Fluoxetine Hydrochloride

Class: Selective Serotonin-reuptake Inhibitors
VA Class: CN609
Chemical Name: N-Methyl-γ-[4-(trifluoromethyl)phenoxy]benzenepropanamine hydrochloride
Molecular Formula: C₁₇H₁₈F₃NO•HCl
CAS Number: 56296-78-7
Brands: Prozac, Prozac Weekly, Sarafem, Symbyax

Special Alerts:

[Posted 02/22/2011] ISSUE: FDA notified healthcare professionals that the Pregnancy section of drug labels for the entire class of antipsychotic drugs has been updated. The new drug labels now contain more and consistent information about the potential risk for abnormal muscle movements (extrapyramidal signs or EPS) and withdrawal symptoms in newborns whose mothers were treated with these drugs during the third trimester of pregnancy.

The symptoms of EPS and withdrawal in newborns may include agitation, abnormally increased or decreased muscle tone, tremor, sleepiness, severe difficulty breathing, and difficulty in feeding. In some newborns, the symptoms subside within hours or days and do not require specific treatment; other newborns may require longer hospital stays.

BACKGROUND: Antipsychotic drugs are used to treat symptoms of psychiatric disorders such as schizophrenia and bipolar disorder.

RECOMMENDATION: Healthcare professionals should be aware of the effects of antipsychotic medications on newborns when the medications are used during pregnancy. Patients should not stop taking these medications if they become pregnant without talking to their healthcare professional, as abruptly stopping antipsychotic medications can cause significant complications for treatment. For more information visit the FDA website at: and .

REMS:

FDA approved a REMS for fluoxetine to ensure that the benefits of a drug outweigh the risks. However, FDA later rescinded REMS requirements. See the FDA REMS page () or the ASHP REMS Resource Center ().

• Suicidality


• 
  

  Antidepressants may increase risk of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults (18–24 years of age) with major depressive disorder and other psychiatric disorders; balance this risk with clinical need.^{1 a b} Fluoxetine is not approved for use in pediatric patients except for patients with major depressive disorder or obsessive-compulsive disorder.¹ (See Pediatric Use under Cautions.)

  
  


• 
  

  In pooled data analyses, risk of suicidality was not increased in adults >24 years of age and apparently was reduced in adults ≥65 years of age with antidepressant therapy compared with placebo.^{a b}

  
  


• 
  

  Depression and certain other psychiatric disorders are themselves associated with an increased risk of suicide.^{a b c}

  
  


• 
  

  Appropriately monitor and closely observe all patients who are started on fluoxetine therapy for clinical worsening, suicidality, or unusual changes in behavior; involve family members and/or caregivers in this process.^{1 a b c} (See Worsening of Depression and Suicidality Risk under Cautions.)

  
  

Introduction

Antidepressant; a selective serotonin-reuptake inhibitor (SSRI).^{1 2 16 28 50 51}

Uses for Fluoxetine Hydrochloride

Major Depressive Disorder

Management of major depressive disorder.^{1 345 406 407 413}

Efficacy in hospital settings not established.¹

Obsessive-Compulsive Disorder (OCD)

Management of OCD.^{1 408 409 413}

Premenstrual Dysphoric Disorder (PMDD)

Management of PMDD (previously late luteal phase dysphoric disorder).^{361 362 363 364 366}

Eating Disorders

Management of moderate to severe bulimia nervosa (at least 3 bulimic episodes per week for 6 months).^{1 410}

SSRIs usually are preferred drugs in management of bulimia because of more favorable adverse effect profile.³⁶⁵

Also has been used for management of anorexia nervosa†.^{77 78 255 355}

Not recommended as the sole or primary treatment of anorexia nervosa†.³⁵⁵

Panic Disorder

Management of panic disorder with or without agoraphobia.^{1 75 177 418 419 435 437}

Bipolar Disorder

Short-term treatment of acute depressive episodes (alone† or in combination with olanzapine) in patients with bipolar disorder (bipolar depression).^{3 217 448 507 508}

May cause manic reactions when used as monotherapy in some patients;^{1 6 70 85 86 87 88 230} should not be used without mood stabilizing agents (e.g., lithium).³⁸⁴

Obesity

Has been used for the short-term treatment of exogenous obesity†.^{123 162 195 228}

Cataplexy

Has been used for the symptomatic management of cataplexy† in a limited number of patients with cataplexy and associated narcolepsy.¹²⁹

