VA Class:CN601

AHFS Class:

• Tricyclics and Other Norepinephrine-reuptake Inhibitors 28:16.04.28

Generic Name(s):

• Trimipramine Maleate

Trimipramine maleate is a dibenzazepine-derivative tricyclic antidepressant.

Trimipramine maleate shares the pharmacologic actions of the other tricyclic antidepressants and is used primarily in the treatment of endogenous depression. Studies comparing trimipramine with amitriptyline or imipramine have not demonstrated superiority of trimipramine over these other tricyclic antidepressants.

In one randomized double-blind study in children 5-14 years of age, trimipramine maleate was no more effective than placebo in the treatment of enuresis†.

Administration

Trimipramine maleate is administered orally. Although trimipramine maleate has been administered in up to 4 divided doses throughout the day, it is long-acting and, when daily dosage does not exceed 200 mg, the entire daily dose may be administered at one time. Administration of most or all of the daily dosage at bedtime may reduce daytime sedation.

Dosage

Dosage of trimipramine maleate is expressed in terms of trimipramine. There is a wide range of dosage requirements, and dosage must be carefully individualized. Initial dosages should be low and generally range from 75-100 mg daily. Dosage may be gradually adjusted to the level that produces maximal therapeutic effect with minimal toxicity and may range up to 300 mg daily. Hospitalized patients under close supervision may generally be given higher dosages than outpatients, and the manufacturer states that dosages greater than 200 mg daily are not recommended for outpatients. Geriatric and adolescent patients should usually be given lower than average dosages. The manufacturer states that therapy should be initiated with 50 mg daily in these patients and the optimal dosage rarely exceeds 100 mg daily. Maximum antidepressant effects may not occur for 2 or more weeks after therapy is begun.

After symptoms are controlled, dosage should be gradually reduced to the lowest level which will maintain relief of symptoms. If maintenance therapy is necessary, the manufacturer recommends 50-150 mg daily, preferably administered as a single daily dose at bedtime. Maintenance therapy should be continued for at least 3 months to prevent relapse.

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.100,101,102,103 (See Cautions: Precautions and Contraindications, in the Tricyclic Antidepressants General Statement 28:16.04.28.)

Trimipramine shares the toxic potentials of the tricyclic antidepressants, and the usual precautions of tricyclic antidepressant administration should be observed. Patients should be fully advised about the risks, especially suicidal thinking and behavior (suicidality), associated with tricyclic antidepressant therapy.100,102,103 For a complete discussion, see Cautions: Precautions and Contraindications and Cautions: Pediatric Precautions, in the Tricyclic Antidepressants General Statement 28:16.04.28. Although effects differ among individual patients, sedative effects with trimipramine may be less than with amitriptyline but greater than with imipramine.

Pediatric Precautions

Safety and efficacy of trimipramine in pediatric patients have not been established.100 Therefore, the manufacturer recommends that the drug not be used in children.100

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.100,102 However, FDA also states that depression and certain other psychiatric disorders are themselves associated with an increased risk of suicide.100,102 Anyone considering the use of trimipramine in a child or adolescent for any clinical use must therefore balance the potential risk of therapy with the clinical need.100,102,103,104 (See Cautions: Precautions and Contraindications and Cautions: Pediatric Precautions, in the Tricyclic Antidepressants General Statement 28:16.04.28.)

Pharmacokinetics

The pharmacokinetics of trimipramine have not been extensively studied. Peak plasma concentrations of trimipramine occur 2 hours after a single oral dose. The plasma half-life is 9.1 hours. Animal studies indicate that trimipramine is metabolized via the same pathways as are other tricyclic antidepressants. In dogs and rabbits, 1.5-8% and 10-20%, respectively, of an oral dose are excreted in urine in 72 hours, primarily as conjugated metabolites. In dogs, 2-25% of an oral dose is excreted in feces and, in rabbits, 2% is excreted in feces.

The effect of age on the pharmacokinetics of trimipramine has not been fully elucidated. Data from a single-dose study suggest that the pharmacokinetics of trimipramine in geriatric individuals (65 years of age and older) do not differ substantially from those in younger adults.

Chemistry and Stability

Chemistry

Trimipramine is a dibenzazepine-derivative tricyclic antidepressant which differs structurally from imipramine in that a methyl group is added to the central carbon atom of the side chain. Trimipramine maleate is commercially available as a racemic mixture. The drug occurs as an almost odorless, white or slightly cream-colored, crystalline substance with a bitter, numbing taste. Trimipramine maleate is very slightly soluble in water and slightly soluble in alcohol. Trimipramine has a pK_a of 8.0.

Stability

Trimipramine maleate capsules should be stored in tight containers at approximately 25°C; unit-dose packages of the drug should be protected from excessive moisture.

Additional Information

For further information on chemistry, pharmacology, pharmacokinetics, uses, cautions, acute toxicity, drug interactions, and dosage and administration of trimipramine, see the Tricyclic Antidepressants General Statement 28:16.04.28.

Only references cited for selected revisions after 1984 are available electronically.

100. Duramed Pharmaceuticals, Inc. Surmontil^® (trimipramine maleate) capsules prescribing information. Ponoma, Ny; 2007 Jun.

101. 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]

102. 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]

103. 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]

104. 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]