Get your patient on Marplan (Isocarboxazid)

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.

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.

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).

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 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.

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.

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.

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.

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

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.

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

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.

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.

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.

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.

Marplan pharmacokinetic information is not available.

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.