsia / Early / 2.0-5.0
yawning / Early / 4.0-5.0
dysmenorrhea / Delayed / 1.0-5.0
back pain / Delayed / 3.0-5.0
myalgia / Early / 2.0-5.0
malaise / Early / 0-4.9
fatigue / Early / 0-4.9
lethargy / Early / 0-4.9
appetite stimulation / Delayed / 2.0-4.0
paresthesias / Delayed / 1.0-4.0
abnormal dreams / Early / 1.0-4.0
rhinitis / Early / 3.0-4.0
pharyngitis / Delayed / 1.0-4.0
weight gain / Delayed / 1.0-3.0
vomiting / Early / 2.0-3.0
rash / Early / 2.0-3.0
increased urinary frequency / Early / 2.0-3.0
chills / Rapid / 2.0-2.0
cough / Delayed / 1.0-2.0
fever / Early / 1.0-2.0
dysgeusia / Early / 2.0-2.0
arthralgia / Delayed / 1.0-2.0
gingivitis / Delayed / 0-1.0
dental pain / Delayed / 0.1-1.0
eructation / Early / 0.1-1.0
gastroesophageal reflux / Delayed / 0.1-1.0
weight loss / Delayed / 0.1-1.0
hyperkinesis / Delayed / 0.1-1.0
vertigo / Early / 0.1-1.0
hypoesthesia / Delayed / 0.1-1.0
purpura / Delayed / 0.1-1.0
leukocytosis / Delayed / 0.1-1.0
ecchymosis / Delayed / 0.1-1.0
syncope / Early / 0.1-1.0
photosensitivity / Delayed / 0.1-1.0
acne vulgaris / Delayed / 0.1-1.0
urticaria / Rapid / 0.1-1.0
xerosis / Delayed / 0.1-1.0
alopecia / Delayed / 0.1-1.0
hyperventilation / Early / 0-1.0
laryngitis / Delayed / 0.1-1.0
ocular pain / Early / 0.1-1.0
mydriasis / Early / 0.1-1.0
otalgia / Early / 0.1-1.0
amenorrhea / Delayed / 0.1-1.0
libido increase / Delayed / 0.1-1.0
menorrhagia / Delayed / 0.1-1.0
urinary urgency / Early / 0.1-1.0
polyuria / Early / 0.1-1.0
nocturia / Early / 0-1.0
polydipsia / Early / 0.1-1.0
dental caries / Delayed / 0-0.1
tongue discoloration / Delayed / 0-0.1
hyporeflexia / Delayed / 0-0.1
pallor / Early / 0-0.1
hypothermia / Delayed / 0-0.1
skin discoloration / Delayed / 0-0.1
seborrhea / Delayed / 0-0.1
vesicular rash / Delayed / 0-0.1
maculopapular rash / Early / 0-0.1
hirsutism / Delayed / 0-0.1
hiccups / Early / 0-0.1
diplopia / Early / 0-0.1
parosmia / Delayed / 0-0.1
ptosis / Delayed / 0-0.1
gynecomastia / Delayed / 0-0.1
leukorrhea / Delayed / 0-0.1
mastalgia / Delayed / 0-0.1
breast enlargement / Delayed / 0-0.1
breast discharge / Delayed / 0-0.1
pelvic pain / Delayed / 0-0.1
muscle cramps / Delayed / 0-0.1
pruritus / Rapid / 1.0
tinnitus / Delayed / 1.0
restless legs syndrome (RLS) / Delayed / Incidence not known
petechiae / Delayed / Incidence not known
anosmia / Delayed / Incidence not known

Children, growth inhibition, suicidal ideation

Paroxetine is not FDA-approved for use in children and adolescents less than 18 years of age. Three well-controlled trials have shown that paroxetine is no more effective than placebo for the treatment of depression in pediatric patients. In a pooled analysis of placebo-controlled trials of antidepressants (n = 4,500 pediatrics and 77,000 adults), there was an increased risk for suicidal thoughts and behaviors in patients 24 years of age and younger receiving an antidepressant versus placebo, with considerable variation in the risk of suicidality among drugs. The difference in absolute risk of suicidal thoughts and behaviors across different indications was highest in those with major depression. No suicides occurred in any of the pediatric trials. Data from a cohort of 36,842 children (age range of 6 to 18 years) suggested those who use multiple antidepressants have a higher risk of suicide behavior, most likely a result of increased severity of depression rather than drug effect. In a meta-analysis conducted by the manufacturer in adult patients with and without psychiatric disorders, a higher frequency of suicidal behavior occurred in young adults and adults treated with paroxetine compared with placebo. The need for an antidepressant in children or adolescents for any use must be weighed against the risk of suicidality; it is unknown if this risk extends to long-term use. All patients should be monitored for symptom worsening or suicidality, especially at treatment initiation or after dose changes. Caregivers and/or patients should immediately notify the prescriber of changes in behavior or suicidal ideation. The potential for growth inhibition in pediatric patients should be monitored during SSRI therapy; monitor height and weight periodically. Data are inadequate to determine whether the chronic use of SSRIs causes long-term growth inhibition; however, decreased weight gain has been observed in children and adolescents receiving SSRIs. The mechanism of growth inhibition in children may be due to the suppression of growth hormone secretion, which is known to occur in adults taking SSRIs.

Brisdelle, Paxil, Paxil CR, Pexeva

Rx

Oral selective serotonin reuptake inhibitor (SSRI) antidepressant
Indicated for depression, OCD, social anxiety, generalized anxiety disorder, panic disorder, PTSD, premenstrual dysphoric disorder, and menopausal hot flashed in adults
Do not use during pregnancy; increased risk of suicidality during treatment initiation in pediatric and young adult patients

For the treatment of major depression. Oral dosage (immediate-release) Adults

20 mg PO once daily, initially. May increase the dose by 10 mg/day at intervals of at least 1 week if inadequate response and depending on tolerability. Max: 50 mg/day.

Older Adults

10 mg PO once daily, initially. May increase the dose by 10 mg/day at intervals of at least 1 week if inadequate response and depending on tolerability. Max: 40 mg/day.

Oral dosage (controlled-release) Adults

25 mg PO once daily, initially. May increase the dose by 12.5 mg/day at intervals of at least 1 week if inadequate response and depending on tolerability. Max: 62.5 mg/day.

Older Adults

12.5 mg PO once daily, initially. May increase the dose by 12.5 mg/day at intervals of at least 1 week if inadequate response and depending on tolerability. Max: 50 mg/day.

For the treatment of generalized anxiety disorder (GAD). Oral dosage (immediate-release; e.g., Paxil, Pexeva) Adults

20 mg PO once daily, initially. May increase the dose by 10 mg/day at weekly intervals as needed and tolerated. Max: 50 mg/day. Additional benefit does not appear to be gained with dosages higher than 20 mg/day.

Older Adults

10 mg PO once daily, initially. May increase the dose by 10 mg/day at weekly intervals as needed and tolerated. Max: 40 mg/day. Additional benefit does not appear to be gained with dosages higher than 20 mg/day.

For the treatment of obsessive-compulsive disorder (OCD). Oral dosage (immediate-release formulations; e.g., Paxil, Pexeva) Adults

20 mg PO once daily initially, usually in the morning. Increase by 10 mg/day at weekly intervals, if tolerated, to the usual target dose of 40 mg PO once daily. Max: 60 mg/day PO. DEBILITATED or GERIATRIC ADULTS: 10 mg PO once daily initially; may titrate by 10 mg at weekly intervals; Max: 40 mg/day PO. Periodically reassess the need for continued treatment.

Children and Adolescents 7 years and older†

10 mg PO once daily for 1 week initially; may titrate at intervals of at least 7 days if needed based upon response and tolerability. Max: 50 mg/day PO. Periodically reassess the need for continued treatment. This regimen was studied in a large randomized, placebo-controlled trial (n = 207); the mean dose in children was 30.1 mg/day and the mean dose in adolescents was 36.5 mg/day. The change in the primary efficacy measure (the Children's Yale-Brown Obsessive-Compulsive Scale) and 3 of 6 secondary efficacy measures were statistically significant in favor of paroxetine. Global assessments showed no change between the groups. Evaluation of the long-term safety and efficacy of paroxetine in the treatment of childhood OCD is needed.

For the treatment of panic disorder, with or without agoraphobia. Oral dosage (immediate-release formulations; e.g., Paxil, Pexeva) Adults

10 mg PO once daily initially, usually in the morning. Doses should be increased by 10 mg/day at weekly intervals as tolerated to the usual target dose of 40 mg/day. Usual Adult Max: 60 mg/day PO. DEBILITATED or GERIATRIC ADULTS Max: 40 mg/day PO. Anxiety disorders are chronic conditions; consider continuation of the drug in a responding patient. Use the lowest effective dosage. Periodically reassess the need for continued treatment.

Children and Adolescents 7 years and older†

Initially, 10 mg/day PO. 10 to 40 mg/day PO has been studied. To minimize the frequency and severity of adverse effects, slowly titrate at weekly intervals based on response and tolerability. Periodically reassess the need for continued treatment. Further study is needed to establish the safety and efficacy of SSRIs in the treatment of childhood panic disorder. Results from 1 naturalistic study (n = 18) used a mean initial dose of 8.9 mg/day PO followed by titration up to 40 mg/day PO depending on response and tolerability. Improvement began after a mean duration of 3 weeks treatment. The final mean dose was 24 mg/day (range: 10 to 40 mg/day). At study end, 83.3% of patients were considered responders, with 55.5% showing marked improvement on the CGI-Improvement scale score and 27.8% with moderate improvement.

Oral dosage (controlled-release tablets; e.g., Paxil CR) Adults

12.5 mg PO once daily initially, usually in the morning. May increase as needed in increments of 12.5 mg, at a minimum of weekly intervals. The effective dosage range for younger adults was 12.5 to 75 mg/day in clinical trials. Usual Adult Max: 75 mg/day PO. DEBILITATED or GERIATRIC ADULTS Max: 50 mg/day PO. Anxiety disorders are chronic conditions; consider continuation of the drug in a responding patient. Use the lowest effective dosage. Periodically reassess the need for continued treatment.

For the treatment of social phobia (social anxiety disorder). Oral dosage (immediate-release formulations; e.g., Paxil, Pexeva) Adults

20 mg/day PO is the initial and usual effective dose, usually given in the morning. May titrate by 10 mg/day at weekly intervals if needed and tolerated. Effective dose range: 20 to 60 mg/day; however, doses above 20 mg/day do not appear to provide additional benefit. Max: 60 mg/day PO. DEBILITATED or GERIATRIC ADULTS: 10 mg PO once daily initially, may titrate by 10 mg/day at weekly intervals if needed and tolerated. Usual target dose is 20 mg/day; Max: 40 mg/day PO. Periodically reassess the need for continued treatment.

Children and Adolescents 8 years and older†

10 mg/day PO initially, then may titrate by 10 mg/day at intervals of at least 7 days based on response and tolerability. Max: 50 mg/day PO. Periodically reassess the need for continued treatment. Further study is needed to evaluate the safety and efficacy of SSRIs in the treatment of childhood anxiety disorders. The suggested regimen was used in a multicenter, placebo-controlled clinical trial (n = 322), at the study end (16 weeks) the mean dose for children was 26.5 mg/day and for adolescents was 35 mg/day. Overall, responders on the primary efficacy measure (CGI-I score) were statistically significant in favor of paroxetine vs. placebo (77.6% vs. 38.3%). The remission rate for paroxetine was also greater vs. placebo (47.8% vs. 14.9%).

Oral dosage (controlled-release formulations; e.g., Paxil CR) Adults

12.5 mg PO once daily initially, usually given in the morning. If needed, titrate at intervals of at least 1 week, in increments of 12.5 mg/day. During clinical trials, effectiveness was demonstrated in a range of 12.5 to 37.5 mg PO once daily. Max: 37.5 mg/day PO. Periodically reassess the need for continued treatment.

For the treatment of posttraumatic stress disorder (PTSD). Oral dosage (immediate-release formulations; e.g., Paxil, Pexeva) Adults

20 mg PO once daily is the initial and usual effective dose, usually administered in the morning. May titrate by 10 mg/week if needed and tolerated. Effective dose range: 20 to 50 mg/day. Max: 50 mg/day PO. DEBILITATED or GERIATRIC ADULTS: 10 mg PO once daily initially, with titration by 10 mg/week if needed; Max: 40 mg/day PO. Paroxetine is effective in treating PTSD symptoms including re-experiencing/intrusion, avoidance/numbing, and hyperarousal. In one fixed-dose study, 40 mg/day PO did not show greater efficacy than 20 mg/day. Anxiety disorders are chronic conditions; consider continuation of the drug in a responding patient. Use the lowest effective dosage. Periodically reassess the need for continued treatment.

For the treatment of premenstrual dysphoric disorder (PMDD). Oral dosage (controlled-release tablets e.g., Paxil CR) Adult females

12.5 mg/day PO initially, either daily throughout the menstrual cycle or limited to the luteal phase of the menstrual cycle, depending on provider assessment. In clinical trials, doses of 12.5 to 25 mg/day were effective. Dose changes should occur at intervals of at least 1 week. Effectiveness has not been evaluated beyond 3 menstrual cycles; however, symptoms generally continue and sometimes worsen. Therefore, it is reasonable to continue treatment in a responding patient.

Oral dosage (immediate-release formulations†, e.g., Paxil, Pexeva) Adult females

Dosages have ranged from 5 to 30 mg/day PO, dependent on clinical response and tolerance. Continuous daily dosing or, alternatively, luteal phase administration during the 7 to 14 days prior to menses, has been effective.

For the treatment of moderate to severe vasomotor symptoms (VMS) (hot flashes) associated with menopause. Oral dosage (i.e., Brisdelle oral capsules or generic equivalents) Postmenopausal Adults

7.5 mg PO once daily at bedtime with or without food. Paroxetine is an effective choice for treating vasomotor symptoms of menopause when hormonal therapy is not desired or is contraindicated.

Oral dosage (controlled-release tablets†, e.g., Paxil CR) Postmenopausal Adults

12.5 mg PO once daily, initially. If 12.5 mg/day PO does not provide relief, may titrate to 25 mg PO once daily after 1 week if needed. Use lowest effective dose. Clinical trials indicate either dose is equally effective. Paroxetine is an effective choice for treating vasomotor symptoms of menopause when hormonal therapy is not desired or is contraindicated. In 165 menopausal women, after 6 weeks, the frequency of hot flashes was reduced by 62.2% in women taking 12.5 mg/day and 64.6% in women taking 25 mg/day versus 37.8% reductions for placebo.

For the treatment of premature ejaculation†. Oral dosage (immediate-release formulations e.g., Paxil, Pexeva) Adult males

10 to 40 mg/day PO has been shown to increase ejaculatory latency; however, the benefit of increasing the dose to 40 mg/day is not well established. Based on the available evidence, treatment guidelines support a daily dose of 20 mg/day. In one study of men with lifelong rapid ejaculation [i.e., an intravaginal ejaculation latency time (IELT) of 1 minute or less], men treated with paroxetine had an increase in IELT to about 110 seconds. In another study, paroxetine 20 mg/day PO increased mean IELT by 480% (from a mean of 83 seconds to a mean of 602 seconds). Alternatively, 20 mg PO given 3 to 4 hours pre-intercourse has demonstrated efficacy and is suggested per treatment guidelines. It is unclear if daily or situational dosing is more effective in the management of premature ejaculation. Likewise, the optimal interval for situational dosing before intercourse is not well defined. The choice of regimen is individualized to each patient.

†Indicates off-label use

Hepatic Impairment

Immediate-release dosage forms (i.e., Paxil, Pexeva): Initially, 10 mg/day PO in adults; final adult dosage should not exceed 40 mg/day PO. There are no guidelines available for pediatric patients.
 
Immediate-release 7.5 mg capsules (i.e., Brisdelle): No dose adjustment is considered necessary in patients with hepatic impairment.
 
Controlled-release tablets (Paxil CR): The initial dose is 12.5 mg/day PO in adults, with final adult dosage not to exceed 50 mg/day PO, regardless of indication. There are no guidelines available for pediatric patients.

Renal Impairment

Patients with renal impairment receiving immediate-release 7.5 mg capsules (i.e., Brisdelle): No dosage adjustment is considered necessary.
 
Patients with renal impairment receiving immediate-release dosage forms including Paxil or Pexeva:
CrCl 30—60 ml/min: Dosage should be modified depending on clinical response and degree of renal impairment, but no quantitative recommendations are available. Lower doses may be needed.
CrCl < 30 ml/min: Initially, 10 mg/day PO in adults; final adult dosage should not exceed 40 mg/day PO. There are no guidelines available for pediatric patients.
 
Patients with severe renal impairment receiving controlled-release dosage forms including Paxil CR:
The initial dose is 12.5 mg/day PO in adults, with final adult dosage not to exceed 50 mg/day PO, regardless of indication. There are no guidelines available for pediatric patients.
 
Intermittent hemodialysis
See dosage for patients with CrCl < 30 ml/min. Dosage adjustments are not necessary in patients receiving the Brisdelle brand. Paroxetine is unlikely to be significantly removed by hemodialysis given its large volume of distribution.

