Drug Criteria & Outcomes: Drug evaluation: Caspofungin for IV infusion
Drug Criteria & Outcomes: Drug evaluation: Caspofungin for IV infusion
By Candace Hodges, PharmD candidate
Samford University
Birmingham, AL
Agents for systemic fungal infections
Agent formulation
- Caspofungin acetate for injection (Cancidas) Intravenous (IV). Synonyms: MK-0991, MK-991, L-743872
- Amphotericin B desoxycholate (Fungizone) IV; lipid preps (Abelcet, AmBisome)
- Itraconazole (Sporanox) IV, Oral
- Fluconazole (Diflucan) IV, Oral
Description
Caspofungin acetate is a sterile, lyophilized, semisynthetic product for IV infusion. It is available as a hygroscopic white to off-white powder and is freely soluble in water and methanol, and slightly soluble in ethanol.
Caspofungin is the first of a new class of antifungals, the echinocandins or glucan synthesis inhibitors, which have a mechanism of action different from all other antifungals. Specifically, the echinocandins disrupt glucan formation by noncompetitively inhibiting the enzyme complex 1,3-b-D-glucan synthase, which is present in most pathogenic fungi and is essential for fungal cell wall formation. This enzyme complex is not present in human cells, so the unique mode of action of caspofungin potentially eliminates toxicity to humans. Echinocandins are considered fungicidal and, based on in vitro studies, their effects appear to depend on fungal growth and metabolism.
Dosage and administration
A single 70 mg loading dose should be administered on day one, followed by 50 mg/day thereafter. Caspofungin should be administered by slow IV infusion over approximately one hour. Limited safety data suggest that an increase in dose to 70 mg/day for patients who do not clinically respond to 50 mg/day is well-tolerated. The highest dose in clinical trials was 100 mg as a single dose to five patients, which was generally well-tolerated. Duration of treatment should be based upon the severity of the patient’s underlying disease, recovery from immunosuppression, and clinical response. The mean duration of therapy in the study of the use of caspofungin for treatment of invasive aspergillosis in patients refractory to or intolerant of other therapies was 33.7 days, with a range of one to 162 days.
During the past year, caspofungin was in short supply due to an increase in demand and production problems at Merck. The manufacturer’s patient allocation program ended in June 2002 when the drug again became available without restriction.
Contraindications
Caspofungin is contraindicated in patients with hypersensitivity to any component of the product. Besides the active ingredient caspofungin, inactive ingredients in caspofungin include sucrose, mannitol, acetic acid, and sodium hydroxide.
Although caspofungin is not metabolized by the CYP450 enzyme system, results from regression analyses of patient pharmacokinetic data suggest that co-administration with inducers or mixed inducer/inhibitors of this system may decrease concentrations of caspofungin. These include drugs such as efavirenz (Sustiva), nelfinavir (Viracept), nevirapine (Viramune), phenytoin (Dilatin), rifampin (Rifadin, others), dexamethasone (Decadron, others) or carbamazepine (Tegretol, others). If patients are concurrently treated with any of these drugs and caspofungin and are not clinically responding to therapy, consider increasing the daily dose to 70 mg, following the usual 70 mg loading dose.
Adverse effects
The Table, below provides drug-related adverse events and laboratory abnormalities occurring in > 5 % of patients. A direct comparison was made between caspofungin and conventional amphotericin B for investigational indications other than aspergillosis. Only data for caspofungin were given for the aspergillosis study. Data for amphotericin B Lipid Complex Injection and itraconazole were taken from their corresponding package inserts and are not necessarily comparable.
Antifungal activity
Caspofungin demonstrates fungicidal or fungistatic activity depending on the isolate tested. The drug exhibits a post-antifungal effect that lasts longer than 12 hours at concentrations above the minimum inhibitory concentrations (MIC), and up to two hours when the concentration is below the MIC, according to in vitro data. In vitro activity has been verified in animal infection models with Candida, Aspergillus, and Histoplasma.
Caspofungin demonstrates significant activity against most clinically important Candida species. In vitro, the drug is at least as potent as fluconazole, itraconazole, voriconazole, and amphotericin B against C. albicans, C. glabrata, and C. tropicalis, and is comparable in potency to amphotericin B against C. krusei. The drug is fungicidal against most Candida species, at concentrations of less than 1-2 mg/L.
