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FLUoxetine

Pronunciation

Pronunciation

(floo OKS e teen)

Index Terms

  • Fluoxetine Hydrochloride

Dosage Forms

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

Capsule, Oral:

PROzac: 10 mg, 20 mg, 40 mg

Generic: 10 mg, 20 mg, 40 mg

Capsule Delayed Release, Oral:

PROzac Weekly: 90 mg

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

Brand Names: U.S.

  • PROzac
  • PROzac Weekly
  • Sarafem

Pharmacologic Category

  • Antidepressant, Selective Serotonin Reuptake Inhibitor

Pharmacology

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

Absorption

Well absorbed; delayed 1 to 2 hours with weekly formulation

Distribution

Vd: 12 to 43 L/kg

Metabolism

Hepatic, via CYP2C19 and 2D6, to norfluoxetine (activity equal to fluoxetine)

Excretion

Urine (10% as norfluoxetine, 2.5% to 5% as fluoxetine)

Onset of Action

Depression: The onset of action is within a week; however, individual response varies greatly and full response may not be seen until 8 to 12 weeks after initiation of treatment.

Time to Peak

Serum: 6 to 8 hours

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)

Protein Binding

95% to albumin and alpha1 glycoprotein

Special Populations: Hepatic Function Impairment

The half-life for fluoxetine and norfluoxetine is prolonged.

Special Populations: Children

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.

Use: Labeled Indications

Treatment of major depressive disorder (MDD); treatment of binge-eating and vomiting in patients with moderate-to-severe bulimia nervosa; obsessive-compulsive disorder (OCD); premenstrual dysphoric disorder (PMDD); panic disorder with or without agoraphobia; in combination with olanzapine for treatment-resistant or bipolar I depression

Use: Unlabeled

Selective mutism; post-traumatic stress disorder (PTSD); social anxiety disorder; Raynaud phenomenon

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)

Dosing: Adult

Depression, obsessive-compulsive disorder: Oral: 20 mg/day in the morning; may increase after several weeks by 20 mg/day increments; maximum: 80 mg/day; doses >20 mg may be given once daily or divided twice daily. Note: Lower doses of 5 to 10 mg/day have been used for initial treatment.

Indication-specific dosing:

Borderline personality disorder (off-label use): 20 mg daily; adjust dose based on response and tolerability up to 80 mg/day (APA [Oldham 2001]; Markovitz 1991; Salzman 1995; Zanarini 2004). Additional data may be necessary to further define the role of fluoxetine in this condition.

Bulimia nervosa: Oral: 60 mg/day; may titrate dose to 60 mg over several days

Depression: Oral: Initial: 20 mg/day; may increase after several weeks if inadequate response (maximum: 80 mg/day). Patients maintained on Prozac 20 mg/day may be changed to Prozac Weekly 90 mg/week, starting dose 7 days after the last 20 mg/day dose

Depression associated with bipolar I disorder (in combination with olanzapine): Oral: Initial: 20 mg in the evening; adjust as tolerated to usual range of 20 to 50 mg/day. See "Note" below.

Fibromyalgia (off-label use): Oral: Initial: 20 mg daily; may adjust 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 (range: 20 to 80 mg/day) (Arnold 2002)

Obsessive-compulsive disorder: Oral: Initial: 20 mg/day; may increase after several weeks if inadequate response; recommended range: 20 to 60 mg/day (maximum: 80 mg/day)

Panic disorder: Oral: Initial: 10 mg/day; after 1 week, increase to 20 mg/day; may increase after several weeks; doses >60 mg/day have not been evaluated

Post-traumatic stress disorder (PTSD) (off-label use): Oral: 20 to 40 mg/day

Premenstrual dysphoric disorder (Sarafem): Oral: 20 mg/day continuously, or 20 mg/day starting 14 days prior to menstruation and through first full day of menses (repeat with each cycle)

Raynaud’s phenomena (off-label use): Oral: 20 mg/day (Coleiro 2001)

Social anxiety disorder (off-label use): Oral: Initial: 10 mg/day for 7 days; continue to increase the dose based on response and tolerability in 10 mg increments at intervals of at least 7 days to a target dose of 40 mg/day; typical range in clinical trial was 30 to 60 mg/day (Davidson 2004)

Treatment-resistant depression (in combination with olanzapine): Oral: Initial: 20 mg in the evening; adjust as tolerated to usual range of 20 to 50 mg/day. See "Note."

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

Discontinuation of therapy: Upon discontinuation of antidepressant therapy, gradually taper the dose to minimize the incidence of withdrawal symptoms and allow for the detection of re-emerging symptoms. Evidence supporting ideal taper rates 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. In addition for long-term treated patients, WFSBP guidelines recommend tapering over 4 to 6 months. If intolerable withdrawal 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; Haddad 2001; NCCMH 2010; Schatzberg 2006; Shelton 2001; Warner 2006).

