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.

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. Sertraline is FDA approved for the treatment of OCD in children 6 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. Use with caution in patients with renal insufficiency or other concurrent illness (due to limited experience). Sertraline acts as a mild uricosuric; use with caution in patients at risk of uric acid nephropathy. Use with caution in patients at risk of bleeding or receiving anticoagulant therapy; may cause impairment in platelet aggregation. Use with caution in patients where weight loss is undesirable. May cause or exacerbate sexual dysfunction. Use oral concentrate formulation with caution in patients with latex sensitivity; dropper dispenser contains dry natural rubber. Monitor growth in pediatric patients. Discontinuation symptoms (eg, dysphoric mood, irritability, agitation, confusion, anxiety, insomnia, hypomania) may occur upon abrupt discontinuation. Taper dose when discontinuing therapy.

>10%:

Central nervous system: Insomnia, somnolence, dizziness, headache, fatigue

Gastrointestinal: Xerostomia, diarrhea, nausea

Genitourinary: Ejaculatory disturbances

1% to 10%:

Cardiovascular: Palpitations

Central nervous system: Agitation, anxiety, nervousness

Dermatologic: Rash

Endocrine & metabolic: Libido decreased

Gastrointestinal: Constipation, anorexia, dyspepsia, flatulence, vomiting, weight gain

Genitourinary: Micturition disorders

Neuromuscular & skeletal: Tremors, paresthesia

Ocular: Visual difficulty, abnormal vision

Otic: Tinnitus

Miscellaneous: Diaphoresis (increased)

Postmarketing and/or case reports: Abdominal pain, acute renal failure, agranulocytosis, allergic reaction, anaphylactoid reaction, angioedema, aplastic anemia, atrial arrhythmia, AV block, bilirubin increased, blindness, bradycardia, cataract, dystonia, extrapyramidal symptoms, galactorrhea, gum hyperplasia, gynecomastia, hallucinations, hepatic failure, hepatitis, hepatomegaly, hyperglycemia, hyperprolactinemia, hypothyroidism, jaundice, leukopenia, lupus-like syndrome, neuroleptic malignant syndrome, oculogyric crisis, serotonin syndrome, SIADH, Stevens-Johnson syndrome (and other severe dermatologic reactions), optic neuritis, pancreatitis (rare), photosensitivity, priapism, psychosis, PT/INR increased, pulmonary hypertension, QTc prolongation, serum sickness, thrombocytopenia, transaminases increased, vasculitis, ventricular tachycardia (including torsade de pointes)

Additional adverse reactions reported in pediatric patients (frequency >2%): Aggressiveness, epistaxis, hyperkinesia, purpura, sinusitis, urinary incontinence

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

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

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

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

Cimetidine: Concurrent use resulted in an increase in sertraline's AUC, Cmax, and half-life; monitor.

Clozapine: Sertraline may increase serum levels of clozapine; monitor for increased effect/toxicity

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

CYP2B6 substrates: Sertraline may increase the levels/effects of CYP2B6 substrates. Example substrates include bupropion, promethazine, propofol, and selegiline.

CYP2C19 inducers: May decrease the levels/effects of sertraline. Example inducers include aminoglutethimide, carbamazepine, phenytoin, and rifampin.

CYP2C19 inhibitors: May increase the levels/effects of sertraline. Example inhibitors include delavirdine, fluconazole, fluvoxamine, gemfibrozil, isoniazid, omeprazole, and ticlopidine.

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

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

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

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

CYP3A4 substrates: Sertraline may increase the levels/effects of CYP3A4 substrates. Example substrates include benzodiazepines, calcium channel blockers, cyclosporine, mirtazapine, nateglinide, nefazodone, sildenafil (and other PDE-5 inhibitors), tacrolimus, and venlafaxine. Selected benzodiazepines (midazolam and triazolam), cisapride, ergot alkaloids, selected HMG-CoA reductase inhibitors (lovastatin and simvastatin), and pimozide are generally contraindicated with strong CYP3A4 inhibitors.

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

Dextromethorphan: Some SSRIs inhibit the metabolism of dextromethorphan; visual hallucinations occurred; monitor for serotonin syndrome

Erythromycin: Serotonin syndrome has been reported when added to sertraline; limited documentation

Haloperidol: Serum concentrations may be increased by sertraline (small increase); monitor

HMG-CoA reductase inhibitors: Sertraline may inhibit the metabolism of lovastatin and simvastatin (metabolized by CYP3A4) resulting in myositis and rhabdomyolysis; although its inhibition is weak, these combinations are best avoided

Lamotrigine: Toxicity has been reported following the addition of sertraline; monitor

Lithium: Patients receiving SSRIs and lithium have developed neurotoxicity; if combination is used, monitor for neurotoxicity

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

MAO inhibitors: Sertraline should not be used with nonselective MAO inhibitors (isocarboxazid, phenelzine); fatal reactions have been reported; this combination is contraindicated.

