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. 3, and magnesium stearate. Chemically, isocarboxazid is 5-methyl-3-isoxazolecarboxylic acid 2-benzylhydrazide. The structural formula is:

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

Last updated on RxList: 9/14/2007

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.

For maximum therapeutic effect, the dosage of Marplan must be individually adjusted on the basis of careful observation of the patient. Dosage should be started with one tablet (10 mg) of Marplan twice daily. If tolerated, dosage may be increased by increments of one tablet (10 mg) every 2 to 4 days to achieve a dosage of four tablets daily (40 mg) by the end of the first week of treatment. Dosage can then be increased by increments of up to 20 mg/week, if needed and tolerated, to a maximum recommended dosage of 60 mg/day. Daily dosage should be divided into two to four dosages. After maximum clinical response is achieved, an attempt should be made to reduce the dosage slowly over a period of several weeks without jeopardizing the therapeutic response. Beneficial effect may not be seen in some patients for 3 to 6 weeks. If no response is obtained by then, continued administration is unlikely to help.

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 (see ADVERSE REACTIONS).

Tablets, 10 mg isocarboxazid each, peach-colored, scored-bottles of 100 (NDC 30698-032-01).

Manufactured by Amneal Pharmaceuticals, Paterson, New Jersey 07504 for Validus Pharmaceuticals, Inc., Parsippany, New Jersey 07054. 1-866-9VALIDUS (1-866-982-5438) info@validuspharma.com. Printed in U.S.A.
Revised: June 2007. FDA rev date: 8/10/2007

Last updated on RxList: 9/14/2007

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

Systematically collected data are available from only 86 patients exposed to Marplan, of whom only 52 received doses of ≥ 50 mg/day, including only 11 who were dosed at ≥ 60 mg/day. 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 (see WARNINGS).

The table that follows enumerates the incidence, rounded to the nearest percent, of treatment emergent adverse events that occurred among 86 depressed patients who received Marplan at doses ranging from 20 to 80 mg/day in placebo-controlled trials of 6 weeks in duration. Events included are those occurring in 1% or more of patients treated with Marplan and for which the incidence in patients treated with Marplan was greater than the incidence in placebo-treated patients.

The prescriber should be aware that these figures cannot be used to predict the incidence of adverse events in the course of usual medical practice where patient characteristics and other factors differ from those which prevailed in clinical trials. Similarly, the cited frequencies cannot be compared with figures obtained from other clinical investigations involving different treatments, uses, and investigators. The cited figures, however, do provide the prescribing physician with some basis for estimating the relative contribution of drug and non-drug factors to the adverse event incidence rate in the population studied.

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 (see Table). In three clinical trials for which the data were pooled, 4 of 85 (5%) patients who received placebo, 10 of 86 (12%) who received < 50 mg of Marplan per day, and 1 of 52 (2%) who received ≥ 50 mg of Marplan per day prematurely discontinued treatment. The most common reasons for discontinuation were dizziness, orthostatic hypotension, syncope, and dry mouth.

Treatment-Emergent Adverse Events Incidence in Placebo-Controlled Clinical Trials with Marplan Doses of 40 to 80 mg/day¹

Other Events Observed During the Postmarketing Evaluation of Marplan

Isolated cases of akathisia, ataxia, black tongue, coma, dysuria, euphoria, hematologic changes, incontinence, neuritis, photosensitivity, sexual disturbances, spider telangiectases, and urinary retention have been reported. These side effects sometimes necessitate discontinuation of therapy. In rare instances, hallucinations have been reported with high dosages, but they have disappeared upon reduction of dosage or discontinuation of therapy. Toxic amblyopia was reported in one psychiatric patient who had received isocarboxazid for about a year; no causal relationship to isocarboxazid was established. Impaired water excretion compatible with the syndrome of inappropriate secretion of antidiuretic hormone (SIADH) has been reported.

DRUG ABUSE AND DEPENDENCE

Controlled Substance Class

Marplan is not a controlled substance.

Physical and Psychological Dependence

Marplan has not been systematically studied in animals or humans for its potential for abuse, tolerance, or physical dependence. There have been reports of drug dependency in patients using doses of Marplan significantly in excess of the therapeutic range. Some of these patients had a history of previous substance abuse. The following withdrawal symptoms have been reported: restlessness, anxiety, depression, confusion, hallucinations, headache, weakness, and diarrhea. Consequently, physicians should carefully evaluate Marplan patients for history of drug abuse and follow such patients closely, observing them for signs of misuse or abuse (eg, development of tolerance, incrementations of dose, drug-seeking behavior).

