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Isocarboxazid


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

 (eye soe kar BOKS a zid)


U.S. Brand Names

 Marplan®


Generic Available

 No


Use

 Treatment of depression


Pregnancy Risk Factor

 C


Contraindications

 Hypersensitivity to isocarboxazid or any component of the formulation; uncontrolled hypertension; pheochromocytoma; hepatic or renal disease; cerebrovascular defect; cardiovascular disease (CHF); concurrent use of sympathomimetics (and related compounds), CNS depressants, ethanol, meperidine, bupropion, buspirone, guanethidine, and serotonergic drugs (including SSRIs) - do not use within 5 weeks of fluoxetine discontinuation or 2 weeks of other antidepressant discontinuation; general anesthesia, local vasoconstrictors; spinal anesthesia (hypotension may be exaggerated). Foods which are high in tyramine, tryptophan, or dopamine, chocolate, or caffeine.


Warnings/Precautions

 Use with caution in patients who are hyperactive, hyperexcitable, or who have glaucoma, suicidal tendencies, hyperthyroidism, or diabetes; avoid use of meperidine within 2 weeks of isocarboxazid use. Toxic reactions have occurred with dextromethorphan. Hypertensive crisis may occur with tyramine, tryptophan, or dopamine-containing foods. Should not be used in combination with other antidepressants. Hypotensive effects of antihypertensives (beta-blockers, thiazides) may be exaggerated. May cause orthostatic hypotension (especially at dosages >30 mg/day) - use with caution in patients with hypotension or patients who would not tolerate transient hypotensive episodes - effects may be additive when used with other agents known to cause orthostasis (phenothiazines).

Has been associated with activation of hypomania and/or mania in bipolar patients. May worsen psychotic symptoms in some patients. 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. Use with caution in patients at risk of seizures, or in patients receiving other drugs which may lower seizure threshold.

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

Discontinue at least 48 hours prior to myelography. Use with caution in patients receiving disulfiram. Use with caution in patients with renal impairment.

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

>10%:

Cardiovascular: Orthostatic hypotension

Central nervous system: Drowsiness

Endocrine & metabolic: Decreased sexual ability

Neuromuscular & skeletal: Weakness, trembling

Ocular: Blurred vision

1% to 10%:

Cardiovascular: Tachycardia, peripheral edema

Central nervous system: Nervousness, chills

Gastrointestinal: Diarrhea, anorexia, constipation, xerostomia

<1%: Hepatitis, leukopenia, parkinsonian syndrome


Drug Interactions

Amphetamines: MAO inhibitors in combination with amphetamines may result in severe hypertensive reaction; these combinations are best avoided

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

CNS stimulants: MAO inhibitors in combination with stimulants (methylphenidate) may result in severe hypertensive reaction; these combinations are best avoided

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

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

Guanadrel and guanethidine: MAO inhibitors inhibit the antihypertensive response to guanadrel or guanethidine; 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; avoid this combination

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

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; these combinations are best avoided

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 (hypertensive crisis may result). May contain tyramine.

Food: Avoid tyramine-containing foods and beverages (hypertensive crisis may result).


Mechanism of Action

 Thought to act by increasing endogenous concentrations of epinephrine, norepinephrine, dopamine, and serotonin through inhibition of the enzyme (monoamine oxidase) responsible for the breakdown of these neurotransmitters


Dosage

 Adults: Oral: 10 mg 2-3 times/day; reduce to 10-20 mg/day in divided doses when condition improves


Patient Education

 Avoid tyramine-containing foods and drinks. Avoid alcohol.


Dental Health: Effects on Dental Treatment

 Key adverse event(s) related to dental treatment: Orthostatic hypotension, xerostomia (normal salivary flow resumes upon discontinuation).


Dental Health: Vasoconstrictor/Local Anesthetic Precautions

 Attempts should be made to avoid use of vasoconstrictor due to possibility of hypertensive episodes with monoamine oxidase inhibitors


Dosage Forms

 Tablet: 10 mg


International Brand Names

 Isocarboxazid® (GB); Marplan® (DK)


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