Marplan

MARPLAN- isocarboxazid tablet
Validus Pharmaceuticals LLC

brand of isocarboxazid t ablets

Suicidality and Antidepressant Drugs

Antidepressants increased the risk compared to placebo of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults in short-term studies with Major Depressive Disorder (MDD) and other psychiatric disorders. Anyone considering the use of Marplan or any other antidepressant in a child, adolescent or young adult must balance this risk with the clinical need. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction in risk with antidepressants compared to placebo in adults aged 65 and older. Depression and certain other psychiatric disorders are themselves associated with increases in the risk of suicide. Patients of all ages who are started on antidepressant therapy should be monitored appropriately and observed closely for clinical worsening, suicidality, or unusual changes in behavior. Families and caregivers should be advised of the need for close observation and communication with the prescriber. Marplan is not approved for use in pediatric patients (see Warnings: Clinical Worsening and Suicide Risk , Precautions: Information for Patients , and Precautions: Pediatric Use ) .

Pooled analyses of short-term (4 to 16 weeks) placebo-controlled trials of 9 antidepressant drugs (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) have revealed a greater risk of adverse events representing suicidal thinking or behavior (suicidality) during the first few months of treatment in those receiving antidepressants. The average risk of such events in patients receiving antidepressants was 4%, twice the placebo risk of 2%. No suicides occurred in these trials.

DESCRIPTION

Marplan (isocarboxazid), a monoamine oxidase inhibitor, is available for oral administration in 10-mg tablets. Each tablet also contains lactose, corn starch, povidone, D&C Red No. 27, FD&C Yellow No. 6, and magnesium stearate. Chemically, isocarboxazid is 5-methyl-3-isoxazolecarboxylic acid 2-benzylhydrazide. The structural formula is:

The structural formula for Marplan (isocarboxazid), a monoamine oxidase inhibitor, is available for oral administration in 10-mg tablets. Each tablet also contains lactose, corn starch, povidone, D&C Red No. 27, FD&C Yellow No. 6, and magnesium stearate. Chemically, isocarboxazid is 5-methyl-3-isoxazolecarboxylic acid 2-benzylhydrazide.

Isocarboxazid is a colorless, crystalline substance with very little taste.

CLINICAL PHARMACOLOGY

Pharmacodynamics

Isocarboxazid is a non-selective hydrazine monoamine oxidase (MAO) inhibitor. In vivo and in vitro studies demonstrated inhibition of MAO in the brain, heart, and liver. The mechanism by which MAO inhibitors act as antidepressants is not fully understood, but it is thought to involve the elevation of brain levels of biogenic amines. However, MAO is a complex enzyme system, widely distributed throughout the body, and drugs that inhibit MAO in the laboratory are associated with a number of clinical effects. Thus, it is unknown whether MAO inhibition per se, other pharmacologic actions, or an interaction of both is responsible for the antidepressant effects observed.

Pharmacokinetics

Marplan pharmacokinetic information is not available.

Clinical Efficacy Data

The effectiveness of Marplan was demonstrated in two 6-week placebo-controlled studies conducted in adult outpatients with depressive symptoms that corresponded to the DSM-IV category of major depressive disorder. The patients often also had signs and symptoms of anxiety (anxious mood, panic, and/or phobic symptoms). Patients were initiated with a dose of 10 mg bid, with increases every 2 to 4 days, as tolerated, until a therapeutic effect was achieved, up to a maximum dose of 80 mg/day. Doses were administered on a divided schedule ranging from 2 to 4 times a day. The mean dose overall for both studies was approximately 40 mg/day, with very few patients receiving doses greater than 60 mg/day. In both studies at the end of 6 weeks, patients receiving Marplan had significantly greater reduction in signs and symptoms of depression evaluated by the Hamilton Depression Scale, for both the Total Score and the Depressed Mood Score, than patients who received placebo.

Marplan Indications and Usage

Marplan is indicated for the treatment of depression. Because of its potentially serious side effects, Marplan is not an antidepressant of first choice in the treatment of newly diagnosed depressed patients.

The efficacy of Marplan in the treatment of depression was established in 6-week controlled trials of depressed outpatients. These patients had symptoms that corresponded to the DSM-IV category of major depressive disorder; however, they often also had signs and symptoms of anxiety (anxious mood, panic, and/or phobic symptoms) ( see CLINICAL PHARMACOLOGY).

