Nefazodone is the newest antidepressant agent to be approved in the United States. This agent has been shown in vitro to be a potent inhibitor of the cytochrome P-450 system, specifically of IIIA4. Several critical drug interactions involving this isozyme are listed in the product information for nefazodone, including interactions with terfenadine, astemizole, triazolam, and alprazolam. Cyclosporine is metabolized through IIIA4, but this fact is not specifically noted in the package insert. The following case report suggests that a clinically significant drug interaction exists between nefazodone and cyclosporine.

A 23-year-old man who had received a kidney transplant in 1992 was transferred to our inpatient psychiatry service for the treatment of depression following a suicide attempt with amoxapine. Admission medications included cyclosporine, 225 mg twice daily. Treatment with nefazodone was begun, and no contraindications to its use were noted. No specific information on a drug interaction between nefazodone and cyclosporine was found in the nefazodone package insert or in a search of Excerpta Medica, Biosis, the MEDLINE database, or Current Contents. Cyclosporine concentrations were monitored, however, because in vitro studies have shown that nefazodone inhibited the pathway that metabolizes cyclosporine.

The initial trough cyclosporine concentration was 122 ng/mL. Nefazodone therapy was initiated at a dosage of 25 mg twice daily. The repeat trough cyclosporine concentration done 3 days later had increased almost 70% to 204 ng/mL. Nefazodone therapy was discontinued. Cyclosporine concentrations were 196 ng/mL, 194 ng/mL, and 123 ng/mL during the next 4 days.

The interaction between nefazodone and cyclosporine is probably caused by nefazodone's inhibition of the cytochrome P-450 system, specifically isozyme IIIA4 [1]. Caution should be used in consulting the product information when nefazodone is used with drugs known to be metabolized by isozyme IIIA4. Cyclosporine, however, is not individually listed. Interaction studies involving concurrent use of nefazodone and either triazolam or alprazolam (both metabolized by IIIA4) have shown that the concentrations of these benzodiazepines increased 1.7-fold and 2-fold, respectively. Coadministration of nefazodone and either terfenadine or astemizole is contraindicated because of the potential for torsade de pointes from inhibition of IIIA4 metabolism of these antihistamines.

If cyclosporine and nefazodone are used concurrently, cyclosporine concentrations should be closely monitored to avoid the potential toxicities of this immunosuppressant agent.