See CONTRAINDICATIONS, WARNINGS, and PRECAUTIONS sections for information on drug interactions.

Marplan should be administered with caution to patients receiving Antabuse® (disulfiram, Wyeth-Ayerst Laboratories). In a single study, rats given high intraperitoneal doses of an MAO inhibitor plus disulfiram experienced severe toxicity, including convulsions and death.

Concomitant use of Marplan and other psychotropic agents is generally not recommended because of possible potentiating effects. This is especially true in patients who may subject themselves to an overdosage of drugs. If combination therapy is needed, careful consideration should be given to the pharmacology of all agents to be used. The monoamine oxidase inhibitory effects of Marplan may persist for a substantial period after discontinuation of the drug, and this should be borne in mind when another drug is prescribed following Marplan. To avoid potentiation, the physician wishing to terminate treatment with Marplan and begin therapy with another agent should allow for an interval of 10 days.

Last updated on RxList: 9/14/2007

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. Suicide is a known risk of depression and certain other psychiatric disorders, and these disorders themselves are the strongest predictors of suicide. There has been a longstanding concern, however, that antidepressants may have a role in inducing worsening of depression and the emergence of suicidality in certain patients during the early phases of treatment. Pooled analyses of short-term placebo-controlled trials of antidepressant drugs (SSRIs and others) showed that these drugs increase the risk of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults (ages 18-24) with major depressive disorder (MDD) and other psychiatric disorders. 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 with antidepressants compared to placebo in adults aged 65 and older.

The pooled analyses of placebo-controlled trials of nine antidepressant drugs (SSRIs) and others) in children and adolescents with MDD, Obsessive compulsive disorder (OCD), or other psychiatric disorders included a total of 24 short-term trials of 9 antidepressant drugs in over 4400 patients. The pooled analyses of placebo-controlled trials in adults with MDD or other psychiatric disorders included 295 short-term trials (median duration of 2 months) of 11 antidepressant drugs in over 77,000 patients. There was considerable variation in risk among drugs, but a tendency toward an increase in the younger patients `for almost all drugs studied. There were differences in absolute risk of suicidality across the different indications, with the highest incidence in MDD. The risk differences (drug vs. placebo), however, were relatively stable within age strata and across indications. These risk differences (drug-placebo difference in the number of cases of suicidality per 1000 patients treated) are provided in Table 1.

Table 1

No suicides occurred in any of the pediatric trials. There were suicides in the adult trials, but the number was not sufficient to reach any conclusion about drug effect on suicide.

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.

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.

The following symptoms, anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, and mania, have been reported in adult and pediatric patients being treated with antidepressants for major depressive disorder as well as for other indications, both psychiatric and nonpsychiatric. Although a casual link between the emergence of such symptoms and either the worsening of depression and/or the emergence of suicidal impulses has not been established, there is concern that such symptoms may represent precursors to emerging suicidality.

Consideration should be given to changing the therapeutic regimen, including possibly discontinuing the medication, in patients whose depression is persistently worse, or who are experiencing emergent suicidality or symptoms that might be precursors to worsening depression or suicidality, especially if these symptoms are severe, abrupt in onset or were not part of the patient's presenting symptoms.

Families and caregivers of patients being treated with antidepressants for major depressive disorder or other indications both psychiatric and nonpsychiatric, should be alerted about the need to monitor patients for the emergence of agitation, irritability, unusual changes in behavior and the other symptoms described above, as well as the emergence if suicidality, and to report such symptoms immediately to health care providers. Such monitoring should include daily observation by families and caregivers. Prescriptions for MARPLAN should be written for the smallest quantity of tablets consistent with good patient management, in order to reduce the risk of overdose

Screening Patients for Bipolar Disorder

A major depressive episode may be the initial presentation of bipolar disorder. It is generally believed (though not established in controlled trials) that treating such an episode with an antidepressant alone may increase the likelihood of precipitation of a mixed/manic episode in patients at risk for bipolar disorder. Whether any of these symptoms described above represent such a conversion is unknown. However, 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. It should be noted that MARPLAN is not approved for use in treating bipolar depression.

WARNINGS: Second Line Status

Marplan can cause serious side effects. It 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 (see CONTRAINDICATIONS).

