Drug Interactions between azithromycin / trovafloxacin and cyclosporine

MONITOR: Available data suggest that azithromycin may rarely increase the blood concentrations of cyclosporine. The mechanism of interaction has not been established. Other macrolide antibiotics such as clarithromycin and erythromycin interfere with the clearance of cyclosporine by inhibiting CYP450 3A4 metabolism and P-glycoprotein efflux, but azithromycin is not known to inhibit either. Pharmacokinetic studies in healthy volunteers and kidney transplant patients have also found no evidence of a clinically significant interaction, and azithromycin has been studied extensively in the treatment of cyclosporine-induced gingival hyperplasia without reports of interaction. Nevertheless, there have been isolated case reports of markedly increased cyclosporine blood levels during coadministration with azithromycin. In one report, cyclosporine trough level increased from 178 ng/mL (taken two weeks before and on the first day of hospitalization) to 400 ng/mL three days after initiation of ceftriaxone (1 gram IV every 12 hours) and azithromycin (500 mg IV once a day) to treat probable pneumonia in a 42-year-old kidney transplant patient who had been stabilized on cyclosporine 100 mg twice a day for two years. His cyclosporine dosage was reduced by 50%, and trough level returned to normal on hospital day 6 and remained normal three days later when azithromycin was discontinued. However, on hospital day 13, cyclosporine trough level dropped to 76 ng/mL, which led to a dosage increase back to 100 mg twice a day. Three days later, cyclosporine trough level was at 170 ng/mL and remained within target when measured on day 19 and at follow-up three weeks after discharge. Confounding factors in the case include active infection and fever, which can alter the level and activity of CYP isoenzymes, as well as the concomitant administration of ceftriaxone, which has been associated with increased cyclosporine levels by approximately 2-fold in isolated case reports. However, the temporal relationship between discontinuation of azithromycin and decreased cyclosporine levels would implicate azithromycin rather than ceftriaxone, which was not stopped until hospital day 17. Other, unpublished reports of adverse events attributed to potential interaction between azithromycin and cyclosporine include tinnitus, elevations in blood urea nitrogen and serum creatinine, and leukopenia.

MANAGEMENT: Caution and closer monitoring of cyclosporine blood levels and renal function may be advisable during coadministration with azithromycin, particularly in patients who are elderly or critically ill. Patients should be advised to notify their physician if they experience possible signs and symptoms of cyclosporine toxicity such as nausea, vomiting, diarrhea, abdominal pain, dizziness, fatigue, headache, tremors, and convulsions.