Version October 2024
Antidepressants increased the risk compared with placebo of suicidal thinking and behavior (suicidality) in short-term studies in children, adolescents, and young adults with major depressive disorder (MDD) and other psychiatric disorders. Anyone considering the use of fluoxetine or any other antidepressant in a child, adolescent, or young adult must balance this risk with the clinical need. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared with placebo in adults older than 24 years; there was a reduction in risk with antidepressants compared with placebo in adults 65 years and older. Depression and certain other psychiatric disorders are themselves associated with increases in the risk of suicide. Appropriately monitor and closely observe patients of all ages who are started on antidepressant therapy for clinical worsening, suicidality, or unusual changes in behavior. Advise families and caregivers of the need for close observation and communication with the prescribing health care provider.
Fluoxetine is approved for use in children with MDD (aged 8 years and older) and obsessive-compulsive disorder (OCD; aged 7 years and older). Sarafem is not approved for use in children.
Dosage guidance:
Dosing: Some experts suggest lower starting doses of 5 to 10 mg/day and gradual titration in increments of ≤10 mg, particularly in patients with anxiety who are sensitive to antidepressant-associated overstimulation effects (eg, anxiety, insomnia) (Ref).
Binge eating disorder (off-label use): Oral: Immediate release: Initial: 10 to 20 mg once daily; may increase dose based on response and tolerability in increments of 10 to 20 mg at intervals ≥1 week up to 80 mg/day (Ref).
Bipolar disorder: Depressive episodes: Oral: Immediate release: Initial: 20 mg once daily in the evening in combination with olanzapine (preferred), another second-generation antipsychotic, or antimanic agent; may increase dose in 10 to 20 mg increments every 1 to 7 days (Ref); usual dose range: 20 to 50 mg/day (Ref). May also use the fixed-dose combination instead of the separate components. See Dosing conversion below for conversion to or from olanzapine/fluoxetine fixed-dose combination.
Body dysmorphic disorder (BDD) (off-label use):
Oral: Immediate release: Initial: 20 mg once daily; may increase dose gradually based on response and tolerability in increments of 20 mg every 2 to 3 weeks to a usual dose of 70 to 80 mg/day by week 6 to 10 (Ref). Doses up to 120 mg/day, if tolerated, may be necessary in some patients for optimal response (Ref). Note: An adequate trial for assessment of effect is 12 to 16 weeks, including a dose of 80 mg for at least 4 of those weeks, if needed and tolerated (Ref).
Bulimia nervosa: Oral: Immediate release: Initial: 20 mg once daily; may increase dose gradually (eg, at intervals ≥1 week) based on response and tolerability in 20 mg increments up to a target dose of 60 mg/day (Ref).
Manufacturer's labeling: Dosing in prescribing information may not reflect current clinical practice. Initial: 60 mg/day.
Fibromyalgia, refractory (alternative agent) (off-label use):
Note: For patients not responsive to first-line agents (Ref).
Oral: Immediate release: Initial: 20 mg once daily; may increase dose based on response and tolerability in 10 to 20 mg increments at ≥2-week intervals up to 80 mg/day. Mean dose in clinical trials was 45 mg/day (Ref). In patients with an insufficient response to first-line monotherapy, some experts suggest low-dose combination therapy (eg, fluoxetine 20 mg/day with a tricyclic antidepressant) (Ref).
Generalized anxiety disorder (off-label use): Oral: Immediate release: Initial: 10 to 20 mg once daily; may gradually increase dose based on response and tolerability in 10 to 20 mg increments at intervals of ≥1 week up to 60 mg/day (Ref). Doses may be increased every 3 to 4 days if warranted in inpatient settings. Some experts suggest maintaining the initial therapeutic dose 4 to 6 weeks to assess for efficacy before increasing further (Ref).
Major depressive disorder (unipolar): Oral: Immediate release: Initial: 20 mg once daily; may increase dose based on response and tolerability in 20 mg increments at intervals ≥1 week up to a maximum dose of 80 mg/day (Ref). Usual dose: 20 to 60 mg/day (Ref). Note: For treatment-resistant depression, combination with olanzapine or another second-generation antipsychotic may be used; in major depression with psychotic features, fluoxetine plus an antipsychotic is standard treatment (Ref). May consider use of the fixed-dose combination instead of the separate components. See Dosing conversions below for conversion to or from the olanzapine/fluoxetine fixed-dose combination.
Obsessive-compulsive disorder: Oral: Immediate release: Initial: 10 to 20 mg once daily; may increase dose gradually in 20 mg increments at intervals ≥1 week based on response and tolerability; recommended range: 40 to 80 mg/day (Ref). Based on clinical experience, some patients may require up to 120 mg/day for a response; however, adverse effects may increase (Ref). Note: An adequate trial for assessment of effect in OCD is considered to be ≥6 weeks at maximum tolerated dose (Ref).
Panic disorder: Oral: Immediate release: Initial: 5 to 10 mg once daily; after 3 to 7 days, may gradually increase dose based on response and tolerability in 5 to 10 mg increments at intervals ≥1 week up to a usual dose of 20 to 40 mg/day (Ref). Maximum dose: 60 mg/day (Ref). Some experts maintain dose at 20 mg for 4 weeks before considering further dose increases. May require 6 weeks at maximally tolerated dose for adequate treatment trial (Ref).
Posttraumatic stress disorder (PTSD) (off-label use): Oral: Immediate release: Initial: 10 to 20 mg once daily; may increase dose based on response and tolerability in 10 to 20 mg increments at intervals ≥1 week up to 80 mg/day. Usual dosage range in clinical trials: 20 to 60 mg/day (Ref).
Premenstrual dysphoric disorder (PMDD):
Continuous daily dosing regimen: Oral: Immediate release: Initial: 10 mg once daily; increase to usual effective dose of 20 mg once daily over the first month; in a subsequent menstrual cycle, a further increase to 30 mg/day may be necessary in some patients for optimal response (Ref).
Intermittent regimens:
Luteal phase dosing regimen: Oral: Immediate release: Initial: 10 mg once daily during the luteal phase of menstrual cycle only (ie, beginning therapy 14 days before anticipated onset of menstruation and continued to the onset of menses); over the first month, may increase to usual effective dose of 20 mg once daily during the luteal phase; in a subsequent menstrual cycle, a further increase to 30 mg/day during the luteal phase may be necessary in some patients for optimal response (Ref).
Symptom-onset dosing regimen (off-label dosing): Oral: Limited data available: Immediate release: 10 mg once daily from the day of symptom onset until a few days after the start of menses; over the first month, may increase dose based on response and tolerability up to 20 mg/day (Ref).
Social anxiety disorder (off-label use): Oral: Immediate release: Initial: 10 to 20 mg once daily; after 4 to 6 weeks may gradually increase dose based on response and tolerability in 10 mg increments at intervals of ≥1 week up to 60 mg/day (Ref).
Dosing conversion:
Delayed release (once-weekly formulation): Immediate-release fluoxetine 20 mg/day = delayed-release fluoxetine 90 mg/week. When converting from immediate-release fluoxetine daily dosing, initiate delayed-release fluoxetine (90 mg once weekly) 7 days after the last 20 mg/day dose of immediate-release fluoxetine. Patients must be stabilized on immediate-release fluoxetine 20 mg once daily prior to switching.
Olanzapine/fluoxetine fixed-dose combination: When using individual components of fluoxetine with olanzapine rather than fixed-dose combination product, corresponding approximate dosage equivalents are as follows:
Olanzapine 2.5 mg + fluoxetine 20 mg = combination strength 3/25
Olanzapine 5 mg + fluoxetine 20 mg = combination strength 6/25
Olanzapine 12.5 mg + fluoxetine 20 mg = combination strength 12/25
Olanzapine 5 mg + fluoxetine 50 mg = combination strength 6/50
Olanzapine 12.5 mg + fluoxetine 50 mg = combination strength 12/50
Discontinuation of therapy: When discontinuing antidepressant treatment that has lasted for >3 weeks, gradually taper the dose (eg, over 1 to 4 weeks) to minimize withdrawal symptoms and detect re-emerging symptoms (Ref). Reasons for a slower taper (eg, over 4 weeks) include prior history of antidepressant withdrawal symptoms or high doses of antidepressants (Ref). If necessary, some clinicians allow for abrupt discontinuation based on fluoxetine's long half-life (Ref). If intolerable withdrawal symptoms occur, resume the previously prescribed dose and/or decrease dose at a more gradual rate (Ref). Select patients (eg, those with a history of discontinuation syndrome) on long-term treatment (>6 months) may benefit from tapering over >3 months (Ref). Evidence supporting ideal taper rates is limited (Ref).
Switching antidepressants: Evidence for ideal antidepressant switching strategies is limited; strategies include cross-titration (gradually discontinuing the first antidepressant while at the same time gradually increasing the new antidepressant) and direct switch (abruptly discontinuing the first antidepressant and then starting the new antidepressant at an equivalent dose or lower dose and increasing it gradually). Cross-titration (eg, over 1 to 4 weeks depending upon sensitivity to discontinuation symptoms and adverse effects) is standard for most switches, but is contraindicated when switching to or from an MAOI. A direct switch may be an appropriate approach when switching to another agent in the same or similar class (eg, when switching between two SSRIs), when the antidepressant to be discontinued has been used for <1 week, or when the discontinuation is for adverse effects. When choosing the switch strategy, consider the risk of discontinuation symptoms, potential for drug interactions, other antidepressant properties (eg, half-life, adverse effects, and pharmacodynamics), and the degree of symptom control desired. If necessary, some clinicians allow for abrupt discontinuation based on fluoxetine's long half-life (Ref).
Switching to or from an MAOI:
Allow 14 days to elapse between discontinuing an MAOI and initiation of fluoxetine.
Allow 5 weeks to elapse between discontinuing fluoxetine and initiation of an MAOI.
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
The renal dosing recommendations are based upon the best available evidence and clinical expertise. Senior Editorial Team: Bruce Mueller, PharmD, FCCP, FASN, FNKF; Jason Roberts, PhD, BPharm (Hons), B App Sc, FSHP, FISAC; Michael Heung, MD, MS.
Altered kidney function: No dosage adjustment necessary for any degree of kidney dysfunction (Ref).
Hemodialysis, intermittent (thrice weekly): Not significantly dialyzed (fluoxetine and its metabolite) (Ref): No supplemental dose or dosage adjustment necessary (Ref).
Peritoneal dialysis: Unlikely to be dialyzed (highly protein bound): No dosage adjustment necessary (Ref).
CRRT: No dosage adjustment necessary (Ref).
PIRRT (eg, sustained, low-efficiency diafiltration): No dosage adjustment necessary (Ref).
Use lower doses (up to 50% reduction) and less frequent dosing intervals in patients with cirrhosis and chronic liver disease; use with caution (Ref).
Major depressive disorder (unipolar): Oral: Some patients may require an initial dose of 10 mg once daily with dosage increases of 10 to 20 mg every several weeks as tolerated; should not be taken at night unless patient experiences sedation. Refer to adult dosing; use with caution given the long half-life of fluoxetine.
Dosing conversion: Refer to adult dosing.
Discontinuation of therapy: Refer to adult dosing.
Switching antidepressants: Refer to adult dosing.
(For additional information see "Fluoxetine: Pediatric drug information")
Dosage guidance:
Dosage form information: When using oral solutions, multiple concentrations may be available (commercially available [4 mg/mL] and compounded solutions [eg, 1 mg/mL, 2 mg/mL]); take precautions to verify appropriate product selection and avoid confusion between the different concentrations; dose should be clearly presented as mg.
Anxiety disorders: Limited data available:
Note: Fluoxetine therapy should be initiated at a low dose with a slow titration to reduce the potential for behavioral activation/agitation that may occur with therapy initiation particularly in younger children. Conservatively, fluoxetine dose titration at 3- to 4-week intervals has been suggested due to its long half-life; however, some patients with more severe symptoms may require more rapid titration; in trials, dose titration in weekly increments has been reported (Ref).
Generalized anxiety, separation anxiety, panic disorders:
Note: In pediatric patients, selective serotonin reuptake inhibitor (SSRI) therapy is considered first-line pharmacologic treatment for moderate to severe anxiety disorders in combination with cognitive behavioral therapy (CBT); of the SSRIs with positive pediatric data evaluated in the AHRQ/Mayo review (fluoxetine, fluvoxamine, paroxetine, and sertraline), a preferred SSRI has not been defined; therapeutic selection should be based on pharmacokinetic and pharmacodynamic data, patient tolerability, cost, and unique risks/precautions with specific agents (Ref).
