Description for Marplan

Marplan (isocarboxazid), amonoamine 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:

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

Uses for Marplan

Marplan is indicated for the treatment of depression.Because of its potentially serious side effects, Marplan is not anantidepressant of first choice in the treatment of newly diagnosed depressedpatients.

The efficacy of Marplan in the treatment of depressionwas established in 6-week controlled trials of depressed outpatients. Thesepatients had symptoms that corresponded to theDSM-IV category of majordepressive disorder; however, they often also had signs and symptoms of anxiety(anxious mood, panic, and/or phobic symptoms) (SeeCLINICAL PHARMACOLOGY).

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

The antidepressant effectiveness of Marplan inhospitalized depressed patients, or in endogenomorphically retarded anddelusionally 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 controlledtrials. Therefore, the physician who elects to use Marplan for extended periodsshould periodically evaluate the long-term usefulness of the drug for theindividual patient.

Dosage for Marplan

For maximum therapeutic effect, the dosage of Marplanmust be individually adjusted on the basis of careful observation of thepatient. 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) every2 to 4 days to achieve a dosage of four tablets daily (40 mg) by the end of thefirst week of treatment. Dosage can then be increased by increments of up to 20mg/week, if needed and tolerated, to a maximum  ecommended dosage of 60 mg/day.Daily dosage should be divided into two to four dosages. After maximum clinicalresponse is achieved, an attempt should be made to reduce the dosage slowlyover 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 noresponse is obtained by then, continued administration is unlikely to help.

Because of the limited experience with systematicallymonitored patients receiving Marplan at the higher end of the currentlyrecommended dose range of up to 60 mg/day, caution is indicated in patients forwhom a dose of 40 mg/day is exceeded (seeADVERSE REACTIONS).

HOW SUPPLIED

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

Distributed by: Validus Pharmaceuticals LLC, Parsippany,New Jersey 07054. Revised: Jun 2016

Side Effects for Marplan

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

Systematically collected data are available from only 86patients exposed to Marplan, of whom only 52 received doses of ≥50mg/day, including only 11 who were dosed at ≥60 mg/day. Because of thelimited experience with systematically monitored patients receiving Marplan atthe 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 (seeWARNINGS).

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

The prescriber should be aware that these figures cannotbe used to predict the incidence of adverse events in the course of usualmedical practice where patient characteristics and other factors differ fromthose which prevailed in clinical trials. Similarly, the cited frequenciescannot be compared with figures obtained from other clinical investigationsinvolving different treatments, uses, and investigators. The cited figures,however, do provide the prescribing physician with some basis for estimatingthe relative contribution of drug and non-drug factors to the adverse eventincidence rate in the population studied.

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

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

Treatment-Emergent Adverse Events Incidence inPlacebo-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 urinaryretention have been reported. These side effects sometimes necessitatediscontinuation of therapy. In rare instances, hallucinations have beenreported with high dosages, but they have disappeared upon reduction of dosageor discontinuation of therapy. Toxic amblyopia was reported in one psychiatricpatient who had received isocarboxazid for about a year; no causal relationshipto isocarboxazid was established. Impaired water excretion compatible with thesyndrome of inappropriate secretion of antidiuretic hormone (SIADH) has beenreported.

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 orhumans for its potential for abuse, tolerance, or physical dependence. Therehave been reports of drug dependency in patients using doses of Marplansignificantly in excess of the therapeutic range. Some of these patients had ahistory of previous substance abuse. The following withdrawal symptoms havebeen reported: restlessness, anxiety, depression, confusion, hallucinations,headache, weakness, and diarrhea. Consequently, physicians should carefullyevaluate Marplan patients for history of drug abuse and follow such patientsclosely, observing them for signs of misuse or abuse (eg, development of tolerance,incrementations of dose, drug-seeking behavior).

Drug Interactions for Marplan

SeeCONTRAINDICATIONS,WARNINGS, andPRECAUTIONSsections for information on drug interactions.

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

Concomitant use of Marplan and other psychotropic agentsis generally not recommended because of possible potentiating effects. This isespecially true in patients who may subject themselves to an overdosage ofdrugs. If combination therapy is needed, careful consideration should be givento the pharmacology of all agents to be used. The monoamine oxidase inhibitoryeffects of Marplan may persist for a substantial period after discontinuationof the drug, and this should be borne in mind when another drug is prescribedfollowing Marplan. To avoid potentiation, the physician wishing to terminatetreatment with Marplan and begin therapy with another agent should allow for aninterval of 10 days.