These crises are characterized by some or all of the following symptoms: occipital headache which may radiate frontally, palpitation, neck stiffness or soreness, nausea or vomiting, sweating (sometimes with fever and sometimes with cold, clammy skin), and photophobia. Either tachycardia or bradycardia may be present, and associated constricting chest pain and dilated pupils may occur. Intracranial bleeding, sometimes fatal, has been reported in association with the increase in blood pressure.

Blood pressure should be followed closely in patients taking Marplan to detect any pressor response.

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. Although there has been no systematic study of treatment of hypertensive crisis, phentolamine (available as Regitine®, Novartis) has been used and is recommended at a dosage of 5 mg IV. Care should be taken to administer the drug slowly in order to avoid producing an excessive hypotensive effect. Fever should be managed by means of external cooling. Other symptomatic and supportive measures may be desirable in particular cases. Parenteral reserpine should not be used.

Warnings to the Patient

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 should be warned against eating the foods listed under CONTRAINDICATIONS while on Marplan therapy and should also be told not to drink alcoholic beverages. The patient should also 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.

Patients should also be cautioned not to take concomitant medications, whether prescription or over-the-counter drugs such as cold, hay fever, or weight-reducing preparations, without the advice of a physician. They should be advised not to consume excessive amounts of caffeine in any form. Likewise, they should inform their physicians and their dentist about the use of Marplan.

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 (see ADVERSE REACTIONS).

Information for Patients

Prescribers or other health professionals should inform patients, their families, and their caregivers about the benefits and risks associated with treatment with Marplan and should counsel them in its appropriate use. A patient Medication Guide about “Antidepressant Medications, Depression and Other Serious Mental Illness, and Suicidal Thoughts and Actions” is available for Marplan. The prescriber or health professional should instruct patients, their families, and their caregivers to read the Medication Guide and should assist them in understanding its contents. Patients should be given the opportunity to discuss the contents of the Medication Guide and to obtain answers to any questions they may have. The complete text of the Medication Guide is reprinted at the end of this document.

Patients should be advised of the following issues and asked to alert their prescriber if these occur while taking Marplan.

Clinical Worsening and Suicide Risk

Patients, their families, and their caregivers should be encouraged to be alert to the emergence of anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, mania, other unusual changes in behavior, worsening of depression, and suicidal ideation, especially early during antidepressant treatment and when the dose is adjusted up or down. Families and caregivers of patients should be advised to observe for the emergence of such symptoms on a day-to-day basis, since changes may be abrupt. Such symptoms should be reported to the patient's prescriber or health professional, especially if they are severe, abrupt in onset, or were not part of the patient's presenting symptoms. Symptoms such as these may be associated with an increased risk for suicidal thinking and behavior and indicate a need for very close monitoring and possibly changes in the medication.

Pediatric Use

Safety and effectiveness in the pediatric population have not been established (see BOX WARNING and WARNINGS-Clinical Worsening and Suicide Risk). Anyone considering the use of Marplan in a child or adolescent must balance the potential risks with the clinical need.

General

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. Postural hypotension may be relieved by having the patient lie down until blood pressure returns to normal.

When Marplan is combined with phenothiazine derivatives or other compounds known to cause hypotension, the possibility of additive hypotensive effects should be considered.

Lower Seizure Threshold

Because Marplan lowers the convulsive threshold in some animal experiments, suitable precautions should be taken if epileptic patients are treated. Marplan appears to have varying effects in epileptic patients; while some have a decrease in frequency of seizures, other have more seizures.

Drugs that lower the seizure threshold, including MAO inhibitors, should not be used with Amipaque® (metrizamide, Sanofi Winthrop Pharmaceuticals). As with other MAO inhibitors, Marplan should be discontinued at least 48 hours before myelography and should not be resumed for at least 24 hours postprocedure.

Hepatotoxicity

There is a low incidence of altered liver function or jaundice in patients treated with Marplan. In the past, it was difficult to differentiate most cases of drug-induced hepatocellular jaundice from viral hepatitis although this is no longer true. Periodic liver chemistry tests should be performed during Marplan therapy; use of the drug should be discontinued at the first sign of hepatic dysfunction or jaundice.

Suicide

In depressed patients, the possibility of suicide should always be considered and adequate precautions taken. Exclusive reliance on drug therapy to prevent suicidal attempts is unwarranted, as there may be a delay in the onset of therapeutic effect or an increase in anxiety or agitation. Also, some patients fail to respond to drug therapy or may respond only temporarily. The strictest supervision, and preferably hospitalization, are required.

