Parnate Description

Chemically, tranylcypromine sulfate is (±)- trans -2-phenylcyclopropylamine sulfate (2:1).

Each round, rose-red, film-coated tablet is debossed with the product name PARNATE and SB and contains tranylcypromine sulfate equivalent to 10 mg of tranylcypromine. Inactive ingredients consist of cellulose, citric acid, croscarmellose sodium, D&C Red No. 7, FD&C Blue No. 2, FD&C Red No. 40, FD&C Yellow No. 6, gelatin, lactose, magnesium stearate, talc, titanium dioxide and trace amounts of other inactive ingredients.

Parnate Summary Of Contraindications

PARNATE (tranylcypromine sulfate) 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; bupropion HCl; buspirone HCI; dextromethorphan; cheese or other foods with a high tyramine content; or excessive quantities of caffeine.

PARNATE should not be administered to any patient witha confirmed or suspected cerebrovascular defect or to any patient with cardiovascular disease, hypertension, or history of headache.

PARNATE (tranylcypromine sulfate) 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 complete discussion of contraindications and warnings, see below.)

Parnate Contraindications

PARNATE (tranylcypromine sulfate) is contraindicated:

• In patients with cerebrovascular defects or cardiovascular disorders

  PARNATE should not be administered to any patient with a confirmed or suspected cerebrovascular defect or to any patient with cardiovascular disease or hypertension.

• In the presence of pheochromocytoma

  PARNATE should not be used in the presence of pheochromocytoma since such tumors secrete pressor substances.

• In combination with MAO inhibitors or with dibenzazepine-related entities

  PARNATE (tranylcypromine sulfate) should not be administered together or in rapid succession with other MAO inhibitors or with dibenzazepine-related entities. Hypertensive crises or severe convulsive seizures may occur in patients receiving such combinations.

  In patients being transferred to PARNATE from another MAO inhibitor or from a dibenzazepine-related entity, allow a medication-free interval of at least a week, then initiate PARNATE using half the normal starting dosage for at least the first week of therapy. Similarly, at least a week should elapse between the discontinuance of PARNATE and the administration of another MAO inhibitor or a dibenzazepine-related entity, or the readministration of PARNATE.

  The following list includes some other MAO inhibitors, dibenzazepine-related entities and tricyclic antidepressants, and the companies which market them.

  Other MAO Inhibitors

  Generic Name	Source
  Furazolidone
  Isocarboxazid	Marplan® (Oxford Pharm Services)
  Pargyline HCl
  Pargyline HCl and methyclothiazide
  Phenelzine sulfate	Nardil® (Pfizer)
  Procarbazine HCl	Matulane® (Sigma Tau)

  Dibenzazepine-Relatedand Other Tricyclics

  Generic Name	Source
  Amitriptyline HCl	l® (Sandoz)
  Perphenazine and amitriptyline HCl	® (Sandoz)
  Clomipramine hydrochloride	Anafranil® (Mallinckrodt)
  Desipramine HCl	(Sandoz)
  Imipramine HCl	(Sandoz) Tofranil® (Mallinckrodt)
  Nortriptyline HCl	(Mylan) Pamelor® (Mallinckrodt)
  Protriptyline HCl	Vivactil® (Odyssey Pharmaceuticals, Inc.)
  Doxepin HCl	Sinequan® (Pfizer)
  Carbamazepine	Tegretol® (Novartis)
  Cyclobenzaprine HCl	(Mylan) Flexeril® (McNeil)
  Amoxapine	(Watson)
  Maprotiline HCl	(Mylan)
  Trimipramine maleate	Surmontil® (Odyssey Pharmaceuticals, Inc.)

• In combination with bupropion

  The concurrent administration of a MAO inhibitor and bupropion hydrochloride (Wellbutrin® , Wellbutrin SR® , Wellbutrin XL® , Zyban® , GlaxoSmithKline) is contraindicated. At least 14 days should elapse between discontinuation of a MAO inhibitor and initiation of treatment with bupropion hydrochloride.

• In combination with dexfenfluramine hydrochloride

  Because dexfenfluramine hydrochloride is a serotonin releaser and reuptake inhibitor, it should not be used concomitantly with PARNATE (tranylcypromine sulfate).

• In combination with selective serotonin reuptake inhibitors (SSRIs)

  As a general rule, PARNATE 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® , Eli Lilly and Company) 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. Therefore, fluoxetine and other SSRIs should not be used in combination with a MAOI, or within 14 days of discontinuing therapy with a 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 a MAOI.

