Action And Clinical Pharmacology: Tranylcypromine is a nonhydrazine (MAO) inhibitor with a rapid onset of activity. It increases the concentration of epinephrine, norepinephrine and serotonin in storage sites in the nervous system. In theory, the increased concentration of monoamines in the brainstem is the basis for its antidepressant activity.
Tranylcypromine differs from other MAO inhibitors in being a reversible inhibitor. When tranylcypromine is withdrawn, monoamine oxidase activity is generally restored within a week, although the drug is excreted in 24 hours.
Indications And Clinical Uses: Tranylcypromine has been used successfully to treat psychotic depressive states such as: depressive phase of manic-depressive psychosis, involutional melancholia, reactive depression, psychoneurotic depression of moderate to severe intensity.
In the psychiatric treatment of severe endogenous depression, it is impossible to predict, with presently known data, which patients will respond best to tranylcypromine and which to electroconvulsive therapy (ECT). The drug may be indicated in some reactive depressions in which ECT is not indicated.
Tranylcypromine is not recommended for use in mild depressive states resulting from temporary situational difficulties.
Note: Because tranylcypromine is a potent agent with the capability of producing serious side effects (e.g., hypertensive crises, sometimes complicated by fatal intracranial bleeding), its use should be reserved for patients who can be closely supervised.
Before prescribing tranylcypromine, the physician should be thoroughly familiar with information on its dosage, side effects and contraindications, as well as the principles of MAO inhibitor therapy and the side effects of this class of drugs as reported in the literature. The physician should also be familiar with the symptomatology of mental depression and alternate methods of treatment to aid in the careful selection of patients for tranylcypromine therapy.
Selecting the Patient: Tranylcypromine should be used for the symptomatic treatment of moderate to severe depression. It is not recommended for those mild depressive reactions where more conservative therapy is indicated.
Tranylcypromine should be reserved for those patients who can be followed closely. Blood pressure should be recorded periodically to detect evidence of pressor response to tranylcypromine therapy.
Tranylcypromine should not be used in patients with cerebrovascular or cardiovascular disorders (e.g., arteriosclerosis, hypertension) (see Contraindications).
Tranylcypromine should not be used in patients receiving any other antidepressant medication (see Contraindications).
Tranylcypromine is not recommended for patients with a history of recurring or frequent headaches, especially the tension and vascular types.
Tranylcypromine should not be used alone in patients with marked psychomotor agitation, since it is recognized that antidepressant drugs can aggravate some coexisting symptoms such as agitation or anxiety.
Tranylcypromine Combined With Trifluoperazine: Tranylcypromine has been combined with trifluoperazine in the treatment of coexisting anxiety and depression. Such combined therapy has been found particularly valuable when used to treat depressed patients in whom a persistent disorder of mood is associated with anxiety, moderate agitation, inappropriate mental symptoms (such as unnatural fears or suspicions and phobias) or improper response to single-agent therapy.
Combined tranylcypromine-trifluoperazine therapy has been used successfully in the treatment of psychiatric conditions such as psychoneurotic depression, agitated depression, schizo-affective disorders and pseudoneurotic schizophrenia. If the patient appears to have a pure depression, tranylcypromine should be used alone and, similarly, if the symptoms appear to indicate a pure anxiety state, trifluoperazine should be used first. The combined therapy has frequently displayed striking effectiveness in patients who obtained little benefit from treatment with a succession of single drugs.
For comprehensive prescribing information on trifluoperazine, refer to Prescribing Information on that product.
Contra-Indications: In patients with cerebrovascular or cardiovascular disorders or a history of recurrent or frequent headaches. As tranylcypromine may cause blood pressure changes, administer with great care to patients with confirmed or suspected cerebrovascular defect, hypertension or cardiac disease. Regulate physical activity in the latter, as tranylcypromine may suppress anginal pain.
The drug should be used with caution in individuals beyond the age of 60 because of the possibility of existing cerebral sclerosis with damaged vessels.
In patients with liver damage or blood dyscrasias. Extensive clinical use and laboratory tests have revealed no evidence of liver toxicity or blood dyscrasias due to tranylcypromine therapy. Because rare cases of hepatitis have been reported, it is recommended that patients with known liver damage or blood dyscrasias should not be treated with tranylcypromine.
In pheochromocytoma. Tranylcypromine should not be used in the presence of known or suspected pheochromocytoma, as such tumors secrete pressor substances.