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.

Use with other MAO inhibitors (linezolid or IV methylene blue):

Do not initiate fluoxetine in patients receiving linezolid or IV methylene blue; consider other interventions for psychiatric condition.

If urgent treatment with linezolid or IV methylene blue is required in a patient already receiving fluoxetine and potential benefits outweigh potential risks, discontinue fluoxetine promptly and administer linezolid or IV methylene blue. Monitor for serotonin syndrome for 5 weeks or until 24 hours after the last dose of linezolid or IV methylene blue, whichever comes first. May resume fluoxetine 24 hours after the last dose of linezolid or IV methylene blue.

Dosing: Geriatric

Depression: Oral: Some patients may require an initial dose of 10 mg/day with dosage increases of 10 mg and 20 mg every several weeks as tolerated; should not be taken at night unless patient experiences sedation. Refer to adult dosing.

Discontinuation of therapy: Refer to adult dosing.

MAO inhibitor recommendations: Refer to adult dosing.

Dosing: Pediatric

Depression: Children ≥8 years and Adolescents: Oral: 10 to 20 mg/day; lower-weight children can be started at 10 mg/day, may increase to 20 mg/day after 1 week if needed

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. See "Note" below.

Obsessive-compulsive disorder: Children ≥7 years and Adolescents: Oral: Initial: 10 mg/day; may increase after 2 weeks if inadequate clinical response to 20 mg/day; further increases may be considered after several weeks to recommended range of 20 to 30 mg/day (lower weight children) or 20 to 60 mg/day (adolescents and higher weight children)

Selective mutism (off-label use): Children ≥5 years and Adolescents: Oral: Initial: 5 mg once daily for 7 days, then increase to 10 mg once daily for 7 days, and 20 mg once daily thereafter; may further titrate in 20 mg/day increments if needed every 2 weeks; maximum daily dose: 60 mg/day (Dummit 1996). Weight-based dosing: 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 in clinical trials: 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; Dummit 1996; Kaakeh 2008).

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

Discontinuation of therapy: Refer to adult dosing.

MAO inhibitor recommendations: Refer to adult dosing.

Dosing: Renal Impairment

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

Elimination half-life of fluoxetine is prolonged in patients with hepatic impairment. A lower dose or less frequent dosing of fluoxetine should be used in these patients.

Cirrhosis patient: Administer a lower dose or less frequent dosing interval.

Compensated cirrhosis without ascites: Administer 50% of normal dose.

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.

Administration

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.

Dietary Considerations

May be taken without regard to meals.

Storage

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

Drug Interactions

Abiraterone Acetate: May increase the serum concentration of CYP2D6 Substrates. Management: Avoid concurrent use of abiraterone with CYP2D6 substrates that have a narrow therapeutic index whenever possible. When concurrent use is not avoidable, monitor patients closely for signs/symptoms of toxicity. Consider therapy modification

Agents with Antiplatelet Properties (e.g., P2Y12 inhibitors, NSAIDs, SSRIs, etc.): May enhance the antiplatelet effect of other Agents with Antiplatelet Properties. 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. Consider therapy modification

Analgesics (Opioid): May enhance the serotonergic effect of Serotonin Modulators. This could result in serotonin syndrome. Monitor therapy

Anticoagulants: Agents with Antiplatelet Properties may enhance the anticoagulant effect of Anticoagulants. Monitor therapy

Antidepressants (Serotonin Reuptake Inhibitor/Antagonist): Selective Serotonin Reuptake Inhibitors may enhance the serotonergic effect of Antidepressants (Serotonin Reuptake Inhibitor/Antagonist). This may cause serotonin syndrome. Management: Consider alternatives, and use conservative initial dosing. Monitor patients receiving these combinations for signs/symptoms of serotonin toxicity. Consider therapy modification

Antiemetics (5HT3 Antagonists): May enhance the serotonergic effect of Serotonin Modulators. This could result in serotonin syndrome. Monitor therapy

Antipsychotic Agents: Serotonin Modulators may enhance the adverse/toxic effect of Antipsychotic Agents. Specifically, serotonin modulators may enhance dopamine blockade, possibly increasing the risk for neuroleptic malignant syndrome. Antipsychotic Agents may enhance the serotonergic effect of Serotonin Modulators. This could result in serotonin syndrome. 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. Monitor therapy

ARIPiprazole: FLUoxetine may enhance the adverse/toxic effect of ARIPiprazole. Specifically, the risk of neuroleptic malignant syndrome may be increased. ARIPiprazole may enhance the serotonergic effect of FLUoxetine. This could result in serotonin syndrome. FLUoxetine may increase the serum concentration of ARIPiprazole. Management: Aripiprazole dose should be reduced by at least half, except when used adjunctively for depression. Consult full interaction monograph or aripiprazole prescribing information for complete details. Consider therapy modification

