Marplan is indicated for the treatment of depression. Because of its potentially serious side effects, Marplan is not an antidepressant of first choice in the treatment of newly diagnosed depressed patients. The efficacy of Marplan in the treatment of depression was established in 6-week controlled trials of depressed outpatients. These patients had symptoms that corresponded to the DSM-IV category of major depressive disorder; however, they often also had signs and symptoms of anxiety (anxious mood, panic, and/or phobic symptoms) ( see CLINICAL PHARMACOLOGY ).
A major depressive episode (DSM-IV) implies a prominent and relatively persistent (nearly every day for at least 2 weeks) depressed or dysphoric mood that usually interferes with daily functioning, and includes at least five of the following nine symptoms: depressed mood, loss of interest in usual activities, significant change in weight and/or appetite, insomnia or hypersomnia, psychomotor agitation or retardation, increased fatigue, feelings of guilt or worthlessness, slowed thinking or impaired concentration, and a suicide attempt or suicidal ideation.
The antidepressant effectiveness of Marplan in hospitalized depressed patients, or in endogenomorphically retarded and delusionally depressed patients, has not been adequately studied. The effectiveness of Marplan in long-term use, that is, for more than 6 weeks, has not been systematically evaluated in controlled trials. Therefore, the physician who elects to use Marplan for extended periods should periodically evaluate the long-term usefulness of the drug for the individual patient.
Contraindications
Marplan (isocarboxazid) should not be administered in combination with any of the following: MAO inhibitors or dibenzazepine derivatives; sympathomimetics (including amphetamines); some central nervous system depressants (including narcotics and alcohol); antihypertensive, diuretic, antihistaminic, sedative or anesthetic drugs, buproprion HCL, buspirone HCL, dextromethorphan, cheese or other foods with a high tyramine content; or excessive quantities of caffeine.
Marplan (isocarboxazid) should not be administered to any patient with a confirmed or suspected cerebrovascular defect or to any patient with cardiovascular disease, hypertension, or history of headache. Contraindicated Patient Populations Hypersensitivity Marplan should not be used in patients with known hypersensitivity to isocarboxazid. Cerebrovascular Disorders Marplan should not be administered to any patient with a confirmed or suspected cerebrovascular defect or to any patient with cardiovascular disease or hypertension.
Pheochromocytoma Marplan should not be used in the presence of pheochromocytoma, as such tumors secrete pressor substances whose metabolism may be inhibited by Marplan. Liver Disease Marplan should not be used in patients with a history of liver disease, or in those with abnormal liver function tests. Renal Impairment Marplan should not be used in patients with severe impairment of renal function. Contraindicated MAOI-Other Drug Combinations Other MAOI Inhibitors or With Dibenzazepine-Related Entities Marplan should not be administered together with, or in close proximity to, other MAO inhibitors or dibenzazepine-related entities.
Hypertensive crises, severe convulsive seizures, coma, or circulatory collapse may occur in patients receiving such combinations. In patients being transferred to Marplan from another MAO inhibitor or from a dibenzazepine-related entity, a medication-free interval of at least 1 week should be allowed, after which Marplan therapy should be started using half the normal starting dosage for at least the first week of therapy.