Alcohol Dependence

Has been used in the management of alcohol dependence†.^{217 219}

Studies of SSRIs have generally shown modest effects on alcohol consumption.^{381 382}

Fluoxetine Hydrochloride Dosage and Administration

General

• 
  

  Allow at least 2 weeks to elapse between discontinuance of an MAO inhibitor and initiation of fluoxetine, and at least 5 weeks to elapse between discontinuance of fluoxetine and initiation of an MAO inhibitor or thioridazine therapy.¹

  
  


• 
  

  Monitor for possible worsening of depression, suicidality, or unusual changes in behavior, especially at the beginning of therapy or during periods of dosage adjustments.^{1 a b c} (See Worsening of Depression and Suicidality Risk under Cautions.)

  
  


• 
  

  Sustained therapy may be required; use lowest effective dosage and periodically reassess need for continued therapy.¹

  
  


• 
  

  Avoid abrupt discontinuance of therapy.¹ To avoid withdrawal reactions, taper dosage gradually.¹ (See Worsening of Depression and Suicidality Risk and also see Withdrawal of Therapy under Cautions.)

  
  


• 
  

  Consider cautiously tapering dosage during third trimester of pregnancy prior to delivery.^{1 480 481 482 491} (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

  
  

Administration

Oral Administration

Administer conventional capsules, tablets, and solution orally once (in the morning)^{1 2 70} or twice daily (preferably in the morning and at noon) without regard to meals.^{1 2 4 7 58 217} If sedation occurs, the second dose may be administered at bedtime.²¹⁷

Administer delayed-release preparation once weekly without regard to meals.^{1 2 4 7 58 400 401}

Administer fixed-combination fluoxetine/olanzapine capsules (Symbyax) once daily in the evening.⁴⁴⁸

Dosage

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

Available as fluoxetine hydrochloride; dosage is expressed in terms of fluoxetine.¹

Consider prolonged elimination half-life of fluoxetine and norfluoxetine when titrating dosage or discontinuing therapy.^{1 2} Several weeks may be required before full effect of dosage alterations is realized.^{1 2 3 48 50 52 53 56}

Pediatric Patients

Major Depressive Disorder

Oral

Children and adolescents ≥8 years of age: initially, 10 or 20 mg daily.^{1 390 391 392} If therapy is initiated at 10 mg daily, it can be increased after 1 week to 20 mg daily.¹

Manufacturer states that both the initial and target dose in lower weight children may be 10 mg daily.¹

An increase in dosage to 20 mg daily may be considered after several weeks in lower weight children if insufficient clinical improvement is observed.¹

Obsessive-Compulsive Disorder

Oral

Children and adolescents ≥7 years of age: initially, 10 mg daily.¹

In adolescents and higher weight children, the dosage should be increased to 20 mg daily after 2 weeks; additional dosage increases may be considered after several more weeks if insufficient clinical improvement is observed.¹

In lower weight children, dosage increases may be considered after several weeks if insufficient clinical improvement is observed.¹

Usual dosages: 20–60 mg daily for adolescents and higher weight children or 20–30 mg daily for lower weight children.¹

Adults

Major Depressive Disorder

Oral

As conventional capsules, tablets, or solution: Initially, 20 mg once daily (in the morning). May initiate with lower dosage (e.g., 5 mg daily, 20 mg every 2–3 days).^{2 212} If no improvement is apparent after several weeks of therapy with 20 mg daily, an increase in dosage may be considered.^{1 2 10}

Usual dosage: 10–80 mg daily.¹

Delayed-release capsules: 90 mg once weekly, beginning 7 days after the last 20 mg daily dose as conventional capsules, tablets, or solution.^{1 400 401}

If a satisfactory response is not maintained, consider reestablishing daily dosage regimen with conventional capsules, tablets, or solution.^{1 400}

Optimum duration not established; may require several months of therapy or longer.^{1 215 216 233}

Obsessive-Compulsive Disorder

Oral

Initially, 20 mg once daily.¹ If no improvement is apparent after several weeks, dosage may be increased.¹

Usual dosage: 20–60 mg daily.¹

Premenstrual Dysphoric Disorder

Oral

20 mg once daily given continuously throughout the menstrual cycle or intermittently (i.e., only during the luteal phase, starting 14 days prior to the anticipated onset of menstruation and continuing through the first full day of menses).³⁶⁶

If the intermittent dosing regimen is used, it should be repeated with each new menstrual cycle.^{366 405}

