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New Type of Antifungal Approved for Invasive Aspergillosis

Cheryl A. Thompson

Caspofungin acetate (Cancidas [PDF], Merck) has been approved for marketing as second-line treatment of invasive aspergillosis. The new agent, which interferes with fungal growth by inhibiting synthesis of an essential component in the cell wall of Aspergillus species, is the first echinocandin available in the United States.

FDA made its decision about the drug's availability on the basis of an open-label study involving 69 adults and no comparative treatment. All patients had invasive aspergillosis and had previously either not improved after seven days of other antifungal therapy or not tolerated it. Caspofungin was administered for a mean of 33.7 days. Of the 52 patients who received caspofungin therapy for more than seven days, 50% responded completely or had clinically meaningful improvement. Seventy percent of patients who had not tolerated previous antifungal therapy responded favorably to treatment with caspofungin; only 36% of patients refractory to previous therapy improved.

Caspofungin is cleared from the plasma in three phases, primarily through distribution. At least 97% of the circulating drug is bound to albumin. The drug slowly metabolizes by hydrolysis and N-acetylation. Less than 2% of a dose is excreted unchanged in urine.

The labeling for caspofungin warns about concomitant use of cyclosporine. During a study on the safety of caspofungin therapy, increases in serum concentrations of alanine transaminase and aspartate transaminase were noted in some of the healthy subjects who also received doses of cyclosporine.

Caspofungin may decrease blood concentrations of tacrolimus, possibly necessitating a dosage adjustment. Certain drugs, such as phenytoin and rifampin, may increase the clearance of caspofungin from the plasma, perhaps producing clinically meaningful reductions in concentration.

The overall safety of caspofungin was studied in 623 people, more than half of whom had invasive aspergillosis or another fungal infection. The most common adverse effects among the patients with invasive aspergillosis were fever, infused-vein complications, nausea, vomiting, and flushing. In the studies involving comparative treatment, patients with a fungal infection other than aspergillosis who received caspofungin generally had a lower frequency of adverse events, except infused-vein complications, than the patients who received amphotericin B. Little information is known about the safety of caspofungin therapy beyond two weeks.

The recommended dosage regimen for caspofungin starts with 70 mg on day 1 followed by 50 mg daily thereafter. All doses should be administered by intravenous infusion over one hour. The duration of therapy depends on the severity of the patient's underlying disease, recovery from immunosuppression, and clinical response. A 70-mg daily dose should be considered for patients who do not respond to the 50-mg regimen and also take phenytoin, rifampin, efavirenz, nelfinavir, nevirapine, dexamethasone, or carbamazepine. Patients with moderate hepatic insufficiency should receive 35 mg, not 50 mg, daily starting on day 2. Clinical experience in patients with severe hepatic insufficiency is lacking.

Cancidas is supplied as color-coded single-use vials containing 50 mg (red aluminum band) or 70 mg (yellow-orange aluminum band) of lyophilized powder for reconstitution and dilution with 0.9% sodium chloride injection. The drug should not be mixed with dextrose solutions. Unused vials should be stored at 2–8 degrees C. Once reconstituted, the concentrated solution may be stored at <25 degrees C for up to one hour. The diluted solution may be stored at <25 degrees C for up to 24 hours. The package insert contains instructions for preparing the standard doses, a 70-mg dose from two 50-mg vials, a reduced-volume 50-mg dose, and a 35-mg dose.