Ranolazine, tacrolimus, and diltiazem might be a hazardous combination in a transplant patient

We report a case of a renal transplant patient who was maintained on tacrolimus and diltiazem therapy and developed tacrolimus toxicity leading to reversible acute kidney injury when started on ranolazine. A 62-year-old Caucasian male status post renal transplant in 2009 (on prednisone and tacrolimus) was evaluated for ischemic heart disease and was initiated on ranolazine 500 mg tablets twice daily, which was later increased to 1000 mg twice daily. After 2 weeks, he developed fatigue, loss of appetite, tremors, and decreased urine output and was admitted to our hospital. His other significant medications included enalapril 2.5 mg and diltiazem 240 mg daily. The patient was awake and alert, but lethargic. He was found to be bradycardic with a heart rate of 42/min. The rest of his physical examination was benign. His electrocardiogram revealed sinus bradycardia. Laboratory studies revealed serum creatinine of 2.4 mg/dL from a baseline of 1.5 mg/dL (stable for the past 2 years). The tacrolimus trough was elevated at 14 ng/mL, which decreased after stopping ranolazine, reaching 7 ng/mL after 3 days, while continuing the same dose of tacrolimus. His creatinine trended downward and reached his baseline of 1.5 mg/dL over the next 2 days. His bradycardia and other symptoms resolved after cessation of ranolazine. He was discharged to follow up, to initiate an alternate agent for ischemic heart disease. Specific pharmacokinetic studies are warranted to study these drug interactions, and tacrolimus levels should be closely monitored in transplant patients who initiate ranolazine treatment.