Abciximab: (Moderate) Platelet aggregation may be impaired by selective serotonin reuptake inhibitors (SSRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication in patients receiving abciximab. Monitor closely for signs and symptoms of bleeding.
Abiraterone: (Moderate) Monitor for an increase in paroxetine-related adverse reactions, including serotonin syndrome, if concomitant use with abiraterone is necessary. Concomitant use may increase paroxetine exposure. Paroxetine is a CYP2D6 substrate and abiraterone is a moderate CYP2D6 inhibitor.
Acetaminophen; Aspirin, ASA; Caffeine: (Moderate) The combined use of selective serotonin reuptake inhibitors and aspirin, ASA may elevate the risk for an upper GI bleed. SSRIs may inhibit serotonin uptake by platelets, augmenting the antiplatelet effects of aspirin. Additionally, aspirin impairs the gastric mucosa defenses by inhibiting prostaglandin formation.
Acetaminophen; Aspirin: (Moderate) The combined use of selective serotonin reuptake inhibitors and aspirin, ASA may elevate the risk for an upper GI bleed. SSRIs may inhibit serotonin uptake by platelets, augmenting the antiplatelet effects of aspirin. Additionally, aspirin impairs the gastric mucosa defenses by inhibiting prostaglandin formation.
Acetaminophen; Aspirin; Diphenhydramine: (Moderate) Monitor for an increase in paroxetine-related adverse reactions, including serotonin syndrome, if concomitant use with diphenhydramine is necessary. Concomitant use may increase paroxetine exposure and risk for additive anticholinergic adverse effects. Paroxetine is a CYP2D6 substrate and diphenhydramine is a moderate CYP2D6 inhibitor. (Moderate) The combined use of selective serotonin reuptake inhibitors and aspirin, ASA may elevate the risk for an upper GI bleed. SSRIs may inhibit serotonin uptake by platelets, augmenting the antiplatelet effects of aspirin. Additionally, aspirin impairs the gastric mucosa defenses by inhibiting prostaglandin formation.
Acetaminophen; Caffeine; Dihydrocodeine: (Moderate) Careful monitoring, particularly during treatment initiation and dose adjustment, is recommended during coadministration of dihydrocodeine and paroxetine because of the potential risk of serotonin syndrome, reduced dihydrocodeine efficacy, and potential for opioid withdrawal symptoms. Discontinue dihydrocodeine if serotonin syndrome is suspected. It is recommended to avoid this combination when dihydrocodeine is being used for cough. Concomitant use may increase dihydrocodeine plasma concentrations, but decrease the plasma concentration of the active metabolite, dihydromorphine, resulting in reduced efficacy or symptoms of opioid withdrawal. Monitor patients closely at frequent intervals and consider a dosage increase of dihydrocodeine until stable drug effects are achieved. Discontinuation of paroxetine could decrease dihydrocodeine plasma concentrations and increase dihydromorphine plasma concentrations resulting in prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If paroxetine is discontinued, monitor the patient carefully and consider reducing the opioid dosage if appropriate. Dihydrocodeine is primarily metabolized by CYP2D6 to dihydromorphine, and by CYP3A4. Paroxetine is a strong inhibitor of CYP2D6. 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.
Acetaminophen; Caffeine; Pyrilamine: (Moderate) Of the selective serotonin reuptake inhibiting antidepressants (SSRIs), paroxetine is considered the most anticholinergic. Additive anticholinergic effects may be seen when paroxetine is used with antihistamines having anticholinergic properties such as pyrilamine. Patients should be informed to read non-prescription cough and cold product labels carefully for additional interacting antihistamines.
Acetaminophen; Chlorpheniramine: (Moderate) Of the selective serotonin reuptake inhibiting antidepressants (SSRIs), paroxetine is considered the most anticholinergic. Additive anticholinergic effects may be seen when paroxetine is used with antihistamines having anticholinergic properties such as chlorpheniramine. Patients should be informed to read non-prescription cough and cold product labels carefully for additional interacting antihistamines.
Acetaminophen; Chlorpheniramine; Dextromethorphan: (Moderate) Monitor for dextromethorphan-related side effects, such as dizziness or drowsiness, if concomitant use of paroxetine is necessary. For patients receiving combination dextromethorphan; bupropion, do not exceed a maximum dose of 45 mg dextromethorphan; 105 mg bupropion once daily. Additionally, monitor patients for signs and symptoms of serotonin syndrome. Concomitant use may increase dextromethorphan exposure and the risk for serotonin syndrome. Dextromethorphan is a CYP2D6 substrate and paroxetine is a strong CYP2D6 inhibitor. Concomitant use with paroxetine increased dextromethorphan overall exposure by 2.69-fold. (Moderate) Of the selective serotonin reuptake inhibiting antidepressants (SSRIs), paroxetine is considered the most anticholinergic. Additive anticholinergic effects may be seen when paroxetine is used with antihistamines having anticholinergic properties such as chlorpheniramine. Patients should be informed to read non-prescription cough and cold product labels carefully for additional interacting antihistamines.
Acetaminophen; Chlorpheniramine; Dextromethorphan; Phenylephrine: (Moderate) Monitor for dextromethorphan-related side effects, such as dizziness or drowsiness, if concomitant use of paroxetine is necessary. For patients receiving combination dextromethorphan; bupropion, do not exceed a maximum dose of 45 mg dextromethorphan; 105 mg bupropion once daily. Additionally, monitor patients for signs and symptoms of serotonin syndrome. Concomitant use may increase dextromethorphan exposure and the risk for serotonin syndrome. Dextromethorphan is a CYP2D6 substrate and paroxetine is a strong CYP2D6 inhibitor. Concomitant use with paroxetine increased dextromethorphan overall exposure by 2.69-fold. (Moderate) Of the selective serotonin reuptake inhibiting antidepressants (SSRIs), paroxetine is considered the most anticholinergic. Additive anticholinergic effects may be seen when paroxetine is used with antihistamines having anticholinergic properties such as chlorpheniramine. Patients should be informed to read non-prescription cough and cold product labels carefully for additional interacting antihistamines.
Acetaminophen; Chlorpheniramine; Dextromethorphan; Pseudoephedrine: (Moderate) Monitor for dextromethorphan-related side effects, such as dizziness or drowsiness, if concomitant use of paroxetine is necessary. For patients receiving combination dextromethorphan; bupropion, do not exceed a maximum dose of 45 mg dextromethorphan; 105 mg bupropion once daily. Additionally, monitor patients for signs and symptoms of serotonin syndrome. Concomitant use may increase dextromethorphan exposure and the risk for serotonin syndrome. Dextromethorphan is a CYP2D6 substrate and paroxetine is a strong CYP2D6 inhibitor. Concomitant use with paroxetine increased dextromethorphan overall exposure by 2.69-fold. (Moderate) Of the selective serotonin reuptake inhibiting antidepressants (SSRIs), paroxetine is considered the most anticholinergic. Additive anticholinergic effects may be seen when paroxetine is used with antihistamines having anticholinergic properties such as chlorpheniramine. Patients should be informed to read non-prescription cough and cold product labels carefully for additional interacting antihistamines.
Acetaminophen; Chlorpheniramine; Phenylephrine : (Moderate) Of the selective serotonin reuptake inhibiting antidepressants (SSRIs), paroxetine is considered the most anticholinergic. Additive anticholinergic effects may be seen when paroxetine is used with antihistamines having anticholinergic properties such as chlorpheniramine. Patients should be informed to read non-prescription cough and cold product labels carefully for additional interacting antihistamines.
Acetaminophen; Codeine: (Moderate) Careful monitoring, particularly during treatment initiation and dose adjustment, is recommended during coadministration of codeine and paroxetine because of the potential risk of serotonin syndrome, reduced codeine efficacy, and potential for opioid withdrawal symptoms. Discontinue codeine if serotonin syndrome is suspected. It is recommended to avoid this combination when codeine is being used for cough. Concomitant use may increase codeine plasma concentrations, but decrease the plasma concentration of the active metabolite, morphine, resulting in reduced efficacy or symptoms of opioid withdrawal. Monitor patients closely at frequent intervals and consider a dosage increase of codeine until stable drug effects are achieved. Discontinuation of paroxetine could decrease codeine plasma concentrations and increase morphine plasma concentrations resulting in prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If paroxetine is discontinued, monitor the patient carefully and consider reducing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Paroxetine is a strong inhibitor of CYP2D6. 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.
Acetaminophen; Dextromethorphan: (Moderate) Monitor for dextromethorphan-related side effects, such as dizziness or drowsiness, if concomitant use of paroxetine is necessary. For patients receiving combination dextromethorphan; bupropion, do not exceed a maximum dose of 45 mg dextromethorphan; 105 mg bupropion once daily. Additionally, monitor patients for signs and symptoms of serotonin syndrome. Concomitant use may increase dextromethorphan exposure and the risk for serotonin syndrome. Dextromethorphan is a CYP2D6 substrate and paroxetine is a strong CYP2D6 inhibitor. Concomitant use with paroxetine increased dextromethorphan overall exposure by 2.69-fold.
Acetaminophen; Dextromethorphan; Doxylamine: (Moderate) Monitor for dextromethorphan-related side effects, such as dizziness or drowsiness, if concomitant use of paroxetine is necessary. For patients receiving combination dextromethorphan; bupropion, do not exceed a maximum dose of 45 mg dextromethorphan; 105 mg bupropion once daily. Additionally, monitor patients for signs and symptoms of serotonin syndrome. Concomitant use may increase dextromethorphan exposure and the risk for serotonin syndrome. Dextromethorphan is a CYP2D6 substrate and paroxetine is a strong CYP2D6 inhibitor. Concomitant use with paroxetine increased dextromethorphan overall exposure by 2.69-fold.
Acetaminophen; Dextromethorphan; Guaifenesin; Phenylephrine: (Moderate) Monitor for dextromethorphan-related side effects, such as dizziness or drowsiness, if concomitant use of paroxetine is necessary. For patients receiving combination dextromethorphan; bupropion, do not exceed a maximum dose of 45 mg dextromethorphan; 105 mg bupropion once daily. Additionally, monitor patients for signs and symptoms of serotonin syndrome. Concomitant use may increase dextromethorphan exposure and the risk for serotonin syndrome. Dextromethorphan is a CYP2D6 substrate and paroxetine is a strong CYP2D6 inhibitor. Concomitant use with paroxetine increased dextromethorphan overall exposure by 2.69-fold.
Acetaminophen; Dextromethorphan; Guaifenesin; Pseudoephedrine: (Moderate) Monitor for dextromethorphan-related side effects, such as dizziness or drowsiness, if concomitant use of paroxetine is necessary. For patients receiving combination dextromethorphan; bupropion, do not exceed a maximum dose of 45 mg dextromethorphan; 105 mg bupropion once daily. Additionally, monitor patients for signs and symptoms of serotonin syndrome. Concomitant use may increase dextromethorphan exposure and the risk for serotonin syndrome. Dextromethorphan is a CYP2D6 substrate and paroxetine is a strong CYP2D6 inhibitor. Concomitant use with paroxetine increased dextromethorphan overall exposure by 2.69-fold.
Acetaminophen; Dextromethorphan; Phenylephrine: (Moderate) Monitor for dextromethorphan-related side effects, such as dizziness or drowsiness, if concomitant use of paroxetine is necessary. For patients receiving combination dextromethorphan; bupropion, do not exceed a maximum dose of 45 mg dextromethorphan; 105 mg bupropion once daily. Additionally, monitor patients for signs and symptoms of serotonin syndrome. Concomitant use may increase dextromethorphan exposure and the risk for serotonin syndrome. Dextromethorphan is a CYP2D6 substrate and paroxetine is a strong CYP2D6 inhibitor. Concomitant use with paroxetine increased dextromethorphan overall exposure by 2.69-fold.
Acetaminophen; Dextromethorphan; Pseudoephedrine: (Moderate) Monitor for dextromethorphan-related side effects, such as dizziness or drowsiness, if concomitant use of paroxetine is necessary. For patients receiving combination dextromethorphan; bupropion, do not exceed a maximum dose of 45 mg dextromethorphan; 105 mg bupropion once daily. Additionally, monitor patients for signs and symptoms of serotonin syndrome. Concomitant use may increase dextromethorphan exposure and the risk for serotonin syndrome. Dextromethorphan is a CYP2D6 substrate and paroxetine is a strong CYP2D6 inhibitor. Concomitant use with paroxetine increased dextromethorphan overall exposure by 2.69-fold.
Acetaminophen; Diphenhydramine: (Moderate) Monitor for an increase in paroxetine-related adverse reactions, including serotonin syndrome, if concomitant use with diphenhydramine is necessary. Concomitant use may increase paroxetine exposure and risk for additive anticholinergic adverse effects. Paroxetine is a CYP2D6 substrate and diphenhydramine is a moderate CYP2D6 inhibitor.
Acetaminophen; Hydrocodone: (Moderate) Careful monitoring, particularly during treatment initiation and dose adjustment, is recommended during coadministration of hydrocodone and paroxetine because of the potential risk of serotonin syndrome and prolonged opioid adverse reactions. Discontinue hydrocodone if serotonin syndrome is suspected. It is recommended to avoid this combination when hydrocodone is being used for cough. Concomitant use of hydrocodone with paroxetine may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. Monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of paroxetine could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If paroxetine is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP2D6. Paroxetine is a strong inhibitor of CYP2D6. 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.
Acetaminophen; Oxycodone: (Moderate) If concomitant use of oxycodone and paroxetine is warranted, monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
Acetaminophen; Pamabrom; Pyrilamine: (Moderate) Of the selective serotonin reuptake inhibiting antidepressants (SSRIs), paroxetine is considered the most anticholinergic. Additive anticholinergic effects may be seen when paroxetine is used with antihistamines having anticholinergic properties such as pyrilamine. Patients should be informed to read non-prescription cough and cold product labels carefully for additional interacting antihistamines.
Adagrasib: (Moderate) Monitor for an increase in paroxetine-related adverse reactions, including serotonin syndrome, if concomitant use with adagrasib is necessary. Concomitant use may increase paroxetine exposure. Paroxetine is a CYP2D6 substrate and adagrasib is a moderate CYP2D6 inhibitor.
Alfentanil: (Moderate) If concomitant use of alfentanil and paroxetine is warranted, monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
Almotriptan: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering almotriptan with paroxetine. Serotonin syndrome has been reported during concurrent use of serotonin-receptor agonists and selective serotonin reuptake inhibitors (SSRIs). Some patients had used the combination previously without incident when serotonin syndrome occurred. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly after a dose increase of the SSRI or the addition of other serotonergic medications to an existing SSRI regimen. Discontinue paroxetine and almotriptan and initiate symptomatic treatment if serotonin syndrome occurs.
Alprazolam: (Minor) The manufacturer of alprazolam states that in vitro studies suggest paroxetine may inhibit the metabolism of alprazolam via inhibition of CYP3A4. However, paroxetine is typically considered a major inhibitor of CYP2D6, for which alprazolam is not a substrate. The potential for clinical interaction is uncertain. Be alert for any change in psychomotor performance or other benzodiazepine-related side effects when paroxetine is combined with alprazolam.
Alteplase: (Moderate) Platelet aggregation may be impaired by selective serotonin reuptake inhibitors (SSRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication in patients receiving thrombolytic agents. Patients should be closely monitored for signs and symptoms of bleeding when a thrombolytic agent is administered with an SSRI.
Amiodarone: (Moderate) Monitor for an increase in paroxetine-related adverse reactions, including serotonin syndrome, if concomitant use with amiodarone is necessary. Concomitant use may increase paroxetine exposure. Paroxetine is a CYP2D6 substrate and amiodarone is a moderate CYP2D6 inhibitor.
Amitriptyline: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering selective serotonin reuptake inhibitors (SSRIs) with other drugs that have serotonergic properties such as tricyclic antidepressants. Additionally, monitor for an increase in amitriptyline-related adverse reactions if coadministration with paroxetine is necessary; a dose reduction of amitriptyline may be necessary. Concurrent use may increase the plasma concentrations of amitriptyline. Amitriptyline is a CYP2D6 substrate and paroxetine is a CYP2D6 inhibitor. Paroxetine and amitriptyline both exhibit significant anticholinergic effects that may be additive during concurrent use.
Amoxapine: (Moderate) Paroxetine, a potent CYP2D6 inhibitor, may increase the plasma concentrations of the tetracyclic antidepressant amoxapine, which is partially metabolized by CYP2D6. In several cases, symptoms of toxicity, including seizures, have been reported when tricyclic antidepressants were coadministered with a selective serotonin reuptake inhibitor (SSRI). At least one case report exists of a death thought to be due to impaired clearance of the tricyclic antidepressant amitriptyline by fluoxetine. Additive anticholinergic effects are possible. This combination may represent duplicative therapy. Patients receiving amoxapine should be monitored closely for toxicity if paroxetine is added.
Amphetamines: (Moderate) Monitor for signs and symptoms of serotonin syndrome, particularly during treatment initiation and dosage increase, during concomitant amphetamine and paroxetine use. If serotonin syndrome occurs, discontinue therapy. Concomitant use increases the risk for serotonin syndrome.
Anagrelide: (Moderate) Platelet aggregation may be impaired by selective serotonin reuptake inhibitors (SSRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving platelet inhibitors (e.g., cilostazol, clopidogrel, dipyridamole, ticlopidine, platelet glycoprotein IIb/IIIa inhibitors). Patients should be instructed to monitor for signs and symptoms of bleeding while taking an SSRI concurrently with an antiplatelet medication and to promptly report any bleeding events to the practitioner.
Anticholinergics: (Moderate) Monitor for signs or symptoms of anticholinergic toxicity during concomitant anticholinergic medication and paroxetine use. Concomitant use may result in additive anticholinergic adverse effects.
Antithrombin III: (Moderate) Advise patients of the increased bleeding risk associated with the concomitant use of selective serotonin reuptake inhibitors (SSRIs) and anticoagulants like antithrombin III. Case reports and epidemiological studies have demonstrated an association between use of drugs that interfere with serotonin reuptake and gastrointestinal bleeding.
Apixaban: (Moderate) Advise patients of the increased bleeding risk associated with the concomitant use of selective serotonin reuptake inhibitors (SSRIs) and anticoagulants like apixaban. Case reports and epidemiological studies have demonstrated an association between use of drugs that interfere with serotonin reuptake and gastrointestinal bleeding.
Aripiprazole: (Major) Recommendations for managing aripiprazole and paroxetine vary by aripiprazole dosage form. For aripiprazole oral dosage forms, administer half of the usual dose. For monthly extended-release aripiprazole injections (Abilify Maintena), reduce the dosage from 400 mg to 300 mg/month or from 300 mg to 200 mg/month. For extended-release aripiprazole injections given once every 2 months (Abilify Asimtufii), reduce the dosage from 960 mg to 720 mg. Further dosage reductions may be required in patients who are also receiving a CYP3A inhibitor; see individual product prescribing information for details. Concomitant use may increase aripiprazole exposure and risk for side effects. Aripiprazole is CYP2D6 and CYP3A substrate; paroxetine is a strong CYP2D6 inhibitor. (Major) Recommendations for managing aripiprazole and paroxetine vary by aripiprazole dosage form. For extended-release aripiprazole lauroxil injections (Aristada), reduce the dose to the next lowest strength; no dosage adjustment is required for patients tolerating 441 mg or for patients known to be poor metabolizers of CYP2D6. For fixed dose extended-release aripiprazole lauroxil injections (Aristada Initio), avoid concomitant use because the dose cannot be modified. Further dosage reductions may be required in patients who are also receiving a CYP3A inhibitor; see individual product prescribing information for details. Concomitant use may increase aripiprazole exposure and risk for side effects. Aripiprazole is CYP2D6 and CYP3A substrate; paroxetine is a strong CYP2D6 inhibitor.
Artemether; Lumefantrine: (Moderate) Monitor for an increase in paroxetine-related adverse reactions, including serotonin syndrome, if concomitant use with lumefantrine is necessary. Concomitant use may increase paroxetine exposure. Paroxetine is a CYP2D6 substrate and lumefantrine is a moderate CYP2D6 inhibitor.
Asenapine: (Moderate) Monitor for an increase in paroxetine-related adverse reactions, including serotonin syndrome, if concomitant use with asenapine is necessary. Concomitant use may increase paroxetine exposure. Paroxetine is a CYP2D6 substrate and asenapine is a weak CYP2D6 inhibitor.
Aspirin, ASA: (Moderate) The combined use of selective serotonin reuptake inhibitors and aspirin, ASA may elevate the risk for an upper GI bleed. SSRIs may inhibit serotonin uptake by platelets, augmenting the antiplatelet effects of aspirin. Additionally, aspirin impairs the gastric mucosa defenses by inhibiting prostaglandin formation.
Aspirin, ASA; Butalbital; Caffeine: (Moderate) The combined use of selective serotonin reuptake inhibitors and aspirin, ASA may elevate the risk for an upper GI bleed. SSRIs may inhibit serotonin uptake by platelets, augmenting the antiplatelet effects of aspirin. Additionally, aspirin impairs the gastric mucosa defenses by inhibiting prostaglandin formation.
Aspirin, ASA; Caffeine: (Moderate) The combined use of selective serotonin reuptake inhibitors and aspirin, ASA may elevate the risk for an upper GI bleed. SSRIs may inhibit serotonin uptake by platelets, augmenting the antiplatelet effects of aspirin. Additionally, aspirin impairs the gastric mucosa defenses by inhibiting prostaglandin formation.
Aspirin, ASA; Caffeine; Orphenadrine: (Moderate) Additive anticholinergic effects may be seen when drugs with anticholinergic properties, like paroxetine and orphenadrine, are used concomitantly. Adverse effects may be seen not only on GI smooth muscle, but also on bladder function, the CNS, the eye, and temperature regulation. (Moderate) The combined use of selective serotonin reuptake inhibitors and aspirin, ASA may elevate the risk for an upper GI bleed. SSRIs may inhibit serotonin uptake by platelets, augmenting the antiplatelet effects of aspirin. Additionally, aspirin impairs the gastric mucosa defenses by inhibiting prostaglandin formation.
Aspirin, ASA; Carisoprodol: (Moderate) The combined use of selective serotonin reuptake inhibitors and aspirin, ASA may elevate the risk for an upper GI bleed. SSRIs may inhibit serotonin uptake by platelets, augmenting the antiplatelet effects of aspirin. Additionally, aspirin impairs the gastric mucosa defenses by inhibiting prostaglandin formation.
Aspirin, ASA; Carisoprodol; Codeine: (Moderate) Careful monitoring, particularly during treatment initiation and dose adjustment, is recommended during coadministration of codeine and paroxetine because of the potential risk of serotonin syndrome, reduced codeine efficacy, and potential for opioid withdrawal symptoms. Discontinue codeine if serotonin syndrome is suspected. It is recommended to avoid this combination when codeine is being used for cough. Concomitant use may increase codeine plasma concentrations, but decrease the plasma concentration of the active metabolite, morphine, resulting in reduced efficacy or symptoms of opioid withdrawal. Monitor patients closely at frequent intervals and consider a dosage increase of codeine until stable drug effects are achieved. Discontinuation of paroxetine could decrease codeine plasma concentrations and increase morphine plasma concentrations resulting in prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If paroxetine is discontinued, monitor the patient carefully and consider reducing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Paroxetine is a strong inhibitor of CYP2D6. 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. (Moderate) The combined use of selective serotonin reuptake inhibitors and aspirin, ASA may elevate the risk for an upper GI bleed. SSRIs may inhibit serotonin uptake by platelets, augmenting the antiplatelet effects of aspirin. Additionally, aspirin impairs the gastric mucosa defenses by inhibiting prostaglandin formation.
Aspirin, ASA; Citric Acid; Sodium Bicarbonate: (Moderate) The combined use of selective serotonin reuptake inhibitors and aspirin, ASA may elevate the risk for an upper GI bleed. SSRIs may inhibit serotonin uptake by platelets, augmenting the antiplatelet effects of aspirin. Additionally, aspirin impairs the gastric mucosa defenses by inhibiting prostaglandin formation.
Aspirin, ASA; Dipyridamole: (Moderate) Platelet aggregation may be impaired by SSRIs due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication in patients receiving platelet inhibitors. Monitor for signs and symptoms of bleeding. (Moderate) The combined use of selective serotonin reuptake inhibitors and aspirin, ASA may elevate the risk for an upper GI bleed. SSRIs may inhibit serotonin uptake by platelets, augmenting the antiplatelet effects of aspirin. Additionally, aspirin impairs the gastric mucosa defenses by inhibiting prostaglandin formation.
Aspirin, ASA; Omeprazole: (Moderate) The combined use of selective serotonin reuptake inhibitors and aspirin, ASA may elevate the risk for an upper GI bleed. SSRIs may inhibit serotonin uptake by platelets, augmenting the antiplatelet effects of aspirin. Additionally, aspirin impairs the gastric mucosa defenses by inhibiting prostaglandin formation.
Aspirin, ASA; Oxycodone: (Moderate) If concomitant use of oxycodone and paroxetine is warranted, monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. (Moderate) The combined use of selective serotonin reuptake inhibitors and aspirin, ASA may elevate the risk for an upper GI bleed. SSRIs may inhibit serotonin uptake by platelets, augmenting the antiplatelet effects of aspirin. Additionally, aspirin impairs the gastric mucosa defenses by inhibiting prostaglandin formation.
Atazanavir; Cobicistat: (Moderate) Close monitoring for antidepressant response and careful dose titrations of the antidepressant therapy is recommended during coadministration of selective serotonin reuptake inhibitors (SSRIs) and cobicistat. Concurrent use may result in elevated SSRI plasma concentrations. Predictions regarding this interaction can be made based on the metabolic pathways of these drugs. All SSRIs are substrates for the hepatic isoenzyme CYP2D6, while citalopram, escitalopram, and sertraline are also substrates for CYP3A4; cobicistat is an inhibitor of both CYP2D6 and CYP3A4.
Atomoxetine: (Major) Dosage reduction of atomoxetine is recommended in patients receiving paroxetine due to the potential for increased atomoxetine exposure and related adverse effects. In children and adolescents up to 70 kg receiving paroxetine, atomoxetine should be initiated at 0.5 mg/kg/day and only increased to the usual target dose of 1.2 mg/kg/day if symptoms fail to improve after 4 weeks and the initial dose is well-tolerated. In children and adolescents over 70 kg and adults receiving paroxetine, atomoxetine should be initiated at 40 mg/day and only increased to the usual target dose of 80 mg/day if symptoms fail to improve after 4 weeks and the initial dose is well-tolerated. Paroxetine is a strong CYP2D6 inhibitor; atomoxetine is a CYP2D6 substrate. Coadministration of a strong CYP2D6 inhibitor and atomoxetine in extensive metabolizers of CYP2D6 increased atomoxetine steady-state plasma concentrations by approximately 6 to 8-fold. This increase is similar to exposures observed in poor metabolizers. Concurrent use of a strong CYP2D6 inhibitor with atomoxetine in poor metabolizers is not expected to increase atomoxetine exposure.
Atropine: (Moderate) Monitor for signs or symptoms of anticholinergic toxicity during concomitant anticholinergic medication and paroxetine use. Concomitant use may result in additive anticholinergic adverse effects.
Atropine; Difenoxin: (Moderate) Monitor for signs or symptoms of anticholinergic toxicity during concomitant anticholinergic medication and paroxetine use. Concomitant use may result in additive anticholinergic adverse effects.
Barbiturates: (Moderate) Barbiturates may induce various hepatic CYP450 isoenzymes, including those responsible for the metabolism of paroxetine. Clinicians should be aware of the potential for reduced SSRI efficacy with concurrent administration of a barbiturate, especially in chronic use.
Belladonna; Opium: (Moderate) Monitor for signs or symptoms of anticholinergic toxicity during concomitant anticholinergic medication and paroxetine use. Concomitant use may result in additive anticholinergic adverse effects.
Benzhydrocodone; Acetaminophen: (Moderate) Careful monitoring, particularly during treatment initiation and dose adjustment, is recommended during coadministration of benzhydrocodone and paroxetine because of the potential risk of serotonin syndrome. Discontinue benzhydrocodone if serotonin syndrome is suspected. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome.
Benzoic Acid; Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate: (Contraindicated) According to the manufacturer of paroxetine, treatment initiation with paroxetine is contraindicated in patients currently receiving intravenous (IV) methylene blue due to an increased risk of serotonin syndrome. If urgent psychiatric treatment is required, interventions other than paroxetine (e.g., alternative medication, hospitalization) should be considered. Conversely, in patients receiving paroxetine and requiring urgent treatment with IV methylene blue, paroxetine should be discontinued immediately and methylene blue therapy initiated only if acceptable alternatives are not available and the potential benefits outweigh the risks. The patient should be monitored for serotonin syndrome for 2 weeks or until 24 hours after the last dose of methylene blue, whichever comes first. Paroxetine may be re-initiated 24 hours after the last dose of methylene blue. Results from an in vitro study indicate that methylene blue is a potent, reversible inhibitor of the monoamine oxidase type A enzyme (MAO-A). MAO-A is responsible for the metabolism of serotonin; therefore, concurrent use of an MAO-A inhibitor with a serotonergic agent may result in a clinically significant interaction. Cases of serotonin syndrome have been reported, primarily following administration of standard infusions of methylene blue (1 to 8 mg/kg) as a visualizing agent, in patients receiving SSRIs, serotonin/norepinephrine reuptake inhibitors, or clomipramine. It is not known if patients receiving other serotonergic psychiatric agents with IV methylene blue are at a comparable risk or if methylene blue administered by other routes (e.g., orally, local injection) or in doses less than 1 mg/kg IV can produce a similar outcome. One case describes a patient receiving citalopram who experienced agitation, restlessness, pupil dilation with sluggish response to light, myoclonic movements of the lower limbs, and brisk reflexes following an infusion of methylene blue, while another patient receiving paroxetine developed tachycardia, agitation, dystonia and abnormal eye movements. During a retrospective study of 193 surgical patients who had received a methylene blue injection, it was found that all 12 of the patients who experienced postoperative neurological sequelae had been taking a serotonin reuptake inhibitor preoperatively. One of the 12 patients experienced cardiopulmonary arrest and died. Of the remaining 181 patients who did not experience neurological sequelae, 8.8% were taking a serotonin reuptake inhibitor. Published interaction reports between IV methylene blue and serotonergic psychiatric agents have documented symptoms including lethargy, confusion, delirium, agitation, aggression, obtundation, myoclonus, expressive aphasia, hypertonia, pyrexia, elevated blood pressure, seizures, and coma. Signs and symptoms of serotonin syndrome include fever, diaphoresis, shivering, myoclonus, tremor, tachycardia, diarrhea, nausea, headache, incoordination, mental status changes (e.g., agitation, confusion), hyperreflexia, seizures, and coma. (Moderate) Monitor for signs or symptoms of anticholinergic toxicity during concomitant anticholinergic medication and paroxetine use. Concomitant use may result in additive anticholinergic adverse effects. (Moderate) The combined use of selective serotonin reuptake inhibitors (SSRIs) and aspirin, ASA or other salicylates which affect hemostasis may elevate the risk for an upper GI bleed. SSRIs may inhibit serotonin uptake by platelets, augmenting the antiplatelet effects of aspirin.
Benztropine: (Moderate) Monitor for signs or symptoms of anticholinergic toxicity during concomitant anticholinergic medication and paroxetine use. Concomitant use may result in additive anticholinergic adverse effects.
Berotralstat: (Moderate) Monitor for an increase in paroxetine-related adverse reactions, including serotonin syndrome, if concomitant use with berotralstat is necessary. Concomitant use may increase paroxetine exposure. Paroxetine is a CYP2D6 substrate and berotralstat is a moderate CYP2D6 inhibitor.
Betrixaban: (Moderate) Advise patients of the increased bleeding risk associated with the concomitant use of selective serotonin reuptake inhibitors (SSRIs) and anticoagulants like betrixaban. Case reports and epidemiological studies have demonstrated an association between use of drugs that interfere with serotonin reuptake and gastrointestinal bleeding.
Bismuth Subsalicylate: (Moderate) The combined use of selective serotonin reuptake inhibitors (SSRIs) and aspirin, ASA or other salicylates which affect hemostasis may elevate the risk for an upper GI bleed. SSRIs may inhibit serotonin uptake by platelets, augmenting the antiplatelet effects of aspirin.
Bismuth Subsalicylate; Metronidazole; Tetracycline: (Moderate) The combined use of selective serotonin reuptake inhibitors (SSRIs) and aspirin, ASA or other salicylates which affect hemostasis may elevate the risk for an upper GI bleed. SSRIs may inhibit serotonin uptake by platelets, augmenting the antiplatelet effects of aspirin.
Brexpiprazole: (Major) Because brexpiprazole is primarily metabolized by CYP3A4 and CYP2D6, the manufacturer recommends that the brexpiprazole dose be reduced to one-half of the usual dose in patients receiving a strong CYP2D6 inhibitor and one-quarter (25%) of the usual dose in patients receiving a moderate to strong inhibitor of CYP3A4 in combination with a moderate to strong inhibitor of CYP2D6. Paroxetine is a strong inhibitor of CYP2D6. If these agents are used in combination, the patient should be carefully monitored for brexpiprazole-related adverse reactions. It should be noted that no dosage adjustment is needed in patients taking a strong CYP2D6 inhibitor who are receiving brexpiprazole as adjunct treatment for major depressive disorder because CYP2D6 considerations are already factored into general dosing recommendations.
Brimonidine; Timolol: (Moderate) Monitor for signs of bradycardia or heart block if coadministration of timolol with paroxetine is necessary. Concomitant use may enhance the beta-blocking properties of timolol resulting in further slowing of the heart rate or cardiac conduction. Timolol is a CYP2D6 substrate and paroxetine is a strong CYP2D6 inhibitor.
Brompheniramine: (Moderate) Of the selective serotonin reuptake inhibiting antidepressants (SSRIs), paroxetine is considered the most anticholinergic. Additive anticholinergic effects may be seen when paroxetine is used with antihistamines having anticholinergic properties such as brompheniramine. Patients should be informed to read non-prescription cough and cold product labels carefully for additional interacting antihistamines.
Brompheniramine; Dextromethorphan; Phenylephrine: (Moderate) Monitor for dextromethorphan-related side effects, such as dizziness or drowsiness, if concomitant use of paroxetine is necessary. For patients receiving combination dextromethorphan; bupropion, do not exceed a maximum dose of 45 mg dextromethorphan; 105 mg bupropion once daily. Additionally, monitor patients for signs and symptoms of serotonin syndrome. Concomitant use may increase dextromethorphan exposure and the risk for serotonin syndrome. Dextromethorphan is a CYP2D6 substrate and paroxetine is a strong CYP2D6 inhibitor. Concomitant use with paroxetine increased dextromethorphan overall exposure by 2.69-fold. (Moderate) Of the selective serotonin reuptake inhibiting antidepressants (SSRIs), paroxetine is considered the most anticholinergic. Additive anticholinergic effects may be seen when paroxetine is used with antihistamines having anticholinergic properties such as brompheniramine. Patients should be informed to read non-prescription cough and cold product labels carefully for additional interacting antihistamines.
Brompheniramine; Phenylephrine: (Moderate) Of the selective serotonin reuptake inhibiting antidepressants (SSRIs), paroxetine is considered the most anticholinergic. Additive anticholinergic effects may be seen when paroxetine is used with antihistamines having anticholinergic properties such as brompheniramine. Patients should be informed to read non-prescription cough and cold product labels carefully for additional interacting antihistamines.
Brompheniramine; Pseudoephedrine: (Moderate) Of the selective serotonin reuptake inhibiting antidepressants (SSRIs), paroxetine is considered the most anticholinergic. Additive anticholinergic effects may be seen when paroxetine is used with antihistamines having anticholinergic properties such as brompheniramine. Patients should be informed to read non-prescription cough and cold product labels carefully for additional interacting antihistamines.
Brompheniramine; Pseudoephedrine; Dextromethorphan: (Moderate) Monitor for dextromethorphan-related side effects, such as dizziness or drowsiness, if concomitant use of paroxetine is necessary. For patients receiving combination dextromethorphan; bupropion, do not exceed a maximum dose of 45 mg dextromethorphan; 105 mg bupropion once daily. Additionally, monitor patients for signs and symptoms of serotonin syndrome. Concomitant use may increase dextromethorphan exposure and the risk for serotonin syndrome. Dextromethorphan is a CYP2D6 substrate and paroxetine is a strong CYP2D6 inhibitor. Concomitant use with paroxetine increased dextromethorphan overall exposure by 2.69-fold. (Moderate) Of the selective serotonin reuptake inhibiting antidepressants (SSRIs), paroxetine is considered the most anticholinergic. Additive anticholinergic effects may be seen when paroxetine is used with antihistamines having anticholinergic properties such as brompheniramine. Patients should be informed to read non-prescription cough and cold product labels carefully for additional interacting antihistamines.
Budesonide; Glycopyrrolate; Formoterol: (Moderate) Monitor for signs or symptoms of anticholinergic toxicity during concomitant anticholinergic medication and paroxetine use. Concomitant use may result in additive anticholinergic adverse effects.
Buprenorphine: (Moderate) If concomitant use of buprenorphine and paroxetine is warranted, monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
Buprenorphine; Naloxone: (Moderate) If concomitant use of buprenorphine and paroxetine is warranted, monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
Bupropion: (Moderate) Monitor for an increase in paroxetine-related adverse reactions, including serotonin syndrome, if concomitant use with bupropion is necessary. Concomitant use may increase paroxetine exposure. Paroxetine is a CYP2D6 substrate and bupropion is a strong CYP2D6 inhibitor.
Bupropion; Naltrexone: (Moderate) Monitor for an increase in paroxetine-related adverse reactions, including serotonin syndrome, if concomitant use with bupropion is necessary. Concomitant use may increase paroxetine exposure. Paroxetine is a CYP2D6 substrate and bupropion is a strong CYP2D6 inhibitor.
Buspirone: (Moderate) Coadministration of buspirone and paroxetine may increase the risk of serotonin syndrome. Serotonin syndrome has been reported with both drugs when taken alone, but especially when coadministered with other serotonergic agents. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome. Discontinue serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
Butalbital; Acetaminophen; Caffeine; Codeine: (Moderate) Careful monitoring, particularly during treatment initiation and dose adjustment, is recommended during coadministration of codeine and paroxetine because of the potential risk of serotonin syndrome, reduced codeine efficacy, and potential for opioid withdrawal symptoms. Discontinue codeine if serotonin syndrome is suspected. It is recommended to avoid this combination when codeine is being used for cough. Concomitant use may increase codeine plasma concentrations, but decrease the plasma concentration of the active metabolite, morphine, resulting in reduced efficacy or symptoms of opioid withdrawal. Monitor patients closely at frequent intervals and consider a dosage increase of codeine until stable drug effects are achieved. Discontinuation of paroxetine could decrease codeine plasma concentrations and increase morphine plasma concentrations resulting in prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If paroxetine is discontinued, monitor the patient carefully and consider reducing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Paroxetine is a strong inhibitor of CYP2D6. 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.
Butalbital; Aspirin; Caffeine; Codeine: (Moderate) Careful monitoring, particularly during treatment initiation and dose adjustment, is recommended during coadministration of codeine and paroxetine because of the potential risk of serotonin syndrome, reduced codeine efficacy, and potential for opioid withdrawal symptoms. Discontinue codeine if serotonin syndrome is suspected. It is recommended to avoid this combination when codeine is being used for cough. Concomitant use may increase codeine plasma concentrations, but decrease the plasma concentration of the active metabolite, morphine, resulting in reduced efficacy or symptoms of opioid withdrawal. Monitor patients closely at frequent intervals and consider a dosage increase of codeine until stable drug effects are achieved. Discontinuation of paroxetine could decrease codeine plasma concentrations and increase morphine plasma concentrations resulting in prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If paroxetine is discontinued, monitor the patient carefully and consider reducing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Paroxetine is a strong inhibitor of CYP2D6. 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. (Moderate) The combined use of selective serotonin reuptake inhibitors and aspirin, ASA may elevate the risk for an upper GI bleed. SSRIs may inhibit serotonin uptake by platelets, augmenting the antiplatelet effects of aspirin. Additionally, aspirin impairs the gastric mucosa defenses by inhibiting prostaglandin formation.
Cangrelor: (Moderate) Platelet aggregation may be impaired by selective serotonin reuptake inhibitors (SSRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymosis, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving platelet inhibitors (e.g., cangrelor). Patients should be instructed to monitor for signs and symptoms of bleeding while taking an SSRI concurrently with an antiplatelet medication and to promptly report any bleeding events to the practitioner.
Capsaicin; Metaxalone: (Moderate) Concomitant use of selective serotonin reuptake inhibitors (SSRIs) and metaxalone may increase the risk for serotonin syndrome. Monitor patients for serotonin syndrome if concomitant use is necessary.
Carbinoxamine: (Moderate) Of the selective serotonin reuptake inhibiting antidepressants (SSRIs), paroxetine is considered the most anticholinergic. Additive anticholinergic effects may be seen when paroxetine is used with antihistamines having anticholinergic properties such as carbinoxamine. Patients should be informed to read non-prescription cough and cold product labels carefully for additional interacting antihistamines.
Carvedilol: (Minor) Inhibitors of the hepatic CYP450 isozyme CYP 2D6, such as paroxetine, may inhibit the hepatic oxidative metabolism of carvedilol.
Celecoxib; Tramadol: (Moderate) Monitor for reduced efficacy of tramadol, signs of opioid withdrawal, seizures, or serotonin syndrome if coadministration with paroxetine is necessary. If paroxetine is discontinued, consider a dose reduction of tramadol and frequently monitor for signs of respiratory depression and sedation. Tramadol is a CYP2D6 substrate and paroxetine is a CYP2D6 inhibitor. Concomitant use of tramadol with CYP2D6 inhibitors can increase the plasma concentration of tramadol and decrease the plasma concentration of the active metabolite M1. Since M1 is a more potent mu-opioid agonist, decreased M1 exposure could result in decreased therapeutic effects, and may result in signs and symptoms of opioid withdrawal in patients who have developed physical dependence to tramadol. Increased tramadol exposure can result in increased or prolonged therapeutic effects and increased risk for serious adverse events including seizures and serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
Cevimeline: (Moderate) Monitor for an increase in cevimeline-related adverse effects if concomitant use of paroxetine is necessary. Concomitant use may increase cevimeline exposure. Cevimeline is a CYP2D6 substrate; paroxetine is a strong CYP2D6 inhibitor.
Chlophedianol; Dexbrompheniramine: (Moderate) Of the selective serotonin reuptake inhibiting antidepressants (SSRIs), paroxetine is considered the most anticholinergic. Additive anticholinergic effects may be seen when paroxetine is used with antihistamines having anticholinergic properties such as dexbrompheniramine. Patients should be informed to read non-prescription cough and cold product labels carefully for additional interacting antihistamines.
Chlophedianol; Dexchlorpheniramine; Pseudoephedrine: (Moderate) Of the selective serotonin reuptake inhibiting antidepressants (SSRIs), paroxetine is considered the most anticholinergic. Additive anticholinergic effects may be seen when paroxetine is used with antihistamines having anticholinergic properties such as dexchlorpheniramine. Patients should be informed to read non-prescription cough and cold product labels carefully for additional interacting antihistamines.
Chlordiazepoxide; Amitriptyline: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering selective serotonin reuptake inhibitors (SSRIs) with other drugs that have serotonergic properties such as tricyclic antidepressants. Additionally, monitor for an increase in amitriptyline-related adverse reactions if coadministration with paroxetine is necessary; a dose reduction of amitriptyline may be necessary. Concurrent use may increase the plasma concentrations of amitriptyline. Amitriptyline is a CYP2D6 substrate and paroxetine is a CYP2D6 inhibitor. Paroxetine and amitriptyline both exhibit significant anticholinergic effects that may be additive during concurrent use.
Chlordiazepoxide; Clidinium: (Moderate) Monitor for signs or symptoms of anticholinergic toxicity during concomitant anticholinergic medication and paroxetine use. Concomitant use may result in additive anticholinergic adverse effects.
Chlorpheniramine: (Moderate) Of the selective serotonin reuptake inhibiting antidepressants (SSRIs), paroxetine is considered the most anticholinergic. Additive anticholinergic effects may be seen when paroxetine is used with antihistamines having anticholinergic properties such as chlorpheniramine. Patients should be informed to read non-prescription cough and cold product labels carefully for additional interacting antihistamines.
Chlorpheniramine; Codeine: (Moderate) Careful monitoring, particularly during treatment initiation and dose adjustment, is recommended during coadministration of codeine and paroxetine because of the potential risk of serotonin syndrome, reduced codeine efficacy, and potential for opioid withdrawal symptoms. Discontinue codeine if serotonin syndrome is suspected. It is recommended to avoid this combination when codeine is being used for cough. Concomitant use may increase codeine plasma concentrations, but decrease the plasma concentration of the active metabolite, morphine, resulting in reduced efficacy or symptoms of opioid withdrawal. Monitor patients closely at frequent intervals and consider a dosage increase of codeine until stable drug effects are achieved. Discontinuation of paroxetine could decrease codeine plasma concentrations and increase morphine plasma concentrations resulting in prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If paroxetine is discontinued, monitor the patient carefully and consider reducing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Paroxetine is a strong inhibitor of CYP2D6. 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. (Moderate) Of the selective serotonin reuptake inhibiting antidepressants (SSRIs), paroxetine is considered the most anticholinergic. Additive anticholinergic effects may be seen when paroxetine is used with antihistamines having anticholinergic properties such as chlorpheniramine. Patients should be informed to read non-prescription cough and cold product labels carefully for additional interacting antihistamines.
Chlorpheniramine; Dextromethorphan: (Moderate) Monitor for dextromethorphan-related side effects, such as dizziness or drowsiness, if concomitant use of paroxetine is necessary. For patients receiving combination dextromethorphan; bupropion, do not exceed a maximum dose of 45 mg dextromethorphan; 105 mg bupropion once daily. Additionally, monitor patients for signs and symptoms of serotonin syndrome. Concomitant use may increase dextromethorphan exposure and the risk for serotonin syndrome. Dextromethorphan is a CYP2D6 substrate and paroxetine is a strong CYP2D6 inhibitor. Concomitant use with paroxetine increased dextromethorphan overall exposure by 2.69-fold. (Moderate) Of the selective serotonin reuptake inhibiting antidepressants (SSRIs), paroxetine is considered the most anticholinergic. Additive anticholinergic effects may be seen when paroxetine is used with antihistamines having anticholinergic properties such as chlorpheniramine. Patients should be informed to read non-prescription cough and cold product labels carefully for additional interacting antihistamines.
Chlorpheniramine; Dextromethorphan; Phenylephrine: (Moderate) Monitor for dextromethorphan-related side effects, such as dizziness or drowsiness, if concomitant use of paroxetine is necessary. For patients receiving combination dextromethorphan; bupropion, do not exceed a maximum dose of 45 mg dextromethorphan; 105 mg bupropion once daily. Additionally, monitor patients for signs and symptoms of serotonin syndrome. Concomitant use may increase dextromethorphan exposure and the risk for serotonin syndrome. Dextromethorphan is a CYP2D6 substrate and paroxetine is a strong CYP2D6 inhibitor. Concomitant use with paroxetine increased dextromethorphan overall exposure by 2.69-fold. (Moderate) Of the selective serotonin reuptake inhibiting antidepressants (SSRIs), paroxetine is considered the most anticholinergic. Additive anticholinergic effects may be seen when paroxetine is used with antihistamines having anticholinergic properties such as chlorpheniramine. Patients should be informed to read non-prescription cough and cold product labels carefully for additional interacting antihistamines.
Chlorpheniramine; Dextromethorphan; Pseudoephedrine: (Moderate) Monitor for dextromethorphan-related side effects, such as dizziness or drowsiness, if concomitant use of paroxetine is necessary. For patients receiving combination dextromethorphan; bupropion, do not exceed a maximum dose of 45 mg dextromethorphan; 105 mg bupropion once daily. Additionally, monitor patients for signs and symptoms of serotonin syndrome. Concomitant use may increase dextromethorphan exposure and the risk for serotonin syndrome. Dextromethorphan is a CYP2D6 substrate and paroxetine is a strong CYP2D6 inhibitor. Concomitant use with paroxetine increased dextromethorphan overall exposure by 2.69-fold. (Moderate) Of the selective serotonin reuptake inhibiting antidepressants (SSRIs), paroxetine is considered the most anticholinergic. Additive anticholinergic effects may be seen when paroxetine is used with antihistamines having anticholinergic properties such as chlorpheniramine. Patients should be informed to read non-prescription cough and cold product labels carefully for additional interacting antihistamines.
Chlorpheniramine; Dihydrocodeine; Phenylephrine: (Moderate) Careful monitoring, particularly during treatment initiation and dose adjustment, is recommended during coadministration of dihydrocodeine and paroxetine because of the potential risk of serotonin syndrome, reduced dihydrocodeine efficacy, and potential for opioid withdrawal symptoms. Discontinue dihydrocodeine if serotonin syndrome is suspected. It is recommended to avoid this combination when dihydrocodeine is being used for cough. Concomitant use may increase dihydrocodeine plasma concentrations, but decrease the plasma concentration of the active metabolite, dihydromorphine, resulting in reduced efficacy or symptoms of opioid withdrawal. Monitor patients closely at frequent intervals and consider a dosage increase of dihydrocodeine until stable drug effects are achieved. Discontinuation of paroxetine could decrease dihydrocodeine plasma concentrations and increase dihydromorphine plasma concentrations resulting in prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If paroxetine is discontinued, monitor the patient carefully and consider reducing the opioid dosage if appropriate. Dihydrocodeine is primarily metabolized by CYP2D6 to dihydromorphine, and by CYP3A4. Paroxetine is a strong inhibitor of CYP2D6. 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. (Moderate) Of the selective serotonin reuptake inhibiting antidepressants (SSRIs), paroxetine is considered the most anticholinergic. Additive anticholinergic effects may be seen when paroxetine is used with antihistamines having anticholinergic properties such as chlorpheniramine. Patients should be informed to read non-prescription cough and cold product labels carefully for additional interacting antihistamines.
Chlorpheniramine; Hydrocodone: (Moderate) Careful monitoring, particularly during treatment initiation and dose adjustment, is recommended during coadministration of hydrocodone and paroxetine because of the potential risk of serotonin syndrome and prolonged opioid adverse reactions. Discontinue hydrocodone if serotonin syndrome

