FDA Approves Expanded Label for CANCIDAS® (caspofungin acetate) as the First and Only Echinocandin Therapy for the Treatment of Pediatric Patients (3 months and older) with Indicated Fungal Infections

WHITEHOUSE STATION, N.J.- Merck & Co., Inc. announced today that the U.S. Food and Drug Administration (FDA) has approved an expanded label for CANCIDAS®, which makes it the first and only echinocandin therapy approved in the United States for the treatment of pediatric patients aged 3 months to 17 years with indicated fungal infections.

In the United States, CANCIDAS is now indicated in adults and pediatric patients (3 months and older) for:

* Empirical therapy for presumed fungal infections in febrile, neutropenic patients
* Treatment of Candidemia and the following Candida infections: intra-abdominal abscesses, peritonitis and pleural space infections. CANCIDAS has not been studied in endocarditis, osteomyelitis and meningitis due to Candida
* Treatment of Esophageal Candidiasis
* Treatment of Invasive Aspergillosis in patients who are refractory to or intolerant of other therapies (i.e., amphotericin B, lipid formulations of amphotericin B, and/or itraconazole). CANCIDAS has not been studied as initial therapy for invasive aspergillosis.

The efficacy and safety of CANCIDAS has not been adequately studied in prospective clinical trials involving neonates and infants under 3 months of age.

“In the pediatric population, safety and tolerability can be especially critical. With the expanded label for CANCIDAS that now includes use in pediatric patients aged 3 months to 17 years, clinicians have a new option – with both a demonstrated efficacy and safety profile – for treating these pediatric patients with indicated fungal infections,” said Dr. Theoklis Zaoutis, assistant professor, Pediatrics and Epidemiology, Division of Infectious Diseases, Children’s Hospital, Philadelphia, and lead study investigator.

The expanded label for CANCIDAS is based on data from five prospective clinical studies involving 171 pediatric patients. Two clinical trials demonstrated the efficacy of CANCIDAS for the treatment of pediatric patients with indicated fungal infections, and demonstrated a safety and tolerability profile comparable to that of adults. The expanded label also includes consistent dosing for pediatric patients across all indications based on multiple pharmacokinetic studies.

As part of the expanded label, precise dosing of CANCIDAS in pediatric patients aged 3 months to 17 years should be based on the patient’s body surface area (BSA). For all indications, a single 70-mg/m² loading dose (not to exceed an actual dose of 70 mg) should be administered on Day One, followed by 50 mg/m² daily thereafter (not to exceed an actual dose of 70 mg daily).² CANCIDAS is the only antifungal with well-studied BSA dosing in pediatric patients.

Safety and efficacy of CANCIDAS evaluated when used as empirical therapy
In one clinical trial, the safety and efficacy profile of CANCIDAS was assessed when used as empirical therapy against suspected fungal infections in patients 2 to 17 years of age with persistent fever and neutropenia (seriously ill patients with persistent fever and low white blood cell counts).

The study was a prospective randomized, double-blind, multi-center, comparative trial involving a total of 82 patients aged 2 to 17 years. Patients were randomized using a 2:1 ratio of CANCIDAS (n= 56) to AmBisome® liposomal amphotericin B, or AmBisome (n=26), a standard treatment option against invasive fungal infections, and were given either CANCIDAS 50 mg/m² daily following a 70 mg/m² loading dose on Day One (not to exceed 70 mg daily) or AmBisome 3 mg/kg daily. Patients were stratified based on risk category (high-risk patients had undergone allogeneic stem cell transplantation or had relapsed acute leukemia). Twenty-seven percent of patients in both treatment groups were high risk.

The study design and criteria for overall favorable response were similar to the corresponding study in adult patients. An overall favorable response required meeting each of the following criteria: no documented breakthrough fungal infections up to seven days after completion of treatment, survival for seven 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.

The favorable overall response rates were 46.4 percent (26 of 56) in the CANCIDAS group versus 32.0 percent (8 of 25) in the AmBisome group. The favorable response rates for high-risk patients were 60 percent (9 of 15) in the CANCIDAS group versus 0 percent (0 of 7) in the AmBisome group. The favorable response rates for low-risk patients were 41.5 percent (17 of 41) in the CANCIDAS group versus 44.4 percent (8 of 18) in the AmBisome group. Fewer patients experienced serious drug-related adverse events with CANCIDAS (0.6 percent; n=1) than AmBisome (11.5 percent; n=3). The therapy discontinuation rate due to drug-related adverse reaction was 1.2 percent with CANCIDAS (n=2) and 11.5 percent with AmBisome (n=3).

