Marplan Information
Marplan (Isocarboxazid) Description
Marplan (Isocarboxazid) (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.
Marplan (Isocarboxazid) Indications And Usage
Marplan (Isocarboxazid) is indicated for the treatment of depression. Because of its potentially serious side effects, Marplan (Isocarboxazid) is not an antidepressant of first choice in the treatment of newly diagnosed depressed patients.
The efficacy of Marplan (Isocarboxazid) 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 ).
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 (Isocarboxazid) in hospitalized depressed patients, or in endogenomorphically retarded and delusionally depressed patients, has not been adequately studied.
The effectiveness of Marplan (Isocarboxazid) 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 (Isocarboxazid) for extended periods should periodically evaluate the long-term usefulness of the drug for the individual patient.
Marplan (Isocarboxazid) 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.
Marplan (Isocarboxazid) Warnings To Physicians
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 18-24) 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.
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.
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 ).
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 (Isocarboxazid) to detect any pressor response.
Therapy should be discontinued immediately if palpitations or frequent headaches occur during Marplan (Isocarboxazid) therapy as these symptoms may be prodromal of a hypertensive crisis.
If a hypertensive crisis occurs, Marplan (Isocarboxazid) 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.
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 while on Marplan (Isocarboxazid) 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 (Isocarboxazid) .
Marplan (Isocarboxazid) Precautions
Prescribers or other health professionals should inform patients, their families, and their caregivers about the benefits and risks associated with treatment with Marplan (Isocarboxazid) 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 (Isocarboxazid) . 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 (Isocarboxazid) .
Safety and effectiveness in the pediatric population have not been established (see and ).
Anyone considering the use of Marplan (Isocarboxazid) in a child or adolescent must balance the potential risks with the clinical need.
See , , and sections for information on drug interactions.
Marplan (Isocarboxazid) 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 (Isocarboxazid) 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 (Isocarboxazid) 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 (Isocarboxazid) . To avoid potentiation, the physician wishing to terminate treatment with Marplan (Isocarboxazid) and begin therapy with another agent should allow for an interval of 10 days.
Marplan (Isocarboxazid) Adverse Reactions
Systematically collected data are available from only 86 patients exposed to Marplan (Isocarboxazid) , 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 (Isocarboxazid) 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 ).
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 (Isocarboxazid) 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 (Isocarboxazid) and for which the incidence in patients treated with Marplan (Isocarboxazid) 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 (Isocarboxazid) 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
Marplan (Isocarboxazid) Overdosage
The lethal dose of Marplan (Isocarboxazid) in humans is not known. There has been one report of a fatality in a patient who ingested 400 mg of Marplan (Isocarboxazid) 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 (Isocarboxazid) ). 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) Dosage And Administration
For maximum therapeutic effect, the dosage of Marplan (Isocarboxazid) must be individually adjusted on the basis of careful observation of the patient. Dosage should be started with one tablet (10 mg) of Marplan (Isocarboxazid) 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 (Isocarboxazid) 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 ).
Marplan (Isocarboxazid) How Supplied
Tablets, 10 mg isocarboxazid each, peach-colored, scored—bottles of 100 (NDC 30698-032-01).