ARIPiprazole Lauroxil: CYP2D6 Inhibitors (Strong) may increase serum concentrations of the active metabolite(s) of ARIPiprazole Lauroxil. Management: Please refer to the full interaction monograph for details concerning the recommended dose adjustments. Consider therapy modification

Aspirin: Selective Serotonin Reuptake Inhibitors may enhance the antiplatelet effect of Aspirin. Monitor therapy

Asunaprevir: May increase the serum concentration of CYP2D6 Substrates. Consider therapy modification

AtoMOXetine: CYP2D6 Inhibitors (Strong) may increase the serum concentration of AtoMOXetine. Management: Initiate atomoxetine at a reduced dose (adult doses -- patients up to 70kg: 0.5mg/kg/day; patients 70kg or more: 40mg/day) in patients receiving a strong CYP2D6 inhibitor. Consider therapy modification

Beta-Blockers: Selective Serotonin Reuptake Inhibitors may increase the serum concentration of Beta-Blockers. Exceptions: Acebutolol; Atenolol; Betaxolol (Ophthalmic); Betaxolol (Systemic); Bisoprolol; Carteolol (Ophthalmic); Esmolol; Labetalol; Levobunolol; Metipranolol; Nadolol; Penbutolol; Sotalol. Monitor therapy

Blood Glucose Lowering Agents: Selective Serotonin Reuptake Inhibitors may enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Monitor therapy

Brexpiprazole: CYP2D6 Inhibitors (Strong) may increase the serum concentration of Brexpiprazole. Management: Reduce brexpiprazole dose to 50% of usual with a strong CYP2D6 inhibitor; this recommendation does not apply if treating major depressive disorder. Reduce to 25% of usual if used with both a strong CYP2D6 inhibitor and a CYP3A4 inhibitor. Consider therapy modification

BuPROPion: May enhance the adverse/toxic effect of FLUoxetine. BuPROPion may increase the serum concentration of FLUoxetine. Monitor therapy

BusPIRone: May enhance the serotonergic effect of Selective Serotonin Reuptake Inhibitors. This may cause serotonin syndrome. Selective Serotonin Reuptake Inhibitors may decrease the metabolism of BusPIRone. Management: The combination of a selective serotonin reuptake inhibitor and buspirone should be undertaken with great caution. When combined treatment is clinically indicated, monitor closely for signs of serotonin toxicity/serotonin syndrome. Consider therapy modification

CarBAMazepine: Selective Serotonin Reuptake Inhibitors may decrease the metabolism of CarBAMazepine. Specifically those SSRIs that inhibit CYP3A4 isoenzymes. CarBAMazepine may increase the metabolism of Selective Serotonin Reuptake Inhibitors. Specifically those agents metabolized via CYP1A2, 2C, and/or 3A4 isoenzymes. Consider therapy modification

Cephalothin: Agents with Antiplatelet Properties may enhance the adverse/toxic effect of Cephalothin. Specifically, the risk for bleeding may be increased. Monitor therapy

Cilostazol: CYP2C19 Inhibitors may increase the serum concentration of Cilostazol. Management: Consider reducing the cilostazol dose to 50 mg twice daily in patients who are also receiving inhibitors of CYP2C19. Consider therapy modification

Cimetidine: May decrease the metabolism of Selective Serotonin Reuptake Inhibitors. Consider therapy modification

Clarithromycin: May enhance the QTc-prolonging effect of FLUoxetine. Clarithromycin may increase the serum concentration of FLUoxetine. Avoid combination

Clopidogrel: CYP2C19 Inhibitors (Moderate) may decrease serum concentrations of the active metabolite(s) of Clopidogrel. Management: Due to a risk for impaired clopidogrel effectiveness with such a combination, carefully consider the need for a moderate CYP2C19 inhibitor in patients receiving clopidogrel. Monitor patients closely for evidence of a diminished response to clopidogrel. Consider therapy modification

CNS Depressants: May enhance the adverse/toxic effect of Selective Serotonin Reuptake Inhibitors. Specifically, the risk of psychomotor impairment may be enhanced. Monitor therapy

Cobicistat: May increase the serum concentration of CYP2D6 Substrates. Monitor therapy

Codeine: CYP2D6 Inhibitors (Strong) may diminish the therapeutic effect of Codeine. These CYP2D6 inhibitors may prevent the metabolic conversion of codeine to its active metabolite morphine. Consider therapy modification

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. Monitor therapy

CYP2C19 Substrates: CYP2C19 Inhibitors (Moderate) may decrease the metabolism of CYP2C19 Substrates. Monitor therapy

