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Phenelzine (Monograph)

Brand name: Nardil
Drug class: Monoamine Oxidase Inhibitors
- MAO Inhibitors
- MAOIs
VA class: CN602
Molecular formula: C8H12N2•H2SO4
CAS number: 156-51-4

Warning

    Suicidality
  • Antidepressants may increase risk of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults (18–24 years of age) with major depressive disorder and other psychiatric disorders; balance this risk with clinical need. Phenelzine is not approved for use in pediatric patients. (See Pediatric Use under Cautions.)

  • In pooled data analyses, risk of suicidality was not increased in adults >24 years of age and apparently was reduced in adults ≥65 years of age with antidepressant therapy compared with placebo.

  • Depression and certain other psychiatric disorders are themselves associated with an increased risk of suicide.

  • Appropriately monitor and closely observe all patients who are started on phenelzine therapy for clinical worsening, suicidality, or unusual changes in behavior; involve family members and/or caregivers in this process. (See Worsening of Depression and Suicidality Risk and also Pediatric Use, under Cautions.)

Introduction

Hydrazine-derivative, MAO inhibitor antidepressant.

Uses for Phenelzine

Major Depressive Disorder

Treatment of major depressive disorder.

Phenelzine is effective in patients with depression clinically characterized as atypical, nonendogenous, or neurotic; these patients often have mixed anxiety and depression and phobic or hypochondriacal features. Less conclusive evidence that drug is useful in severely depressed patients with endogenous features.

Because of potential for serious adverse effects and necessity of dietary restrictions, MAO inhibitors (e.g., phenelzine, tranylcypromine) generally are not used as initial therapy for major depressive disorder, but are reserved for carefully selected patients who can be closely supervised and who have depression refractory to other antidepressants (e.g., SSRIs, SNRIs, TCAs) or in whom other therapies are contraindicated.

Eating Disorders

Phenelzine has been used with some success in the management of bulimia nervosa [off-label].

However, MAO inhibitors are potentially dangerous (e.g., risk of hypertensive crisis) in patients with eating disorders and should be used with caution in patients with chaotic binge eating and purging behaviors. MAO inhibitors currently are not recommended as first-line therapy in the management of bulimia nervosa.

Phenelzine Dosage and Administration

General

Administration

Oral Administration

Administer orally.

Dosage

Available as phenelzine sulfate; dosage expressed in terms of phenelzine.

Individualize dosage carefully according to individual requirements and tolerance; use lowest possible effective dosage.

Adults

Major Depressive Disorder
Oral

Usual initial dosage: 15 mg 3 times daily; dosage should then be increased fairly rapidly, depending on the patient’s tolerance and therapeutic response, to ≥60 mg daily. Dosages ≤90 mg daily may be required in some patients to obtain sufficient MAO inhibition. Many patients do not respond clinically until receiving 60 mg daily for ≥4 weeks.

Maintenance dosage: After maximum benefit is obtained, usually in 2–6 weeks, slowly reduce dosage over several weeks to a maintenance level. Maintenance dosage may be as low as 15 mg daily or every other day.

Eating Disorders
Oral

Dosages used for management of bulimia nervosa [off-label] have been similar to those used for the treatment of major depressive disorder. (See Major Depressive Disorder under Dosage and Administration.)

Special Populations

Geriatric Patients

Select dosage cautiously, usually starting with dosage at the lower end of recommended range since renal, hepatic, and cardiovascular function and concomitant disease and other drug therapy are more common. (See Geriatric Use under Cautions.)

Cautions for Phenelzine

Contraindications

Warnings/Precautions

Warnings

Shares the toxic potentials of other MAO inhibitors; observe the usual precautions and contraindications associated with therapy with these drugs. Fully advise patients about risks, especially hypertensive crisis and suicidal thinking and behavior (suicidality), associated with MAO inhibitor therapy.