Caspofungin’s in vitro activity against Aspergillus compares well with that of amphotericin B, itraconazole, and flucytosine; MIC90 values against both A. flavus and A. fumigatus have been reported as 0.12 mg/L. Against histoplasmosis in mice, caspofungin was less effective than amphotericin B, and possesses only limited activity against Cryptococcus neoformans, Fusarium spp., Rhizopus spp., and Scedosporium prolificans. Caspofungin demonstrates potency against Pneumocystis carinii in immunocompromised animal models, but benefits in acute infection are yet unknown.
There are no published reports of resistance development in the clinical setting with caspofungin. Research has shown synergistic action with caspofungin and amphotericin B against A. fumigatus, C. neoformans, and Fusarium.
Clinical studies
Clinical data on the use of caspofungin in humans with invasive fungal infections is limited to three trials. One examined the use of caspofungin in invasive aspergillosis; the data were presented in a poster, and the study resulted in Food and Drug Administration (FDA) approval of the drug. The other two trials examined the use of caspofungin in oropharyngeal candidiasis (OPC) and/or esophageal candidiasis (EC) in patients who were mostly HIV patients. One of the two trials studied the use of caspofungin in EC, and the other studied its use in both EC and OPC; the unpublished data were presented to the FDA as abstracts. The Table, below provides results from the oropharyngeal and esophageal candidal trials.
Both studies in the Table, above were randomized, double-blind comparative trials. In the Arathoon et al. study, minimum therapy was seven days for OPC and 10 days for EC. Efficacy was assessed three to four days after the end of therapy and was defined as complete resolution of symptoms and a reduction in disease grade to 0 or ½. The authors concluded that caspofungin appears to be effective for treatment of OPC and EC, with high efficacy rates and generally few drug-related adverse events.
In the Sable et al. study, patients had endoscopically proven esophageal candidiasis and were randomized to receive one of the above-mentioned regimens for 14 days. Clinical response (efficacy) was defined as a resolution of symptoms and a significant reduction in endoscopic lesions 14 days after completing therapy.
The clinical study on the use of caspofungin in aspergillosis patients refractory to other antifungal therapy was important for the drug’s FDA approval. A review of this trial follows:
Maertens J, Raad I, Sable CA, et al. Multicenter, noncomparative study to evaluate safety and efficacy of caspofungin in adults with invasive aspergillosis refractory or intolerant to amphotericin B, amphotericin B lipid formulations or azoles [poster]. 40th Interscience Conference on Antimicrobial Agents and Chemotherapy. Toronto; Sept. 18, 2000.
Objective: To evaluate the safety, tolerability, and efficacy of caspofungin in patients with invasive aspergillosis refractory to or intolerant of other antifungal therapies (e.g., amphotericin B, lipid formulations of amphotericin B, and/or itraconazole).
Design: Open-label, multicenter, non-comparative study; four-week follow-up period after discontinuation of caspofungin for patients with favorable response.
Endpoints:
Efficacy: Favorable response rate, evaluated by independent expert panel.
Safety/tolerability: Clinical adverse experiences, laboratory abnormalities.
Inclusion criteria:
- Adults ages 18-80.
- Refractory patients (had disease progression OR failed to improve despite > seven days with amphotericin B/lipid preps, itraconazole, or investigational azole with reported aspergillosis activity).
- Intolerant patients (doubling of creatinine OR creatinine > 2.5mg/dL while on therapy OR other acute reactions, OR infusion-related toxicity).
- Patients with pulmonary disease must have had definite (positive tissue histopathology OR positive culture from tissue obtained by invasive procedure) OR probable invasive aspergillosis (positive radiographic or computed tomography evidence with supporting culture from bronchoalveolar lavage or sputum, glactomannan ELISA, and/or polymerase chain reaction).
- Patients with extrapulmonary disease had to have definite invasive aspergillosis.
Regimen: Caspofungin 70 mg loading dose, followed by 50 mg daily. Mean duration of therapy was 33.7 days (range: one to 162 days).
Baseline characteristics of patients:
- Fifty-two out of 63 (83%) patients received treatment for more than seven days.
- Among 53 refractory patients were:
— 10 to standard amphotericin B;
— 10 to lipid amphotericin B preps;
— 13 to itraconazole;
— 1 to voriconazole;
— 19 to more than one antifungal agent.
- Eight out of 10 intolerant patients had shown no clinical improvement during prior therapy.
- Forty-five (71%) patients had pulmonary disease; 18 (29%) had extrapulmonary disease.
