Fluoxetine

Pharmacologic Category

Antidepressant, Selective Serotonin Reuptake Inhibitor

Dosing: Adult

Note: In patients sensitive to adverse effects, some experts suggest lower starting doses of 5 to 10 mg/day and gradual titration in increments of no more than 10 mg, particularly in patients with anxiety who are generally more sensitive to overstimulation effects (eg, anxiety, insomnia) with antidepressants (Hirsch 2018c; Stein 2018; WFSBP [Bandelow 2012]).

Binge eating disorder (off-label use): Limited data available: Oral: 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 (Arnold 2002a; Leombruni 2008; Sysko 2018).

Bipolar major depression: Oral: 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 (Kupka 2018; Shelton 2019; Tohen 2003; WFSBP [Grunze 2010]; manufacturer's labeling); usual dose range: 20 to 50 mg/day (Kupka 2018; manufacturer's labeling). 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: 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 (Phillips 2002; Phillips 2018). Doses up to 120 mg/day, if tolerated, may be necessary in some patients for optimal response (Phillips 2018). Note: An adequate trial for assessment of effect in BDD is 12 to 16 weeks, including maximum tolerated doses for at least 3 to 4 of those weeks (Phillips 2018).

Bulimia nervosa: Oral: 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 (Leombruni 2006).

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 (EULAR [Macfarlane 2017]). Oral: 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 (Arnold 2002b; EULAR [Macfarlane 2017]). 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) (Goldenberg 1996; Goldenberg 2018).

Generalized anxiety disorder (off-label use): Limited data available: Oral: 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 (Bystritsky 2018; Hirsch 2018c)

Major depressive disorder (unipolar): Oral: 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 (Fava 1998). Usual dose: 20 to 60 mg/day (APA 2010). 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 (APA 2010; Brunner 2014; Rothschild 2004). 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: 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 (APA [Koran 2007]; Romano 2001; Simpson 2018; manufacturer's labeling). Based on clinical experience, some patients may require up to 120 mg/day for a response; however, adverse effects may increase (APA [Koran 2007]; Simpson 2018). Note: An adequate trial for assessment of effect in OCD is considered to be ≥6 weeks at maximum tolerated dose (Issari 2016).

Panic disorder: Oral: Initial: 5 to 10 mg once daily; after 3 to 7 days, 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 (APA 2009). Maximum dose: 60 mg/day (manufacturer's labeling).

Posttraumatic stress disorder (PTSD) (off-label use): Oral: 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 (Connor 1999; Martenyi 2002a).

Premature ejaculation (off-label use): Limited data available: Oral: Initial: 20 mg once daily; may increase dose based on response and tolerability after ≥1 week (some experts suggest 3- to 4-week titration intervals [Khera 2018]) to 40 mg once daily (Kara 1996).

Premenstrual dysphoric disorder (PMDD):

Continuous daily dosing regimen: Oral: 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 (Casper 2020).

Intermittent regimens:

Luteal phase dosing regimen: Oral: 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 (Casper 2020).

Symptom-onset dosing regimen (off-label dosing): Oral: Limited data available: Initial 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 (Casper 2020).

Social anxiety disorder (off-label use): Oral: Initial: 10 to 20 mg once daily; after ~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 (Davidson 2004; Stein 2018)

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 (APA 2010; WFSBP [Bauer 2015]). Reasons for a slower taper (eg, over 4 weeks) include prior history of antidepressant withdrawal symptoms or high doses of antidepressants (APA 2010; Hirsch 2019a ). If necessary, some clinicians allow for abrupt discontinuation based on fluoxetine's long half-life (Hirsch 2019a). If intolerable withdrawal symptoms occur, resume the previously prescribed dose and/or decrease dose at a more gradual rate (Shelton 2001). Select patients (eg, those with a history of discontinuation syndrome) on long-term treatment (>6 months) may benefit from tapering over >3 months (WFSBP [Bauer 2015]). Evidence supporting ideal taper rates is limited (Shelton 2001; WFSBP [Bauer 2015]).

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 (Hirsch 2018b; Ogle 2013; WFSBP [Bauer 2013]).

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.

* See Dosage and Administration in AHFS Essentials for additional information.

Dosing: Geriatric

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.

Dosing: Renal Impairment: Adult

Single-dose studies: Pharmacokinetics of fluoxetine and norfluoxetine were similar among subjects with all levels of impaired renal function, including anephric patients on chronic hemodialysis.

Chronic administration: Additional accumulation of fluoxetine or norfluoxetine may occur in patients with severely impaired renal function.

Not removed by hemodialysis; use of lower dose or less frequent dosing is not usually necessary.

Dosing: Hepatic Impairment: Adult

Use lower doses (up to 50% reduction) and less frequent dosing intervals in patients with cirrhosis and chronic liver disease; use with caution (Mauri 2014; Mullish 2014).

Dosing: Pediatric

Anxiety with associated phobias and panic attacks: Very limited data available: Children 2 to 6 years: Oral: 5 mg/dose or 0.25 mg/kg/dose once daily; adequate trial is considered to be 8 to 10 weeks; continuation of therapy should be evaluated at 6 to 9 months after initiation; dosing based on case report in a 2.5-year old child and expert recommendations (Gleason 2007).

Bulimia nervosa adjunct therapy with cognitive behavioral therapy: Limited data available: Children ≥12 years and Adolescents: Oral: 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 (Gable 2005; Kotler 2003; Rosen 2010).

Depression:

Manufacturer's labeling: Children ≥8 years and Adolescents:

Lower weight Children: Oral: Initial: 10 mg once daily; usual daily dose: 10 mg/day; if needed, may increase dose to 20 mg once daily after several weeks; maximum daily dose: 20 mg/day.

Higher weight Children and Adolescents: Oral: Initial: 10 to 20 mg once daily; in patients started at 10 mg once daily, may increase dose to 20 mg after 1 week; maximum daily dose: 20 mg/day.

Alternate dosing: Limited data available: Lower initial dosing has been recommended by some experts (Dopheide 2006; Gleason 2007):

Children ≤11 years: Oral: Initial: 5 mg once daily; clinically, doses have been titrated up to 40 mg once daily in pediatric patients.

Children ≥12 years and Adolescents: Oral: Initial: 10 mg once daily; clinically, doses have been titrated up to 40 mg once daily in pediatric patients.

Depression associated with bipolar I disorder (in combination with olanzapine): Children ≥10 years and Adolescents: Oral: 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:

Children <7 years: Limited data available: Oral: Initial: 5 mg once daily (Gleason 2007).

Children ≥7 years and Adolescents: Oral:

Lower weight Children: Initial: 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, if needed; usual daily dose: 20 to 60 mg/day.

