Regulatory Decision Summary for Cubicin, Cubicin RF

The safety and efficacy profile of Cubicin is well established, based on its use in adult populations since its first approval in September 2007. A reformulated product (Cubicin RF) has been subsequently approved in June 2017. The nonclinical pharmacology, pharmacokinetics and toxicology of daptomycin have been well characterized as previously assessed during the original approval in 2007. Two pre-clinical studies in juvenile dogs and one study in neonatal dogs have been previously submitted to support the extension of daptomycin use in pediatric patients. One pre-clinical study submitted with the current submission indicates no difference in pharmacokinetic (PK) parameters of daptomycin between the two formulations.

The safety and efficacy in pediatric populations is based on PK modelling studies to determine the appropriate dose in children, followed by two phase-4 clinical studies in pediatric patients, one each in patients with complicated skin and skin structure infections (cSSSI) and Staphylococcus aureus bloodstream (SAB) infections respectively.

Daptomycin was shown to be effective in the treatment of cSSSI caused by Gram-positive pathogens. Protocol specified clinical success rates at test of cure visit were 88.3% and 86.4% in daptomycin and comparator arms, respectively. Microbiological success was high and similar in the two arms for the most commonly isolated pathogens. Similarly, daptomycin was observed to be effective in the treatment of SAB infections in the pediatric population aged 1 to 17 years. The clinical trial conducted with SAB infection had no pediatric patient enrolled between 1-2 years but the efficacy in this population was supported by pharmacokinetic data and modelling studies.

Daptomycin has been shown to be well tolerated at the proposed doses for the treatment of cSSSI and SAB infections. The incidence of treatment emergent adverse events (TEAEs), drug-related TEAEs and TEAEs leading to discontinuation of study drug reported for daptomycin were comparable to those reported for comparator. No new safety concerns were identified for daptomycin in pediatric subjects when compared with those in adults. The observed events of peripheral neuropathy or skeletal muscle toxicity (Rhabdomyolysis/Myopathy) showed no difference in frequency, severity, or outcomes of skeletal muscle adverse events observed in adult subjects. There were no reported cases of drug hypersensitivity, eosinophilic pneumonia, bone marrow toxicity, or hepatotoxicity in the daptomycin group. The majority of reported Adverse Events (AEs) were mild to moderate in severity.

In conclusion, daptomycin has been shown to be well tolerated and efficacious for treatment of cSSSI and SAB at the proposed doses. The once daily dosing of Cubicin or Cubicin RF by IV infusion provides a convenient and additional option for the treatment of cSSSI and SAB infection in pediatric patients. The overall benefit-harm-uncertainty balance of daptomycin in the pediatric population with cSSSI and SAB is considered to be favorable.