CYP2C9 Inducers (Strong): May increase the metabolism of CYP2C9 Substrates. Management: Consider an alternative for one of the interacting drugs. Some combinations may be specifically contraindicated. Consult appropriate manufacturer labeling. Consider therapy modification

CYP2C9 Inhibitors (Moderate): May decrease the metabolism of CYP2C9 Substrates. Monitor therapy

CYP2C9 Inhibitors (Strong): May decrease the metabolism of CYP2C9 Substrates. Consider therapy modification

CYP2D6 Inhibitors (Moderate): May decrease the metabolism of CYP2D6 Substrates. Monitor therapy

CYP2D6 Inhibitors (Strong): May decrease the metabolism of CYP2D6 Substrates. Consider therapy modification

CYP2D6 Substrates: CYP2D6 Inhibitors (Strong) may decrease the metabolism of CYP2D6 Substrates. Exceptions: Ajmaline; Dapoxetine; Tamoxifen; Timolol (Ophthalmic); Tropisetron. Consider therapy modification

Cyproheptadine: May diminish the therapeutic effect of Selective Serotonin Reuptake Inhibitors. 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. Monitor therapy

Dabrafenib: May decrease the serum concentration of CYP2C9 Substrates. Management: Seek alternatives to the CYP2C9 substrate when possible. If concomitant therapy cannot be avoided, monitor clinical effects of the substrate closely (particularly therapeutic effects). Consider therapy modification

Dapoxetine: May enhance the adverse/toxic effect of Serotonin Modulators. Avoid combination

Darunavir: May increase the serum concentration of CYP2D6 Substrates. 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. Monitor therapy

Desmopressin: Selective Serotonin Reuptake Inhibitors may enhance the adverse/toxic effect of Desmopressin. Monitor therapy

Dextromethorphan: Selective Serotonin Reuptake Inhibitors may enhance the serotonergic effect of Dextromethorphan. Selective Serotonin Reuptake Inhibitors may increase the serum concentration of Dextromethorphan. Management: Avoid the concurrent use of dextromethorphan and SSRIs, particularly fluoxetine and paroxetine, when possible. The risk for this interaction may persist for several weeks following discontinuation of fluoxetine or paroxetine. Consider therapy modification

Dosulepin: Selective Serotonin Reuptake Inhibitors may increase the serum concentration of Dosulepin. Avoid combination

DOXOrubicin (Conventional): CYP2D6 Inhibitors (Strong) may increase the serum concentration of DOXOrubicin (Conventional). Management: Seek alternatives to strong CYP2D6 inhibitors in patients treated with doxorubicin whenever possible. One U.S. manufacturer (Pfizer Inc.) recommends that these combinations be avoided. Consider therapy modification

DULoxetine: CYP2D6 Inhibitors (Strong) may increase the serum concentration of DULoxetine. Monitor therapy

Edoxaban: Agents with Antiplatelet Properties may enhance the adverse/toxic effect of Edoxaban. Specifically, the risk of bleeding may be increased. Monitor therapy

Enzalutamide: May decrease the serum concentration of CYP2C9 Substrates. Management: Concurrent use of enzalutamide with CYP2C9 substrates that have a narrow therapeutic index should be avoided. Use of enzalutamide and any other CYP2C9 substrate should be performed with caution and close monitoring. Consider therapy modification

Fesoterodine: CYP2D6 Inhibitors may increase serum concentrations of the active metabolite(s) of Fesoterodine. Monitor therapy

Fosphenytoin: May enhance the QTc-prolonging effect of FLUoxetine. FLUoxetine may increase the serum concentration of Fosphenytoin. Consider therapy modification

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

Haloperidol: FLUoxetine may enhance the QTc-prolonging effect of Haloperidol. FLUoxetine may increase the serum concentration of Haloperidol. Avoid combination

Herbs (Anticoagulant/Antiplatelet Properties) (eg, Alfalfa, Anise, Bilberry): May enhance the adverse/toxic effect of Agents with Antiplatelet Properties. Bleeding may occur. Consider therapy modification

Highest Risk QTc-Prolonging Agents: May enhance the QTc-prolonging effect of other Highest Risk QTc-Prolonging Agents. Avoid combination

HYDROcodone: CYP2D6 Inhibitors (Strong) may decrease serum concentrations of the active metabolite(s) of HYDROcodone. Specifically, concentrations of hydromorphone may be decreased. Monitor therapy

Ibritumomab: Agents with Antiplatelet Properties may enhance the adverse/toxic effect of Ibritumomab. Both agents may contribute to impaired platelet function and an increased risk of bleeding. Monitor therapy

Ibrutinib: May enhance the adverse/toxic effect of Agents with Antiplatelet Properties. Monitor therapy

Imatinib: May increase the serum concentration of CYP2D6 Substrates. Monitor therapy

Indapamide: May enhance the QTc-prolonging effect of Highest Risk QTc-Prolonging Agents. Consider therapy modification