Efficacy and safety studied in documented fungal infections
Another prospective, open-label, non-comparative study estimated the safety and efficacy of CANCIDAS in pediatric patients aged 3 months to 17 years with candidemia and other Candida infections, esophageal candidiasis, and invasive aspergillosis (as salvage therapy).

The study design and criteria for favorable response were similar to the corresponding studies in adult patients. A favorable response for patients with candidemia and other Candida infections required both symptom/sign resolution/improvement and microbiological clearance of the Candida infection. Favorable overall response at five to seven days following discontinuation of study therapy for patients with esophageal candidiasis required both complete resolution of symptoms and significant endoscopic improvement. A favorable response for patients with invasive aspergillosis was defined as either complete resolution (complete response) or clinically meaningful improvement (partial response) of all signs and symptoms and attributable radiographic findings.

The efficacy of CANCIDAS in pediatric patients with these documented fungal infections was supported by the study results. Specifically, the favorable response rates were 81 percent (30 of 37) of patients with candidemia and other Candida infections, 100 percent (1 of 1) of patients with esophageal candidiasis, and 50 percent (5 of 10) of patients with invasive aspergillosis as salvage therapy.

Selected important risk information about CANCIDAS
CANCIDAS is contraindicated in patients with hypersensitivity to any component of the product. Concomitant use of CANCIDAS with cyclosporine should be limited to patients for whom the potential benefit outweighs the potential risk of increased hepatic enzyme abnormalities.

Laboratory abnormalities in liver function tests have been seen in healthy volunteers and patients treated with CANCIDAS. In some patients with serious underlying conditions who were receiving multiple medications concomitantly with CANCIDAS, isolated cases of clinically significant hepatic dysfunction, hepatitis, or hepatic failure have been reported; a causal relationship to CANCIDAS has not been established. Patients who develop abnormal liver function tests during therapy with CANCIDAS should be monitored for evidence of worsening hepatic function and evaluated for risk/benefit of continuing therapy with CANCIDAS. There is no clinical experience in adult patients with severe hepatic insufficiency (Child-Pugh score 9) and in pediatric patients with any degree of hepatic insufficiency.

Possible histamine mediated symptoms have been reported, including rash, facial swelling, pruritus, sensation of warmth and bronchospasm. Anaphylaxis has been reported during administration of CANCIDAS.

The most common adverse reactions in adult patients treated with CANCIDAS (greater than or equal to 10 percent), irrespective of causality, are: diarrhea, pyrexia, chills, alanine aminotransferase/aspartate aminotransferase (ALT/AST) increase, blood alkaline phosphatase increase and decrease of blood potassium.

The most common adverse reactions in pediatric patients treated with CANCIDAS, irrespective of causality, were pyrexia (29.2 percent), blood potassium decreased (15.2 percent), diarrhea (14.0 percent), increased AST (11.7 percent), rash (11.7 percent), increased ALT (11.1 percent), hypotension (11.1 percent), and chills (11.1 percent). The proportion of patients who experienced an infusion-related adverse reaction was 21.6 percent in the group treated with CANCIDAS and 34.6 percent in the group treated with AmBisome.

When CANCIDAS is co-administered to pediatric patients with inducers of drug clearance, such as rifampin, efavirenz, nevirapine, phenytoin, dexamethasone, or carbamazepine, a dose of CANCIDAS of 70 mg/m² daily (not to exceed 70 mg) should be considered. For patients receiving CANCIDAS and tacrolimus, standard monitoring of tacrolimus blood concentrations and appropriate tacrolimus dosage adjustments are recommended.

The efficacy and safety of CANCIDAS has not been adequately studied in prospective clinical trials involving neonates and infants under 3 months of age. Although limited pharmacokinetic data were collected in neonates and infants below 3 months of age, these data are insufficient to establish a safe and effective dose of caspofungin in the treatment of neonatal candidiasis. Invasive candidiasis in neonates has a higher rate of central nervous system and multi-organ involvement than in older patients; the ability of CANCIDAS to penetrate the blood-brain barrier and to treat patients with meningitis and endocarditis is unknown.

For more details about CANCIDAS, please see the prescribing information.

About CANCIDAS
CANCIDAS is a member of the echinocandin class of antifungals. CANCIDAS inhibits the synthesis of (1,3)-D-glucan, an integral component of the fungal cell wall. CANCIDAS should be administered via slow intravenous infusion over approximately one hour. CANCIDAS should not be administered by I.V. bolus administration.