In combination with certain drugs. Because the effect of many antidepressant drugs may persist for 10 to 20 days, do not commence tranylcypromine therapy within a week of discontinuing treatment with such drugs; then use half the normal dosage for the first week. Similarly, allow 1 week to elapse between the discontinuance of tranylcypromine and the administration of any other drug that is contraindicated with tranylcypromine such as: Other MAO Inhibitors: Other MAO inhibitors such as isocarboxazid and phenelzine sulfate. Dibenzazepine Derivatives: Dibenzazepine derivatives such as amitriptyline, nortriptyline, protriptyline, desipramine, imipramine, doxepin, perphenazine, carbamazepine, cyclobenzaprine, amoxapine, maprotiline and trimipramine, as combination with these drugs may induce hypertensive crises or severe convulsive seizures. Sympathomimetics: Sympathomimetics including amphetamines, ephedrine and over-the-counter preparations for colds, hay fever and weight reduction that contain vasoconstrictors (e.g., phenylephrine, phenylpropanolamine) as well as with methyldopa, dopamine, levodopa and tryptophan, as such combinations may precipitate hypertension, severe headache, hyperpyrexia and rarely even cerebral (subarachnoid) hemorrhage. The combination of MAOI’s 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 signs. In Combination With Fluoxetine: Although a causal relationship has not been established, death has been reported to occur following the initiation of MAOI inhibitor therapy shortly after discontinuation of fluoxetine. Therefore, tranylcypromine should not be used in combination with fluoxetine. Allow at least 5 weeks between discontinuation of fluoxetine and initiation of tranylcypromine. Other Drugs: dextromethorphan, buspirone HCl.
In combination with cheese or other foods with a high tyramine content. Hypertensive crises have sometimes occurred during tranylcypromine therapy after ingestion of foods with a high tyramine content. Tyramine is normally metabolized by monoamine oxidase in the intestinal and hepatic cells. When monoamine oxidase is inhibited, tyramine absorbed from the gastrointestinal tract passes freely into the circulation. It releases norepinephrine from adrenergic neurones causing exaggerated hypertensive and other effects.
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 (exceptions: cream cheese and cottage cheese), sour cream, pickled herring, liver, meat prepared with tenderizers, Bovril, yeast extracts like Marmite, soy sauce, pods of broad beans (fava beans), canned figs, raisins, bananas (peel) or avocados (especially if overripe), chocolate and caviar.
Alcoholic beverages have been known to precipitate a severe reaction. Therefore, the patient should avoid alcoholic drinks, especially red wines (such as chianti), sherry, beer (including nonalcoholic beer), etc.
Patients on tranylcypromine therapy should also be advised not to consume excessive amounts of caffeine in any form (coffee, tea, cola drinks, etc.) because of possible enhanced effects of caffeine on the CNS.
Manufacturers’ Warnings In Clinical States: Hypertensive Crisis: The most important adverse reaction associated with tranylcypromine is hypertensive crisis which has sometimes been fatal. This response is not usually dose-related. It is associated with a distinctive reaction 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, sometimes associated with constricting chest pain. Pupillary dilation may occur.
The occipital headache, together with pain and stiffness in the cervical muscles, may mimic subarachnoid hemorrhage, but can equally be associated with actual intracranial bleeding, as in other conditions where a sudden rise in blood pressure occurs. Cases of such bleeding have been reported, some of which have been fatal.
Blood pressure should be followed closely in patients taking tranylcypromine 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 headache during tranylcypromine therapy. These signs may be prodromal of a hypertensive reaction. Patients should be instructed to report promptly the occurrence of headache or other symptoms.
If a hypertensive reaction occurs, tranylcypromine should be discontinued and therapy to lower blood pressure should be given immediate consideration. Headache tends to abate as blood pressure decreases. On the basis of present evidence, phentolamine is recommended for use in acute cases (the dosage reported for phentolamine is 5 mg i.v. administered slowly). Do not use parenteral reserpine or rauwolfia alkaloids for the treatment of a hypertensive crisis as they may, by releasing catecholamines, exacerbate the condition. For milder reactions, the more moderate adrenolytic action of injectable chlorpromazine may be more appropriate.
Care should be taken to administer these drugs in such a way as 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. Acute distress generally subsides in 24 hours or less.
Hypotension: Hypotension, which may be postural, has been observed during tranylcypromine therapy, particularly at doses above 30 mg daily. It is seen most commonly (but not exclusively) in patients with pre-existing hypertension. In most instances, it affects the systolic readings. Rare instances of syncope have been seen. Dosage increases should be made more gradually in patients showing a tendency toward hypotension at the starting dose. Postural hypotension can usually be relieved by having the patient lie down until blood pressure returns to normal.