is suspected. It is recommended to avoid this combination when hydrocodone is being used for cough. Concomitant use of hydrocodone with paroxetine may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. Monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of paroxetine could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If paroxetine is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP2D6. Paroxetine is a strong inhibitor of CYP2D6. 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. (Moderate) Of the selective serotonin reuptake inhibiting antidepressants (SSRIs), paroxetine is considered the most anticholinergic. Additive anticholinergic effects may be seen when paroxetine is used with antihistamines having anticholinergic properties such as chlorpheniramine. Patients should be informed to read non-prescription cough and cold product labels carefully for additional interacting antihistamines.
Chlorpheniramine; Ibuprofen; Pseudoephedrine: (Moderate) Of the selective serotonin reuptake inhibiting antidepressants (SSRIs), paroxetine is considered the most anticholinergic. Additive anticholinergic effects may be seen when paroxetine is used with antihistamines having anticholinergic properties such as chlorpheniramine. Patients should be informed to read non-prescription cough and cold product labels carefully for additional interacting antihistamines.
Chlorpheniramine; Phenylephrine: (Moderate) Of the selective serotonin reuptake inhibiting antidepressants (SSRIs), paroxetine is considered the most anticholinergic. Additive anticholinergic effects may be seen when paroxetine is used with antihistamines having anticholinergic properties such as chlorpheniramine. Patients should be informed to read non-prescription cough and cold product labels carefully for additional interacting antihistamines.
Chlorpheniramine; Pseudoephedrine: (Moderate) Of the selective serotonin reuptake inhibiting antidepressants (SSRIs), paroxetine is considered the most anticholinergic. Additive anticholinergic effects may be seen when paroxetine is used with antihistamines having anticholinergic properties such as chlorpheniramine. Patients should be informed to read non-prescription cough and cold product labels carefully for additional interacting antihistamines.
Chlorpromazine: (Moderate) Monitor for an increase in chlorpromazine- and paroxetine-related adverse reactions, including QT prolongation, anticholinergic effects, orthostasis, somnolence, and serotonin syndrome, if coadministration is necessary. Concomitant use may increase the exposure of both drugs. Both chlorpromazine and paroxetine are CYP2D6 substrates; paroxetine is a strong CYP2D6 inhibitor and chlorpromazine is a moderate CYP2D6 inhibitor.
Choline Salicylate; Magnesium Salicylate: (Moderate) Monitor for signs and symptoms of bleeding during concomitant magnesium salicylate and selective serotonin reuptake inhibitor (SSRI) use due to increased risk for bleeding. Serotonin release by platelets plays an important role in hemostasis. Epidemiological studies have demonstrated an association between use of psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper gastrointestinal bleeding. (Moderate) The combined use of selective serotonin reuptake inhibitors (SSRIs) and aspirin, ASA or other salicylates which affect hemostasis may elevate the risk for an upper GI bleed. SSRIs may inhibit serotonin uptake by platelets, augmenting the antiplatelet effects of aspirin. Additionally, aspirin impairs the gastric mucosa defenses by inhibiting prostaglandin formation. A cohort study in > 26,000 patients found that SSRI use alone increased the risk for serious GI bleed by 3.6-fold; when an SSRI was combined with aspirin the risk was increased by > 5-fold. The absolute risk of GI bleed from concomitant therapy with aspirin and a SSRI was low (20/2640 patients) in this cohort study and the clinician may determine that the combined use of these drugs is appropriate.
Cilostazol: (Moderate) Platelet aggregation may be impaired by selective serotonin reuptake inhibitors (SSRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication in patients receiving platelet inhibitors. Monitor for signs and symptoms of bleeding.
Cimetidine: (Moderate) Monitor for an increase in paroxetine-related adverse reactions, including serotonin syndrome, if concomitant use with cimetidine is necessary. Concomitant use may increase paroxetine exposure. Paroxetine is a CYP2D6 substrate and cimetidine is a weak CYP2D6 inhibitor.
Cinacalcet: (Moderate) Monitor for an increase in paroxetine-related adverse reactions, including serotonin syndrome, if concomitant use with cinacalcet is necessary. Concomitant use may increase paroxetine exposure. Paroxetine is a CYP2D6 substrate and cinacalcet is a strong CYP2D6 inhibitor.
Citalopram: (Moderate) Monitor patients for an increase in paroxetine-related adverse reactions and signs and symptoms of serotonin syndrome during concomitant use of paroxetine and citalopram, particularly during treatment initiation and dosage increases. If serotonin syndrome occurs, consider discontinuation of therapy. The concomitant use of serotonergic drugs increases the risk of serotonin syndrome. Concomitant use may increase paroxetine exposure. Paroxetine is a CYP2D6 substrate and citalopram is a weak CYP2D6 inhibitor.
Clemastine: (Moderate) Of the selective serotonin reuptake inhibiting antidepressants (SSRIs), paroxetine is considered the most anticholinergic. Additive anticholinergic effects may be seen when paroxetine is used with antihistamines having anticholinergic properties such as clemastine. Patients should be informed to read non-prescription cough and cold product labels carefully for additional interacting antihistamines.
Clobazam: (Moderate) Monitor for an increase in paroxetine-related adverse reactions, including serotonin syndrome, if concomitant use with clobazam is necessary. Concomitant use may increase paroxetine exposure. Paroxetine is a CYP2D6 substrate and clobazam is a weak CYP2D6 inhibitor. Coadministration with a weak CYP2D6 inhibitor increased paroxetine overall exposure by 50%.
Clomipramine: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering selective serotonin reuptake inhibitors (SSRIs) with other drugs that have serotonergic properties such as tricyclic antidepressants. In addition, paroxetine is a potent CYP2D6 inhibitor and may decrease the metabolism of clomipramine, a CYP2D6 substrate. Because there is a risk of QT prolongation and torsade de pointes (TdP) with tricyclics at elevated serum concentrations, coadministration should be approached with caution and close monitoring. Lastly, both paroxetine and clomipramine may exhibit significant anticholinergic effects that may be additive during concurrent use.
Clopidogrel: (Moderate) Carefully monitor patients for signs and symptoms of bleeding during coadministration of paroxetine and clopidogrel. Selective serotonin reuptake inhibitors (SSRIs) affect platelet activation; therefore, concomitant use may increase the risk of bleeding.
Clozapine: (Moderate) Consider a clozapine dose reduction if coadministered with paroxetine and monitor for adverse reactions. If paroxetine is discontinued, monitor for lack of clozapine effect and increase dose if necessary. A clinically relevant increase in the plasma concentration of clozapine may occur during concurrent use. Clozapine is partially metabolized by CYP2D6 and paroxetine is a strong CYP2D6 inhibitor.
Cobicistat: (Moderate) Close monitoring for antidepressant response and careful dose titrations of the antidepressant therapy is recommended during coadministration of selective serotonin reuptake inhibitors (SSRIs) and cobicistat. Concurrent use may result in elevated SSRI plasma concentrations. Predictions regarding this interaction can be made based on the metabolic pathways of these drugs. All SSRIs are substrates for the hepatic isoenzyme CYP2D6, while citalopram, escitalopram, and sertraline are also substrates for CYP3A4; cobicistat is an inhibitor of both CYP2D6 and CYP3A4.
Cocaine: (Major) Concomitant use of cocaine with drugs that have CNS serotonergic properties, such as SSRIs, could potentiate serotonin neurotransmission, and result in the serotonin syndrome. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. Patients receiving this combination should be monitored for the emergence of serotonin syndrome or neuroleptic malignant syndrome-like reactions. Additionally, citalopram causes dose-dependent QT interval prolongation. Local anesthetics (e.g., cocaine) are associated with a possible risk for QT prolongation and according to the manufacturer of citalopram, concurrent use of citalopram with other drugs that prolong the QT interval is not recommended. If concurrent therapy is considered essential, ECG monitoring is recommended.
Codeine: (Moderate) Careful monitoring, particularly during treatment initiation and dose adjustment, is recommended during coadministration of codeine and paroxetine because of the potential risk of serotonin syndrome, reduced codeine efficacy, and potential for opioid withdrawal symptoms. Discontinue codeine if serotonin syndrome is suspected. It is recommended to avoid this combination when codeine is being used for cough. Concomitant use may increase codeine plasma concentrations, but decrease the plasma concentration of the active metabolite, morphine, resulting in reduced efficacy or symptoms of opioid withdrawal. Monitor patients closely at frequent intervals and consider a dosage increase of codeine until stable drug effects are achieved. Discontinuation of paroxetine could decrease codeine plasma concentrations and increase morphine plasma concentrations resulting in prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If paroxetine is discontinued, monitor the patient carefully and consider reducing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Paroxetine is a strong inhibitor of CYP2D6. 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.
Codeine; Guaifenesin: (Moderate) Careful monitoring, particularly during treatment initiation and dose adjustment, is recommended during coadministration of codeine and paroxetine because of the potential risk of serotonin syndrome, reduced codeine efficacy, and potential for opioid withdrawal symptoms. Discontinue codeine if serotonin syndrome is suspected. It is recommended to avoid this combination when codeine is being used for cough. Concomitant use may increase codeine plasma concentrations, but decrease the plasma concentration of the active metabolite, morphine, resulting in reduced efficacy or symptoms of opioid withdrawal. Monitor patients closely at frequent intervals and consider a dosage increase of codeine until stable drug effects are achieved. Discontinuation of paroxetine could decrease codeine plasma concentrations and increase morphine plasma concentrations resulting in prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If paroxetine is discontinued, monitor the patient carefully and consider reducing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Paroxetine is a strong inhibitor of CYP2D6. 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.
Codeine; Guaifenesin; Pseudoephedrine: (Moderate) Careful monitoring, particularly during treatment initiation and dose adjustment, is recommended during coadministration of codeine and paroxetine because of the potential risk of serotonin syndrome, reduced codeine efficacy, and potential for opioid withdrawal symptoms. Discontinue codeine if serotonin syndrome is suspected. It is recommended to avoid this combination when codeine is being used for cough. Concomitant use may increase codeine plasma concentrations, but decrease the plasma concentration of the active metabolite, morphine, resulting in reduced efficacy or symptoms of opioid withdrawal. Monitor patients closely at frequent intervals and consider a dosage increase of codeine until stable drug effects are achieved. Discontinuation of paroxetine could decrease codeine plasma concentrations and increase morphine plasma concentrations resulting in prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If paroxetine is discontinued, monitor the patient carefully and consider reducing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Paroxetine is a strong inhibitor of CYP2D6. 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.
Codeine; Phenylephrine; Promethazine: (Moderate) Careful monitoring, particularly during treatment initiation and dose adjustment, is recommended during coadministration of codeine and paroxetine because of the potential risk of serotonin syndrome, reduced codeine efficacy, and potential for opioid withdrawal symptoms. Discontinue codeine if serotonin syndrome is suspected. It is recommended to avoid this combination when codeine is being used for cough. Concomitant use may increase codeine plasma concentrations, but decrease the plasma concentration of the active metabolite, morphine, resulting in reduced efficacy or symptoms of opioid withdrawal. Monitor patients closely at frequent intervals and consider a dosage increase of codeine until stable drug effects are achieved. Discontinuation of paroxetine could decrease codeine plasma concentrations and increase morphine plasma concentrations resulting in prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If paroxetine is discontinued, monitor the patient carefully and consider reducing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Paroxetine is a strong inhibitor of CYP2D6. 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. (Moderate) Monitor for signs or symptoms of anticholinergic toxicity during concomitant paroxetine and promethazine use. Concomitant use may result in additive anticholinergic adverse effects.
Codeine; Promethazine: (Moderate) Careful monitoring, particularly during treatment initiation and dose adjustment, is recommended during coadministration of codeine and paroxetine because of the potential risk of serotonin syndrome, reduced codeine efficacy, and potential for opioid withdrawal symptoms. Discontinue codeine if serotonin syndrome is suspected. It is recommended to avoid this combination when codeine is being used for cough. Concomitant use may increase codeine plasma concentrations, but decrease the plasma concentration of the active metabolite, morphine, resulting in reduced efficacy or symptoms of opioid withdrawal. Monitor patients closely at frequent intervals and consider a dosage increase of codeine until stable drug effects are achieved. Discontinuation of paroxetine could decrease codeine plasma concentrations and increase morphine plasma concentrations resulting in prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If paroxetine is discontinued, monitor the patient carefully and consider reducing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Paroxetine is a strong inhibitor of CYP2D6. 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. (Moderate) Monitor for signs or symptoms of anticholinergic toxicity during concomitant paroxetine and promethazine use. Concomitant use may result in additive anticholinergic adverse effects.
Cyclobenzaprine: (Moderate) Monitor for signs and symptoms of serotonin syndrome, particularly during treatment initiation and dosage increase, during concomitant cyclobenzaprine and paroxetine use. If serotonin syndrome occurs, discontinue therapy. Concomitant use increases the risk for serotonin syndrome.
Cyproheptadine: (Moderate) Cyproheptadine is a serotonin antagonist in the CNS and can oppose the pharmacologic actions of selective serotonin reuptake inhibitors (SSRIs) such as paroxetine. Cyproheptadine has been used for the management of orgasm dysfunction caused by the SSRIs and for the adjunctive treatment of SSRI overdose (i.e., serotonin syndrome) in emergency situations; however, a reversal of antidepressant effects may occur when cyproheptadine is given in a routine manner along with the SSRIs due to the serotonin antagonistic effects of cyproheptadine. In addition, additive anticholinergic effects may be seen when paroxetine is used with antihistamines having anticholinergic properties such as cyproheptadine. Patients should be informed to read non-prescription cough and cold product labels carefully for additional interacting antihistamines.
Dabigatran: (Moderate) Advise patients of the increased bleeding risk associated with the concomitant use of selective serotonin reuptake inhibitors (SSRIs) and anticoagulants like dabigatran. Case reports and epidemiological studies have demonstrated an association between use of drugs that interfere with serotonin reuptake and gastrointestinal bleeding.
Dacomitinib: (Moderate) Monitor for an increase in paroxetine-related adverse reactions, including serotonin syndrome, if concomitant use with dacomitinib is necessary. Concomitant use may increase paroxetine exposure. Paroxetine is a CYP2D6 substrate and dacomitinib is a strong CYP2D6 inhibitor.
Dalteparin: (Moderate) Monitor for signs and symptoms of bleeding during concomitant low molecular weight heparin and selective serotonin reuptake inhibitor (SSRI) use due to increased risk for bleeding. Serotonin release by platelets plays an important role in hemostasis. Epidemiological studies have demonstrated an association between use of psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper gastrointestinal bleeding. Altered anticoagulant effects, including increased bleeding, have been reported when SSRIs are coadministered with another anticoagulant.
Darifenacin: (Moderate) Monitor for an increase in paroxetine-related adverse reactions, including serotonin syndrome, if concomitant use with darifenacin is necessary. Concomitant use may increase paroxetine exposure. Paroxetine is a CYP2D6 substrate and darifenacin is a moderate CYP2D6 inhibitor.
Darunavir: (Moderate) Use caution when coadministering darunavir with paroxetine, as decreased SSRI concentrations may be seen. If paroxetine is coadministered with darunavir, carefully titrate the dose of paroxetine based on a clinical assessment of antidepressant response.
Darunavir; Cobicistat: (Moderate) Close monitoring for antidepressant response and careful dose titrations of the antidepressant therapy is recommended during coadministration of selective serotonin reuptake inhibitors (SSRIs) and cobicistat. Concurrent use may result in elevated SSRI plasma concentrations. Predictions regarding this interaction can be made based on the metabolic pathways of these drugs. All SSRIs are substrates for the hepatic isoenzyme CYP2D6, while citalopram, escitalopram, and sertraline are also substrates for CYP3A4; cobicistat is an inhibitor of both CYP2D6 and CYP3A4. (Moderate) Use caution when coadministering darunavir with paroxetine, as decreased SSRI concentrations may be seen. If paroxetine is coadministered with darunavir, carefully titrate the dose of paroxetine based on a clinical assessment of antidepressant response.
Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide: (Moderate) Close monitoring for antidepressant response and careful dose titrations of the antidepressant therapy is recommended during coadministration of selective serotonin reuptake inhibitors (SSRIs) and cobicistat. Concurrent use may result in elevated SSRI plasma concentrations. Predictions regarding this interaction can be made based on the metabolic pathways of these drugs. All SSRIs are substrates for the hepatic isoenzyme CYP2D6, while citalopram, escitalopram, and sertraline are also substrates for CYP3A4; cobicistat is an inhibitor of both CYP2D6 and CYP3A4. (Moderate) Use caution when coadministering darunavir with paroxetine, as decreased SSRI concentrations may be seen. If paroxetine is coadministered with darunavir, carefully titrate the dose of paroxetine based on a clinical assessment of antidepressant response.
Delavirdine: (Moderate) Monitor for an increase in paroxetine-related adverse reactions, including serotonin syndrome, if concomitant use with delavirdine is necessary. Concomitant use may increase paroxetine exposure. Paroxetine is a CYP2D6 substrate and delavirdine is a moderate CYP2D6 inhibitor.
Desipramine: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering selective serotonin reuptake inhibitors (SSRIs) with other drugs that have serotonergic properties such as tricyclic antidepressants. In addition, paroxetine is a potent CYP2D6 inhibitor and may decrease the metabolism of desipramine, a CYP2D6 substrate. Because there is a risk of QT prolongation and torsade de pointes (TdP) with tricyclics at elevated serum concentrations, coadministration should be approached with caution and close monitoring. Lastly, both paroxetine and desipramine may exhibit significant anticholinergic effects that may be additive during concurrent use.
Desmopressin: (Minor) Additive hyponatremic effects may be seen in patients treated with desmopressin and drugs associated with water intoxication, hyponatremia, or SIADH including SSRIs. Use combination with caution, and monitor patients for signs and symptoms of hyponatremia, which may include monitoring serum sodium or electrolytes periodically. Ensure the patient is compliant with fluid restrictions and intake.
Desvenlafaxine: (Moderate) Monitor patients for an increase in paroxetine-related adverse reactions and signs and symptoms of serotonin syndrome during concomitant use of paroxetine and desvenlafaxine, particularly during treatment initiation and dosage increases. If serotonin syndrome occurs, consider discontinuation of therapy. The concomitant use of serotonergic drugs increases the risk of serotonin syndrome. Concomitant use may increase paroxetine exposure. Paroxetine is a CYP2D6 substrate and desvenlafaxine is a weak CYP2D6 inhibitor at doses of 400 mg/day.
Deutetrabenazine: (Major) Do not exceed 18 mg/dose or 36 mg/day of deutetrabenazine if must use concurrently with a strong CYP2D6 inhibitor. Paroxetine is a strong CYP2D6 inhibitor, and the metabolites of deutetrabenazine, alpha- and beta-HTBZ, are CYP2D6 substrates. The systemic exposure of alpha- and beta-HTBZ may be increased resulting in an increase in deutetrabenazine-related adverse reactions, like QT prolongation and drowsiness. After 8 days of paroxetine 20 mg PO daily, systemic exposure (AUC) of alpha- and beta-HTBZ increased 1.9-fold and 6.5-fold, respectively, following a single 22.5 mg dose of deutetrabenazine. The clearance of alpha- and beta-HTBZ was reduced, with corresponding increases in mean half-life of 1.5-fold and 2.7-fold, respectively. The Cmax of alpha- and beta-HTBZ increased 1.2-fold and 2.2-fold, respectively.
Dexbrompheniramine: (Moderate) Of the selective serotonin reuptake inhibiting antidepressants (SSRIs), paroxetine is considered the most anticholinergic. Additive anticholinergic effects may be seen when paroxetine is used with antihistamines having anticholinergic properties such as dexbrompheniramine. Patients should be informed to read non-prescription cough and cold product labels carefully for additional interacting antihistamines.
Dexbrompheniramine; Pseudoephedrine: (Moderate) Of the selective serotonin reuptake inhibiting antidepressants (SSRIs), paroxetine is considered the most anticholinergic. Additive anticholinergic effects may be seen when paroxetine is used with antihistamines having anticholinergic properties such as dexbrompheniramine. Patients should be informed to read non-prescription cough and cold product labels carefully for additional interacting antihistamines.
Dexchlorpheniramine: (Moderate) Of the selective serotonin reuptake inhibiting antidepressants (SSRIs), paroxetine is considered the most anticholinergic. Additive anticholinergic effects may be seen when paroxetine is used with antihistamines having anticholinergic properties such as dexchlorpheniramine. Patients should be informed to read non-prescription cough and cold product labels carefully for additional interacting antihistamines.
Dexchlorpheniramine; Dextromethorphan; Pseudoephedrine: (Moderate) Monitor for dextromethorphan-related side effects, such as dizziness or drowsiness, if concomitant use of paroxetine is necessary. For patients receiving combination dextromethorphan; bupropion, do not exceed a maximum dose of 45 mg dextromethorphan; 105 mg bupropion once daily. Additionally, monitor patients for signs and symptoms of serotonin syndrome. Concomitant use may increase dextromethorphan exposure and the risk for serotonin syndrome. Dextromethorphan is a CYP2D6 substrate and paroxetine is a strong CYP2D6 inhibitor. Concomitant use with paroxetine increased dextromethorphan overall exposure by 2.69-fold. (Moderate) Of the selective serotonin reuptake inhibiting antidepressants (SSRIs), paroxetine is considered the most anticholinergic. Additive anticholinergic effects may be seen when paroxetine is used with antihistamines having anticholinergic properties such as dexchlorpheniramine. Patients should be informed to read non-prescription cough and cold product labels carefully for additional interacting antihistamines.
Dextromethorphan: (Moderate) Monitor for dextromethorphan-related side effects, such as dizziness or drowsiness, if concomitant use of paroxetine is necessary. For patients receiving combination dextromethorphan; bupropion, do not exceed a maximum dose of 45 mg dextromethorphan; 105 mg bupropion once daily. Additionally, monitor patients for signs and symptoms of serotonin syndrome. Concomitant use may increase dextromethorphan exposure and the risk for serotonin syndrome. Dextromethorphan is a CYP2D6 substrate and paroxetine is a strong CYP2D6 inhibitor. Concomitant use with paroxetine increased dextromethorphan overall exposure by 2.69-fold.
Dextromethorphan; Bupropion: (Moderate) Monitor for an increase in paroxetine-related adverse reactions, including serotonin syndrome, if concomitant use with bupropion is necessary. Concomitant use may increase paroxetine exposure. Paroxetine is a CYP2D6 substrate and bupropion is a strong CYP2D6 inhibitor. (Moderate) Monitor for dextromethorphan-related side effects, such as dizziness or drowsiness, if concomitant use of paroxetine is necessary. For patients receiving combination dextromethorphan; bupropion, do not exceed a maximum dose of 45 mg dextromethorphan; 105 mg bupropion once daily. Additionally, monitor patients for signs and symptoms of serotonin syndrome. Concomitant use may increase dextromethorphan exposure and the risk for serotonin syndrome. Dextromethorphan is a CYP2D6 substrate and paroxetine is a strong CYP2D6 inhibitor. Concomitant use with paroxetine increased dextromethorphan overall exposure by 2.69-fold.
Dextromethorphan; Diphenhydramine; Phenylephrine: (Moderate) Monitor for an increase in paroxetine-related adverse reactions, including serotonin syndrome, if concomitant use with diphenhydramine is necessary. Concomitant use may increase paroxetine exposure and risk for additive anticholinergic adverse effects. Paroxetine is a CYP2D6 substrate and diphenhydramine is a moderate CYP2D6 inhibitor. (Moderate) Monitor for dextromethorphan-related side effects, such as dizziness or drowsiness, if concomitant use of paroxetine is necessary. For patients receiving combination dextromethorphan; bupropion, do not exceed a maximum dose of 45 mg dextromethorphan; 105 mg bupropion once daily. Additionally, monitor patients for signs and symptoms of serotonin syndrome. Concomitant use may increase dextromethorphan exposure and the risk for serotonin syndrome. Dextromethorphan is a CYP2D6 substrate and paroxetine is a strong CYP2D6 inhibitor. Concomitant use with paroxetine increased dextromethorphan overall exposure by 2.69-fold.
Dextromethorphan; Guaifenesin: (Moderate) Monitor for dextromethorphan-related side effects, such as dizziness or drowsiness, if concomitant use of paroxetine is necessary. For patients receiving combination dextromethorphan; bupropion, do not exceed a maximum dose of 45 mg dextromethorphan; 105 mg bupropion once daily. Additionally, monitor patients for signs and symptoms of serotonin syndrome. Concomitant use may increase dextromethorphan exposure and the risk for serotonin syndrome. Dextromethorphan is a CYP2D6 substrate and paroxetine is a strong CYP2D6 inhibitor. Concomitant use with paroxetine increased dextromethorphan overall exposure by 2.69-fold.
Dextromethorphan; Guaifenesin; Phenylephrine: (Moderate) Monitor for dextromethorphan-related side effects, such as dizziness or drowsiness, if concomitant use of paroxetine is necessary. For patients receiving combination dextromethorphan; bupropion, do not exceed a maximum dose of 45 mg dextromethorphan; 105 mg bupropion once daily. Additionally, monitor patients for signs and symptoms of serotonin syndrome. Concomitant use may increase dextromethorphan exposure and the risk for serotonin syndrome. Dextromethorphan is a CYP2D6 substrate and paroxetine is a strong CYP2D6 inhibitor. Concomitant use with paroxetine increased dextromethorphan overall exposure by 2.69-fold.