Warnings for Marplan

Second Line Status

Marplan can cause serious side effects. It is notrecommended as initial therapy but should be reserved for patients who have notresponded satisfactorily to other antidepressants.

Hypertensive Crises

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

These crises are characterized by some or all of thefollowing 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 constrictingchest pain and dilated pupils may occur. Intracranial bleeding, sometimesfatal, has been reported in association with the increase in blood pressure.

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

Therapy should be discontinued immediately ifpalpitations or frequent headaches occur during Marplan therapy as thesesymptoms may be prodromal of a hypertensive crisis.

If a hypertensive crisis occurs, Marplan should bediscontinued, and therapy to lower blood pressure should be institutedimmediately. Although there has been no systematic study of treatment ofhypertensive crisis, phentolamine (available as Regitine®, Novartis) has beenused and is recommended at a dosage of 5 mg IV. Care should be taken toadminister the drug slowly in order to avoid producing an excessive hypotensiveeffect. Fever should be managed by means of external cooling. Other symptomaticand supportive measures may be desirable in particular cases. Parenteral reserpineshould not be used.

Warnings To The Patient

Patients should be instructed to report promptly theoccurrence of headache or other unusual symptoms, i.e., palpitation and/ortachycardia, a sense of constriction in the throat or chest, sweating, dizziness,neck stiffness, nausea, or vomiting. Patients should be warned against eatingthe foods listed under CONTRAINDICATIONS while on Marplan therapy and shouldalso be told not to drink alcoholic beverages. The patient should also bewarned about the possibility of hypotension and faintness, as well asdrowsiness sufficient to impair performance of potentially hazardous tasks,such as driving a car or operating machinery.

Patients should also be cautioned not to take concomitantmedications, whether prescription or over-thecounter drugs such as cold, hayfever, or weight-reducing preparations, without the advice of a physician. Theyshould be advised not to consume excessive amounts of caffeine in any form.Likewise, they should inform their physicians and their dentist about the useof Marplan.

Limited Experience With Marplan At Higher Doses

Because of the limited experience with systematicallymonitored patients receiving Marplan at the higher end of the currentlyrecommended dose range of up to 60 mg/day, caution is indicated in patients forwhom a dose of 40 mg/day is exceeded (seeADVERSE REACTIONS).

Precautions for Marplan

Information For Patients

Prescribers or other health professionals should informpatients, their families, and their caregivers about the benefits and risksassociated with treatment with Marplan and should counsel them in itsappropriate 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 instructpatients, their families, and their caregivers to read the Medication Guide andshould assist them in understanding its contents. Patients should be given theopportunity to discuss the contents of the Medication Guide and to obtainanswers to any questions they may have. The complete text of the MedicationGuide is reprinted at the end of this document.

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

Clinical Worsening And Suicide Risk

Patients, their families, and their caregivers should beencouraged to be alert to the emergence of anxiety, agitation, panic attacks,insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia(psychomotor restlessness), hypomania, mania, other unusual changes inbehavior, worsening of depression, and suicidal ideation, especially earlyduring antidepressant treatment and when the dose is adjusted up or down.Families and caregivers of patients should be advised to observe for theemergence 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 healthprofessional, especially if they are severe, abrupt in onset, or were not partof the patient's presenting symptoms. Symptoms such as these may be associatedwith an increased risk for suicidal thinking and behavior and indicate a needfor very close monitoring and possibly changes in the medication.

Pediatric Use

Safety and effectiveness in the pediatric population havenot been established (seeBOX WARNING andWARNINGS -ClinicalWorsening and Suicide Risk).

Anyone considering the use of Marplan in a child oradolescent 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 rapidlyto pretreatment levels upon discontinuation of the drug. Dosage increasesshould be made more gradually in patients showing a tendency toward hypotensionat the beginning of therapy. Postural hypotension may be relieved by having thepatient lie down until blood pressure returns to normal. When Marplan iscombined with phenothiazine derivatives or other compounds known to causehypotension, the possibility of additive hypotensive effects should beconsidered.

Lower Seizure Threshold

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

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

Hepatotoxicity

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

Suicide

In depressed patients, the possibility of suicide shouldalways be considered and adequate precautions taken. Exclusive reliance on drugtherapy to prevent suicidal attempts is unwarranted, as there may be a delay inthe 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 wouldotherwise serve as a warning of myocardial ischemia.

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

Some MAO inhibitors have contributed to hypoglycemicepisodes in diabetic patients receiving insulin or glycemic agents. Marplanshould 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 becauseof their increased sensitivity to pressor amines.