  At least 2 weeks should be allowed after stopping sertraline (Zoloft® , Pfizer) or paroxetine (Paxil® , GlaxoSmithKline) before starting a MAOI.

• In combination with buspirone

  PARNATE (tranylcypromine sulfate) should not be used in combination with buspirone HCl (BuSpar® , Bristol-Myers Squibb), 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 PARNATE and the institution of buspirone HCl.

• In combination with sympathomimetics

  PARNATE (tranylcypromine sulfate) 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 PARNATE 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, reserpine, dopamine, levodopa and tryptophan with PARNATE may precipitate hypertension, headache and related symptoms. The combination of MAOIs and tryptophan has been reported to cause behavioral and neurologic syndromes including disorientation, confusion, amnesia, delirium, agitation, hypomanic signs, ataxia, myoclonus, hyperreflexia, shivering, ocular oscillations and Babinski's signs.

• In combination with meperidine

  Do not use meperidine concomitantly with MAO inhibitors or within 2 or 3 weeks following MAOI 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.

• In combination with dextromethorphan

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

• In combination with cheese or other foods with a high tyramine content

  Hypertensive crises have sometimes occurred during PARNATE 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 nonalcoholic beer), liqueurs, pickled herring, anchovies, caviar, liver, canned figs, dried fruits (raisins, prunes, etc.), bananas, raspberries, avocados, overripe fruit, chocolate, soy sauce, sauerkraut, the pods of broad beans (fava beans), yeast extracts, yogurt, meat extracts or meat prepared with tenderizers.

• In patients undergoing elective surgery

  Patients taking PARNATE 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 PARNATE and spinal anesthesia should be kept in mind. PARNATE should be discontinued at least 10 days prior to elective surgery.

Parnate Additional Contraindications

In general, the physician should bear in mind the possibility of a lowered margin of safety when PARNATE (tranylcypromine sulfate) is administered in combination with potent drugs.

• PARNATE should not be used in combination with some central nervous system depressants such as narcotics and alcohol, or with hypotensive agents. A marked potentiating effect on these classes of drugs has been reported.
• Anti-parkinsonism drugs should be used with caution in patients receiving PARNATE since severe reactions have been reported.
• PARNATE should not be used in patients with a history of liver disease or in those with abnormal liver function tests.
• Excessive use of caffeine in any form should be avoided in patients receiving PARNATE.

Parnate Side Effects

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 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 4,400 patients. The pooled analyses of placebo-controlled trials in adults with MDD or other psychiatric disorders included a total of 295 short-term trials (median duration of 2 months) of 11 antidepressant drugs in over 77,000 patients. There was considerable variation in risk of suicidality 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 1,000 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 causal 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.

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 healthcare providers. Such monitoring should include daily observation by families and caregivers. Prescriptions for PARNATE 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 the 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 PARNATE is not approved for use in treating bipolar depression.

PARNATE (tranylcypromine sulfate) is a potent agent with the capability of producing serious side effects. PARNATE 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 on these pages, 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 alternate methods of treatment to aid in the careful selection of patients for therapy with PARNATE.

Pregnancy Warning

Use of any drug in pregnancy, during lactation or in women of childbearing age requires that the potential benefits of the drug be weighed against its possible hazards to mother and child.

Animal reproductive studies show that PARNATE passes through the placental barrier into the fetus of the rat, and into the milk of the lactating dog. The absence of a harmful action of Parnate on fertility or on postnatal development by either prenatal treatment or from the milk of treated animals has not been demonstrated. Tranylcypromine is excreted in human milk.

Parnate Side Effects

Hypertensive Crises

The most important reaction associated with PARNATE (tranylcypromine sulfate) 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 all patients taking PARNATE 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 PARNATE therapy. These signs may be prodromal of a hypertensive crisis.

Important

Recommended Treatment In Hypertensive Crises

If a hypertensive crisis occurs, PARNATE (tranylcypromine sulfate) 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 is recommended. (The dosage reported for phentolamine is 5 mg I.V.) Care should be taken to administer this 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.

Parnate Precautions

Hypotension

Hypotension has been observed during PARNATE (tranylcypromine sulfate) therapy. Symptoms of postural hypotension are seen most commonly but not exclusively in patients with pre-existent hypertension; blood pressure usually returns rapidly to pretreatment levels upon discontinuation of the drug. At doses above 30 mg daily, postural hypotension is a major side effect and may result in syncope. 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 PARNATE 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 tranylcypromine 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 which lower the seizure threshold, including MAO inhibitors, should not be used with Amipaque® . As with other MAO inhibitors, PARNATE (tranylcypromine sulfate) should be discontinued at least 48 hours before myelography and should not be resumed for at least 24 hours postprocedure.

