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
Marplan should not be used in patients with known
hypersensitivity to isocarboxazid.
Marplan should not be administered to any patient with a
confirmed or suspected cerebrovascular defect or to any patient with
cardiovascular disease or hypertension.
Marplan should not be used in the presence of
pheochromocytoma, as such tumors secrete pressor substances whose metabolism
may be inhibited by Marplan.
Marplan should not be used in patients with a history of
liver disease, or in those with abnormal liver function tests.
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
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
|Other MAO Inhibitors
||Furoxone® (Roberts Laboratories)
||Eutonyl® (Abbott Laboratories)
|Pargyline HCL and methyclothiazide
||Eutron® (Abbott Laboratories)
||Matulane® (Roche Laboratories)
||Parnate® (SmithKline Beecham Pharmaceuticals)
|Dibenzazepine-Related and Other Tricyclics
|Endep® (Roche Products)
|Perphenazine and amitriptyline HCL
|Triavil® (Merck Sharp & Dohme)
||Norpramin® (Hoechst Marion Roussel)
|Pertofrane® (Rhone-Poulenc Rorer Pharmaceuticals)
||Janimine® (Abbott Laboratories)
||Aventyl® (Eli Lilly & Co.)
||Vivactil® (Merck Sharp & Dohme)
||Flexeril® (Merck Sharp & Dohme)
||Surmontil® (Wyeth-Ayerst Laboratories)
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 Reuptake 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
or 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
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.
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 nonalcoholic 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
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.
Warnings 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 18-24) 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.
||Drug-Placebo Difference in Number of Cases of Suicidality Per 1000 Patients Treated
|Increases Compared to Placebo
||14 additional cases
||5 additional cases
|Decreases Compared to Placebo
||1 fewer case
||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
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