Trimipramine

Drug Interactions Cimetidine There is evidence that cimetidine inhibits the elimination of tricyclic antidepressants. Downward adjustment of trimipramine capsules dosage may be required if cimetidine therapy is initiated; upward adjustment if cimetidine therapy is discontinued. Alcohol Patients should be warned that the concomitant use of alcoholic beverages may be associated with exaggerated effects. Catecholamines/Anticholinergics It has been reported that tricyclic antidepressants can potentiate the effects of catecholamines. Similarly, atropine-like effects may be more pronounced in patients receiving anticholinergic therapy.

Therefore, particular care should be exercised when it is necessary to administer tricyclic antidepressants with sympathomimetic amines, local decongestants, local anesthetics containing epinephrine, atropine or drugs with an anticholinergic effect. In resistant cases of depression in adults, a dose of 2.5 mg/kg/day may have to be exceeded. If a higher dose is needed, ECG monitoring should be maintained during the initiation of therapy and at appropriate intervals during stabilization of dose.

Drugs Metabolized by P450 2D6 The biochemical activity of the drug metabolizing isozyme cytochrome P450 2D6 (debrisoquin hydroxylase) is reduced in a subset of the caucasian population (about 7-10% of caucasians are so called "poor metabolizers"); reliable estimates of the prevalence of reduced P450 2D6 isozyme activity among Asian, African, and other populations are not yet available. Poor metabolizers have higher than expected plasma concentrations of tricyclic antidepressants (TCAs) when given usual doses. Depending on the fraction of drug metabolized by P450 2D6, the increase in plasma concentration may be small, or quite large (8 fold increase in plasma AUC of the TCA).

In addition, certain drugs inhibit the activity of the isozyme and make normal metabolizers resemble poor metabolizers. An individual who is stable on a given dose of TCA may become abruptly toxic when given one of these inhibiting drugs as concomitant therapy. The drugs that inhibit cytochrome P450 2D6 include some that are not metabolized by the enzyme (quinidine; cimetidine) and many that are substrates for P450 2D6 (many other antidepressants, phenothiazines, and the Type 1C antiarrhythmics propafenone and flecainide). While all the selective serotonin reuptake inhibitors (SSRIs), e.g., fluoxetine, sertraline, and paroxetine, inhibit P450 2D6, they may vary in the extent of inhibition.

The extent to which SSRI TCA interactions may pose clinical problems will depend on the degree of inhibition and the pharmacokinetics of the SSRI involved. Nevertheless, caution is indicated in the co-administration of TCAs with any of the SSRIs and also in switching from one class to the other. Of particular importance, sufficient time must elapse before initiating TCA treatment in a patient being withdrawn from fluoxetine, given the long half-life of the parent and active metabolite (at least 5 weeks may be necessary).

Concomitant use of tricyclic antidepressants with drugs that can inhibit cytochrome P450 2D6 may require lower doses than usually prescribed for either the tricyclic antidepressant or the other drug. Furthermore, whenever one of these other drugs is withdrawn from co-therapy, an increased dose of tricyclic antidepressant may be required. It is desirable to monitor TCA plasma levels whenever a TCA is going to be co-administered with another drug known to be an inhibitor of P450 2D6. Monoamine Oxidase Inhibitors (MAOIs) (See CONTRAINDICATIONS , WARNINGS , and DOSAGE AND ADMINISTRATION .) Serotonergic Drugs (See CONTRAINDICATIONS , WARNINGS , and DOSAGE AND ADMINISTRATION .)

Pregnancy Teratogenic Effects Pregnancy Category C Trimipramine capsules have shown evidence of embryotoxicity and/or increased incidence of major anomalies in rats or rabbits at doses 20 times the human dose. There are no adequate and well-controlled studies in pregnant women. Trimipramine capsules should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.