Phenelzine

Nardil® (phenelzine sulfate) is a potent inhibitor of monoamine oxidase (MAO). Phenelzine sulfate is a hydrazine derivative. It is a molecular weight of 234.27 and is chemically described as C ₈ H ₁₂ N ₂ ·N ₂ SO ₄ .Molecular weight: 234.27

Each Nardil tablet for oral administration contains phenelzine sulfate equivalent to 15 mg of phenelzine base. Inactive ingredients include: acacia NF; calcium carbonate; carnauba wax, NF; corn-starch, NF; FD and C yellow No. 6; gelatin, NF; kaolin, USP; magnesium stearate, NF; mannitol, USP; pharmaceutical glaze, NF; povidone, USP; sucrose, NF; talc, USP; white wax, NF; white wheat flour.

CLINICAL PHARMACOLOGY

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. Therefore, the physician should become familiar with all the effects produced by drugs of this class.

INDICATIONS

Nardil has been found to be effective in 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 with severely depressed patients with endogenous features.

Nardil should rarely be the first antidepressant drug used. Rather, it is more suitable for use with patients who have failed to respond to the drugs more commonly used for these conditions.

DOSAGE AND ADMINISTRATION

Initial dose:   The usual starting dose of Nardil is one tablet (15 mg) three times a day.

Early phase treatment:   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.

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

  HOW SUPPLIED

Each Nardil tablet is orange, biconvex, glossy sugar-coated, and imprinted with "P-D 270" in brown ink and contains phenelzine sulfate equivalent to 15 mg of phenelzine base.

N 0071-0270-24 Bottles of 100

Storage:   Store between 15°-30° C (59°-86°F).

Rx only

SIDE EFFECTS

Nardil is a potent inhibitor of monoamine oxidase. Because this enzyme is widely distributed throughout the body, diverse pharmacologic effects can be expected to occur. When they occur, such effects tend to be mild or moderate in severity (see below), often subside as treatment continues, and can 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), fatigue, weakness, tremors, twitching, myoclonic movements, 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, eg, anorgasmia and 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.

General  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.

DRUG INTERACTIONS

In patients receiving nonselective monoamine oxidase (MOA) inhibitors in combination with serotoninergic agents (e.g., dexfenfluramine, fluoxetine, fluvoxamine, paroxetine, sertraline, venlafexine) there have been reports of serious, sometimes fatal, reactions. Because Nardil is a monoamine oxidase (MAO) inhibitor, Nardil should not be used concomitantly with a serotoninergic agent (See CONTRAINDICATIONS).

WARNINGS

The most serious reactions to Nardil 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 all 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 should be 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.

Warning to the Patient: All patients should be warned that the following foods, beverages, and medications must be avoided while taking Nardil, and for two weeks after discontinuing use.

Foods and Beverages To Avoid

Meat and Fish

Pickled herring

Liver

Dry sausage (including Genoa salami, hard salami, pepperoni, and Lebanon bologna) Vegetables

Broad bean pods (fava bean pods)

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 and caffeine

Also, 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 changes by aging, pickling, fermentation, or smoking to improve flavor should be avoided.

OTC Medications To Avoid

Cold and cough preparations (including those containing dextromethorphan)

Nasal decongestants (tablets, drops, or spray)

Hay-fever medications

Sinus medications

Asthma inhalant medications

Antiappetite medicines

Weight-reducing preparations

"Pep" pills

L-tryptophan containing preparations

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

Patients should be warned that the use of the above foods, beverages, or medications 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. Also, there has been a report of an interaction between Nardil and dextromethorphan (ingested as a lozenge) causing drowsiness and bizarre behavior.

Patients should be instructed to report promptly the occurrence of headache or other unusual symptoms.

Concomitant Use with Dibenzazepine Derivative Drugs

If the decision is made to administer Nardil concurrently with other antidepressant drugs, or within less than 10 days after discontinuation of antidepressant therapy, the patient should be cautioned by the physician regarding the possibility of adverse drug interaction.

A List of Dibenzazepine Derivative Drugs by generic name follows:

nortriptyline hydrochloride

amitriptyline hydrochloride

amitriptyline hydrochloride

perphenazine and amitriptyline
  hydrochloride

perphenazine and amitriptyline
  hydrochloride

clomipramine hydrochloride

desipramine hydrochloride

desipramine hydrochloride

imipramine hydrochloride

doxepin

doxepin

carbamazepine

cyclobenzaprine HCl

amoxapine

maprotiline HCl

trimipremine maleate

protriptyline HCl

mirtazapine

Nardil should be used with caution in combination with antihypertensive drugs, including thiazide diuretics and (beta) -blockers, since exaggerated hypotensive effects may result.

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.

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.

Use in Pediatric Patients:   Nardil is not recommended for pediatric patients under 16 years of age, since there are no controlled studies of safety in this age group. Nardil, as with other hydrazine derivatives, has been reported to induce pulmonary and vascular tumors in an uncontrolled lifetime study in mice.

PRECAUTIONS

In depressed patients, the possibility of suicide should always be considered and adequate precautions taken. It is recommended that careful observations of patients undergoing Nardil 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 normotensive 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 affect; hypomania usually appeared as depression improved. If agitation is present, it may be increased with Nardil. Hypomania and agitation have also 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 hypoglycemic agents. This should be kept in mind if Nardil is administered to diabetics.

Drug Interactions

In patients receiving nonselective monoamine oxidase (MOA) inhibitors in combination with serotoninergic agents (e.g., dexfenfluramine, fluoxetine, fluvoxamine, paroxetine, sertraline, venlafexine) there have been reports of serious, sometimes fatal, reactions. Because Nardil is a monoamine oxidase (MAO) inhibitor, Nardil should not be used concomitantly with a serotoninergic agent (See CONTRAINDICATIONS).

Geriatric Use

Clinical studies of Nardil did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.