Similarly, at least 1 week should elapse between the discontinuation of Marplan and initiation of another MAO inhibitor or dibenzazepine-related entity, or the readministration of Marplan. The following list includes some other MAO inhibitors, dibenzazepine-related entities, and tricyclic antidepressants. Generic Name Trademark (Manufacturer) Other MAO Inhibitors Furazolidone Furoxone ® (Roberts Laboratories) Pargyline HCL Eutonyl ® (Abbott Laboratories) Pargyline HCL and methyclothiazide Eutron ® (Abbott Laboratories) Phenelzine sulfate Nardil ® (Parke-Davis) Procarbazine Matulane ® (Roche Laboratories) Tranylcypromine sulfate Parnate ® (SmithKline Beecham Pharmaceuticals) Dibenzazepine-Related and Other Tricyclics Amitriptyline HCL Elavil ® (Zeneca) Endep ® (Roche Products) Perphenazine and amitriptyline HCL Etrafon ® (Schering) Triavil ® (Merck Sharp & Dohme) Clomipramine hydrochloride Anafranil ® (Novartis) Desipramine HCL Norpramin ® (Hoechst Marion Roussel) Pertofrane ® (Rhône-Poulenc Rorer Pharmaceuticals) Imipramine HCL Janimine ® (Abbott Laboratories) Tofranil ® (Novartis) Nortriptyline HCL Aventyl ® (Eli Lilly & Co.) Pamelor ® (Novartis) Protripyline HCL Vivactil ® (Merck Sharp & Dohme) Doxepin HCL Adapin ® (Fisons) Sinequan ® (Pfizer) Carbamazepine Tegretol ® (Novartis) Cyclobenzaprine HCL Flexeril ® (Merck Sharp & Dohme) Amoxapine Asendin ® (Lederle) Maprotiline HCL Ludiomil ® (Novartis) Trimipramine maleate Surmontil ® (Wyeth-Ayerst Laboratories) 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 Re - uptake 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 of 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 extra
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Warnings and precautions
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 long-standing 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 to 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 Age Range Drug-Placebo Difference in Number of Cases of Suicidality Per 1000 Patients Treated Increases Compared to Placebo <18 14 additional cases 18 to 24 5 additional cases Decreases Compared to Placebo 25 to 64 1 fewer case > 65 6 fewer cases 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 of 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, di
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Interactions
Drug Interactions 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.
Pregnancy and breastfeeding
Pregnancy There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to antidepressant, including MARPLAN, during pregnancy. Healthcare providers are encouraged to register patients by calling the National Pregnancy Registry for Antidepressants at 1-844-405-6185 or visiting online at http://womensmentalhealth.org/clinical-and-research-programs/pregnancyregistry/antidepressants 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.
Adverse reactions
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/day 1 BODY SYSTEM/ ADVERSE EVENT PLACEBO (N=85) MARPLAN <50 mg (N=86) MARPLAN ≥ 50 mg (N=52) 2 MISCELLANEOUS Drowsy 0 4% 0% Anxiety 1 2% 0% Chills 0% 2% 0% Forgetful 1% 2% 2% Hyperactive 0% 2% 0% Lethargy 0% 2% 2% Sedation 1% 2% 0% Syncope 0% 2% 0% INTEGUMENTARY Sweating 0% 2% 2% MUSCULOSKELETAL Heavy feeling 0% 2% 0% CARDIOVASCULAR Orthostatic hypotension 1% 4% 4% Palpitations 1% 2% 0% GASTROINTESTINAL Dry mouth 4% 9% 6% Constipation 6% 7% 4% Nausea 2% 6% 4% Diarrhea 1% 2% 0% UROGENITAL Impotence 0% 2% 0% Urinary frequency 1% 2% 0% Urinary hesitancy 0% 1% 4% CENTRAL NERVOUS SYSTEM Headache 13% 15% 6% Insomnia 4% 4% 6% Sleep disturbance 0% 5% 2% Tremor 0% 4% 4% Myoclonic jerks 0% 2% 0% Paresthesia 1% 2% 0% SPECIAL SENSES Dizziness 14% 29% 15% 1 Events reported by at least 1% of patients treated with Marplan are presented, except for those that had an incidence on placebo greater than or equal to that on Marplan. 2 All patients also received Marplan at doses <50 mg.
Other Events Observed During the Post - marketing 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. To report SUSPECTED ADVERSE REACTIONS, contact Lifsa Drugs LLC at 1-833-627-0070 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
Composition
Active ingredients
ISOCARBOXAZID 10MG
Official product information
Drugs@FDA lists the approved labels, letters and reviews for application NDA011961.
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