Iobenguane I 123: Selective Serotonin Reuptake Inhibitors may diminish the therapeutic effect of Iobenguane I 123. Avoid combination

Ioflupane I 123: Selective Serotonin Reuptake Inhibitors may diminish the diagnostic effect of Ioflupane I 123. Monitor therapy

Ivabradine: May enhance the QTc-prolonging effect of Highest Risk QTc-Prolonging Agents. Avoid combination

Limaprost: May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Monitor therapy

Linezolid: May enhance the serotonergic effect of Selective Serotonin Reuptake Inhibitors. This could result in serotonin syndrome. Avoid combination

Lithium: May enhance the serotonergic effect of Selective Serotonin Reuptake Inhibitors. This could increase the risk of serotonin toxicity/serotonin syndrome. Management: This combination should be undertaken with great caution. When combined treatment is clinically indicated, monitor closely for signs of serotonin toxicity/serotonin syndrome. Consider therapy modification

Lumacaftor: May decrease the serum concentration of CYP2C9 Substrates. Lumacaftor may increase the serum concentration of CYP2C9 Substrates. Monitor therapy

MAO Inhibitors: May enhance the serotonergic effect of Selective Serotonin Reuptake Inhibitors. This may cause serotonin syndrome. While methylene blue and linezolid are expected to interact via this mechanism, management recommendations differ from other monoamine oxidase inhibitors. Refer to monographs specific to those agents for details. Exceptions: Linezolid; Methylene Blue; Tedizolid. Avoid combination

Mequitazine: CYP2D6 Inhibitors (Strong) may increase the serum concentration of Mequitazine. Avoid combination

Metaxalone: May enhance the serotonergic effect of Serotonin Modulators. This could result in serotonin syndrome. Monitor therapy

Methylene Blue: Selective Serotonin Reuptake Inhibitors may enhance the serotonergic effect of Methylene Blue. This could result in serotonin syndrome. Avoid combination

Methylene Blue: May enhance the serotonergic effect of Serotonin Modulators. This could result in serotonin syndrome. Avoid combination

Metoclopramide: May enhance the adverse/toxic effect of Selective Serotonin Reuptake Inhibitors. Management: Seek alternatives to this combination when possible. Monitor patients receiving metoclopramide with selective serotonin reuptake inhibitors for signs of extrapyramidal symptoms, neuroleptic malignant syndrome, and serotonin syndrome. Consider therapy modification

Metoprolol: CYP2D6 Inhibitors may increase the serum concentration of Metoprolol. Management: Consider an alternative for one of the interacting drugs in order to avoid metoprolol toxicity. If the combination must be used, monitor response to metoprolol closely. Metoprolol dose reductions may be necessary. Consider therapy modification

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

Mexiletine: Selective Serotonin Reuptake Inhibitors may decrease the metabolism of Mexiletine. Consider therapy modification

MiFEPRIStone: May enhance the QTc-prolonging effect of Highest Risk QTc-Prolonging Agents. Avoid combination

Moderate Risk QTc-Prolonging Agents: May enhance the QTc-prolonging effect of Highest Risk QTc-Prolonging Agents. Avoid combination

Multivitamins/Fluoride (with ADE): May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Monitor therapy

Multivitamins/Minerals (with ADEK, Folate, Iron): May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Monitor therapy

Multivitamins/Minerals (with AE, No Iron): May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Monitor therapy

Nebivolol: CYP2D6 Inhibitors (Strong) may increase the serum concentration of Nebivolol. 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. Monitor therapy

NIFEdipine: FLUoxetine may enhance the adverse/toxic effect of NIFEdipine. Monitor therapy

NiMODipine: FLUoxetine may increase the serum concentration of NiMODipine. Monitor therapy

NSAID (COX-2 Inhibitor): Selective Serotonin Reuptake Inhibitors may enhance the antiplatelet effect of NSAID (COX-2 Inhibitor). NSAID (COX-2 Inhibitor) may diminish the therapeutic effect of Selective Serotonin Reuptake Inhibitors. Monitor therapy

NSAID (Nonselective): Selective Serotonin Reuptake Inhibitors may enhance the antiplatelet effect of NSAID (Nonselective). NSAID (Nonselective) may diminish the therapeutic effect of Selective Serotonin Reuptake Inhibitors. Management: Consider using alternative analgesics, when appropriate, and/or addition of a gastroprotective agent. Monitor patients closely for signs/symptoms of bleeding, and for evidence of diminished SSRI effectiveness with concurrent use. Consider therapy modification

Obinutuzumab: Agents with Antiplatelet Properties may enhance the adverse/toxic effect of Obinutuzumab. Specifically, the risk of serious bleeding-related events may be increased. Monitor therapy

Omega-3 Fatty Acids: May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Monitor therapy

