NARDIL (phenelzine sulfate) is a potent monoamine oxidase (MAO) inhibitor. 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. All the currently employed MAO inhibitors are readily absorbed after oral administration. They are not given parenterally. These drugs produce maximal inhibition of MAO in biopsy samples from man within 5 to 10 days. However, although their biological activity is prolonged due to the characteristics of their interaction with the enzyme, their clinical efficacy appears to be reduced when given less frequently than once daily. In chronically treated phenelzine patients on 60 mg/day, steady-state trough and peak levels are between 1 and 10 ng/mL.

CONTRAINDICATIONS

NARDIL (phenelzine sulfate) is contraindicated in patients with known hypersensitivity to the drug or its ingredients, with pheochromocytoma, congestive heart failure, a history of liver disease, or abnormal liver function tests. The potentiation of sympathomimetic substances and related compounds by MAO inhibitors may result in hypertensive crises (see WARNINGS). Therefore, patients taking NARDIL should not be given sympathomimetic drugs (including amphetamines, cocaine, methylphenidate, dopamine, epinephrine and norepinephrine), or related compounds (including methyldopa, L-dopa, L-tryptophan, L-tyrosine and phenylalanine). Hypertensive crises during NARDIL therapy may also be caused by ingestion of foods with a high concentration of tyramine or dopamine. Therefore patients being treated with NARDIL should avoid high protein food that has undergone protein breakdown by ageing, fermentation, pickling, smoking, or bacterial contamination; patients should also avoid cheeses (especially aged varieties), pickled herring, beer, wine, liver, yeast extract (including brewer's yeast in large quantities), dry sausage (including Genoa salami, hard salami, pepperoni and Lebanon Bologna), pods of broad beans (Fava beans) and yogurt. Excessive amounts of caffeine or chocolate can also potentiate hypertensive reactions. NARDIL should not be used in combination with dextromethorphan or with CNS depressants such as alcohol and certain narcotics. Excitation, seizures, delirium, hyperpyrexia, circulatory collapse, coma and death have been reported in patients receiving MAO inhibitor therapy, who have been given a single dose of meperidine. NARDIL should not be administered together with or in rapid succession to other MAO inhibitors or dibenzazepine derivative drugs or other antidepressant drugs (listed below), because HYPERTENSIVE CRISES and convulsive seizures, fever, marked sweating, excitation, delirium, tremor, coma and circulatory collapse may occur.

Amitriptyline, amitriptyline and perphenazine, amoxapine, carbamazepine, clomipramine, cyclobenzaprine, desipramine, doxepin, imipramine, maprotiline, nortriptyline, protriptyline, trimipramine.

At least 10 days should elapse between the discontinuation of another MAO inhibitor and the institution of NARDIL therapy. NARDIL should not be used in combination with buspirone hydrochloride, 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 NARDIL and the institution of another antidepressant or buspirone HCl, or the discontinuation of another MAO inhibitor and the institution of NARDIL therapy. The concurrent administration of an MAO inhibitor and bupropion HCl is contraindicated. There have been reports of serious reactions (including hyperthermia, rigidity, myoclonic movements and death) when serotonin re-uptake inhibitors or venlafaxine have been combined with an MAO inhibitor. Therefore, NARDIL should not be used in combination with venlafaxine or serotonin re-uptake inhibitors. Allow at least five weeks between discontinuation of fluoxetine and initiation of NARDIL, and at least 10 days between discontinuation of NARDIL and initiation of fluoxetine or other serotonin re-uptake inhibitors. Before initiating NARDIL treatment, after having used other serotonin re-uptake inhibitors, a sufficient amount of time must be allowed for clearance of the serotonin re-uptake inhibitor and its active metabolites. The combination of MAO inhibitors and tryptophan has been reported to cause behavioural and neurologic symptoms including disorientation, confusion, amnesia, delirium, agitation, hypomanic signs, ataxia, myoclonus, hyperflexia, shivering, ocular oscillations and Babinski signs. Patients taking NARDIL should not undergo elective surgery requiring general anaesthesia. Also, they should not be given cocaine or local anaesthesia containing sympathomimetic vasoconstrictors. The possible combined hypotensive effects of NARDIL and spinal anaesthesia should be kept in mind. NARDIL should be discontinued at least 10 days prior to elective surgery. MAO inhibitors including NARDIL are contraindicated in patients receiving guanethidine or reserpine.

WARNINGS

The most serious reactions to NARDIL (phenelzine sulfate) involve changes in blood pressure.

Hypertensive Crises

The most important reaction associated with NARDIL administration 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, vomiting, sweating (sometimes with fever and sometimes with cold, clammy skin), dilated pupils, and photophobia. Either tachycardia or bradycardia may be present and can be associated with constricting chest pain. NOTE: Intracranial bleeding has been reported in association with the increase in blood pressure. Blood pressure should be observed frequently to detect evidence of any pressor response in patients receiving NARDIL. Therapy should be discontinued immediately upon the occurrence of palpitation or frequent headaches during therapy.

