Special Alerts:

Antidepressant Use in Pediatric Patients - October 15, 2004

In March 2004, the Food and Drug Administration (FDA) issued a Public Health Advisory concerning the use of antidepressant medications in which they called attention to reports of both suicidal ideation and suicide attempts in children taking antidepressant drugs for the treatment of major depressive disorder (MDD). In September 2004, a review of the existing data was completed by two FDA Advisory Committees. The FDA has now instructed the manufacturers of ALL antidepressants to revise the labeling for their products to include a boxed warning and expanded warning statements that alert healthcare providers to an increased risk of suicidality (suicidal thinking and behavior) in children and adolescents being treated with these agents, and to include additional information about the results of pediatric studies. The FDA also informed manufacturers that a Patient Medication Guide (MedGuide), which will be given to patients receiving the drugs advising them of the risk and precautions, is appropriate for these drug products.

The risk of suicidality for these drugs was identified in a combined analysis of short-term (up to 4 months) placebo-controlled trials of nine antidepressant drugs, including the selective serotonin reuptake inhibitors (SSRIs) and others, in children and adolescents with major depressive disorder (MDD), obsessive compulsive disorder (OCD), or other psychiatric disorders. A total of 24 trials involving over 4400 patients were included. The analysis showed a greater risk of suicidality during the first few months of treatment in those receiving antidepressants. The average risk of such events on drug was 4%, compared to a rate of 2% in groups receiving placebo. No suicides occurred in these trials. Based on this data, the FDA has determined that the following points are appropriate for inclusion in the boxed warning:

Antidepressants increase the risk of suicidal thinking and behavior (suicidality) in children and adolescents with MDD and other psychiatric disorders.

Anyone considering the use of an antidepressant in a child or adolescent for any clinical use must balance the risk of increased suicidality with the clinical need.

Patients who are started on therapy should be observed closely for clinical worsening, suicidality, or unusual changes in behavior.

Families and caregivers should be advised to closely observe the patient and to communicate with the prescriber.

A statement regarding whether the particular drug is approved for any pediatric indication(s) and, if so, which one(s).

Among the antidepressants, only fluoxetine is approved for use in treating MDD in pediatric patients. Clomipramine, fluoxetine, fluvoxamine, and sertraline are approved for OCD in pediatric patients. None of the drugs is FDA approved for other psychiatric indications in children.

Pediatric patients being treated with antidepressants for any indication should be closely observed for clinical worsening, as well as agitation, irritability, suicidality, and unusual changes in behavior, especially during the initial few months of a course of drug therapy, or at times of dose changes (either increases or decreases). This monitoring should include daily observation by families and caregivers and frequent contact with the physician. It is also recommended that prescriptions for antidepressants be written for the smallest quantity of tablets consistent with good patient management, in order to reduce the risk of overdose.

In addition to the boxed warning and other information in professional labeling on antidepressants, MedGuides are being prepared for all of the antidepressants to provide information about the risk of suicidality in children and adolescents for patients and their families and caregivers. MedGuides are intended to be distributed by the pharmacist with each prescription or refill of a medication.

The FDA plans to work closely with the manufacturers of all approved antidepressant products to optimize the safe use of these drugs and implement the proposed labeling changes and other safety communications in a timely manner.

Additional information can be found on the FDA website at: http://www.fda.gov/medwatch/SAFETY/2004/safety04.htm#ssri, last accessed October 21, 2004.

Pronunciation:

(floo OKS e teen)

U.S. Brand Names:

Synonyms:

Generic Available:

Canadian Brand Names:

Use:

Use - Unlabeled/Investigational:

Pregnancy Risk Factor:

Pregnancy Implications:

Lactation:

Contraindications:

Note: MAO inhibitor therapy must be stopped for 14 days before fluoxetine is initiated. Treatment with MAO inhibitors, thioridazine, or mesoridazine should not be initiated until 5 weeks after the discontinuation of fluoxetine.

