VA Class:CN601

AHFS Class:

• Tricyclics and Other Norepinephrine-reuptake Inhibitors 28:16.04.28

Generic Name(s):

• Imipramine Hydrochloride

• Imipramine Pamoate

Imipramine is a dibenzazepine-derivative tricyclic antidepressant.

Administration

Imipramine hydrochloride and imipramine pamoate are administered orally. Although imipramine hydrochloride has been administered in up to 4 divided doses throughout the day, it is long-acting and the entire oral daily dose may be administered at one time. Imipramine pamoate may also be used to administer the daily oral dose of imipramine, but it has no advantages over the hydrochloride. Administration of the entire daily dose at bedtime may reduce daytime sedation; patients who experience insomnia and stimulation may be given the entire daily dose in the morning.

Dosage

Dosage of imipramine salts is expressed in terms of imipramine hydrochloride.

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.102,103,104 (See Cautions: Precautions and Contraindications, in the Tricyclic Antidepressants General Statement 28:16.04.28.)

Major Depressive Disorder

There is a wide range of oral dosage requirements, and dosage must be carefully individualized. Initial dosages of imipramine should be low and generally range from 75-100 mg daily, depending on the severity of the condition being treated. 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 manufacturers state that dosages of greater than 200 mg daily are not recommended for outpatients. Geriatric patients should usually be given lower than average dosages. Manufacturers state that therapy should be initiated with 25-50 mg daily as imipramine hydrochloride (e.g., Tofranil^®) in these patients and that optimal dosage rarely exceeds 100 mg daily. If the daily dosage is established at 75 mg or more, imipramine pamoate (e.g., Tofranil^® PM) may be administered. 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 that will maintain relief of symptoms. If maintenance therapy is necessary, manufacturers recommend an adult dosage of 50-150 mg daily. To avoid the possibility of precipitating withdrawal symptoms, imipramine should not be terminated abruptly in patients who have received high dosage for prolonged periods.

Functional Enuresis in Children

For the treatment of functional enuresis in children who are at least 6 years of age, the usual initial oral dosage of imipramine hydrochloride is 25 mg daily, administered 1 hour prior to bedtime. If a satisfactory response is not obtained within 1 week, dosage may be increased to 50 mg nightly for children younger than 12 years of age or 75 mg nightly for children 12 years of age and older. Dosages higher than 75 mg daily do not improve results and may increase the risk of adverse reactions. For children who are early-night bedwetters, better results may be obtained by administering 25 mg in midafternoon and again at bedtime. Dosage of imipramine hydrochloride for the treatment of functional enuresis in children should not exceed 2.5 mg/kg daily. Long-term effects of the drug in children have not been determined; therefore, after a satisfactory response has been maintained, imipramine hydrochloride should be gradually withdrawn. If dosage is gradually reduced after a favorable response of many weeks, relapses may be less frequent; children who relapse may not respond to subsequent treatment with imipramine. (See Cautions: Pediatric Precautions.)

Imipramine shares the pharmacologic actions, uses, and 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.103,104 For a complete discussion, see Cautions: Precautions and Contraindications and Cautions: Pediatric Precautions, in the Tricyclic Antidepressants General Statement 28:16.04.28.

Although the clinical importance is not known, ECG changes have been reported in pediatric patients receiving twice the recommended maximum daily dosage.

Pediatric Precautions

Imipramine hydrochloride is used for the treatment of enuresis in children 6 years of age or older, but safety and efficacy of the drug for the treatment of this condition in younger children or for the treatment of any other condition in pediatric patients have not been established. The manufacturer of imipramine pamoate states that the drug should not be used in children of any age because of the high potency and risk of acute overdose.

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.103,104 However, FDA also states that depression and certain other psychiatric disorders are themselves associated with an increased risk of suicide.103 Anyone considering the use of imipramine in a child or adolescent for any clinical use must therefore balance the potential risk of therapy with the clinical need.103,104,105 (See Cautions: Precautions and Contraindications and Cautions: Pediatric Precautions, in the Tricyclic Antidepressants General Statement 28:16.04.28.)

Pharmacokinetics

Absorption

In studies with radiolabeled imipramine, the drug was completely absorbed from the GI tract. Peak plasma concentrations of imipramine occur within 1-2 hours after oral administration and 30 minutes after IM administration (no longer commercially available in the US).

Distribution

Limited data indicate that imipramine and its active metabolite, desipramine, are distributed into milk100,101 in concentrations similar to those present in maternal plasma.101

Elimination

The plasma half-life of imipramine ranges from 8-16 hours. Imipramine is metabolized via the same pathways as are other tricyclic antidepressants; desipramine, its N -monodemethylated metabolite, is pharmacologically active. Approximately 40% of a dose of imipramine is excreted in urine as inactive metabolites within 24 hours and 70% within 72 hours; small amounts are excreted in feces via biliary elimination.

Chemistry and Stability

Chemistry

Imipramine is a dibenzazepine-derivative tricyclic antidepressant. The drug is commercially available as the hydrochloride and pamoate salts.

Imipramine hydrochloride occurs as a white to off-white, odorless or practically odorless, crystalline powder and is freely soluble in water and in alcohol. Imipramine pamoate occurs as a fine yellow powder and is insoluble in water and soluble in alcohol. Imipramine hydrochloride has a pK_a of 9.5.

Stability

Imipramine hydrochloride turns yellowish or reddish on exposure to light; slight discoloration does not affect potency, but marked discoloration is associated with loss of potency. Solutions of imipramine hydrochloride are stable at pH 4-5. During storage, minute crystals may form in imipramine hydrochloride injection (no longer commercially available in the US); the efficacy of the preparation is unaltered if the crystals are redissolved by immersing the ampul in hot water for 1 minute.

Imipramine hydrochloride tablets and impramine pamoate capsules should be stored in tight containers at a temperature between 15-30°C. Commercially available oral imipramine hydrochloride preparations have expiration dates of 3-5 years (depending on the manufacturer) following the date of manufacture. Commercially available imipramine pamoate capsules have an expiration date of 3 years following the date of manufacture.

Additional Information

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

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

100. Geigy Pharmaceuticals. Tofranil^® prescribing information. In: Huff BB, ed. Physicians' desk reference. 39th ed. Oradell, NJ: Medical Economics Company Inc; 1985:969-70.

101. Sovner R, Orsulak PJ. Excretion of imipramine and desipramine in human breast milk. Am J Psychiatry . 1979; 136:451-2. [PubMed 426114]

102. 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]

103. 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]

104. 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]

105. 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]