Repetitive behavior associated with autism spectrum disorders (ASD): Limited data available: Children ≥5 years and Adolescents: Oral: Initial: 2.5 mg once daily for 7 days; then may titrate at weekly intervals using weight-based dosing: 0.3 mg/kg/day during week 2; followed by 0.5 mg/kg/day during week 3, up to a maximum of 0.8 mg/kg/day; dosing based on a double-blind, crossover, placebo-controlled trial in 39 pediatric patients (age: 5 to 16 years) which showed statistically significant improvement in behavior scores compared to placebo; mean final dose: 9.9 mg/day (range: 2.4 to 20 mg/day) or 0.36 ± 0.116 mg/kg/day (Hollander 2005).

Selective mutism: Limited data available: Children ≥5 years and Adolescents: Oral: Initial: 5 mg once daily for 7 days, then increase to 10 mg daily for 7 days, and then increase to 20 mg daily; may further titrate in 20 mg/day increments if needed every 2 weeks; maximum daily dose: 60 mg/day. 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) (Dummitt 1996). Weight-based dosing has been reported in a double-blind placebo-controlled trial (treatment group: n=6; placebo: n=9; age: 6-12 years) using the following titration: 0.2 mg/kg/day for 1 week, then 0.4 mg/kg/day for 1 week, then 0.6 mg/kg/day for 10 weeks; mean final dose: 21.4 mg/day (Black 1994). To fully assess therapeutic response, a therapeutic trial of at least 9 to 12 weeks or longer has been suggested (Black 1994; Dummitt 1996; Kaakeh 2008).

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 (Hathaway 2018). 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 (APA 2010; Bauer 2002; Fenske 2009; Haddad 2001; NCCMH 2010; Schatzberg 2006; Shelton 2001; Warner 2006).

Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.

MAO inhibitor recommendations:

Switching to or from an MAO inhibitor intended to treat psychiatric disorders:

Allow 14 days to elapse between discontinuing an MAO inhibitor intended to treat psychiatric disorders and initiation of fluoxetine.

Allow 5 weeks to elapse between discontinuing fluoxetine and initiation of an MAO inhibitor intended to treat psychiatric disorders.

Dosing: Renal Impairment: Pediatric

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.

Dosing: Hepatic Impairment: Pediatric

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

Use: Labeled Indications

Bipolar major depression (excluding Sarafem): Acute treatment of major depressive episodes (in combination with olanzapine [preferred], other antipsychotics, or antimanic agents) (WFSBP [Grunze 2010]) associated with bipolar I disorder

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)

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

Treatment-resistant depression (excluding Sarafem): Acute treatment of treatment-resistant depression (patients with 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)

* See Uses in AHFS Essentials for additional information.

Use: Off-Label: Adult

​Binge eating disorderLevel of Evidence [C]

Data from a limited number of patients studied suggest that fluoxetine may be beneficial to improve binge frequency, weight loss, body mass index, and severity of illness in patients with binge eating disorder Ref.

​Body dysmorphic disorderLevel of Evidence [B]

Data from a double-blind, randomized, placebo-controlled trial support the use of fluoxetine in the treatment of body dysmorphic disorder (with or without delusions) Ref.

​Fibromyalgia, refractoryLevel of Evidence [B, G]

Data from 2 double-blind, randomized trials support the use of fluoxetine in the treatment of pain, depression, sleep disturbance, and other symptoms of fibromyalgia Ref.

Based on Canadian Pain Society guidelines on the management of fibromyalgia syndrome, antidepressants, including SSRIs such as fluoxetine, are suggested for treatment of pain and other symptoms of fibromyalgia. European League Against Rheumatism guidelines make a weak recommendation against use of SSRIs based on lack of efficacy. Access Full Off-Label Monograph

​Generalized anxiety disorderLevel of Evidence [G]

Based on the World Federation of Societies of Biological Psychiatry (WFSBP) guidelines for the pharmacological treatment of anxiety disorders, SSRIs are effective and recommended in the management of generalized anxiety disorder; however, evidence for fluoxetine is limited Ref.

​Posttraumatic stress disorderLevel of Evidence [B, G]

Data from double-blind, randomized controlled trials support the use of fluoxetine for acute treatment and relapse prevention in patients with posttraumatic stress disorder (PTSD) Ref.

Based on the American Psychiatric Association guidelines for the treatment of patients with acute stress disorder and PTSD and WFSBP guidelines for the pharmacological treatment of anxiety, obsessive-compulsive, and posttraumatic stress disorders, SSRIs (including fluoxetine) are effective and recommended as first-line treatments for the management of PTSD. In addition, the Veterans Affairs and Department of Defense guidelines for the management of PTSD and acute stress disorder, recommend use of fluoxetine in the management of PTSD for patients who choose not to engage in or are unable to access trauma-focused psychotherapy. Access Full Off-Label Monograph

​Premature ejaculationLevel of Evidence [C, G]

Data from a limited number of patients suggest that fluoxetine may have some benefit in the treatment of premature ejaculation Ref.

According to the International Society for Sexual Medicine guidelines, SSRIs such as fluoxetine are effective and recommended in the management of premature ejaculation. Access Full Off-Label Monograph

​Selective mutismLevel of Evidence [C]

Data from a limited number of patients studied in an open-label clinical trial and a double-blind, randomized, placebo-controlled trial suggest that fluoxetine may be beneficial for the treatment of selective mutism in children and adolescents Ref.

​Social anxiety disorderLevel of Evidence [B, G]

Data from a large randomized, double-blind, placebo-controlled trial support the use of fluoxetine in the treatment of social anxiety disorder Ref.

Based on the WFSBP guidelines for the pharmacological treatment of anxiety, obsessive-compulsive, and posttraumatic stress disorders, SSRIs such as fluoxetine are effective and recommended for first-line treatment of social anxiety disorder; however, evidence for fluoxetine is more limited in comparison to other SSRIs.

Level of Evidence Definitions

​Level of Evidence Scale

Class and Related Monographs

Selective Serotonin Reuptake Inhibitors

Clinical Practice Guidelines

Anxiety Disorders:

American Psychiatric Association, "Practice Guideline for the Treatment of Patients with Panic Disorder," 2009

WFSBP, "Guidelines for the Pharmacological Treatment of Anxiety, Obsessive-Compulsive and Post-Traumatic Stress Disorders, First Revision," 2008

WFSBP, "Guidelines for the Pharmacological Treatment of Anxiety, Obsessive-Compulsive and Post-Traumatic Stress Disorder in Primary Care," 2012

Bipolar Disorder:

CANMAT/ISBD, "2018 Guidelines for the Management of Patients with Bipolar Disorder," March 2018

WFSBP, “Guidelines for the Biological Treatment of Bipolar Disorders: Update 2010 on the Treatment of Acute Bipolar Depression,” 2010

Depression:

American Psychiatric Association, Practice Guideline for the Treatment of Patients with Major Depressive Disorder, Third Edition, May 2010

CANMAT, “Clinical Guidelines for the Management of Major Depressive Disorder in Adults,” October 2009

WFSBP, “Guidelines for Biological Treatment of Unipolar Depressive Disorders, Part 1: Update 2013 on the Acute and Continuation Treatment of Unipolar Depressive Disorders,” 2013.

WFSBP, “Guidelines for Biological Treatment of Unipolar Depressive Disorders, Part 2: Maintenance Treatment of Major Depressive Disorder and Treatment of Chronic Depressive Disorders and Subthreshold Depressions,” 2002.

Eating Disorders:

WFSBP, “Guidelines for the Pharmacological Treatment of Eating Disorders,” 2011

Obsessive-Compulsive Disorder (OCD):

American Psychiatric Association, "Practice Guideline for the Treatment of Patients with Obsessive-Compulsive Disorder," 2007

WFSBP, "Guidelines for the Pharmacological Treatment of Anxiety, Obsessive-Compulsive and Post-Traumatic Stress Disorders, First Revision," 2008

WFSBP, "Guidelines for the Pharmacological Treatment of Anxiety, Obsessive-Compulsive and Post-Traumatic Stress Disorder in Primary Care," 2012

Posttraumatic Stress Disorder (PTSD):

American Psychiatric Association, "Practice Guideline for the Treatment of Patients with Acute Stress Disorder and Posttraumatic Stress Disorder," 2004

American Psychiatric Association, "Practice Guideline for the Treatment of Patients with Acute Stress Disorder and Posttraumatic Stress Disorder," Guideline Watch (March 2009)

US Department of Veterans Affairs/Department of Defense (VA/DoD), “Clinical Practice Guideline for the Management of Posttraumatic Stress Disorder and Acute Stress Disorder,” June 2017

WFSBP, "Guidelines for the Pharmacological Treatment of Anxiety, Obsessive-Compulsive and Post-Traumatic Stress Disorders, First Revision," 2008

WFSBP, "Guidelines for the Pharmacological Treatment of Anxiety, Obsessive-Compulsive and Post-Traumatic Stress Disorder in Primary Care," 2012

Administration: Oral

Administer without regard to meals.

Bipolar I disorder and treatment-resistant depression: Take once daily in the evening.

Major depressive disorder and obsessive compulsive disorder: Once daily doses should be taken in the morning, or twice daily (morning and noon).

Bulimia: Take once daily in the morning.

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.

Administration: Pediatric

Oral: May be administered without regard to food

Indication specific:

Major depressive disorder and obsessive compulsive disorder: Take in the morning; if twice daily dosing, take at morning and noon

Bipolar I disorder and treatment-resistant depression (with concurrent olanzapine): Take in the evening

Bulimia: Take in the morning

Storage/Stability

All dosage forms should be stored at controlled room temperature. Protect from light.

Extemporaneously Prepared

Note: Commercial oral solution is available (4 mg/mL)

A 1 mg/mL fluoxetine oral solution may be prepared using the commercially available preparation (4 mg/mL). In separate graduated cylinders, measure 5 mL of the commercially available fluoxetine preparation and 15 mL of Simple Syrup, NF. Mix thoroughly in incremental proportions. For a 2 mg/mL solution, mix equal proportions of both the commercially available fluoxetine preparation and Simple Syrup, NF. Label "refrigerate". Both concentrations are stable for up to 56 days.

Nahata MC, Pai VB, and Hipple TF, Pediatric Drug Formulations, 5th ed, Cincinnati, OH: Harvey Whitney Books Co, 2004.

Medication Patient Education with HCAHPS Considerations

What is this drug used for?

• It is used to treat low mood (depression).

• It is used to treat obsessive-compulsive problems.

• It is used to treat mood problems caused by monthly periods.

• It is used to treat eating problems.

• It is used to treat panic attacks.

• It may be given to you for other reasons. Talk with the doctor.

All drugs may cause side effects. However, many people have no side effects or only have minor side effects. Call your doctor or get medical help if any of these side effects or any other side effects bother you or do not go away:

• Upset stomach

• Throwing up

• Not hungry

• Dry mouth

• Feeling sleepy

• Diarrhea

• Constipation

• Nightmares

• Trouble sleeping

• Loss of strength and energy

• Hot flashes

• Tremors

• Flu-like symptoms

• Yawning

• Nose irritation

• Throat irritation

• Sweating a lot

• Headache

WARNING/CAUTION: Even though it may be rare, some people may have very bad and sometimes deadly side effects when taking a drug. Tell your doctor or get medical help right away if you have any of the following signs or symptoms that may be related to a very bad side effect:

• Depression like thoughts of suicide, anxiety, agitation, irritability, panic attacks, mood changes, behavioral changes, or confusion

• Liver problems like dark urine, feeling tired, not hungry, upset stomach, stomach pain, light-colored stools, throwing up, or yellow skin or eyes

• Low sodium like headache, trouble focusing, trouble with memory, confusion, weakness, seizures, or change in balance.

• Passing out

• Fast heartbeat

• Abnormal heartbeat

• Dizziness

• Excessive weight gain

• Excessive weight loss

• Sexual dysfunction

• Decreased sex drive

• More thirst

• Seizures

• Slow heartbeat

• Bruising

• Bleeding

• Anxiety

• Menstrual changes

• Passing urine more often

• Trouble controlling body movements

• Eye redness

• Eye swelling

• Vision changes

• Eye pain

• Serotonin syndrome like dizziness, severe headache, agitation, sensing things that seem real but are not, fast heartbeat, abnormal heartbeat, flushing, tremors, sweating a lot, change in balance, severe upset stomach, prescriber or severe diarrhea

• Erection that lasts more than 4 hours

• Signs of an allergic reaction, like rash; hives; itching; red, swollen, blistered, or peeling skin with or without fever; wheezing; tightness in the chest or throat; trouble breathing, swallowing, or talking; unusual hoarseness; or swelling of the mouth, face, lips, tongue, or throat.

Note: This is not a comprehensive list of all side effects. Talk to your doctor if you have questions.

Consumer Information Use and Disclaimer: This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a limited summary of general information about the medicine's uses from the patient education leaflet and is not intended to be comprehensive. This limited summary does NOT include all information available about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not intended to provide medical advice, diagnosis or treatment and does not replace information you receive from the healthcare provider. For a more detailed summary of information about the risks and benefits of using this medicine, please speak with your healthcare provider and review the entire patient education leaflet.