Eating Disorders

Bulimia Nervosa

Oral

60 mg daily (in the morning);¹ dosage may be decreased as necessary to minimize adverse effects.³⁵⁵ Alternatively, dosage may be titrated up to recommended initial dosage over several days.¹

Anorexia Nervosa†

Oral

40 mg daily in weight-restored patients.³⁴⁵

Panic Disorder

Oral

Initially, 10 mg daily.^{1 418} Increase dosage after 1 week to 20 mg daily.^{1 418} 10–60 mg is effective; 20 mg daily most frequently used.^{1 48} Dosages >60 mg daily not systematically evaluated.¹

Bipolar Disorder

Monotherapy†

Oral

20–60 mg daily in conjunction with a mood-stabilizing agent (e.g., lithium).³⁸⁴

Combination Therapy

Oral

Initially, 25 mg of fluoxetine and 6 mg of olanzapine once daily in the evening as a fixed-combination capsule (Symbyax 6/25).⁴⁴⁸

This dosage generally should be used as initial and maintenance therapy in patients with a predisposition to hypotensive reactions, patients with hepatic impairment, or those with factors that may slow metabolism of the drugs(s) (e.g., female gender, geriatric age, nonsmoking status); when indicated, dosage should be escalated with caution.⁴⁴⁸

In other patients, increase dosages according to patient response and tolerance as indicated.⁴⁴⁸ In clinical trials, antidepressive efficacy was demonstrated at olanzapine dosages ranging from 6–12 mg daily and fluoxetine dosages ranging from 25–50 mg daily.^{448 507 508} Dosages exceeding 18 mg of olanzapine and 75 mg of fluoxetine not evaluated in clinical studies.⁴⁴⁸

Although the manufacturer states that long-term efficacy (>8 weeks) not established, patients have received the fixed combination ≤24 weeks in clinical trials.^{448 507 508} If used for >8 weeks, periodically reassess need for continued therapy.⁴⁴⁸

Cataplexy†

Oral

20 mg once or twice daily in conjunction with CNS stimulant therapy (e.g., dextroamphetamine, methylphenidate).³⁸⁰

Alcohol Dependence†

Oral

60 mg daily has been used.²⁸⁹

Higher than average antidepressant SSRI dosage apparently is required for reduced alcohol intake; fluoxetine 40 mg daily is comparable to placebo in efficacy.²⁸⁹

Prescribing Limits

Adults

Oral

Conventional capsules, tablets, or solution: Maximum 80 mg daily.^{1 2 366}

Special Populations

Hepatic Impairment

Reduce dose and/or frequency;^{1 2 4 51} some clinicians recommend a 50% reduction in initial dosage for patients with well-compensated cirrhosis.⁵¹

Carefully individualize dosage in substantial hepatic impairment; adjust based on tolerance and therapeutic response.⁵¹

Renal Impairment

Consider reduction in dosage and/or frequency particularly in severe renal impairment.^{1 2 217} Supplemental doses after hemodialysis not necessary.^{4 50}

Geriatric Patients

Consider reducing dose and/or frequency.¹

Cautions for Fluoxetine Hydrochloride

Contraindications

• 
  

  Concurrent or recent (i.e., within 2 weeks) therapy with an MAO inhibitor.¹ MAO inhibitors and thioridazine are contraindicated within 5 weeks after discontinuance of fluoxetine.^{2 298 365 366} (See Drug Interactions under Warnings and see Interactions.)

  
  


• 
  

  Concurrent pimozide therapy.¹ (See Specific Drugs under Interactions.)

  
  


• 
  

  Known hypersensitivity to fluoxetine or any ingredient in the formulation.¹

  
  

Warnings/Precautions

Warnings

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

Drug Interactions

Concomitant use with MAO inhibitors associated with serious, sometimes fatal reactions, including manifestations resembling serotonin syndrome (e.g., hyperthermia, rigidity, myoclonus, autonomic instability, mental status changes) or neuroleptic malignant syndrome (NMS).¹ (See Serotonin Syndrome under Cautions and also see Interactions.)

Concomitant use with thioridazine expected to be associated with prolonged QT_c interval and serious ventricular arrhythmias (e.g., torsades de pointes-type arrhythmias) and sudden death.¹ (See Specific Drugs under Interactions.)

