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:

(FEN el zeen)

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Use - Unlabeled/Investigational:

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Warnings/Precautions:

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. Phenelzine is FDA approved for the treatment of depression in children 16 years of age.

The MAO inhibitors are effective and generally well tolerated by older patients. It is the potential interactions with tyramine or tryptophan-containing foods and other drugs, and their effects on blood pressure that have limited their use.

Adverse Reactions:

Cardiovascular: Orthostatic hypotension, edema

Central nervous system: Dizziness, headache, drowsiness, sleep disturbances, fatigue, hyper-reflexia, twitching, ataxia, mania

Dermatologic: Rash, pruritus

Endocrine & metabolic: Decreased sexual ability (anorgasmia, ejaculatory disturbances, impotence), hypernatremia, hypermetabolic syndrome

Gastrointestinal: Xerostomia, constipation, weight gain

Genitourinary: Urinary retention

Hematologic: Leukopenia

Hepatic: Hepatitis

Neuromuscular & skeletal: Weakness, tremor, myoclonus

Ocular: Blurred vision, glaucoma

Miscellaneous: Diaphoresis

Overdosage/Toxicology:

Drug Interactions:

Amphetamines: MAO inhibitors in combination with amphetamines may result in severe hypertensive reaction; concurrent use is contraindicated.

Anorexiants: Concurrent use of anorexiants may result in serotonin syndrome; these combinations are best avoided; includes dexfenfluramine, fenfluramine, or sibutramine

Barbiturates: MAO inhibitors may inhibit the metabolism of barbiturates and prolong their effect

Bupropion: Concurrent use is contraindicated; allow at least 14 days between discontinuing MAO inhibitor and starting bupropion.

Buspirone: May cause hypertension; wait at least 10 days between discontinuing one agent and starting the other.

CNS stimulants: MAO inhibitors in combination with stimulants (methylphenidate) may result in severe hypertensive reaction; concurrent use is contraindicated.

Dextromethorphan: Concurrent use of MAO inhibitors may result in serotonin syndrome; concurrent use is contraindicated.

Disulfiram: MAO inhibitors may produce delirium in patients receiving disulfiram; monitor.

Guanadrel and guanethidine: MAO inhibitors inhibit the antihypertensive response to guanadrel or guanethidine; concurrent use is contraindicated; use an alternative antihypertensive agent.

Hypoglycemic agents: MAO inhibitors may produce hypoglycemia in patients with diabetes; monitor.

Levodopa: MAO inhibitors in combination with levodopa may result in hypertensive reactions; monitor.

Lithium: MAO inhibitors in combination with lithium have resulted in malignant hyperpyrexia; this combination is best avoided.

Meperidine: May cause serotonin syndrome when combined with an MAO inhibitor; concurrent use is contraindicated; avoid use of meperidine within 2 weeks of phenelzine use.

Nefazodone: Concurrent use of MAO inhibitors may result in serotonin syndrome; these combinations are best avoided

Norepinephrine: MAO inhibitors may increase the pressor response of norepinephrine (effect is generally small); monitor

Reserpine: MAO inhibitors in combination with reserpine may result in hypertensive reactions; monitor

Serotonin agonists: Theoretically may increase the risk of serotonin syndrome; includes sumatriptan, naratriptan, rizatriptan, and zolmitriptan

SSRIs: May cause serotonin syndrome when combined with an MAO inhibitor; avoid this combination. Allow 5 weeks between discontinuing fluoxetine and starting an MAO inhibitor; allow at least 10 days after discontinuing MAO inhibitor and starting fluoxetine.

Succinylcholine: MAO inhibitors may prolong the muscle relaxation produced by succinylcholine via decreased plasma pseudocholinesterase

Sympathomimetics (indirect-acting): MAO inhibitors in combination with sympathomimetics such as dopamine, metaraminol, phenylephrine, and decongestants (pseudoephedrine) may result in severe hypertensive reaction; concurrent use is contraindicated.

Tramadol: May increase the risk of seizures and serotonin syndrome in patients receiving an MAO inhibitor

Trazodone: Concurrent use of MAO inhibitors may result in serotonin syndrome; these combinations are best avoided

Tricyclic antidepressants: May cause serotonin syndrome when combined with an MAO inhibitor; avoid this combination

Tyramine: Foods (eg, cheese) and beverages (eg, ethanol) containing tyramine, should be avoided in patients receiving an MAO inhibitor; hypertensive crisis may result

Venlafaxine: Concurrent use of MAO inhibitors may result in serotonin syndrome; these combinations are best avoided

Ethanol/Nutrition/Herb Interactions:

Ethanol: Avoid ethanol (alcoholic beverages containing tyramine may induce a severe hypertensive response).

Food: Clinically-severe elevated blood pressure may occur if phenelzine is taken with tyramine-containing foods. Avoid foods containing tryptophan, dopamine, chocolate, or caffeine.

Stability:

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Pharmacodynamics/Kinetics:

Onset of action: Therapeutic: 2-4 weeks; geriatric patients receiving an average of 55 mg/day developed a mean platelet MAO activity inhibition of about 85%.

Duration: May continue to have a therapeutic effect and interactions 2 weeks after discontinuing therapy

Absorption: Well absorbed

Metabolism: Oxidized via monoamine oxidase (primary pathway) and acetylation (minor pathway)

Half-life elimination: 11 hours

Excretion: Urine (primarily as metabolites and unchanged drug)

Dosage:

Children: Selective mutism (unlabeled use): 30-60 mg/day

Adults: Depression: 15 mg 3 times/day; may increase to 60-90 mg/day during early phase of treatment, then reduce dose for maintenance therapy slowly after maximum benefit is obtained; takes 2-4 weeks for a significant response to occur

Elderly: Depression: Initial: 7.5 mg/day; increase by 7.5-15 mg/day every 3-4 days as tolerated; usual therapeutic dose: 15-60 mg/day in 3-4 divided doses

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Additional Information:

The MAO inhibitors are usually reserved for patients who do not tolerate or respond to other antidepressants. The brain activity of monoamine oxidase increases with age and even more so in patients with Alzheimer's disease. Therefore, the MAO inhibitors may have an increased role in patients with Alzheimer's disease who are depressed. Phenelzine is less stimulating than tranylcypromine.

Anesthesia and Critical Care Concerns/Other Considerations:

Dental Health: Effects on Dental Treatment:

Dental Health: Vasoconstrictor/Local Anesthetic Precautions:

Mental Health: Child/Adolescent Considerations:

Golwyn DH and Sevlie CP, "Phenelzine Treatment of Selective Mutism in Four Prepubertal Children,"J Child Adolesc Psychopharmacol, 1999, 9(2):109-13.

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