Medication Safety Issues

​Sound-alike/look-alike issues:

​Geriatric Patients: High-Risk Medication:

​International issues:

Medication Guide and/or Vaccine Information Statement (VIS)

An FDA-approved patient medication guide, which is available with the product information and as follows, must be dispensed with this medication:

Fluoxetine tablets: http://www.accessdata.fda.gov/drugsatfda_docs/label/2017/202133s004s005lbl.pdf#page=40

Prozac: https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/018936s109lbl.pdf#page=26

Sarafem: http://www.accessdata.fda.gov/drugsatfda_docs/label/2017/021860s011lbl.pdf#page=33

Contraindications

Hypersensitivity to fluoxetine or any component of the formulation; use of MAO inhibitors intended to treat psychiatric disorders (concurrently, within 5 weeks of discontinuing fluoxetine, or within 2 weeks of discontinuing the MAO inhibitor); initiation of fluoxetine in a patient receiving linezolid or intravenous methylene blue; use with pimozide or thioridazine (Note: Thioridazine should not be initiated until 5 weeks after the discontinuation of fluoxetine.)

Canadian labeling: Additional contraindications (not in the US labeling): Initiation of fluoxetine within 2 weeks of thioridazine discontinuation

Warnings/Precautions

Major psychiatric warnings:

• Suicidal thinking/behavior: [US Boxed Warning]: Antidepressants increase the risk of suicidal thinking and behavior in children, adolescents, and young adults (18 to 24 years of age) with major depressive disorder (MDD) and other psychiatric disorders; consider risk prior to prescribing. Short-term studies did not show an increased risk in patients >24 years of age and showed a decreased risk in patients ≥65 years. Closely monitor all patients for clinical worsening, suicidality, or unusual changes in behavior, particularly during the initial 1 to 2 months of therapy or during periods of dosage adjustments (increases or decreases); the patient's family or caregiver should be instructed to closely observe the patient and communicate condition with health care provider. A medication guide concerning the use of antidepressants should be dispensed with each prescription. Fluoxetine is FDA approved for the treatment of obsessive compulsive disorder in children ≥7 years of age and MDD in children ≥8 years of age.

- The possibility of a suicide attempt is inherent in major depression and may persist until remission occurs. Worsening depression and severe abrupt suicidality that are not part of the presenting symptoms may require discontinuation or modification of drug therapy. Use caution in high-risk patients during initiation of therapy.

- Prescriptions should be written for the smallest quantity consistent with good patient care. The patient's family or caregiver should be alerted to monitor patients for the emergence of suicidality and associated behaviors such as anxiety, agitation, panic attacks, insomnia, irritability, hostility, impulsivity, akathisia, hypomania, and mania; patients should be instructed to notify their health care provider if any of these symptoms or worsening depression occur.

Concerns related to adverse effects:

• Allergic events and rash: Fluoxetine use has been associated with occurrences of significant rash and allergic events, including vasculitis, lupus-like syndrome, laryngospasm, anaphylactoid reactions, and pulmonary inflammatory disease. Discontinue if underlying cause of rash cannot be identified.

• Bleeding risk: May impair platelet aggregation resulting in increased risk of bleeding events, particularly if used concomitantly with aspirin, nonsteroidal anti-inflammatory drugs, (NSAIDs), warfarin or other anticoagulants. Bleeding related to selective serotonin reuptake inhibitor (SSRI) use has been reported to range from relatively minor bruising and epistaxis to life-threatening hemorrhage.

• CNS depression: Has a low potential to impair cognitive or motor performance; caution operating hazardous machinery or driving.

• CNS effects: May cause insomnia, anxiety, nervousness, or anorexia.

• Fractures: Bone fractures have been associated with antidepressant treatment. Consider the possibility of a fragility fracture if an antidepressant-treated patient presents with unexplained bone pain, point tenderness, swelling, or bruising (Rabenda 2013; Rizzoli 2012).

• Ocular effects: May cause mild pupillary dilation, which in susceptible individuals can lead to an episode of narrow-angle glaucoma. Consider evaluating patients who have not had an iridectomy for narrow-angle glaucoma risk factors.

• 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.

• Serotonin syndrome: Potentially life-threatening serotonin syndrome (SS) has occurred with serotonergic agents (eg, SSRIs, serotonin–norepinephrine reuptake inhibitors [SNRIs]), particularly when used in combination with other serotonergic agents (eg, triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, buspirone, St John's wort, tryptophan) or agents that impair metabolism of serotonin (eg, monoamine oxidase inhibitors [MAOIs] intended to treat psychiatric disorders, other MAOIs [ie, linezolid and intravenous methylene blue]). Monitor patients closely for signs of SS such as mental status changes (eg, agitation, hallucinations, delirium, coma); autonomic instability (eg, tachycardia, labile BP, diaphoresis); neuromuscular changes (eg, tremor, rigidity, myoclonus); GI symptoms (eg, nausea, vomiting, diarrhea); and/or seizures. Discontinue treatment (and any concomitant serotonergic agent) immediately if signs/symptoms arise.

• Syndrome of inappropriate antidiuretic hormone secretion and hyponatremia: SSRIs and SNRIs have been associated with the development of syndrome of inappropriate antidiuretic hormone secretion; hyponatremia has been reported rarely (including severe cases with serum sodium <110 mmol/L), predominately in the elderly. Volume depletion and/or concurrent use of diuretics likely increases risk. Consider discontinuation if symptomatic hyponatremia occurs.

• Weight loss: May cause anorexia and/or weight loss. Use caution in patients where weight loss is undesirable.

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.

• Diabetes: Use with caution in patients with diabetes mellitus; may alter glycemic control and may require adjustment of antidiabetic medication; hypoglycemia and hyperglycemia has been observed during and after cessation of therapy, respectively.

• 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).

• Mania/hypomania: May precipitate a shift to mania or hypomania in patients with bipolar disorder. Monotherapy in patients with bipolar disorder should be avoided. Combination therapy with an antidepressant and a mood stabilizer may be effective for acute treatment of bipolar major depressive episodes, but should be avoided in acute mania or mixed episodes, as well as maintenance treatment in bipolar disorder due to the mood-destabilizing effects of antidepressants (CANMAT [Yatham 2018]; WFSBP [Grunze 2018]). Patients presenting with depressive symptoms should be screened for bipolar disorder.

• Renal impairment: Use with caution in patients with severe renal impairment; a lower dosage or less frequent dosing may be needed.

