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

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

• Allow at least 2 weeks to elapse between discontinuance of phenelzine therapy and initiation of a TCA or buspirone or discontinuance of another MAO inhibitor and initiation of phenelzine.

• Allow at least 2 weeks to elapse between discontinuance of an SSRI and initiation of phenelzine and vice versa. Also allow at least 5 weeks to elapse when switching from fluoxetine.

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

• 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.

• Patients receiving phenelzine should be monitored for possible worsening of depression, suicidality, or unusual changes in behavior, especially at the beginning of therapy or during periods of dosage adjustment. (See Worsening of Depression and Suicidality Risk under Cautions.)

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

• Concomitant use of other MAO inhibitors (e.g., isocarboxazid, transdermal selegiline, tranylcypromine), dibenzazepine derivatives (e.g., amitriptyline, amoxapine, clomipramine, desipramine, doxepin, imipramine, maprotiline, nortriptyline, protriptyline, trimipramine, carbamazepine, cyclobenzaprine), centrally acting sympathomimetic agents (e.g., amphetamines) or peripherally acting sympathomimetic agents (prescription or OTC cold, hay fever, or weight-reducing preparations that contain vasoconstrictors), bupropion, buspirone, SNRIs (e.g., duloxetine, venlafaxine), SSRIs (e.g., citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline), dexfenfluramine (no longer commercially available in the US), other serotonergic drugs; meperidine and certain other CNS depressants (e.g., opiate analgesics, sedatives, anesthetics, alcohol); dextromethorphan; guanethidine; methyldopa; tryptophan; levodopa; consumption of excessive quantities of caffeine or chocolate; foods or beverages high in tyramine content. (See Interactions.)

• Elective surgery requiring general anesthesia. Use of cocaine or local anesthesia containing sympathomimetic vasoconstrictors also not recommended. Consider possible combined hypotensive effects of phenelzine and spinal anesthesia. Discontinue phenelzine ≥10 days prior to elective surgery. (See Specific Drugs and Foods under Interactions.)

• Pheochromocytoma.

• CHF.

• Severe renal impairment or renal disease.

• History of liver disease or abnormal liver function test results.

• Known hypersensitivity to phenelzine or any ingredient in the formulation.

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

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

• Principal pharmacologic effects of phenelzine are similar to those of other nonselective MAO inhibitors (e.g., tranylcypromine).

• Potent inhibitor of the MAO enzyme. Phenelzine binds irreversibly to the MAO enzyme while tranylcypromine binds reversibly to the enzyme.

• Precise mechanism of antidepressant action is unknown but may involve increases in free serotonin and norepinephrine and/or alterations in other amine concentrations within the CNS.

Advice to Patients

• Risk of suicidality; importance of patients, family, and caregivers being alert to and immediately reporting emergence of suicidality, worsening depression, or unusual changes in behavior, especially during the first few months of therapy or during periods of dosage adjustment. FDA recommends providing written patient information (medication guide) explaining risks of suicidality each time the drug is dispensed.

• Importance of informing patients to avoid foods and beverages with a high tyramine content during therapy and for 2 weeks following phenelzine discontinuance.

• Importance of informing patients to avoid consumption of excessive amounts of caffeine in any form and/or excessive amounts of chocolate.

• Importance of informing patients to avoid certain OTC (e.g., cough and cold preparations [including those containing dextromethorphan], nasal decongestants, hay fever and sinus medications, inhaled asthma medications, appetite suppressants and weight-reducing medications, “pep” pills, tryptophan-containing preparations) and certain prescription medications during therapy and for 2 weeks following phenelzine discontinuance.

• Importance of informing patients to avoid alcoholic beverages during therapy and for 2 weeks following phenelzine discontinuance.

• Risk of serious adverse effects (e.g., hypertensive reactions). Importance of promptly informing clinicians if headache or other unusual symptoms (e.g., palpitation and/or tachycardia, constriction in throat or chest, sweating, dizziness, neck stiffness, nausea or vomiting) occur.

• Risk of hypotension, faintness, and drowsiness.

• Importance of patients informing their clinicians and dentist that they are taking phenelzine.

• Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.

• Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and herbal or nutritional supplements, as well as any concomitant illnesses.

• Importance of informing patients of other important precautionary information. (See Cautions.)

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.

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Frequently asked questions

• What are some common side effects of antidepressants?

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