Serotonin Syndrome

Potentially life-threatening serotonin syndrome reported during concurrent therapy with SSRIs or selective serotonin- and norepinephrine-reuptake inhibitors (SNRIs) and other serotonergic drugs (e.g., 5-HT₁ receptor agonists [“triptans”]) or drugs that impair serotonin metabolism (e.g., MAO inhibitors).^{1 492} Symptoms may include mental status changes (e.g., agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, labile BP, hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination), and/or GI symptoms (e.g., nausea, vomiting, diarrhea).^{1 492} (See Interactions.)

Worsening of Depression and Suicidality Risk

Possible worsening of depression and/or the emergence of suicidal ideation and behavior (suicidality) or unusual changes in behavior in both adult and pediatric patients with major depressive disorder, whether or not they are taking antidepressants; may persist until clinically important remission occurs.^{1 512 a b c} However, suicide is a known risk of depression and certain other psychiatric disorders, and these disorders themselves are the strongest predictors of suicide.^{a b c}

Appropriately monitor and closely observe patients receiving fluoxetine for any reason, particularly during initiation of therapy (i.e., the first few months) and during periods of dosage adjustments.^{1 512 a b c} (See Boxed Warning and also see Pediatric Use under Cautions.)

Anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia, hypomania, and/or mania may be precursors to emerging suicidality.^{b c} Consider changing or discontinuing therapy in patients whose depression is persistently worse or in those with emerging suicidality or symptoms that might be precursors to worsening depression or suicidality, particularly if severe, abrupt in onset, or not part of patient’s presenting symptoms.^{1 a b c} If decision is made to discontinue therapy, taper fluoxetine dosage as rapidly as is feasible but consider risks of abrupt discontinuance.^{1 b} (See General under Dosage and Administration.)

Prescribe in smallest quantity consistent with good patient management to reduce risk of overdosage.^{1 b}

Observe these precautions for patients with psychiatric (e.g., major depressive disorder, OCD) or nonpsychiatric disorders.^{1 b}

Bipolar Disorder

May unmask bipolar disorder.^{1 b} (See Activation of Mania or Hypomania under Cautions.)

Screen for risk of bipolar disorder by obtaining detailed psychiatric history (e.g., family history of suicide, bipolar disorder, depression) prior to initiating therapy.^{1 b}

Fetal/Neonatal Morbidity and Mortality

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

Possible complications, sometimes severe and requiring prolonged hospitalization, respiratory support, enteral nutrition, and other forms of supportive care, reported in neonates exposed to fluoxetine, other SSRIs, or SNRIs late in the third trimester; may arise immediately upon delivery.^{1 461 462 480 489 490 491}

Increased risk of persistent pulmonary hypertension of the newborn (PPHN) in infants exposed to SSRIs during late pregnancy; PPHN is associated with substantial neonatal morbidity and mortality.^{493 495}

Carefully consider potential risks and benefits of treatment when used during third trimester of pregnancy.^{1 480 490 491} Consider cautiously tapering dosage during third trimester prior to delivery.^{1 480 481 482 491} (See Pregnancy under Cautions.)

Sensitivity Reactions

Hypersensitivity Reactions

Possible anaphylactoid reactions (e.g., bronchospasm, angioedema, laryngospasm, and/or urticaria).¹

Rash and/or urticaria, sometimes associated with systemic manifestations (e.g., fever, leukocytosis, arthralgia, edema, carpal tunnel syndrome, respiratory distress, lymphadenopathy, proteinuria, mild elevation in serum aminotransferase concentrations, vasculitis, lupus-like syndrome) reported; systemic manifestations may be serious.^{1 2 234 279}

If rash, urticaria, and/or other manifestations of hypersensitivity for which alternative etiologies cannot be identified occur, discontinue therapy.^{1 2 22 217}

General Precautions

Abnormal Bleeding

Possible increased risk of bleeding, including upper GI bleeding; use with caution.^{1 452 487 488}

Concomitant use of an NSAIA (e.g., aspirin) or warfarin may potentiate such risk.^{1 452 487 488} (See Interactions.)

Nervous System Effects

Possible dose-related^{4 69 211 217} nervousness,^{1 2 15 60 61 63 65 66 67 70 71 72 122 234} anxiety,^{1 2 10 15 61 63 65 67 70 75 122 234} and insomnia.^{1 2 10 15 61 63 66 67 69 70 71 72 75 122 176 234}

Altered Appetite and Weight

Possible anorexia and weight loss.^{1 2 15 60 61 63 65 66 67 69 72 122 161 176} Use with caution in patients who may be adversely affected (e.g., underweight patients).¹

Activation of Mania or Hypomania

Possible hypomania,^{70 86 234} mania,^{70 85 86 87 88 217 230 234 258 267 268} and manic reaction.^{1 6 70 234} May be more likely in patients with bipolar disorder.^{85 192} (See Bipolar Disorder under Cautions.)