• 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:

• Elderly: 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:

• Discontinuation syndrome: Abrupt discontinuation or interruption of antidepressant therapy has been associated with a discontinuation syndrome. Symptoms arising may vary with antidepressant however commonly include nausea, vomiting, diarrhea, headaches, light-headedness, dizziness, diminished appetite, sweating, chills, tremors, paresthesias, fatigue, somnolence, and sleep disturbances (eg, vivid dreams, insomnia). Less common symptoms include electric shock-like sensations, cardiac arrhythmias (more common with tricyclic antidepressants), myalgias, parkinsonism, arthralgias, and balance difficulties. Psychological symptoms may also emerge such as agitation, anxiety, akathisia, panic attacks, irritability, aggressiveness, worsening of mood, dysphoria, mood lability, hyperactivity, mania/hypomania, depersonalization, decreased concentration, slowed thinking, confusion, and memory or concentration difficulties. Greater risks for developing a discontinuation syndrome have been associated with antidepressants with shorter half-lives, longer durations of treatment, and abrupt discontinuation. For antidepressants of short or intermediate half-lives, symptoms may emerge within 2 to 5 days after treatment discontinuation and last 7 to 14 days (APA 2010; Fava 2006; Haddad 2001; Shelton 2001; Warner 2006).

• Electroconvulsive therapy: May increase the risks associated with electroconvulsive therapy (ECT); consider discontinuing, when possible, prior to ECT treatment.

• 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.

* See Cautions in AHFS Essentials for additional information.

Geriatric Considerations

Fluoxetine's potential stimulating and anorexic effects may be bothersome to some patients and has not been shown to be superior in efficacy to other SSRIs. The long half-life in the elderly makes it less attractive compared to other SSRIs. The elderly are more prone to SSRI/SNRI-induced hyponatremia.

A systematic review and meta-analysis of antidepressant placebo-controlled trials in persons with depression and dementia found evidence "suggestive" of efficacy but not of sufficient strength to "confirm" efficacy (Nelson 2011). Older patients with depression being treated with an antidepressant should be closely monitored for response and adverse effects.

Warnings: Additional Pediatric Considerations

SSRI-associated behavioral activation (ie, restlessness, hyperkinesis, hyperactivity, agitation) is two- to threefold more prevalent in children compared to adolescents; it is more prevalent in adolescents compared to adults. Somnolence (including sedation and drowsiness) is more common in adults compared to children and adolescents (Safer 2006). SSRI-associated vomiting is two- to threefold more prevalent in children compared to adolescents and is more prevalent in adolescents compared to adults (Safer 2006). May cause abnormal bleeding (eg, ecchymosis, purpura, upper GI bleeding); use with caution in patients with impaired platelet aggregation and with concurrent use of aspirin, NSAIDs, or other drugs that affect coagulation. A recent report describes five children (age: 8 to 15 years) who developed epistaxis (n=4) or bruising (n=1) while receiving SSRI therapy (sertraline) (Lake 2000). Fluoxetine may cause decreased growth (smaller increases in weight and height) in children and adolescent patients; currently, no studies directly evaluate fluoxetine's long-term effects on growth, development, and maturation of pediatric patients; periodic monitoring of height and weight in pediatric patients is recommended. Case reports of decreased growth in children receiving fluoxetine or fluvoxamine (n=4; age: 11.6 to 13.7 years) for 6 months to 5 years suggest a suppression of growth hormone secretion during SSRI therapy (Weintrob 2002).

Reproductive Considerations

If treatment for major depressive disorder is initiated for the first time in females planning a pregnancy, agents other than fluoxetine are preferred (use of fluoxetine is not preferred in pregnant women) (Larsen 2015).

Selective serotonin reuptake inhibitors may be associated with male and female sexual dysfunction (WFSBP [Bauer 2013]). This may also be a manifestation of the psychiatric disorder. The actual risk associated with fluoxetine is not known. Fluoxetine is used off label for the treatment of premature ejaculation (Althof 2014; Siroosbakht 2019).

Pregnancy Considerations

Fluoxetine and its metabolite cross the placenta.

Available studies evaluating teratogenic effects following maternal use of fluoxetine in the first trimester have shown inconsistent results. An increased risk of cardiovascular events was observed in one study; however, no specific pattern was observed and a causal relationship has not been established. Nonteratogenic effects in the newborn following selective serotonin reuptake inhibitor (SSRI)/serotonin–norepinephrine reuptake inhibitor (SNRI) exposure late in the third trimester include respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding difficulty, vomiting, hypoglycemia, hypo- or hypertonia, hyper-reflexia, jitteriness, irritability, constant crying, and tremor. Prolonged hospitalization, respiratory support, or tube feedings may be required. Symptoms may be due to the toxicity of the SSRIs/SNRIs or a discontinuation syndrome and may be consistent with serotonin syndrome associated with SSRI treatment. Persistent pulmonary hypertension of the newborn has also been reported with SSRI exposure. The long-term effects of in utero SSRI exposure on infant development 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. If dosing is increased during pregnancy, a gradual taper to the prepregnancy range should be done postpartum (Betcher 2020; Schoretsanitis 2020; Sit 2010).

Untreated or inadequately treated psychiatric illness may lead to poor compliance with prenatal care. Therapy with antidepressants during pregnancy should be individualized (ACOG 92 2008; CANMAT [MacQueen 2016]). Psychotherapy or other nonmedication therapies may be considered for some women; however, antidepressant medication should be considered for pregnant women with moderate to severe major depressive disorder (APA 2010). If treatment for major depressive disorder is initiated for the first time during pregnancy, fluoxetine is not recommended (CANMAT [MacQueen 2016]; Larsen 2015; WFSBP [Bauer 2013]); fluoxetine is considered a third-line agent for the treatment of mild to moderate depression during pregnancy (CANMAT [MacQueen 2016]). 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).

Data collection to monitor pregnancy and infant outcomes following exposure to antidepressants is ongoing. Pregnant women exposed to antidepressants during pregnancy are encouraged to enroll in the National Pregnancy Registry for Antidepressants (NPRAD). Women 18 to 45 years of age or their health care providers may contact the registry by calling 1-844-405-6185. Enrollment should be done as early in pregnancy as possible.

Breast-Feeding Considerations

Fluoxetine and its active metabolite (norfluoxetine) are present in breast milk.

Using pooled data, the relative infant dose (RID) of fluoxetine is reported as <12% of the weight-adjusted maternal dose (Berle 2011), but may be higher in specific infants (Lester 1993; Taddio 1996). 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). Concentrations of norfluoxetine in breast milk should also be considered. Both fluoxetine and norfluoxetine can be detected in the serum of breastfeeding infants. In some rare cases, infant plasma concentrations of fluoxetine are up to 80% of the maternal concentration (Berle 2011).