This side effect is usually temporary, but if it persists, the drug should be discontinued. Blood pressure usually returns rapidly to pretreatment levels upon discontinuation of the drug.
Also, when tranylcypromine is combined with those phenothiazine derivatives or other compounds known to cause hypotension, the possibility of additive hypotensive effects should be considered.
Drug Interactions (see also Contraindications): In general, the physician should bear in mind the possibility of a lowered margin of safety when tranylcypromine is administered in combination with potent drugs and should adjust dosage carefully.
A marked potentiating effect has been reported on some CNS depressants such as morphine, meperidine, barbiturates and alcohol. For this reason, narcotics and barbiturates should be used conservatively with tranylcypromine, and patients should be warned that the drug may potentiate the effects of alcoholic beverages.
Caution should be exercised when giving tranylcypromine with hypotensive agents: guanethidine, as its action may be antagonized; reserpine, as hyperactivity may occur; alpha-methyldopa, since the combination may give rise to central excitation.
When tranylcypromine is combined with those phenothiazine derivatives or other compounds known to affect blood pressure, patients should be observed more closely because of the possibility of additive hypotensive effects.
Caution should also be exercised when giving tranylcypromine with antiparkinson agents as the combination may result in potentiation, with profuse sweating, tremulousness and rise in body temperature.
Drugs which lower the seizure threshold, including MAO inhibitors, should not be used with Amipaque. As with other MAO inhibitors, tranylcypromine should be discontinued at least 48 hours before myelography and should not be resumed for at least 24 hours after the procedure.
Caution should be exercised when giving tranylcypromine with clomipramine HCl, as this drug, in combination with a MAO inhibitor, has been reported to result in hyperpyrexia, diffuse intravascular coagulation and status epilepticus.
Tranylcypromine should be administered with caution to patients receiving disulfiram. In a single study, rats given high intraperitoneal doses of d-or l-isomers of tranylcypromine plus disulfiram experienced severe toxicity including convulsions and death. Additional studies in rats given high oral doses of racemic tranylcypromine and disulfiram produced no adverse interaction.
Angina: MAO inhibitors may have the capacity to suppress anginal pain that would otherwise serve as a warning of myocardial ischemia.
Depression: Tranylcypromine may aggravate coexisting symptoms in depression, such as anxiety and agitation. 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 and agitation. Also, some patients fail to respond to drug therapy or may respond only temporarily.
Diabetes: Some MAO inhibitors have contributed to hypoglycemic episodes in diabetic patients receiving insulin or oral hypoglycemic agents. Therefore, tranylcypromine should be used with caution in diabetics under treatment with these drugs.
Epilepsy: Because the influence of tranylcypromine on the convulsive threshold is variable in animal experiments, suitable precautions should be taken if epileptic patients are treated.
Hyperthyroidism: Use tranylcypromine with caution in hyperthyroid patients because of their increased sensitivity to pressor amines.
Renal Dysfunction: The usual precautions should be observed in patients with impaired renal function, since there is a possibility of cumulative effects in such patients.
Pregnancy and Lactation: Tranylcypromine has been shown to pass through the placental barrier to the fetus of the rat and into the milk of the lactating dog. However, animal reproduction studies and clinical experience in pregnancy to date have not exhibited any teratogenic affect. Nevertheless, as with any potent drug, the physician must assess the definite medical need when prescribing for the pregnant patient, particularly during the first trimester.
Surgery: It is suggested that the drug be discontinued at least 7 days before elective surgery to allow time for recovery of monoamine oxidase activity before anesthetic agents are given.
Drug Dependency: 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, diarrhea.
Instructions to the Patient: Patients should be warned against self-medication with proprietary (over-the-counter) drugs such as cold, hay fever or reducing preparations that contain sympathomimetic amines such as phenylpropanolamine and phenylephrine.
Patients should be instructed not to eat cheese, particularly the aged varieties, or those foods listed under Contraindications, nor to drink wines which are high in tyramine content, such as chianti. They should also be advised not to consume excessive amounts of caffeine in any form.
Patients should be warned that tranylcypromine may potentiate the effects of alcoholic beverages.
Patients should be instructed to report the occurrence of headache or other unusual symptoms.
Patients should be encouraged to carry a card or other notification of the fact that they are receiving a MAO inhibitor, so that this fact may be readily ascertained in case of accident, travel or transfer to the care of another physician.
Patients should be instructed to adhere to the above instructions for at least 1 week following discontinuation of tranylcypromine therapy.
Adverse Reactions: The most frequently seen side effect is insomnia, which can usually be overcome by giving the last dose of the day not later than 3 p.m., by reducing the dose, or by prescribing a mild hypnotic.