Children 6 to <12 years: Oral: Immediate release: Initial: 5 mg once daily, may slowly titrate as needed; suggested target dose range: 10 to 20 mg once daily; maximum daily dose: 40 mg/day (Ref).
Children ≥12 years and Adolescents: Oral: Immediate release: Initial: 10 mg once daily, may slowly titrate as needed; suggested target dose range: 20 to 40 mg once daily; usual maximum daily dose: 60 mg/day although use of doses up to 80 mg/day has been reported (Ref).
Selective mutism:
Limited data available: Children ≥5 years and Adolescents: Oral: Immediate release: Initial: 5 or 10 mg once daily for ≥7 days, then increase by doubling dose to 10 or 20 mg once daily for 7 days; may further titrate in 20 mg/day increments, if needed, every 2 weeks; maximum daily dose: 60 mg/day (Ref). Dosing is based on an open-label study of 21 pediatric patients (age: 5 to 14 years); positive responses were reported in 76% of patients and required a dose of at least 20 mg/day; mean final dose: 28.1 mg/day (1.1 mg/kg/day) (Ref) and a small (n= 5) single-case design, placebo-controlled trial (ages: 5 to 14 years) with a final dose of 20 mg/day (Ref). To fully assess therapeutic response, a therapeutic trial of at least 9 to 12 weeks or longer has been suggested (Ref).
Anorexia nervosa: Limited data available; efficacy results variable:
Note: Use in combination with psychosocial intervention or CBT; SSRI antidepressants have not been shown effective during the acute phases of illness; however, they may be considered for comorbid mental health conditions once weight has been restored (Ref).
Adolescents: Oral: Immediate release: Initial: 20 mg once daily; may titrate in 20 mg increments (similar to other indications in adolescents) at monthly intervals; typical reported dosing range: 20 to 40 mg/day; reported maximum daily dose: 60 mg/day (Ref). Dosing based on a small, prospective, double-blind, placebo-controlled trial of 35 patients (fluoxetine: n=16; mean age: 23 ± 9 years) which showed reduced relapse (increased weight, decrease in symptoms) with 1 year of fluoxetine and mean dose of 38 ± 21 mg/day (Ref). Other randomized controlled trials with similar dosing have not shown fluoxetine therapy effective (Ref).
Bulimia nervosa: Limited data available: Note: Antidepressant therapy is recommended to target symptoms of obsessionality, anxiety, and depression in combination with CBT (Ref).
Children ≥12 years and Adolescents: Oral: Immediate release: Initial: 20 mg once daily for 3 days, then 40 mg once daily for 3 days, then 60 mg once daily; dosing based on an open-label study of 10 pediatric patients (age: 12 to 18 years) which showed significant decrease in number of weekly purges; other reports describe use in adolescents (Ref).
Depression:
Note: In the management of depression in children and adolescents, if pharmacotherapy is deemed necessary with/without psychotherapeutic interventions, an SSRI should be used first-line; fluoxetine has the strongest efficacy evidence and is preferred as first-line SSRI option in absence of drug-drug interactions, risk factors for bipolar comorbidity, or family (eg, parent, sibling) history of poor response to fluoxetine (Ref). Therapy should be initiated at a low dose and titrated every 1 to 2 weeks (Ref).
Children 8 to <12 years: Oral: Immediate release: Initial: 5 or 10 mg once daily; usual daily dose: 10 mg once daily; if needed, may increase dose to 20 mg once daily after 1 to 2 weeks; some pediatric patients may require higher doses up to 40 mg/day; maximum daily dose: 40 mg/day (Ref).
Children ≥12 years and Adolescents: Oral: Immediate release: Initial: 10 to 20 mg once daily; may increase in 10 to 20 mg increments every 1 to 2 weeks; usual effective dose: 20 to 40 mg once daily; maximum daily dose: 60 mg/day (Ref).
Depression associated with bipolar I disorder (in combination with olanzapine):
Children ≥10 years and Adolescents: Oral: Immediate release: Initial: 20 mg in the evening; adjust dose, if needed, as tolerated; safety of fluoxetine doses >50 mg in combination with doses >12 mg of olanzapine has not been studied in pediatrics.
Note: When using individual components of fluoxetine with olanzapine rather than fixed-dose combination product (Symbyax), approximate dosage correspondence is as follows:
Olanzapine 2.5 mg + fluoxetine 20 mg = Symbyax 3/25.
Olanzapine 5 mg + fluoxetine 20 mg = Symbyax 6/25.
Olanzapine 12.5 mg + fluoxetine 20 mg = Symbyax 12/25.
Olanzapine 5 mg + fluoxetine 50 mg = Symbyax 6/50.
Olanzapine 12.5 mg + fluoxetine 50 mg = Symbyax 12/50.
Obsessive-compulsive disorder (OCD):
Note: In the management of OCD in children and adolescents, if pharmacotherapy deemed necessary it should be in combination with CBT and an SSRI should be used first-line; a preferred agent has not been identified (Ref).
Children preschool to <7 years: Limited data available:
Note: Use should be reserved for patients with moderate to severe symptoms which cause significant distress or significant impairment in the child's relationships, daily routine at home, or child care setting, and continue despite psychotherapeutic interventions (Ref).
Oral: Immediate release: 2.5 to 5 mg once daily initially; continue for 10 to 12 weeks to assess initial response; monitor closely (Ref).
Children ≥7 years and Adolescents: Oral: Immediate release (Ref).
Lower weight Children: Initial: 5 to 10 mg once daily; if needed, may increase dose after several weeks; usual daily dose: 20 to 30 mg/day; minimal experience with doses >20 mg/day; no experience with doses >60 mg/day.
Higher weight Children and Adolescents: Initial: 10 mg once daily; increase dose to 20 mg once daily after 2 weeks; may increase dose after several more weeks; usual daily dose: 20 to 60 mg/day; however, doses of 80 mg/day may be considered in some cases.
Discontinuation of therapy: Consider planning antidepressant discontinuation for lower-stress times, recognizing non-illness-related factors could cause stress or anxiety and be misattributed to antidepressant discontinuation (Ref). Upon discontinuation of antidepressant therapy, gradually taper the dose to minimize the incidence of discontinuation syndromes (withdrawal) and allow for the detection of reemerging disease state symptoms (eg, relapse). Evidence supporting ideal taper rates after illness remission is limited. APA and NICE guidelines suggest tapering therapy over at least several weeks with consideration to the half-life of the antidepressant; antidepressants with a shorter half-life may need to be tapered more conservatively. After long-term (years) antidepressant treatment, WFSBP guidelines recommend tapering over 4 to 6 months, with close monitoring during and for 6 months after discontinuation. If intolerable discontinuation symptoms occur following a dose reduction, consider resuming the previously prescribed dose and/or decrease dose at a more gradual rate (Ref).
Switching antidepressants: Evidence for ideal antidepressant switching strategies in pediatric patients is sparse; strategies described in pediatric guidelines include a conservative approach (tapering and discontinuing the first SSRI before adding the second) and cross-titration (gradually discontinuing the first antidepressant while at the same time gradually increasing the new antidepressant). While consensus does not exist regarding which approach to utilize, it is important to note that the conservative approach runs the risk for exacerbation of symptoms or discontinuation syndrome; cross-titration may avoid these risks (Ref). Cross-titration (eg, over 1 to 4 weeks depending upon sensitivity to discontinuation symptoms and adverse effects) is standard for most switches, but is contraindicated when switching to or from a monamine oxidase inhibitors. While not as common of a strategy, a direct switch may be considered when switching to another agent in the same or similar class (eg, when switching between 2 SSRIs), when the antidepressant to be discontinued has been used for <1 week, or when the discontinuation is for adverse effects. When choosing the switch strategy, consider the risk of discontinuation symptoms, potential for drug interactions, other antidepressant properties (eg, half-life, adverse effects, pharmacodynamics), and the degree of symptom control desired (Ref).
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
Children ≥7 years and Adolescents: Adjustment not routinely needed. With chronic administration, additional accumulation of fluoxetine or norfluoxetine may occur in patients with severely impaired renal function. Based on experience in adult patients, not removed by hemodialysis; use of lower dose or less frequent dosing is not usually necessary.
Children ≥7 years and Adolescents: Elimination half-life of fluoxetine is prolonged in patients with hepatic impairment; lower doses or less frequent administration are recommended.
Antidepressants (when used as monotherapy) may precipitate a mixed/manic episode in patients with bipolar disorder. Treatment-emergent mania or hypomania in patients with unipolar major depressive disorder (MDD) have been reported, as many cases of bipolar disorder present in episodes of MDD (Ref).
Mechanism: Non-dose-related; idiosyncratic. Unclear to what extent mood switches represent an uncovering of unrecognized bipolar disorder or a more direct pharmacologic effect independent of diagnosis (Ref).
Onset: Varied; a systematic review observed that the risk of switching increased significantly within the initial 2 years of antidepressant treatment in patients with unipolar MDD receiving an antidepressant as monotherapy, but not thereafter (up to 4.6 years) (Ref).
Risk factors:
• Family history of bipolar disorder (Ref)
• Depressive episode with psychotic symptoms (Ref)
• Younger age at onset of depression (Ref)
• Antidepressant resistance (Ref)
• Female sex (Ref)
Selective serotonin reuptake inhibitors (SSRIs), including fluoxetine, may increase the risk of bleeding, particularly if used concomitantly with antiplatelets and/or anticoagulants in adult and pediatric patients. Multiple observational studies have found an association with SSRI use and a variety of bleeding complications, ranging from bruise, hematoma, petechia, purpuric disease, and epistaxis to cerebrovascular accident, upper gastrointestinal hemorrhage, intracranial hemorrhage, postpartum hemorrhage, and intraoperative bleeding, although conflicting evidence also exists (Ref).
Mechanism: Possibly via decreased platelet serotonin concentrations and inhibition of serotonin-mediated platelet activation leading to subsequent platelet dysfunction. Fluoxetine is considered to display high affinity for the serotonin receptor (Ref). SSRIs may also increase gastric acidity, which can increase the risk of GI bleeding (Ref).
Onset: Varied; bleeding risk is likely delayed for several weeks until SSRI-induced platelet serotonin depletion becomes clinically significant (Ref); although the onset of bleeding may be more unpredictable if patients are taking concomitant antiplatelets, anticoagulants, or nonsteroidal anti-inflammatory drugs (NSAIDs). For upper GI bleeding, some studies have found risk to be the highest in the first 28 to 30 days (Ref), whereas another study reported a median time of onset of 25 weeks (Ref).
Risk factors:
• Concomitant use of anticoagulants and/or antiplatelets (Ref)
• Preexisting platelet dysfunction or coagulation disorders (eg, von Willebrand factor) (Ref)
• Concomitant use of NSAIDs increase the risk for upper GI bleeding (Ref)
Limited data from observational studies involving mostly older adults (≥50 years of age) suggest selective serotonin reuptake inhibitors (SSRIs) are associated with an increased risk of bone fractures (Ref).
Mechanism: Time-related; mechanism not fully elucidated; postulated to be through a direct effect by SSRIs on bone metabolism via interaction with 5-HT and osteoblast, osteocyte, and/or osteoclast activity (Ref). SSRIs may also contribute to fall risk, contributing to the incidence of fractures (Ref).
Onset: Delayed; risk appears to increase after initiation and may continue to increase with long-term use. A meta-analysis found risk of fracture increased from 2.9% over 1 year to 5.4% over 2 years; within 5 years, risk increased to 13.4% (Ref).
Risk factors:
• Long-term use may be a risk factor (Ref)
A wide variety of hypersensitivity reactions have been reported rarely with fluoxetine, including severe systemic reactions; reactions include dermatitis, urticaria, angioedema, eosinophilia, Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS), serum-like sickness reaction, vasculitis (eg, leukocytoclastic vasculitis, Henoch-Schönlein purpura), and certain pulmonary inflammatory diseases (eg, hypersensitivity pneumonitis, pulmonary granuloma) (Ref).
Mechanism: Non-dose-related; immunologic. Severe cutaneous adverse reactions, namely SJS/TEN, DRESS, acute generalized exanthematous pustulosis), are delayed type IV hypersensitivity reactions involving a T-cell mediated drug-specific immune response (Ref).