Dextromethorphan; Guaifenesin; Potassium Guaiacolsulfonate: (Moderate) Monitor for dextromethorphan-related side effects, such as dizziness or drowsiness, if concomitant use of paroxetine is necessary. For patients receiving combination dextromethorphan; bupropion, do not exceed a maximum dose of 45 mg dextromethorphan; 105 mg bupropion once daily. Additionally, monitor patients for signs and symptoms of serotonin syndrome. Concomitant use may increase dextromethorphan exposure and the risk for serotonin syndrome. Dextromethorphan is a CYP2D6 substrate and paroxetine is a strong CYP2D6 inhibitor. Concomitant use with paroxetine increased dextromethorphan overall exposure by 2.69-fold.
Dextromethorphan; Guaifenesin; Pseudoephedrine: (Moderate) Monitor for dextromethorphan-related side effects, such as dizziness or drowsiness, if concomitant use of paroxetine is necessary. For patients receiving combination dextromethorphan; bupropion, do not exceed a maximum dose of 45 mg dextromethorphan; 105 mg bupropion once daily. Additionally, monitor patients for signs and symptoms of serotonin syndrome. Concomitant use may increase dextromethorphan exposure and the risk for serotonin syndrome. Dextromethorphan is a CYP2D6 substrate and paroxetine is a strong CYP2D6 inhibitor. Concomitant use with paroxetine increased dextromethorphan overall exposure by 2.69-fold.
Dextromethorphan; Quinidine: (Moderate) Monitor for an increase in paroxetine-related adverse reactions, including serotonin syndrome, if concomitant use with quinidine is necessary. Concomitant use may increase paroxetine exposure. Paroxetine is a CYP2D6 substrate and quinidine is a strong CYP2D6 inhibitor. (Moderate) Monitor for dextromethorphan-related side effects, such as dizziness or drowsiness, if concomitant use of paroxetine is necessary. For patients receiving combination dextromethorphan; bupropion, do not exceed a maximum dose of 45 mg dextromethorphan; 105 mg bupropion once daily. Additionally, monitor patients for signs and symptoms of serotonin syndrome. Concomitant use may increase dextromethorphan exposure and the risk for serotonin syndrome. Dextromethorphan is a CYP2D6 substrate and paroxetine is a strong CYP2D6 inhibitor. Concomitant use with paroxetine increased dextromethorphan overall exposure by 2.69-fold.
Dicyclomine: (Moderate) Monitor for signs or symptoms of anticholinergic toxicity during concomitant anticholinergic medication and paroxetine use. Concomitant use may result in additive anticholinergic adverse effects.
Digoxin: (Minor) Paroxetine may slightly decrease mean digoxin area under the curve values. Until more clinical data are known, patients should be monitored for loss of digoxin clinical effect if paroxetine is added.
Dihydroergotamine: (Moderate) Use paroxetine and ergot alkaloids together with caution due to a potential for serotonin syndrome. Weakness, hyperreflexia, and incoordination have been reported rarely when ergot alkaloids or other serotonin agonists have been coadministered with SSRIs, which may be indicative of serotonin excess. If serotonin syndrome occurs, discontinue the offending agents and institute appropriate treatment.
Diphenhydramine: (Moderate) Monitor for an increase in paroxetine-related adverse reactions, including serotonin syndrome, if concomitant use with diphenhydramine is necessary. Concomitant use may increase paroxetine exposure and risk for additive anticholinergic adverse effects. Paroxetine is a CYP2D6 substrate and diphenhydramine is a moderate CYP2D6 inhibitor.
Diphenhydramine; Ibuprofen: (Moderate) Monitor for an increase in paroxetine-related adverse reactions, including serotonin syndrome, if concomitant use with diphenhydramine is necessary. Concomitant use may increase paroxetine exposure and risk for additive anticholinergic adverse effects. Paroxetine is a CYP2D6 substrate and diphenhydramine is a moderate CYP2D6 inhibitor.
Diphenhydramine; Naproxen: (Moderate) Monitor for an increase in paroxetine-related adverse reactions, including serotonin syndrome, if concomitant use with diphenhydramine is necessary. Concomitant use may increase paroxetine exposure and risk for additive anticholinergic adverse effects. Paroxetine is a CYP2D6 substrate and diphenhydramine is a moderate CYP2D6 inhibitor.
Diphenhydramine; Phenylephrine: (Moderate) Monitor for an increase in paroxetine-related adverse reactions, including serotonin syndrome, if concomitant use with diphenhydramine is necessary. Concomitant use may increase paroxetine exposure and risk for additive anticholinergic adverse effects. Paroxetine is a CYP2D6 substrate and diphenhydramine is a moderate CYP2D6 inhibitor.
Diphenoxylate; Atropine: (Moderate) Monitor for signs or symptoms of anticholinergic toxicity during concomitant anticholinergic medication and paroxetine use. Concomitant use may result in additive anticholinergic adverse effects.
Dipyridamole: (Moderate) Platelet aggregation may be impaired by SSRIs due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication in patients receiving platelet inhibitors. Monitor for signs and symptoms of bleeding.
Disopyramide: (Moderate) Additive anticholinergic effects may be seen when drugs with anticholinergic properties like disopyramide and paroxetine are used concomitantly. Adverse effects may be seen not only on GI smooth muscle, but also on bladder function, the CNS, the eye, and temperature regulation.
Diuretics: (Moderate) Monitor for signs and symptoms of hyponatremia during concomitant diuretic and paroxetine use; consider discontinuing paroxetine if symptomatic hyponatremia occurs and institute appropriate medical intervention. Concomitant use increases the risk for developing hyponatremia.
Dolasetron: (Major) Because of the potential risk and severity of serotonin syndrome, use caution when administering dolasetron with other drugs that have serotonergic properties such as paroxetine. 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 is suspected, discontinue dolasetron and concurrent serotonergic agents and initiate appropriate medical treatment. In addition, because dolasetron is a CYP2D6 substrate and has a possible risk of QT prolongation and torsade de pointes, concurrent use of a potent CYP2D6 inhibitor such as paroxetine may increase the risk of such events.
Donepezil: (Moderate) Clinical monitoring for drug efficacy, GI or cholinergic effects (e.g., bradycardia or irregular heartbeat), or unusual changes in mood or behavior is recommended during coadministration of donepezil and paroxetine. The plasma concentrations of donepezil may be increased when administered concurrently with paroxetine. Paroxetine is a strong inhibitor of CYP2D6 inhibitor and donepezil undergoes some metabolism by CYP2D6. Paroxetine exhibits anticholinergic effects that may be problematic in the dementia population.
Donepezil; Memantine: (Moderate) Clinical monitoring for drug efficacy, GI or cholinergic effects (e.g., bradycardia or irregular heartbeat), or unusual changes in mood or behavior is recommended during coadministration of donepezil and paroxetine. The plasma concentrations of donepezil may be increased when administered concurrently with paroxetine. Paroxetine is a strong inhibitor of CYP2D6 inhibitor and donepezil undergoes some metabolism by CYP2D6. Paroxetine exhibits anticholinergic effects that may be problematic in the dementia population.
Dorzolamide; Timolol: (Moderate) Monitor for signs of bradycardia or heart block if coadministration of timolol with paroxetine is necessary. Concomitant use may enhance the beta-blocking properties of timolol resulting in further slowing of the heart rate or cardiac conduction. Timolol is a CYP2D6 substrate and paroxetine is a strong CYP2D6 inhibitor.
Doxepin: (Moderate) Monitor patients for an increase in doxepin-related adverse reactions and signs and symptoms of serotonin syndrome during concomitant use of doxepin and paroxetine, particularly during treatment initiation and dosage increases; a dose reduction of doxepin may be necessary. If serotonin syndrome occurs, consider discontinuation of therapy. The concomitant use of serotonergic drugs increases the risk of serotonin syndrome. Concurrent use may also increase the exposure of doxepin. Doxepin is a CYP2D6 substrate and paroxetine is a CYP2D6 inhibitor.
Doxercalciferol: (Moderate) Doxercalciferol is converted in the liver to 1,25-dihydroxyergocalciferol, the major active metabolite, and 1-alpha, 24-dihydroxyvitamin D2, a minor metabolite. Although not specifically studied, cytochrome P450 enzyme inhibitors, including selective serotonin reuptake inhibitors (SSRIs), may inhibit the 25-hydroxylation of doxercalciferol, thereby decreasing the formation of the active metabolite and thus, decreasing efficacy. Patients should be monitored for a decrease in efficacy if SSRIs are coadministered with doxercalciferol.
Doxorubicin Liposomal: (Major) Avoid coadministration of paroxetine with doxorubicin due to increased systemic exposure of doxorubicin resulting in increased treatment-related adverse reactions. Paroxetine is a strong CYP2D6 inhibitor and doxorubicin is a major substrate of CYP3D6. Concurrent use of CYP2D6 inhibitors with doxorubicin has resulted in clinically significant interaction.
Doxorubicin: (Major) Avoid coadministration of paroxetine with doxorubicin due to increased systemic exposure of doxorubicin resulting in increased treatment-related adverse reactions. Paroxetine is a strong CYP2D6 inhibitor and doxorubicin is a major substrate of CYP3D6. Concurrent use of CYP2D6 inhibitors with doxorubicin has resulted in clinically significant interaction.
Dronedarone: (Moderate) Monitor for an increase in paroxetine-related adverse reactions, including serotonin syndrome, if concomitant use with dronedarone is necessary. Concomitant use may increase paroxetine exposure. Paroxetine is a CYP2D6 substrate and dronedarone is a moderate CYP2D6 inhibitor.
Duloxetine: (Moderate) Monitor patients for an increase in paroxetine-related adverse reactions and signs and symptoms of serotonin syndrome during concomitant use of paroxetine and duloxetine, particularly during treatment initiation and dosage increases. If serotonin syndrome occurs, consider discontinuation of therapy. The concomitant use of serotonergic drugs increases the risk of serotonin syndrome. Concomitant use may increase paroxetine exposure. Paroxetine is a CYP2D6 substrate and duloxetine is a moderate CYP2D6 inhibitor.
Dutasteride; Tamsulosin: (Moderate) Use caution if coadministration of paroxetine with tamsulosin is necessary, especially at a tamsulosin dose higher than 0.4 mg, as the systemic exposure of tamsulosin may be increased resulting in increased treatment-related adverse reactions including hypotension, dizziness, and vertigo. Tamsulosin is a CYP2D6 substrate and paroxetine is a strong CYP2D6 inhibitor. Concomitant treatment with paroxetine increased the Cmax and AUC of tamsulosin by a factor of 1.3 and 1.6, respectively.
Edoxaban: (Moderate) Advise patients of the increased bleeding risk associated with the concomitant use of selective serotonin reuptake inhibitors (SSRIs) and anticoagulants like edoxaban. Case reports and epidemiological studies have demonstrated an association between use of drugs that interfere with serotonin reuptake and gastrointestinal bleeding.
Eletriptan: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering eletriptan with paroxetine. Serotonin syndrome has been reported during concurrent use of serotonin-receptor agonists and selective serotonin reuptake inhibitors (SSRIs). Some patients had used the combination previously without incident when serotonin syndrome occurred. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly after a dose increase of the SSRI or the addition of other serotonergic medications to an existing SSRI regimen. Discontinue paroxetine and eletriptan and initiate symptomatic treatment if serotonin syndrome occurs.
Eliglustat: (Major) Reduce the dose of eliglustat to 84 mg once daily in patients who are extensive or intermediate CYP2D6 metabolizers (EMs or IMs) and receiving paroxetine. Eliglustat is contraindicated in EMs and IMs who are receiving paroxetine plus a strong or moderate CYP3A inhibitor. Eliglustat is contraindicated in poor metabolizers (PMs) who are receiving paroxetine plus a strong CYP3A inhibitor and should be avoided, if possible, in patients who are receiving paroxetine plus a moderate CYP3A inhibitor. Concomitant use may increase eliglustat exposure. Also, monitor for an increase in paroxetine-related adverse reactions, including serotonin syndrome, if concomitant use with eliglustat is necessary. Concomitant use may increase paroxetine exposure. Eliglustat is a substrate and moderate inhibitor of CYP2D6 and paroxetine is a substrate and strong inhibitor of CYP2D6. A strong CYP2D6 inhibitor is predicted to increase eliglustat overall exposure by 8.4-fold and 2.3-fold in extensive and intermediate metabolizers, respectively. Strong CYP2D6s inhibitors alone are not expected to affect eliglustat concentrations in CYP2D6 poor metabolizers (PMs).
Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Alafenamide: (Moderate) Close monitoring for antidepressant response and careful dose titrations of the antidepressant therapy is recommended during coadministration of selective serotonin reuptake inhibitors (SSRIs) and cobicistat. Concurrent use may result in elevated SSRI plasma concentrations. Predictions regarding this interaction can be made based on the metabolic pathways of these drugs. All SSRIs are substrates for the hepatic isoenzyme CYP2D6, while citalopram, escitalopram, and sertraline are also substrates for CYP3A4; cobicistat is an inhibitor of both CYP2D6 and CYP3A4.
Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Disoproxil Fumarate: (Moderate) Close monitoring for antidepressant response and careful dose titrations of the antidepressant therapy is recommended during coadministration of selective serotonin reuptake inhibitors (SSRIs) and cobicistat. Concurrent use may result in elevated SSRI plasma concentrations. Predictions regarding this interaction can be made based on the metabolic pathways of these drugs. All SSRIs are substrates for the hepatic isoenzyme CYP2D6, while citalopram, escitalopram, and sertraline are also substrates for CYP3A4; cobicistat is an inhibitor of both CYP2D6 and CYP3A4.
Enoxaparin: (Moderate) Monitor for signs and symptoms of bleeding during concomitant low molecular weight heparin and selective serotonin reuptake inhibitor (SSRI) use due to increased risk for bleeding. Serotonin release by platelets plays an important role in hemostasis. Epidemiological studies have demonstrated an association between use of psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper gastrointestinal bleeding. Altered anticoagulant effects, including increased bleeding, have been reported when SSRIs are coadministered with another anticoagulant.
Eptifibatide: (Moderate) Platelet aggregation may be impaired by SSRIs due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication in patients receiving platelet inhibitors. Monitor for signs and symptoms of bleeding.
Ergoloid Mesylates: (Moderate) Use paroxetine and ergot alkaloids together with caution due to a potential for serotonin syndrome. Weakness, hyperreflexia, and incoordination have been reported rarely when ergot alkaloids or other serotonin agonists have been coadministered with SSRIs, which may be indicative of serotonin excess. If serotonin syndrome occurs, discontinue the offending agents and institute appropriate treatment.
Ergot alkaloids: (Moderate) Use paroxetine and ergot alkaloids together with caution due to a potential for serotonin syndrome. Weakness, hyperreflexia, and incoordination have been reported rarely when ergot alkaloids or other serotonin agonists have been coadministered with SSRIs, which may be indicative of serotonin excess. If serotonin syndrome occurs, discontinue the offending agents and institute appropriate treatment.
Ergotamine: (Moderate) Use paroxetine and ergot alkaloids together with caution due to a potential for serotonin syndrome. Weakness, hyperreflexia, and incoordination have been reported rarely when ergot alkaloids or other serotonin agonists have been coadministered with SSRIs, which may be indicative of serotonin excess. If serotonin syndrome occurs, discontinue the offending agents and institute appropriate treatment.
Ergotamine; Caffeine: (Moderate) Use paroxetine and ergot alkaloids together with caution due to a potential for serotonin syndrome. Weakness, hyperreflexia, and incoordination have been reported rarely when ergot alkaloids or other serotonin agonists have been coadministered with SSRIs, which may be indicative of serotonin excess. If serotonin syndrome occurs, discontinue the offending agents and institute appropriate treatment.
Escitalopram: (Moderate) Monitor patients for an increase in paroxetine-related adverse reactions and signs and symptoms of serotonin syndrome during concomitant use of paroxetine and escitalopram, particularly during treatment initiation and dosage increases. If serotonin syndrome occurs, consider discontinuation of therapy. The concomitant use of serotonergic drugs increases the risk of serotonin syndrome. Concomitant use may increase paroxetine exposure. Paroxetine is a CYP2D6 substrate and escitalopram is a moderate CYP2D6 inhibitor.
Everolimus: (Moderate) Monitor for an increase in paroxetine-related adverse reactions, including serotonin syndrome, if concomitant use with everolimus is necessary. Concomitant use may increase paroxetine exposure. Paroxetine is a CYP2D6 substrate and everolimus is a weak CYP2D6 inhibitor. Coadministration with a weak CYP2D6 inhibitor increased paroxetine overall exposure by 50%.
Fedratinib: (Moderate) Monitor for an increase in paroxetine-related adverse reactions, including serotonin syndrome, if concomitant use with fedratinib is necessary. Concomitant use may increase paroxetine exposure. Paroxetine is a CYP2D6 substrate and fedratinib is a moderate CYP2D6 inhibitor.
Fenfluramine: (Major) Concomitant use of fenfluramine and paroxetine may increase fenfluramine plasma concentrations and the risk of adverse reactions, including serotonin syndrome. Avoid concomitant use if possible and monitor for serotonin syndrome if use is necessary. If concomitant use is unavoidable, do not exceed a maximum dose of fenfluramine 20 mg/day PO if coadministered with paroxetine and 17 mg/day PO if patient is also receiving stiripentol plus clobazam. Fenfluramine is a CYP2D6 substrate and paroxetine is a strong CYP2D6 inhibitor. Coadministration with paroxetine increased fenfluramine overall exposure by 81% and decreased norfenfluramine overall exposure by 13%.
Fentanyl: (Moderate) If concomitant use of fentanyl and paroxetine is warranted, monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
Flavoxate: (Moderate) Monitor for signs or symptoms of anticholinergic toxicity during concomitant anticholinergic medication and paroxetine use. Concomitant use may result in additive anticholinergic adverse effects.
Flecainide: (Moderate) Monitor for an increase in flecainide-related adverse reactions, including QT prolongation, if coadministration with paroxetine is necessary. Flecainide is a CYP2D6 substrate and paroxetine is a strong CYP2D6 inhibitor. Plasma concentrations of flecainide may increase, especially in extensive CYP2D6 metabolizers.
Fluoxetine: (Moderate) Monitor patients for an increase in adverse reactions and signs and symptoms of serotonin syndrome during concomitant use of paroxetine and fluoxetine, particularly during treatment initiation and dosage increases. If serotonin syndrome occurs, consider discontinuation of therapy. The concomitant use of serotonergic drugs increases the risk of serotonin syndrome. Concomitant use may increase paroxetine and/or fluoxetine exposure. Paroxetine is a substrate and strong inhibitor of CYP2D6 and fluoxetine is a substrate and strong inhibitor of CYP2D6.
Fluphenazine: (Moderate) Monitor for an increase in paroxetine- and fluphenazine-related adverse reactions, including serotonin syndrome, extrapyramidal symptoms, and somnolence, if coadministration is necessary. Concomitant use may increase the exposure of both drugs. Both drugs are CYP2D6 substrates; paroxetine is a strong CYP2D6 inhibitor and fluphenazine is a weak CYP2D6 inhibitor.
Fluvoxamine: (Moderate) Monitor patients for an increase in paroxetine-related adverse reactions and signs and symptoms of serotonin syndrome during concomitant use of paroxetine and fluvoxamine, particularly during treatment initiation and dosage increases. If serotonin syndrome occurs, consider discontinuation of therapy. The concomitant use of serotonergic drugs increases the risk of serotonin syndrome. Concomitant use may increase paroxetine exposure. Paroxetine is a CYP2D6 substrate and fluvoxamine is a weak CYP2D6 inhibitor.
Fondaparinux: (Moderate) Advise patients of the increased bleeding risk associated with the concomitant use of selective serotonin reuptake inhibitors (SSRIs) and anticoagulants like fondaparinux. Case reports and epidemiological studies have demonstrated an association between use of drugs that interfere with serotonin reuptake and gastrointestinal bleeding.
Fosamprenavir: (Moderate) The combined use of fosamprenavir, boosted with ritonavir, and paroxetine significantly reduced plasma concentrations of paroxetine. Adjust paroxetine dosage based upon tolerability and efficacy of the combined regimen.
Fosphenytoin: (Moderate) Monitor for loss of paroxetine efficacy during concomitant fosphenytoin use; a paroxetine dosage adjustment may be necessary. Fosphenytoin may impair paroxetine efficacy.
Frovatriptan: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering frovatriptan with selective serotonin reuptake inhibitors (SSRIs). Serotonin syndrome has been reported during concurrent use of serotonin-receptor agonists and SSRIs. Some patients had used the combination previously without incident when serotonin syndrome occurred. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly after a dose increase of the SSRI or the addition of other serotonergic medications to an existing SSRI regimen. Discontinue the SSRI and frovatriptan and initiate symptomatic treatment if serotonin syndrome occurs.
Gefitinib: (Moderate) Monitor for an increase in gefitinib- and paroxetine-related adverse reactions, including serotonin syndrome, if coadministration is necessary. Concomitant use may increase exposure of both drugs; the risk of gefitinib-related adverse reactions is increased in CYP2D6 poor metabolizers. Based on in vitro data, gefitinib is metabolized to O-desmethyl gefitinib by CYP2D6 and is a weak CYP2D6 inhibitor; paroxetine is a CYP2D6 substrate and strong CYP2D6 inhibitor. In healthy CYP2D6 poor metabolizers, the concentration of O-desmethyl gefitinib was not measurable and mean exposure to gefitinib was 2-fold higher compared to extensive metabolizers. The impact of CYP2D6 inhibitors on gefitinib pharmacokinetics has not been evaluated; however, the manufacturer recommends precautions based on exposure in patients with poor CYP2D6 metabolism. Coadministration with a weak CYP2D6 inhibitor increased paroxetine overall exposure by 50%.
Gilteritinib: (Major) Avoid coadministration of paroxetine with gilteritinib if possible due to the potential for decreased response to paroxetine. Gilteritinib inhibits human 5HT2B receptor or sigma nonspecific receptors, which may reduce the effects of drugs like paroxetine that target these receptors.
Givosiran: (Moderate) Monitor for an increase in paroxetine-related adverse reactions, including serotonin syndrome, if concomitant use with givosiran is necessary. Concomitant use may increase paroxetine exposure. Paroxetine is a CYP2D6 substrate and givosiran is a moderate CYP2D6 inhibitor.
Glycopyrrolate: (Moderate) Monitor for signs or symptoms of anticholinergic toxicity during concomitant anticholinergic medication and paroxetine use. Concomitant use may result in additive anticholinergic adverse effects.
Glycopyrrolate; Formoterol: (Moderate) Monitor for signs or symptoms of anticholinergic toxicity during concomitant anticholinergic medication and paroxetine use. Concomitant use may result in additive anticholinergic adverse effects.
Granisetron: (Major) Because of the potential risk and severity of serotonin syndrome, use caution when administering granisetron with other drugs that have serotonergic properties such as paroxetine. If serotonin syndrome is suspected, discontinue granisetron 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.
Grapefruit juice: (Major) Advise patients to avoid grapefruit and grapefruit juice during paroxetine treatment due to the risk of increased paroxetine exposure and adverse reactions. Paroxetine is a CYP2D6 substrate and grapefruit juice is a CYP2D6 inhibitor.
Guaifenesin; Hydrocodone: (Moderate) Careful monitoring, particularly during treatment initiation and dose adjustment, is recommended during coadministration of hydrocodone and paroxetine because of the potential risk of serotonin syndrome and prolonged opioid adverse reactions. Discontinue hydrocodone if serotonin syndrome is suspected. It is recommended to avoid this combination when hydrocodone is being used for cough. Concomitant use of hydrocodone with paroxetine may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. Monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of paroxetine could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If paroxetine is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP2D6. Paroxetine is a strong inhibitor of CYP2D6. 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.
Guselkumab: (Moderate) Monitor for an increase in paroxetine-related adverse reactions, including serotonin syndrome, if concomitant use with guselkumab is necessary. Concomitant use may increase paroxetine exposure. Paroxetine is a CYP2D6 substrate and guselkumab is a moderate CYP2D6 inhibitor.
Haloperidol: (Moderate) Monitor for an increase in haloperidol- and paroxetine-related side effects, such as QT prolongation, extrapyramidal symptoms, and serotonin syndrome, if coadministration is necessary. Coadministration may increase the exposure of both drugs. Both drugs are CYP2D6 substrates; paroxetine is a strong CYP2D6 inhibitor and haloperidol is a CYP2D6 inhibitor.
Heparin: (Moderate) Advise patients of the increased bleeding risk associated with the concomitant use of selective serotonin reuptake inhibitors (SSRIs) and anticoagulants like heparin. Case reports and epidemiological studies have demonstrated an association between use of drugs that interfere with serotonin reuptake and gastrointestinal bleeding.
Homatropine; Hydrocodone: (Moderate) Careful monitoring, particularly during treatment initiation and dose adjustment, is recommended during coadministration of hydrocodone and paroxetine because of the potential risk of serotonin syndrome and prolonged opioid adverse reactions. Discontinue hydrocodone if serotonin syndrome is suspected. It is recommended to avoid this combination when hydrocodone is being used for cough. Concomitant use of hydrocodone with paroxetine may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. Monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of paroxetine could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If paroxetine is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP2D6. Paroxetine is a strong inhibitor of CYP2D6. Serotonin syndrome is characterized by rapid development of hyperthermia, hyperten sion, 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. (Moderate) Monitor for signs or symptoms of anticholinergic toxicity during concomitant anticholinergic medication and paroxetine use. Concomitant use may result in additive anticholinergic adverse effects.
Hydrocodone: (Moderate) Careful monitoring, particularly during treatment initiation and dose adjustment, is recommended during coadministration of hydrocodone and paroxetine because of the potential risk of serotonin syndrome and prolonged opioid adverse reactions. Discontinue hydrocodone if serotonin syndrome is suspected. It is recommended to avoid this combination when hydrocodone is being used for cough. Concomitant use of hydrocodone with paroxetine may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. Monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of paroxetine could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If paroxetine is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP2D6. Paroxetine is a strong inhibitor of CYP2D6. 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.