Use in Patients With Concomitant Illness

MAO inhibitors can suppress anginal pain that would otherwise serve as a warning of myocardial ischemia.

In patients with impaired renal function, Marplan should be used cautiously to prevent accumulation.

Some MAO inhibitors have contributed to hypoglycemic episodes in diabetic patients receiving insulin or glycemic agents. Marplan should therefore be used with caution in diabetics using these drugs.

Marplan may aggravate coexisting symptoms in depression, such as anxiety and agitation.

Use Marplan with caution in hyperthyroid patients because of their increased sensitivity to pressor amines.

Marplan should be used cautiously in hyperactive or agitated patients, as well as in schizophrenic patients, because it may cause excessive stimulation. Activation of mania/hypomania has been reported in a small proportion of patients with major affective disorder who were treated with marketed antidepressants.

Carcinogenesis, Mutagenesis, Impairment of Fertility

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

Pregnancy Category C

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.

Nursing Mothers

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.

Pediatric Use

Marplan is not recommended for use in patients under 16 years of age, as safety and effectiveness in pediatric populations have not been demonstrated.

Last updated on RxList: 9/14/2007

The lethal dose of Marplan in humans is not known. There has been one report of a fatality in a patient who ingested 400 mg of Marplan together with an unspecified amount of another drug. Symptoms: Major overdosage may be evidenced by tachycardia, hypotension, coma, convulsions, respiratory depression, sluggish reflexes, pyrexia, and diaphoresis; these signs may persist for 8 to 14 days. Treatment: General supportive measures should be used, along with immediate gastric lavage or emetics. If the latter are given, the danger of aspiration must be borne in mind. An adequate airway should be maintained, with supplemental oxygen if necessary. The mechanism by which amine-oxidase inhibitors produce hypotension is not fully understood, but there is evidence that these agents block the vascular bed response. Thus it is suggested that plasma may be of value in the management of this hypotension. Administration of pressor amines such as Levophed^® (levarterenol bitartrate) may be of limited value (note that their effects may be potentiated by Marplan). Continue treatment for several days until homeostasis is restored. Liver function studies are recommended during the 4 to 6 weeks after recovery, as well as the time of overdosage.

In managing overdosage, consider the possibility of multiple drug involvement. The physician should consider contacting a poison control center on the treatment of any overdose.

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.

Bupropion

The concurrent administration of a MAO inhibitor and buproprion hydrochloride (Wellbutrin®, and Zyban®, Glaxo Wellcome) is contraindicated. At least 14 days should elapse between discontinuation of an MAO inhibitor and initiation of treatment with buproprion hydrochloride.

Selective Serotonin Reuptake Inhibitors (SSRIs)

Marplan should not be administered in combination with any SSRI. 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 (Prozac®, Lilly) 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. Fluoxetine and other SSRIs should therefore not be used in combination with Marplan, or within 14 days of discontinuing therapy with Marplan. As fluoxetine and its major metabolite have very long elimination half-lives, at least 5 weeks should be allowed after stopping fluoxetine before starting Marplan. At least 2 weeks should be allowed after stopping sertraline (Zoloft®, Pfizer) or paroxetine (Paxil®, SmithKline Beecham Pharmaceuticals) before starting Marplan. In addition, there should be an interval of least 10 days between discontinuation of Marplan and initiation or fluoxetine or other SSRIs.

Buspirone

Marplan should not be used in combination with buspirone HCL (Buspar®, Bristol Myers Squibb); several cases of elevated blood pressure have been reported in patients taking MAO inhibitors who were then given buspirone HCL. At least 10 days should elapse between the discontinuation of Marplan and the institution of buspirone HCL. Serious reactions may also occur when MAO inhibitors are given with serotoninergic drugs (e.g., dexfenfluramine, fluoxetine, fluvoxamine, paroxetine, sertraline, citalopram, venlafaxine).

Sympathomimetics

Marplan should not be administered in combination with sympathomimetics, including amphetamines, or with over-the-counter drugs such as cold, hay fever, or weight-reducing preparations that contain vasoconstrictors.