Warnings/Precautions:

May precipitate a shift to mania or hypomania in patients with bipolar disorder. Monotherapy in patients with bipolar disorder should be avoided. May cause insomnia, anxiety, nervousness or anorexia. Use with caution in patients where weight loss is undesirable. May impair cognitive or motor performance; caution operating hazardous machinery or driving. The possibility of a suicide attempt is inherent in major depression and may persist until remission occurs. Monitor for worsening of depression or suicidality, especially during initiation of therapy or with dose increases or decreases. 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.

Antidepressants increase the risk of suicidal thinking and behavior in children and adolescents with MDD and other depressive disorders; consider risk prior to prescribing. Closely monitor for clinical worsening, suicidality, or unusual changes in behavior; the child's family or caregiver should be instructed to closely observe the patient and communicate condition with healthcare provider. A medication guide 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.

Use caution in patients with a previous seizure disorder or condition predisposing to seizures such as brain damage, alcoholism, or concurrent therapy with other drugs which lower the seizure threshold. Use with caution in patients with hepatic or renal dysfunction and in elderly patients. May cause hyponatremia/SIADH. May increase the risks associated with electroconvulsive treatment. Use with caution in patients at risk of bleeding or receiving concurrent anticoagulant therapy - may cause impairment in platelet function. May alter glycemic control in patients with diabetes. Due to the long half-life of fluoxetine and its metabolites, the effects and interactions noted may persist for prolonged periods following discontinuation. May cause or exacerbate sexual dysfunction. Discontinuation symptoms (eg, dysphoric mood, irritability, agitation, confusion, anxiety, insomnia, hypomania) may occur upon abrupt discontinuation. Taper dose when discontinuing therapy.

Adverse Reactions:

>10%:

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

Endocrine & metabolic: Libido decreased (1% to 11%)

Gastrointestinal: Nausea (12% to 29%), diarrhea (8% to 18%), anorexia (4% to 11%), xerostomia (4% to 12%)

Neuromuscular & skeletal: Weakness (7% to 21%), tremor (3% to 13%)

Respiratory: Pharyngitis (3% to 11%), yawn (<1% to 11%)

1% to 10%:

Cardiovascular: Vasodilation (1% to 5%), fever (2%), chest pain, hemorrhage, hypertension, palpitation

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

Dermatologic: Rash (2% to 6%), pruritus (4%)

Endocrine & metabolic: Ejaculation abnormal (<1% to 7%), impotence (<1% to 7%)

Gastrointestinal: Dyspepsia (6% to 10%), constipation (5%), flatulence (3%), vomiting (3%), weight loss (2%), appetite increased, taste perversion, weight gain

Genitourinary: Urinary frequency

Ocular: Vision abnormal (2%)

Otic: Ear pain, tinnitus

Respiratory: Sinusitis (1% to 6%)

Miscellaneous: Flu-like syndrome (3% to 10%), diaphoresis (2% to 8%)

<1%, postmarketing and/or case reports: Acne, albuminuria, allergies, alopecia, amenorrhea, anaphylactoid reactions, anemia, angina, aphthous stomatitis, arrhythmia, arthritis, asthma, bone pain, bruising, bursitis, cataract, CHF, cholelithiasis, cholestatic jaundice, colitis, dehydration, dyskinesia, dysphagia, ecchymosis, edema, eosinophilic pneumonia, epistaxis, erythema nodosum, esophagitis, euphoria, exfoliative dermatitis, extrapyramidal symptoms (rare), gastritis, glossitis, gout, gynecomastia, hallucinations, hepatic failure/necrosis, hemorrhage, hiccup, hostility, hypercholesteremia, hyperprolactinemia, hyperventilation, hypoglycemia, hypokalemia, hypotension, hypothyroidism, immune-related hemolytic anemia, kidney failure, laryngospasm, leg cramps, liver function test abnormalities, lupus-like syndrome, malaise, migraine, misuse/abuse, MI, neuroleptic malignant syndrome (NMS), optic neuritis, pancreatitis, pancytopenia, photosensitivity reaction, postural hypotension, priapism, pulmonary embolism, pulmonary hypertension, QT prolongation, serotonin syndrome, Stevens-Johnson syndrome, suicidal ideation, syncope, tachycardia, tinnitus, thrombocytopenia, thrombocytopenic purpura, vasculitis, ventricular tachycardia (including torsade de pointes)

Overdosage/Toxicology:

Drug Interactions:

Amphetamines: SSRIs may increase the sensitivity to amphetamines, and amphetamines may increase the risk of serotonin syndrome.