Some of the following unwanted reactions have been reported in the literature; others are possible. They are classified according to their seriousness and probable cause – an arrangement intended to help the physician view them in proper perspective.
Pharmacologic Reactions of a Serious Nature: Hypertensive Crisis: see Warnings.
Hypotension: see Warnings.
Overstimulation: see Warnings. Overstimulation, which may include increased anxiety, agitation and manic symptoms, is usually evidence of excessive therapeutic action. Dosage should be reduced, or a phenothiazine tranquilizer should be administered concomitantly.
Pharmacologic Reactions of a Less Serious Nature: Patients may experience restlessness, insomnia, drowsiness, dizziness, weakness, dry mouth, nausea, abdominal pain, anorexia, diarrhea or constipation. Tachycardia, palpitation, blurred vision, headache without blood pressure elevation, chills, sweating, urinary retention, edema and impotence have each been reported in at least 1 patient.
Toxic or Allergic Reactions: Blood dyscrasias, including anemia, leukopenia, agranulocytosis and thrombocytopenia have been reported. Rare instances of hepatitis (e.g., one case of mild jaundice, not of the serious type associated with hydrazine MAO inhibitors) and skin rash have been reported.
Other Reactions: Tinnitus, muscle spasm and tremors, paresthesia and habituation have been reported so rarely that the role of tranylcypromine cannot be established.
Symptoms And Treatment Of Overdose: Symptoms: The characteristic symptoms that may arise as a result of tranylcypromine overdosage are usually those which have already been described under Warnings and Adverse Effects. 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: Treatment normally consists of general supportive measures, close observation of vital signs and steps to counteract specific symptoms as they occur. Gastric lavage is helpful if performed early.
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 tranylcypromine may prolong barbiturate activity.
The management of hypertensive reactions is described under Warnings.
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. MAO inhibitors may sometimes increase the pressor response as has been demonstrated with norepinephrine.
Although tranylcypromine is rapidly excreted, its MAO inhibiting action may persist for approximately 1 week.
Dosage And Administration: Dosage should be adjusted to the requirements of the individual patient. If the patient responds to therapy, the response is usually seen within 48 hours to 3 weeks after starting medication.
Recommended starting dosage is 20 mg/day (10 mg in the morning and 10 mg in the afternoon).
Continue this dosage for 2 to 3 weeks.
If no signs of a response appear, increase dosage to 30 mg daily (20 mg upon arising and 10 mg in the afternoon).
Continue this dosage for at least 1 week. If no improvement occurs, continued administration is unlikely to be beneficial. Although dosages above 30 mg/day have been used, it should be borne in mind that the incidence and severity of side effects may increase as dosage is raised. Dosage increases should be made in increments of 10 mg/day and ordinarily at intervals of 1 to 3 weeks.
When a satisfactory response is obtained, dosage may be reduced to a maintenance level.
Some patients will be maintained on 20 mg/day; many will need only 10 mg daily.
Reduction from peak to maintenance dosage may be desirable before withdrawal. If withdrawn prematurely, original symptoms will recur. No tendency to produce rebound depressions of greater intensity has been seen, although this is a theoretical possibility in patients treated at high doses. Experimental work indicates that tranylcypromine is rapidly excreted. Inhibition of MAO activity may, however, persist for up to 1 week.
Combined Tranylcypromine-Trifluoperazine Therapy: For those physicians wishing to combine tranylcypromine with trifluoperazine, the usual dosage is tranylcypromine 10 mg plus trifluoperazine 1 mg or 2 mg twice daily (morning and afternoon) depending on the individual patient requirements. After a satisfactory response is secured, medication can often be reduced to one dose daily, usually administered in the morning. Patients displaying marked mental disturbance, especially psychotic manifestations or severe agitation, will usually require larger initial doses of trifluoperazine.
Note: When ECT is being administered concurrently with tranylcypromine, 10 mg b.i.d. can usually be given during the series, then reduced to 10 mg daily for maintenance therapy.
Availability And Storage: Each red, round, biconvex, sugar-coated tablet, monogrammed “SKF N71”, contains: tranylcypromine 10 mg, as the sulfate. Nonmedicinal ingredients: acacia, Black Opacode, calcium sulfate, candeilla wax, cellulose, ethylcellulose, FD&C red no. 3, gelatin, glycerin, magnesium stearate, Opaglos, Red Opalux, sodium benzoate, sugar and wheat starch. Sodium:
PARNATE® SmithKline Beecham Tranylcypromine Sulfate Antidepressant