During Marplan therapy, it appears that some patients are particularly vulnerable to the effects of sympathomimetics when the activity of metabolizing enzymes is inhibited. Use of sympathomimetics and compounds such as guanethidine, methyldopa, methylphenidate, reserpine, epinephrine, norepinephrine, phenylalanine, dopamine, levodopa, tyrosine, and tryptophan 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

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. It is thought that these reactions may be mediated by accumulation of 5-HT (serotonin) consequent to MAO inhibition.

Dextromethorphan

Marplan should not be used in combination with dextromethorphan. The combination of MAO inhibitors and dextromethorphan has been reported to cause brief episodes of psychosis or bizarre behavior.

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. Also, 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. Marplan should be discontinued at least 10 days before elective surgery.

CNS Depressants

Marplan should not be used in combination with some central nervous system depressants, such as narcotics, barbiturates, or alcohol.

Antihypertensives

Marplan should not be used in combination with antihypertensive agents, including thiazide diuretics. A marked potentiating effect on these drugs has been reported, resulting in hypotension.

Caffeine

Excessive use of caffeine in any form should be avoided in patients receiving Marplan.

Last updated on RxList: 9/14/2007

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.

Last updated on RxList: 9/14/2007

Medication Guide
Antidepressant Medicines, Depression and other Serious Mental Illnesses,
and Suicidal Thoughts or Actions

Read the Medication Guide that comes with you or your family member's antidepressant medicine. This Medication Guide is only about the risk of suicidal thoughts and actions with antidepressant medicines. Talk to your, or your family member's, healthcare provider about:

• all risks and benefits of treatment with antidepressant medicines
• all treatment choices for depression or other serious mental illness

What is the most important information I should know about antidepressant medicines, depression and other serious mental illnesses, and suicidal thoughts or actions?

1. Antidepressant medicines may increase suicidal thoughts or actions in some children, teenagers, and young adults within the first few months of treatment.
2. Depression and other serious mental illnesses are the most important causes of suicidal thoughts and actions. Some people may have a particularly high risk of having suicidal thoughts or actions. These include people who have (or have a family history of) bipolar illness also called manic-depressive illness) or suicidal thoughts or actions.
3. How can I watch for and try to prevent suicidal thoughts and actions in myself or a family member?
   • Pay close attention to any changes, especially sudden changes, in mood, behaviors, thoughts, or feelings. This is very important when an antidepressant medicine is started or when the dose is changed.
   • Call the healthcare provider right away to report new or sudden changes in mood, behavior, thoughts, or feelings.
   • Keep all follow-up visits with the healthcare provider as scheduled. Call the healthcare provider between visits as needed, especially if you have concerns about symptoms.

Call a healthcare provider right away if you or your family member has any of the following symptoms, especially if they are new, worse, or worry you:

• thoughts about suicide or dying
• attempts to commit suicide
• new or worse depression
• new or worse anxiety
• feeling very agitated or restless
• panic attacks
• trouble sleeping (insomnia)
• new or worse irritability
• acting aggressive, being angry, or violent
• acting on dangerous impulses
• an extreme increase in activity and talking (mania)
• other unusual changes in behavior or mood

What else do I need to know about antidepressant medicines?

• Never stop an antidepressant medicine without first talking to a healthcare provider. Stopping an antidepressant medicine suddenly can cause other symptoms.
• Antidepressants are medicines used to treat depression and other illnesses. It is important to discuss all the risks of treating depression and also the risks of not treating it. Patients and their families or other caregivers should discuss all treatment choices with the healthcare provider, not just the use of antidepressants.
• Antidepressant medicines have other side effects. Talk to the healthcare provider about the side effects of the medicine prescribed for you or your family member.
• Antidepressant medicines can interact with other medicines. Know all of the medicines that you or your family member takes. Keep a list of all medicines to show the healthcare provider. Do not start new medicines without first checking with your healthcare provider.
• Not all antidepressant medicines prescribed for children are FDA approved for use in children. Talk to your child's healthcare provider for more information.

This Medication Guide has been approved by the U.S. Food and Drug Administration for all antidepressants.

Last updated on RxList: 9/14/2007

IMPORTANT NOTE: This is a summary and does not contain all possible information about this product. For complete information about this product or your specific health needs, ask your health care professional. Always seek the advice of your health care professional if you have any questions about this product or your medical condition. This information is not intended as individual medical advice and does not substitute for the knowledge and judgment of your health care professional. This information does not contain any assurances that this product is safe, effective, or appropriate for you.