Seizures

Possible seizures;^{1 2 6 15 56 89 91} use with caution in patients with a history of seizures.^{1 2 91}

Long Elimination Half-Lives

Long elimination half-lives of fluoxetine and its metabolites affect dosage titration, withdrawal, duration of adverse effects, and drug interactions.^{1 2 3 48 50 52 53 56 217} Adverse effects may resolve slowly following discontinuance of the drug.^{1 2 217}

Withdrawal of Therapy

Possibly severe withdrawal reactions (e.g., dysphoric mood, irritability, agitation, dizziness, sensory disturbances, anxiety, confusion, headache, lethargy, emotional lability, insomnia, hypomania); avoid abrupt discontinuance of therapy.¹ Taper dosage gradually (e.g., over a period of several weeks).¹ Plasma concentrations of fluoxetine and norfluoxetine decline gradually after cessation of therapy, which may minimize risk of withdrawal symptoms.¹ (See Half-life under Pharmacokinetics.)

Concomitant Illnesses

Safety in patients with recent history of MI or those with unstable heart disease not established.^{1 2 3}

Use with caution in patients with concomitant illnesses affecting metabolism or hemodynamic response.¹

May alter blood glucose concentrations; adjust insulin and/or oral antidiabetic dosage as necessary when therapy is initiated or discontinued in patients with diabetes mellitus.¹

Cognitive/Physical Impairment

Risk of impaired mental alertness or physical coordination required for performing hazardous tasks (e.g., driving, operating machinery).¹

Hyponatremia

Possible hyponatremia in older patients,^{1 90 281} patients with depleted fluid volume, and those receiving diuretics.¹

Use of Fixed Combinations

When fluoxetine is used in fixed combination with olanzapine, precautions associated with olanzapine must be considered.⁴⁴⁸

Electroconvulsive Therapy (ECT)

Effects of concomitant use with ECT have not been systematically evaluated.^{1 4} Prolonged seizures have occurred rarely.¹

Specific Populations

Pregnancy

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

Category C.¹ (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

Increased risk of depression relapse observed in women who discontinued antidepressant therapy during pregnancy compared with those who remained on antidepressant therapy.^{493 494}

Lactation

Distributed into milk; use not recommended.¹

Pediatric Use

Safety and efficacy not established in children <8 years of age for major depressive disorder and in children <7 years of age for OCD.¹

FDA warns that a greater risk of suicidal thinking or behavior (suicidality) occurred during first few months of antidepressant treatment (4%) compared with placebo (2%) in children and adolescents with major depressive disorder, OCD, or other psychiatric disorders based on pooled analyses of 24 short-term, placebo-controlled trials of 9 antidepressant drugs (SSRIs and others).^{1 b} However, a more recent meta-analysis of 27 placebo-controlled trials of 9 antidepressants (SSRIs, including fluoxetine, and others) in patients <19 years of age with major depressive disorder, OCD, or non-OCD anxiety disorders suggests that the benefits of antidepressant therapy in treating these conditions may outweigh the risks of suicidal behavior or suicidal ideation.⁵¹² No suicides occurred in these pediatric trials.^{1 512 b}

Carefully consider these findings when assessing potential benefits and risks of fluoxetine in a child or adolescent for any clinical use.^{1 512 a b c} (See Worsening of Depression and Suicidality Risk under Cautions.)

Geriatric Use

No substantial differences in safety and efficacy relative to younger adults.¹

In pooled data analyses, a reduced risk of suicidality was observed in adults ≥65 years of age with antidepressant therapy compared with placebo.^{a b} (See Boxed Warning and also see Worsening of Depression and Suicidality Risk under Cautions.)

Hepatic Impairment

Decreased clearance with cirrhosis; use with caution and at reduced dose and/or frequency.^{1 2 51} (See Hepatic Impairment under Dosage and Administration.)

Common Adverse Effects

Anxiety, nervousness, insomnia, drowsiness, fatigue or asthenia, tremor, dizziness or lightheadedness, anorexia, nausea, diarrhea, vasodilation, dry mouth, abnormal vision, decreased libido, abnormal ejaculation, rash, and sweating.^{1 2 3 5 6 10 61 63 71 72 234}

Interactions for Fluoxetine Hydrochloride

Extensively metabolized;^{1 2 3 51 53} inhibits CYP2D6^{1 366 386 399} and to much less extent CYP3A4.^{1 366}

Drugs Associated with Serotonin Syndrome

Potential pharmacologic interaction (serotonin syndrome) with serotonergic agents.^{1 283 299 300 301 303 492} Avoid such use, or use with caution.^{1 200 299 492} (See Serotonin Syndrome under Cautions.)