Hydrocodone; Ibuprofen: (Moderate) Careful monitoring, particularly during treatment initiation and dose adjustment, is recommended during coadministration of hydrocodone and paroxetine because of the potential risk of serotonin syndrome and prolonged opioid adverse reactions. Discontinue hydrocodone if serotonin syndrome is suspected. It is recommended to avoid this combination when hydrocodone is being used for cough. Concomitant use of hydrocodone with paroxetine may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. Monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of paroxetine could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If paroxetine is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP2D6. Paroxetine is a strong inhibitor of CYP2D6. 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.
Hydrocodone; Pseudoephedrine: (Moderate) Careful monitoring, particularly during treatment initiation and dose adjustment, is recommended during coadministration of hydrocodone and paroxetine because of the potential risk of serotonin syndrome and prolonged opioid adverse reactions. Discontinue hydrocodone if serotonin syndrome is suspected. It is recommended to avoid this combination when hydrocodone is being used for cough. Concomitant use of hydrocodone with paroxetine may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. Monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of paroxetine could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If paroxetine is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP2D6. Paroxetine is a strong inhibitor of CYP2D6. 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.
Hydromorphone: (Moderate) If concomitant use of hydromorphone and paroxetine is warranted, monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
Hyoscyamine: (Moderate) Monitor for signs or symptoms of anticholinergic toxicity during concomitant anticholinergic medication and paroxetine use. Concomitant use may result in additive anticholinergic adverse effects.
Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate; Sodium Biphosphate: (Contraindicated) According to the manufacturer of paroxetine, treatment initiation with paroxetine is contraindicated in patients currently receiving intravenous (IV) methylene blue due to an increased risk of serotonin syndrome. If urgent psychiatric treatment is required, interventions other than paroxetine (e.g., alternative medication, hospitalization) should be considered. Conversely, in patients receiving paroxetine and requiring urgent treatment with IV methylene blue, paroxetine should be discontinued immediately and methylene blue therapy initiated only if acceptable alternatives are not available and the potential benefits outweigh the risks. The patient should be monitored for serotonin syndrome for 2 weeks or until 24 hours after the last dose of methylene blue, whichever comes first. Paroxetine may be re-initiated 24 hours after the last dose of methylene blue. Results from an in vitro study indicate that methylene blue is a potent, reversible inhibitor of the monoamine oxidase type A enzyme (MAO-A). MAO-A is responsible for the metabolism of serotonin; therefore, concurrent use of an MAO-A inhibitor with a serotonergic agent may result in a clinically significant interaction. Cases of serotonin syndrome have been reported, primarily following administration of standard infusions of methylene blue (1 to 8 mg/kg) as a visualizing agent, in patients receiving SSRIs, serotonin/norepinephrine reuptake inhibitors, or clomipramine. It is not known if patients receiving other serotonergic psychiatric agents with IV methylene blue are at a comparable risk or if methylene blue administered by other routes (e.g., orally, local injection) or in doses less than 1 mg/kg IV can produce a similar outcome. One case describes a patient receiving citalopram who experienced agitation, restlessness, pupil dilation with sluggish response to light, myoclonic movements of the lower limbs, and brisk reflexes following an infusion of methylene blue, while another patient receiving paroxetine developed tachycardia, agitation, dystonia and abnormal eye movements. During a retrospective study of 193 surgical patients who had received a methylene blue injection, it was found that all 12 of the patients who experienced postoperative neurological sequelae had been taking a serotonin reuptake inhibitor preoperatively. One of the 12 patients experienced cardiopulmonary arrest and died. Of the remaining 181 patients who did not experience neurological sequelae, 8.8% were taking a serotonin reuptake inhibitor. Published interaction reports between IV methylene blue and serotonergic psychiatric agents have documented symptoms including lethargy, confusion, delirium, agitation, aggression, obtundation, myoclonus, expressive aphasia, hypertonia, pyrexia, elevated blood pressure, seizures, and coma. Signs and symptoms of serotonin syndrome include fever, diaphoresis, shivering, myoclonus, tremor, tachycardia, diarrhea, nausea, headache, incoordination, mental status changes (e.g., agitation, confusion), hyperreflexia, seizures, and coma. (Moderate) Monitor for signs or symptoms of anticholinergic toxicity during concomitant anticholinergic medication and paroxetine use. Concomitant use may result in additive anticholinergic adverse effects. (Moderate) The combined use of selective serotonin reuptake inhibitors (SSRIs) and aspirin, ASA or other salicylates which affect hemostasis may elevate the risk for an upper GI bleed. SSRIs may inhibit serotonin uptake by platelets, augmenting the antiplatelet effects of aspirin.
Ibuprofen; Oxycodone: (Moderate) If concomitant use of oxycodone and paroxetine is warranted, monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
Iloperidone: (Major) Reduce the iloperidone dose by one-half if coadministered with paroxetine. If paroxetine is discontinued, increase the iloperidone dose to the previous level. Increased iloperidone exposure may occur with concurrent use. Iloperidone is a CYP2D6 substrate. Paroxetine is a strong inhibitor of CYP2D6. Coadministration of paroxetine increased mean steady-state peak concentrations of iloperidone and its metabolite P88, by about 1.6 fold, and decreased mean steady-state peak concentrations of its metabolite P95 by one-half.
Imatinib: (Moderate) Monitor for an increase in paroxetine-related adverse reactions, including serotonin syndrome, if concomitant use with imatinib is necessary. Concomitant use may increase paroxetine exposure. Paroxetine is a CYP2D6 substrate and imatinib is a weak CYP2D6 inhibitor. Coadministration with a weak CYP2D6 inhibitor increased paroxetine overall exposure by 50%.
Imipramine: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering selective serotonin reuptake inhibitors (SSRIs) with other drugs that have serotonergic properties such as tricyclic antidepressants. 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. In addition, paroxetine is a potent CYP2D6 inhibitor and may decrease the metabolism of imipramine, a CYP2D6 substrate. Because there is a risk of QT prolongation and torsade de pointes (TdP) with tricyclics at elevated serum concentrations, coadministration should be approached with caution and close monitoring. Lastly, both paroxetine and imipramine may exhibit significant anticholinergic effects that may be additive during concurrent use.
Indacaterol; Glycopyrrolate: (Moderate) Monitor for signs or symptoms of anticholinergic toxicity during concomitant anticholinergic medication and paroxetine use. Concomitant use may result in additive anticholinergic adverse effects.
Indinavir: (Moderate) Monitor for an increase in paroxetine-related adverse reactions, including serotonin syndrome, if concomitant use with indinavir is necessary. Concomitant use may increase paroxetine exposure. Paroxetine is a CYP2D6 substrate and indinavir is a weak CYP2D6 inhibitor. Coadministration with a weak CYP2D6 inhibitor increased paroxetine overall exposure by 50%.
Iobenguane I 123: (Major) Discontinue medications that decrease norepinephrine uptake, such as selective serotonin reuptake inhibitors (SSRIs), for at least 5 biological half-lives prior to iobenguane I 123 administration. Consider medication tapering or additional supportive therapy as appropriate to minimize the risk for precipitating SSRI withdrawal symptoms. Medications that decrease the uptake of norepinephrine can cause false negative imaging results. Increasing the dose of iobenguane I 123 will not overcome any potential uptake limiting effect of this medication.
Isocarboxazid: (Contraindicated) Due to the risk of serotonin syndrome, monoamine oxidase inhibitors (MAOIs) intended to treat psychiatric disorders are contraindicated for use with selective serotonin reuptake inhibitors (SSRIs). MAOIs should not be used within 5 weeks of discontinuing treatment with fluoxetine or within 14 days of discontinuing treatment with other SSRIs. Conversely, SSRIs should not be initiated within 14 days of stopping an MAOI. Monitor the patient for serotonin-related effects during therapy transitions.
Isoniazid, INH: (Major) Concurrent use of isoniazid and selective serotonin reuptake inhibitors (SSRIs) should be avoided if possible. Isoniazid is chemically related to iproniazid, a drug that was known to possess MAO inhibiting activity. Although isoniazid does not inhibit mitochondrial MAO, it does appear to inhibit plasma MAO. Isoniazid may possess enough MAO inhibiting activity to produce clinical symptoms consistent with serotonergic excess when combined with SSRIs. Concurrent use of SSRIs and MAOIs may lead to serious reactions including serotonin syndrome or neuroleptic malignant syndrome-like reactions. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. If combination therpay is necessary, patients should be monitored for the emergence of serotonin syndrome or neuroleptic malignant syndrome-like reactions.
Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Major) Concurrent use of isoniazid and selective serotonin reuptake inhibitors (SSRIs) should be avoided if possible. Isoniazid is chemically related to iproniazid, a drug that was known to possess MAO inhibiting activity. Although isoniazid does not inhibit mitochondrial MAO, it does appear to inhibit plasma MAO. Isoniazid may possess enough MAO inhibiting activity to produce clinical symptoms consistent with serotonergic excess when combined with SSRIs. Concurrent use of SSRIs and MAOIs may lead to serious reactions including serotonin syndrome or neuroleptic malignant syndrome-like reactions. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. If combination therpay is necessary, patients should be monitored for the emergence of serotonin syndrome or neuroleptic malignant syndrome-like reactions.
Isoniazid, INH; Rifampin: (Major) Concurrent use of isoniazid and selective serotonin reuptake inhibitors (SSRIs) should be avoided if possible. Isoniazid is chemically related to iproniazid, a drug that was known to possess MAO inhibiting activity. Although isoniazid does not inhibit mitochondrial MAO, it does appear to inhibit plasma MAO. Isoniazid may possess enough MAO inhibiting activity to produce clinical symptoms consistent with serotonergic excess when combined with SSRIs. Concurrent use of SSRIs and MAOIs may lead to serious reactions including serotonin syndrome or neuroleptic malignant syndrome-like reactions. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. If combination therpay is necessary, patients should be monitored for the emergence of serotonin syndrome or neuroleptic malignant syndrome-like reactions.
Lasmiditan: (Moderate) Serotonin syndrome may occur during coadministration of lasmiditan and selective serotonin reuptake inhibitors. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome, particularly after a dose increase or the addition of other serotonergic medications to an existing regimen. Discontinue all serotonergic agents if serotonin syndrome occurs and implement appropriate medical management.
Levomilnacipran: (Major) Because of the potential risk and severity of serotonin syndrome, concurrent use of levomilnacipran with other drugs that have serotonergic properties, such as selective serotonin reuptake inhibitors (SSRIs), should generally be avoided. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. If serotonin syndrome is suspected, levomilnacipran and concurrent serotonergic agents should be discontinued.
Levorphanol: (Moderate) If concomitant use of levorphanol and paroxetine is warranted, monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
Linezolid: (Contraindicated) According to the manufacturer of paroxetine, treatment initiation with paroxetine is contraindicated in patients currently receiving linezolid due to an increased risk of serotonin syndrome. If urgent psychiatric treatment is required, interventions other than paroxetine (e.g., alternative medication, hospitalization) should be considered. Conversely, in patients receiving paroxetine and requiring urgent treatment with linezolid, paroxetine 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 two weeks or until 24 hours after the last dose of linezolid, whichever comes first. Paroxetine may be re-initiated 24 hours after the last dose of linezolid. Linezolid is an antibiotic that is also a non-selective monoamine oxidase (MAO) inhibitor. Since monoamine oxidase type A deaminates serotonin, administration of a non-selective MAO inhibitor concurrently with paroxetine can lead to serious reactions including serotonin syndrome or neuroleptic malignant syndrome-like reactions. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. Serotonin syndrome has been reported in patients receiving either citalopram, escitalopram, fluoxetine, or paroxetine in combination with linezolid.
Lithium: (Moderate) Lithium is an effective augmenting agent to antidepressants in treatment-resistant depression; however, lithium has central serotonin-enhancing effects and may increase the risk of serotonin syndrome when combined with selective serotonin reuptake inhibitors (SSRIs) such as paroxetine. Inform patients of the possible increased risk and monitor for serotonin syndrome, particularly during treatment initiation and dosage increases. If serotonin syndrome occurs, serotonergic agents should be discontinued and symptomatic treatment should be initiated.
Lofexidine: (Moderate) Monitor for orthostatic hypotension and bradycardia during concurrent use of lofexidine and paroxetine. Coadministration may increase lofexidine exposure. Lofexidine is a CYP2D6 substrate; paroxetine is a strong CYP2D6 inhibitor. Coadministration with paroxetine increased the lofexidine AUC by 28%.
Lopinavir; Ritonavir: (Moderate) Monitor for an increase in paroxetine-related adverse reactions, including serotonin syndrome, if concomitant use with ritonavir is necessary. Concomitant use may increase paroxetine exposure. Paroxetine is a CYP2D6 substrate and ritonavir is a weak CYP2D6 inhibitor.
Lorcaserin: (Major) Based on the mechanism of action of lorcaserin and the theoretical potential for serotonin syndrome, use with extreme caution in combination with other drugs that may affect the serotonergic neurotransmitter systems, including, selective serotonin reuptake inhibitors (SSRIs). Patients receiving this combination should be monitored for the emergence of serotonin syndrome or Neuroleptic Malignant Syndrome (NMS) like signs and symptoms.
Low Molecular Weight Heparins: (Moderate) Monitor for signs and symptoms of bleeding during concomitant low molecular weight heparin and selective serotonin reuptake inhibitor (SSRI) use due to increased risk for bleeding. Serotonin release by platelets plays an important role in hemostasis. Epidemiological studies have demonstrated an association between use of psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper gastrointestinal bleeding. Altered anticoagulant effects, including increased bleeding, have been reported when SSRIs are coadministered with another anticoagulant.
Loxapine: (Moderate) Additive anticholinergic effects may be seen when drugs with anticholinergic properties like paroxetine and loxapine are used concomitantly. Adverse effects may be seen not only on GI smooth muscle, but also on bladder function, the CNS, the eye, and temperature regulation.
Magnesium Salicylate: (Moderate) Monitor for signs and symptoms of bleeding during concomitant magnesium salicylate and selective serotonin reuptake inhibitor (SSRI) use due to increased risk for bleeding. Serotonin release by platelets plays an important role in hemostasis. Epidemiological studies have demonstrated an association between use of psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper gastrointestinal bleeding.
Maprotiline: (Major) Paroxetine is a potent inhibitor of CYP2D6, the primary isoenzyme responsible for the metabolism of maprotiline. In several cases, symptoms of toxicity, including seizures, have been reported when SSRIs and cyclic antidepressants have been used together. In addition, because maprotiline is a CYP2D6 substrate and has a possible risk of QT prolongation and torsade de pointes, concurrent use of a potent CYP2D6 inhibitor such as paroxetine may increase the risk of such events. Patients receiving maprotiline should be monitored closely for toxicity if paroxetine is added.
Meclizine: (Moderate) Of the selective serotonin reuptake inhibiting antidepressants (SSRIs), paroxetine is considered the most anticholinergic. Additive anticholinergic effects may be seen when paroxetine is used with other medications having anticholinergic properties such as meclizine. Patients should be informed to read non-prescription cough and cold product labels carefully for additional interacting antihistamines.
Meperidine: (Moderate) If concomitant use of meperidine and paroxetine is warranted, monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
Metaxalone: (Moderate) Concomitant use of selective serotonin reuptake inhibitors (SSRIs) and metaxalone may increase the risk for serotonin syndrome. Monitor patients for serotonin syndrome if concomitant use is necessary.
Methadone: (Moderate) Monitor patients for respiratory depression and sedation at frequent intervals if concomitant administration of methadone and paroxetine is necessary; consider reducing the methadone dose until stable effects are achieved. Concomitant use of methadone and paroxetine may increase the plasma concentration of methadone, resulting in increased or prolonged opioid effects. If paroxetine is discontinued, consider increasing the methadone dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Methadone is a CYP2D6 substrate and paroxetine is a CYP2D6 inhibitor. 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.
Methenamine; Sodium Acid Phosphate; Methylene Blue; Hyoscyamine: (Contraindicated) According to the manufacturer of paroxetine, treatment initiation with paroxetine is contraindicated in patients currently receiving intravenous (IV) methylene blue due to an increased risk of serotonin syndrome. If urgent psychiatric treatment is required, interventions other than paroxetine (e.g., alternative medication, hospitalization) should be considered. Conversely, in patients receiving paroxetine and requiring urgent treatment with IV methylene blue, paroxetine should be discontinued immediately and methylene blue therapy initiated only if acceptable alternatives are not available and the potential benefits outweigh the risks. The patient should be monitored for serotonin syndrome for 2 weeks or until 24 hours after the last dose of methylene blue, whichever comes first. Paroxetine may be re-initiated 24 hours after the last dose of methylene blue. Results from an in vitro study indicate that methylene blue is a potent, reversible inhibitor of the monoamine oxidase type A enzyme (MAO-A). MAO-A is responsible for the metabolism of serotonin; therefore, concurrent use of an MAO-A inhibitor with a serotonergic agent may result in a clinically significant interaction. Cases of serotonin syndrome have been reported, primarily following administration of standard infusions of methylene blue (1 to 8 mg/kg) as a visualizing agent, in patients receiving SSRIs, serotonin/norepinephrine reuptake inhibitors, or clomipramine. It is not known if patients receiving other serotonergic psychiatric agents with IV methylene blue are at a comparable risk or if methylene blue administered by other routes (e.g., orally, local injection) or in doses less than 1 mg/kg IV can produce a similar outcome. One case describes a patient receiving citalopram who experienced agitation, restlessness, pupil dilation with sluggish response to light, myoclonic movements of the lower limbs, and brisk reflexes following an infusion of methylene blue, while another patient receiving paroxetine developed tachycardia, agitation, dystonia and abnormal eye movements. During a retrospective study of 193 surgical patients who had received a methylene blue injection, it was found that all 12 of the patients who experienced postoperative neurological sequelae had been taking a serotonin reuptake inhibitor preoperatively. One of the 12 patients experienced cardiopulmonary arrest and died. Of the remaining 181 patients who did not experience neurological sequelae, 8.8% were taking a serotonin reuptake inhibitor. Published interaction reports between IV methylene blue and serotonergic psychiatric agents have documented symptoms including lethargy, confusion, delirium, agitation, aggression, obtundation, myoclonus, expressive aphasia, hypertonia, pyrexia, elevated blood pressure, seizures, and coma. Signs and symptoms of serotonin syndrome include fever, diaphoresis, shivering, myoclonus, tremor, tachycardia, diarrhea, nausea, headache, incoordination, mental status changes (e.g., agitation, confusion), hyperreflexia, seizures, and coma. (Moderate) Monitor for signs or symptoms of anticholinergic toxicity during concomitant anticholinergic medication and paroxetine use. Concomitant use may result in additive anticholinergic adverse effects.
Methscopolamine: (Moderate) Monitor for signs or symptoms of anticholinergic toxicity during concomitant anticholinergic medication and paroxetine use. Concomitant use may result in additive anticholinergic adverse effects.
Methylene Blue: (Contraindicated) According to the manufacturer of paroxetine, treatment initiation with paroxetine is contraindicated in patients currently receiving intravenous (IV) methylene blue due to an increased risk of serotonin syndrome. If urgent psychiatric treatment is required, interventions other than paroxetine (e.g., alternative medication, hospitalization) should be considered. Conversely, in patients receiving paroxetine and requiring urgent treatment with IV methylene blue, paroxetine should be discontinued immediately and methylene blue therapy initiated only if acceptable alternatives are not available and the potential benefits outweigh the risks. The patient should be monitored for serotonin syndrome for 2 weeks or until 24 hours after the last dose of methylene blue, whichever comes first. Paroxetine may be re-initiated 24 hours after the last dose of methylene blue. Results from an in vitro study indicate that methylene blue is a potent, reversible inhibitor of the monoamine oxidase type A enzyme (MAO-A). MAO-A is responsible for the metabolism of serotonin; therefore, concurrent use of an MAO-A inhibitor with a serotonergic agent may result in a clinically significant interaction. Cases of serotonin syndrome have been reported, primarily following administration of standard infusions of methylene blue (1 to 8 mg/kg) as a visualizing agent, in patients receiving SSRIs, serotonin/norepinephrine reuptake inhibitors, or clomipramine. It is not known if patients receiving other serotonergic psychiatric agents with IV methylene blue are at a comparable risk or if methylene blue administered by other routes (e.g., orally, local injection) or in doses less than 1 mg/kg IV can produce a similar outcome. One case describes a patient receiving citalopram who experienced agitation, restlessness, pupil dilation with sluggish response to light, myoclonic movements of the lower limbs, and brisk reflexes following an infusion of methylene blue, while another patient receiving paroxetine developed tachycardia, agitation, dystonia and abnormal eye movements. During a retrospective study of 193 surgical patients who had received a methylene blue injection, it was found that all 12 of the patients who experienced postoperative neurological sequelae had been taking a serotonin reuptake inhibitor preoperatively. One of the 12 patients experienced cardiopulmonary arrest and died. Of the remaining 181 patients who did not experience neurological sequelae, 8.8% were taking a serotonin reuptake inhibitor. Published interaction reports between IV methylene blue and serotonergic psychiatric agents have documented symptoms including lethargy, confusion, delirium, agitation, aggression, obtundation, myoclonus, expressive aphasia, hypertonia, pyrexia, elevated blood pressure, seizures, and coma. Signs and symptoms of serotonin syndrome include fever, diaphoresis, shivering, myoclonus, tremor, tachycardia, diarrhea, nausea, headache, incoordination, mental status changes (e.g., agitation, confusion), hyperreflexia, seizures, and coma.
Methylergonovine: (Moderate) Use paroxetine and ergot alkaloids together with caution due to a potential for serotonin syndrome. Weakness, hyperreflexia, and incoordination have been reported rarely when ergot alkaloids or other serotonin agonists have been coadministered with SSRIs, which may be indicative of serotonin excess. If serotonin syndrome occurs, discontinue the offending agents and institute appropriate treatment.
Methylphenidate Derivatives: (Moderate) Caution should be observed when coadministering methylphenidate derivatives and the selective serotonin reuptake inhibitors (SSRIs). There are postmarketing reports of serotonin syndrome during concurrent use of methylphenidate derivatives with other serotonergic medications. Human pharmacologic studies have shown that methylphenidate may inhibit the metabolism of some SSRIs and downward dose adjustment of the SSRI may be required in some patients. Inform patients of the possible increased risk and monitor for the emergence of serotonin syndrome. If serotonin syndrome occurs, serotonergic agents should be discontinued and appropriate medical management should be implemented.
Metoclopramide: (Major) When metoclopramide is used with a potent CYP2D6 inhibitor for the treatment of gastroesophageal reflux (GERD), dosage reductions of oral metoclopramide are required, with maximum oral dosage not to exceed 30 mg/day (e.g., 5 mg 4 times daily or 10 mg 3 times daily). There is a known increase in metoclopramide exposure and an increased risk for extrapyramidal adverse reactions. Metoclopramide is a substrate of CYP2D6 and paroxetine is a strong CYP2D6 inhibitor. The manufacturer recommends avoidance of paroxetine and consideration of alternative SSRI antidepressants when oral metoclopramide is used in patients with diabetic gastroparesis. Healthy patients given 20 mg of metoclopramide and a strong CYP2D6 inhibitor for 8 days had a 40% and 90% increase in metoclopramide Cmax and AUC, respectively, compared to patients who received metoclopramide alone. Additionally, concomitant use of metoclopramide and SSRIs such as paroxetine may increase the risk for serotonin syndrome. In rare cases postmarketing, NMS-like symptoms, which may overlap with serotonin syndrome symptoms, have been reported with metoclopramide when used with serotonergic agents.
Metoprolol: (Moderate) Monitor for metoprolol-related adverse reactions, including bradycardia and hypotension, during coadministration with paroxetine. Concomitant use may increase metoprolol serum concentrations which would decrease the cardioselectivity of metoprolol. Metoprolol is a CYP2D6 substrate and paroxetine is a CYP2D6 inhibitor.
Metoprolol; Hydrochlorothiazide, HCTZ: (Moderate) Monitor for metoprolol-related adverse reactions, including bradycardia and hypotension, during coadministration with paroxetine. Concomitant use may increase metoprolol serum concentrations which would decrease the cardioselectivity of metoprolol. Metoprolol is a CYP2D6 substrate and paroxetine is a CYP2D6 inhibitor.
Mexiletine: (Moderate) Paroxetine impairs metabolism of the cytochrome P-450 isoenzyme CYP2D6 pathway at therapeutic doses. Although no clinical data are available, paroxetine should be used cautiously in patients receiving mexiletine since this antiarrhythmic is metabolized by this isozyme. Inhibition of CYP2D6 can result in increased concentrations of drugs metabolized via the same pathway, including mexiletine, which may increase the risk of side effects or proarrhythmia.
Milnacipran: (Major) Because of the potential risk and severity of serotonin syndrome, concurrent use of milnacipran with other drugs that have serotonergic properties, such as the selective serotonin reuptake inhibitors (SSRIs), should generally be avoided. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. If serotonin syndrome is suspected, milnacipran and concurrent serotonergic agents should be discontinued.