ISOCARBOXAZID - ORAL

(eye-soe-kar-BOX-a-zid)

COMMON BRAND NAME(S): Marplan

WARNING: Antidepressant medications are used to treat a variety of conditions, including depression and other mental/mood disorders. These medications can help prevent suicidal thoughts/attempts and provide other important benefits. However, studies have shown that a small number of people (especially people younger than 25) who take antidepressants for any condition may experience worsening depression, other mental/mood symptoms, or suicidal thoughts/attempts. Therefore, it is very important to talk with the doctor about the risks and benefits of antidepressant medication (especially for people younger than 25), even if treatment is not for a mental/mood condition.

Tell the doctor immediately if you notice worsening depression/other psychiatric conditions, unusual behavior changes (including possible suicidal thoughts/attempts), or other mental/mood changes (including new/worsening anxiety, panic attacks, trouble sleeping, irritability, hostile/angry feelings, impulsive actions, severe restlessness, very rapid speech). Be especially watchful for these symptoms when a new antidepressant is started or when the dose is changed.

USES: Isocarboxazid is an antidepressant (monoamine oxidase inhibitor). This medication treats depression by restoring the balance of certain natural substances (neurotransmitters) in the brain. Isocarboxazid can improve your mood and feelings of well-being. Usually, this medication is used in persons who have not responded to treatment with other drugs.

HOW TO USE: Read the Medication Guide available from your pharmacist before you start using isocarboxazid and each time you get a refill. If you have any questions, consult your doctor or pharmacist.

Take this medication by mouth, usually 2 to 4 times a day as directed by your doctor. This medication may be taken with or without food. Dosage is based on your medical condition and response to therapy and usually will not be more than 60 milligrams per day.

To reduce your risk of side effects, your doctor may start you at a low dose and then gradually increase your dose. Once your condition improves and you are better for a while, your doctor may work with you to reduce your regular dose. Follow your doctor's instructions carefully. Do not take more or less medication or take it more frequently than prescribed. Your condition will not improve any faster and your risk of side effects will increase.

Use this medication regularly in order to get the most benefit from it. To help you remember, use it at the same time(s) each day. It may take several weeks for the full benefits of this medication to be noticed. Do not stop taking this medication without consulting your doctor.

This medication may cause dependence, especially if it has been used regularly for an extended time (more than a few weeks) or if it has been used in high doses. In such cases, if you suddenly stop this drug, withdrawal reactions may occur. Such reactions can include restlessness, confusion, hallucinations, headache, weakness, and diarrhea. Report any such reactions to your doctor immediately. When stopping extended, regular treatment with this drug, gradually reducing the dosage as directed will help prevent withdrawal reactions. Consult your doctor or pharmacist for more details.

Inform your doctor if your condition persists or worsens.

SIDE EFFECTS: See also Warning section.

Dizziness, drowsiness, tiredness, weakness, problems sleeping, constipation, and dry mouth may occur. If any of these effects persist or worsen, notify your doctor or pharmacist promptly.

Remember that your doctor has prescribed this medication because he or she has judged that the benefit to you is greater than the risk of side effects. Many people using this medication do not have serious side effects.

Tell your doctor immediately if any of these unlikely but serious side effects occur: fainting, mental/mood changes (e.g., agitation, confusion), muscle stiffness/twitching, changes in sexual ability/interest, shaking (tremor), shivering, swollen ankles/legs, unusual weight gain, vision changes (e.g., double/blurred vision).

Tell your doctor immediately if any of these highly unlikely but very serious side effects occur: severe stomach/abdominal pain, persistent nausea/vomiting, seizures, dark urine, yellowing eyes/skin.

This drug may rarely cause an attack of extremely high blood pressure (hypertensive crisis), which may be fatal. Many drug and food interactions can increase this risk (See also Drug Interaction section.) Stop taking isocarboxazid and seek immediate medical attention if any of these serious side effects occur: frequent/severe headache, fast/slow/irregular/pounding heartbeat, chest pain, neck stiffness/soreness, severe nausea/vomiting, sweating/clammy skin (sometimes with fever), widened pupils, sudden sensitivity to light (photophobia).

A serious allergic reaction to this drug is unlikely, but seek immediate medical attention if it occurs. Symptoms of a serious allergic reaction include: rash, itching, swelling, dizziness, trouble breathing.

This is not a complete list of possible side effects. If you notice other effects not listed above, contact your doctor or pharmacist.

Contact your doctor for medical advice about side effects. The following numbers do not provide medical advice, but in the US you may report side effects to the Food and Drug Administration (FDA) at 1-800-FDA-1088. In Canada, you may call Health Canada at 1-866-234-2345.