Recommended treatment in hypertensive crisis

If a hypertensive crisis occurs, NARDIL should be discontinued immediately and therapy to lower blood pressure instituted immediately. On the basis of present evidence, phentolamine is recommended. (The dosage reported for phentolamine is 5 mg intravenously). 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.

Information for the Patient

All patients, should be warned that the following foods, beverages and medications (Tables 1 and 2) must be avoided while taking NARDIL, and for two weeks after discontinuing use:

Table 1. Foods and Beverages to Avoid During NARDIL Therapy

MEAT AND FISH: Pickled herring, liver, dry sausage (including Genoa salami, hard salami, pepperoni and Lebanon bologna) VEGETABLES: Broad bean pods (Fava beans) and sauerkraut DAIRY PRODUCTS: Cheese, yogurt (cottage cheese and cream cheese are allowed) BEVERAGES: Beer and wine, alcohol-free and reduced-alcohol beer and wine products MISCELLANEOUS: Yeast extract (including brewer's yeast in large quantities), meat extract, excessive amounts of chocolate or caffeine Patients being treated with NARDIL should also avoid any spoiled or improperly refrigerated, handled or stored protein-rich foods such as meats, fish and dairy products, including foods that may have undergone protein breakdown by ageing, pickling, fermentation, or smoking to improve flavour.

Table 2. OTC Medications to Avoid During NARDIL Therapy

Certain prescription drugs should be avoided. Therefore, patients under the care of another physician or dentist, should inform him/her that they are taking NARDIL. Patients should be warned that the use of the above foods, beverages or medicines may cause a reaction characterized by headache and other serious symptoms due to a rise in blood pressure, with the exception of dextromethorphan, which may cause reactions similar to those seen with meperidine. Patients should be instructed to report promptly the occurrence of headache or other unusual symptoms.

General

PRECAUTIONS

In depressed patients, the possibility of suicide should always be considered and adequate precautions taken. It is recommended that careful observation of patients undergoing NARDIL (phenelzine sulfate) treatment be maintained until control of depression is achieved. If necessary, additional measures (ECT, hospitalization, etc.) should be instituted. All patients undergoing treatment with NARDIL should be closely followed for symptoms of postural hypotension. Hypotensive side effects have occurred in hypertensive as well as normal and hypotensive patients. Blood pressure usually returns to pretreatment levels rapidly when the drug is discontinued or the dosage is reduced. Because the effect of NARDIL on the convulsive threshold may be variable, adequate precautions should be taken when treating epileptic patients. Of the more severe side effects that have been reported with any consistency, hypomania has been the most common. This reaction has been largely limited to patients in whom disorders characterized by hyperkinetic symptoms coexist with, but are obscured by, depressive effect; hypomania usually appears as depression improves. If agitation is present, it may be increased with NARDIL. Hypomania and agitation have been reported at higher than recommended doses, or following long-term therapy. NARDIL may cause excessive stimulation in schizophrenic patients; in manic-depressive states it may result in a swing from a depressive to a manic phase. MAO inhibitors, including NARDIL, potentiate hexobarbital hypnosis in animals. Therefore, barbiturates should be given at a reduced dose with NARDIL. MAO inhibitors inhibit the destruction of serotonin and norepinephrine, which are believed to be released from tissue stores by rauwolfia alkaloids. Accordingly, caution should be exercised when rauwolfia is used concomitantly with an MAO inhibitor, including NARDIL. There is conflicting evidence as to whether or not MAO inhibitors affect glucose metabolism or potentiate the effect of hypoglycemic agents. This should be kept in mind if NARDIL is administered to diabetic patients. NARDIL, as with other hydrazine derivatives has been reported to induce pulmonary and vascular tumours in an uncontrolled lifetime study in mice.

Drug Interactions

NARDIL should be used with caution in combination with antihypertensive drugs, including thiazide diuretics and ss-blockers, since exaggerated hypotension may result. See CONTRAINDICATIONS and WARNINGS for additional drug interactions.

Use in Pregnancy

The safe use of NARDIL during pregnancy or lactation has not been established. The potential benefit of this drug, if used during pregnancy, lactation, or in women of childbearing age, should be weighed against the possible hazard to the mother or fetus.

Lactation

The safe use of NARDIL during lactation has not been established. There are insufficient adequate and well-controlled studies in lactating women. Therefore, NARDIL should be used in lactating women only if clearly needed. It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants to NARDIL, a decision should be made whether to discontinue the drug, taking into account the importance of the drug to the mother, or to discontinue nursing.