Peginterferon Alfa-2b: May decrease the serum concentration of FLUoxetine. 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. Monitor therapy

Pentoxifylline: May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Monitor therapy

Perhexiline: CYP2D6 Inhibitors may increase the serum concentration of Perhexiline. Management: Consider alternatives to this combination if possible. If combined, monitor for increased perhexiline serum concentrations and toxicities (eg, hypoglycemia, neuropathy, liver dysfunction). Perhexiline dose reductions will likely be required. Consider therapy modification

Phenytoin: FLUoxetine may increase the serum concentration of Phenytoin. Monitor therapy

Pimozide: FLUoxetine may enhance the QTc-prolonging effect of Pimozide. FLUoxetine may increase the serum concentration of Pimozide. Avoid combination

Propafenone: May enhance the QTc-prolonging effect of FLUoxetine. FLUoxetine may increase the serum concentration of Propafenone. Avoid combination

Prostacyclin Analogues: May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Monitor therapy

QTc-Prolonging Agents (Indeterminate Risk and Risk Modifying): May enhance the QTc-prolonging effect of Highest Risk QTc-Prolonging Agents. Management: Avoid such combinations when possible. Use should be accompanied by close monitoring for evidence of QT prolongation or other alterations of cardiac rhythm. 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. Monitor therapy

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

Serotonin Modulators: May enhance the adverse/toxic effect of other Serotonin Modulators. The development of serotonin syndrome may occur. Exceptions: Nicergoline; Tedizolid. 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. Avoid combination

Tamsulosin: CYP2D6 Inhibitors (Strong) may increase the serum concentration of Tamsulosin. Monitor therapy

Tedizolid: May enhance the serotonergic effect of Serotonin Modulators. This could result in serotonin syndrome. Monitor therapy

Thiazide and Thiazide-Like Diuretics: Selective Serotonin Reuptake Inhibitors may enhance the hyponatremic effect of Thiazide and Thiazide-Like Diuretics. Monitor therapy

Thioridazine: FLUoxetine may enhance the QTc-prolonging effect of Thioridazine. FLUoxetine may increase the serum concentration of Thioridazine. Avoid combination

Thrombolytic Agents: Agents with Antiplatelet Properties may enhance the anticoagulant effect of Thrombolytic Agents. Monitor therapy

Thyroid Products: Selective Serotonin Reuptake Inhibitors may diminish the therapeutic effect of Thyroid Products. Thyroid product dose requirements may be increased. Monitor therapy

Timolol (Ophthalmic): CYP2D6 Inhibitors (Strong) may increase the serum concentration of Timolol (Ophthalmic). Monitor therapy

TiZANidine: CYP1A2 Inhibitors (Weak) may increase the serum concentration of TiZANidine. Management: Avoid these combinations when possible. If combined use cannot be avoided, initiate tizanidine at an adult dose of 2 mg and increase in 2-4 mg increments based on patient response. Monitor for increased effects of tizanidine, including adverse reactions. Consider therapy modification

Tositumomab and Iodine I 131 Tositumomab: Agents with Antiplatelet Properties may enhance the adverse/toxic effect of Tositumomab and Iodine I 131 Tositumomab. Specifically, the risk of bleeding-related adverse events may be increased. Monitor therapy

TraMADol: CYP2D6 Inhibitors (Strong) may diminish the therapeutic effect of TraMADol. CYP2D6 Inhibitors (Strong) may decrease serum concentrations of the active metabolite(s) of TraMADol. CYP2D6 Inhibitors (Strong) may increase the serum concentration of TraMADol. Monitor therapy

TraMADol: Serotonin Modulators may enhance the adverse/toxic effect of TraMADol. The risk of seizures may be increased. TraMADol may enhance the serotonergic effect of Serotonin Modulators. This could result in serotonin syndrome. Monitor therapy

Tricyclic Antidepressants: FLUoxetine may enhance the adverse/toxic effect of Tricyclic Antidepressants. FLUoxetine may increase the serum concentration of Tricyclic Antidepressants. Management: Consider alternatives to this combination when possible. Monitor for adverse effects of tricyclic antidepressants (TCAs), including serotonin syndrome and QT-interval prolongation, when a TCA is being used in combination with fluoxetine. Consider therapy modification

Tryptophan: May enhance the serotonergic effect of Selective Serotonin Reuptake Inhibitors. This may cause serotonin syndrome. Avoid combination

Urokinase: Agents with Antiplatelet Properties may enhance the anticoagulant effect of Urokinase. Avoid combination

Vinflunine: May enhance the QTc-prolonging effect of Highest Risk QTc-Prolonging Agents. Avoid combination

Vitamin E (Systemic): May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Monitor therapy

Vitamin K Antagonists (eg, warfarin): Selective Serotonin Reuptake Inhibitors may enhance the anticoagulant effect of Vitamin K Antagonists. Monitor therapy