Benzodiazepines: Fluoxetine may inhibit the metabolism of alprazolam and diazepam resulting in elevated serum levels; monitor for increased sedation and psychomotor impairment.

Beta-blockers: Fluoxetine may inhibit the metabolism of metoprolol and propranolol resulting in cardiac toxicity; monitor for bradycardia, hypotension, and heart failure if combination is used; not established for all beta-blockers (unlikely with atenolol or nadolol due to renal elimination).

Buspirone: Fluoxetine inhibits the reuptake of serotonin; combined use with a serotonin agonist (buspirone) may cause serotonin syndrome.

Carbamazepine: Fluoxetine may inhibit the metabolism of carbamazepine resulting in increased carbamazepine levels and toxicity; monitor for altered carbamazepine response.

Carvedilol: Serum concentrations may be increased; monitor carefully for increased carvedilol effect (hypotension and bradycardia).

Clozapine: Fluoxetine may increase serum levels of clozapine; levels may increase by 76%; monitor for increased effect/toxicity.

Cyclosporine: Fluoxetine may increase serum levels of cyclosporine (and possibly tacrolimus); monitor.

CYP1A2 substrates: Fluoxetine may increase the levels/effects of CYP1A2 substrates. Example substrates include aminophylline, fluvoxamine, mexiletine, mirtazapine, ropinirole, theophylline, and trifluoperazine.

CYP2C8/9 inducers: May decrease the levels/effects of fluoxetine. Example inducers include carbamazepine, phenobarbital, phenytoin, rifampin, rifapentine, and secobarbital.

CYP2C8/9 inhibitors: May increase the levels/effects of fluoxetine. Example inhibitors include delavirdine, fluconazole, gemfibrozil, ketoconazole, nicardipine, NSAIDs, pioglitazone, and sulfonamides.

CYP2C19 substrates: Fluoxetine may increase the levels/effects of CYP2C19 substrates. Example substrates include citalopram, diazepam, methsuximide, phenytoin, propranolol, and sertraline.

CYP2D6 inhibitors: May increase the levels/effects of fluoxetine. Example inhibitors include chlorpromazine, delavirdine, miconazole, paroxetine, pergolide, quinidine, quinine, ritonavir, and ropinirole.

CYP2D6 substrates: Fluoxetine may increase the levels/effects of CYP2D6 substrates. Example substrates include amphetamines, selected beta-blockers, dextromethorphan, lidocaine, mirtazapine, nefazodone, paroxetine, risperidone, ritonavir, thioridazine, tricyclic antidepressants, and venlafaxine.

CYP2D6 prodrug substrates: Fluoxetine may decrease the levels/effects of CYP2D6 prodrug substrates. Example prodrug substrates include codeine, hydrocodone, oxycodone, and tramadol.

Cyproheptadine: May inhibit the effects of serotonin reuptake inhibitors (fluoxetine); monitor for altered antidepressant response; cyproheptadine acts as a serotonin agonist.

Dextromethorphan: Fluoxetine inhibits the metabolism of dextromethorphan; visual hallucinations occurred in a patient receiving this combination; monitor for serotonin syndrome.

Digoxin: Fluoxetine may increase serum levels of digoxin; monitor.

Haloperidol: Fluoxetine may inhibit the metabolism of haloperidol and cause extrapyramidal symptoms (EPS); monitor patients for EPS if combination is utilized.

HMG-CoA reductase inhibitors: Fluoxetine may inhibit the metabolism of lovastatin and simvastatin resulting in myositis and rhabdomyolysis; these combinations are best avoided.

Lithium: Reports of both increased and decreased lithium levels when used concomitantly with fluoxetine. Patients receiving fluoxetine and lithium have developed neurotoxicity. If combination is used; monitor lithium levels and for neurotoxicity.

Loop diuretics: Fluoxetine may cause hyponatremia; additive hyponatremic effects may be seen with combined use of a loop diuretic (bumetanide, furosemide, torsemide); monitor for hyponatremia.

