× IMPORTANT SAFETY INFORMATION 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® (isocarboxazid) Tablets 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.



CONTRAINDICATIONS

Marplan is contraindicated with: MAO inhibitors or dibenzazepine derivatives; sympathomimetics (including amphetamines); some central nervous system depressants (including narcotics and alcohol); antihypertensive agents, such as thiazide diuretics, antihistaminic, sedative or anesthetic drugs, buproprion HCL, buspirone HCL, dextromethorphan, over-the-counter drugs that contain vasoconstrictors; meperidine; dextromethorphan; cheese or other foods with a high tyramine content; or excessive quantities of caffeine.

Marplan is contraindicated in patients with:

a confirmed or suspected cerebrovascular defect or any patients with cardiovascular disease or confirmed or suspected cerebrovascular defect, hypertension, or history of headache.

known hypersensitivity to isocarboxazid.

pheochromocytoma, as such tumors secrete pressor substances whose metabolism may be inhibited by Marplan.

a history of liver disease, or in those with abnormal liver function tests.

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.

Marplan should not be administered in combination with buproprion hydrochloride and SSRI’s. There have been reports of serious, sometimes fatal, reactions (including hyperthermia, rigidity, myoclonus, autonomic instability with possible rapid fluctuations of vital signs, and mental status changes that include extreme agitation and confusion progressing to delirium and coma) in patients receiving fluoxetine in combination with a monoamine oxidase inhibitor (MAOI), and in patients who have recently discontinued fluoxetine and are then started on a MAOI. Some cases presented with features resembling neuroleptic malignant syndrome. Marplan should not be used with buspirone HCL due to several cases of elevated blood pressure when given together.

Serious reactions may also occur when MAO inhibitors are given with seratoninergic drugs (e.g., dexfenfluramine, fluoxetine, fluvoxamine, paroxetine, sertaline, citalopram and venlafaxine). Marplan should not be administered in combination with sympathomimetics, including amphetimines, or with over-the-counter drugs such as cold, hay fever, or weight-reducing preparations that contain vasoconstrictors. Use of these products with Marplan may precipitate hypertension, headache and related symptoms. The combination of MAO inhibitors and tryptophan has been reported to cause behavioral and neurologic symptoms, including disorientation, confusion, amnesia, delirium, agitation, hypomanic signs, ataxia, myoclonus, hyperreflexia, shivering, ocular oscillations, and Babinski signs. Meperidine should not be used concomitantly with MAO inhibitors or within 2 or 3 weeks following MAO therapy. Serious reactions have been precipitated with concomitant use, including coma, severe hypertension or hypotension, severe respiratory depression, convulsions, malignant hyperpyrexia, excitation, peripheral vascular collapse and death. The combination of MAO inhibitors and dextromethorphan has been reported to cause brief episodes of psychosis or bizarre behavior. For additional information on the use of Marplan with other drug combinations, please refer to Contraindicated MAOI-Other Drug Combinations section of the full prescribing information.

Cheese or Other Foods With a High Tyramine Content

Hypertensive crises have sometimes occurred during Marplan therapy after ingestion of foods with a high tyramine content. In general, patients should avoid protein foods in which aging or protein breakdown is used to increase flavor. In particular, patients should be instructed not to take foods such as cheese (particularly strong or aged varieties), sour cream, Chianti wine, sherry, beer (including non-alcoholic beer), liqueurs, pickled herring, anchovies, caviar, liver, canned figs, raisins, bananas or avocados (particularly if overripe), chocolate, soy sauce, sauerkraut, the pods of broad beans (fava beans), yeast extracts, yogurt, meat extracts, meat prepared with tenderizers, or dry sausage.

Anesthetic Agents

Patients taking Marplan should not undergo elective surgery requiring general anesthesia. They should not be given cocaine or local anesthesia containing sympathomimetic vasoconstrictors. The possible combined hypotensive effects of Marplan and spinal anesthesia should be kept in mind.

Hypertensive Crises

The most important reaction associated with MAOI’s is the occurrence of hypertensive crises, which have sometimes been fatal, resulting from co-administration of MAOI’s and certain drugs and foods. If a hypertensive crisis occurs, Marplan should be discontinued, and therapy to lower blood pressure should be instituted immediately. Patients should be instructed to report promptly the occurrence of headache or other unusual symptoms, i.e., palpitation and/or tachycardia, a sense of constriction in the throat or chest, sweating, dizziness, neck stiffness, nausea, or vomiting. Patients on Marplan therapy should also be told not to drink alcoholic beverages. Patients should be warned about the possibility of hypotension and faintness, as well as drowsiness sufficient to impair performance of potentially hazardous tasks, such as driving a car or operating machinery.