Drugs Affecting Hepatic Microsomal Enzymes

Inhibitors of CYP2D6 or CYP3A4: clinically important pharmacokinetic interaction unlikely.¹

Drugs Metabolized by Hepatic Microsomal Enzymes

Substrates of CYP2D6: potential pharmacokinetic interaction.¹ Fluoxetine inhibits CYP2D6 activity, may increase plasma concentrations of drugs metabolized by CYP2D6.¹

Substrates of CYP3A4; pharmacokinetic interaction not likely to be clinically important.¹

Drugs Affecting Hemostasis

Potential pharmacologic interaction (increased risk of bleeding) with concomitant use of drugs that affect coagulation; use with caution.^{1 452 487 488}

Specific Drugs

Drug	Interaction	Comments
Alcohol	Does not potentiate cognitive and motor effects of alcohol;7 99 114 206 207 possible serotonergically-mediated pharmacodynamic interaction in CNS99 115 134 138 157 173 213 214	Concomitant use is not recommended1
Amphetamine	Decreased amphetamine metabolism; potential serotonin syndrome392
Anticoagulants (e.g., warfarin)	Altered anticoagulant effects, including increased bleeding1 366	Carefully monitor patients receiving warfarin when fluoxetine is initiated or discontinued1 366
Antidiabetic agents	May alter blood glucose concentrations in patients with diabetes mellitus1	Adjust insulin and/or antidiabetic dosages as needed when fluoxetine therapy is initiated or discontinued1
β-Adrenergic blocking agents (e.g., metoprolol, propranolol)	Increased plasma concentrations of β-adrenergic blocking agents metabolized by CYP2D6;365 possible cardiac toxicity365	Renally eliminated β-adrenergic blocking agents (e.g., atenolol) may be a safer choice365
Antidepressants, tricyclic (TCAs)	Increased plasma TCA concentrations1 366	Observe patient closely for adverse effects.227 259 Plasma TCA concentrations may need to be monitored and TCA dosages reduced when fluoxetine is administered concurrently or has been recently discontinued1
Benzodiazepines	Increased plasma concentrations of diazepam and alprazolam366	Clinically important interaction possible in geriatric or other susceptible patients217
Buspirone	Possible serotonin syndrome303 324
Carbamazepine	Increased plasma concentrations of carbamazepine and its active metabolite;260 261 262 263 264 carbamazepine toxicity has been reported260 261 263	Monitor patient and plasma carbamazepine concentrations closely when fluoxetine therapy is initiated or discontinued and adjust carbamazepine dosage accordingly262 263 264
Clozapine	Increased plasma clozapine concentrations1 366 396	Use with caution, monitor closely, and consider decreasing clozapine dosage367
Diuretics	Increased risk of hyponatremia
Haloperidol	Increased plasma haloperidol concentrations;1 366 severe extrapyramidal symptoms have occurred118
5-HT1 receptor agonists (“triptans”)	Potentially life-threatening serotonin syndrome1 492	Observe carefully if used concomitantly, particularly during treatment initiation, dosage increases, or when another serotonergic agent is initiated1 366 492
Isoniazid	Potential for serotonin syndrome304 Isoniazid has some MAO-inhibiting activity304
Linezolid	Possible serotonin syndrome1 511	Use with caution1 511
Lithium	Increased or decreased serum lithium concentrations1 107 250 303 324 Lithium toxicity and/or serotonin syndrome has been reported1 107 250 303 324	Use with caution 1 107 324 and monitor serum lithium concentrations closely1
MAO inhibitors	Potentially fatal serotonin syndrome1 300 303 323	Concomitant use is contraindicated1 Allow at least 5 weeks to elapse between discontinuance of fluoxetine therapy and initiation of MAO inhibitor therapy 1 120 295 298 and at least 2 weeks between discontinuance of MAO inhibitor therapy and initiation of fluoxetine1 2 298
NSAIAs (e.g., aspirin)	Increased risk of bleeding1 452 487 488	Use with caution1
Pentazocine	Adverse effects resembling serotonin syndrome303
Phenytoin	Increased p