Marplan should be used cautiously in hyperactive oragitated patients, as well as in schizophrenic patients, because it may causeexcessive stimulation. Activation of mania/hypomania has been reported in asmall proportion of patients with major affective disorder who were treatedwith marketed antidepressants.

Carcinogenesis, Mutagenesis, Impairment Of Fertility

Long-term studies to evaluate carcinogenic potential havenot been conducted with this drug, and there is no information concerningmutagenesis or impairment of fertility.

Pregnancy Category C

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

Nursing Mothers

Levels of excretion of isocarboxazid and/or itsmetabolites in human milk have not been determined, and effects on the nursinginfant are unknown. Marplan should be used in women who are nursing only ifclearly needed.

Pediatric Use

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

Overdose Information for Marplan

The lethal dose of Marplan in humans is not known. Therehas been one report of a fatality in a patient who ingested 400 mg of Marplantogether with an unspecified amount of another drug. Symptoms: Major overdosagemay be evidenced by tachycardia, hypotension, coma, convulsions, respiratory depression,sluggish reflexes, pyrexia, and diaphoresis; these signs may persist for 8 to14 days. Treatment: General supportive measures should be used, along withimmediate gastric lavage or emetics. If the latter are given, the danger ofaspiration must be borne in mind. An adequate airway should be maintained, withsupplemental oxygen if necessary. The mechanism by which amine-oxidase inhibitorsproduce hypotension is not fully understood, but there is evidence that theseagents block the vascular bed response. Thus it is suggested that plasma may beof value in the management of this hypotension. Administration of pressoramines such as Levophed® (levarterenol bitartrate) may be of limited value(note that their effects may be potentiated by Marplan). Continue treatment forseveral days until homeostasis is restored. Liver function studies arerecommended during the 4 to 6 weeks after recovery, as well as the time ofoverdosage.

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

Contraindications for Marplan

Marplan (isocarboxazid) should not be administered incombination with any of the following: MAO inhibitors or dibenzazepinederivatives; sympathomimetics (including amphetamines); some central nervoussystem depressants (including narcotics and alcohol); antihypertensive,diuretic, antihistaminic, sedative or anesthetic drugs, buproprion HCL,buspirone HCL, dextromethorphan, cheese or other foods with a high tyraminecontent; or excessive quantities of caffeine.

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

Contraindicated Patient Populations

Hypersensitivity

Marplan should not be used in patients with knownhypersensitivity to isocarboxazid.

Cerebrovascular Disorders

Marplan should not be administered to any patient with aconfirmed or suspected cerebrovascular defect or to any patient withcardiovascular disease or hypertension.

Pheochromocytoma

Marplan should not be used in the presence ofpheochromocytoma, as such tumors secrete pressor substances whose metabolismmay be inhibited by Marplan.

Liver Disease

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

Renal Impairment

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

Contraindicated MAOI-Other Drug Combinations

Other MAOI Inhibitors Or With Dibenzazepine-Related Entities

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

In patients being transferred to Marplan from another MAOinhibitor or from a dibenzazepine-related entity, a medication-free interval ofat least 1 week should be allowed, after which Marplan therapy should bestarted using half the normal starting dosage for at least the first week oftherapy. Similarly, at least 1 week should elapse between the discontinuationof Marplan and initiation of another MAO inhibitor or dibenzazepine-relatedentity, or the readministration of Marplan. The following list includes someother MAO inhibitors, dibenzazepine-related entities, and tricyclicantidepressants.

Bupropion

The concurrent administration of aMAO inhibitor andbuproprion hydrochloride (Wellbutrin®, and Zyban®, Glaxo Wellcome) iscontraindicated. At least 14 days should elapse between discontinuation of anMAO inhibitor and initiation of treatment with buproprion hydrochloride.

Selective Serotonin Reuptake Inhibitors (SSRIs)

Marplan should not be administered in combination withanySSRI. There have been reports of serious, sometimes fatal, reactions(includinghyperthermia, rigidity,myoclonus, autonomic instability withpossible rapid fluctuations of vital signs, and mental status changes thatinclude extreme agitation and confusion progressing todelirium and coma) inpatients receiving fluoxetine (Prozac®, Lilly) in combination with a monoamineoxidase inhibitor (MAOI), and in patients who have recently discontinuedfluoxetine and are then started on a MAOI. Some cases presented with featuresresemblingneurolepticmalignant syndrome. Fluoxetine and other SSRIs shouldtherefore not be used in combination with Marplan, or within 14 days ofdiscontinuing therapy with Marplan. As fluoxetine and its major metabolite havevery long elimination half-lives, at least 5 weeks should be allowed afterstopping fluoxetine before starting Marplan. At least 2 weeks should be allowedafter stopping sertraline (Zoloft®, Pfizer) or paroxetine (Paxil®, SmithKlineBeecham Pharmaceuticals) before starting Marplan. In addition, there should bean interval of least 10 days between discontinuation of Marplan and initiationor fluoxetine or other SSRIs.