Worsening of Depression and Suicidality Risk

Possible worsening of depression and/or emergence of suicidal ideation and behavior (suicidality) or unusual changes in behavior in both adult and pediatric patients with major depressive disorder, whether or not they are taking antidepressants; may persist until clinically important remission occurs. However, suicide is a known risk of depression and certain other psychiatric disorders, and these disorders themselves are the strongest predictors of suicide.

Appropriately monitor and closely observe patients receiving phenelzine for any reason, particularly during initiation of therapy (i.e., the first few months) and during periods of dosage adjustments. (See Boxed Warning and also see Pediatric Use under Cautions.)

Anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia, hypomania, and/or mania may be precursors to emerging suicidality. Consider changing or discontinuing therapy in patients whose depression is persistently worse or in those with emerging suicidality or symptoms that might be precursors to worsening depression or suicidality, particularly if severe, abrupt in onset, or not part of patient’s presenting symptoms.

Prescribe in smallest quantity consistent with good patient management to reduce risk of overdosage.

Observe these precautions for patients with psychiatric (e.g., major depressive disorder, obsessive-compulsive disorder) or nonpsychiatric disorders.

Bipolar Disorder

May unmask bipolar disorder. (See Activation of Mania or Hypomania under Cautions.) Phenelzine is not approved for use in treating bipolar depression.

Screen for risk of bipolar disorder by obtaining detailed psychiatric history (e.g., family history of suicide, bipolar disorder, depression) prior to initiating therapy.

Hypertensive Crises

Hypertensive crises, sometimes fatal, are one of the most serious adverse effects associated with MAO inhibitors, including phenelzine. Although spontaneous cases reported, most cases occurred following ingestion of foods or beverages containing large amounts of tyramine (i.e., cheese reaction) or when MAO inhibitors were used concomitantly with certain prescription or OTC drugs. (See Specific Drugs and Foods under Interactions and see also Advice to Patients.)

Characterized by occipital headache (which may radiate frontally), palpitation, neck stiffness or soreness, nausea or vomiting, sweating (sometimes with fever or cold, clammy skin), mydriasis and/or visual disturbances (e.g., photophobia). Tachycardia or bradycardia with associated constricting chest pain and dilated pupils and intracranial hemorrhage, sometimes fatal, also reported.

Closely monitor BP in all patients to detect evidence of pressor response; however, full reliance should not be placed on BP determinations alone. Frequently observe patient’s clinical status, particularly for signs and symptoms of hypertension.

If a hypertensive crisis or prodromal signs of hypertensive crisis occur, discontinue MAO inhibitor therapy and immediately institute appropriate therapy to lower BP. Phentolamine considered hypotensive drug of choice for treating MAO inhibitor-induced hypertensive crisis. Manage fever by external cooling. Other symptomatic and supportive measures may be necessary in some patients; however, avoid administration of parenteral reserpine. (See Specific Drugs and Foods under Interactions.)

General Precautions

Activation of Mania or Hypomania

Possible activation of mania and hypomania, particularly in patients with bipolar disorder. (See Bipolar Disorder under Cautions.)

Orthostatic Hypotension

Possible orthostatic hypotension. Most commonly observed in patients with preexisting hypertension, but has occurred in normotensive and hypotensive patients. Closely monitor patients for postural hypotension; BP generally returns rapidly to pretreatment levels upon drug discontinuance or dosage reduction.

Seizures

MAO inhibitors have a variable effect on seizure threshold; use with caution in patients with a seizure disorder.

Nervous System Effects

Possible hypomania; usually occurs in patients with accompanying hyperkinetic symptoms obscured by depressive symptoms. Hypomania usually appears as depression improves. Phenelzine may worsen preexisting agitation. (See Worsening of Depression and Suicidality Risk under Cautions.)

Hypomania and agitation also reported with higher than recommended phenelzine dosages or following long-term therapy.

Possible excessive stimulation in patients with schizophrenia.

Endocrine and Metabolic Effects

MAO inhibitors may cause hypoglycemic episodes in diabetic patients receiving insulin or oral antidiabetic agents; use phenelzine with caution in diabetic patients receiving these drugs concurrently.