Mirabegron: (Moderate) Monitor for an increase in paroxetine-related adverse reactions, including serotonin syndrome, if concomitant use with mirabegron is necessary. Concomitant use may increase paroxetine exposure. Paroxetine is a CYP2D6 substrate and mirabegron is a moderate CYP2D6 inhibitor.
Mirtazapine: (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.
Monoamine oxidase inhibitors: (Contraindicated) Due to the risk of serotonin syndrome, monoamine oxidase inhibitors (MAOIs) intended to treat psychiatric disorders are contraindicated for use with selective serotonin reuptake inhibitors (SSRIs). MAOIs should not be used within 5 weeks of discontinuing treatment with fluoxetine or within 14 days of discontinuing treatment with other SSRIs. Conversely, SSRIs should not be initiated within 14 days of stopping an MAOI. Monitor the patient for serotonin-related effects during therapy transitions.
Morphine: (Moderate) If concomitant use of morphine and paroxetine is warranted, monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
Morphine; Naltrexone: (Moderate) If concomitant use of morphine and paroxetine is warranted, monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
Nalbuphine: (Moderate) If concomitant use of nalbuphine and paroxetine is warranted, monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
Naratriptan: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering naratriptan with selective serotonin reuptake inhibitors (SSRIs). Serotonin syndrome has been reported during concurrent use of serotonin-receptor agonists ("triptans") and SSRIs. Inform patients of the possible increased risk and monitor for the emergence of serotonin syndrome, particularly after initiation of SSRI treatment or any dose increases. Discontinue serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
Nebivolol: (Major) Avoid the concomitant use of nebivolol and paroxetine. Concomitant use may increase the exposure of nebivolol and the risk of adverse effects. Nebivolol is a CYP2D6 substrate and paroxetine is a strong CYP2D6 inhibitor. Coadministration with another strong CYP2D6 inhibitor caused an 8-fold increase in the AUC of d-nebivolol.
Nebivolol; Valsartan: (Major) Avoid the concomitant use of nebivolol and paroxetine. Concomitant use may increase the exposure of nebivolol and the risk of adverse effects. Nebivolol is a CYP2D6 substrate and paroxetine is a strong CYP2D6 inhibitor. Coadministration with another strong CYP2D6 inhibitor caused an 8-fold increase in the AUC of d-nebivolol.
Nefazodone: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when coadministering drugs that have serotonergic properties such as nefazodone and paroxetine. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. At least one case report of serotonin syndrome from the concurrent use of nefazodone and a selective serotonin reuptake inhibitor (i.e., paroxetine) has been published. Additionally, when a 200 mg dose of nefazodone was administered to subjects who had been receiving fluoxetine for 1 week, there was an increased incidence of transient serotonin-related adverse events. If serotonin syndrome occurs, all serotonergic agents should be discontinued and appropriate medical treatment should be implemented.
Neostigmine; Glycopyrrolate: (Moderate) Monitor for signs or symptoms of anticholinergic toxicity during concomitant anticholinergic medication and paroxetine use. Concomitant use may result in additive anticholinergic adverse effects.
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 paroxetine. If serotonin syndrome is suspected, discontinue palonosetron and concurrent serotonergic agents and initiate appropriate medical treatment. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death.
Nicardipine: (Moderate) Monitor for an increase in paroxetine-related adverse reactions, including serotonin syndrome, if concomitant use with nicardipine is necessary. Concomitant use may increase paroxetine exposure. Paroxetine is a CYP2D6 substrate and nicardipine is a weak CYP2D6 inhibitor. Coadministration with a weak CYP2D6 inhibitor increased paroxetine overall exposure by 50%.
Niraparib; Abiraterone: (Moderate) Monitor for an increase in paroxetine-related adverse reactions, including serotonin syndrome, if concomitant use with abiraterone is necessary. Concomitant use may increase paroxetine exposure. Paroxetine is a CYP2D6 substrate and abiraterone is a moderate CYP2D6 inhibitor.
Nirmatrelvir; Ritonavir: (Moderate) Monitor for an increase in paroxetine-related adverse reactions, including serotonin syndrome, if concomitant use with ritonavir is necessary. Concomitant use may increase paroxetine exposure. Paroxetine is a CYP2D6 substrate and ritonavir is a weak CYP2D6 inhibitor.
Nitroglycerin: (Minor) Nitroglycerin can cause hypotension. This action may be additive with other agents that can cause hypotension such as antidepressants. Patients should be monitored more closely for hypotension if nitroglycerin is used concurrently with antidepressants.
Nonsteroidal antiinflammatory drugs: (Moderate) Monitor for signs and symptoms of bleeding during concomitant selective serotonin reuptake inhibitor (SSRI) and nonsteroidal antiinflammatory drug (NSAID) use due to increased risk for bleeding. Serotonin release by platelets plays an important role in hemostasis. Epidemiological studies have demonstrated an association between use of psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper gastrointestinal bleeding.
Nortriptyline: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering selective serotonin reuptake inhibitors (SSRIs) with other drugs that have serotonergic properties such as tricyclic antidepressants. In addition, paroxetine is a potent CYP2D6 inhibitor and may decrease the metabolism of nortriptyline, a CYP2D6 substrate. Because there is a risk of QT prolongation and torsade de pointes (TdP) with tricyclics at elevated serum concentrations, coadministration should be approached with caution and close monitoring. Lastly, both paroxetine and nortriptyline may exhibit significant anticholinergic effects that may be additive during concurrent use.
Olanzapine: (Major) Concurrent use of paroxetine and olanzapine may result in additive anticholinergic effects, such as urinary retention, constipation, blurred vision, and xerostomia. In addition, paroxetine is a potent inhibitor of CYP2D6, which is a minor isoenzyme pathway for the metabolism of olanzapine. Adverse effects of olanzapine that may become evident include fatigue, dizziness, weight gain, prolactin elevation, orthostatic hypotension, sedation, or extrapyramidal symptoms. In addition, olanzapine is associated with a possible risk of QT prolongation and should be used cautiously with strong CYP2D6 inhibitors such as paroxetine.
Olanzapine; Fluoxetine: (Major) Concurrent use of paroxetine and olanzapine may result in additive anticholinergic effects, such as urinary retention, constipation, blurred vision, and xerostomia. In addition, paroxetine is a potent inhibitor of CYP2D6, which is a minor isoenzyme pathway for the metabolism of olanzapine. Adverse effects of olanzapine that may become evident include fatigue, dizziness, weight gain, prolactin elevation, orthostatic hypotension, sedation, or extrapyramidal symptoms. In addition, olanzapine is associated with a possible risk of QT prolongation and should be used cautiously with strong CYP2D6 inhibitors such as paroxetine. (Moderate) Monitor patients for an increase in adverse reactions and signs and symptoms of serotonin syndrome during concomitant use of paroxetine and fluoxetine, particularly during treatment initiation and dosage increases. If serotonin syndrome occurs, consider discontinuation of therapy. The concomitant use of serotonergic drugs increases the risk of serotonin syndrome. Concomitant use may increase paroxetine and/or fluoxetine exposure. Paroxetine is a substrate and strong inhibitor of CYP2D6 and fluoxetine is a substrate and strong inhibitor of CYP2D6.
Olanzapine; Samidorphan: (Major) Concurrent use of paroxetine and olanzapine may result in additive anticholinergic effects, such as urinary retention, constipation, blurred vision, and xerostomia. In addition, paroxetine is a potent inhibitor of CYP2D6, which is a minor isoenzyme pathway for the metabolism of olanzapine. Adverse effects of olanzapine that may become evident include fatigue, dizziness, weight gain, prolactin elevation, orthostatic hypotension, sedation, or extrapyramidal symptoms. In addition, olanzapine is associated with a possible risk of QT prolongation and should be used cautiously with strong CYP2D6 inhibitors such as paroxetine.
Oliceridine: (Moderate) Monitor patients closely for respiratory depression and sedation at frequent intervals and base subsequent doses on the patient's severity of pain and response to treatment if concomitant administration of oliceridine and paroxetine is necessary; less frequent dosing of oliceridine may be required. Concomitant use of oliceridine and paroxetine may increase the plasma concentration of oliceridine, resulting in increased or prolonged opioid effects. If paroxetine is discontinued, consider increasing the oliceridine dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Oliceridine is a CYP2D6 substrate and paroxetine is a strong CYP2D6 inhibitor. 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.
Ondansetron: (Major) Concomitant use of ondansetron and paroxetine increases the risk for serotonin syndrome. Avoid concomitant use if possible and monitor for serotonin syndrome if use is necessary.
Oritavancin: (Moderate) Paroxetine is metabolized by CYP2D6; oritavancin is a weak CYP2D6 inducer. Plasma concentrations and efficacy of paroxetine may be reduced if these drugs are administered concurrently.
Orphenadrine: (Moderate) Additive anticholinergic effects may be seen when drugs with anticholinergic properties, like paroxetine and orphenadrine, are used concomitantly. Adverse effects may be seen not only on GI smooth muscle, but also on bladder function, the CNS, the eye, and temperature regulation.
Osilodrostat: (Moderate) Monitor for an increase in paroxetine-related adverse reactions, including serotonin syndrome, if concomitant use with osilodrostat is necessary. Concomitant use may increase paroxetine exposure. Paroxetine is a CYP2D6 substrate and osilodrostat is a weak CYP2D6 inhibitor. Coadministration with a weak CYP2D6 inhibitor increased paroxetine overall exposure by 50%.
Oxybutynin: (Moderate) Monitor for signs or symptoms of anticholinergic toxicity during concomitant anticholinergic medication and paroxetine use. Concomitant use may result in additive anticholinergic adverse effects.
Oxycodone: (Moderate) If concomitant use of oxycodone and paroxetine is warranted, monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
Oxymorphone: (Moderate) If concomitant use of oxymorphone and paroxetine is warranted, monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
Ozanimod: (Major) Coadministration of ozanimod with paroxetine is not recommended due to the potential for hypertensive crisis and serotonin syndrome. If coadministration is necessary, closely monitor patients for hypertension and serotonergic effects. An active metabolite of ozanimod inhibits MAO-B, which may increase the potential for hypertensive crisis or serotonin syndrome. Paroxetine may increase blood pressure or sertonergic side effects by increasing serotonin concentrations.
Paliperidone: (Minor) Paroxetine is a potent inhibitor of CYP2D6, which may result in decreased clearance of partial CYP2D6 substrates such as paliperidone. Decreased metabolism of paliperidone may lead to clinically important adverse reactions such as extrapyramidal symptoms. In addition, paliperidone is associated with a risk for QT prolongation and torsade de pointes (TdP), and should be used cautiously with potent CYP2D6 inhibitors such as paroxetine. In one study of healthy subjects, paliperidone exposure was an average of 16% higher in extensive metabolizers of CYP2D6 who were receiving paroxetine 20 mg/day concurrently. The clinical significance of this interaction is unknown.
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 paroxetine. 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: (Moderate) Monitor for an increase in paroxetine-related adverse reactions, including serotonin syndrome, if concomitant use with panobinostat is necessary. Concomitant use may increase paroxetine exposure. Paroxetine is a CYP2D6 substrate and panobinostat is a moderate CYP2D6 inhibitor.
Pazopanib: (Moderate) Monitor for an increase in paroxetine-related adverse reactions, including serotonin syndrome, if concomitant use with pazopanib is necessary. Concomitant use may increase paroxetine exposure. Paroxetine is a CYP2D6 substrate and pazopanib is a weak CYP2D6 inhibitor. Coadministration with a weak CYP2D6 inhibitor increased paroxetine overall exposure by 50%.
Peginterferon Alfa-2b: (Moderate) Monitor for an increase in paroxetine-related adverse reactions, including serotonin syndrome, if concomitant use with peginterferon alfa-2b is necessary. Concomitant use may increase paroxetine exposure. Paroxetine is a CYP2D6 substrate and peginterferon alfa-2b is a weak CYP2D6 inhibitor.
Pentamidine: (Moderate) Pentamidine is a substrate of CYP2D6 and paroxetine is a potent inhibitor of CYP2D6. Because pentamidine is a CYP2D6 substrate and has a possible risk of QT prolongation and torsade de pointes, concurrent use of a potent CYP2D6 inhibitor such as paroxetine may increase the risk of such events.
Pentazocine: (Major) Because of the potential risk and severity of serotonin syndrome reactions, caution should be observed when administering selective serotonin reuptake inhibitors (SSRIs) with other drugs that have serotonergic properties such as pentazocine. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. If serotonin syndrome occurs, discontinue the offending agent(s) and institute appropriate therapy.
Pentazocine; Naloxone: (Major) Because of the potential risk and severity of serotonin syndrome reactions, caution should be observed when administering selective serotonin reuptake inhibitors (SSRIs) with other drugs that have serotonergic properties such as pentazocine. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. If serotonin syndrome occurs, discontinue the offending agent(s) and institute appropriate therapy.
Pentosan: (Moderate) Advise patients of the increased bleeding risk associated with the concomitant use of selective serotonin reuptake inhibitors (SSRIs) and pentosan, which has weak anticoagulant properties. Case reports and epidemiological studies have demonstrated an association between use of drugs that interfere with serotonin reuptake and gastrointestinal bleeding.
Perphenazine: (Moderate) Monitor for an increase in paroxetine- and perphenazine-related adverse reactions, including serotonin syndrome, extrapyramidal symptoms, and somnolence, if coadministration is necessary. Concomitant use may increase the exposure of both drugs. Both drugs are CYP2D6 substrates; paroxetine is a strong CYP2D6 inhibitor and perphenazine is a weak CYP2D6 inhibitor.
Perphenazine; Amitriptyline: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering selective serotonin reuptake inhibitors (SSRIs) with other drugs that have serotonergic properties such as tricyclic antidepressants. Additionally, monitor for an increase in amitriptyline-related adverse reactions if coadministration with paroxetine is necessary; a dose reduction of amitriptyline may be necessary. Concurrent use may increase the plasma concentrations of amitriptyline. Amitriptyline is a CYP2D6 substrate and paroxetine is a CYP2D6 inhibitor. Paroxetine and amitriptyline both exhibit significant anticholinergic effects that may be additive during concurrent use. (Moderate) Monitor for an increase in paroxetine- and perphenazine-related adverse reactions, including serotonin syndrome, extrapyramidal symptoms, and somnolence, if coadministration is necessary. Concomitant use may increase the exposure of both drugs. Both drugs are CYP2D6 substrates; paroxetine is a strong CYP2D6 inhibitor and perphenazine is a weak CYP2D6 inhibitor.
Phenelzine: (Contraindicated) Due to the risk of serotonin syndrome, monoamine oxidase inhibitors (MAOIs) intended to treat psychiatric disorders are contraindicated for use with selective serotonin reuptake inhibitors (SSRIs). MAOIs should not be used within 5 weeks of discontinuing treatment with fluoxetine or within 14 days of discontinuing treatment with other SSRIs. Conversely, SSRIs should not be initiated within 14 days of stopping an MAOI. Monitor the patient for serotonin-related effects during therapy transitions.
Phenobarbital; Hyoscyamine; Atropine; Scopolamine: (Moderate) Monitor for signs or symptoms of anticholinergic toxicity during concomitant anticholinergic medication and paroxetine use. Concomitant use may result in additive anticholinergic adverse effects.
Phentermine: (Moderate) Use phentermine and selective serotonin reuptake inhibitors (SSRIs) together with caution due to a potential for serotonin syndrome. Monitor weight, cardiovascular status, and for potential serotonergic adverse effects. Phentermine is related to the amphetamines, and there has been historical concern that phentermine might exhibit potential to cause serotonin syndrome when combined with serotonergic agents. However, recent data suggest that phentermine's effect on MAO inhibition and serotonin augmentation is minimal at therapeutic doses and some large controlled clinical studies have allowed patients to start phentermine-based therapy for obesity along with their SSRI as long as the antidepressant dose had been stable for at least 3 months prior. Such therapy was generally well-tolerated, especially at lower phentermine doses. Because depression and obesity often coexist, the study data may be important to providing optimal co-therapies.
Phentermine; Topiramate: (Moderate) Use phentermine and selective serotonin reuptake inhibitors (SSRIs) together with caution due to a potential for serotonin syndrome. Monitor weight, cardiovascular status, and for potential serotonergic adverse effects. Phentermine is related to the amphetamines, and there has been historical concern that phentermine might exhibit potential to cause serotonin syndrome when combined with serotonergic agents. However, recent data suggest that phentermine's effect on MAO inhibition and serotonin augmentation is minimal at therapeutic doses and some large controlled clinical studies have allowed patients to start phentermine-based therapy for obesity along with their SSRI as long as the antidepressant dose had been stable for at least 3 months prior. Such therapy was generally well-tolerated, especially at lower phentermine doses. Because depression and obesity often coexist, the study data may be important to providing optimal co-therapies.
Phenytoin: (Moderate) Monitor for loss of paroxetine efficacy during concomitant phenytoin use; a paroxetine dosage adjustment may be necessary. Phenytoin may impair paroxetine efficacy.
Pimozide: (Contraindicated) Pimozide is contraindicated for use with selective serotonin reuptake inhibitors (SSRIs) due to an increased risk of QT prolongation and torsade de pointes (TdP). Pimozide is thought to be primarily metabolized through CYP3A4, and to a lesser extent, CYP1A2 and CYP2D6. Elevated plasma concentrations of pimozide occurring through inhibition of one or more of these isoenzymes by SSRIs can lead to QT prolongation, ventricular arrhythmias, and sudden death. Additionally, most SSRIs are also associated with QT prolongation, further increasing the risk of additive QT prolongation.
Pirfenidone: (Moderate) Pirfenidone is primarily metabolized by CYP1A2 with minor contributions from other CYP isoenzymes including CYP2D6. Paroxetine is a potent inhibitor of CYP2D6. Because pirfenidone is a CYP2D6 substrate and has a possible risk of QT prolongation and torsade de pointes, concurrent use of a potent CYP2D6 inhibitor such as paroxetine may increase the risk of such events and should be approached with caution.
Pitolisant: (Major) Initiate pitolisant at 8.9 mg once daily in patients taking paroxetine; increase pitolisant after 7 days to a maximum dosage of 17.8 mg once daily. If paroxetine is initiated in a patient on a stable dose of pitolisant, reduce the pitolisant dose by half. Pitolisant is a CYP2D6 substrate; paroxetine is a strong CYP2D6 inhibitor. Coadministration of paroxetine increased pitolisant exposure by 2.2-fold.
Prasugrel: (Moderate) Platelet aggregation may be impaired by selective serotonin reuptake inhibitors (SSRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication in patients receiving prasugrel. Patients should be instructed to monitor for signs and symptoms of bleeding while taking an SSRI concurrently with an antiplatelet medication and to promptly report any bleeding events to the practitioner.
Procarbazine: (Major) Procarbazine is a weak monoamine oxidase inhibitor (MAOI). Although procarbazine appears to be less likely than other MAOIs to produce serious drug interactions, clinicians should avoid the use of selective serotonin reuptake inhibitors (SSRIs) in patients receiving MAOIs. Fatalities have been reported when fluoxetine was administered to patients receiving MAOIs. Confusion, seizures, severe hypertension, and other, less severe symptoms have also been reported with this drug combination. Non-selective MAOIs inhibit both MAO types A and B. Since serotonin is metabolized by MAO type A, it is thought that this drug interaction may lead to serotonin syndrome or neuroleptic malignant syndrome-like reactions. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. At least 2 weeks should elapse between the discontinuation of MAOI therapy and the start of therapy with an SSRI except fluoxetine. At least 5 weeks should elapse between the discontinuation of fluoxetine therapy and commencement of MAOI therapy. This 5-week period is needed because of the long half-lives of fluoxetine and its principle metabolite norfluoxetine.
Prochlorperazine: (Moderate) Substantial increases in concentrations of phenothiazines may occur due to CYP2D6 inhibition by paroxetine, which may increase the risk of adverse effects, including extrapyramidal symptoms or QT prolongation. Phenothiazines with a possible risk of QT prolongation include prochlorperazine. Additive anticholinergic effects are also possible.
Promethazine: (Moderate) Monitor for signs or symptoms of anticholinergic toxicity during concomitant paroxetine and promethazine use. Concomitant use may result in additive anticholinergic adverse effects.
Promethazine; Dextromethorphan: (Moderate) Monitor for dextromethorphan-related side effects, such as dizziness or drowsiness, if concomitant use of paroxetine is necessary. For patients receiving combination dextromethorphan; bupropion, do not exceed a maximum dose of 45 mg dextromethorphan; 105 mg bupropion once daily. Additionally, monitor patients for signs and symptoms of serotonin syndrome. Concomitant use may increase dextromethorphan exposure and the risk for serotonin syndrome. Dextromethorphan is a CYP2D6 substrate and paroxetine is a strong CYP2D6 inhibitor. Concomitant use with paroxetine increased dextromethorphan overall exposure by 2.69-fold. (Moderate) Monitor for signs or symptoms of anticholinergic toxicity during concomitant paroxetine and promethazine use. Concomitant use may result in additive anticholinergic adverse effects.
Promethazine; Phenylephrine: (Moderate) Monitor for signs or symptoms of anticholinergic toxicity during concomitant paroxetine and promethazine use. Concomitant use may result in additive anticholinergic adverse effects.
Propafenone: (Moderate) Monitor for increased propafenone toxicity if coadministered with paroxetine; concurrent use may increase propafenone exposure and therefore increase the risk of proarrhythmias. Avoid simultaneous use of propafenone and paroxetine with a CYP3A4 inhibitor. Propafenone is a CYP3A4 and CYP2D6 substrate; paroxetine is a strong CYP2D6 inhibitor.
Propantheline: (Moderate) Monitor for signs or symptoms of anticholinergic toxicity during concomitant anticholinergic medication and paroxetine use. Concomitant use may result in additive anticholinergic adverse effects.
Propranolol: (Minor) Paroxetine impairs metabolism of the hepatic CYP2D6 isoenzyme pathway at therapeutic doses, resulting in substantial increases in concentrations of other drugs metabolized via the same pathway, including propranolol. Clinicians should use paroxetine cautiously with propranolol; downward dose adjustments of the beta-blocker may be required if paroxetine is initiated; alternatively an upward dose adjustment of the beta blocker may be needed if paroxetine is discontinued. Patients should be advised to report increased effects of these medications, including hypotension or increased dizziness to their health care professional.
Propranolol; Hydrochlorothiazide, HCTZ: (Minor) Paroxetine impairs metabolism of the hepatic CYP2D6 isoenzyme pathway at therapeutic doses, resulting in substantial increases in concentrations of other drugs metabolized via the same pathway, including propranolol. Clinicians should use paroxetine cautiously with propranolol; downward dose adjustments of the beta-blocker may be required if paroxetine is initiated; alternatively an upward dose adjustment of the beta blocker may be needed if paroxetine is discontinued. Patients should be advised to report increased effects of these medications, including hypotension or increased dizziness to their health care professional.
Protriptyline: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering selective serotonin reuptake inhibitors (SSRIs) with other drugs that have serotonergic properties such as tricyclic antidepressants. 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. In addition, paroxetine is a potent CYP2D6 inhibitor and may decrease the metabolism of protriptyline, a CYP2D6 substrate. Because there is a risk of QT prolongation and torsade de pointes (TdP) with tricyclics at elevated serum concentrations, coadministration should be approached with caution and close monitoring. Lastly, both paroxetine and protriptyline may exhibit significant anticholinergic effects that may be additive during concurrent use.
Pseudoephedrine; Triprolidine: (Moderate) Of the selective serotonin reuptake inhibiting antidepressants (SSRIs), paroxetine is considered the most anticholinergic. Additive anticholinergic effects may be seen when paroxetine is used with antihistamines having anticholinergic properties such as triprolidine. Patients should be informed to read non-prescription cough and cold product labels carefully for additional interacting antihistamines.
Pyrilamine: (Moderate) Of the selective serotonin reuptake inhibiting antidepressants (SSRIs), paroxetine is considered the most anticholinergic. Additive anticholinergic effects may be seen when paroxetine is used with antihistamines having anticholinergic properties such as pyrilamine. Patients should be informed to read non-prescription cough and cold product labels carefully for additional interacting antihistamines.
Quetiapine: (Moderate) Monitor patients for signs and symptoms of serotonin syndrome during concomitant use of paroxetine and quetiapine, 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.
Quinidine: (Moderate) Monitor for an increase in paroxetine-related adverse reactions, including serotonin syndrome, if concomitant use with quinidine is necessary. Concomitant use may increase paroxetine exposure. Paroxetine is a CYP2D6 substrate and quinidine is a strong CYP2D6 inhibitor.
Quinine: (Moderate) Monitor for an increase in paroxetine-related adverse reactions, including serotonin syndrome, if concomitant use with quinine is necessary. Concomitant use may increase paroxetine exposure. Paroxetine is a CYP2D6 substrate and quinine is a moderate CYP2D6 inhibitor.
Ranolazine: (Moderate) Monitor for an increase in paroxetine-related adverse reactions, including serotonin syndrome, if concomitant use with ranolazine is necessary. Concomitant use may increase paroxetine exposure. Paroxetine is a CYP2D6 substrate and ranolazine is a moderate CYP2D6 inhibitor.
Rasagiline: (Major) It is recommended to avoid concurrent use of rasagiline and selective serotonin reuptake inhibitors (SSRIs). Severe CNS toxicity with hyperpyrexia has been reported during concurrent use of antidepressants and selective or non-selective MAOIs. During postmarketing use of rasagiline, non-fatal cases of serotonin syndrome have been reported during concomitant antidepressant administration. At least 2 weeks should elapse between stopping rasagiline treatment and beginning therapy with any SSRI. Conversely, when discontinuing an SSRI, it is advisable to wait the length of 4 to 5 half-lives of the individual agent being discontinued prior to initiation with rasagiline. At least 5 weeks should elapse between the discontinuation of fluoxetine therapy and initiation of rasagiline. If coadministration of rasagiline and fluvoxamine is required, do not exceed a rasagiline dose of 0.5 mg once daily. Rasagiline is primarily metabolized by CYP1A2; fluvoxamine is a strong CYP1A2 inhibitor. When rasagiline was administered with another strong CYP1A2 inhibitor, the AUC of rasagiline increased by 83%.