Onset: Intermediate; in the majority of cases, onset of symptoms generally occurred from 1 to 4 weeks after initiation of therapy (Ref).
Selective serotonin reuptake inhibitors (SSRIs) are associated with syndrome of inappropriate antidiuretic hormone secretion (SIADH) and/or hyponatremia, including severe cases, predominantly in the elderly (Ref). Hyponatremia is reversible with discontinuation of therapy (Ref).
Mechanism: May cause SIADH via release of antidiuretic hormone (ADH) (Ref) or may cause nephrogenic SIADH by increasing the sensitivity of the kidney to ADH (Ref).
Onset: Intermediate; usually develops within the first few weeks of treatment (Ref).
Risk factors:
• Older age (Ref)
• Females (Ref)
• Concomitant use of diuretics (Ref)
• Low body weight (Ref)
• Lower baseline serum sodium concentration (Ref)
• Volume depletion (Ref)
• History of hyponatremia (potential risk factors) (Ref)
• Symptoms of psychosis (potential risk factors) (Ref)
Selective serotonin reuptake inhibitors (SSRIs) are associated with acute angle-closure glaucoma (AACG) in case reports and a case-controlled study. AACG may cause symptoms including eye pain, changes in vision, swelling, and redness, which can rapidly lead to permanent blindness if not treated (Ref). In addition, SSRIs may be associated with an increased risk of cataract development (Ref).
Mechanism: AACG: Unclear; hypothesized SSRIs may increase the intraocular pressure via serotonergic effects on ciliary body muscle activation and pupil dilation (Ref).
Risk factors:
For AACG:
• Females (Ref)
• ≥50 years of age (slight increase) (Ref)
• Hyperopia (slight increase) (Ref)
• Personal or family history of AACG (Ref)
• Inuit or Asian descent (Ref)
Serotonin syndrome has been reported and typically occurs with coadministration of multiple serotonergic drugs but can occur following a single serotonergic agent at therapeutic doses, particularly with fluoxetine use (Ref). The diagnosis of serotonin syndrome is made based on the Hunter Serotonin Toxicity Criteria (Ref) and may result in a spectrum of symptoms, such as anxiety, agitation, confusion, delirium, hyperreflexia, muscle rigidity, myoclonus, tachycardia, tachypnea, and tremor. Severe cases may cause hyperthermia, significant autonomic instability (ie, rapid and severe changes in blood pressure and pulse), coma, and seizures (Ref).
Mechanism: Dose-related; overstimulation of serotonin receptors by serotonergic agents (Ref).
Onset: Rapid; in the majority of cases (74%), onset occurred within 24 hours of treatment initiation, overdose, or change in dose (Ref).
Risk factors:
• Concomitant use of drugs that increase serotonin synthesis, block serotonin reuptake and/or impair serotonin metabolism (eg, monamine oxidase inhibitors [MAOIs]). Of note, concomitant use of some serotonergic agents, such as MAOIs, are contraindicated.
Selective serotonin reuptake inhibitors (SSRIs) are commonly associated with sexual disorders in both men and women. The following adverse reactions have been associated with SSRI use: Ejaculatory delay, orgasm disturbance, anorgasmia, erectile dysfunction, decreased libido, and loss of libido (Ref). Priapism and decreased genital anesthesia have also been reported (Ref).
Mechanism: Increases in serotonin may affect other hormones and neurotransmitters involved in sexual function; in particular, testosterone's effect on sexual arousal and dopamine's role in achieving orgasm (Ref).
Onset: Varied; one longitudinal study observed an onset of sexual dysfunction within the first 6 weeks of treatment with fluoxetine (Ref).
Risk factors:
• Depression (sexual dysfunction is commonly associated with depression; SSRI-associated sexual dysfunction may be difficult to differentiate in treated patients) (Ref)
Antidepressants are associated with an increased risk of suicidal ideation and suicidal tendencies in pediatric and young adult patients (18 to 24 years of age) in short-term studies. In adults >24 years of age, short-term studies did not show an increased risk of suicidal thinking and behavior, and in older adults ≥65 years of age a decreased risk was observed. Although data have yielded inconsistent results regarding the association of antidepressants and risk of suicide, particularly among adults, collective evidence shows a trend of an elevated risk of suicidality in younger age groups (Ref). Of note, the risk of a suicide attempt is inherent in major depression and may persist until remission occurs.
Mechanism: Not established; one of several postulated mechanisms is antidepressants may energize suicidal patients to act on impulses; another suggests that antidepressants may produce a worsening of depressive symptoms leading to the emergence of suicidal thoughts and actions (Ref).
Onset: Varied; increased risk observed in short-term studies (ie, <4 months) in pediatric and young adults; it is unknown whether this risk extends to longer-term use (ie, >4 months).
Risk factors:
• Children and adolescents (Ref)
• Depression (risk of suicide associated with major depression and may persist until remission occurs)
Withdrawal syndrome, consisting of both somatic symptoms (eg, dizziness, chills, light-headedness, vertigo, shock-like sensations, paresthesia, fatigue, headache, nausea, tremor, diarrhea, visual disturbances) and psychological symptoms (eg, anxiety, agitation, confusion, insomnia, irritability, mania), have been reported, primarily following abrupt discontinuation. Withdrawal symptoms may also occur following gradual tapering (Ref).
Mechanism: Withdrawal; due to reduced availability of serotonin in the CNS with decreasing levels of the selective serotonin reuptake inhibitor. Other neurotransmission systems, including increased glutamine and dopamine, may also be affected as well as the hypothalamic-pituitary-adrenal axis (Ref).
Onset: Intermediate; expected onset is 1 to 10 days (following either abrupt or tapered discontinuation) (Ref).
Risk factors:
• Abrupt discontinuation (rather than dose taper) or tapering the antidepressant too quickly (Ref)
• Drugs with a half-life <24 hours (eg, paroxetine, venlafaxine) (Ref)
• Higher doses (Ref)
• Longer duration of treatment (eg, ≥4 weeks) (Ref)
• Prior history of antidepressant withdrawal symptoms (Ref)
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified. As reported in adults, unless otherwise noted.
>10%:
Endocrine & metabolic: Decreased libido (1% to 11%) (table 1)
|
Drug (Fluoxetine) |
Placebo |
Indication |
Number of Patients (Fluoxetine) |
Number of Patients (Placebo) |
|---|---|---|---|---|
|
5% |
1% |
Bulimia |
450 |
267 |
|
3% |
N/A |
MDD |
1728 |
975 |
|
11% |
2% |
OCD |
266 |
89 |
|
1% |
2% |
Panic disorder |
425 |
342 |
Gastrointestinal: Anorexia (4% to 17%), diarrhea (8% to 18%), nausea (12% to 29%), xerostomia (9% to 12%)
Genitourinary: Sexual disorder (literature suggests an incidence ranging from 54% to 58%; can persist after discontinuation) (Csoka 2006; Higgins 2010; Montejo 2001; Montejo-Gonzalez 1997)
Nervous system: Anxiety (6% to 15%), asthenia (9% to 21%), drowsiness (5% to 17%; literature suggests it is more common in adults compared to children and adolescents) (Safer 2006), headache (21%), insomnia (10% to 33%), nervousness (8% to 14%), tremor (3% to 13%), yawning (≤11%)
Respiratory: Pharyngitis (10% to 11%)
1% to 10%:
Cardiovascular: Chest pain (≥1%), hypertension (≥1%), palpitations (≥1%), prolonged QT interval on ECG (≥1%; QTcF ≥450 msec3), vasodilation (1% to 5%)
Dermatologic: Diaphoresis (7% to 8%), pruritus (3%), skin rash (2% to 6%) (table 2)
|
Drug (Fluoxetine) |
Placebo |
Indication |
Number of Patients (Fluoxetine) |
Number of Patients (Placebo) |
|---|---|---|---|---|
|
4% |
4% |
Bulimia |
450 |
267 |
|
4% |
3% |
MDD |
1728 |
975 |
|
6% |
3% |
OCD |
266 |
89 |
|
2% |
2% |
Panic disorder |
425 |
342 |
Endocrine & metabolic: Heavy menstrual bleeding (children and adolescents: ≥2%), increased thirst (children and adolescents: ≥2%), weight loss (2%)
Gastrointestinal: Constipation (5%), dysgeusia (≥1%), dyspepsia (6% to 10%), flatulence (3%), increased appetite (≥1%), vomiting (3%; literature suggests prevalence is higher in adolescents compared to adults and is two- to threefold more prevalent in children compared to adults) (Safer 2006)
Genitourinary: Ejaculatory disorder (2% to 7%) (table 3), erectile dysfunction (≤7%), urinary frequency (children and adolescents: ≥2%), urination disorder (≥1%)
|
Drug (Fluoxetine) |
Placebo |
Indication |
Number of Patients (Fluoxetine) |
Number of Patients (Placebo) |
|---|---|---|---|---|
|
7% |
N/A |
Bulimia |
14 |
1 |
|
7% |
N/A |
OCD |
116 |
43 |
|
2% |
1% |
Panic disorder |
162 |
121 |
Nervous system: Abnormal dreams (5%), agitation (children and adolescents: ≥2%), amnesia (≥1%), changes in thinking (2%), chills (≥1%), dizziness (9%), emotional lability (≥1%), personality disorder (children and adolescents: ≥2%), sleep disturbance (≥1%)
Neuromuscular & skeletal: Hyperkinetic muscle activity (children and adolescents: ≥2%)
Ophthalmic: Visual disturbance (2%)
Otic: Otalgia (≥1%), tinnitus (≥1%)
Respiratory: Epistaxis (children and adolescents: ≥2%), flu-like symptoms (8% to 10%), sinusitis (5% to 6%)
<1%:
Cardiovascular: Acute myocardial infarction, angina pectoris, cardiac arrhythmia, edema, heart failure, hypotension, orthostatic hypotension, syncope, vasculitis
Dermatologic: Acne vulgaris, alopecia, ecchymoses, purpuric rash, skin photosensitivity
Endocrine & metabolic: Albuminuria, amenorrhea, hypercholesterolemia, hypothyroidism, increased libido
Gastrointestinal: Aphthous stomatitis, bloody diarrhea, bruxism, cholelithiasis, colitis, duodenal ulcer, esophageal ulcer, gastritis, gastroenteritis, gastrointestinal ulcer, glossitis, hematemesis, melena, peptic ulcer
Genitourinary: Gynecological bleeding
Hematologic & oncologic: Anemia, petechia
Hepatic: Abnormal hepatic function tests, hepatitis
Nervous system: Akathisia, ataxia, balance impairment, delusion, depersonalization, euphoria, extrapyramidal reaction, hostility, hypertonia, migraine, myoclonus, paranoid ideation, suicidal tendencies
Neuromuscular & skeletal: Arthritis, bursitis, gout, lower limb cramp, ostealgia
Ophthalmic: Mydriasis
Respiratory: Asthma, laryngeal edema
Postmarketing:
Cardiovascular: Atrial fibrillation, pulmonary embolism, ventricular tachycardia (including torsades de pointes) (Wenzel-Seifert 2011)
Dermatologic: Dermatitis (Agrawal 2019), erythema multiforme, erythema nodosum, exfoliative dermatitis, psoriasis (new onset) (Tan Pei Lin 2010), Stevens-Johnson syndrome (Agrawal 2019), toxic epidermal necrolysis (Jonsson 2008)
Endocrine & metabolic: Galactorrhea not associated with childbirth, gynecomastia, hyperprolactinemia, hypoglycemia, hypokalemia, hyponatremia (literature suggests incidence among selective serotonin reuptake inhibitors [SSRIs] ranges from <1% to as high as 32%) (Jacob 2006; Kaya 2016), SIADH (Blacksten 1993)
Gastrointestinal: Esophagitis, pancreatitis, upper gastrointestinal hemorrhage (Wee 2017)
Genitourinary: Anorgasmia (Kline 1989), priapism (Javed 1996), sexual difficulty (decreased genital sensation) (Michael 2000)
Hematologic & oncologic: Aplastic anemia, bruise (Pai 1996), hemolytic anemia (immune-related), Henoch-Schonlein purpura (Süleyman 2016), immune thrombocytopenia, pancytopenia, thrombocytopenia (Yucel 2015)
Hepatic: Cholestatic jaundice, hepatic failure, hepatic necrosis, hepatotoxicity (Agrawal 2019)
Hypersensitivity: Drug reaction with eosinophilia and systemic symptoms (Vignesh 2017), hypersensitivity reaction (Beer 1994), nonimmune anaphylaxis, serum sickness-like reaction (Miller 1989)
Nervous system: Anosmia (including hyposmia), cerebrovascular accident, hallucination, hyperactive behavior (including agitation, hyperactivation, hyperkinesis, restlessness; occurring in children at a two- to threefold higher incidence compared to adolescents) (Safer 2006), hypomania (Jerome 1991), mania (Settle 1984), memory impairment (Chavant 2011), neuroleptic malignant syndrome, obsessive compulsive disorder (worsening symptoms of trichotillomania) (Yektaş 2017), seizure (Hargrave 1992; Levine 1994), serotonin syndrome (Patel 2016), suicidal ideation (Teicher 1990), violent behavior
Neuromuscular & skeletal: Dyskinesia (Mander 1994), dystonia (Bilen 2008), laryngospasm, linear skeletal growth rate below expectation (children) (Weintrob 2006), lupus-like syndrome, tardive dyskinesia (Dubovsky 1996)
Ophthalmic: Acute angle-closure glaucoma (Ahmad 1991), cataract, optic neuritis
Renal: Renal failure syndrome
Respiratory: Eosinophilic pneumonitis, hypersensitivity pneumonitis (Gonzalez-Rothi 1995), hyperventilation, pulmonary fibrosis, pulmonary granuloma (de Kerviler 1996), pulmonary hypertension
Hypersensitivity to fluoxetine or any component of the formulation; use of monoamine oxidase inhibitors (MAOIs) intended to treat psychiatric disorders (concurrently, within 5 weeks of discontinuing fluoxetine, or within 2 weeks of discontinuing the MAOI); initiation of fluoxetine in a patient receiving IV methylene blue; use with pimozide or thioridazine (Note: Thioridazine should not be initiated until 5 weeks after the discontinuation of fluoxetine).
