VA Class:CN602

AHFS Class:

• Monoamine Oxidase Inhibitors 28:16.04.12

Generic Name(s):

• Tranylcypromine Sulfate

Chemical Name:

• (±)- trans -2-Phenylcyclopropylamine sulfate

Molecular Formula:

• (C₉H₁₁N)₂•H₂SO₄

Tranylcypromine sulfate is a monoamine oxidase (MAO) inhibitor antidepressant.

Major Depressive Disorder

Tranylcypromine is used in the treatment of major depressive disorder.101,102 Tranylcypromine has been shown to be effective in adult outpatients with major depressive episodes without melancholia; effectiveness of the drug for the treatment of major depressive episodes with melancholia (endogenous features) has not been established.101 Because of the potential for serious adverse effects, monoamine oxidase (MAO) inhibitors (e.g., phenelzine, tranylcypromine) generally are not used as initial therapy in the management of major depressive disorder, but are reserved for patients who do not respond adequately to other antidepressant agents (e.g., selective serotonin-reuptake inhibitors [SSRIs], tricyclic antidepressants) or in whom other therapies are contraindicated.101,102 (See Uses in the Monoamine Oxidase Inhibitors General Statement 28:16.04.12.) Patient response to antidepressant agents is variable, and patients who do not respond to one drug may be successfully treated with a different agent.

Administration

Tranylcypromine sulfate is administered orally.

Dosage

Dosage of tranylcypromine sulfate is expressed in terms of tranylcypromine.

Major Depressive Disorder

Dosage of tranylcypromine must be carefully adjusted according to individual requirements and tolerance, using the lowest possible effective dosage.

Patients 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.101,103,104,105 (See Worsening of Depression and Suicidality Risk under Cautions: Precautions and Contraindications, in the Monoamine Oxidase Inhibitors General Statement 28:16.04.12.)

For the symptomatic treatment of major depressive disorder, the usual adult dosage of tranylcypromine is 30 mg daily, usually given in 2 divided doses in the morning and in the afternoon. If no signs of therapeutic response appear after a reasonable period (up to 2-3 weeks), dosage may be increased in increments of 10 mg daily at 1- to 3-week intervals until optimum therapeutic response or a dosage of 60 mg daily is achieved. An increase in the frequency and severity of adverse effects should be anticipated when dosages in excess of 30 mg daily are used. Once an adequate response has been achieved, it may be possible to reduce dosage to a lower maintenance level. To avoid recurrence of depressive symptoms and/or manifestations of withdrawal (e.g., restlessness, anxiety, depression, confusion, hallucinations, headache, weakness, diarrhea), a gradual reduction in dosage is recommended during withdrawal of tranylcypromine therapy.

Tranylcypromine shares the toxic potentials of other MAO inhibitors, and the usual precautions and contraindications associated with these drugs should be observed. Patients should be fully advised about the risks, especially hypertensive crisis and suicidal thinking and behavior (suicidality), associated with MAO inhibitor therapy.101,103,104,105,106 For a complete discussion, see Cautions in the Monoamine Oxidase Inhibitors General Statement 28:16.04.12.

Pediatric Precautions

Safety and efficacy of tranylcypromine in pediatric patients have not been established.101

The US Food and Drug Administration (FDA) has determined that antidepressants increase the risk of suicidal thinking and behavior (suicidality) in children and adolescents with major depressive disorder and other psychiatric disorders.104 However, FDA also states that depression and certain other psychiatric disorders are themselves associated with an increased risk of suicide.104 Anyone considering the use of tranylcypromine in a child or adolescent for any clinical use must balance the potential risk of therapy with the clinical need.101,104,105,106 (See Cautions: Precautions and Contraindications and Cautions: Pediatric Precautions, in the Monoamine Oxidase Inhibitors General Statement 28:16.04.12.)

Pharmacology

The principal pharmacologic effects of tranylcypromine are similar to those of other MAO inhibitors (e.g., phenelzine). Although not clearly established, it has been suggested that tranylcypromine may produce greater CNS stimulation, but not antidepressant effect, than phenelzine.

