Cancidas Drug Interactions

Studies in vitro show that caspofungin acetate is not an inhibitor of any enzyme in the cytochrome P450 (CYP) system. In clinical studies, caspofungin did not induce the CYP3A4 metabolism of other drugs. Caspofungin is not a substrate for P-glycoprotein and is a poor substrate for cytochrome P450 enzymes.
In two adult clinical studies, cyclosporine (one 4 mg/kg dose or two 3 mg/kg doses) increased the AUC of caspofungin by approximately 35%. These AUC increases are probably due to reduced uptake of caspofungin by the liver. CANCIDAS did not increase the plasma levels of cyclosporine. There were transient increases in liver ALT and AST when CANCIDAS and cyclosporine were co-administered. In a retrospective study of 40 patients treated during marketed use with CANCIDAS and/or cyclosporine for 1 to 290 days (median 17.5 days), no serious hepatic adverse events were noted (see Precautions).
Clinical studies in adult healthy volunteers show that the pharmacokinetics of CANCIDAS are not altered by itraconazole, amphotericin B, mycophenolate, nelfinavir or tacrolimus. CANCIDAS has no effect on the pharmacokinetics of itraconazole, amphotericin B, rifampin or the active metabolite of mycophenolate.
CANCIDAS reduced the 12-hour blood concentration (C_12hr) of tacrolimus (FK-506) by 26% in healthy adult volunteers. For patients receiving both therapies, standard monitoring of tacrolimus blood concentrations and appropriate tacrolimus dosage adjustments are recommended.
Results from two clinical drug interaction studies in healthy adult volunteers indicate that rifampin both induces and inhibits caspofungin disposition with net induction at steady state. In one study, rifampin and caspofungin were co-administered for 14 days with both therapies initiated on the same day. In the second study, rifampin was administered alone for 14 days to allow the induction effect to reach steady state, and then rifampin and caspofungin were co-administered for an additional 14 days. When the induction effect of rifampin was at steady state, there was little change in caspofungin AUC or end-of-infusion concentration, but caspofungin trough concentrations were reduced by approximately 30%. The inhibitory effect of rifampin was demonstrated when rifampin and caspofungin treatments were initiated on the same day, and a transient elevation in caspofungin plasma concentrations occurred on Day 1 (approximately 60% increase in AUC). This inhibitory effect was not seen when caspofungin was added to preexisting rifampin therapy, and no elevation in caspofungin concentrations occurred. In addition, results from population pharmacokinetic screening in adults suggest that co-administration of other inducers of drug clearance (efavirenz, nevirapine, phenytoin, dexamethasone, or carbamazepine) with CANCIDAS may also result in clinically meaningful reductions in caspofungin concentrations. Available data suggest that the inducible drug clearance mechanism involved in caspofungin disposition is likely an uptake transport process, rather than metabolism. Therefore, when CANCIDAS is co-administered to adult patients with inducers of drug clearance, such as efavirenz, nevirapine, rifampin, dexamethasone, phenytoin, or carbamazepine, use of a daily dose of 70 mg of CANCIDAS should be considered (see Dosage & Administration).
In pediatric patients, results from regression analyses of pharmacokinetic data suggest that co-administration of dexamethasone with CANCIDAS may result in clinically meaningful reductions in caspofungin trough concentrations. This finding may indicate that pediatric patients will have similar reductions with inducers as seen in adults. When CANCIDAS is co-administered to pediatric patients with inducers of drug clearance, such as rifampin, efavirenz, nevirapine, phenytoin, dexamethasone, or carbamazepine, a CANCIDAS dose of 70-mg/m² daily (not to exceed an actual daily dose of 70 mg) should be considered.