In addition, regular monitoring of renal function is advised during concomitant administration of potentially nephrotoxic agents, regardless of the patient's pre-existing renal function (see also section 4.5).

Obesity

In obese subjects with Body Mass Index (BMI) > 40 kg/m2 but with creatinine clearance > 70 ml/min, the AUC0- daptomycin was significantly increased (mean 42% higher) compared with non-obese matched controls. There is limited information on the safety and efficacy of daptomycin in the very obese and so caution is recommended. However, there is currently no evidence that a dose reduction is required (see section 5.2).

4.5 Interaction with other medicinal products and other forms of interaction

 Daptomycin undergoes little to no Cytochrome P450 (CYP450)-mediated metabolism. It is unlikely that daptomycin will inhibit or induce the metabolism of medicinal products metabolised by the P450 system.

Interaction studies for Cubicin were performed with aztreonam, tobramycin, warfarin and probenecid. Daptomycin had no effect on the pharmacokinetics of warfarin or probenecid, nor did these medicinal products alter the pharmacokinetics of daptomycin. The pharmacokinetics of daptomycin were not significantly altered by aztreonam.

Although small changes in the pharmacokinetics of daptomycin and tobramycin were observed during coadministration using a Cubicin dose of 2 mg/kg, the changes were not statistically significant. The interaction between daptomycin and tobramycin with an approved dose of Cubicin is unknown. Caution is warranted when Cubicin is co-administered with tobramycin.

Experience with the concomitant administration of Cubicin and warfarin is limited. Studies of Cubicin with anticoagulants other than warfarin have not been conducted. Anticoagulant activity in patients receiving Cubicin and warfarin should be monitored for the first several days after therapy with Cubicin is initiated.

There is limited experience regarding concomitant administration of daptomycin with other medicinal products that may trigger myopathy (e.g. HMG-CoA reductase inhibitors). However, some cases of marked rises in CPK levels and cases of rhabdomyolysis occurred in patients taking one of these medicinal products at the same time as Cubicin. It is recommended that other medicinal products associated with myopathy should if possible be temporarily discontinued during treatment with Cubicin unless the benefits of concomitant administration outweigh the risk. If co-administration cannot be avoided, CPK levels should be measured more frequently than once weekly and patients should be closely monitored for any signs or symptoms that might represent myopathy. See sections 4.4, 4.8 and 5.3.

Daptomycin is primarily cleared by renal filtration and so plasma levels may be increased during co-administration with medicinal products that reduce renal filtration (e.g. NSAIDs and COX-2 inhibitors). In addition, there is a potential for a pharmacodynamic interaction to occur during co-administration due to additive renal effects. Therefore, caution is advised when daptomycin is co-administered with any other medicinal product known to reduce renal filtration.

During post–marketing surveillance, cases of interferen