- Twenty-seven out of 45 (60%) patients with pulmonary disease had definite invasive aspergillosis.
- Underlying conditions included:
— hematologic malignancy (N=24, 38%);
— allogenic bone marrow/stem cell transplant (N=18, 28%);
— organ transplant (N=8, 13%);
— solid tumor (N=3, 5%);
— other conditions (N=10, 16%).
All participants received concomitant therapies for underlying conditions.
- Eighteen patients received tacromilus and caspofungin concomitantly; 8/18 (44%) also received mycophenolate mofetil.
Efficacy (response rates):
- Forty-one percent (26/63) of patients receiving at least one dose of caspofungin had favorable response.
- For patients receiving more than seven days caspofungin therapy, 50% (26/52) had favorable response.
- Thirty-six percent (19/53) refractory vs. 70% (7/10) intolerant to previous therapies had favorable response.
- Forty-seven percent (21/45) pulmonary disease patients vs. 28% (5/18) extrapulmonary disease patients had response.
- Twenty-five percent (2/8) extrapulmonary disease patients who also had definite, probable, or possible central nervous system involvement had favorable response.
- Response rates according to underlying conditions were: 50% — hematologic malignancy, 16.7% — bone marrow/peripheral stem cell transplant, 37.5% — organ transplant, 100% — solid tumor, and 50% — other diseases.
- Eighteen out of 23 in four-week follow-up maintained favorable response; remainder of follow-up patients had one documented relapse of aspergillosis, one new chest X-ray abnormality considered to be relapse, two lost to follow-up, and one dying during follow-up.
Conclusions:
- Caspofungin is well-tolerated and effective for treatment of invasive aspergillosis in patients refractory to or intolerant of itraconazole, amphotericin B, and/or lipid forms of amphotericin B.
- Efficacy of caspofungin has not been evaluated in concurrently controlled clinical studies with other antifungal therapies.
Strengths:
- All patients were accounted for.
- Included inclusion criteria.
Weaknesses:
- Did not include exclusion criteria.
- Complete demographics were not given (e.g., age, sex).
- P-values and statistical tests were not given.
- Other information from unpublished data.
Animal studies:
Efficacy has been show by caspofungin acetate in a wide range of murine models for fungal infections, including Candida spp., Aspergillus spp., Histoplasma, and Pneumocystis carinii. In contrast, the drug did not protect immunodeficient mice against lethal challenge with Cryptococcus neoformans.
Potential for medication error(s):
Caspofungin should be administered over a one-hour infusion.
Caspofungin should not be used with diluents containing dextrose (b-D-glucose).
An example of patient selection criteria is presented in the Caspofungin Order Form HHS.
As additional studies are completed, caspofungin’s usage for different indications may expand.
Resources
• Abelcet, amphotericin B lipid complex [monograph in electronic version]. DRUGDEX System. MICROMEDEX. Englewood, CO: MICROMEDEX; 2001.
• Arathoon E, Gotuzzo E, Noriega L, et al. A randomized, double-blind, multicenter trial of MK-0991, an echinocandin antifungal agent vs. amphotericin B for the treatment of oropharyngeal and esophageal candidiasis in adults [abstract]. Clin Infect Dis 1998; 27:939.
• Cancidas, caspofungin. In: Package Insert. Whitehouse Station, NJ: Merck & Co.; 2001.
• Diflucan, fluconazole. In: Package Insert. New York: Pfizer; 1998.
• Cancidas, caspofungin acetate. In: Formulary Kit. West Point, PA: Merck & Co.; 2001.
• Fungizone IV, amphotericin B for injection. In: Patient Package Insert. Princeton, NJ: Apothecon - a Bristol-Myers Squibb Co.; 1998.
• Hoang, A. Caspofungin acetate: An antifungal agent. Am J Health-Syst Pharm 2001; 58:1206-14.
• Sporanox, itraconazole. In: Package Insert. North Chicago, IL: Abbott Laboratories; 2001.
• Lomaestro BM. An echinocandin antifungal for the treatment of invasive aspergillosis. Formulary 2001; 36:427-436.
• Drug Product Shortages Management Resource Center. Available at www.ashp.org. Accessed June 8, 2002.
Caspofungin acetate is a sterile, lyophilized, semisynthetic product for IV infusion. It is available as a hygroscopic white to off-white powder and is freely soluble in water and methanol, and slightly soluble in ethanol.Subscribe Now for Access
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