MAO inhibitors: Combined use of fluoxetine with nonselective MAOIs (ie, isocarboxazid, phenelzine) is contraindicated; fatal reactions have been reported; wait 5 weeks after stopping fluoxetine before starting an MAO inhibitor and 2 weeks after stopping an MAO inhibitor before starting fluoxetine.

Meperidine: Combined use with fluoxetine theoretically may increase the risk of serotonin syndrome.

Mesoridazine: Fluoxetine may inhibit the metabolism of mesoridazine, resulting in increased plasma levels and increasing the risk of QTc interval prolongation. This may lead to serious ventricular arrhythmias, such as torsade de pointes-type arrhythmias and sudden death. Do not use concurrently. Wait at least 5 weeks after discontinuing fluoxetine prior to starting mesoridazine.

Nefazodone: May increase the risk of serotonin syndrome with SSRIs; monitor.

NSAIDs: Concomitant use of fluoxetine and NSAIDs, aspirin, or other drugs affecting coagulation has been associated with an increased risk of bleeding; monitor.

Phenytoin: Fluoxetine inhibits the metabolism of phenytoin and may result in phenytoin toxicity; monitor for phenytoin toxicity (ataxia, confusion, dizziness, nystagmus, involuntary muscle movement).

Propafenone: Serum concentrations and/or toxicity may be increased by fluoxetine; avoid concurrent administration.

Ritonavir: Combined use of fluoxetine with ritonavir may cause serotonin syndrome in HIV-positive patients; monitor.

Selegiline: Fluoxetine has been reported to cause mania or hypertension when combined with selegiline; this combination is best avoided. Concurrent use with SSRIs has also been reported to cause serotonin syndrome. As a MAO type B inhibitor, the risk of serotonin syndrome may be less than with nonselective MAO inhibitors.

Sibutramine: May increase the risk of serotonin syndrome with SSRIs; avoid coadministration.

SSRIs: Fluoxetine inhibits the reuptake of serotonin; combined use with other drugs which inhibit the reuptake may cause serotonin syndrome.

Sumatriptan (and other serotonin agonists): Concurrent use may result in toxicity; weakness, hyper-reflexia, and incoordination have been observed with sumatriptan and SSRIs. In addition, concurrent use may theoretically increase the risk of serotonin syndrome; includes sumatriptan, naratriptan, rizatriptan, and zolmitriptan.

Sympathomimetics: May increase the risk of serotonin syndrome with SSRIs.

Thioridazine: Fluoxetine may inhibit the metabolism of thioridazine, resulting in increased plasma levels and increasing the risk of QTc interval prolongation. This may lead to serious ventricular arrhythmias, such as torsade de pointes-type arrhythmias and sudden death. Do not use together. Wait at least 5 weeks after discontinuing fluoxetine prior to starting thioridazine.

Tramadol: Fluoxetine combined with tramadol (serotonergic effects) may cause serotonin syndrome; monitor.

Trazodone: Fluoxetine may inhibit the metabolism of trazodone resulting in increased toxicity; monitor.

Tricyclic antidepressants: Fluoxetine inhibits the metabolism of tricyclic antidepressants (amitriptyline, desipramine, imipramine, nortriptyline) resulting is elevated serum levels; if combination is warranted, a low dose of TCA (10-25 mg/day) should be utilized.

Tryptophan: Fluoxetine inhibits the reuptake of serotonin; combination with tryptophan, a serotonin precursor, may cause agitation and restlessness; this combination is best avoided.

Valproic acid: Fluoxetine may increase serum levels of valproic acid; monitor.

Venlafaxine: Fluoxetine may increase the risk of serotonin syndrome.

Warfarin: Fluoxetine may alter the hypoprothrombinemic response to warfarin; monitor.

Ethanol/Nutrition/Herb Interactions:

Ethanol: Avoid ethanol (may increase CNS depression). Depressed patients should avoid/limit intake.

Herb/Nutraceutical: Avoid valerian, St John's wort, kava kava, gotu kola (may increase CNS depression).