Meperidine: Concurrent use may result in serotonin syndrome; these combinations are best avoided

Nefazodone: May increase the risk of serotonin syndrome

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

Phenothiazines: Sertraline may inhibit metabolism of thioridazine or mesoridazine, potentially leading to malignant ventricular arrhythmias. Avoid concurrent use. Wait at least 5 weeks after discontinuing sertraline prior to starting thioridazine.

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

Pimozide: Sertraline may increase serum levels of pimozide. Concurrent use is contraindicated.

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

Selegiline: SSRIs have been reported to cause mania or hypertension when combined with selegiline; this combination is best avoided. Concurrent use with SSRIs has been reported to cause serotonin syndrome. As an 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; monitor.

SSRIs: 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

Tolbutamide: Sertraline may decrease the metabolism of tolbutamide; monitor for changes in glucose control.

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

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

Tricyclic antidepressants: Sertraline may inhibit 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: Sertraline may inhibit the reuptake of serotonin; combination with tryptophan, a serotonin precursor, may cause agitation and restlessness; this combination is best avoided

Venlafaxine: Sertraline may increase the risk of serotonin syndrome

Warfarin: Sertraline may alter the hypoprothrombinemic response to warfarin; monitor

Zolpidem: Onset of hypnosis may be shortened in patients receiving sertraline; monitor

Ethanol: Avoid ethanol (may increase CNS depression).

Food: Sertraline average peak serum levels may be increased if taken with food.

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

Absorption: Slow

Protein binding: 98%

Metabolism: Hepatic; extensive first-pass metabolism

Bioavailability: 88%

Half-life elimination: Parent drug: 26 hours; Metabolite N-desmethylsertraline: 66 hours (range: 62-104 hours)

Time to peak, plasma: 4.5-8.4 hours

Excretion: Urine and feces

Children and Adolescents: OCD:

6-12 years: Initial: 25 mg once daily

13-17 years: Initial: 50 mg once daily

Note: May increase daily dose, at intervals of not less than 1 week, to a maximum of 200 mg/day. If somnolence is noted, give at bedtime.

Adults:

Depression/OCD: Oral: Initial: 50 mg/day (see "Note" above)

Panic disorder, PTSD, social anxiety disorder: Initial: 25 mg once daily; increase to 50 mg once daily after 1 week (see "Note" above)

PMDD: 50 mg/day either daily throughout menstrual cycle or limited to the luteal phase of menstrual cycle, depending on physician assessment. Patients not responding to 50 mg/day may benefit from dose increases (50 mg increments per menstrual cycle) up to 150 mg/day when dosing throughout menstrual cycle or up to 100 mg day when dosing during luteal phase only. If a 100 mg/day dose has been established with luteal phase dosing, a 50 mg/day titration step for 3 days should be utilized at the beginning of each luteal phase dosing period.

Elderly: Depression/OCD: Start treatment with 25 mg/day in the morning and increase by 25 mg/day increments every 2-3 days if tolerated to 50-100 mg/day; additional increases may be necessary; maximum dose: 200 mg/day

Dosage adjustment/comment in renal impairment: Multiple-dose pharmacokinetics are unaffected by renal impairment.

Hemodialysis: Not removed by hemodialysis

Dosage adjustment/comment in hepatic impairment: Sertraline is extensively metabolized by the liver; caution should be used in patients with hepatic impairment; a lower dose or less frequent dosing should be used.

The efficacy of sertraline in the treatment of OCD was demonstrated in a 12-week, multicenter, placebo-controlled study with 187 outpatients 6-17 years of age. The safety of sertraline use in children and adolescents (6-18 years of age) was evaluated in a 12-week, multicenter, placebo-controlled study with 187 outpatients (6-17 years of age), and in a flexible dose, 52-week open extension study of 137 patients (6-18 years of age), who had completed the initial 12-week, double-blind, placebo-controlled study. Sertraline was administered at doses of either 25 mg/day (children 6-12 years of age) or 50 mg/day (adolescents 13-18 years of age). The dose was then titrated in weekly 25 mg/day or 50 mg/day increments, respectively, to a maximum dose of 200 mg/day based upon clinical response. The mean dose for completers was 157 mg/day. In the acute 12-week pediatric study and in the 52 week study, sertraline had an adverse event profile generally similar to that observed in adults (Zoloft® package insert, Pfizer, November, 2001).

A recent report describes 5 children (8-15 years of age) who developed epistaxis (n=4) or bruising (n=1) while receiving sertraline (Lake, 2000). Another recent report describes the SSRI discontinuation syndrome in 6 children; the syndrome was similar to that reported in adults (Diler, 2002).

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Solution, oral concentrate: 20 mg/mL (60 mL) [contains alcohol 12%]

Tablet: 25 mg, 50 mg, 100 mg

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