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:

(a mee TRIP ti leen)

U.S. Brand Names:

Synonyms:

Generic Available:

Canadian Brand Names:

Use:

Use - Unlabeled/Investigational:

Pregnancy Risk Factor:

Pregnancy Implications:

Lactation:

Contraindications:

Warnings/Precautions:

May cause orthostatic hypotension; the risk of this problem is very 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 with caution in patients with urinary retention, benign prostatic hyperplasia, narrow-angle glaucoma, xerostomia, visual problems, constipation, or a history of bowel obstruction. May alter glucose control - use with caution in patients with diabetes.

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 health care provider. A medication guide should be dispensed with each prescription. Amitriptyline is not FDA approved for use in children <12 years of age.

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

Adverse Reactions:

Frequency not defined.

Cardiovascular: Orthostatic hypotension, tachycardia, nonspecific ECG changes, changes in AV conduction, cardiomyopathy (rare), MI, stroke, heart block, arrhythmia, syncope, hypertension, palpitation

Central nervous system: Restlessness, dizziness, insomnia, sedation, fatigue, anxiety, impaired cognitive function, seizure, extrapyramidal symptoms, coma, hallucinations, confusion, disorientation, impaired coordination, ataxia, headache, nightmares, hyperpyrexia

Dermatologic: Allergic rash, urticaria, photosensitivity, alopecia

Endocrine & metabolic: Syndrome of inappropriate ADH secretion

Gastrointestinal: Weight gain, xerostomia, constipation, paralytic ileus, nausea, vomiting, anorexia, stomatitis, peculiar taste, diarrhea, black tongue

Genitourinary: Urinary retention

Hematologic: Bone marrow depression, purpura, eosinophilia

Ocular: Blurred vision, mydriasis, ocular pressure increased

Otic: Tinnitus

Neuromuscular & skeletal: Numbness, paresthesia, peripheral neuropathy, tremor, weakness

Miscellaneous: Diaphoresis; withdrawal reactions (nausea, headache, malaise)

Postmarketing and/or case reports: Neuroleptic malignant syndrome (rare), serotonin syndrome (rare)

Overdosage/Toxicology:

Drug Interactions:

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: Amitriptyline inhibits 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

Cisapride: May increase the risk of QTc prolongation and/or arrhythmia; concurrent use is contraindicated.

Clonidine: Abrupt discontinuation of clonidine may cause hypertensive crisis, amitriptyline may enhance the response (also see note on antihypertensives)

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

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

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 amitriptyline may be decreased

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): Amitriptyline may increase the anticoagulant effect in patients stabilized on warfarin; monitor INR

Ethanol/Nutrition/Herb Interactions:

Ethanol: Avoid ethanol (may increase CNS depression).

Food: Grapefruit juice may inhibit the metabolism of some TCAs and clinical toxicity may result.

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

Stability:

Mechanism of Action:

Pharmacodynamics/Kinetics:

Onset of action: Migraine prophylaxis: 6 weeks, higher dosage may be required in heavy smokers because of increased metabolism; Depression: 4-6 weeks, reduce dosage to lowest effective level

Distribution: Crosses placenta; enters breast milk

Metabolism: Hepatic to nortriptyline (active), hydroxy and conjugated derivatives; may be impaired in the elderly

Half-life elimination: Adults: 9-27 hours (average: 15 hours)

Time to peak, serum: ~4 hours

Excretion: Urine (18% as unchanged drug); feces (small amounts)

Dosage:

Children:

Chronic pain management (unlabeled use): Oral: Initial: 0.1 mg/kg at bedtime, may advance as tolerated over 2-3 weeks to 0.5-2 mg/kg at bedtime

Depressive disorders (unlabeled use): Oral: Initial doses of 1 mg/kg/day given in 3 divided doses with increases to 1.5 mg/kg/day have been reported in a small number of children (n=9) 9-12 years of age; clinically, doses up to 3 mg/kg/day (5 mg/kg/day if monitored closely) have been proposed

Migraine prophylaxis (unlabeled use): Oral: Initial: 0.25 mg/kg/day, given at bedtime; increase dose by 0.25 mg/kg/day to maximum 1 mg/kg/day. Reported dosing ranges: 0.1-2 mg/kg/day; maximum suggested dose: 10 mg

Adolescents: Depressive disorders: Oral: Initial: 25-50 mg/day; may administer in divided doses; increase gradually to 100 mg/day in divided doses

Adults:

Depression:

Oral: 50-150 mg/day single dose at bedtime or in divided doses; dose may be gradually increased up to 300 mg/day

I.M.: 20-30 mg 4 times/day

Migraine prophylaxis (unlabeled use): Oral: Initial: 10-25 mg at bedtime; usual dose: 150 mg; reported dosing ranges: 10-400 mg/day

Pain management (unlabeled use): Oral: Initial: 25 mg at bedtime; may increase as tolerated to 100 mg/day

Elderly: Depression: Oral: Initial: 10-25 mg at bedtime; dose should be increased in 10-25 mg increments every week if tolerated; dose range: 25-150 mg/day

Dosing interval in hepatic impairment: Use with caution and monitor plasma levels and patient response

Hemodialysis: Nondialyzable

Administration:

Monitoring Parameters:

Reference Range:

Test Interactions:

Patient Education:

Anesthesia and Critical Care Concerns/Other Considerations:

Tricyclic antidepressants affect conduction and have anticholinergic effects and, therefore, should be used with caution in patients with underlying cardiovascular disease. Therapy is relatively contraindicated in patients with conduction abnormalities or in patients with symptomatic hypotension. Heart block may be precipitated in patients with pre-existing conduction system disease. Cardiovascular signs of toxicity may include tachycardia, ventricular arrhythmia, impaired conduction, and shock.

Cardiovascular Considerations:

Dental Health: Effects on Dental Treatment:

Dental Health: Vasoconstrictor/Local Anesthetic Precautions:

Dosage Forms:

Injection, as hydrochloride: 10 mg/mL (10 mL) [DSC]

Tablet, as hydrochloride: 10 mg, 25 mg, 50 mg, 75 mg, 100 mg, 150 mg

International Brand Names: