Information for Healthcare Professionals

MARPLAN®
brand of isocarboxazid

TABLETS

DESCRIPTION: Marplan (isocarboxazid), an amine-oxidase inhibitor, is available for oral administration in 10-mg tablets. Each tablet also contains gelatin, lactose, magnesium stearate, corn starch, talc, FD&C Red No. 3 and FD&C Yellow No. 6. Chemically, isocarboxazid is 5-methyl-3-isoxazolecarboxylic acid 2-benzylhydrazide. The structural formula is:

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

CLINICAL PHARMACOLOGY:

PHARMACODYNAMICS: Isocarboxazid, a potent inhibitor of amine-oxidase, exhibits antidepressant activity. In vivo and in vitro studies demonstrated inhibition of amine-oxidase in the brain, heart, and liver.

Platelet monoamine oxidase activity was measured in 13 patients who fulfilled DSM-III criteria for major depression. Isocarboxazid 50 mg daily resulted in significantly greater enzyme inhibition than did 30 mg at two of the four time points, using phenethylamine as substrate. It was noted that 85% inhibition was rarely attained with 30 mg. This difference was statistically significant (p=0.01, Fisher’s exact test). Isocarboxazid 50 mg produced significantly higher elevations of plasma serotonin than did 30 mg (p<0.01, Mann-Whitney test).

Monoamine oxidase is a complex enzyme system, widely distributed throughout the body. Drugs that inhibit monoamine oxidase 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 clinical effects observed. Therefore, the physician should become familiar with all the effects produced by drugs of this class.

PHARMACOKINETICS: Marplan pharmacokinetic information is not available.

CLINICAL TRIALS: The effectiveness of Marplan was demonstrated in two 6-week placebo-controlled studies conducted in depressed outpatients with 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). 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.

 Time of Evaluation  

Controlled Study 1

 

Controlled Study 2

Marplan

(N=15)

Placebo

(N=14)

 

P-Value

Marplan

(N=24)

Placebo

(N=21)

 

P-Value

Global Improvement Score (Physician Rated)a
Week 6b

1.40

2.64

0.000c

2.39e

3.52

0.000c

Hamilton Depression Scale Total Score (Range 0-76)
Baselineb

29.93

32.14

0.001c

30.88

31.43

0.001c

Week 6b

7.31

18.10

14.35e

25.15

Percentage of Patients with ³ 50% Improvement in the Hamilton Depression Scale Total Score
Week 6b

86.7

35.7

0.007d

60.9

19.0

0.005d

Hamilton Depression Scale Score for Depression (Range 0-4)
Baselineb

2.53

2.64

0.001c

2.63

2.81

0.000c

Week 6b

0.51

1.52

0.87e

2.15

a Global ratings: 1=Very much better; 2=Much better; 3=A little better; 4=No change; 5=Worse.
b Estimated means adjusted to average baseline value.
c Significant, p<0.05 from analysis of covariance.
d Significant, p<0.05 from Fisher’s exact test.
e Number of patients=23.

The data from both studies were pooled and evaluated with respect to the dose level attained at 6 weeks. Patients who received Marplan at doses of <50 mg per day were compared with those who received doses of 50 mg per day or higher. There was some evidence of a dose/response effect in that Marplan at doses of ³ 50 mg per day reduced the signs and symptoms of depression to a significantly greater extent than doses less than 50 mg per day.

 

Pooled Data from Controlled Studies

 

Time of Evaluation

 

Marplan Daily Dose

 

P-Value

<50 mg

(N=17)

³ 50 mg

(N=16)

Hamilton Depression Scale Total Score (Range 0-76)
Baseline

29.59

32.81

Week 6

13.47

9.25

Mean Change

– 16.12

– 23.56

0.052b

Mean % Change

– 54.48

– 71.81

0.188b

Hamilton Depression Scale Score for Depression (Range 0-4)
Baseline

2.53

2.69

Week 6

0.88

0.31

Mean Change

– 1.65

– 2.38

0.028b

Mean % Change

– 69.61

– 90.63

0.067b

Number (%) of Patients with Depression Scores of 0-4 at the Week 6 Visit
0 Absent

8 (47)

14 (88)

0.031a

1 Doubtful

5 (29)

0 (0)

2 Mild

2 (12)

1 (6)

3 Moderate

2 (12)

1 (6)

4 Severe

0 (0)

0 (0)

a Mann-Whitney test.
b T-test.

INDICATIONS AND USAGE: Marplan is indicated for the treatment of depression.

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).

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.

For these reasons, and because of the potentially serious consequences of its side effect profile, Marplan is not to be considered as an antidepressant of first choice in the treatment of newly diagnosed depressed patients with prominent endogenous features.

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.

For a complete discussion of contraindications and warnings, see below.

Marplan is contraindicated:

  1. In patients with known hypersensitivity to isocarboxazid.
  2. In patients with 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.
  3. In the presence of pheochromocytoma. Marplan should not be used in the presence of pheochromocytoma, since such tumors secrete pressor substances.
  4. In combination with MAO inhibitors or with dibenzazepine-related entities. Marplan should not be administered together or in rapid succession with other MAO inhibitors or with 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, allow a medication-free interval of at least 1 week, then initiate Marplan therapy 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 another MAO inhibitor or a 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® (Merck Sharp & Dohme)
Endep® (Roche Products)
Perphenazine and amitriptyline HCl Etrafon® (Schering)
Triavil® (Merck Sharp & Dohme)
Clomipramine hydrochloride Anafranil® (CIBA-GEIGY)
Desipramine HCl Norpramin® (Marian Merrell Dow)
Pertofrane® (Rhône-Poulenc Rorer Pharmaceuticals)
Imipramine HCl Janimine® (Abbott Laboratories)
Tofranil® (GEIGY Pharmaceuticals)
Nortriptyline HCl Aventyl® (Eli Lilly & Co.)
Pamelor® (Sandoz)
Protripyline HCl Vivactil® (Merck Sharp & Dohme)
Doxepin HCl Adapin® (Fisons)
Sinequan® (Roerig)
Carbamazepine Tegretol® (GEIGY Pharmaceuticals)
Cyclobenzaprine HCl Flexeril® (Merck Sharp & Dohme)
Amoxapine Asendin® (Lederle)
Maprotiline HCl Ludiomil® (CIBA)
Trimipramine maleate Surmontil® (Wyeth-Ayerst Laboratories)
    1. In combination with bupropion. The concurrent administration of an MAO inhibitor and buproprion hydrochloride (Wellbutrin®, Burroughs Wellcome) is contraindicated. At least 14 days should elapse between discontinuation of an MAO inhibitor and initiation of treatment with buproprion hydrochloride.
    2. In combination with selective serotonin reuptake inhibitors (SSRIs). As a general rule, 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 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 an MAOI. Some cases presented with features resembling neuroleptic malignant syndrome. Therefore, fluoxetine and other SSRIs should not be used in combination with an MAOI, or within 14 days of discontinuing therapy with an MAOI. Since fluoxetine and its major metabolite have very long elimination half-lives, at least 5 weeks should be allowed after stopping fluoxetine before starting an MAOI.

At least 2 weeks should be allowed after stopping sertraline (Zoloft®, Roerig) or paroxetine (Paxil®, SmithKline Beecham Pharmaceuticals) before starting an MAOI.

    1. In combination with buspirone. Marplan should not be used in combination with buspirone HCl (Buspar®, Mead Johnson), since 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.
    2. In combination with sympathomimetics. Marplan should not be administered in combination with sympathomimetics, including amphetamines, and over-the-counter drugs such as cold, hay fever, or weight-reducing preparations that contain vasoconstrictors.

During Marplan therapy, it appears that certain patients are particularly vulnerable to the effects of sympathomimetics when the activity of certain 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. In addition, use with tryptophan may precipitate disorientation, memory impairment, and other neurologic and behavioral signs.

  1. In combination with meperidine. Do not use meperidine 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.
  2. In combination with dextromethorphan. The combination of MAO inhibitors and dextromethorphan has been reported to cause brief episodes of psychosis or bizarre behavior.
  3. In combination with 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, the patient 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.
  4. In patients undergoing elective surgery. 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.
  5. Marplan should not be used in combination with some central nervous system depressants, such as narcotics, barbiturates, or alcohol, or with hypotensive agents. A marked potentiating effect on these classes of drugs has been reported. Marplan should not be used in combination with antihypertensive drugs, including rauwolfia alkaloids and thiazide diuretics, since hypotension may result.
  6. Anti-parkinsonism drugs should be used with caution in patients receiving Marplan, since severe reactions have been reported.
  7. Marplan should not be used in patients with a history of liver disease, or in those with abnormal liver function tests.
  8. Marplan should not be used in patients with severe impairment of renal function.
  9. Excessive use of caffeine in any form should be avoided in patients receiving Marplan.
  10. Patients with severe or frequent headaches should not be considered candidates for therapy with Marplan, because headaches during therapy may be the first symptom of a hypertensive reaction to the drug.

 

WARNINGS: Marplan is a potent agent with the capability of producing serious side effects. Marplan is not recommended in those depressive reactions where other antidepressant drugs may be effective. It should be reserved for patients who can be closely supervised and who have not responded satisfactorily to the drugs more commonly administered for depression.

Before prescribing, the physician should be completely familiar with the full material on dosage, side effects, and contraindications, with the principles of MAO inhibitor therapy, and the side effects of this class of drugs. Also, the physician should be familiar with the symptomatology of mental depressions and alternative methods of treatment to aid in the careful selection of patients for Marplan therapy. In depressed patients, the possibility of suicide should always be considered and adequate precautions taken.

The most important reaction associated with MAO inhibitors is the occurrence of hypertensive crises, which have sometimes been fatal.

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 in outcome, has been reported in association with the paradoxical increase in blood pressure.

In patients taking Marplan, blood pressure should be followed closely to detect evidence of any pressor response. It is emphasized that full reliance should not be placed on blood pressure readings, but that the patient should also be observed frequently.

Therapy should be discontinued immediately upon the occurrence of palpitation or frequent headaches during Marplan therapy. These signs 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. Headache tends to abate as blood pressure is lowered. On the basis of present evidence, phentolamine (available as Regitine®, CIBA) is recommended. (The dosage reported for phentolamine is 5 mg I.V.) 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. Do not use parenteral reserpine.

The combination of MAO inhibitors and dextromethorphan has been reported to cause brief episodes of psychosis or bizarre behavior.

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.

There have been reports of serious reactions (including hyperthermia, rigidity, myoclonus, hypertension, and mental changes, particularly confusion and hypomania) in patients receiving fluoxetine in combination with an MAO inhibitor, or even in patients who have very recently discontinued from fluoxetine and are then started on an MAO inhibitor. Therefore, Marplan should not be used in combination with fluoxetine, or even shortly after fluoxetine is stopped. Fluoxetine and its major metabolite have very long elimination half-lives, and at least 5 weeks should be allowed after fluoxetine is discontinued and Marplan is initiated. In addition, there should be an interval of at least 10 days between discontinuation of Marplan and initiation of fluoxetine.

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).

 

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. Also, they should 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.

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

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. 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.

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.

MAO inhibitors have the capacity to suppress anginal pain that would otherwise serve as a warning of myocardial ischemia.

The usual precautions should be observed in patients with impaired renal function, since there is the possibility of cumulative effects in such patients. Older patients may suffer more morbidity than younger patients during and following an episode of hypertension or malignant hyperthermia. Older patients have less compensatory reserve to cope with any serious adverse reaction. Therefore, Marplan should be used with caution in the elderly population.

Inhibition of MAO may persist up to 10 days after discontinuation of Marplan.

Because the influence of Marplan on the convulsive threshold is variable in animal experiments, suitable precautions should be taken if epileptic patients are treated.

Some MAO inhibitors have contributed to hypoglycemic episodes in diabetic patients receiving insulin or glycemic agents. Therefore, Marplan should 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 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 not recommended because of possible potentiating effects and decreased margin of safety. This is especially true in patients who may subject themselves to an overdosage of drugs. If combination therapy is indicated, careful consideration should be given to the pharmacology of all agents to be used. The 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.

Marplan should be used cautiously in hyperactive or agitated patients, as well as in schizophrenic patients, because it may cause excessive stimulation. Characteristically, in manic-depressive states, there may be a tendency for patients to swing from a depressive to a manic phase. If such a swing occurs during Marplan therapy, brief discontinuation of the drug, followed by resumption of therapy at a reduced dosage, is advised.