WARNINGS TO PHYSICIANS

Clinical Worsening and Suicide Risk

Patients with major depressive disorder (MDD), both adult and pediatric, may experience worsening of their depression and/or the emergence of suicidal ideation and behavior (suicidality) or unusual changes in behavior, whether or not they are taking antidepressant medications, and this risk may persist until significant remission occurs. Antidepressants increased the risk compared to placebo of suicidal thinking and behavior (suicidality) in children, adolescents and young adults with MDD and other psychiatric disorders in short-term studies. 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.

Marplan is not approved for use in pediatric patients.

Families and caregivers should be advised of the need for close observation and communication with the prescriber. Marplan is not approved for treating bipolar depression.

All patients being treated with antidepressants for any indication should be monitored appropriately and observed closely for clinical worsening, 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.

It is unknown whether the suicidality risk extends to longer–term use, i.e., beyond several months. However, there is substantial evidence from placebo-controlled maintenance trials in adults with depression that the use of antidepressants can delay the recurrence of depression.

Screening Patients for Bipolar Disorder

Prior to initiating treatment with an antidepressant, patients with depressive symptoms should be adequately screened to determine if they are at risk for bipolar disorder; such screening should include a detailed psychiatric history, including a family history of suicide, bipolar disorder, and depression.

WARNINGS: Second Line Status

Marplan is not recommended as initial therapy but should be reserved for patients who have not responded satisfactorily to other antidepressants.

Hypertensive Crises

The most important reaction associated with MAO inhibitors is the occurrence of hypertensive crises, which have sometimes been fatal, resulting from the co-administration of MAOIs and certain drugs and foods.

Therapy should be discontinued immediately if palpitations or frequent headaches occur during Marplan therapy as these symptoms may be prodromal of a hypertensive crisis.

If a hypertensive crisis occurs, Marplan should be discontinued, and therapy to lower blood pressure should be instituted immediately.

Limited Experience With Marplan at Higher Doses

Because of the limited experience with systematically monitored patients receiving Marplan at the higher end of the currently recommended dose range of up to 60 mg/day, caution is indicated in patients for whom a dose of 40 mg/day is exceeded.

Hypotension

Hypotension has been observed during Marplan therapy. Symptoms of postural hypotension are seen most commonly, but not exclusively, in patients with preexistent hypertension; blood pressure usually returns rapidly to pretreatment levels upon discontinuation of the drug. Dosage increases should be made more gradually in patients showing a tendency toward hypotension at the beginning of therapy.

Lower Seizure Threshold

Because Marplan lowers the convulsive threshold in some animal experiments, suitable precautions should be taken if epileptic patients are treated.

Hepatotoxicity

There is a low incidence of altered liver function or jaundice in patients treated with Marplan.

Important Safety Information

Long-term studies to evaluate carcinogenic potential have not been conducted in this drug, and there is no information concerning mutagenesis or impairment of fertility.

The potential reproductive toxicity of isocarboxazid has not been adequately evaluated in animals. It is also not known whether isocarboxazid can cause embryo/fetal harm when administered to a pregnant woman or can affect reproductive capacity. Marplan should be given to a pregnant woman only if clearly needed.

Levels of excretion of isocarboxazid and/or its metabolites in human milk have not been determined, and effects on the nursing infant are unknown. Marplan should be used in women who are nursing only if clearly needed. Physicians should carefully evaluate Marplan patients for history of drug abuse (e.g., development of tolerance, increments of dose, drug-seeking behavior).

Pediatric Use-Safety and effectiveness in the pediatric population have not been established.

OVERDOSAGE

Seek emergency medical attention or call the Poison Help Line at 1-800-222-1222.

ADVERSE REACTIONS

Adverse Findings Observed in Short-Term, Placebo-Controlled Trials

The commonly observed adverse event that occurred in Marplan patients with an incidence of 5% or greater and at least twice the incidence in placebo patients were nausea, dry mouth, and dizziness.

Call your doctor for medical advice about any side effects you may experience. You may report side effects to Validus Pharmaceuticals LLC at 1-866-982-5438.