Tacrolimus and Clotrimazole Topical: Interaction Details

a) In a retrospective study in patients with recent heart transplantation who received clotrimazole 10 mg troches orally 3 times daily for prophylaxis of oral candidiasis (N=95; about 30 days of clotrimazole prophylaxis) along with combination immunosuppression including tacrolimus (with therapeutic drug monitoring to maintain a trough level of 8 to 16 nanograms/mL), median tacrolimus dose increased significantly by 66.7% (interquartile range, 28.6% to 100%) after discontinuation of clotrimazole. Mean tacrolimus dose requirement was 4 mg daily (interquartile range, 3 to 5.6 mg) before discontinuation of clotrimazole compared with 7 mg daily (interquartile range, 5 to 9 mg) after clotrimazole was discontinued. Five subjects who had subtherapeutic tacrolimus levels after discontinuation of clotrimazole experienced acute rejection, although other factors likely contributed to rejection episodes. Patients in this study needed at least a 28.6% dose increase of tacrolimus after clotrimazole was stopped ⁴.

b) A 23-year-old woman experienced calcineurin inhibitor-induced pain syndrome with severe back pain from high tacrolimus trough concentrations following administration of clotrimazole troche. She had ESRD from lupus nephritis and had just received a kidney allograft. Medications upon discharge included tacrolimus 8 mg/day (tacrolimus trough concentration 4.6 nanograms (ng)/ml), mycophenolate mofetil, prednisoLONE, cotrimoxazole, and acyclovir. She received clotrimazole troche 3 times a day for oral candidiasis prophylaxis. Two days later she presented with severe dull aching back pain from thoracic to lumbar level, with a pain score of 10/10, which was unresponsive to pain medications. MRI of the spine revealed bone marrow edema. The tacrolimus trough concentration was 28.2 ng/mL (9.1 ng/mL 2 weeks earlier). Clotrimazole was discontinued and pain improved to 3/10 within 30 minutes of pregabalin initiation. Tacrolimus trough decreased to 6 to 7 ng/mL and she had complete resolution 3 weeks after onset ⁵.

c) A 23-year-old female with ESRD receiving concomitant tacrolimus and clotrimazole following renal transplant surgery, experienced decreasing tacrolimus trough levels when clotrimazole was discontinued, and increasing tacrolimus levels when clotrimazole was restarted. During her first postoperative month, she was receiving an immunosuppressive regimen consisting of tacrolimus 5 mg twice daily, mycophenolate mofetil 1000 mg twice daily, and predniSONE 30 mg/day (tapered over time to 5 mg/day), and routine prophylaxis with clotrimazole troches 10 mg four times daily. During this month, her tacrolimus trough levels were within goal range at 12 to 15 nanograms (ng)/mL. On postoperative day 31, clotrimazole was discontinued and over the next 6 days, her tacrolimus trough levels decreased from 13.7 ng/mL to a subtherapeutic level of 5.4 ng/mL. Other causes for the decrease in tacrolimus trough levels were ruled-out. On postoperative day 38, clotrimazole was resumed and tacrolimus was increased to 6 mg twice daily. On postoperative day 40, her tacrolimus trough level had increased to 19.2 ng/mL (target range, 10 to 12 ng/mL), and thus tacrolimus was decreased to 4.5 mg twice daily. On postoperative day 44, her tacrolimus trough level was 13.4 ng/mL. To obtain a target tacrolimus trough level of 11 to 12 ng/mL, tacrolimus was further reduced to 4 mg twice daily. After the third posttransplant month, clotrimazole was discontinued when target tacrolimus trough levels were between 4 and 7 ng/mL. The patient had no side effects from this drug interaction ³.

d) Clotrimazole therapy causes a significant rise in tacrolimus trough levels that could lead to tacrolimus-associated toxicities in the early post-transplant period. Thirty-five tacrolimus-treated renal allograft recipients were randomized to treatment with either clotrimazole (N=17) or nystatin, control group (N=18), for oral thrush prophylaxis immediately following transplant surgery. A tacrolimus loading dose (approximately 0.3 mg/kg orally) was administered pre-transplant. Tacrolimus (0.15 mg/kg orally) was administered twice daily. Clotrimazole therapy consisted of a 10 mg troche administered three times daily. Oral nystatin suspension (5 mL) was administered as a 'swish and swallow' four times daily. Tacrolimus blood levels were significantly higher in clotrimazole-treated patients on days 3, 5, and 7 (42 +/- 14, 53 +/- 7, and 33 +/- 17 nanograms (ng)/mL) compared with nystatin-treated patients (15 +/- 8, 15 +/- 7, and 14 +/- 6 ng/mL). Mean tacrolimus doses were significantly lower in the clotrimazole group when compared with nystatin-treated patients by day 7. This interaction is due to inhibition of CYP3A4 or P-glycoprotein in the gut wall. Clotrimazole therapy may cause significantly higher tacrolimus trough blood levels ⁶.