Remifentanil: (Moderate) If concomitant use of remifentanil and selective serotonin reuptake inhibitors (SSRIs) is warranted, monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
Reteplase, r-PA: (Moderate) Platelet aggregation may be impaired by selective serotonin reuptake inhibitors (SSRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication in patients receiving thrombolytic agents. Patients should be closely monitored for signs and symptoms of bleeding when a thrombolytic agent is administered with an SSRI.
Risperidone: (Moderate) Monitor for an increase in risperidone-related adverse effects if concomitant use with paroxetine is necessary and reduce risperidone dosage as appropriate based on response. For patients receiving long-acting risperidone dosage forms, an anticipatory dosage decrease may be considered prior to initiation of paroxetine. Concomitant use may increase risperidone exposure. Risperidone is a CYP2D6 substrate and paroxetine is a strong CYP2D6 inhibitor. Concomitant use has been observed to increase risperidone overall exposure by 3- to 9-fold.
Ritonavir: (Moderate) Monitor for an increase in paroxetine-related adverse reactions, including serotonin syndrome, if concomitant use with ritonavir is necessary. Concomitant use may increase paroxetine exposure. Paroxetine is a CYP2D6 substrate and ritonavir is a weak CYP2D6 inhibitor.
Rivaroxaban: (Moderate) Advise patients of the increased bleeding risk associated with the concomitant use of selective serotonin reuptake inhibitors (SSRIs) and anticoagulants like rivaroxaban. Case reports and epidemiological studies have demonstrated an association between use of drugs that interfere with serotonin reuptake and gastrointestinal bleeding.
Rizatriptan: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering rizatriptan with selective serotonin reuptake inhibitors (SSRIs). Serotonin syndrome has been reported during concurrent use of serotonin-receptor agonists ("triptans") and SSRIs. Some patients had used the combination previously without incident when serotonin syndrome occurred. Inform patients of the possible increased risk and monitor for the emergence of serotonin syndrome, particularly after the initiation of the SSRI or dose increases. Discontinue serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
Rolapitant: (Moderate) Monitor for an increase in paroxetine-related adverse reactions, including serotonin syndrome, if concomitant use with rolapitant is necessary. Concomitant use may increase paroxetine exposure. Paroxetine 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.
Safinamide: (Major) The concurrent use of selective serotonin reuptake inhibitors (SSRIs) and monoamine oxidase inhibitors (MAOIs) is generally avoided; however, the manufacturer of safinamide recommends monitoring for serotonin syndrome and using the lowest effective dose of the SSRI during concurrent use. During clinical trial evaluation of safinamide, 1 case of serotonin syndrome occurred during co-administration with an SSRI. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death.
Salsalate: (Moderate) The combined use of selective serotonin reuptake inhibitors (SSRIs) and aspirin, ASA or other salicylates which affect hemostasis may elevate the risk for an upper GI bleed. SSRIs may inhibit serotonin uptake by platelets, augmenting the antiplatelet effects of aspirin. Additionally, aspirin impairs the gastric mucosa defenses by inhibiting prostaglandin formation. A cohort study in > 26,000 patients found that SSRI use alone increased the risk for serious GI bleed by 3.6-fold; when an SSRI was combined with aspirin the risk was increased by > 5-fold. The absolute risk of GI bleed from concomitant therapy with aspirin and a SSRI was low (20/2640 patients) in this cohort study and the clinician may determine that the combined use of these drugs is appropriate.
Scopolamine: (Moderate) Monitor for signs or symptoms of anticholinergic toxicity during concomitant anticholinergic medication and paroxetine use. Concomitant use may result in additive anticholinergic adverse effects.
Selegiline: (Contraindicated) Selective serotonin reuptake inhibitors (SSRIs) are contraindicated for use with selegiline, a selective monoamine oxidase type B inhibitor (MAO-B inhibitor). At least 14 days should elapse between discontinuation of selegiline and initiation of treatment with an SSRI. With the exception of fluoxetine, a time period equal to 4 to 5 half-lives of the SSRI or any active metabolite should elapse after discontinuing treatment with the SSRI and before starting therapy with selegiline. Because of the long half-life of fluoxetine and its active metabolite, at least 5 weeks should elapse between discontinuation of fluoxetine and initiation of treatment with selegiline. Serotonin syndrome has occurred in patients receiving selective MAO-B inhibitors and serotonin-augmenting antidepressants simultaneously. Monitor for serotonergic side effects during therapy transitions.
Sertraline: (Moderate) Monitor patients for an increase in paroxetine-related adverse reactions and signs and symptoms of serotonin syndrome during concomitant use of paroxetine and sertraline, particularly during treatment initiation and dosage increases. If serotonin syndrome occurs, consider discontinuation of therapy. The concomitant use of serotonergic drugs increases the risk of serotonin syndrome. Concomitant use may increase paroxetine exposure. Paroxetine is a CYP2D6 substrate and sertraline is a weak CYP2D6 inhibitor.
St. John's Wort, Hypericum perforatum: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when coadministering paroxetine and St. John's Wort. Inform patients of the possible increased risk and monitor for the emergence of serotonin syndrome, particularly during treatment initiation and dose increases. If serotonin syndrome occurs, serotonergic drugs should be discontinued and appropriate medical treatment should be initiated.
Sufentanil: (Moderate) If concomitant use of sufentanil and paroxetine is warranted, monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
Sumatriptan: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering sumatriptan with selective serotonin reuptake inhibitors (SSRIs). Serotonin syndrome has been reported during concurrent use of serotonin-receptor agonists ("triptans") and SSRIs. Inform patients of the possible increased risk and monitor for the emergence of serotonin syndrome, particularly after initiation of SSRI treatment or any dose increases. Discontinue serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
Sumatriptan; Naproxen: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering sumatriptan with selective serotonin reuptake inhibitors (SSRIs). Serotonin syndrome has been reported during concurrent use of serotonin-receptor agonists ("triptans") and SSRIs. Inform patients of the possible increased risk and monitor for the emergence of serotonin syndrome, particularly after initiation of SSRI treatment or any dose increases. Discontinue serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
Tamoxifen: (Moderate) Monitor for decreased efficacy of tamoxifen if coadministration with paroxetine is necessary. Tamoxifen is metabolized by CYP2D6 to endoxifen and 4-hydroxytamoxifen, both of which are minor metabolites but have 100-fold greater affinity for the estrogen receptor and 30- to 100-fold greater potency in suppressing estrogen-dependent cell proliferation than tamoxifen. Paroxetine is a strong CYP2D6 inhibitor. In one study, the mean steady-state plasma concentration of endoxifen in CYP2D6 normal metabolizers who were not receiving CYP2D6 inhibitors were 3.6-fold higher compared to normal metabolizers who were receiving strong CYP2D6 inhibitors (e.g., paroxetine); plasma levels in CYP2D6 normal metabolizers receiving strong CYP2D6 inhibitors were similar to levels observed in CYP2D6 poor metabolizers taking no CYP2D6 inhibitors. In another study, the mean steady-state endoxifen plasma concentration was significantly reduced in patients taking CYP2D6 inhibitors compared to those not taking concomitant CYP2D6 inhibitors. Some studies have shown that the efficacy of tamoxifen may be reduced when concomitant drugs decrease the levels of potent active metabolites; however, others have failed to demonstrate such an effect. The clinical significance is not well established.
Tamsulosin: (Moderate) Use caution if coadministration of paroxetine with tamsulosin is necessary, especially at a tamsulosin dose higher than 0.4 mg, as the systemic exposure of tamsulosin may be increased resulting in increased treatment-related adverse reactions including hypotension, dizziness, and vertigo. Tamsulosin is a CYP2D6 substrate and paroxetine is a strong CYP2D6 inhibitor. Concomitant treatment with paroxetine increased the Cmax and AUC of tamsulosin by a factor of 1.3 and 1.6, respectively.
Tapentadol: (Moderate) If concomitant use of tapentadol and selective serotonin reuptake inhibitors (SSRIs) is warranted, monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
Tedizolid: (Minor) Caution is warranted with the concurrent use of tedizolid and selective serotonin reuptake inhibitors (SSRIs) due to the theoretical risk of serotonin syndrome. Animal studies did not predict serotonergic effects; however, patients on concurrent SSRIs were excluded from clinical trials. Addtionally, tedizolid is an antibiotic that is also a weak reversible, non-selective MAO inhibitor and monoamine oxidase type A deaminates serotonin; therefore, coadministration theoretically could lead to serious reactions including serotonin syndrome. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome has been reported in patients receiving either citalopram, escitalopram, fluoxetine, or paroxetine in combination with linezolid, which is structurally similar to tedizolid.
Tenecteplase: (Moderate) Platelet aggregation may be impaired by selective serotonin reuptake inhibitors (SSRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication in patients receiving thrombolytic agents. Patients should be closely monitored for signs and symptoms of bleeding when a thrombolytic agent is administered with an SSRI.
Terbinafine: (Moderate) Systemic terbinafine inhibits hepatic isoenzyme CYP2D6, and thus may inhibit the clearance of drugs metabolized by this isoenzyme, such as selective serotonin reuptake inhibitors (SSRIs). The clinical relevance of the interaction is not known. Topical forms of terbinafine do not interact.
Tetrabenazine: (Major) The primary metabolites of tetrabenazine, alpha-dihydrotetrabenzaine (alpha-HTBZ) and beta-dihydrotetrabenazine (beta-HTBZ), are substrates for CYP2D6. Coadministration of 50 mg of tetrabenazine following 10 days of 20 mg of paroxetine, a potent CYP2D6 inhibitor, resulted in an increase in Cmax of approximately 30% and a 3-fold increase in AUC for alpha-HTBZ. The Cmax and AUC for beta-HTBZ increased 2.4-fold and 9-fold, respectively. The elimination half-life of alpha-HTBZ and beta-HTBZ was approximately 14 hours when tetrabenazine was given with paroxetine. When tetrabenazine is given with a strong inhibitor of CYP2D6 such as paroxetine, the maximum single dose of tetrabenazine should not exceed 25 mg and the daily dose should not exceed 50 mg. In addition, because tetrabenazine is a CYP2D6 substrate and has a possible risk of QT prolongation and torsade de pointes, concurrent use of a potent CYP2D6 inhibitor such as paroxetine may increase the risk of such events. During use of this combination, monitor for adverse effects associated with tetrabenazine such as QT prolongation, excess sedation, and extrapyramidal symptoms.
Theophylline, Aminophylline: (Major) Paroxetine has been reported to cause elevations of theophylline serum concentrations. Monitor aminophylline serum concentrations when paroxetine is given concurrently with aminophylline. Observe patients for signs or symptoms of aminophylline toxicity. (Major) Paroxetine has been reported to cause elevations of theophylline serum concentrations. The interaction has not been formally studied. It is recommended that theophylline serum concentrations be monitored when paroxetine is given concurrently with theophylline or aminophylline. Observe patients for signs or symptoms of theophylline toxicity.
Thioridazine: (Contraindicated) Coadministration of thioridazine and paroxetine is contraindicated due to the potential for increased thioridazine exposure. Increased plasma concentrations of thioridazine are expected to increase the prolongation of the QTc interval associated with thioridazine and may increase the risk of serious, potentially fatal, cardiac arrhythmias, such as torsade de pointes type arrhythmias. Thioridazine is a CYP2D6 substrate and paroxetine is a strong CYP2D6 inhibitor.
Thiothixene: (Moderate) Monitor for an increase in paroxetine-related adverse reactions, including serotonin syndrome, if concomitant use with thiothixene is necessary. Concomitant use may increase paroxetine exposure. Paroxetine is a CYP2D6 substrate and thiothixene is a weak CYP2D6 inhibitor. Coadministration with a weak CYP2D6 inhibitor increased paroxetine overall exposure by 50%.
Thrombin Inhibitors: (Moderate) Advise patients of the increased bleeding risk associated with the concomitant use of selective serotonin reuptake inhibitors (SSRIs) and other drugs that affect coagulation like thrombin inhibitors. Case reports and epidemiological studies have demonstrated an association between use of drugs that interfere with serotonin reuptake and gastrointestinal bleeding.
Thrombolytic Agents: (Moderate) Platelet aggregation may be impaired by selective serotonin reuptake inhibitors (SSRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication in patients receiving thrombolytic agents. Patients should be closely monitored for signs and symptoms of bleeding when a thrombolytic agent is administered with an SSRI.
Ticagrelor: (Moderate) Platelet aggregation may be impaired by selective serotonin reuptake inhibitors (SSRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication in patients receiving ticagrelor. Patients should be instructed to monitor for signs and symptoms of bleeding while taking an SSRI concurrently with an antiplatelet medication and to promptly report any bleeding events to the practitioner.
Ticlopidine: (Moderate) Platelet aggregation may be impaired by selective serotonin reuptake inhibitors (SSRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving platelet inhibitors (e.g., cilostazol, clopidogrel, dipyridamole, ticlopidine, platelet glycoprotein IIb/IIIa inhibitors). Patients should be instructed to monitor for signs and symptoms of bleeding while taking an SSRI concurrently with an antiplatelet medication and to promptly report any bleeding events to the practitioner.
Timolol: (Moderate) Monitor for signs of bradycardia or heart block if coadministration of timolol with paroxetine is necessary. Concomitant use may enhance the beta-blocking properties of timolol resulting in further slowing of the heart rate or cardiac conduction. Timolol is a CYP2D6 substrate and paroxetine is a strong CYP2D6 inhibitor.
Tipranavir: (Moderate) Monitor for an increase in paroxetine-related adverse reactions, including serotonin syndrome, if concomitant use with tipranavir is necessary. Concomitant use may increase paroxetine exposure. Paroxetine is a CYP2D6 substrate and tipranavir is a strong CYP2D6 inhibitor.
Tirofiban: (Moderate) Platelet aggregation may be impaired by SSRIs due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication in patients receiving platelet inhibitors. Monitor for signs and symptoms of bleeding.
Tolterodine: (Moderate) Paroxetine, a potent CYP2D6 inhibitor, may inhibit the metabolism of tolterodine, a CYP2D6 substrate. In a study assessing another potent CYP2D6 inhibitor (fluoxetine) and tolterodine, the metabolism of tolterodine immediate release was significantly decreased in CYP2D6 extensive metabolizers, resulting in a 4.8-fold increase in tolterodine AUC. There was a 52% decrease in Cmax and a 20% decrease in AUC of 5-hydroxymethyl tolterodine (5-HMT), the active metabolite of tolterodine. The sums of unbound serum concentrations of tolterodine and 5-HMT were only 25% higher during the interaction. Although the manufacturer requires no dose adjustment during concurrent use of tolterodine and fluoxetine, the kinetic and clinical effects of paroxetine use are unknown. Both drugs exhibit anticholinergic effects that may be additive. In addition, because tolterodine is a primary substrate of CYP2D6 and has a possible risk of QT prolongation and torsade de pointes, concurrent use of a potent CYP2D6 inhibitor such as paroxetine may increase the risk of such events.
Tramadol: (Moderate) Monitor for reduced efficacy of tramadol, signs of opioid withdrawal, seizures, or serotonin syndrome if coadministration with paroxetine is necessary. If paroxetine is discontinued, consider a dose reduction of tramadol and frequently monitor for signs of respiratory depression and sedation. Tramadol is a CYP2D6 substrate and paroxetine is a CYP2D6 inhibitor. Concomitant use of tramadol with CYP2D6 inhibitors can increase the plasma concentration of tramadol and decrease the plasma concentration of the active metabolite M1. Since M1 is a more potent mu-opioid agonist, decreased M1 exposure could result in decreased therapeutic effects, and may result in signs and symptoms of opioid withdrawal in patients who have developed physical dependence to tramadol. Increased tramadol exposure can result in increased or prolonged therapeutic effects and increased risk for serious adverse events including seizures and serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
Tramadol; Acetaminophen: (Moderate) Monitor for reduced efficacy of tramadol, signs of opioid withdrawal, seizures, or serotonin syndrome if coadministration with paroxetine is necessary. If paroxetine is discontinued, consider a dose reduction of tramadol and frequently monitor for signs of respiratory depression and sedation. Tramadol is a CYP2D6 substrate and paroxetine is a CYP2D6 inhibitor. Concomitant use of tramadol with CYP2D6 inhibitors can increase the plasma concentration of tramadol and decrease the plasma concentration of the active metabolite M1. Since M1 is a more potent mu-opioid agonist, decreased M1 exposure could result in decreased therapeutic effects, and may result in signs and symptoms of opioid withdrawal in patients who have developed physical dependence to tramadol. Increased tramadol exposure can result in increased or prolonged therapeutic effects and increased risk for serious adverse events including seizures and serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
Tranylcypromine: (Contraindicated) Due to the risk of serotonin syndrome, monoamine oxidase inhibitors (MAOIs) intended to treat psychiatric disorders are contraindicated for use with selective serotonin reuptake inhibitors (SSRIs). MAOIs should not be used within 5 weeks of discontinuing treatment with fluoxetine or within 14 days of discontinuing treatment with other SSRIs. Conversely, SSRIs should not be initiated within 14 days of stopping an MAOI. Monitor the patient for serotonin-related effects during therapy transitions.
Trazodone: (Moderate) Coadministration of trazodone and paroxetine may increase the risk of serotonin syndrome. Serotonin syndrome has been reported with both drugs when taken alone, but especially when coadministered with other serotonergic agents. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome. Discontinue serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
Trifluoperazine: (Moderate) Substantial increases in concentrations of phenothiazines may occur due to CYP2D6 inhibition by paroxetine, which may increase the risk of adverse effects, including extrapyramidal symptoms or QT prolongation. Phenothiazines with a possible risk of QT prolongation include trifluoperazine. Additive anticholinergic effects are also possible.
Trihexyphenidyl: (Moderate) Monitor for signs or symptoms of anticholinergic toxicity during concomitant anticholinergic medication and paroxetine use. Concomitant use may result in additive anticholinergic adverse effects.
Trimipramine: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering selective serotonin reuptake inhibitors (SSRIs) with other drugs that have serotonergic properties such as tricyclic antidepressants. 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. In addition, paroxetine is a potent CYP2D6 inhibitor and may decrease the metabolism of trimipramine, a CYP2D6 substrate. Because there is a risk of QT prolongation and torsade de pointes (TdP) with tricyclics at elevated serum concentrations, coadministration should be approached with caution and close monitoring. Lastly, both paroxetine and trimipramine may exhibit significant anticholinergic effects that may be additive during concurrent use.
Triprolidine: (Moderate) Of the selective serotonin reuptake inhibiting antidepressants (SSRIs), paroxetine is considered the most anticholinergic. Additive anticholinergic effects may be seen when paroxetine is used with antihistamines having anticholinergic properties such as triprolidine. Patients should be informed to read non-prescription cough and cold product labels carefully for additional interacting antihistamines.
Tryptophan, 5-Hydroxytryptophan: (Major) Concurrent use of tryptophan and a selective serotonin reuptake inhibitor (SSRI) is not recommended. Since tryptophan is converted to serotonin, the use of tryptophan in patients receiving SSRIs could lead to serotonin excess and, potentially, serotonin syndrome. Discontinuation of tryptophan usually resolves symptoms.
Valbenazine: (Major) Consider reducing the dose of valbenazine, based on tolerability, during co-administration with a strong CYP2D6 inhibitor, such as paroxetine. QT prolongation is not clinically significant at valbenazine concentrations expected with recommended dosing; however, concentrations of the active metabolite of valbenazine may be higher in patients taking a strong CYP2D6 inhibitor and QT prolongation may become clinically significant.
Valerian, Valeriana officinalis: (Moderate) Substances that act on the CNS, including psychoactive drugs, may theoretically interact with valerian, Valeriana officinalis. These interactions are probably pharmacodynamic in nature, or result from additive mechanisms of action. Persons taking medications such as SSRIs should discuss the use of herbal supplements with their health care professional prior to consuming these herbs. Patients should not abruptly stop taking their prescribed psychoactive medication.
Vasopressin, ADH: (Moderate) Monitor hemodynamics and adjust the dose of vasopressin as needed when used concomitantly with drugs suspected of causing syndrome of inappropriate antidiuretic hormone (SIADH), such as selective serotonin reuptake inhibitors. Use together may increase the pressor and antidiuretic effects of vasopressin.
Vemurafenib: (Moderate) Concomitant use of vemurafenib and paroxetine may result in increased paroxetine concentrations. Paroxetine is metabolized by CYP2D6 and vemurafenib is a weak CYP2D6 inhibitor. Monitor patients for toxicity.
Venlafaxine: (Moderate) Monitor patients for an increase in paroxetine-related adverse reactions and signs and symptoms of serotonin syndrome during concomitant use of paroxetine and venlafaxine, particularly during treatment initiation and dosage increases. If serotonin syndrome occurs, consider discontinuation of therapy. The concomitant use of serotonergic drugs increases the risk of serotonin syndrome. Concomitant use may increase paroxetine exposure. Paroxetine is a CYP2D6 substrate and venlafaxine is a weak CYP2D6 inhibitor.
Vilazodone: (Major) Due to possible additive effects on serotonin concentrations, it is advisable to avoid combining selective serotonin reuptake inhibitors (SSRIs) such as paroxetine with vilazodone. Interactions between vilazodone and serotonergic agents can lead to 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 receiving vilazodone and paroxetine should be monitored for the emergence of serotonin syndrome, particularly during treatment initiation and during dosage increases. Vilazodone and paroxetine should be discontinued if serotonin syndrome occurs and supportive symptomatic treatment should be initiated.
Viloxazine: (Moderate) Monitor for an increase in paroxetine-related adverse reactions, including serotonin syndrome, if concomitant use with viloxazine is necessary. Concomitant use may increase paroxetine exposure. Paroxetine is a CYP2D6 substrate and viloxazine is a weak CYP2D6 inhibitor. Coadministration with a weak CYP2D6 inhibitor increased paroxetine overall exposure by 50%.
Vorapaxar: (Moderate) Because vorapaxar inhibits platelet aggregation, a potential additive risk for bleeding exists if vorapaxar is given in combination with other agents that affect hemostasis such as selective serotonin reuptake inhibitors (SSRIs). Platelet aggregation may be impaired by SSRIs due to platelet serotonin depletion. In addition, fluoxetine and fluvoxamine are CYP3A4 inhibitors and coadministration with vorapaxar, a CYP3A4 substrate, may result in increased serum concentrations of vorapaxar. Increased exposure to vorapaxar may increase the risk of bleeding complications. Patients should be instructed to monitor for signs and symptoms of bleeding while taking a SSRI with vorapaxar and to promptly report any bleeding events.
Vortioxetine: (Major) Due to similarity of pharmacology and the potential for additive adverse effects, including serotonin syndrome, vortioxetine should generally not be co-administered with selective serotonin reuptake inhibitors (SSRIs). 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. Monitor for serotonin syndrome during a transition from vortioxetine to an SSRI. If coadministration is necessary, the manufacturer recommends a reduction in the vortioxetine dose by one-half when strong inhibitors of CYP2D6 such as paroxetine are used since CYP2D6 is the primary isoenzyme responsible for the metabolism of vortioxetine to its inactive metabolite. The vortioxetine dose should be increased to the original level when the CYP2D6 inhibitor is discontinued.
Warfarin: (Moderate) Advise patients of the increased bleeding risk associated with the concomitant use of paroxetine and warfarin. Carefully monitor patients receiving warfarin therapy if paroxetine is initiated or discontinued. Some data suggest there may be a pharmacodynamic interaction that causes increased bleeding without a change in prothrombin time. Case reports and epidemiological studies have demonstrated an association between use of drugs that interfere with serotonin reuptake and gastrointestinal bleeding.
Ziprasidone: (Major) Because of the potential risk and severity of serotonin syndrome or neuroleptic malignant syndrome-like reactions, caution should be observed when administering selective serotonin reuptake inhibitors (SSRIs) with drugs that are dopamine antagonists such as ziprasidone. 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 ziprasidone and an SSRI should be monitored for the emergence of serotonin syndrome, neuroleptic malignant syndrome-like reactions, or other adverse effects.
Zolmitriptan: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering zolmitriptan with selective serotonin reuptake inhibitors (SSRIs). Serotonin syndrome has been reported during concurrent use of serotonin-receptor agonists ("triptans") and SSRIs. Inform patients of the possible increased risk and monitor for the emergence of serotonin syndrome, particularly after initiation of SSRI treatment or any dose increases. Discontinue serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
Zolpidem: (Moderate) Disorientation, delusions, or hallucinations have been reported rarely during co-administration of zolpidem and antidepressants. The duration of the visual hallucinations has ranged from 30 minutes to 7 hours. The interaction is thought to be pharmacodynamic in nature; therefore, a similar reaction is possible with paroxetine. Data from a clinical study in which SSRI-treated patients were given immediate-release zolpidem revealed that four of the seven discontinuations during double-blind treatment with zolpidem (n = 95) were associated with impaired concentration, continuing or aggravated depression, and manic reaction.