Adverse events in the breastfeeding infant have been reported following maternal use of fluoxetine, including crying, sleep disturbance, vomiting, and watery stools. Infants of mothers using psychotropic medications should be monitored daily for changes in sleep, feeding patterns, and behavior (WFSBP [Bauer 2013]) as well as infant growth and neurodevelopment (ABM [Sriraman 2015]; Sachs 2013). Maternal use of a selective serotonin reuptake inhibitor during pregnancy may cause delayed lactogenesis (Marshall 2010).

According to the manufacturer, the decision to breastfeed during therapy should consider the risk of infant exposure, the benefits of breastfeeding to the infant, and the benefits of treatment to the mother. When first initiating an antidepressant in a breastfeeding woman, agents other than fluoxetine are preferred (CANMAT [MacQueen 2016]; Larsen 2015). Women successfully treated with fluoxetine during pregnancy may continue use while breastfeeding if there are no other contraindications (Berle 2011).

Lexicomp Pregnancy & Lactation, In-Depth

• FLUoxetine

Briggs' Drugs in Pregnancy & Lactation

• Fluoxetine

Adverse Reactions

As reported in adults, unless otherwise noted.

>10%:

Endocrine & metabolic: Decreased libido (4% to 11% [placebo: 1% to 2%])

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) (Higgins 2010; Montejo 2001; Montejo-Gonzalez 1997; Csoka 2006)

Nervous system: Anxiety (6% to 15%), 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%), yawning (≤11%)

Neuromuscular & skeletal: Asthenia (9% to 21%), tremor (3% to 13%)

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 (4% to 6% [placebo: 2% to 3%])

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 (≤7% [placebo: 1%]), impotence (≤7%), urinary frequency (children and adolescents: ≥2%), urination disorder (≥1%)

Nervous system: Abnormal dreams (5%), abnormality in thinking (2%), agitation (children and adolescents: ≥2%), amnesia (≥1%), chills (≥1%), dizziness (9%), emotional lability (≥1%), personality disorder (children and adolescents: ≥2%), sleep disorder (≥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, cardiac failure, edema, hypotension, orthostatic hypotension, syncope, vasculitis

Dermatologic: Acne vulgaris, alopecia, ecchymoses, psoriasis (new onset) (Tan Pei Lin 2010), skin photosensitivity

Endocrine & metabolic: Albuminuria, amenorrhea, gout, 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, purpuric rash, upper gastrointestinal hemorrhage (Wee 2017)

Hepatic: Abnormal hepatic function tests, hepatitis (Capellà 1999; Friedenberg 1996)

Nervous system: Akathisia, anorgasmia (Kline 1989), ataxia, balance impairment, delusion, depersonalization, euphoria, extrapyramidal reaction (rare), hostility, hypertonia, migraine, myoclonus, obsessive compulsive disorder (trichotillomania) (Yektaş 2017), paranoid ideation, seizure (Hargrave 1992; Levine 1994), suicidal ideation (Teicher 1990), suicidal tendencies

Neuromuscular & skeletal: Arthritis, bursitis, lower limb cramp, ostealgia

Ophthalmic: Mydriasis

Respiratory: Asthma, laryngeal edema

Postmarketing:

Cardiovascular: Atrial fibrillation, cerebrovascular accident, pulmonary embolism, ventricular tachycardia (including torsades de pointes)

Dermatologic: Dermatitis (Agrawal 2019), erythema multiforme, erythema nodosum, exfoliative dermatitis, Stevens-Johnson syndrome (rare: <1%) (Agrawal 2019), toxic epidermal necrolysis (rare: <1%) (Jonsson 2008)

Endocrine & metabolic: 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 (rare: <1%) (Blacksten 1993)

Gastrointestinal: Esophagitis, pancreatitis

Genitourinary: Priapism (rare: <1%) (Javed 1996), sexual difficulty (decreased genital sensation) (Michael 2000)

Hematologic & oncologic: Aplastic anemia, bruise (rare: <1%) (Pai 1996), hemolytic anemia (immune-related), Henoch-Schonlein purpura (rare: <1%) (Süleyman 2016), immune thrombocytopenia, pancytopenia, thrombocytopenia (Yucel 2015)

Hepatic: Cholestatic jaundice, hepatic failure, hepatic necrosis, hepatotoxicity (Agrawal 2019)

Hypersensitivity: Hypersensitivity reaction (rare: <1%) (Beer 1994), nonimmune anaphylaxis

Immunologic: Drug reaction with eosinophilia and systemic symptoms (rare: <1%) (Vignesh 2017), serum-like sickness reaction (Miller 1989)

Nervous system: Dystonia (Bilen 2008), hallucination, hyperactive behavior (including agitation, hyperactivation, hyperkinesis, restlessness; occurring in children at a two- to threefold higher incidence compared to adolescents) (Safer 2006), hypomania (rare: <1%) (Jerome 1991), mania (rare: <1%) (Settle 1984), memory impairment, neuroleptic malignant syndrome, serotonin syndrome (rare: <1%) (Patel 2016), tardive dyskinesia (Dubovsky 1996), violent behavior

Neuromuscular & skeletal: Dyskinesia (Mander 1994), laryngospasm, linear skeletal growth rate below expectation (children) (Weintrob 2006), lupus-like syndrome

Ophthalmic: Acute angle-closure glaucoma (rare: <1%) (Ahmad 1991), cataract, optic neuritis

Renal: Renal failure syndrome

Respiratory: Eosinophilic pneumonitis, hypersensitivity pneumonitis (rare: <1%) (Gonzalez-Rothi 1995), hyperventilation, pulmonary fibrosis, pulmonary granuloma (rare: <1%) (de Kerviler 1996), pulmonary hypertension

* See Cautions in AHFS Essentials for additional information.

Allergy and Idiosyncratic Reactions

• Selective Serotonin Reuptake Inhibitor (SSRI) Allergy

Toxicology

• Antidepressants, Selective Serotonin Reuptake Inhibitors

Metabolism/Transport Effects

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)

Drug Interactions Open Interactions

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

Anticoagulants: Agents with Antiplatelet Properties may enhance the anticoagulant effect of Anticoagulants. Exceptions: Bemiparin; Enoxaparin; Heparin. 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. Exceptions: Alosetron; Ondansetron; Ramosetron. 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 are required for indications other than major depressive disorder. Dose reductions vary based on formulation, initial starting dose, and the additional use of CYP3A4 inhibitors. See full interaction 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

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

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

Cannabidiol: CYP2C19 Inhibitors (Moderate) may increase the serum concentration of Cannabidiol. Risk C: Monitor therapy

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

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. Exceptions: BuPROPion; FLUoxetine; PARoxetine. 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. Management: Drugs listed as exceptions to this monograph are discussed in further detail in separate drug interaction monographs. 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: Selective Serotonin Reuptake Inhibitors may enhance the adverse/toxic 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, and the maximum single dose of deutetrabenazine should not exceed 18 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. If combined, monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes). Risk D: Consider therapy modification

