Clarithromycin × Tacrolimus

Tacrolimus, an immunosuppressant used after organ transplantation, is cleared by CYP3A4 in the liver and gut. Clarithromycin strongly inhibits CYP3A4. According to the tacrolimus SmPC, a strong CYP3A4 inhibitor raises tacrolimus levels rapidly and sharply, within 1–3 days and even after an immediate dose reduction, and overall exposure may increase more than 5-fold. With a narrow therapeutic range such a rise is dangerous: the label lists nephrotoxicity, neurotoxicity and QT prolongation.

Acute nephrotoxicity: rising creatinine and falling glomerular filtration rate. Tremor, headache, hypertension, hyperglycaemia, hyperkalaemia. In transplant patients, accelerated graft function decline.

The tacrolimus SmPC advises avoiding the combination, so the first step is to replace clarithromycin, usually with azithromycin if the spectrum fits. If clarithromycin cannot be avoided, a transplant specialist runs the regimen. Per the label, omitting the tacrolimus dose on the day clarithromycin starts is considered, and tacrolimus is restarted the next day at a reduced dose guided by blood levels. Trough levels are measured at baseline, frequently from the first days of co-administration, when clarithromycin stops and afterwards, because the effect lasts several days. Creatinine and the QT interval on ECG are monitored in parallel.