Drug Interactions between Caduet and itraconazole

MONITOR CLOSELY: Itraconazole exhibits a dose-related negative inotropic effect which may be additive to those of calcium channel blockers (CCBs). Theoretically, coadministration may potentiate the risk of ventricular dysfunction, congestive heart failure, and peripheral and pulmonary edema, particularly in patients with preexisting risk factors (e.g., a history of congestive heart failure; cardiac disease such as ischemic and valvular disease; significant pulmonary disease such as chronic obstructive pulmonary disorder; edematous disorders such as renal failure). In addition, both itraconazole and its major metabolite, hydroxyitraconazole, inhibit CYP450 3A4 metabolism and may interfere with the clearance of certain CCBs like the dihydropyridines (amlodipine, felodipine, isradipine, lacidipine, nicardipine, nifedipine, nimodipine, nisoldipine), diltiazem, and verapamil. Significant increases of severalfold in felodipine and nifedipine plasma concentrations have been observed during coadministration with itraconazole, and there have been case reports of leg and ankle edema in patients treated with various itraconazole-dihydropyridine combinations. Itraconazole alone has also been associated with postmarketing reports of congestive heart failure, peripheral edema, and pulmonary edema in patients treated for onychomycosis and/or systemic fungal infections. Heart failure was more frequently reported in patients receiving a dosage of 400 mg/day, although there were also cases reported among those receiving lower daily dosages.

MANAGEMENT: Caution is advised if itraconazole must be used concomitantly with CCBs. Close monitoring of clinical response and tolerance is recommended, and patients should be advised to seek medical attention if they experience edema or swelling of the lower extremities; sudden, unexplained weight gain; difficulty breathing; chest pain or tightness; or hypotension as indicated by dizziness, fainting, or orthostasis. Appropriate dosage adjustment of the CCB may be necessary when used with itraconazole. Some authorities consider concomitant administration of bepridil and itraconazole to be contraindicated during and for 2 weeks after treatment with itraconazole.

ADJUST DOSE: Coadministration with itraconazole may significantly increase the plasma concentrations of atorvastatin and potentiate the risk of statin-induced myopathy. The proposed mechanism is itraconazole inhibition of atorvastatin metabolism via intestinal and hepatic CYP450 3A4. When single doses of atorvastatin 20 mg and 40 mg were coadministered with itraconazole 200 mg daily for 4 days, atorvastatin systemic exposure (AUC) increased by 2.5- and 3.3-fold, respectively, compared to atorvastatin administered alone. High levels of statin or 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.

MANAGEMENT: The benefits of using atorvastatin in combination with itraconazole should be carefully weighed against the potentially increased risk of myopathy including rhabdomyolysis. The lowest effective dosage of atorvastatin should be used, and should not exceed 20 mg/day when prescribed with itraconazole. Fluvastatin, pitavastatin, pravastatin, and rosuvastatin may be safer alternatives, since they are not metabolized by CYP450 3A4. 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.

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.