DiazePAM: CYP2C19 Inhibitors (Moderate) may increase the serum concentration of DiazePAM. 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

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. Exceptions: Lisuride; Nicergoline. Risk C: Monitor therapy

Etravirine: CYP2C19 Inhibitors (Moderate) may increase the serum concentration of Etravirine. Risk C: Monitor therapy

Fat Emulsion (Fish Oil Based): May enhance the adverse/toxic effect of Agents with Antiplatelet Properties. Risk C: Monitor therapy

Fenfluramine: May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Risk C: Monitor therapy

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

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

Glucosamine: May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Risk C: Monitor therapy

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

Herbs (Anticoagulant/Antiplatelet Properties) (eg, Alfalfa, Anise, Bilberry): May enhance the adverse/toxic effect of Agents with Antiplatelet Properties. Bleeding may occur. Management: Avoid combination when possible. If used, monitor more closely for evidence of bleeding. Discontinue herbal products with anticoagulant or antiplatelet actions 2 weeks prior to surgical, dental, or invasive procedures. Risk D: Consider therapy modification

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

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

Lofexidine: CYP2D6 Inhibitors (Strong) may increase the serum concentration of Lofexidine. Risk C: Monitor therapy

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

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

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 EPS when combined. Risk D: Consider therapy modification

Metoprolol: CYP2D6 Inhibitors (Strong) may increase the serum concentration of Metoprolol. Risk C: Monitor therapy

MetyroSINE: May enhance the adverse/toxic effect of Selective Serotonin Reuptake Inhibitors. Risk C: Monitor therapy

Mexiletine: CYP2D6 Inhibitors (Strong) may increase the serum concentration of Mexiletine. 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 enhance the adverse/toxic effect 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. Exceptions: Alfentanil; Benzhydrocodone; Buprenorphine; Butorphanol; Codeine; Dihydrocodeine; FentaNYL; HYDROcodone; Levomethadone; Meperidine; Methadone; Oliceridine; OxyCODONE; SUFentanil; TraMADol. 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. Exceptions: Oliceridine. 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. Exceptions: Levomethadone; Methadone. 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). Management: Concomitant use of ozanimod with serotonergic agents is not recommended. If combined, monitor patients closely for the development of hypertension, including hypertensive crises. Risk D: Consider therapy modification

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

Peginterferon Alfa-2b: May decrease the serum concentration of FLUoxetine. 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: FLUoxetine may enhance the QTc-prolonging effect of Pimozide. FLUoxetine may increase the serum concentration of Pimozide. Risk X: Avoid combination

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

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

Salicylates: Agents with Antiplatelet Properties may enhance the adverse/toxic effect of Salicylates. Increased risk of bleeding may result. Risk C: Monitor therapy

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. Exceptions: Citalopram; Dapoxetine; Vortioxetine. 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. Exceptions: TraMADol. 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. Exceptions: Almotriptan; Eletriptan. 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. Exceptions: DULoxetine. Risk C: Monitor therapy

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 the serum concentration 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 enhance the QTc-prolonging effect of 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

Tropisetron: CYP2D6 Inhibitors (Strong) may increase the serum concentration of Tropisetron. Risk C: Monitor therapy

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

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

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

Gene Testing May Be Considered

• CYP2D6 - Fluoxetine

Genes of Interest

• Brain-Derived Neurotropic Factor
• Cytochrome P450 2C9
• FK506 Binding Protein 5
• G protein beta subunit 3
• Monoamine Oxidase A
• Potassium Voltage-Gated Channel, Isk-Related Family, Member 1
• Serotonin Receptor 2A
• Solute Carrier 6A4
• Voltage-Gated Sodium Channel 5A

Monitoring Parameters

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; mental status for depression, suicidal ideation (especially at the beginning of therapy or when doses are increased or decreased), anxiety, social functioning, mania, panic attacks; signs/symptoms of serotonin syndrome; akathisia; sleep status

Reference Range

Therapeutic levels have not been well established.

Therapeutic: Fluoxetine: 100 to 800 ng/mL (SI: 289 to 2,314 nmol/L); Norfluoxetine: 100 to 600 ng/mL (SI: 289 to 1,735 nmol/L)

Toxic: Fluoxetine plus norfluoxetine: >2,000 ng/mL

Advanced Practitioners Physical Assessment/Monitoring

Taper dosage slowly when discontinuing. Assess mental status for depression, signs of clinical worsening, suicide ideation, anxiety, social functioning, mania, or panic attack.

Nursing Physical Assessment/Monitoring

Assess therapeutic response (eg, mental status, mode, affect) at beginning of therapy and periodically throughout. Monitor for CNS and gastrointestinal disturbances. Taper dosage slowly when discontinuing. Assess mental status for depression, signs of clinical worsening, suicide ideation, anxiety, social functioning, mania, or panic attack.

Dosage Forms: US

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:

PROzac Weekly: 90 mg [DSC]

Generic: 90 mg

Solution, Oral:

Generic: 20 mg/5 mL (5 mL, 120 mL)

Tablet, Oral:

Sarafem: 10 mg, 20 mg [contains fd&c yellow #10 aluminum lake, fd&c yellow #6 aluminum lake]

Generic: 10 mg, 20 mg, 60 mg

Dosage Forms: Canada

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Capsule, Oral:

PROzac: 10 mg, 20 mg [contains brilliant blue fcf (fd&c blue #1), butylparaben, edetate (edta) calcium disodium, methylparaben, propylparaben]

Generic: 10 mg, 20 mg, 40 mg, 60 mg

Solution, Oral:

Generic: 20 mg/5 mL (120 ea, 120 mL)

Anatomic Therapeutic Chemical (ATC) Classification

• N06AB03

Generic Available (US)

Yes

Pricing: US

Capsule, delayed release (FLUoxetine HCl Oral)

90 mg (per each): $39.21

Capsules (FLUoxetine HCl Oral)

10 mg (per each): $2.42 - $2.60

20 mg (per each): $2.48 - $2.67

40 mg (per each): $5.34 - $5.56

Capsules (PROzac Oral)

10 mg (per each): $19.02

20 mg (per each): $19.56

40 mg (per each): $39.12

Solution (FLUoxetine HCl Oral)

20 mg/5 mL (per mL): $0.98

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 - $4.20

20 mg (per each): $4.20 - $17.34

60 mg (per each): $10.44 - $11.61

Tablets (Sarafem Oral)

10 mg (per each): $25.06

20 mg (per each): $25.06

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.

Mechanism of Action

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

Pharmacodynamics/Kinetics

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 2012]); 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 2012]).

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).

