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.

May cause orthostatic hypotension (risk is moderate-high relative to other antidepressants) - use with caution in patients at risk of hypotension or in patients where transient hypotensive episodes would be poorly tolerated (cardiovascular disease or cerebrovascular disease). The degree of anticholinergic blockade produced by this agent is very high relative to other cyclic antidepressants - use caution in patients with urinary retention, benign prostatic hyperplasia, narrow-angle glaucoma, xerostomia, visual problems, constipation, or history of bowel obstruction.

The possibility of a suicide attempt is inherent in major depression and may persist until remission occurs. 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. Clomipramine is FDA approved for the treatment of OCD in children 10 years of age.

Use with caution in patients with a history of cardiovascular disease (including previous MI, stroke, tachycardia, or conduction abnormalities). The risk conduction abnormalities with this agent is high relative to other antidepressants. Use with caution in hyperthyroid patients or those receiving thyroid supplementation. Use with caution in patients with hepatic or renal dysfunction and in elderly patient.

>10%:

Central nervous system: Dizziness, drowsiness, headache, insomnia, nervousness

Endocrine & metabolic: Libido changes

Gastrointestinal: Xerostomia, constipation, increased appetite, nausea, weight gain, dyspepsia, anorexia, abdominal pain

Neuromuscular & skeletal: Fatigue, tremor, myoclonus

Miscellaneous: Diaphoresis increased

1% to 10%:

Cardiovascular: Hypotension, palpitation, tachycardia

Central nervous system: Confusion, hypertonia, sleep disorder, yawning, speech disorder, abnormal dreaming, paresthesia, memory impairment, anxiety, twitching, impaired coordination, agitation, migraine, depersonalization, emotional lability, flushing, fever

Dermatologic: Rash, pruritus, dermatitis

Gastrointestinal: Diarrhea, vomiting

Genitourinary: Difficult urination

Ocular: Blurred vision, eye pain

<1%: Abnormal accommodation, alopecia, breast enlargement, decreased lower esophageal sphincter tone may cause GE reflux, galactorrhea, hyperacusis, increased liver enzymes, marrow depression, photosensitivity, prostatic disorder, seizure, SIADH, trouble with gums

Altretamine: Concurrent use may cause orthostatic hypertension

Amphetamines: TCAs may enhance the effect of amphetamines; monitor for adverse CV effects

Anticholinergics: Combined use with TCAs may produce additive anticholinergic effects

Antihypertensives: TCAs inhibit the antihypertensive response to bethanidine, clonidine, debrisoquin, guanadrel, guanethidine, guanabenz, guanfacine; monitor BP; consider alternate antihypertensive agent

Beta-agonists: When combined with TCAs may predispose patients to cardiac arrhythmias

Bupropion: May increase the levels of tricyclic antidepressants; based on limited information; monitor response

Carbamazepine: Tricyclic antidepressants may increase carbamazepine levels; monitor

Cholestyramine and colestipol: May bind TCAs and reduce their absorption; monitor for altered response

Clonidine: Abrupt discontinuation of clonidine may cause hypertensive crisis, amitriptyline may enhance the response

CNS depressants: Sedative effects may be additive with TCAs; monitor for increased effect; includes benzodiazepines, barbiturates, antipsychotics, ethanol, and other sedative medications

CYP1A2 inducers: May decrease the levels/effects of clomipramine. Example inducers include aminoglutethimide, carbamazepine, phenobarbital, and rifampin.

CYP1A2 inhibitors: May increase the levels/effects of clomipramine. Example inhibitors include amiodarone, ciprofloxacin, fluvoxamine, ketoconazole, norfloxacin, ofloxacin, and rofecoxib.

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

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

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

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

Epinephrine (and other direct alpha-agonists): Pressor response to I.V. epinephrine, norepinephrine, and phenylephrine may be enhanced in patients receiving TCAs (Note: Effect is unlikely with epinephrine or levonordefrin dosages typically administered as infiltration in combination with local anesthetics)

Fenfluramine: May increase tricyclic antidepressant levels/effects

Hypoglycemic agents (including insulin): TCAs may enhance the hypoglycemic effects of tolazamide, chlorpropamide, or insulin; monitor for changes in blood glucose levels; reported with chlorpropamide, tolazamide, and insulin

Levodopa: Tricyclic antidepressants may decrease the absorption (bioavailability) of levodopa; rare hypertensive episodes have also been attributed to this combination

Linezolid: Hyperpyrexia, hypertension, tachycardia, confusion, seizures, and deaths have been reported with agents which inhibit MAO (serotonin syndrome); this combination should be avoided

Lithium: Concurrent use with a TCA may increase the risk for neurotoxicity

MAO inhibitors: Hyperpyrexia, hypertension, tachycardia, confusion, seizures, and deaths have been reported (serotonin syndrome); this combination should be avoided

Methylphenidate: Metabolism of some TCAs may be decreased

Olanzapine: When used in combination, clomipramine and olanzapine have been reported to be associated with the development of seizures; limited documentation (case report)

Phenothiazines: Serum concentrations of some TCAs may be increased; in addition, TCAs may increase concentration of phenothiazines; monitor for altered clinical response

QTc-prolonging agents: Concurrent use of tricyclic agents with other drugs which may prolong QTc interval may increase the risk of potentially fatal arrhythmias; includes type Ia and type III antiarrhythmics agents, selected quinolones (sparfloxacin, gatifloxacin, moxifloxacin, grepafloxacin), cisapride, and other agents

Ritonavir: Combined use of high-dose tricyclic antidepressants with ritonavir may cause serotonin syndrome in HIV-positive patients; monitor

Sucralfate: Absorption of tricyclic antidepressants may be reduced with coadministration

Sympathomimetics, indirect-acting: Tricyclic antidepressants may result in a decreased sensitivity to indirect-acting sympathomimetics; includes dopamine and ephedrine; also see interaction with epinephrine (and direct-acting sympathomimetics)

Tramadol: Tramadol's risk of seizures may be increased with TCAs

Valproic acid: May increase serum concentrations/adverse effects of some tricyclic antidepressants

Warfarin (and other oral anticoagulants): TCAs may increase the anticoagulant effect in patients stabilized on warfarin; monitor INR

Ethanol: Avoid ethanol (may increase CNS depression).

Food: Serum concentrations/toxicity may be increased by grapefruit juice.

Herb/Nutraceutical: Avoid valerian, St John's wort, SAMe, kava kava.

Absorption: Rapid

Metabolism: Hepatic to desmethylclomipramine (active); extensive first-pass effect

Half-life elimination: 20-30 hours

Children:

<10 years: Safety and efficacy have not been established.

10 years: OCD: 25 mg/day; gradually increase, as tolerated, to a maximum of 3 mg/kg/day or 200 mg/day (whichever is smaller)

Adults: OCD: 25 mg/day and gradually increase, as tolerated, to 100 mg/day the first 2 weeks, may then be increased to a total of 250 mg/day maximum

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