PRECAUTIONS: Before taking isocarboxazid, tell your doctor or pharmacist if you are allergic to it; or if you have any other allergies.

This medication should not be used if you have certain medical conditions. Before using this medicine, consult your doctor or pharmacist if you have: a certain kind of adrenal gland tumor (pheochromocytoma), cerebrovascular disease (e.g., stroke), heart problems (e.g., congestive heart failure, heart attack), high blood pressure, history of severe/frequent headaches, liver problems.

Before using this medication, tell your doctor or pharmacist your medical history, especially of: personal/family history of mental/mood disorders (e.g., schizophrenia, bipolar disorder), family history of high blood pressure, heart disease (e.g., coronary artery disease, history of chest pain), kidney disease, certain nervous system diseases (Parkinson's syndrome, seizures), overactive thyroid (hyperthyroidism).

This drug may make you dizzy or drowsy; use caution while engaging in activities requiring alertness such as driving or using machinery. Avoid alcoholic beverages.

To minimize dizziness and the risk of fainting, get up slowly when rising from a sitting or lying position.

Before having surgery or any procedures requiring use of contrast dye (e.g., myelography), tell your doctor or dentist you are on this medication. You may need to stop taking this drug beforehand. Follow your doctor's instructions carefully.

If you have heart disease, this medication may mask chest pain. Avoid strenuous exercise while taking this medication.

If you have diabetes, isocarboxazid may lower your blood sugar levels. Check your blood sugar regularly, and share the results with your doctor. Tell your doctor immediately if you have symptoms of low blood sugar such as cold sweat, shaking, rapid heart rate, fainting, and hunger. Your anti-diabetic medication or diet may need to be adjusted.

Caution is advised when using this drug in the elderly because they may be more sensitive to the effects of the drug, especially the effects on blood pressure.

This medication should be used only when clearly needed during pregnancy. Discuss the risks and benefits with your doctor.

It is not known whether this drug passes into breast milk. Breast-feeding while using this medication is not recommended. Consult your doctor before breast-feeding.

DRUG INTERACTIONS: Your healthcare professionals (e.g., doctor or pharmacist) may already be aware of any possible drug interactions and may be monitoring you for them. Do not start, stop or change the dosage of any medicine before checking with them first.

This drug should not be used with the following medications because very serious (possibly fatal) interactions may occur: other antidepressants (e.g., TCAs such as amitriptyline/nortriptyline, nefazodone, SSRIs such as citalopram/fluoxetine/paroxetine, venlafaxine), appetite suppressants (e.g., diethylpropion, sibutramine), drugs for attention deficit disorder (e.g., atomoxetine, methylphenidate), certain antihistamines (azatadine, carbetapentane, chlorpheniramine), bronchodilators (e.g., albuterol, salmeterol), bupropion, buspirone, carbamazepine, cyclobenzaprine, dextromethorphan, certain drugs for glaucoma (e.g., apraclonidine, brimonidine), certain drugs for high blood pressure (e.g., guanethidine, methyldopa), other MAO inhibitors (e.g., furazolidone, linezolid, moclobemide, phenelzine, procarbazine, rasagiline, selegiline, tranylcypromine), certain narcotic medications (e.g., fentanyl, meperidine), certain drugs for Parkinson's (e.g., entacapone, levodopa, tolcapone), street drugs (e.g., MDMA/"ecstasy", LSD, mescaline), stimulants (e.g., amphetamines, cocaine, dopamine, epinephrine, phenylalanine), "triptan" migraine drugs (e.g., sumatriptan, rizatriptan), tramadol, tyrosine, tryptophan.

If you are currently using any of these medications listed above, tell your doctor or pharmacist before starting isocarboxazid. Do not take these medications within the 2 weeks before, during or after treatment with isocarboxazid. If you have been taking fluoxetine, wait at least 5 weeks after stopping fluoxetine before starting isocarboxazid. Discuss with your doctor how much time to wait between starting or stopping any of these drugs and taking isocarboxazid.

Before using this medication, tell your doctor or pharmacist of all prescription and nonprescription/herbal products you may use, especially of: drugs for diabetes (e.g., glyburide, insulin), drugs for high blood pressure (e.g., beta blockers such as atenolol, clonidine, rauwolfia alkaloids such as reserpine, "water pills"/diuretics such as hydrochlorothiazide).