Vortioxetine: CYP2D6 Inhibitors (Strong) may increase the serum concentration of Vortioxetine. Management: The vortioxetine dose should be reduced by 50% when used together with a strong CYP2D6 inhibitor. Following cessation of the strong CYP2D6 inhibitor, the vortioxetine dose should be returned to the normal level. Consider therapy modification

Ziprasidone: FLUoxetine may enhance the QTc-prolonging effect of Ziprasidone. Ziprasidone may enhance the serotonergic effect of FLUoxetine. This could result in serotonin syndrome. Avoid combination

Adverse Reactions

Percentages listed for adverse effects as reported in placebo-controlled trials and were generally similar in adults and children; actual frequency may be dependent upon diagnosis and in some cases the range presented may be lower than or equal to placebo for a particular disorder.

>10%:

Central nervous system: Insomnia (10% to 33%), headache (21%), drowsiness (5% to 17%), anxiety (6% to 15%), nervousness (8% to 14%), yawning (≤11%)

Endocrine & metabolic: Decreased libido (1% to 11%)

Gastrointestinal: Nausea (12% to 29%), diarrhea (8% to 18%), anorexia (4% to 17%), xerostomia (4% to 12%)

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

Respiratory: Pharyngitis (10% to 11%)

1% to 10%:

Cardiovascular: Vasodilation (1% to 5%), chest pain, hypertension, palpitations

Central nervous system: Dizziness (9%), abnormal dreams (1% to 5%), abnormality in thinking (2%), agitation, amnesia, chills, confusion, emotional lability, sleep disorder

Dermatologic: Diaphoresis (2% to 8%), skin rash (2% to 6%), pruritus (3%)

Endocrine & metabolic: Weight loss (2%), hypermenorrhea (≥2%), increased thirst (≥2%), weight gain

Gastrointestinal: Dyspepsia (6% to 10%), constipation (5%), flatulence (3%), vomiting (3%), dysgeusia, increased appetite

Genitourinary: Ejaculatory disorder (≤7%), impotence (≤7%), urinary frequency

Neuromuscular & skeletal: Hyperkinesia (≥2%)

Ophthalmic: Visual disturbance (2%)

Otic: Otalgia, tinnitus

Respiratory: Flu-like symptoms (3% to 10%), sinusitis (2% to 6%), epistaxis (≥2%)

<1% (Limited to important or life-threatening): Abnormal hepatic function tests, acne vulgaris, acute abdominal condition, akathisia, albuminuria, alopecia, amenorrhea, anaphylactoid reaction, anemia, angina pectoris, angle-closure glaucoma, aphthous stomatitis, aplastic anemia, arthritis, asthma, ataxia, atrial fibrillation, bruise, bruxism, bursitis, cardiac arrest, cardiac arrhythmia, cataract, cerebrovascular accident, cholelithiasis, cholestatic jaundice, colitis, congestive heart failure, dehydration, delusions, depersonalization, dyskinesia, dysphagia, dysuria, ecchymoses, edema, eosinophilic pneumonitis, equilibrium disturbance, erythema multiforme, erythema nodosum, esophagitis, euphoria, exfoliative dermatitis, extrapyramidal reaction (rare), gastritis, gastroenteritis, gastrointestinal ulcer, glossitis, gout, gynecological bleeding, gynecomastia, hallucination, hemolytic anemia (immune-related), hepatic failure, hepatic necrosis, hepatitis, hiccups, hostility, hypercholesteremia, hyperprolactinemia, hypersensitivity reaction, hypertonia, hyperventilation, hypoglycemia, hypokalemia, hyponatremia (possibly in association with SIADH), hypotension, hypothyroidism, immune thrombocytopenia, laryngeal edema, laryngospasm, leg cramps, lupus-like syndrome, malaise, melena, migraine, mydriasis, myocardial infarction, myoclonus, neuroleptic malignant syndrome (Stevens, 2008), optic neuritis, orthostatic hypotension, ostealgia, pancreatitis, pancytopenia, paranoia, petechia, priapism, prolonged Q-T interval on ECG, pulmonary embolism, pulmonary fibrosis, pulmonary hypertension, purpuric rash, renal failure, serotonin syndrome, skin photosensitivity, Stevens-Johnson syndrome, suicidal ideation, syncope, tachycardia, thrombocytopenia, toxic epidermal necrolysis, vasculitis, ventricular tachycardia (including torsades de pointes), violent behavior

ALERT: U.S. Boxed Warning

Suicidality and antidepressant drugs:

Antidepressants increased the risk compared with placebo of suicidal thinking and behavior (suicidality) in short-term studies in children, adolescents, and young adults with major depressive disorder (MDD) and other psychiatric disorders. Anyone considering the use of fluoxetine or any other antidepressant in a child, adolescent, or young adult must balance this risk with the clinical need. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared with placebo in adults older than 24 years; there was a reduction in risk with antidepressants compared with placebo in adults 65 years and older. Depression and certain other psychiatric disorders are themselves associated with increases in the risk of suicide. Appropriately monitor and closely observe patients of all ages who are started on antidepressant therapy for clinical worsening, suicidality, or unusual changes in behavior. Advise families and caregivers of the need for close observation and communication with the prescribing health care provider.