A major depressive episode (DSM-IV) implies a prominent and relatively persistent (nearly every day for at least 2 weeks) depressed or dysphoric mood that usually interferes with daily functioning, and includes at least five of the following nine symptoms: depressed mood, loss of interest in usual activities, significant change in weight and/or appetite, insomnia or hypersomnia, psychomotor agitation or retardation, increased fatigue, feelings of guilt or worthlessness, slowed thinking or impaired concentration, and a suicide attempt or suicidal ideation.

The antidepressant effectiveness of Marplan in hospitalized depressed patients, or in endogenomorphically retarded and delusionally depressed patients, has not been adequately studied.

The effectiveness of Marplan in long-term use, that is, for more than 6 weeks, has not been systematically evaluated in controlled trials. Therefore, the physician who elects to use Marplan for extended periods should periodically evaluate the long-term usefulness of the drug for the individual patient.

CONTRAINDICATIONS

Marplan (isocarboxazid) should not be administered in combination with any of the following: MAO inhibitors or dibenzazepine derivatives; sympathomimetics (including amphetamines); some central nervous system depressants (including narcotics and alcohol); antihypertensive, diuretic, antihistaminic, sedative or anesthetic drugs, buproprion HCL, buspirone HCL, dextromethorphan, cheese or other foods with a high tyramine content; or excessive quantities of caffeine.

Marplan (isocarboxazid) should not be administered to any patient with a confirmed or suspected cerebrovascular defect or to any patient with cardiovascular disease, hypertension, or history of headache.

Contraindicated Patient Populations

Hypersensitivity

Marplan should not be used in patients with known hypersensitivity to isocarboxazid.

Cerebrovascular Disorders

Marplan should not be administered to any patient with a confirmed or suspected cerebrovascular defect or to any patient with cardiovascular disease or hypertension.

Pheochromocytoma

Marplan should not be used in the presence of pheochromocytoma, as such tumors secrete pressor substances whose metabolism may be inhibited by Marplan.

Liver Disease

Marplan should not be used in patients with a history of liver disease, or in those with abnormal liver function tests.

Renal Impairment

Marplan should not be used in patients with severe impairment of renal function.

Contraindicated MAOI-Other Drug Combinations

Other MAOI Inhibitors or With Dibenzazepine-Related Entities

Marplan should not be administered together with, or in close proximity to, other MAO inhibitors or dibenzazepine-related entities. Hypertensive crises, severe convulsive seizures, coma, or circulatory collapse may occur in patients receiving such combinations.

In patients being transferred to Marplan from another MAO inhibitor or from a dibenzazepine-related entity, a medication-free interval of at least 1 week should be allowed, after which Marplan therapy should be started using half the normal starting dosage for at least the first week of therapy. Similarly, at least 1 week should elapse between the discontinuation of Marplan and initiation of another MAO inhibitor or dibenzazepine-related entity, or the readministration of Marplan. The following list includes some other MAO inhibitors, dibenzazepine-related entities, and tricyclic antidepressants.

Generic Name Trademark (Manufacturer)
Other MAO Inhibitors
Furazolidone Furoxone® (Roberts Laboratories)
Pargyline HCL Eutonyl® (Abbott Laboratories)
Pargyline HCL and methyclothiazide Eutron® (Abbott Laboratories)
Phenelzine sulfate Nardil® (Parke-Davis)
Procarbazine Matulane® (Roche Laboratories)
Tranylcypromine sulfate Parnate® (SmithKline Beecham Pharmaceuticals)
Dibenzazepine-Related and Other Tricyclics
Amitriptyline HCL Elavil® (Zeneca)
Endep® (Roche Products)
Perphenazine and amitriptyline HCL Etrafon® (Schering)
Triavil® (Merck Sharp & Dohme)
Clomipramine hydrochloride Anafranil® (Novartis)
Desipramine HCL Norpramin® (Hoechst Marion Roussel)
Pertofrane® (Rhône-Poulenc Rorer Pharmaceuticals)
Imipramine HCL Janimine® (Abbott Laboratories)
Tofranil® (Novartis)
Nortriptyline HCL Aventyl® (Eli Lilly & Co.)
Pamelor® (Novartis)
Protripyline HCL Vivactil® (Merck Sharp & Dohme)
Doxepin HCL Adapin® (Fisons)
Sinequan® (Pfizer)
Carbamazepine Tegretol® (Novartis)
Cyclobenzaprine HCL Flexeril® (Merck Sharp & Dohme)
Amoxapine Asendin® (Lederle)
Maprotiline HCL Ludiomil® (Novartis)
Trimipramine maleate Surmontil® (Wyeth-Ayerst Laboratories)
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