For a complete discussion of the pharmacology of tranylcypromine, see Pharmacology in the Monoamine Oxidase Inhibitors General Statement 28:16.04.12.

Pharmacokinetics

Following oral administration of a 20-mg dose, tranylcypromine sulfate is rapidly absorbed, achieving peak plasma concentrations of about 110 ng/mL (range: 65-190 ng/mL) within about 1.5 hours (range: 0.7-3.5 hours).100 GI absorption of the drug shows interindividual variation and may be biphasic in some individuals, achieving an initial (highest) peak within about 1 hour and a secondary peak within 2-3 hours.100 It has been suggested that this apparent biphasic absorption in some individuals may represent different absorption rates for the stereoisomers of the drug, but additional study is necessary.100

Following oral administration of a single dose of tranylcypromine sulfate in a limited number of depressed patients with normal renal and hepatic functions, the volume of distribution of the drug ranged from 1.1-5.7 L/kg.100 In these patients, the elimination half-life averaged 2.5 hours (range: 1.5-3.2 hours).100

The onset of pharmacologic action of tranylcypromine is more rapid than that of hydrazine-derivative MAO inhibitors, and unlike the hydrazine-derivative MAO inhibitors, tranylcypromine does not produce a prolonged inhibitory effect on the enzyme. In one study, maximum orthostatic decrease in blood pressure and increase in heart rate occurred at about 2 hours after a single oral dose of the drug.100 Following discontinuance of tranylcypromine, the drug is excreted within 24 hours; however, urinary tryptamine concentrations, which are used to measure MAO activity, return to normal within 72-120 hours.

Chemistry and Stability

Chemistry

Tranylcypromine sulfate is a monoamine oxidase (MAO) inhibitor antidepressant agent. The drug is a nonhydrazine derivative and is structurally similar to amphetamine. Tranylcypromine sulfate occurs as a white, crystalline powder that is odorless or may have a faint cinnamaldehyde-like odor. The drug is very slightly soluble in alcohol and has a solubility of approximately 40 mg/mL in water at 25°C.

Stability

Commercially available tranylcypromine sulfate tablets should be stored in well-closed, light-resistant containers at 15-30°C.

Additional Information

For further information on chemistry, pharmacology, uses, cautions, acute toxicity, drug interactions, and dosage and administration of tranylcypromine sulfate, see the Monoamine Oxidase Inhibitors General Statement 28:16.04.12.

100. Mallinger AG, Edwards DJ, Himmelhoch JM et al. Pharmacokinetics of tranylcypromine in patients who are depressed: relationship to cardiovascular effects. Clin Pharmacol Ther . 1986; 40:444-50. [PubMed 3757407]

101. GlaxoSmithKline. Parnate^® (tranylcypromine sulfate) tablets prescribing information. Research Triangle Park, NC; 2007 Jun.

102. American Psychiatric Association. Practice guideline for the treatment of patients with major depressive disorder (revision). Am J Psychiatry . 2000; 157(Suppl 4):1-45.

103. Food and Drug Administration. FDA news: FDA proposes new warnings about suicidal thinking, behavior in young adults who take antidepressant medications. Rockville, MD; 2007 May 2. From the FDA web site. [Web]

104. Food and Drug Administration. Antidepressant use in children, adolescents, and adults: class revisions to product labeling. Rockville, MD; 2007 May 2. From the FDA web site. [Web]

105. Food and Drug Administration. Revisions to medication guide: antidepressant medicines, depression and other serious mental illnesses and suicidal thoughts or actions. Rockville, MD; 2007 May 2. From the FDA web site. [Web]

106. Bridge JA, Iyengar S, Salary CB. Clinical response and risk for reported suicidal ideation and suicide attempts in pediatric antidepressant treatment: a meta-analysis of randomized controlled trials. JAMA . 2007; 297:1683-96. [PubMed 17440145]