Clinical evidence indicates only a low incidence of altered liver function or jaundice in patients treated with Marplan. It is difficult to differentiate most cases of drug-induced hepatocellular jaundice from viral hepatitis, since they are histopathologically and biochemically indistinguishable. Moreover, many of the clinical signs and symptoms are identical. While some of the few cases of jaundice reported during Marplan therapy may have been drug-induced, the reaction is rare. Nevertheless, Marplan is an amine-oxidase inhibitor and, as with the use of all these agents, it is advisable to watch for hepatic complications. It is suggested that periodic liver function tests, such as bilirubin, alkaline phosphatase, or transaminases, be performed during Marplan therapy; use of the drug should be discontinued at the first sign of hepatic dysfunction or jaundice. In patients with impaired renal function, Marplan should be used cautiously to prevent accumulation.

Marplan appears to have varying effects in epileptic patients; while some have a decrease in frequency of seizures, others have more seizures. Appropriate consideration must be given to the latter possibility if Marplan is prescribed for such patients.

 

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

Use in Children: Marplan is not recommended for use in patients under 16 years of age, since there are no controlled studies of safety or efficacy in this group.

Use in Pregnancy: Safe use of Marplan during pregnancy or lactation has not been established. Before prescribing Marplan in pregnancy, lactation, or in women of childbearing age, the potential benefit of the drug should be weighed against its possible hazard to mother and child.

Teratogenic Effects: Reproduction studies were carried out in rats given 0.5 and 5 mg/kg/day of isocarboxazid as a dietary mixture for 10 weeks prior to mating and continuing through two mating cycles to the weaning of the second litter. The parent animals remained in good condition throughout the test period. Litters of the treated groups compared favorably with those of the controls. No evidence of teratogenic effects was seen in any of the young.

Nursing Mothers: Marplan is not recommended for use in nursing mothers.

ADVERSE REACTIONS: Marplan is a potent therapeutic agent with a relatively low incidence of adverse reactions. Since Marplan affects many enzyme systems of the body, a variety of side effects may be anticipated. The most commonly reported adverse events in three controlled clinical trials were dizziness, headache, dry mouth, constipation, nausea, and blurred vision. Postmarketing, 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.

Systematically collected data are available from only 86 patients exposed to Marplan, of whom only 52 received doses of ³ 50 mg/day, including only 11 who were dosed at ³ 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 following table presents adverse events that occurred at an incidence of ³ 1% for Marplan.

Treatment-Emergent Adverse Events

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

 

ORGAN SYSTEM CLASS/

ADVERSE EVENT

 

PERCENTAGE OF PATIENTS

PLACEBO

(N=85)

MARPLAN <50 mg

(N=86)

MARPLAN ³ 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
Nausea

2

10

4

Dry mouth

4

9

6

Constipation

6

7

4

Diarrhea

1

2

0

UROGENITAL
Urinary hesitancy

0

1

4

Urinary frequency

1

2

0

Impotence

0

2

0

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.

Four of 85 (5%) patients who received placebo, 10 of 86 (12%) patients who received <50 mg of Marplan per day, and 1 of 52 patients who received ³ 50 mg of Marplan per day prematurely discontinued from pooled data of three clinical trials. Patients who received placebo discontinued because of dizziness, irritability, increased appetite, nervousness, claustrophobia, diarrhea, stomachache, paresthesia, headache, and facial rash. Patients who received <50 mg of Marplan per day discontinued because of facial swelling, follicular papules, heavy feeling, edema, urinary frequency, lethargy, headache, numbness, dizziness, orthostatic hypotension, paresthesia, constipation, syncope, dizziness, panic, tremor, dry mouth, impotence, blurred vision, urinary retention, hyperactivity, SGOT abnormality, racing thoughts, sleep disturbance, insomnia, palpitations, sweating, nervousness, and urinary hesitancy. The patient who discontinued from clinical trials on Marplan in doses of ³ 50 mg of Marplan per day discontinued because of weakness, sweating, urinary retention, and hyperreflexia.

DRUG ABUSE AND DEPENDENCE:

OVERDOSAGE: 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 at the time of overdosage. As with the management of intentional overdosage with any drug, it should be borne in mind that multiple agents may have been ingested.

DOSAGE AND ADMINISTRATION: 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 doses. 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).

HOW SUPPLIED: Tablets, 10 mg isocarboxazid each, peach-colored, scored—bottles of 100 (NDC 0004-0032-01).

Oxford Pharmaceutical Services, Inc.
1585 US Highway 46 West
Totowa, New Jersey 07512

Revised: January 2000

For more information on Marplan, please call Dr. Richard Guarino at 973-256-0600 or email admin@oxfordpharm.com.