Note: Although fluoxetine is contraindicated per the manufacturer labeling when used in combination with linezolid, new evidence suggests that the combination is unlikely to cause serotonin syndrome (0.06% to 3% risk), and therefore these agents can be administered concomitantly when necessary. Monitor patients on this combination; average duration of serotonin toxicity is ~4 days; however, risks may be greater with longer durations of concurrent therapy. Educate patients on the signs and symptoms of serotonin syndrome (Bai 2022; Butterfield 2012; Karkow 2017; Kufel 2023; Narita 2007; Taylor 2006).
Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
Canadian labeling: Additional contraindications (not in the US labeling): Initiation of fluoxetine within 2 weeks of thioridazine discontinuation
Concerns related to adverse effects:
• CNS depression: Has a low potential to impair cognitive or motor performance; caution operating hazardous machinery or driving.
• QT prolongation: QT prolongation and ventricular arrhythmia, including torsades de pointes, have occurred. Use with caution in patients with risk factors for QT prolongation (eg, congenital long QT syndrome, history of prolonged QT, family history of prolonged QT or sudden cardiac death), other conditions that predispose to arrhythmias (eg, hypokalemia, hypomagnesemia, recent myocardial infarction [MI], uncompensated heart failure, bradyarrhythmias or other arrhythmias, concomitant use of other agents that prolong QT interval), or increased fluoxetine exposure (eg, overdose, hepatic impairment, use of CYP2D6 inhibitors, poor CYP2D6 metabolizer status, concomitant use of other highly protein-bound drugs). Consider ECG monitoring when initiating therapy in patients with risk factors for QT prolongation and ventricular arrhythmia. Consider discontinuing fluoxetine if ventricular arrhythmia suspected and initiate cardiac evaluation.
Disease-related concerns:
• Cardiovascular disease: Use with caution in patients with a history of MI or unstable heart disease; experience in these patients is limited.
• Hepatic impairment: Use with caution in patients with hepatic impairment; clearance is decreased and half-life and plasma concentrations are increased; a lower dosage may be needed in patients with cirrhosis. However, selective serotonin reuptake inhibitors such as fluoxetine are considered the safest antidepressants to use in chronic liver disease because of their relative lack of side effects and high therapeutic index (Mullish 2014).
• Seizure disorders: Use with caution in patients with a previous seizure disorder or conditions predisposing to seizures such as brain damage or alcoholism.
Special populations:
• Older adult: May also cause agitation, sleep disturbances, and excessive CNS stimulation in older adults. Given the long half-life and nonlinear disposition of the drug, use caution, particularly if they have systemic illness or are receiving multiple drugs for concomitant diseases.
Dosage form specific issues:
• Benzyl alcohol and derivatives: Some dosage forms may contain sodium benzoate/benzoic acid; benzoic acid (benzoate) is a metabolite of benzyl alcohol; large amounts of benzyl alcohol (≥99 mg/kg/day) have been associated with a potentially fatal toxicity (“gasping syndrome”) in neonates; the “gasping syndrome” consists of metabolic acidosis, respiratory distress, gasping respirations, CNS dysfunction (including convulsions, intracranial hemorrhage), hypotension, and cardiovascular collapse (AAP ["Inactive" 1997]; CDC 1982); some data suggest that benzoate displaces bilirubin from protein binding sites (Ahlfors 2001); avoid or use dosage forms containing benzyl alcohol derivative with caution in neonates. See manufacturer's labeling.
Other warnings/precautions:
• Long half-life: Due to the long half-life of fluoxetine and its metabolites, the effects and interactions noted may persist for prolonged periods following discontinuation.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product
Capsule, Oral:
PROzac: 10 mg, 20 mg, 40 mg
Generic: 10 mg, 20 mg, 40 mg
Capsule Delayed Release, Oral:
Generic: 90 mg
Solution, Oral:
Generic: 20 mg/5 mL (5 mL, 120 mL)
Tablet, Oral:
Sarafem: 10 mg [DSC], 20 mg [DSC] [contains fd&c yellow #6(sunset yellow)alumin lake, quinoline (d&c yellow #10) aluminum lake]
Generic: 10 mg, 20 mg, 60 mg
Yes
Capsule, delayed release (FLUoxetine HCl Oral)
90 mg (per each): $39.21
Capsules (FLUoxetine HCl Oral)
10 mg (per each): $0.07 - $2.60
20 mg (per each): $0.07 - $2.67
40 mg (per each): $0.91 - $5.34
Capsules (PROzac Oral)
10 mg (per each): $17.03
20 mg (per each): $17.51
40 mg (per each): $30.41
Solution (FLUoxetine HCl Oral)
20 mg/5 mL (per mL): $0.98 - $2.50
Tablets (FLUoxetine HCl (PMDD) Oral)
10 mg (per each): $16.25
20 mg (per each): $16.25
Tablets (FLUoxetine HCl Oral)
10 mg (per each): $2.87 - $2.90
20 mg (per each): $4.20 - $4.94
60 mg (per each): $10.44 - $12.19
Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursement or purchasing functions or considered to be an exact price for a single product and/or manufacturer. Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions. In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data. Pricing data is updated monthly.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Capsule, Oral:
PROzac: 10 mg, 20 mg [contains butylparaben, edetate (edta) calcium disodium, fd&c blue #1 (brilliant blue), methylparaben, propylparaben]
Generic: 10 mg, 20 mg, 40 mg, 60 mg
Solution, Oral:
Generic: 20 mg/5 mL (120 ea, 120 mL)
Administer without regard to meals.
Bariatric surgery: Capsule, delayed release: Some institutions may have specific protocols that conflict with these recommendations; refer to institutional protocols as appropriate. Delayed-release capsule cannot be opened. Switch to IR tablet or oral solution dosed daily.
Oral: May be administered without regard to food. For most pediatric uses (ie, anxiety, obsessive-compulsive disorder, depression, anorexia, bulimia), doses should be administered in the morning. When used concomitantly with olanzapine for bipolar I disorder and treatment-resistant depression, doses should be administered in the evening.
An FDA-approved patient medication guide, which is available with the product information and as follows, must be dispensed with this medication:
Fluoxetine tablets: https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/202133s009s016lbl.pdf#page=36
Prozac: https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/018936%20s112lbl.pdf#page=26
Sarafem: https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/021860s015lbl.pdf#page=32
Bipolar disorder (excluding Sarafem): As an adjunct to olanzapine (preferred), other antipsychotics, or antimanic agents for the treatment of depressive episodes associated with bipolar disorder (WFSBP [Grunze 2010]; manufacturer’s labeling).
Bulimia nervosa (excluding Sarafem): Acute and maintenance treatment of binge eating and vomiting behaviors in patients with moderate to severe bulimia nervosa.
Major depressive disorder (unipolar) (excluding Sarafem): Acute and maintenance treatment of unipolar major depressive disorder (MDD). Also, approved for acute treatment of treatment-resistant unipolar depression (patients with unipolar MDD who do not respond to 2 separate trials of different antidepressants of adequate dose and duration in the current episode) in combination with olanzapine or other antipsychotics (APA 2010).
Obsessive-compulsive disorder (excluding Sarafem): Acute and maintenance treatment of obsessions and compulsions in patients with obsessive-compulsive disorder.
Panic disorder (excluding Sarafem): Acute treatment of panic disorder with or without agoraphobia.
Premenstrual dysphoric disorder (Sarafem only): Treatment of premenstrual dysphoric disorder.
Binge eating disorder; Body dysmorphic disorder; Fibromyalgia, refractory; Generalized anxiety disorder; Posttraumatic stress disorder; Premature ejaculation; Selective mutism; Social anxiety disorder
FLUoxetine may be confused with DULoxetine, famotidine, Feldene, fluconazole, fluvastatin, fluvoxaMINE, fosinopril, furosemide, Loxitane [DSC], PARoxetine, thiothixene, vortioxetine
PROzac may be confused with Paxil, Prelone, PriLOSEC, Prograf, Proscar, ProSom, Provera
Beers Criteria: Selective Serotonin Reuptake Inhibitors (SSRIs) are identified in the Beers Criteria as a potentially inappropriate medications to be used with caution in patients 65 years and older due to the potential to cause or exacerbate syndrome of inappropriate antidiuretic hormone secretion (SIADH) or hyponatremia; monitor sodium concentration closely when initiating or adjusting the dose in older adults (Beers Criteria [AGS 2023]).
Fluoxetine is identified in the Screening Tool of Older Person's Prescriptions (STOPP) criteria as a potentially inappropriate medication in older adults (≥65 years of age) with a history of recurrent falls due to an increased risk of falls. In addition, some disease states of concern include hyponatremia and recent or current significant bleeding (O’Mahony 2023).
Reneuron [Spain] may be confused with Remeron brand name for mirtazapine [US, Canada, and multiple international markets]
Sarafem [US, Puerto Rico] may be confused with Serophene brand name for clomiPHENE [multiple international markets]
Substrate of CYP1A2 (minor), CYP2B6 (minor), CYP2C19 (minor), CYP2C9 (minor), CYP2D6 (minor), CYP2E1 (minor), CYP3A4 (minor); Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potential; Inhibits CYP2C19 (moderate), CYP2D6 (strong)
Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the drug interactions program by clicking on the “Launch drug interactions program” link above.