Stability:

Mechanism of Action:

Pharmacodynamics/Kinetics:

Absorption: Well absorbed; delayed 1-2 hours with weekly formulation

Protein binding: 95%

Metabolism: Hepatic to norfluoxetine (active; equal to fluoxetine)

Half-life elimination: Adults:

Parent drug: 1-3 days (acute), 4-6 days (chronic), 7.6 days (cirrhosis)

Metabolite (norfluoxetine): 9.3 days (range: 4-16 days), 12 days (cirrhosis)

Due to long half-life, resolution of adverse reactions after discontinuation may be slow

Time to peak: 6-8 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 91-302 ng/mL; norfluoxetine 72-258 ng/mL).

Dosage:

Children:

Depression: 8-18 years: 10-20 mg/day; lower-weight children can be started at 10 mg/day, may increase to 20 mg/day after 1 week if needed

OCD: 7-18 years: Initial: 10 mg/day; in adolescents and higher-weight children, dose may be increased to 20 mg/day after 2 weeks. Range: 10-60 mg/day

Selective mutism (unlabeled use):

<5 years: No dosing information available

5-18 years: Initial: 5-10 mg/day; titrate upwards as needed (usual maximum dose: 60 mg/day)

Adults: 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 5-10 mg/day have been used for initial treatment.

Usual dosage range:

Bulimia nervosa: 60-80 mg/day

Depression: 20-40 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

OCD: 40-80 mg/day

Panic disorder: 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

PMDD (Sarafem™): 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)

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

Dosing adjustment in 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

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

Dosing adjustment in hepatic impairment: Elimination half-life of fluoxetine is prolonged in patients with hepatic impairment; a lower or less frequent dose of fluoxetine should be used in these patients

Cirrhosis patients: Administer a lower dose or less frequent dosing interval

Compensated cirrhosis without ascites: Administer 50% of normal dose

Monitoring Parameters:

Reference Range:

Therapeutic: Fluoxetine: 100-800 ng/mL (SI: 289-2314 nmol/L); Norfluoxetine: 100-600 ng/mL (SI: 289-1735 nmol/L)

Toxic: Fluoxetine plus norfluoxetine: >2000 ng/mL

Dietary Considerations:

Patient Education:

Nursing Implications:

Additional Information:

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.

Anesthesia and Critical Care Concerns/Other Considerations:

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.

Cardiovascular Considerations:

Dental Health: Effects on Dental Treatment:

Dental Health: Vasoconstrictor/Local Anesthetic Precautions:

Mental Health: Child/Adolescent Considerations:

Black B and Uhde TW, "Treatment of Elective Mutism With Fluoxetine: A Double Blind, Placebo-Controlled Study,"J Am Acad Child Adolesc Psychiatry, 1994, 33(7):1000-6.

Dummit ES 3rd, Klein RG, Tancer NK, et al, "Fluoxetine Treatment of Children With Selective Mutism: An Open Trial,"J Am Acad Child Adolesc Psychiatry, 1996, 35(5):615-21.

Emslie GJ, Rush AJ, Weinberg WA, et al, "A Double-Blind, Randomized, Placebo-Controlled Trial of Fluoxetine in Children and Adolescents With Depression,"Arch Gen Psychiatry, 1997, 54(11):1031-7.

Kurlan R, Como PG, Deeley C, et al, "A Pilot Controlled Study of Fluoxetine for Obsessive-Compulsive Symptoms in Children With Tourette's Syndrome,"Clin Neuropharmacol, 1993, 16(2):167-72.

Riddle MA, Scahill L, King RA, et al, "Double-Blind, Crossover Trial of Fluoxetine and Placebo in Children and Adolescents With Obsessive-Compulsive Disorder,"J Am Acad Child Adolesc Psychiatry, 1992, 31(6):1062-9.

Dosage Forms:

Capsule, as hydrochloride: 10 mg, 20 mg, 40 mg

Prozac®: 10 mg, 20 mg, 40 mg

Sarafem™: 10 mg, 20 mg

Capsule, delayed release, as hydrochloride (Prozac® Weekly™): 90 mg

Solution, oral, as hydrochloride (Prozac®): 20 mg/5 mL (120 mL) [contains alcohol 0.23% and benzoic acid; mint flavor]

Tablet, as hydrochloride: 10 mg, 20 mg

Prozac® [scored]: 10 mg

Extemporaneously Prepared:

International Brand Names: