Drug Interactions between ivacaftor / lumacaftor and temsirolimus

GENERALLY AVOID: Coadministration of temsirolimus with potent inducers of CYP450 3A4 may significantly decrease the plasma concentrations of sirolimus, a major active metabolite of temsirolimus and known substrate of CYP450 3A4. According to the product labeling, administration of temsirolimus in combination with the CYP450 3A4 inducer rifampin resulted in a 65% and 56% decrease in sirolimus peak plasma concentration (Cmax) and systemic exposure (AUC), respectively, compared to administration of temsirolimus alone. No significant effect on the pharmacokinetics of temsirolimus was reported.

MANAGEMENT: Concomitant use of temsirolimus with potent CYP450 3A4 inducers should generally be avoided. If coadministration is required in patients treated with temsirolimus for renal cell carcinoma, the manufacturer recommends increasing the temsirolimus dosage from 25 mg to 50 mg once a week depending on patient tolerability. Based on pharmacokinetic studies, this dosage is predicted to adjust the sirolimus systemic exposure (AUC) to the range observed without inducers. However, clinical data are lacking. The dosage should be reduced to the normally recommended dosage (i.e., 25 mg once a week) following discontinuation of the potent CYP450 3A4 inducer.

MONITOR: Coadministration of temsirolimus with inhibitors of CYP450 3A4 may increase the plasma concentrations of sirolimus, a major active metabolite of temsirolimus and known substrate of CYP450 3A4. According to the product labeling, administration of temsirolimus in combination with the potent CYP450 3A4 inhibitor ketoconazole resulted in a 2.2-fold and 3.1-fold increase in sirolimus peak plasma concentration (Cmax) and systemic exposure (AUC), respectively, compared to administration of temsirolimus alone. No significant effect on the pharmacokinetics of temsirolimus was reported.

MANAGEMENT: Caution is advised if temsirolimus is prescribed in combination with CYP450 3A4 inhibitors. Pharmacologic response to temsirolimus should be monitored more closely whenever a CYP450 3A4 inhibitor is added to or withdrawn from therapy, and the temsirolimus dosage adjusted as necessary. Patients should be advised to contact their physician if they experience increased adverse effects of temsirolimus such as hyperglycemia (e.g., excessive thirst; increased volume and/or frequency of urination), infections, fever, dyspnea, abdominal pain, diarrhea, and bloody stools.