Abrocitinib: Selective Serotonin Reuptake Inhibitors may enhance the antiplatelet effect of Abrocitinib. Risk X: Avoid combination
Acalabrutinib: May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Risk C: Monitor therapy
Agents with Antiplatelet Properties (e.g., P2Y12 inhibitors, NSAIDs, SSRIs, etc.): May enhance the antiplatelet effect of other Agents with Antiplatelet Properties. Risk C: Monitor therapy
Agents with Blood Glucose Lowering Effects: Selective Serotonin Reuptake Inhibitors may enhance the hypoglycemic effect of Agents with Blood Glucose Lowering Effects. Risk C: Monitor therapy
Ajmaline: CYP2D6 Inhibitors (Strong) may increase the serum concentration of Ajmaline. Risk C: Monitor therapy
Alcohol (Ethyl): May enhance the adverse/toxic effect of Selective Serotonin Reuptake Inhibitors. Specifically, the risk of psychomotor impairment may be enhanced. Management: Patients receiving selective serotonin reuptake inhibitors should be advised to avoid alcohol. Monitor for increased psychomotor impairment in patients who consume alcohol during treatment with selective serotonin reuptake inhibitors. Risk D: Consider therapy modification
Almotriptan: May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor therapy
Alosetron: May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor therapy
Amphetamines: May enhance the serotonergic effect of Selective Serotonin Reuptake Inhibitors (Strong CYP2D6 Inhibitors). This could result in serotonin syndrome. Selective Serotonin Reuptake Inhibitors (Strong CYP2D6 Inhibitors) may increase the serum concentration of Amphetamines. Management: Monitor for amphetamine toxicities, including serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability). Initiate amphetamines at lower doses, monitor frequently, and adjust dose as needed. Risk C: Monitor therapy
Anagrelide: May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Risk C: Monitor therapy
Anticoagulants: Agents with Antiplatelet Properties may enhance the anticoagulant effect of Anticoagulants. Risk C: Monitor therapy
Antiemetics (5HT3 Antagonists): May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor therapy
Antiplatelet Agents (P2Y12 Inhibitors): Selective Serotonin Reuptake Inhibitors may enhance the antiplatelet effect of Antiplatelet Agents (P2Y12 Inhibitors). Risk C: Monitor therapy
Antipsychotic Agents: Serotonergic Agents (High Risk) may enhance the adverse/toxic effect of Antipsychotic Agents. Specifically, serotonergic agents may enhance dopamine blockade, possibly increasing the risk for neuroleptic malignant syndrome. Antipsychotic Agents may enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Risk C: Monitor therapy
Apixaban: Agents with Antiplatelet Properties may enhance the adverse/toxic effect of Apixaban. Specifically, the risk for bleeding may be increased. Management: Carefully consider risks and benefits of this combination and monitor closely. Risk C: Monitor therapy
ARIPiprazole: CYP2D6 Inhibitors (Strong) may increase the serum concentration of ARIPiprazole. Management: Aripiprazole dose reductions or avoidance are required for indications other than major depressive disorder. Dose adjustments vary based on formulation, initial starting dose, and the additional use of CYP3A4 inhibitors. See interact monograph for details Risk D: Consider therapy modification
ARIPiprazole Lauroxil: CYP2D6 Inhibitors (Strong) may increase serum concentrations of the active metabolite(s) of ARIPiprazole Lauroxil. Management: Decrease aripiprazole lauroxil dose to next lower strength if used with strong CYP2D6 inhibitors for over 14 days. No dose adjustment needed if using the lowest dose (441 mg) or if a CYP2D6 PM. Max dose is 441 mg if also taking strong CYP3A4 inhibitors. Risk D: Consider therapy modification
Aspirin: Selective Serotonin Reuptake Inhibitors may enhance the antiplatelet effect of Aspirin. Risk C: Monitor therapy
Atomoxetine: CYP2D6 Inhibitors (Strong) may increase the serum concentration of Atomoxetine. Management: Initiate atomoxetine at a reduced dose (patients who weigh up to 70 kg: 0.5 mg/kg/day; adults or patients who weigh 70 kg or more: 40 mg/day) in patients receiving a strong CYP2D6 inhibitor. Increase to usual target dose after 4 weeks if needed. Risk D: Consider therapy modification
Belzutifan: CYP2C19 Inhibitors (Moderate) may increase the serum concentration of Belzutifan. Risk C: Monitor therapy
Bemiparin: Agents with Antiplatelet Properties may enhance the anticoagulant effect of Bemiparin. Management: Avoid concomitant use of bemiparin with antiplatelet agents. If concomitant use is unavoidable, monitor closely for signs and symptoms of bleeding. Risk D: Consider therapy modification
Brexanolone: Selective Serotonin Reuptake Inhibitors may enhance the CNS depressant effect of Brexanolone. Risk C: Monitor therapy
Brexpiprazole: CYP2D6 Inhibitors (Strong) may increase the serum concentration of Brexpiprazole. Management: Reduce brexpiprazole dose to 50% of usual with strong CYP2D6 inhibitors, reduce to 25% of usual if used with both a strong CYP2D6 inhibitor and a strong or moderate CYP3A4 inhibitor; these recommendations do not apply if treating major depressive disorder Risk D: Consider therapy modification
Brivaracetam: CYP2C19 Inhibitors (Moderate) may increase the serum concentration of Brivaracetam. Risk C: Monitor therapy
Bromopride: May enhance the adverse/toxic effect of Selective Serotonin Reuptake Inhibitors. Risk X: Avoid combination
Broom: CYP2D6 Inhibitors (Strong) may increase the serum concentration of Broom. Specifically, the concentrations of sparteine, a constituent of broom, may be increased. Risk C: Monitor therapy
BuPROPion: FLUoxetine may enhance the neuroexcitatory and/or seizure-potentiating effect of BuPROPion. BuPROPion may increase the serum concentration of FLUoxetine. Risk C: Monitor therapy
BusPIRone: May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor therapy
Caplacizumab: Agents with Antiplatelet Properties may enhance the adverse/toxic effect of Caplacizumab. Specifically, the risk of bleeding may be increased. Management: Avoid coadministration of caplacizumab with antiplatelets if possible. If coadministration is required, monitor closely for signs and symptoms of bleeding. Interrupt use of caplacizumab if clinically significant bleeding occurs. Risk D: Consider therapy modification
CarBAMazepine: FLUoxetine may increase the serum concentration of CarBAMazepine. Risk C: Monitor therapy
Carisoprodol: CYP2C19 Inhibitors (Moderate) may decrease serum concentrations of the active metabolite(s) of Carisoprodol. CYP2C19 Inhibitors (Moderate) may increase the serum concentration of Carisoprodol. Risk C: Monitor therapy
Carvedilol: CYP2D6 Inhibitors (Strong) may increase the serum concentration of Carvedilol. Risk C: Monitor therapy
Cephalothin: Agents with Antiplatelet Properties may enhance the adverse/toxic effect of Cephalothin. Specifically, the risk for bleeding may be increased. Risk C: Monitor therapy
Charcoal, Activated: May decrease serum concentrations of the active metabolite(s) of FLUoxetine. Charcoal, Activated may decrease the serum concentration of FLUoxetine. Risk C: Monitor therapy
Chlorpheniramine: CYP2D6 Inhibitors (Strong) may increase the serum concentration of Chlorpheniramine. Risk C: Monitor therapy
Cilostazol: CYP2C19 Inhibitors (Moderate) may increase serum concentrations of the active metabolite(s) of Cilostazol. CYP2C19 Inhibitors (Moderate) may increase the serum concentration of Cilostazol. Management: Reduce the cilostazol dose to 50 mg twice daily in patients who are also receiving moderate inhibitors of CYP2C19. Monitor clinical response to cilostazol closely. Risk D: Consider therapy modification
Cimetidine: May increase the serum concentration of FLUoxetine. Risk C: Monitor therapy
Citalopram: May enhance the antiplatelet effect of FLUoxetine. Citalopram may enhance the serotonergic effect of FLUoxetine. This could result in serotonin syndrome. FLUoxetine may increase the serum concentration of Citalopram. Management: Limit citalopram dose to a maximum of 20 mg/day. Monitor for signs and symptoms of bleeding, QTc interval prolongation, or serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor) if combined. Risk D: Consider therapy modification
Clarithromycin: FLUoxetine may enhance the QTc-prolonging effect of Clarithromycin. Clarithromycin may increase the serum concentration of FLUoxetine. Risk C: Monitor therapy
CloBAZam: CYP2C19 Inhibitors (Moderate) may increase serum concentrations of the active metabolite(s) of CloBAZam. CYP2C19 Inhibitors (Moderate) may increase the serum concentration of CloBAZam. Risk C: Monitor therapy
Clopidogrel: CYP2C19 Inhibitors (Moderate) may decrease serum concentrations of the active metabolite(s) of Clopidogrel. Risk C: Monitor therapy
CloZAPine: CYP2D6 Inhibitors (Strong) may increase the serum concentration of CloZAPine. Risk C: Monitor therapy
Collagenase (Systemic): Agents with Antiplatelet Properties may enhance the adverse/toxic effect of Collagenase (Systemic). Specifically, the risk of injection site bruising and or bleeding may be increased. Risk C: Monitor therapy
Cyclobenzaprine: May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor therapy
CYP2D6 Inhibitors (Strong): May increase the serum concentration of FLUoxetine. Risk C: Monitor therapy
Cyproheptadine: May diminish the therapeutic effect of Selective Serotonin Reuptake Inhibitors. Risk C: Monitor therapy
Dabigatran Etexilate: Agents with Antiplatelet Properties may enhance the anticoagulant effect of Dabigatran Etexilate. Agents with Antiplatelet Properties may increase the serum concentration of Dabigatran Etexilate. This mechanism applies specifically to clopidogrel. Management: Carefully consider risks and benefits of this combination and monitor closely; Canadian labeling recommends avoiding prasugrel or ticagrelor. Risk C: Monitor therapy
Dapoxetine: May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Do not use serotonergic agents (high risk) with dapoxetine or within 7 days of serotonergic agent discontinuation. Do not use dapoxetine within 14 days of monoamine oxidase inhibitor use. Dapoxetine labeling lists this combination as contraindicated. Risk X: Avoid combination
Dasatinib: May enhance the anticoagulant effect of Agents with Antiplatelet Properties. Risk C: Monitor therapy
Deoxycholic Acid: Agents with Antiplatelet Properties may enhance the adverse/toxic effect of Deoxycholic Acid. Specifically, the risk for bleeding or bruising in the treatment area may be increased. Risk C: Monitor therapy
Desmopressin: Hyponatremia-Associated Agents may enhance the hyponatremic effect of Desmopressin. Risk C: Monitor therapy
Deutetrabenazine: CYP2D6 Inhibitors (Strong) may increase serum concentrations of the active metabolite(s) of Deutetrabenazine. Management: The total daily dose of deutetrabenazine should not exceed 36 mg with concurrent use of a strong CYP2D6 inhibitor. Risk D: Consider therapy modification
Dexlansoprazole: CYP2C19 Inhibitors (Moderate) may increase the serum concentration of Dexlansoprazole. Risk C: Monitor therapy
Dexmethylphenidate-Methylphenidate: May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor therapy
Dextromethorphan: May enhance the serotonergic effect of Selective Serotonin Reuptake Inhibitors (Strong CYP2D6 Inhibitors). This could result in serotonin syndrome. Selective Serotonin Reuptake Inhibitors (Strong CYP2D6 Inhibitors) may increase the serum concentration of Dextromethorphan. Management: Consider alternatives to this drug combination. The dose of dextromethorphan/bupropion product should not exceed 1 tablet once daily. Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity. Risk D: Consider therapy modification
DiazePAM: CYP2C19 Inhibitors (Moderate) may increase the serum concentration of DiazePAM. Risk C: Monitor therapy
Digoxin: FLUoxetine may increase the serum concentration of Digoxin. Risk C: Monitor therapy
DOXOrubicin (Conventional): CYP2D6 Inhibitors (Strong) may increase the serum concentration of DOXOrubicin (Conventional). Risk X: Avoid combination
DULoxetine: May enhance the antiplatelet effect of Selective Serotonin Reuptake Inhibitors (Strong CYP2D6 Inhibitors). DULoxetine may enhance the serotonergic effect of Selective Serotonin Reuptake Inhibitors (Strong CYP2D6 Inhibitors). This could result in serotonin syndrome. Selective Serotonin Reuptake Inhibitors (Strong CYP2D6 Inhibitors) may increase the serum concentration of DULoxetine. Management: Monitor for increased duloxetine effects/toxicities and signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperthermia, tremor, mental status changes) when these agents are combined. In addition, monitor for signs and symptoms of bleeding. Risk C: Monitor therapy
Edoxaban: Agents with Antiplatelet Properties may enhance the adverse/toxic effect of Edoxaban. Specifically, the risk of bleeding may be increased. Risk C: Monitor therapy