Buspirone

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

Sympathomimetics

Marplan should not be administered in combination withsympathomimetics, including amphetamines, or with over-the-counter drugs suchas cold,hay fever, or weight-reducing preparations that containvasoconstrictors.

During Marplan therapy, it appears that some patients areparticularly vulnerable to the effects of sympathomimetics when the activity ofmetabolizing enzymes is inhibited. Use of sympathomimetics and compounds suchas guanethidine, methyldopa, methylphenidate, reserpine,epinephrine,norepinephrine,phenylalanine,dopamine, levodopa,tyrosine, andtryptophanwith Marplan may precipitatehypertension, headache, and related symptoms. Thecombination of MAO inhibitors and tryptophan has been reported to causebehavioral 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 MAOinhibitors or within 2 or 3 weeks following MAO therapy. Serious reactions havebeen precipitated with concomitant use, including coma, severe hypertension orhypotension, severerespiratory depression, convulsions, malignanthyperpyrexia, excitation, peripheralvascular collapse, and death. It isthought that these reactions may be mediated by accumulation of 5-HT(serotonin) consequent to MAO inhibition.

Dextromethorphan

Marplan should not be used in combination withdextromethorphan. The combination of MAO inhibitors and dextromethorphan hasbeen reported to cause brief episodes ofpsychosis or bizarre behavior.

Cheese Or Other Foods With A High Tyramine Content

Hypertensive crises have sometimes occurred duringMarplan therapy after ingestion of foods with a high tyramine content. In general,patients should avoid protein foods in whichaging or protein breakdown is usedto increase flavor. In particular, patients should be instructed not to takefoods such as cheese (particularly strong or aged varieties), sour cream,Chiantiwine, sherry,beer (including nonalcoholic beer), liqueurs, pickledherring, anchovies, caviar, liver, canned figs, raisins, bananas or avocados(particularly if overripe), chocolate,soy sauce, sauerkraut, the pods of broadbeans (fava beans),yeast extracts,yogurt, meat extracts, meat prepared withtenderizers, or dry sausage.

Anesthetic Agents

Patients taking Marplan should not undergoelectivesurgery requiringgeneral anesthesia. Also, they should not be givencocaine orlocalanesthesia containing sympathomimetic vasoconstrictors. The possiblecombinedhypotensive effects of Marplan and spinal anesthesia should be kept inmind. Marplan should be discontinued at least 10 days beforeelective surgery.

CNS Depressants

Marplan should not be used in combination with somecentral nervous system depressants, such as narcotics, barbiturates, oralcohol.

Antihypertensives

Marplan should not be used in combination withantihypertensive agents, including thiazide diuretics. A marked potentiatingeffect on these drugs has been reported, resulting in hypotension.

Caffeine

Excessive use ofcaffeine in any form should be avoidedin patients receiving Marplan.

Warnings To Physicians

Clinical Worsening And Suicide Risk

Patients with major depressive disorder (MDD), both adultand pediatric, may experience worsening of their depression and/or theemergence of suicidal ideation and behavior (suicidality) or unusual changes inbehavior, whether or not they are taking antidepressant medications, and thisrisk may persist until significantremission occurs. Suicide is a known risk ofdepression and certain other psychiatric disorders, and these disordersthemselves are the strongest predictors of suicide. There has been along-standing concern, however, thatantidepressants may have a role ininducing worsening of depression and the emergence of suicidality in certainpatients during the early phases of treatment. Pooled analyses of short-termplacebo-controlled trials of antidepressant drugs (SSRIs and others) showedthat these drugs increase the risk of suicidal thinking and behavior(suicidality) in children, adolescents, and young adults (ages 18-24) withmajor depressive disorder (MDD) and other psychiatric disorders. Short-termstudies did not show an increase in the risk of suicidality withantidepressants compared to placebo in adults beyond age 24; there was areduction with antidepressants compared to placebo in adults aged 65 and older.