Fluoxetine is approved for use in children with MDD (aged 8 years and older) and obsessive-compulsive disorder (OCD; aged 7 years and older). Sarafem is not approved for use in children.

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 OCD 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 healthcare provider if any of these symptoms or worsening depression or psychosis 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.

• Anticholinergic effects: Relatively devoid of these side effects

• Bleeding risk: May impair platelet aggregation resulting in increased risk of bleeding events, particularly if used concomitantly with aspirin, NSAIDs, warfarin or other anticoagulants. Bleeding related to 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 torsade de pointes has 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 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, SNRIs), particularly when used in combination with other serotonergic agents (eg, triptans, TCAs, fentanyl, lithium, tramadol, buspirone, St. John’s wort, tryptophan) or agents that impair metabolism of serotonin (eg, MAO inhibitors intended to treat psychiatric disorders, other MAO inhibitors [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 blood pressure, 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.

• Sexual dysfunction: May cause or exacerbate sexual dysfunction.

• SIADH and hyponatremia: SSRIs and SNRIs have been associated with the development of SIADH; 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 plasma concentrations are increased; a lower dosage may be needed in patients with cirrhosis.

• Mania/hypomania: May worsen psychosis in some patients or precipitate a shift to mania or hypomania in patients with bipolar disorder. Monotherapy in patients with bipolar disorder should be avoided. Patients presenting with depressive symptoms should be screened for bipolar disorder. Fluoxetine monotherapy is not FDA approved for the treatment of bipolar depression.

• 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.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Special populations:

• Elderly: May also cause agitation, sleep disturbances, and excessive CNS stimulation in older adults.

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 suggests 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; 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.

Monitoring Parameters

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; blood glucose (for diabetic patients), baseline liver function; ECG assessment and periodic monitoring in patients with risk factors for QT prolongation and ventricular arrhythmia

Pregnancy Risk Factor

C

Pregnancy Considerations

Adverse events have been observed in animal reproduction studies. Fluoxetine and its metabolite cross the human placenta. An increased risk of teratogenic effects, including cardiovascular defects, may be associated with maternal use of fluoxetine or other SSRIs; however, available information is conflicting. Nonteratogenic effects in the newborn following SSRI/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. 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 (PPHN) has also been reported with SSRI exposure. The long-term effects of in utero SSRI exposure on infant development and behavior are not known.

Due to pregnancy-induced physiologic changes, women who are pregnant may require dose adjustments of fluoxetine to achieve euthymia. The ACOG recommends that therapy with SSRIs or SNRIs during pregnancy be individualized; treatment of depression during pregnancy should incorporate the clinical expertise of the mental health clinician, obstetrician, primary health care provider, and pediatrician. According to the American Psychiatric Association (APA), the risks of medication treatment should be weighed against other treatment options and untreated depression. For women who discontinue antidepressant medications during pregnancy and who may be at high risk for postpartum depression, the medications can be restarted following delivery. Treatment algorithms have been developed by the ACOG and the APA for the management of depression in women prior to conception and during pregnancy.

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 844-405-6185. Enrollment should be done as early in pregnancy as possible.

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience nausea, dry mouth, fatigue, diarrhea, nightmares, insomnia, loss of strength and energy, flu-like symptoms, or yawning. Have patient report immediately to prescriber signs of depression (suicidal ideation, anxiety, emotional instability, illogical thinking), signs of low sodium (headache, trouble focusing, memory problems, illogical thinking, weakness, seizures, or change in balance), signs of bleeding (vomiting; blood or vomit that looks like coffee grounds; coughing up blood; blood in the urine; black, red, or tarry stools; bleeding from the gums; abnormal vaginal bleeding; bruises without a reason or that get bigger; or any bleeding that is very bad or that will not stop), severe dizziness, passing out, excessive weight gain or loss, sexual dysfunction, loss of libido, change in amount of urine passed, dark urine, lack or appetite, severe nausea, vomiting, severe abdominal pain, light-colored stools, jaundice, shortness of breath, vision changes, eye pain, eye irritation, signs of serotonin syndrome (dizziness, severe headache, agitation, hallucinations, tachycardia, arrhythmia, flushing, tremors, sweating a lot, change in balance, severe nausea, severe diarrhea), or priapism (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for healthcare professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience and judgment in diagnosing, treating and advising patients.

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