Eletriptan: May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor therapy
Eliglustat: CYP2D6 Inhibitors (Strong) may increase the serum concentration of Eliglustat. Management: Eliglustat dose is 84 mg daily with CYP2D6 inhibitors. Use is contraindicated (COI) when also combined with strong CYP3A4 inhibitors. When also combined with a moderate CYP3A4 inhibitor, use is COI in CYP2D6 EMs or IMs and should be avoided in CYP2D6 PMs. Risk D: Consider therapy modification
Enoxaparin: Agents with Antiplatelet Properties may enhance the anticoagulant effect of Enoxaparin. Management: Discontinue antiplatelet agents prior to initiating enoxaparin whenever possible. If concomitant administration is unavoidable, monitor closely for signs and symptoms of bleeding. Risk D: Consider therapy modification
Epinephrine (Racemic): Selective Serotonin Reuptake Inhibitors may enhance the adverse/toxic effect of Epinephrine (Racemic). Risk X: Avoid combination
Ergot Derivatives: May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor therapy
Etravirine: CYP2C19 Inhibitors (Moderate) may increase the serum concentration of Etravirine. Risk C: Monitor therapy
Fenfluramine: CYP2D6 Inhibitors (Strong) may increase the serum concentration of Fenfluramine. Management: Limit fenfluramine dose to 20 mg/day without concurrent stiripentol or to 17 mg/day with concomitant stiripentol and clobazam when used with a strong CYP2D6 inhibitor. Risk D: Consider therapy modification
Fesoterodine: CYP2D6 Inhibitors (Strong) may increase serum concentrations of the active metabolite(s) of Fesoterodine. Risk C: Monitor therapy
Flecainide: CYP2D6 Inhibitors (Strong) may increase the serum concentration of Flecainide. Risk C: Monitor therapy
Flibanserin: CYP2C19 Inhibitors (Moderate) may increase the serum concentration of Flibanserin. Risk C: Monitor therapy
FluPHENAZine: CYP2D6 Inhibitors (Strong) may increase the serum concentration of FluPHENAZine. Risk C: Monitor therapy
Fosphenytoin-Phenytoin: CYP2C19 Inhibitors (Moderate) may increase the serum concentration of Fosphenytoin-Phenytoin. Risk C: Monitor therapy
Galantamine: CYP2D6 Inhibitors (Strong) may increase the serum concentration of Galantamine. Risk C: Monitor therapy
Gefitinib: CYP2D6 Inhibitors (Strong) may increase the serum concentration of Gefitinib. Risk C: Monitor therapy
Gepirone: May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Risk C: Monitor therapy
Gilteritinib: May diminish the therapeutic effect of Selective Serotonin Reuptake Inhibitors. Management: Avoid use of this combination if possible. If the combination cannot be avoided, monitor closely for evidence of reduced response to the selective serotonin reuptake inhibitor. Risk D: Consider therapy modification
Haloperidol: QT-prolonging Agents (Indeterminate Risk - Caution) may enhance the QTc-prolonging effect of Haloperidol. Risk C: Monitor therapy
Haloperidol: CYP2D6 Inhibitors (Strong) may increase the serum concentration of Haloperidol. Risk C: Monitor therapy
Heparin: Agents with Antiplatelet Properties may enhance the anticoagulant effect of Heparin. Management: Decrease the dose of heparin or agents with antiplatelet properties if coadministration is required. Risk D: Consider therapy modification
Herbal Products with Anticoagulant/Antiplatelet Effects (eg, Alfalfa, Anise, Bilberry): May enhance the adverse/toxic effect of Agents with Antiplatelet Properties. Bleeding may occur. Risk C: Monitor therapy
Iboga: CYP2D6 Inhibitors (Strong) may increase the serum concentration of Iboga. Risk C: Monitor therapy
Ibritumomab Tiuxetan: Agents with Antiplatelet Properties may enhance the adverse/toxic effect of Ibritumomab Tiuxetan. Both agents may contribute to impaired platelet function and an increased risk of bleeding. Risk C: Monitor therapy
Ibrutinib: May enhance the adverse/toxic effect of Agents with Antiplatelet Properties. Risk C: Monitor therapy
Icosapent Ethyl: May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Risk C: Monitor therapy
Iloperidone: CYP2D6 Inhibitors (Strong) may increase serum concentrations of the active metabolite(s) of Iloperidone. Specifically, concentrations of the metabolite P88 may be increased. CYP2D6 Inhibitors (Strong) may decrease serum concentrations of the active metabolite(s) of Iloperidone. Specifically, concentrations of the metabolite P95 may be decreased. CYP2D6 Inhibitors (Strong) may increase the serum concentration of Iloperidone. Management: Reduce iloperidone dose by half when administered with a strong CYP2D6 inhibitor and monitor for increased iloperidone toxicities, including QTc interval prolongation and arrhythmias. Risk D: Consider therapy modification
Indoramin: CYP2D6 Inhibitors (Strong) may increase the serum concentration of Indoramin. Risk C: Monitor therapy
Inotersen: May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Risk C: Monitor therapy
Ioflupane I 123: Selective Serotonin Reuptake Inhibitors may diminish the diagnostic effect of Ioflupane I 123. Risk C: Monitor therapy
Lansoprazole: CYP2C19 Inhibitors (Moderate) may increase the serum concentration of Lansoprazole. Risk C: Monitor therapy
Lasmiditan: May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor therapy
Lecanemab: May enhance the adverse/toxic effect of Agents with Antiplatelet Properties. Specifically, the risk of hemorrhage may be increased. Risk C: Monitor therapy
Levomethadone: May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor therapy
Limaprost: May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Risk C: Monitor therapy
Linezolid: May enhance the serotonergic effect of Selective Serotonin Reuptake Inhibitors. This could result in serotonin syndrome. Risk X: Avoid combination
Lipid Emulsion (Fish Oil Based): May enhance the adverse/toxic effect of Agents with Antiplatelet Properties. Risk C: Monitor therapy
Lofexidine: CYP2D6 Inhibitors (Strong) may increase the serum concentration of Lofexidine. Risk C: Monitor therapy
Lomitapide: FLUoxetine may increase the serum concentration of Lomitapide. Management: Patients taking lomitapide 10 mg/day or more should decrease the lomitapide dose by half with concurrent fluoxetine; the lomitapide dose may then be increased to a max adult dose of 30 mg/day (patients on lomitapide 5 mg/day may continue that dose). Risk D: Consider therapy modification
Lorcaserin (Withdrawn From US Market): May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor therapy
Maprotiline: CYP2D6 Inhibitors (Strong) may increase the serum concentration of Maprotiline. Risk C: Monitor therapy
Mavacamten: CYP2C19 Inhibitors (Moderate) may increase the serum concentration of Mavacamten. Risk X: Avoid combination
Mequitazine: CYP2D6 Inhibitors (Strong) may increase the serum concentration of Mequitazine. Risk X: Avoid combination
Metaxalone: May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor therapy
Methadone: May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor therapy
Methadone: CYP2D6 Inhibitors (Strong) may increase the serum concentration of Methadone. Risk C: Monitor therapy
Methylene Blue: Selective Serotonin Reuptake Inhibitors may enhance the serotonergic effect of Methylene Blue. This could result in serotonin syndrome. Risk X: Avoid combination
Metoclopramide: CYP2D6 Inhibitors (Strong) may increase the serum concentration of Metoclopramide. Management: For gastroparesis: reduce metoclopramide dose to 5mg 4 times/day and limit to 20mg/day; nasal spray not recommended. For GERD: reduce metoclopramide dose to 5mg 4 times/day or to 10mg 3 times/day and limit to 30mg/day. Monitor for toxicity when combined. Risk D: Consider therapy modification
Metoprolol: CYP2D6 Inhibitors (Strong) may increase the serum concentration of Metoprolol. Risk C: Monitor therapy
Mexiletine: CYP2D6 Inhibitors (Strong) may increase the serum concentration of Mexiletine. Risk C: Monitor therapy
Mivacurium: Selective Serotonin Reuptake Inhibitors may increase the serum concentration of Mivacurium. Risk C: Monitor therapy
Monoamine Oxidase Inhibitors (Antidepressant): Selective Serotonin Reuptake Inhibitors may enhance the serotonergic effect of Monoamine Oxidase Inhibitors (Antidepressant). This could result in serotonin syndrome. Risk X: Avoid combination
Multivitamins/Fluoride (with ADE): May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Risk C: Monitor therapy
Multivitamins/Minerals (with ADEK, Folate, Iron): May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Risk C: Monitor therapy
Multivitamins/Minerals (with AE, No Iron): May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Risk C: Monitor therapy
Nebivolol: CYP2D6 Inhibitors (Strong) may increase the serum concentration of Nebivolol. Risk C: Monitor therapy
Nefazodone: May enhance the serotonergic effect of Selective Serotonin Reuptake Inhibitors. This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor therapy
Nicergoline: CYP2D6 Inhibitors (Strong) may increase serum concentrations of the active metabolite(s) of Nicergoline. Specifically, concentrations of the MMDL metabolite may be increased. CYP2D6 Inhibitors (Strong) may decrease serum concentrations of the active metabolite(s) of Nicergoline. Specifically, concentrations of the MDL metabolite may be decreased. Risk C: Monitor therapy
NIFEdipine: FLUoxetine may increase the serum concentration of NIFEdipine. Risk C: Monitor therapy
NiMODipine: FLUoxetine may increase the serum concentration of NiMODipine. Risk C: Monitor therapy
Nonsteroidal Anti-Inflammatory Agents (COX-2 Selective): Selective Serotonin Reuptake Inhibitors may enhance the antiplatelet effect of Nonsteroidal Anti-Inflammatory Agents (COX-2 Selective). Nonsteroidal Anti-Inflammatory Agents (COX-2 Selective) may diminish the therapeutic effect of Selective Serotonin Reuptake Inhibitors. Risk C: Monitor therapy
Nonsteroidal Anti-Inflammatory Agents (Nonselective): Selective Serotonin Reuptake Inhibitors may enhance the antiplatelet effect of Nonsteroidal Anti-Inflammatory Agents (Nonselective). Nonsteroidal Anti-Inflammatory Agents (Nonselective) may diminish the therapeutic effect of Selective Serotonin Reuptake Inhibitors. Management: Consider alternatives to NSAIDs. Monitor for evidence of bleeding and diminished antidepressant effects. It is unclear whether COX-2-selective NSAIDs reduce risk. Risk D: Consider therapy modification
Nonsteroidal Anti-Inflammatory Agents (Topical): May enhance the antiplatelet effect of Selective Serotonin Reuptake Inhibitors. Risk C: Monitor therapy
Obinutuzumab: Agents with Antiplatelet Properties may enhance the adverse/toxic effect of Obinutuzumab. Specifically, the risk of serious bleeding-related events may be increased. Risk C: Monitor therapy
Oliceridine: May enhance the serotonergic effect of Selective Serotonin Reuptake Inhibitors (Strong CYP2D6 Inhibitors). This could result in serotonin syndrome. Selective Serotonin Reuptake Inhibitors (Strong CYP2D6 Inhibitors) may increase the serum concentration of Oliceridine. Management: Monitor for increased opioid effects (eg, respiratory depression, sedation) and for serotonin syndrome/serotonin toxicity when these agents are combined. Risk C: Monitor therapy
Olmutinib: CYP2D6 Inhibitors (Strong) may increase the serum concentration of Olmutinib. Risk C: Monitor therapy
Omega-3 Fatty Acids: May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Risk C: Monitor therapy
Omeprazole: CYP2C19 Inhibitors (Moderate) may increase the serum concentration of Omeprazole. Risk C: Monitor therapy
Ondansetron: May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor therapy
Opioid Agonists: May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor therapy
Opioid Agonists (metabolized by CYP3A4 and CYP2D6): May enhance the serotonergic effect of Selective Serotonin Reuptake Inhibitors (Strong CYP2D6 Inhibitors). This could result in serotonin syndrome. Selective Serotonin Reuptake Inhibitors (Strong CYP2D6 Inhibitors) may diminish the therapeutic effect of Opioid Agonists (metabolized by CYP3A4 and CYP2D6). Management: Monitor for decreased therapeutic response (eg, analgesia) and opioid withdrawal when coadministered with SSRIs that strongly inhibit CYP2D6. Additionally, monitor for serotonin syndrome/serotonin toxicity if these drugs are combined. Risk C: Monitor therapy
Opioid Agonists (metabolized by CYP3A4): May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor therapy
Oxitriptan: Serotonergic Agents (High Risk) may enhance the serotonergic effect of Oxitriptan. This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor therapy
Ozanimod: May enhance the adverse/toxic effect of Serotonergic Agents (High Risk). Risk C: Monitor therapy
PARoxetine: FLUoxetine may enhance the antiplatelet effect of PARoxetine. FLUoxetine may enhance the serotonergic effect of PARoxetine. This could result in serotonin syndrome. FLUoxetine may increase the serum concentration of PARoxetine. PARoxetine may increase the serum concentration of FLUoxetine. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, mental status changes), bleeding, and increased SSRI toxicities when these agents are combined. Risk C: Monitor therapy
