Drug Interactions between Caduet and sirolimus

MONITOR: Coadministration with inhibitors of CYP450 3A4 may increase the plasma concentrations of HMG-CoA reductase inhibitors (i.e., statins) that are metabolized by the isoenzyme. Lovastatin and simvastatin are particularly susceptible because of their low oral bioavailability, but others such as atorvastatin and cerivastatin may also be affected. High levels of HMG-CoA reductase inhibitory activity in plasma is associated with an increased risk of musculoskeletal toxicity. Myopathy manifested as muscle pain and/or weakness associated with grossly elevated creatine kinase exceeding ten times the upper limit of normal has been reported occasionally. Rhabdomyolysis has also occurred rarely, which may be accompanied by acute renal failure secondary to myoglobinuria and may result in death. Clinically significant interactions have been reported with potent CYP450 3A4 inhibitors such as macrolide antibiotics, azole antifungals, protease inhibitors and nefazodone, and moderate inhibitors such as amiodarone, cyclosporine, danazol, diltiazem and verapamil.

MANAGEMENT: Caution is recommended if atorvastatin, cerivastatin, lovastatin, simvastatin, or red yeast rice (which contains lovastatin) is prescribed with a CYP450 3A4 inhibitor. It is advisable to monitor lipid levels and use the lowest effective statin dose. All patients receiving statin therapy should be advised to promptly report any unexplained muscle pain, tenderness or weakness, particularly if accompanied by fever, malaise and/or dark colored urine. Therapy should be discontinued if creatine kinase is markedly elevated in the absence of strenuous exercise or if myopathy is otherwise suspected or diagnosed. Fluvastatin, pravastatin, and rosuvastatin are not expected to interact with CYP450 3A4 inhibitors.

MONITOR: The use of mTOR (mammalian target of rapamycin) inhibitors has been associated with the development of angioedema, and coadministration with amlodipine may increase the risk. The mechanism of this interaction has not been established. The onset of angioedema may sometimes be delayed up to two months following initiation of therapy. In addition, amlodipine, a weak CYP450 3A4 inhibitor, may increase the plasma concentrations of mTOR inhibitors, which are primarily metabolized by the isoenzyme.

MANAGEMENT: Caution is advised if amlodipine is administered with mTOR inhibitors. Clinicians and patients should be aware of the potential for increased plasma levels as well as the risk of angioedema when mTOR inhibitors are prescribed with amlodipine. Dosage adjustments as well as clinical and laboratory monitoring should be considered whenever amlodipine is added to or withdrawn from therapy. Patients should be advised to promptly discontinue these medications and seek medical attention if they develop signs or symptoms suggestive of angioedema such as swelling of the face, extremities, eyes, lips, or tongue, and difficulty swallowing or breathing. Patients should be monitored for development of other adverse effects including hypertension, hyperlipidemia, renal impairment, proteinuria, infections, and various types of malignancies.

GENERALLY AVOID: Coadministration of a macrolide immunosuppressant with certain HMG-CoA reductase inhibitors may result in elevated plasma concentrations of both due to competitive inhibition of CYP450 3A4 metabolism. High levels of HMG-CoA reductase inhibitory activity in plasma is associated with an increased risk of musculoskeletal toxicity including rhabdomyolysis, which can be fatal. In one case report, severe rhabdomyolysis complicated by acute renal transplant failure occurred in a diabetic woman whose drug regimen at the time of hospital admission consisted of tacrolimus, azathioprine, prednisolone, felodipine, citalopram, aspirin, insulin, simvastatin, and fusidic acid. The patient developed muscle pain accompanied by a grossly elevated serum creatine kinase level several weeks after simvastatin was increased from 10 to 20 mg/day and fusidic acid was initiated to treat soft tissue infection and osteomyelitis of a toe. She recovered after discontinuation of simvastatin and fusidic acid and institution of supportive therapy. Simvastatin was later replaced with fluvastatin, and fusidic acid was administered on another occasion without incident. The authors suggest that use of tacrolimus with simvastatin at a dosage exceeding 10 mg/day may increase the risk of rhabdomyolysis. The use of fusidic acid may have presented an additional risk factor in the case patient. In another report, a transplant patient developed significantly elevated sirolimus serum trough levels following addition of atorvastatin to her regimen. No adverse effects were reported, but a 50% reduction in sirolimus dosage was required.

MANAGEMENT: In general, lovastatin, red yeast rice (which contains lovastatin), and simvastatin should preferably be avoided in patients treated with sirolimus or tacrolimus due to the potential for serious interaction. Atorvastatin may be used with caution, although the dosage should start low, and immunosuppressant blood levels should be closely monitored. Pravastatin and fluvastatin are probably the safest alternatives, since they are not metabolized by CYP450 3A4. All patients treated with HMG-CoA reductase inhibitors should be advised to promptly report any unexplained muscle pain, tenderness, or weakness, particularly if accompanied by malaise or fever. Therapy should be discontinued if creatine kinase is markedly elevated in the absence of strenuous exercise or if myopathy is otherwise suspected or diagnosed.