Pharmacodynamics/Kinetics: Additional Considerations

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.

Local Anesthetic/Vasoconstrictor Precautions

Although caution should be used in patients taking tricyclic antidepressants, no interactions have been reported with vasoconstrictors and fluoxetine, a nontricyclic antidepressant which acts to increase serotonin; no precautions appear to be needed. Fluoxetine is one of the drugs confirmed to prolong the QT interval and is accepted as having a risk of causing torsade de pointes. The risk of drug-induced torsade de pointes is extremely low when a single QT interval prolonging drug is prescribed. In terms of epinephrine, it is not known what effect vasoconstrictors in the local anesthetic regimen will have in patients with a known history of congenital prolonged QT interval or in patients taking any medication that prolongs the QT interval. Until more information is obtained, it is suggested that the clinician consult with the physician prior to the use of a vasoconstrictor in suspected patients, and that the vasoconstrictor (epinephrine, mepivacaine and levonordefrin [Carbocaine 2% with Neo-Cobefrin]) be used with caution.

Dental Health Professional Considerations

Problems with SSRI-induced bruxism have been reported and may preclude their use; clinicians attempting to evaluate any patient with bruxism or involuntary muscle movement, who is simultaneously being treated with an SSRI drug, should be aware of the potential association (see Local Anesthetic/Vasoconstrictor Precautions)

Effects on Dental Treatment

Key adverse event(s) related to dental treatment: Xerostomia (normal salivary flow resumes upon discontinuation) and taste perversion. Problems with SSRI-induced bruxism have been reported and may preclude their use. Clinicians attempting to evaluate any patient with bruxism or involuntary muscle movement, who is simultaneously being treated with an SSRI drug, should be aware of this potential association (see Effects on Bleeding and Dental Health Professional Considerations)

Effects on Bleeding

Selective serotonin reuptake inhibitors such as fluoxetine may impair platelet aggregation due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication. The risk of a bleeding complication can be increased by coadministration of other antiplatelet agents such as NSAIDs and aspirin.

Related Information

• Agents Approved for Bipolar Disorder
• Antidepressant Receptor Profile
• Beers Criteria 2019: Potentially Inappropriate Medication Use in Older Adults ≥65 Years of Age
• Comparison of Antidepressant Adverse Effects
• Oral Medications That Should Not Be Crushed or Altered
• Relative Infant Dose
• Selective Serotonin Reuptake Inhibitors (SSRIs) Pharmacokinetics
• Selective Serotonin Reuptake Inhibitors (SSRIs) Receptor Profile

Pharmacotherapy Pearls

ECG may reveal S-T segment depression. Not shown to be teratogenic in rodents; 15 to 60 mg/day, buspirone and cyproheptadine, may be useful in treatment of sexual dysfunction during treatment with a selective serotonin reuptake inhibitor.

Weekly capsules are a delayed release formulation containing enteric-coated pellets of fluoxetine hydrochloride, equivalent to 90 mg fluoxetine. Therapeutic equivalence of weekly formulation with daily formulation for delaying time to relapse has not been established.

Index Terms

Fluoxetine Hydrochloride

FDA Approval Date

December 29, 1987

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Brand Names: International

Actan (CL, PY); Actisac (TH); Adef-XL (LK); Adep (PH); Adepssir (PH); Adofen (ES); Alzac (EG); Anextin (BH, QA); Ansi (ID); Ansilan (CO); Antiprestin (ID); Azur (IT); Bellzac (IE); Biozac (BG); Captaton (AR); Daforin (BR); Dagrilan (GR); Dawnex (LK, ZW); Deprexin (BM, BS, BZ, GY, HU, JM, SR, TT); Deprizac (PH); Deproxin (TH); Dominium (EC); Drafzin (PH); Elevamood (EG); Elizac (ID); Exostrept (GR); Flocept (ET); Flonital (GR); Flotina (IT); Floxet (HK, HU, UY); Flozak (BH); Fluctine (AT, CH); Fludac (BF, BJ, CI, ET, GH, GM, GN, IN, KE, LR, MA, ML, MR, MU, MW, NE, NG, SC, SD, SL, SN, TN, TZ, UG, ZM); Fludec (LK); Fluketin (SG); Fluneurin (BH); Flunil (IN); Fluovex (MY); Fluox (NZ); Fluoxeren (IT); Fluoxone (FI, SG); Fluronin (TW); Flush (BD); Flustad (NL); Flutin (AE, CO, KW, MY, QA, SA); Flutine (IL, TH); Fluval (HR); Flux (LV); Fluxen (TW, UA); Fluxetin (HK); Fluxil (AE, CY, IQ, IR, JO, LY, MT, OM, SA, SG, SY, TR, YE); Fluzac (BD, IE); Fluzyn-20 (BH); Fontex (BE, DK, FI, IS, NO, SE); Fropine (KR); Fuloren (KR); Fuxetine (KR); Gerozac (IE); Huma-Fluoxetin (HU); Lanclic (KR); Linz (QA); Lorien (ZA); Lovan (AU); Luramon (ES); Magrilan (HK); Margrilan (AE, CY, IQ, IR, JO, LY, OM, PH, SA, SG, SY, YE); Modipran (BD); Motivest (PH); Neupax (EC, PE); Nopres (ID); Nuzak (ZA); Nycoflox (EE); Octozac (EG); Olena (GB); Oxactin (MT); Oxedep (CN, ZW); Oxetin (BD); Oxetine (AE, JO, LB, SA); Oxexin (DK); Plazeron (MT); Portal (HR, HU, UA); Praxin (HU); Prazac (KR); Prizma (IL); Prodep (IN, UA); Prolert (LK); Prozac (AE, AR, AU, BB, BE, BF, BJ, BR, CI, CL, CN, CR, CZ, DO, EG, ES, ET, FR, GB, GH, GM, GN, GT, HK, HN, HR, HU, IE, IL, JO, KE, KR, LR, LU, MA, ML, MR, MT, MU, MW, NE, NG, NI, NL, NZ, PA, PE, PK, PT, QA, RO, RU, SA, SC, SD, SG, SK, SL, SN, SV, TH, TN, TR, TZ, UG, VE, VN, ZM); Prozac 20 (KR, MY, PH, TW); Prozac Dispersible (KR); Prozac Weekly (BB, KR); Prozet (AU); Prozit (TR); Qualisac (HK); Reneuron (ES); Salipax (BM, BS, BZ, GY, JM, MY, PL, QA, SR, TT); Seromex (FI); Seronil (FI); Sinzac (TW); Symbyax (MX); U-Zet (TW); Youke (CN); Zactin (AU, SG, TW); Zatin (CR, DO, GT, HN, NI, PA, SV)

Last Updated 10/22/20