VA Class:CN601

AHFS Class:

• Tricyclics and Other Norepinephrine-reuptake Inhibitors 28:16.04.28

Generic Name(s):

• Desipramine Hydrochloride

Desipramine is a dibenzazepine-derivative tricyclic antidepressant.

Administration

Desipramine hydrochloride is administered orally. Although desipramine has been administered in up to 3 divided doses throughout the day, it is long-acting and the entire daily dose may be administered at one time. Administration of the entire daily dose at bedtime may reduce daytime sedation; patients who experience insomnia and stimulation from the drug may receive the entire daily dose in the morning.

Dosage

There is a wide range of dosage requirements, and dosage of desipramine hydrochloride must be carefully individualized. Initial dosages in adults should be low and generally range from 75-150 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. In seriously ill patients, desipramine dosage may be gradually increased to 300 mg daily if necessary. Desipramine hydrochloride dosages exceeding 300 mg daily are not recommended. Hospitalized patients under close supervision may generally be given higher doses than outpatients. Geriatric and adolescent patients should usually be given lower than average doses. Manufacturers state that therapy should be initiated with 25-50 mg daily in these patients and that dosages greater than 100 mg daily are usually not necessary. In geriatric and adolescent patients who are seriously ill, desipramine dosage may be further increased to 150 mg daily if necessary. Desipramine hydrochloride dosages exceeding 150 mg daily are not recommended in these age groups. 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. To avoid the possibility of precipitating withdrawal symptoms, desipramine should not be terminated abruptly in patients who have received high dosages for prolonged periods.

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.108,109,110 (See Cautions: Precautions and Contraindications, in the Tricyclic Antidepressants General Statement 28:16.04.28.)

Desipramine 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.109,110 For a complete discussion, see Cautions: Precautions and Contraindications and see Cautions: Pediatric Precautions, in the Tricyclic Antidepressants General Statement 28:16.04.28.

Desipramine should be used with extreme caution in patients with preexisting cardiovascular disease because of the possibility of conduction defects, arrhythmias, tachycardia, strokes, and acute myocardial infarction.112 The drug should also be used with extreme caution in patients with a family history of sudden death, cardiac dysrhythmias, or cardiac conduction disturbances.112,113,114 In addition, overdosage with desipramine has resulted in a higher death rate compared with overdosages of other tricyclic antidepressants.112,113,114,115 For a complete discussion on the cardiovascular effects of tricyclic antidepressants, see Cautions: Cardiovascular Effects and Cautions: Precautions and Contraindications, in the Tricyclic Antidepressants General Statement 28:16.04.28. For a complete discussion on the pathogenesis, manifestations, and treatment of overdosage due to tricyclic antidepressants, see Acute Toxicity, in the Tricyclic Antidepressants General Statement 28:16.04.28.

Pediatric Precautions

Because collapse and sudden death occurred in at least one child (an 8-year-old boy) receiving desipramine for 2 years for attention deficit hyperactivity disorder (ADHD)104 and sudden death also has been reported in other children receiving the drug,101,102,103,104 at least one manufacturer of desipramine recommends that the drug not be used in children.104,105 Although a causal relationship between the use of desipramine and the risk of sudden death has not been established, many clinicians recommend that desipramine not be used in children with this disorder when tricyclic antidepressant therapy is contemplated.101,102,103

The US Food and Drug Administration (FDA) also 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.109 However, FDA also states that depression and certain other psychiatric disorders are themselves associated with an increased risk of suicide.109 Anyone considering the use of desipramine in a child or adolescent for any clinical use must therefore balance the potential risk of therapy with the clinical need.109,110,111 (See Cautions: Precautions and Contraindications and see Cautions: Pediatric Precautions, in the Tricyclic Antidepressants General Statement 28:16.04.28.)

Geriatric Precautions

Geriatric patients may be at risk of drug-induced toxicity when treated with desipramine, a tricyclic antidepressant that is known to be eliminated mainly by the kidneys.104 In this patient population, the ratio of plasma concentrations of the principal metabolite, 2-hydroxydesipramine, to desipramine appears to be increased, most likely because of decreased renal elimination that occurs with aging.104 Therefore, particular attention should be paid to desipramine dosage and it may be useful to monitor renal function in these patients.104 Desipramine use in geriatric patients also has been associated with an increased risk of falling and mental confusion.104 (See Cautions: Geriatric Precautions, in the Tricyclic Antidepressants General Statement 28:16.04.28.)

Pharmacokinetics

Absorption

Desipramine hydrochloride appears to be well absorbed from the GI tract. Peak plasma concentrations occur within 4-6 hours after oral administration.

Distribution

Limited data indicate that desipramine is distributed into milk in concentrations similar to those present in maternal plasma.100

Elimination

The plasma half-life of desipramine ranges from 7 to longer than 60 hours. Desipramine is metabolized principally via oxidation to 2-hydroxydesipramine, which retains some of the parent compound's ability to block the uptake of amines and may have particularly prominent cardiac depressant activity.104,106,107

Chemistry and Stability

Chemistry

Desipramine is a dibenzazepine-derivative tricyclic antidepressant that is the active metabolite of imipramine. Desipramine hydrochloride occurs as a white to off-white crystalline powder and is soluble in water and in alcohol. The drug has pK_as of 1.5 and 10.2.

Stability

Desipramine hydrochloride tablets should be stored in tight containers at room temperature, preferably less than 30°C, and protected from excessive heat. Commercially available desipramine hydrochloride tablets have expiration dates of 5 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 desipramine, see the Tricyclic Antidepressants General Statement 28:16.04.28.

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105. American Academy of Pediatrics Committee on Quality Improvement and Subcommittee on Attention-Deficit/Hyperactivity Disorder. Clinical treatment guideline: treatment of the school-aged child with attention-deficit/hyperactivity disorder. Pediatrics . 2001; 108:1033-44. [PubMed 11581465]

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