Pentosan Polysulfate Sodium: May enhance the adverse/toxic effect of Agents with Antiplatelet Properties. Specifically, the risk of bleeding may be increased by concurrent use of these agents. Risk C: Monitor therapy
Pentoxifylline: May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Risk C: Monitor therapy
Perhexiline: CYP2D6 Inhibitors (Strong) may increase the serum concentration of Perhexiline. Risk C: Monitor therapy
Perphenazine: CYP2D6 Inhibitors (Strong) may increase the serum concentration of Perphenazine. Risk C: Monitor therapy
Pimozide: CYP2D6 Inhibitors (Strong) may increase the serum concentration of Pimozide. Risk X: Avoid combination
Pirtobrutinib: May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Risk C: Monitor therapy
Pitolisant: CYP2D6 Inhibitors (Strong) may increase the serum concentration of Pitolisant. Management: Reduce the pitolisant dose by 50% if a strong CYP2D6 inhibitor is initiated. For patients receiving strong CYP2D6 inhibitors, initiate pitolisant at 8.9 mg once daily and increase after 7 days to a maximum of 17.8 mg once daily. Risk D: Consider therapy modification
Primaquine: CYP2D6 Inhibitors (Strong) may diminish the therapeutic effect of Primaquine. CYP2D6 Inhibitors (Strong) may decrease serum concentrations of the active metabolite(s) of Primaquine. Risk C: Monitor therapy
Proguanil: CYP2C19 Inhibitors (Moderate) may decrease serum concentrations of the active metabolite(s) of Proguanil. CYP2C19 Inhibitors (Moderate) may increase the serum concentration of Proguanil. Risk C: Monitor therapy
Propafenone: CYP2D6 Inhibitors (Strong) may increase the serum concentration of Propafenone. Risk C: Monitor therapy
Propranolol: CYP2D6 Inhibitors (Strong) may increase the serum concentration of Propranolol. Risk C: Monitor therapy
Prostacyclin Analogues: May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Risk C: Monitor therapy
Psilocybin: Antidepressants may diminish the therapeutic effect of Psilocybin. Risk C: Monitor therapy
QT-prolonging Agents (Highest Risk): QT-prolonging Agents (Indeterminate Risk - Caution) may enhance the QTc-prolonging effect of QT-prolonging Agents (Highest Risk). Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapy
Ramosetron: May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor therapy
Rasagiline: Selective Serotonin Reuptake Inhibitors may enhance the serotonergic effect of Rasagiline. This could result in serotonin syndrome. Risk X: Avoid combination
RisperiDONE: CYP2D6 Inhibitors (Strong) may increase the serum concentration of RisperiDONE. Management: Careful monitoring for risperidone toxicities and possible dose adjustment are recommended when combined with strong CYP2D6 inhibitors. See full interaction monograph for details. Risk D: Consider therapy modification
Rivaroxaban: Agents with Antiplatelet Properties may enhance the anticoagulant effect of Rivaroxaban. Management: Carefully consider risks and benefits of this combination and monitor closely; Canadian labeling recommends avoiding prasugrel or ticagrelor. Risk C: Monitor therapy
Safinamide: May enhance the serotonergic effect of Selective Serotonin Reuptake Inhibitors. This could result in serotonin syndrome. Management: Use the lowest effective dose of SSRIs in patients treated with safinamide and monitor for signs and symptoms of serotonin syndrome/serotonin toxicity. Risk D: Consider therapy modification
Selective Serotonin Reuptake Inhibitors: May enhance the antiplatelet effect of other Selective Serotonin Reuptake Inhibitors. Selective Serotonin Reuptake Inhibitors may enhance the serotonergic effect of other Selective Serotonin Reuptake Inhibitors. This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, mental status changes) when these agents are combined. In addition, monitor for signs and symptoms of bleeding. Risk C: Monitor therapy
Selegiline: Selective Serotonin Reuptake Inhibitors may enhance the serotonergic effect of Selegiline. This could result in serotonin syndrome. Risk X: Avoid combination
Selumetinib: May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Risk C: Monitor therapy
Serotonergic Agents (High Risk, Miscellaneous): May enhance the serotonergic effect of Selective Serotonin Reuptake Inhibitors. This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor therapy
Serotonergic Non-Opioid CNS Depressants: Selective Serotonin Reuptake Inhibitors may enhance the serotonergic effect of Serotonergic Non-Opioid CNS Depressants. This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor therapy
Serotonergic Opioids (High Risk): May enhance the serotonergic effect of Selective Serotonin Reuptake Inhibitors. This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) if these agents are combined. Risk C: Monitor therapy
Serotonin 5-HT1D Receptor Agonists (Triptans): May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor therapy
Serotonin/Norepinephrine Reuptake Inhibitors: Selective Serotonin Reuptake Inhibitors may enhance the antiplatelet effect of Serotonin/Norepinephrine Reuptake Inhibitors. Selective Serotonin Reuptake Inhibitors may enhance the serotonergic effect of Serotonin/Norepinephrine Reuptake Inhibitors. This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, mental status changes) when these agents are combined. In addition, monitor for signs and symptoms of bleeding. Risk C: Monitor therapy
Sertindole: CYP2D6 Inhibitors (Strong) may increase the serum concentration of Sertindole. Management: Consider alternatives to this combination when possible. If combined, consider using lower doses of sertindole and monitor the ECG closely for evidence of QTc interval prolongation. Risk D: Consider therapy modification
St John's Wort: May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. St John's Wort may decrease the serum concentration of Serotonergic Agents (High Risk). Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor therapy
Syrian Rue: May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor therapy
Tamoxifen: CYP2D6 Inhibitors (Strong) may decrease serum concentrations of the active metabolite(s) of Tamoxifen. Specifically, strong CYP2D6 inhibitors may decrease the metabolic formation of highly potent active metabolites. Management: Avoid concurrent use of strong CYP2D6 inhibitors with tamoxifen when possible, as the combination may be associated with a reduced clinical effectiveness of tamoxifen. Risk D: Consider therapy modification
Tamsulosin: CYP2D6 Inhibitors (Strong) may increase the serum concentration of Tamsulosin. Risk C: Monitor therapy
Tetrabenazine: CYP2D6 Inhibitors (Strong) may increase serum concentrations of the active metabolite(s) of Tetrabenazine. Specifically, concentrations of the active alpha- and beta-dihydrotetrabenazine metabolites may be increased. Management: Limit the tetrabenazine dose to 50 mg per day (25 mg per single dose) in patients taking strong CYP2D6 inhibitors. Risk D: Consider therapy modification
Thiazide and Thiazide-Like Diuretics: Selective Serotonin Reuptake Inhibitors may enhance the hyponatremic effect of Thiazide and Thiazide-Like Diuretics. Risk C: Monitor therapy
Thioridazine: FLUoxetine may increase the serum concentration of Thioridazine. Risk X: Avoid combination
Thrombolytic Agents: Agents with Antiplatelet Properties may enhance the anticoagulant effect of Thrombolytic Agents. Risk C: Monitor therapy
Thyroid Products: Selective Serotonin Reuptake Inhibitors may diminish the therapeutic effect of Thyroid Products. Thyroid product dose requirements may be increased. Risk C: Monitor therapy
Timolol (Ophthalmic): CYP2D6 Inhibitors (Strong) may increase the serum concentration of Timolol (Ophthalmic). Risk C: Monitor therapy
Timolol (Systemic): CYP2D6 Inhibitors (Strong) may increase the serum concentration of Timolol (Systemic). Risk C: Monitor therapy
Tipranavir: May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Risk C: Monitor therapy
Tolterodine: CYP2D6 Inhibitors (Strong) may increase the serum concentration of Tolterodine. Risk C: Monitor therapy
TraMADol: Selective Serotonin Reuptake Inhibitors (Strong CYP2D6 Inhibitors) may enhance the adverse/toxic effect of TraMADol. Specifically, the risk for serotonin syndrome/serotonin toxicity and seizures may be increased. Selective Serotonin Reuptake Inhibitors (Strong CYP2D6 Inhibitors) may diminish the therapeutic effect of TraMADol. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes), seizures, and decreased tramadol efficacy when these agents are combined. Risk C: Monitor therapy
Tricyclic Antidepressants: FLUoxetine may enhance the serotonergic effect of Tricyclic Antidepressants. FLUoxetine may increase the serum concentration of Tricyclic Antidepressants. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) and increased TCA concentrations/effects if these agents are combined. Risk D: Consider therapy modification
Urokinase: Agents with Antiplatelet Properties may enhance the anticoagulant effect of Urokinase. Risk X: Avoid combination
Valbenazine: CYP2D6 Inhibitors (Strong) may increase serum concentrations of the active metabolite(s) of Valbenazine. Management: Reduce valbenazine dose to 40 mg once daily when combined with a strong CYP2D6 inhibitor. Monitor for increased valbenazine effects/toxicities. Risk D: Consider therapy modification
Vasopressin: Drugs Suspected of Causing SIADH may enhance the therapeutic effect of Vasopressin. Specifically, the pressor and antidiuretic effects of vasopressin may be increased. Risk C: Monitor therapy
Venlafaxine: May enhance the antiplatelet effect of Selective Serotonin Reuptake Inhibitors (Strong CYP2D6 Inhibitors). Venlafaxine may enhance the serotonergic effect of Selective Serotonin Reuptake Inhibitors (Strong CYP2D6 Inhibitors). This could result in serotonin syndrome. Selective Serotonin Reuptake Inhibitors (Strong CYP2D6 Inhibitors) may decrease serum concentrations of the active metabolite(s) of Venlafaxine. Selective Serotonin Reuptake Inhibitors (Strong CYP2D6 Inhibitors) may increase the serum concentration of Venlafaxine. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, mental status changes) when these agents are combined. In addition, monitor for signs and symptoms of bleeding. Risk C: Monitor therapy
Vitamin E (Systemic): May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Risk C: Monitor therapy
Vitamin K Antagonists (eg, warfarin): Selective Serotonin Reuptake Inhibitors may enhance the anticoagulant effect of Vitamin K Antagonists. Risk C: Monitor therapy
Volanesorsen: May enhance the antiplatelet effect of Agents with Antiplatelet Effects. Risk C: Monitor therapy
Voriconazole: CYP2C19 Inhibitors (Moderate) may increase the serum concentration of Voriconazole. Risk C: Monitor therapy
Vortioxetine: Selective Serotonin Reuptake Inhibitors (Strong CYP2D6 Inhibitors) may enhance the antiplatelet effect of Vortioxetine. Selective Serotonin Reuptake Inhibitors (Strong CYP2D6 Inhibitors) may enhance the serotonergic effect of Vortioxetine. This could result in serotonin syndrome. Selective Serotonin Reuptake Inhibitors (Strong CYP2D6 Inhibitors) may increase the serum concentration of Vortioxetine. Management: Consider alternatives to this drug combination. If combined, reduce the vortioxetine dose by half and monitor for signs and symptoms of bleeding and serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, autonomic instability). Risk D: Consider therapy modification
Zanubrutinib: May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Risk C: Monitor therapy
Zuclopenthixol: CYP2D6 Inhibitors (Strong) may increase the serum concentration of Zuclopenthixol. Risk C: Monitor therapy
Fluoxetine is approved for the treatment of unipolar major depressive disorder. If treatment for major depressive disorder is initiated for the first time in patients planning to become pregnant, agents other than fluoxetine are preferred (use of fluoxetine is not preferred for use during pregnancy) (Larsen 2015).
Fluoxetine is also used off label for the treatment of premenstrual dysphoric disorder. For patients attempting to conceive, symptom onset dosing may be beneficial to minimize potential fetal exposure (Ismaili 2016; Lanza di Scalea 2019).
Selective serotonin reuptake inhibitors (SSRIs) may be associated with male and female treatment-emergent sexual dysfunction (Coskuner 2018; WFSBP [Bauer 2013]). Decreased libido and anorgasmia have been reported in females; abnormal ejaculation, decreased libido, and impotence have been reported in males with fluoxetine use. This may also be a manifestation of the psychiatric disorder. The actual risk associated with fluoxetine is not known. SSRI-related sexual dysfunction may resolve with dose reduction or discontinuation of the SSRI; in some cases, sexual dysfunction may persist once therapy is discontinued (Coskuner 2018; Jing 2016; Waldinger 2015).