Use MAO inhibitors with caution in patients with hyperthyroidism, since these patients have an increased sensitivity to pressor amines.

Withdrawal of Therapy

A withdrawal syndrome has been reported infrequently following abrupt discontinuance of phenelzine. Signs and symptoms of withdrawal evident within 24–72 hours after phenelzine was discontinued included nausea, vomiting, malaise, vivid nightmares with agitation, psychosis, and/or seizures. The syndrome generally responds to reinitiation of low-dose phenelzine therapy followed by cautious downward titration and discontinuance.

Specific Populations

Pregnancy

Category C.

Lactation

Not known but considered likely to distribute into breast milk. Caution if used in nursing women; carefully assess potential benefits and risks.

Pediatric Use

Safety and efficacy in pediatric patients not established.

FDA warns that a greater risk of suicidal thinking or behavior (suicidality) occurred during first few months of antidepressant treatment (4%) compared with placebo (2%) in children and adolescents with major depressive disorder, obsessive-compulsive disorder (OCD), or other psychiatric disorders based on pooled analyses of 24 short-term, placebo-controlled trials of 9 antidepressant drugs (SSRIs and others). However, a more recent meta-analysis of 27 placebo-controlled trials of 9 antidepressants (SSRIs and others) in patients <19 years of age with major depressive disorder, OCD, or non-OCD anxiety disorders suggests that the benefits of antidepressant therapy in treating these conditions may outweigh the risks of suicidal behavior or suicidal ideation. No suicides occurred in these pediatric trials.

Carefully consider these findings when assessing potential benefits and risks of phenelzine in a child or adolescent for any clinical use. (See Worsening of Depression and Suicidality Risk under Cautions.)

Geriatric Use

Insufficient experience with phenelzine in patients ≥65 years to determine whether they respond differently than younger patients. Other clinical experience with MAO inhibitors has not identified differences in responses between geriatric and younger adults.

In pooled data analyses, a reduced risk of suicidality was observed in adults ≥65 years of age with antidepressant therapy compared with placebo. (See Boxed Warning and also see Worsening of Depression and Suicidality Risk under Cautions.)

Possible increased morbidity during or following episodes of hypertension or malignant hyperthermia; geriatric patients have less compensatory reserve to cope with any serious adverse reaction.

Use with caution. Use low initial dosage and closely observe patients since renal, hepatic, and cardiovascular dysfunction and concomitant disease or other drug therapy are more common in this age group than in younger patients. (See Geriatric Patients under Dosage and Administration.)

Hepatic Impairment

Contraindicated in patients with history of hepatic disease or abnormal liver function test results.

Renal Impairment

Contraindicated in patients with severe renal impairment or renal disease.

Common Adverse Effects

Adverse nervous system effects (e.g., dizziness, headache, drowsiness, sleep disturbances [e.g., insomnia, hypersomnia], fatigue, weakness, tremors, twitching, myoclonic movements, hyperreflexia), adverse GI effects (e.g., constipation, dry mouth, GI disturbances), elevated serum transaminase concentrations (without accompanying signs or symptoms of hepatotoxicity), weight gain, adverse cardiovascular effects (e.g., orthostatic hypotension, edema), adverse GU effects (e.g., anorgasmia, ejaculatory disturbances, impotence).

Drug Interactions

Drugs Associated with Serotonin Syndrome

Potential pharmacologic interaction (serotonin syndrome) with serotonergic agents. Avoid concomitant administration of phenelzine and serotonergic agents and allow sufficient amount of time to elapse between discontinuance of serotonergic drugs and initiation of phenelzine. (See Specific Drugs and Foods under Interactions.)