The pooled analyses of placebo-controlled trials of nineantidepressant drugs (SSRIs) and others) in children and adolescents with MDD,Obsessive compulsive disorder (OCD), or other psychiatric disorders included atotal 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 otherpsychiatric disorders included 295 short-term trials (median duration of 2months) of 11 antidepressant drugs in over 77,000 patients. There wasconsiderable variation in risk among drugs, but a tendency toward an increasein the younger patients `for almost all drugs studied. There were differencesin absolute risk of suicidality across the different indications, with thehighest incidence in MDD. The risk differences (drug vs. placebo), however,were relatively stable within age strata and across indications. These riskdifferences (drug-placebo difference in the number of cases of suicidality per1000 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 toreach any conclusion about drug effect on suicide.

It is unknown whether the suicidality risk extends tolonger-term use, i.e., beyond several months. However, there is substantialevidence from placebo-controlled maintenance trials in adults with depressionthat the use of antidepressants can delay the recurrence of depression.

All patients being treated with antidepressants forany indication should be monitored appropriately and observed closely forclinical worsening, suicidality, and unusual changes in behavior, especiallyduring the initial few months of a course of drug therapy, or at times of dosechanges, either increases or decreases.

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

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

Families and caregivers of patients being treated withantidepressants for major depressive disorder or other indications bothpsychiatric and nonpsychiatric, should be alerted about the need to monitorpatients for the emergence of agitation, irritability, unusual changes inbehavior and the other symptoms described above, as well as the emergence ofsuicidality, and to report such symptoms immediately to health care providers.Such monitoring should include daily observation by families and caregivers.Prescriptionsfor MARPLAN should be written for the smallest quantity of tablets consistentwith good patient management, in order to reduce the risk of overdose

Screening Patients For Bipolar Disorder

A major depressive episode may be the initialpresentation ofbipolar disorder. It is generally believed (though notestablished in controlled trials) that treating such an episode with anantidepressant alone may increase the likelihood of precipitation of amixed/manic episode in patients at risk for bipolar disorder. Whether any ofthese symptoms described above represent such a conversion is unknown. However,prior to initiating treatment with an antidepressant, patients with depressivesymptoms should be adequately screened to determine if they are at risk forbipolar disorder; such screening should include a detailed psychiatric history,including a family history of suicide, bipolar disorder, and depression. Itshould be noted that MARPLAN is not approved for use in treating bipolardepression.

Clinical Pharmacology for Marplan

Pharmacodynamics

Isocarboxazid is a non-selective hydrazine monoamineoxidase (MAO) inhibitor. In vivo and in vitro studies demonstrated inhibitionof MAO in the brain, heart, and liver. The mechanism by which MAO inhibitorsact as antidepressants is not fully understood, but it is thought to involvethe elevation of brain levels of biogenic amines. However, MAO is a complexenzyme system, widely distributed throughout the body, and drugs that inhibitMAO in the laboratory are associated with a number of clinical effects. Thus,it is unknown whether MAO inhibition per se, other pharmacologic actions, or aninteraction 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 two6-week placebo-controlled studies conducted in adult outpatients withdepressive symptoms that corresponded to the DSM-IV category of majordepressive disorder. The patients often also had signs and symptoms of anxiety(anxious mood, panic, and/or phobic symptoms). Patients were initiated with adose of 10 mg bid, with increases every 2 to 4 days, as tolerated, until atherapeutic effect was achieved, up to a maximum dose of 80 mg/day. Doses wereadministered on a divided schedule ranging from 2 to 4 times a day. The meandose overall for both studies was approximately 40 mg/day, with very fewpatients receiving doses greater than 60 mg/day. In both studies at the end of6 weeks, patients receiving Marplan had significantly greater reduction insigns and symptoms of depression evaluated by the Hamilton Depression Scale,for both the Total Score and the Depressed Mood Score, than patients whoreceived placebo.

Patient Information for Marplan

Antidepressant Medicines, Depression and other SeriousMental Illnesses, and Suicidal Thoughts or Actions

Read the Medication Guide that comes with your or yourfamily member's antidepressant medicine.

This Medication Guide is only about the risk of suicidalthoughts and actions with antidepressant medicines.Talk to your, or yourfamily 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 knowabout antidepressant medicines, depression and other serious mental illnesses,and suicidal thoughts or actions ?

1. Antidepressant medicines may increase suicidalthoughts or actions in some children, teenagers, and young adults within thefirst few months of treatment.

2. Depression and other serious mental illnesses arethe most important causes of suicidal thoughts and actions. Some people mayhave a particularly high risk of having suicidal thoughts or actions.Theseinclude people who have (or have a family history of) bipolar illness (alsocalled manic-depressive illness) or suicidal thoughts or actions.

3. How can I watch for and try to prevent suicidalthoughts 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 yourfamily 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 antidepressantmedicines ?

• 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.