Use in Children

NARDIL is not recommended for patients under 16 year of age since there are no controlled studies of safety in this age group.

ADVERSE REACTIONS

NARDIL (phenelzine sulfate) is a potent inhibitor of monoamine oxidase. Because this enzyme is widely distributed throughout the body, diverse pharmacologic effects may be expected to occur. When they occur, such effects tend to be mild to moderate in severity (see below), often subside with continuing treatment, and may be minimized by adjusting dosage; rarely is it necessary to institute counteracting measures or to discontinue NARDIL. Common side effects include:

Nervous System:

Dizziness, headache, drowsiness, sleep disturbances (including insomnia and hypersomnia), weakness and fatigue, tremors, twitching, myoclonic movements and hyperreflexia.

Gastrointestinal:

Constipation, dry mouth, GI disturbances, elevated serum transaminases (without accompanying signs and symptoms).

Metabolic:

Weight gain.

Cardiovascular:

Postural hypotension, edema.

Genitourinary:

Sexual disturbances, i.e., anorgasmia, ejaculatory disturbances and impotence.

Less common mild to moderate side effects (some of which have been reported in a single patient or by a single physician), include:

Nervous System:

Jitteriness, palilalia, euphoria, nystagmus, paresthesias.

Genitourinary:

Urinary retention.

Metabolic:

Hypernatremia.

Dermatologic:

Pruritus, skin rash, sweating.

Special Senses:

Blurred vision, glaucoma.

Although reported less frequently, and sometimes only once, additional severe side effects include:

Nervous System:

Ataxia, shock-like coma, toxic delirium, manic reaction, convulsions, acute anxiety reaction, precipitation of schizophrenia, transient respiratory and cardiovascular depression following ECT.

Gastrointestinal:

To date, fatal progressive necrotizing hepatocellular damage has been reported in a very few patients. Reversible jaundice.

Hematologic:

Leukopenia.

Immunologic:

Lupus-like syndrome

Metabolic:

Hypermetabolic syndrome (which may include, but is not limited to, hyperpyrexia, tachycardia, tachypnea, muscular rigidity, elevated CK levels, metabolic acidosis, hypoxia, coma, and may resemble an overdose).

Respiratory:

Edema of the glottis.

Other:

Fever associated with increased muscle tone

Withdrawal may be associated with nausea, vomiting and malaise. An uncommon withdrawal syndrome following abrupt withdrawal of NARDIL has been infrequently reported. Signs and symptoms of this syndrome generally commence 24 to 72 hours after drug discontinuation and may range from vivid nightmares with agitation to frank psychosis and convulsions. This syndrome generally responds to reinstitution of low-dose NARDIL therapy followed by cautious downward titration and discontinuation.

SYMPTOMS AND TREATMENT OF OVERDOSAGE

NOTE: For management of hypertensive crises, see WARNINGS. Accidental or intentional overdosage may be more common in patients who are depressed. It should be remembered that multiple drugs and/or alcohol may have been ingested. Depending on the amount of overdosage with NARDIL (phenelzine sulfate), a varying and mixed clinical picture may develop, including signs and symptoms of central nervous system and cardiovascular stimulation and/or depression. Signs and symptoms may be absent or minimal during the initial 12-hour period following ingestion and may develop slowly thereafter, reaching a maximum in 24 to 48 hours. Death has been reported following overdosage. Therefore, immediate hospitalization, with continuous patient observation and monitoring throughout this period, is essential. Signs and symptoms of overdosage may include, alone or in combination, any of the following: drowsiness, dizziness, faintness, irritability, hyperactivity, agitation, severe headache, hallucinations, trismus, opisthotonos, rigidity, convulsions and coma, rapid and irregular pulse, hypertension, hypotension and vascular collapse, precordial pain, respiratory depression and failure, hyperpyrexia, diaphoresis, and cool, clammy skin. Intensive symptomatic and supportive treatment may be required. Induction of emesis or gastric lavage with instillation of charcoal slurry may be helpful in early poisoning, provided the airway has been protected against aspiration. Signs and symptoms of central nervous system stimulation, including convulsions, should be treated with diazepam, given slowly intravenously. Phenothiazine derivatives and central nervous system stimulants should be avoided. Hypotension and vascular collapse should be treated with intravenous fluids, and if necessary, blood pressure titration with an intravenous infusion of dilute pressor agent. It should be noted that adrenergic agents may produce a markedly increased pressor response. Respiration should be supported by appropriate measures, including management of the airway, use of supplemental oxygen, and mechanical ventilatory assistance, as required. Body temperature should be monitored closely. Intensive management of hyperpyrexia may be required. Maintenance of fluid and electrolyte balance is essential. There are no data on the lethal dose in man. The pathophysiologic effects of massive overdosage may persist for several days, since the drug acts by inhibiting physiologic enzyme systems. With symptomatic and supportive measures, recovery from mild overdosage may be expected within 3 to 4 days. Hemodialysis, peritoneal dialysis, and charcoal hemoperfusion may be of value in massive overdosage, but sufficient data are not available to recommend their routine use in these cases. Toxic blood levels of phenelzine have not been established, and assay methods are not practical for clinical or toxicological use.