Specific Drugs and Foods

Drug or Food

Interaction

Comments

Alcohol

May potentiate action of alcohol

Possible hypertensive crisis with tyramine-containing alcoholic beverages (e.g., Chianti wine, beer, liqueurs)

Avoid alcoholic beverages during therapy and for 2 weeks following phenelzine discontinuance

Anesthetics

General anesthetics: Possible exaggeration of hypotensive and CNS depressant effects

Local anesthesia with cocaine or local anesthetics that contain sympathomimetic vasoconstrictors: Possible hypertension

Spinal anesthesia: Possible potentiation of the hypotensive effect of local anesthetics

For elective surgery, discontinue phenelzine for ≥10 days prior to elective surgery with general anesthetics; for emergency surgery, carefully adjust dosage of general anesthetics

Local anesthesia with cocaine or local anesthetics that contain sympathomimetic vasoconstrictors: Avoid concomitant use

Spinal anesthesia: Use with caution

Antidepressants, SNRIs (e.g., duloxetine, venlafaxine)

Potentially life-threatening serotonin syndrome

Concomitant use contraindicated

Allow at least 5 or 7 days to elapse between discontinuance of duloxetine or venlafaxine, respectively, and initiation of phenelzine and at least 2 weeks between discontinuance of phenelzine and initiation of duloxetine or venlafaxine

Antidepressants, SSRIs (e.g., citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline)

Potentially life-threatening serotonin syndrome or neuroleptic malignant syndrome (NMS)

Concomitant use contraindicated

Allow at least 2 weeks to elapse between discontinuance of phenelzine and initiation of an SSRI, and vice versa

Allow at least 5 weeks to elapse between discontinuance of fluoxetine and initiation of phenelzine

Antidepressants, tricyclic (TCAs) (e.g., amitriptyline, desipramine, imipramine, nortriptyline, protriptyline)

Potentially life-threatening serotonin syndrome

Concomitant use contraindicated

Allow at least 2 weeks to elapse when switching to or from these drugs

Antidiabetic agents, oral

Possible hypoglycemic episodes

Use with caution; oral antidiabetic agent requirements may decrease during concurrent administration

Barbiturates

Potentiated hypnotic effects reported in animals; may potentiate action of barbiturates in humans

Reduce barbiturate dosage during concomitant administration

Bupropion

Possible enhanced toxicity of bupropion

Concomitant administration contraindicated

Allow at least 2 weeks to elapse between discontinuance of phenelzine and initiation of bupropion

Buspirone

Elevated BP reported with concomitant use; possible serotonin syndrome

Concomitant use contraindicated

Allow at least 2 weeks to elapse between discontinuance of phenelzine and initiation of buspirone

Caffeine

May precipitate hypertensive crisis if taken in excessive quantities

Concomitant use of excessive quantities of caffeine contraindicated

Carbamazepine

Possible serotonin syndrome

Concomitant use contraindicated

Allow at least 2 weeks to elapse between discontinuance of phenelzine and initiation of carbamazepine

CNS depressants (e.g., opiate analgesics)

May potentiate the action of CNS depressants

Concomitant use contraindicated

Cyclobenzaprine

Possible hypertensive crises or severe seizures; serotonin syndrome reported

Concomitant use contraindicated

Allow at least 2 weeks to elapse between discontinuance of phenelzine and initiation of cyclobenzaprine

Dextromethorphan

Brief episodes of psychosis or bizarre behavior reported; possible serotonin syndrome

Concomitant use contraindicated

Foods and beverages, tyramine-containing (e.g., cheese, sour cream, Chianti wine, sherry, beer, liqueurs, pickled herring, anchovies, caviar, liver, canned figs, dried fruits, bananas, raspberries, overripe fruit, chocolate, soy sauce, sauerkraut, fava beans, yeast extracts, yogurt, dry sausage, meat extracts or meat prepared with tenderizers)

Serious, sometimes fatal hypertensive reactions (e.g., palpitation, headache, nausea, vomiting, photophobia, diaphoresis) reported

Avoid foods and beverages with high tyramine content (e.g., cheese)

Consult specialized references on food constituents or dietician for specific information on tyramine content of foods and beverages