Fluoxetine is used off label for the treatment of premature ejaculation. Although data is limited, some studies have shown SSRIs may impair the motility of spermatozoa, therefore use of other treatments may be preferred in patients planning to father a child (Althof 2014; Siroosbakht 2019; Sylvester 2019).
Fluoxetine and its metabolite cross the placenta. Fluoxetine is cleared slowly by the newborn (Larsen 2015).
As a class, selective serotonin reuptake inhibitors (SSRIs) have been evaluated extensively in pregnant patients. Studies focusing on newborn outcomes following first trimester exposure often have inconsistent results due to differences in study design and confounders such as maternal disease and social factors. An increased risk of adverse cardiovascular events following in utero exposure to fluoxetine has been observed in some studies; however, a causal relationship has not been established (Anderson 2020; Biffi 2020; Fitton 2020; Reefhuis 2015; Womersley 2017).
Adverse effects in the newborn following SSRI exposure late in the third trimester can include apnea, constant crying, cyanosis, feeding difficulty, hyperreflexia, hypo- or hypertonia, hypoglycemia, irritability, jitteriness, respiratory distress, seizures, temperature instability, tremor, and vomiting. Prolonged hospitalization, respiratory support, or tube feedings may be required. Symptoms may be due to the toxicity of the SSRIs or a discontinuation syndrome and may be consistent with serotonin syndrome associated with SSRI treatment. Persistent pulmonary hypertension of the newborn has been reported with SSRI exposure; although the absolute risk is small, monitoring of infants exposed to SSRIs late in pregnancy is recommended (Masarwa 2019; Ng 2019). The long-term effects of in utero SSRI exposure on infant neurodevelopment and behavior are not known (CANMAT [MacQueen 2016]).
Due to pregnancy-induced physiologic changes, some pharmacokinetic parameters of fluoxetine may be altered (Heikkinen 2003; Hostetter 2000; Kim 2006; Sit 2010). However, dose adjustments may only be needed if symptoms recur or worsen during pregnancy. Close clinical monitoring as pregnancy progresses and therapeutic drug monitoring to detect patterns of changing plasma concentrations is recommended to assist dose adjustment when needed. If dosing is increased during pregnancy, a gradual taper to the prepregnancy range should be done postpartum (Betcher 2020; Schoretsanitis 2020; Sit 2010).
If treatment for major depressive disorder is initiated for the first time during pregnancy, fluoxetine is not one of the preferred SSRIs (CANMAT [MacQueen 2016]; Larsen 2015; WFSBP [Bauer 2013]). If pregnancy occurs during fluoxetine therapy, a change in treatment is only recommended if it can be safely done in relation to maternal disease (Larsen 2015). Untreated or inadequately treated psychiatric illness may lead to poor adherence with prenatal care and adverse pregnancy outcomes. Therapy with antidepressants during pregnancy should be individualized; treatment with antidepressant medication is recommended for pregnant patients with severe major depressive disorder (ACOG 2008; CANMAT [MacQueen 2016]). Patients treated for major depression and who are euthymic prior to pregnancy are more likely to experience a relapse when medication is discontinued (68%) as compared to pregnant patients who continue taking antidepressant medications (26%) (Cohen 2006).
Data collection to monitor pregnancy and infant outcomes following exposure to antidepressant medications is ongoing. Patients exposed to antidepressants during pregnancy are encouraged to enroll in the National Pregnancy Registry for Antidepressants. Pregnant patients 18 to 45 years of age or their health care providers may contact the registry to enroll; enrollment should be done as early in pregnancy as possible (1-866-961-2388 or https://womensmentalhealth.org/research/pregnancyregistry/antidepressants/).
Fluoxetine and its active metabolite (norfluoxetine) are present in breast milk.
Information related to the presence of fluoxetine in breast milk is available from multiple studies. The relative infant dose (RID) of fluoxetine has been calculated in review articles to be <12% of the weight adjusted maternal dose (Berle 2011; Orsolini 2015); RIDs up to 20% have also been located (Pogliani 2019).
- In one review, the RID of fluoxetine was calculated using pooled data from 149 mother/infant pairs providing an estimated daily infant dose via breast milk of 0.14 mg/day. The maternal dose and actual breast milk concentrations for the calculation were not provided. Infant plasma concentrations were up to 80% of those in the maternal plasma (Berle 2011).
- A second review included information from 280 cases; maternal daily doses of fluoxetine were 10 to 80 mg/day. The highest breast milk concentrations of fluoxetine presented were 17 to 293 ng/mL following maternal doses of 20 to 40 mg/day from a study of 11 women 2 to 23 weeks postpartum, providing a RID of 6.5%; norfluoxetine was also present in breast milk. Fluoxetine and norfluoxetine were detected in the serum of some infants (Orsolini 2015).
- A study published since these reviews reports a fluoxetine RID of 20%, following a maternal dose of 20 mg/day taken by one woman throughout pregnancy and continuing postpartum; sampling occurred within 7 days after delivery (fluoxetine concentrations 323.3 ng/mL [breast milk]; 216.8 ng/mL [maternal serum]) (Pogliani 2019).
- Concentrations of norfluoxetine in breast milk should also be considered. In a study of 19 women (20 infants), maternal and infant serum samples were obtained 5 to 34 weeks after delivery following maternal use of fluoxetine 10 to 60 mg/day. Fluoxetine was present in 30% of infant serum samples (range: <1 to 84 ng/mL) and norfluoxetine was present in 85% (range: <1 to 265 ng/mL). Breast milk was sampled in 9 cases. Peak breast milk concentrations of fluoxetine and norfluoxetine occurred 8 hours after the maternal dose and correlated highly with infant serum concentrations for norfluoxetine. The highest milk concentration of fluoxetine in this study was 235 ng/mL and the same mother also had the highest norfluoxetine milk concentration (222 ng/mL). These concentrations were obtained following a maternal dose of 40 mg/day. Women with serum concentrations of fluoxetine plus norfluoxetine <150 ng/mL had infants with low (<5 ng/mL) to nondetectable serum concentrations (Hendrick 2001).
- Based on available data, infants exposed to fluoxetine via breast milk are more likely to have elevated plasma concentrations in comparison to those exposed to other selective serotonin reuptake inhibitors (SSRIs) (Weissman 2004).
- In general, breastfeeding is considered acceptable when the RID is <10% (Anderson 2016; Ito 2000); however, some sources note breastfeeding should only be considered if the RID is <5% for psychotropic agents (Larsen 2015). When an RID is >25%, breastfeeding should generally be avoided (Anderson 2016; Ito 2000).
Adverse events in the breastfeeding infant have been reported following maternal use of fluoxetine, including agitation, irritability, poor feeding, and poor weight gain; crying, sleep disturbance, vomiting, and watery stools have also been reported (Kristensen 1999; Lester 1993). Infants exposed to an SSRI via breast milk should be monitored for irritability and changes in sleep, feeding patterns, and behavior, as well as growth and development (ABM [Sriraman 2015]; Sachs 2013; Weissman 2004; WFSBP [Bauer 2013]).
Maternal use of an SSRI during pregnancy may cause delayed lactogenesis (Marshall 2010), however the underlying maternal illness may also influence this outcome (Grzeskowiak 2018). Untreated severe or chronic depression in the postpartum period also has negative effects on the mother and the infant (Slomian 2019).
According to the manufacturer, the decision to breastfeed during fluoxetine therapy should consider the risk of infant exposure, the benefits of breastfeeding to the infant, and the benefits of treatment to the mother.
Psychotherapy or other nonmedication therapies are recommended for the initial treatment of mild depression in breastfeeding patients; antidepressant medication is recommended when psychotherapy is not an option or symptoms are moderate to severe. If a specific SSRI was used effectively during pregnancy, it can be continued while breastfeeding if no contraindications exist (ABM [Sriraman 2015]).
When first initiating an antidepressant in a breastfeeding patient, agents other than fluoxetine are preferred (ABM [Sriraman 2015]; CANMAT [MacQueen 2016]; Larsen 2015).
Serum sodium in at-risk populations (as clinically indicated); blood glucose (for diabetic patients); liver and renal function (baseline and as clinically indicated); ECG assessment and periodic monitoring in patients with risk factors for QT prolongation and ventricular arrhythmia; closely monitor patients for depression, clinical worsening, suicidality, or unusual changes in behavior (eg, anxiety, agitation, panic attacks, insomnia, irritability, hostility, impulsivity, akathisia, hypomania, mania, social functioning), particularly during the initial 1 to 2 months of therapy or during periods of dosage adjustments (increases or decreases); akathisia; sleep status.
Therapeutic levels have not been well established.
Therapeutic: Fluoxetine plus norfluoxetine: 120 to 500 ng/mL (Hiemke 2018)
Laboratory alert level: Fluoxetine plus norfluoxetine: >1,000 ng/mL (Hiemke 2018)
Inhibits CNS neuron serotonin reuptake; minimal or no effect on reuptake of norepinephrine or dopamine; does not significantly bind to alpha-adrenergic, histamine, or cholinergic receptors
Onset of action:
Anxiety disorders (generalized anxiety, panic, obsessive-compulsive disorder, posttraumatic stress disorder): Initial effects may be observed within 2 weeks of treatment, with continued improvements through 4 to 6 weeks (Issari 2016; Varigonda 2016; WFSBP [Bandelow 2023a]); some experts suggest up to 12 weeks of treatment may be necessary for response, particularly in patients with obsessive-compulsive disorder and posttraumatic stress disorder (BAP [Baldwin 2014]; Katzman 2014; WFSBP [Bandelow 2023a]; WFSBP [Bandelow 2023b]).
Body dysmorphic disorder: Initial effects may be observed within 2 weeks; some experts suggest up to 12 to 16 weeks of treatment may be necessary for response in some patients (Phillips 2008).
Depression: Initial effects may be observed within 1 to 2 weeks of treatment, with continued improvements through 4 to 6 weeks (Papakostas 2006; Posternak 2005; Szegedi 2009; Taylor 2006).
Premenstrual dysphoric disorder: Initial effects may be observed within the first few days of treatment, with response at the first menstrual cycle of treatment (ISPMD [Nevatte 2013]).
Absorption: Well absorbed; delayed 1 to 2 hours with weekly formulation
Distribution: Vd: 12 to 43 L/kg
Protein binding: 95% to albumin and alpha1 glycoprotein
Metabolism: Hepatic, via CYP2C19 and 2D6, to norfluoxetine (activity equal to fluoxetine)
Half-life elimination: Adults:
Parent drug: 1 to 3 days (acute), 4 to 6 days (chronic), 7.6 days (cirrhosis)
Metabolite (norfluoxetine): 9.3 days (range: 4 to 16 days), 12 days (cirrhosis)
Time to peak, serum: 6 to 8 hours
Excretion: Urine (10% as norfluoxetine, 2.5% to 5% as fluoxetine)
Note: Weekly formulation results in greater fluctuations between peak and trough concentrations of fluoxetine and norfluoxetine compared to once-daily dosing (24% daily/164% weekly; 17% daily/43% weekly, respectively). Trough concentrations are 76% lower for fluoxetine and 47% lower for norfluoxetine than the concentrations maintained by 20 mg once-daily dosing. Steady-state fluoxetine concentrations are ~50% lower following the once-weekly regimen compared to 20 mg once daily. Average steady-state concentrations of once-daily dosing were highest in children ages 6 to <13 (fluoxetine 171 ng/mL; norfluoxetine 195 ng/mL), followed by adolescents ages 13 to <18 (fluoxetine 86 ng/mL; norfluoxetine 113 ng/mL); concentrations were considered to be within the ranges reported in adults (fluoxetine 91 to 302 ng/mL; norfluoxetine 72 to 258 ng/mL).
Hepatic function impairment: The half-life for fluoxetine and norfluoxetine is prolonged. Elimination half-life increased from 2.2 days in controls to 6.6 days and clearance decreased by 50% following a single dose of fluoxetine in patients with stable alcoholic cirrhosis (Mullish 2014; Schenker 1988).
Pediatric: Average steady-state fluoxetine serum concentrations in children (n=10; 6 to <13 years of age) were 2-fold higher than in adolescents (n=11; 13 to <18 years of age); all patients received 20 mg/day; average steady-state norfluoxetine serum concentrations were 1.5-fold higher in the children compared with adolescents; differences in weight almost entirely explained the differences in serum concentrations.
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