DOSAGE AND ADMINISTRATION

The usual starting dose for NARDIL (phenelzine sulfate) is one tablet (15 mg) three times a day.

Dosage should be increased to at least 60 mg per day at a fairly rapid pace consistent with patient tolerance. It may be necessary to increase dosage up to 90 mg per day to obtain sufficient MAO inhibition. Many patients do not show a clinical response until treatment at 60 mg has been continued for at least 4 weeks.

After maximum benefit from NARDIL is achieved, dosage should be reduced slowly over several weeks. Maintenance dose may be as low as 1 tablet, 15 mg a day or every other day, and should be continued for as long as is required.

PHARMACEUTICAL INFORMATION

Drug Substance

PROPER NAME: Phenelzine Sulfate CHEMICAL NAME: 2-Phenylethylhydrazine Sulfate CHEMICAL STRUCTURE: MOLECULAR FORMULA: C8H12N2 *H2SO4 MOLECULAR WEIGHT: 234.27 DESCRIPTION: Phenelzine sulfate is a hydrazine derivative. It is a white to yellowish powder with a characteristic odour. It is freely soluble in water and has a melting point of 164-168oC.

Composition

Each film coated tablet contains phenelzine sulfate, equivalent to 15 mg of phenelzine base. Inactive ingredients include: crosscarmellose sodium, editate disodium, magnesium stearate, mannitol, opadry orange, povidone, simethicone emulsion.

Stability and Storage Recommendations

Store at controlled room temperature 15 - 30degC. Protect from heat and moisture.

AVAILABILITY

NARDIL is available as orange, biconvex, film-coated tablets engraved with "PD 270", in bottles of 100 . Each tablet contains phenelzine sulfate, equivalent to 15 mg of phenelzine base.

PHARMACOLOGY

The pharmacologic properties of NARDIL (phenelzine sulfate) are similar to other MAO inhibitors (nialamide and tranylcypromine). The drug does not appear to potentiate the cardiovascular action of epinephrine or serotonin; however, it has a hypotensive action. In reserpinized-cats, MAO inhibitors are antagonists for almost all activities of this neuroleptic; sometimes, there is even a reversal of effect, i.e. the sedative effect of reserpine is replaced by hyperexcitability. Other central effects exhibited by MAO inhibitors include an increase in spontaneous motor activity in mice and rats. In addition, the conditioned avoidance response is generally diminished or blocked, whereas the escape response is unaffected. Phenelzine has little effect on the potentiation of hexobarbital narcosis in mice.

TOXICOLOGY

Species Route of

Median Lethal Dose (mg/kg)

Rat Oral 210 Phenelzine sulfate, as with other hydrazine derivatives, has been reported to exhibit tumorigenic action in laboratory animals. Lifelong administration of phenelzine in drinking water of random-bred Swiss albino mice gave rise to pulmonary and vascular tumours. The lung tumour incidence rose from 21% to 56% in females and from 23% to 36% in males, while the vascular tumour incidence increased from 5% to 44% in females and from 6% to 8% in males, as compared with the untreated controls. However, the induction of pulmonary tumour in mice (mainly adenomas) cannot be considered as representative of tumorigenicity in other species. Doses of NARDIL in pregnant mice, well exceeding the maximum recommended human dose, have caused a significant decrease in the number of viable offspring per mouse. In addition, the growth of young dogs and rats has been retarded by doses exceeding the maximum human dose.

PHARMACOLOGICAL CLASSIFICATION

ACTIONS AND CLINICAL PHARMACOLOGY

INDICATIONS AND CLINICAL USE

CONTRAINDICATIONS

WARNINGS

Hypertensive Crises

Recommended treatment in hypertensive crisis

Information for the Patient

Table 1. Foods and Beverages to Avoid During NARDIL Therapy

Table 2. OTC Medications to Avoid During NARDIL Therapy

General

PRECAUTIONS

Drug Interactions

Use in Pregnancy

Lactation

Use in Children

ADVERSE REACTIONS

SYMPTOMS AND TREATMENT OF OVERDOSAGE

DOSAGE AND ADMINISTRATION

PHARMACEUTICAL INFORMATION

Drug Substance

Composition

Stability and Storage Recommendations

AVAILABILITY

PHARMACOLOGY

TOXICOLOGY

Species Route of

Median Lethal Dose (mg/kg)

BIBLIOGRAPHY