Also report the use of drugs which might increase seizure risk (decrease seizure threshold) when combined with isocarboxazid such as isoniazid (INH), phenothiazines (e.g., thioridazine), theophylline, or tricyclic antidepressants (e.g., imipramine) among others. Consult your doctor or pharmacist for details.

Tell your doctor or pharmacist if you also take drugs that cause drowsiness such as: certain antihistamines (e.g., diphenhydramine), anti-seizure drugs (e.g., phenytoin), medicine for sleep or anxiety (e.g., alprazolam, diazepam, zolpidem), muscle relaxants, narcotic pain relievers (e.g., codeine), psychiatric medicines (e.g., chlorpromazine, lithium, risperidone, trazodone).

Check the labels on all your medicines (e.g., allergy, cough-and-cold products, diet pills) because they may contain dextromethorphan, decongestants, stimulants, or drowsiness-causing ingredients. Ask your pharmacist about the safe use of those products.

It is very important that you follow special dietary restrictions in order to limit the amount of tyramine in your diet. Avoid drinking large amounts of beverages containing caffeine (coffee, tea, colas) or eating large amounts of chocolate. Caffeine can increase the side effects of this medication. Foods and beverages high in tyramine should be avoided while you are taking this medication and for at least 2 weeks after you stop using this medication.

Foods high in tyramine include: aged cheeses (cheddar, camembert, emmenthaler, brie, stilton blue, gruyere, gouda, brick, bleu, roquefort, boursault, parmesan, romano, provolone, liederdranz, colby, edam), aged/dried/fermented/salted/smoked/pickled/processed meats and fish (includes bacon, summer sausage, liverwurst, hot dogs, corned beef, pepperoni, salami, bologna, ham, mortadella, pickled or dried herring), banana peel, beef/chicken liver (stored, not fresh), bouillon cubes, commercial gravies, concentrated yeast extracts, fava beans, Italian green beans, broad beans, fermented bean curd, homemade yeast-leavened bread, kim chee (Korean fermented cabbage), orange pulp, overripe or spoiled fruits, packaged soups, red wine, sauerkraut, sherry, snow pea pods, sourdough bread, soy sauce, soybeans, soybean paste/miso, tofu, tap beer and ale, vermouth.

Moderate-to-low tyramine content foods include: alcohol-free beer, avocados, bananas, bottled beer and ale, chocolate and products made with chocolate, coffee, cola, cultured dairy products (e.g. buttermilk, yogurt, sour cream), distilled spirits, eggplant, canned figs, fish roe (caviar), green bean pods, pate, peanuts, port wine, raisins, raspberries, red plums, spinach, tomatoes, white wine.

Tell your doctor or pharmacist immediately if you notice symptoms of high blood pressure such as fast/slow heartbeat, vomiting, sweating, headache, chest pain, sudden vision changes, weakness on one side of the body, or slurred speech.

Contact your healthcare professionals (e.g., doctor, pharmacist, dietician) for more information, including recommendations for your diet.

This document does not contain all possible interactions. Therefore, before using this product, tell your doctor or pharmacist of all the products you use. Keep a list of all your medications with you, and share the list with your doctor and pharmacist.

OVERDOSE: If overdose is suspected, contact your local poison control center or emergency room immediately. US residents can call the US national poison hotline at 1-800-222-1222. Canadian residents should call their local poison control center directly.

NOTES: Do not share this medication with others.

Laboratory and/or medical tests (e.g., blood pressure, liver function) should be performed periodically to monitor your progress or check for side effects. Consult your doctor for more details.

MISSED DOSE: If you miss a dose, take as soon as you remember unless the next scheduled dose is within 2 hours. In that case, skip the missed dose and resume your usual dosing schedule. Do not double the dose to catch up.

STORAGE: Store at room temperature between 59-86 degrees F (15-30 degrees C) away from light and moisture. Do not store in the bathroom. Keep all medicines away from children and pets.

Do not flush medications down the toilet or pour them into a drain unless instructed to do so. Properly discard this product when it is expired or no longer needed. Consult your pharmacist or local waste disposal company for more details about how to safely discard your product.

MEDICAL ALERT: Your condition can cause complications in a medical emergency. For enrollment information call MedicAlert at 1-800-854-1166 (USA) or 1-800-668-1507 (Canada).

Information last revised July 2008 Copyright(c) 2008 First DataBank, Inc.