Drug Interactions between mirabegron and sirolimus

MONITOR: Coadministration with mirabegron may increase the plasma concentrations of sirolimus. The proposed mechanism is inhibition of intestinal P-glycoprotein (P-gp) efflux transporter by mirabegron, resulting in the enhanced oral bioavailability of sirolimus, a known P-gp substrate. In one case report, sirolimus serum concentration increased from 6.7 to 19.2 mcg/L six days following the initiation of mirabegron in a 31-year-old hematopoietic cell transplant patient who was receiving sirolimus 2 mg daily with mycophenolate mofetil for graft versus host disease prophylaxis. Other medications that were added around the same time as mirabegron were inhaled pentamidine, tolterodine and acyclovir, none of which are known to interact with sirolimus or have a plausible mechanism of interaction with sirolimus. Mirabegron was discontinued and sirolimus withheld until serum concentration fell to within therapeutic range. The patient was restarted on sirolimus and subsequently maintained on 1 mg and 2 mg per day alternating dosages for a total weekly dose of 10 mg until a taper was initiated per protocol.

MANAGEMENT: Caution is advised when sirolimus is used with a P-gp inhibitor such as mirabegron. Sirolimus levels and renal function should be checked frequently and the dosage adjusted accordingly, particularly following initiation or discontinuation of mirabegron. Patients should be monitored closely for adverse effects associated with sirolimus such as nephrotoxicity, malignancies, infections, angioedema, fluid retention, interstitial lung disease (e.g., pneumonitis, bronchiolitis obliterans organizing pneumonia, pulmonary fibrosis), diabetes, hyperlipidemia, and hypertension.