Nardil (Phenelzine)

NARDIL®

Parke-Davis

Phenelzine Sulfate

Antidepressant

Action And Clinical Pharmacology: Phenelzine 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.

Indications And Clinical Uses: In the treatment of depressed patients clinically characterized as “atypical”, “nonendogenous” or “neurotic”. These patients often have mixed anxiety and depression and phobic or hypochondriacal features. There is less conclusive evidence of its usefulness for severely depressed patients with endogenous features. Phenelzine is indicated for patients who have failed to respond to the drugs more commonly used for these conditions.

Contra-Indications: Known hypersensitivity to the drug or its ingredients, pheochromocytoma, congestive heart failure, 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 phenelzine 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 phenelzine therapy may also be caused by ingestion of foods with a high concentration of tyramine or dopamine. Therefore patients being treated with phenelzine should avoid high protein food that has undergone protein breakdown by aging, 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.

Phenelzine 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. Phenelzine should not be administered together with or in rapid succession to other MAO inhibitors (see Table I) or dibenzazepine derivative drugs (see below), because hypertensive crises and convulsive seizures, fever, marked sweating, excitation, delirium, tremor, coma and circulatory collapse may occur. Dibenzazepine Derivative Drugs: 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 phenelzine therapy.

Phenelzine should not be used in combination with buspirone HCl, 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 phenelzine and the institution of another antidepressant or buspirone HCl, or the discontinuation of another MAO inhibitor and the institution of phenelzine 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, phenelzine should not be used in combination with venlafaxine or serotonin re-uptake inhibitors. Allow at least 5 weeks between discontinuation of fluoxetine and initiation of phenelzine, and at least 10 days between discontinuation of phenelzine and initiation of fluoxetine or other serotonin re-uptake inhibitors. Before initiating phenelzine 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 behavioral and neurologic symptoms including disorientation, confusion, amnesia, delirium, agitation, hypomanic signs, ataxia, myoclonus, hyperflexia, shivering, ocular oscillations and Babinski signs.

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

MAO inhibitors including phenelzine are contraindicated in patients receiving guanethidine.

Manufacturers’ Warnings In Clinical States: The most serious reactions to phenelzine involve changes in blood pressure.

Hypertensive Crises: The most important reaction associated with phenelzine 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 phenelzine. Therapy should be discontinued immediately upon the occurrence of palpitation or frequent headaches during therapy.

Recommended Treatment in Hypertensive Crises: If a hypertensive crises occurs, phenelzine 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 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.

Information for the Patient: All patients, should be warned that the following foods, beverages and medications (Tables II and III) must be avoided while taking phenelzine, and for 2 weeks after discontinuing use.

Nardil Foods and Beverages to Avoid During Phenelzine 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 (cottage cheese and cream cheese are allowed), yogurt

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 phenelzine 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 aging, pickling, fermentation, or smoking to improve flavor.

Nardil OTC Medications to Avoid During Phenelzine Therapy- 1.-Cold and cough preparations (including those containing dextromethorphan) 2.-Nasal decongestants (tablets, drops or spray) 3.-Hay-fever medications 4.-Sinus medications 5.-Asthma inhalant medications 6.-Anti-appetite medicines 7.-Weight-reducing preparations 8.-L-tryptophan containing preparations

Certain prescription drugs should be avoided. Therefore, patients under the care of another physician or dentist, should inform him/her they are taking phenelzine.

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.

Precautions: General: In depressed patients, the possibility of suicide should always be considered and adequate precautions taken. It is recommended that careful observation of patients undergoing phenelzine treatment should be maintained until control of depression is achieved. If necessary, additional measures (ECT, hospitalization, etc.) should be instituted.

All patients undergoing treatment with phenelzine 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 phenelzine 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 phenelzine. Hypomania and agitation have been reported at higher than recommended doses, or following long-term therapy.

Phenelzine 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 phenelzine, potentiate hexobarbital hypnosis in animals. Therefore, barbiturates should be given at a reduced dose with phenelzine.

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 phenelzine.

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 phenelzine is administered to diabetic patients.

Phenelzine as with other hydrazine derivatives has been reported to induce pulmonary and vascular tumors in an uncontrolled lifetime study in mice.

Drug Interactions: Phenelzine should be used with caution in combination with antihypertensive drugs, including thiazide diuretics and b-blockers, since exaggerated hypotensive effects may result. See Contraindications and Warnings for additional drug interactions.

Pregnancy: The safe use of phenelzine 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.

Doses of phenelzine 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.

Lactation: The safe use of phenelzine sulfate during lactation has not been established. There are insufficient adequate and well-controlled studies in lactating women. Therefore, phenelzine 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 phenelzine, 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.

Children: Phenelzine is not recommended for patients under 16 years of age since there are no controlled studies of safety in this age group.

Adverse Reactions: Phenelzine 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 phenelzine.

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, gastrointestinal disturbances, elevated serum transaminases (without accompanying signs and symptoms).

Metabolic: weight gain.

Cardiovascular: postural hypotension, edema.

Genitourinary: sexual disturbances, i.e., anorgasmic, 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 phenelzine 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 phenelzine therapy followed by cautious downward titration and discontinuation.

Symptoms And Treatment Of Overdose: Symptoms: 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 phenelzine, a varying and mixed clinical picture may develop, involving signs and symptoms of CNS 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.

Treatment: 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 CNS stimulation, including convulsions, should be treated with diazepam, given slowly i.v. Phenothiazine derivatives and CNS stimulants should be avoided. Hypotension and vascular collapse should be treated with i.v. fluids, and if necessary, blood pressure titration with an i.v. 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: Initial Dose: The usual starting dose is 1 tablet (15 mg) 3 times/day.

Early Phase Treatment: Dosage should be increased to at least 60 mg/day at a fairly rapid pace consistent with patient tolerance. It may be necessary to increase dosage up to 90 mg/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.

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

Availability And Storage: Each orange, biconvex glossy, sugar-coated tablet contains: phenelzine sulfate, equivalent to phenelzine base 15 mg. Nonmedicinal ingredients: acacia, calcium carbonate, candelilla wax, cornstarch, FD&C Yellow No. 6, gelatin, kaolin, magnesium stearate, mannitol, pharmaceutical glaze, povidone, sucrose and talc. Energy: 3.1 kJ (0.75 kcal). Gluten-, lactose-, paraben-, sodium-, sulfite- and tartrazine-free. Bottles of 100 and 500. Store between 15 and 30°C. (Shown in Product Recognition Section)

NARDIL® Parke-Davis Phenelzine Sulfate Antidepressant

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