MAO inhibitors may 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 a 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, PARNATE should be used with caution in the elderly population.

Although excretion of PARNATE is rapid, inhibition of MAO may persist up to 10 days following discontinuation.

Because the influenceof PARNATE 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 oral hypoglycemic agents. Therefore, PARNATE should be used with caution in diabetics using these drugs.

PARNATE may aggravate coexisting symptoms in depression, such as anxiety and agitation.

Use PARNATE (tranylcypromine sulfate) with caution in hyperthyroid patients because of their increased sensitivity to pressor amines.

PARNATE should be administered with caution to patients receiving Antabuse®? . In a single study, rats given high intraperitoneal doses of d or l isomers of tranylcypromine sulfate plus disulfiram experienced severe toxicity including convulsions and death. Additional studies in rats given high oral doses of racemic tranylcypromine sulfate (PARNATE) and disulfiram produced no adverse interaction.

Information For Patients

Prescribers or other health professionals should inform patients, their families, and their caregivers about the benefits and risks associated with treatment with PARNATE and should counsel them in its appropriate use. A patient Medication Guide about ?Antidepressant Medicines, Depression and Other Serious Mental Illnesses, and Suicidal Thoughts or Action? is available for PARNATE. 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 PARNATE.

Clinical Worsening and Suicide Risk

Patients, their families, and their caregivers should be encouraged to be alert to the emergence of anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, mania, other unusual changes in behavior, worsening of depression, and suicidal ideation, especially early during antidepressant treatment and when the dose is adjusted up or down. Families and caregivers of patients should be advised to look for the emergence of such symptoms on a day-to-day basis, since changes may be abrupt. Such symptoms should be reported to the patient's prescriber or health professional, especially if they are severe, abrupt in onset, or were not part of the patient's presenting symptoms. Symptoms such as these may be associated with an increased risk for suicidal thinking and behavior and indicate a need for very close monitoring and possibly changes in the medication.

Pediatric Use

Safety and effectiveness in the pediatric population have not been established (see BOX WARNING and WARNINGS?Clinical Worsening and Suicide Risk). Anyone considering the use of PARNATE in a child or adolescent must balance the potential risks with the clinical need.

Parnate Overdosage

Symptoms

The characteristic symptoms that may be caused by overdosage are usually those described above.

However, an intensification of these symptoms and sometimes severe additional manifestations may be seen, depending on the degree of overdosage and on individual susceptibility. Some patients exhibit insomnia, restlessness and anxiety, progressing in severe cases to agitation, mental confusion and incoherence. Hypotension, dizziness, weakness and drowsiness may occur, progressing in severe cases to extreme dizziness and shock. A few patients have displayed hypertension with severe headache and other symptoms. Rare instances have been reported in which hypertension was accompanied by twitching or myoclonic fibrillation of skeletal muscles with hyperpyrexia, sometimes progressing to generalized rigidity and coma.

Treatment

Gastric lavage is helpful if performed early. Treatment should normally consist of general supportive measures, close observation of vital signs and steps to counteract specific symptoms as they occur, since MAO inhibition may persist. The management of hypertensive crises is described under WARNINGS in the HYPERTENSIVE CRISES section.

External cooling is recommended if hyperpyrexia occurs. Barbiturates have been reported to help relieve myoclonic reactions, but frequency of administration should be controlled carefully because PARNATE (tranylcypromine sulfate) may prolong barbiturate activity. When hypotension requires treatment, the standard measures for managing circulatory shock should be initiated. If pressor agents are used, the rate of infusion should be regulated by careful observation of the patient because an exaggerated pressor response sometimes occurs in the presence of MAO inhibition. Remember that the toxic effect of PARNATE may be delayed or prolonged following the last dose of the drug. Therefore, the patient should be closely observed for at least a week. It is not known if tranylcypromine is dialyzable.

Parnate Information For Patients

Prescribers or other health professionals should inform patients, their families, and their caregivers about the benefits and risks associated with treatment with PARNATE and should counsel them in its appropriate use. A patient Medication Guide about ?Antidepressant Medicines, Depression and Other Serious Mental Illnesses, and Suicidal Thoughts or Action? is available for PARNATE. 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 PARNATE.