Brisdelle/Paroxetine Oral Cap: 7.5mg
Paroxetine/Paroxetine Hydrochloride/Paxil CR Oral Tab ER: 12.5mg, 25mg, 37.5mg
Paroxetine/Paroxetine Hydrochloride/Paxil Oral Susp: 5mL, 10mg
Paroxetine/Paroxetine Hydrochloride/Paxil/Pexeva Oral Tab: 10mg, 20mg, 30mg, 40mg

Adults

60 mg/day PO for immediate-release formulation; 75 mg/day PO for controlled-release formulation.

Geriatric

40 mg/day PO for immediate-release formulation; 50 mg/day PO for controlled-release formulation.

Adolescents

Safety and efficacy have not been established; however, doses up to 50 mg/day PO have been used off-label for anxiety disorders.

Children

7 to 12 years: Safety and efficacy have not been established; however, doses up to 50 mg/day PO have been used off-label for anxiety disorders.
1 to 6 years: Safety and efficacy have not been established.

Infants

Safety and efficacy have not been established.

Neonates

Safety and efficacy have not been established.

The precise antidepressant effect of the selective serotonin reuptake inhibitors (SSRIs) is not fully understood, but involves selective serotonin reuptake blockade at the neuronal membrane, which enhances the actions of serotonin (5-HT). Initially, SSRIs increase availability of serotonin in the somatodendritic area through serotonin reuptake blockade at the serotonin transport pump. During long-term administration of SSRIs, serotonin autoreceptors are down-regulated and desensitized, allowing the neuron to increase serotonin release in the axon terminal synapses and increase its neuronal impulses. Because of the delay in therapeutic response to SSRIs, it is theorized that the change in the balance of serotonin receptors over time is an important mechanism of effect. The therapeutic action of SSRIs in treating anxiety disorders is thought to occur from potent central serotonin reuptake blockade although the exact mechanism is unknown. SSRIs exhibit less sedative, anticholinergic, and cardiovascular effects than do tricyclic antidepressants due to decreased binding to histaminergic, muscarinic, and alpha-adrenergic receptors. However, paroxetine is noted to have the most anticholinergic activity of all the SSRIs. The mechanism of action of paroxetine in the treatment of vasomotor symptoms associated with menopause is unknown.

Paroxetine formulations are administered orally. The drug is widely distributed, including into the CNS, with only 1% of paroxetine remaining in the plasma. Paroxetine is 93% to 95% bound to plasma protein; however, the drug does not displace other highly protein-bound drugs. Based on pharmacokinetic studies, the steady-state paroxetine exposure based on AUC is several-fold higher than with a single dose. The excess accumulation is a consequence of a saturable metabolic pathway. Paroxetine is extensively metabolized via oxidation, methylation and conjugation to several metabolites, none of which shows any appreciable pharmacological activity. Conjugates with glucuronic acid and sulfate predominate. Metabolism is achieved predominantly by CYP2D6. Due to saturation of CYP2D6 by paroxetine, the relationship between pharmacokinetics and dosage or duration of treatment is nonlinear. At steady-state, when the CYP2D6 is essentially saturated, paroxetine clearance becomes governed by CYP3A4, which, unlike CYP2D6, does not show evidence of saturation. The mean elimination half-life of the immediate-release paroxetine is approximately 21 hours while the elimination half-life for the controlled-release product is 15 to 20 hours. Excretion is mainly renal (about 62%), mostly as metabolites and about 2% as unchanged drug. Roughly 36% is excreted in the feces, mainly via the bile as metabolites.
 
Affected cytochrome P450 (CYP450) isoenzymes and drug transporters: CYP2D6
Paroxetine is a substrate and potent inhibitor of CYP2D6. In more than 90% of patients, CYP2D6 is saturated early in dosing with paroxetine (in roughly 10 to 14 days). Due to saturation of CYP2D6 by paroxetine, the relationship between pharmacokinetics and dosage or duration of treatment is nonlinear. At steady-state, when the CYP2D6 is essentially saturated, paroxetine clearance becomes governed by CYP3A4, which, unlike CYP2D6, does not show evidence of saturation. Paroxetine does not appear to inhibit other CYP isoenzymes, including CYP3A4, to any clinically significant degree.

Oral Route

Paroxetine is absorbed completely after oral administration. Paroxetine immediate-release tablets and oral suspension are bioequivalent. Paxil CR controlled-release tablets are enteric coated to delay the start of drug release until the tablets have left the stomach; they are also designed via the Geomatrix polymeric matrix to allow for a 4 to 5 hour dissolution rate, with a Tmax occurring roughly 6 to 10 hours after dosing. The bioavailability of paroxetine, regardless of dosage form, is not affected by food. There appears to be individual patient variation in response, but steady-state concentrations are achieved in about 10 to 14 days with either the immediate-release or controlled-release formulations. The onset of action, however, typically requires 1 to 4 weeks of therapy.

Pregnancy

Paroxetine may cause fetal harm during human pregnancy; the paroxetine capsule for treatment of menopause (e.g., Brisdelle) is contraindicated for use during pregnancy because menopausal vasomotor symptoms do not occur during pregnancy. Unless the benefits of continuing treatment with paroxetine outweigh the potential risks to the infant, either discontinue paroxetine or switch to another antidepressant. For those who intend to become pregnant or are in their first trimester of pregnancy, paroxetine should only be initiated after careful consideration of the risks and ruling out the possibility of other treatment options. Epidemiological studies have shown that infants exposed to paroxetine in the first trimester of pregnancy have an increased risk of congenital malformations, particularly cardiovascular (CV) malformations. A retrospective, epidemiologic study derived from the Swedish National Registry comprised of 6896 women prescribed antidepressants in early pregnancy (5,123 of these women exposed to SSRIs; 815 to paroxetine) suggests an increased risk of CV malformations, primarily ventricular (VSDs) and atrial (ASDs) septal defects in those with exposure to paroxetine. This increased risk was seen compared to the entire registry population (OR 1.8; 95% CI 1.1 to 2.8). The rate of CV malformations following paroxetine exposure was 2% vs. 1% in the entire registry population; however, there was no increase in the overall risk for congenital malformations in either group. In another retrospective, cohort study (a US health insurance claims database), that evaluated outcomes of infants exposed to antidepressants in the first trimester (n = 5,956 total; 815 for paroxetine), a 1.5-fold elevated risk for cardiac malformations and a 1.8-fold elevated risk for overall congenital malformations was seen in the paroxetine group compared to infants exposed to other antidepressants (OR 1.5; 95% CI 0.8 to 2.9). The prevalence of cardiac malformations when drug was received in the first trimester was 1.5% for paroxetine and 1% for other antidepressants. Nine out of 12 newborns with cardiac malformations whose mothers received paroxetine in the first trimester had VSDs. There was an increased risk of overall major congenital malformations (inclusive of the CV defects) for paroxetine compared to other antidepressants (OR 1.8; 95% CI 1.2 to 2.8). The prevalence of all congenital malformations following first trimester exposure was 4% for paroxetine vs. 2% for other antidepressants. Results from 2 large case-control studies (each with more than 9,000 birth defect cases and more than 4,000 controls) showed a 2- to 3-fold increased risk of right ventricular outflow tract obstructions from infant exposures to paroxetine in utero during the first trimester of pregnancy, with 7 exposed in one study (OR 2.5; 95% CI, 1 to 6), and 6 exposed in the other study (OR 3.3; 95% CI 1.3 to 8.8). All of these studies were limited to first trimester exposure only, therefore the risk of fetal exposure to paroxetine in the second and third trimesters is not known. There have been postmarketing reports of premature births in pregnant patients exposed to paroxetine; however, causality has not been established. A prospective, cohort study was conducted to evaluate the outcome of newborns born to 267 women who took an SSRI during pregnancy (of whom 97 took paroxetine). Compared with a neonatal control group, SSRI-exposed neonates had similar rates of major malformation, spontaneous and elective abortion, stillbirth; mean birth weight and gestational age at birth were also similar. There are also risks associated with SSRI use during the third trimester of pregnancy, particularly the risk of persistent pulmonary hypertension of the newborn (PPHN). Some neonates exposed to SSRIs late in the third trimester have also experienced poor neonatal adaptation resulting in complications requiring prolonged hospitalization, respiratory support, and tube feeding upon delivery. Symptoms have included respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding difficulty, vomiting, hypoglycemia, hypotonia, hypertonia, hyperreflexia, tremor, jitteriness, irritability, and constant crying. These features are consistent with direct SSRI toxicity, serotonin syndrome, or a drug discontinuation syndrome. Data from published observational studies have reported that exposure to SSRIs, particularly in the month before obstetric delivery, has been associated with a less than 2-fold increase in the risk of postpartum hemorrhage. There is a pregnancy exposure registry that monitors outcomes in pregnant patients exposed to paroxetine; information about the registry can be obtained at information about the registry can be obtained at https://womensmentalhealth.org/research/pregnancyregistry/antidepressants/ or by calling 1-866-961-2388.