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FDA approves Cancidas for invasive aspergillosis
New Merck treatment for invasive fungal infection receives FDA approval
Merck & Co. has received approval from the Food & Drug Administration to market Cancidas (caspofungin acetate). The drug is indicated for the treatment of invasive aspergillosis (IA) in patients refractory to or intolerant of the other antifungal therapies, amphotericin B, lipid formulations of amphotericin B, and/or itraconazole. The drug has not been studied as initial therapy for IA.
Caspofungin is the first member of a new class of antifungals, called echinocandins or glucan synthesis inhibitors, which work by attacking the fungal cell wall rather than interfering with the cell membrane as other antifungals do. The drug inhibits the synthesis of B (1,3)-D-glucan, an integral component of the fungal cell wall that is not found in human cells.
Invasive aspergillosis is one of the most serious, life-threatening invasive fungal infections. High-risk populations include bone marrow transplant recipients, cancer patients, and patients with HIV/AIDS. "Approximately 10% of all deaths in patients with bone marrow transplants are attributed to IA, and it has a mortality rate of around 85% to 90%," said Isaam Raad, M.D., FACP. A noted investigator, Raad is professor/chairman, Department of Infectious Diseases, Infection Control, & Employee Health, University of Texas, M. D. Anderson Cancer Center.
Aspergillus is a fungus commonly found in the environment. It primarily infects the sinuses and lungs, but it can be spread through the bloodstream to other major organs and the central nervous system. Amphotericin B remains the treatment of choice for IA; however, response to therapy is still poor in immunocompromised patients. "Despite the use of lipid formulations of amphotericin B or nonlipid amphotericin B, there is still a failure rate of around 84%," Raad noted.
The FDA based its approval of caspofungin largely on the results of a small, multicenter, open-label, noncomparative study in 69 immunocompromised patients with IA who were unresponsive to or intolerant of other antifungal therapies. Overall, 41% of patients (26 out of 63) who received at least one dose of caspofungin had a favorable response as determined by an independent expert panel. Of those patients who received more than seven days of therapy with caspofungin, 50% had a favorable response. The most common adverse effects seen in 2% or more of these patients were fever, infused vein complications, nausea, vomiting, and flushing. The mean duration of therapy was 33.7 days, with a range of one day to 162 days. In IA, the duration of therapy is not standardized; rather, it is patient specific based on patient response. Raad's impression was that therapy would usually need to last at least one month.
"Cancidas is a promising drug," said Raad. "I think in the future it will become a first-line treatment because it is well tolerated compared with amphotericin B and its lipid formulations." While the trial was not comparative, he noted, the adverse events described with caspofungin occurred at a frequency of about 3% to 4%, whereas the adverse events associated with amphotericin B and its lipid formulations include renal toxicity, fever, and chills in about 20% of patients.
Concomitant use of caspofungin and the antirejection drug cyclosporine is not recommended unless the potential benefit outweighs the potential risk to the patient. This recommendation is based on mild (< threefold upper limits of normal) elevations in alanine transaminase (SGPT) seen in healthy subjects in a phase I drug interaction study.
The recommended dosage of caspofungin is a single 70-mg loading dose on day one, followed by 50 mg once daily thereafter. The cost of the drug was estimated at $288 for the standard 50-mg dose. The daily dose of 70 mg should be considered in those patients who are not clinically responding or are concurrently taking inducers and/or mixed inducers/inhibitors of drug clearance, such as efavirenz, nelfinavir, nevirapine, phenytoin, rifampin, dexamethasone, or carbamazepine. Doses above 70 mg have not be adequately studied.
Ongoing phase III studies are also being conducted to determine the efficacy of caspofungin in the treatment of Candida infections.
Tammy Chernin, R.Ph.
Tammy Chernin. New Merck treatment for invasive fungal infection receives FDA approval. Drug Topics 2001;4:11.