Fertility and reproductive performance were not affected by the intravenous administration of caspofungin to rats at doses up to 5 mg/kg. At 5 mg/kg exposures were similar to those seen in patients treated with the 70-mg dose.
13.2 Animal Toxicology And/Or Pharmacology
In one 5-week study in monkeys at doses which produced exposures approximately 4 to 6 times those seen in patients treated with a 70-mg dose, scattered small foci of subcapsular necrosis were observed microscopically in the livers of some animals (2/8 monkeys at 5 mg/kg and 4/8 monkeys at 8 mg/kg); however, this histopathological finding was not seen in another study of 27 weeks duration at similar doses.
No treatment-related findings were seen in a 5-week study in infant monkeys at doses which produced exposures approxmately 3 times those achieved in pediatric patients receiving a maintenance dose of 50 mg/m2 daily.
14. CLINICAL STUDIES
The results of the adult clinical studies are presented by indications in Section 14.1 to 14.4. Results of pediatric clinical trials are in Section 14.5.
14.1 Empirical Therapy in Febrile, Neutropenic Patients
A double-blind study enrolled 1111 febrile, neutropenic (<500 cells/mm3) patients who were randomized to treatment with daily doses of CANCIDAS (50 mg/day following a 70-mg loading dose on Day 1) or AmBisome (3.0 mg/kg/day). Patients were stratified based on risk category (high-risk patients had undergone allogeneic stem cell transplantation or had relapsed acute leukemia) and on receipt of prior antifungal prophylaxis. Twenty-four percent of patients were high risk and 56% had received prior antifungal prophylaxis. Patients who remained febrile or clinically deteriorated following 5 days of therapy could receive 70 mg/day of CANCIDAS or 5.0 mg/kg/day of AmBisome. Treatment was continued to resolution of neutropenia (but not beyond 28 days unless a fungal infection was documented).
An overall favorable response required meeting each of the following criteria: no documented breakthrough fungal infections up to 7 days after completion of treatment, survival for 7 days after completion of study therapy, no discontinuation of the study drug because of drug-related toxicity or lack of efficacy, resolution of fever during the period of neutropenia, and successful treatment of any documented baseline fungal infection.
Based on the composite response rates, CANCIDAS was as effective as AmBisome in empirical therapy of persistent febrile neutropenia (see Table 10).
Table 10: Favorable Response of Patients with Persistent Fever and Neutropenia
CANCIDAS*
AmBisome* % Difference
(Confidence
Interval)†
*
CANCIDAS: 70 mg on Day 1, then 50 mg daily for the remainder of treatment (daily dose increased to 70 mg for 73 patients); AmBisome: 3.0 mg/kg/day (daily dose increased to 5.0 mg/kg for 74 patients).
†
Overall Response: estimated % difference adjusted for strata and expressed as CANCIDAS – AmBisome (95.2% CI); Individual criteria presented above are not mutually exclusive. The percent difference calculated as CANCIDAS – AmBisome.
‡
Analysis population excluded subjects who did not have fever or neutropenia at study entry.
Number of Patients‡ 556 539
Overall Favorable Response 190 (33.9%) 181 (33.7%) 0.2 (-5.6, 6.0)
No documented breakthrough fungal infection 527 (94.8%) 515 (95.5%) -0.8