Ginseng (e.g., Panax ginseng)

Manic-like symptoms reported

Guanethidine

Possible moderate to severe hypertension

Concomitant use contraindicated

Allow at least 2 weeks to elapse between discontinuance of phenelzine and initiation of guanethidine

Insulin

Possible hypoglycemic episodes

Use with caution; insulin requirements may decrease during concurrent use

Levodopa-carbidopa

Potential for hypertension, headache, hyperexcitability, and related symptoms

Concomitant use contraindicated

Discontinue phenelzine ≥2 weeks prior to initiation of levodopa

MAO inhibitors (e.g., isocarboxazid, transdermal selegiline, tranylcypromine)

Hypertensive crises or severe seizures may occur with concomitant use

Concomitant use contraindicated

Allow at least 2 weeks to elapse between discontinuance of phenelzine and initiation of another MAO inhibitor, or vice versa

Meperidine

Severe, generally immediate reactions, including excitation, sweating, rigidity, respiratory depression, seizures, hypertension or hypotension, coma, and death, suggestive of serotonin syndrome reported

Concomitant use contraindicated

Allow at least 2 weeks to elapse between discontinuance of phenelzine and administration of meperidine

Methyldopa

Potential for hypertension, headache, hyperexcitability, and related symptoms

Concomitant use contraindicated

Modafinil

Acute dyskinesia, confusion, and hyperthermia reported during concurrent use of modafinil and tranylcypromine, another MAO inhibitor; possible increased dopaminergic and serotonergic activity

Use with caution

Reserpine

Possible enhanced serotonergic and noradrenergic effects and severe pressor response

Use with caution (see Hypertensive Crises under Cautions)

Sympathomimetic agents (e.g., amphetamine, dopamine, OTC cold, hay fever, or weight-reducing preparations)

Possible hypertensive crisis and/or serotonin syndrome

Concomitant use contraindicated

Allow at least 2 weeks to elapse between discontinuance of phenelzine and initiation of therapy with sympathomimetic agents

Tryptophan

Possible behavioral and neurologic symptoms suggestive of serotonin syndrome

Concomitant use contraindicated

Phenelzine Pharmacokinetics

Absorption

Bioavailability

Rapidly and well absorbed following single-dose (30 mg) oral administration, with mean peak plasma concentrations of approximately 20 ng/mL achieved at 43 minutes. Steady-state plasma concentrations gradually increase over initial 6–8 weeks of therapy.

Onset

Pharmacologic effects of MAO inhibitors are cumulative; onset of action of phenelzine is slower that that of the nonhydrazine-derivative MAO inhibitor tranylcypromine. Antidepressant effect usually evident within 2–3 weeks.

Duration

Inhibition of MAO may persist for several days to weeks following drug discontinuance.

Distribution

Extent

Crosses placenta in mice. Not known but considered likely to distribute into human breast milk.

Elimination

Metabolism

Rapidly and extensively metabolized following oral administration principally by oxidation via monoamine oxidase; acetylation appears to be a minor metabolic pathway. Role of acetylator status in phenelzine's metabolism unclear; some studies suggest slow acetylators of phenelzine may exhibit greater antidepressant efficacy and/or toxicity compared with fast acetylators while other studies do not support these findings.

Elimination Route

Rapidly eliminated from body; excreted principally in urine as metabolites (about 73% as phenylacetic acid and P-hydroxyphenylacetic acid).

Half-life

1.2–11.6 hours following single-dose administration; multiple-dose pharmacokinetics not studied.

Stability

Storage

Oral

Tablets

Tight containers at 15–30°C; protect from excessive exposure to heat and light.

Actions

Advice to Patients

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Phenelzine Sulfate

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets, film-coated

15 mg (of phenelzine)

Nardil (with povidone)

Pfizer

AHFS DI Essentials™. © Copyright 2024, Selected Revisions July 1, 2008. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

† Off-label: Use is not currently included in the labeling approved by the US Food and Drug Administration.

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