Caspofungin

Caspofungin is an antifungal drug, the first of a new class termed the echinocandins. It shows activity against infections with Aspergillus and Candida, and works by inhibiting β(1,3)-D-Glucan of the fungal cell wall. Caspofungin is administered intravenously.

Indications
Caspofungin acetate for injection was originally approved by both the FDA, in the US, and the EMEA, in Europe, in 2001. Its currently approved therapeutic indications by both organisms include the empirical therapy of presumed fungal infections in febrile, neutropenic adult patients and the treatment of invasive aspergillosis in adult patients whose disease is refractory to, or who are intolerant of, other antifungal agents (i.e., conventional or lipid formulations of amphotericin B and/or itraconazole). Additionally, the FDA approval includes indication for the treatment of candidemia and some specific Candida infections (intra-abdominal abscesses, peritonitis, pleural cavity infections and oesophagitis) and the EMEA approval includes indication for the treatment of general invasive candidiasis in adult patients.

Clinical Efficacy
36% of patients refractory to other therapies responded well to caspofungin therapy, while even 70% of patients intolerant to other therapies were classified as responders. Direct comparative studies to other drugs in the treatment of invasive aspergillosis have so far not been undertaken.

Contraindications
Known hypersensitivity to caspofungin acetate or any other ingredient contained in the formulation

Warnings

 * Hepatic Effects

The concomitant use of caspofungin and cyclosporine in healthy volunteers led to a more frequent increase of liver enzymes (ALT=SGPT and AST=SGOT) than noted with cyclosporine alone. Combination treatment is only indicated, if the potential benefit for the patient outweighs the potential risk.

Dosage reduction in patients with moderately impaired liver function is recommended. No clinical data exists regarding the use of caspofungin in patients with severely impaired liver function.

Reactions due to histamine release (rash, facial swelling, pruritus, sensation of warmth and one case of anaphylaxis) have been seen. Those reactions should be carefully watched for.
 * Sensitivity Reactions

In a few patients with infections caused by C. albicans mutants with reduced sensitivity to caspofungin have been noticed. Currently there is no data regarding development of resistance in other fungi than C. albicans.
 * Drug Resistance

Pregnancy and lactation
Caspofungin has in animal studies been shown to have embroyotoxic properties and therefore has been assigned to class C. It should only be given to pregnant women, if the benefit to the mother clearly outweighs the potenial risk to the unborn.

The drug is found in the milk of lactating rats; it is not known, whether this effect can be seen in women, too. Lactating women should be treated cautiously.

Geriatric patients
Ordinarily, no dose adjustments are necessary.

Pediatric patients
There is no sufficient clinical experience to judge the safety and efficacy in patients younger than 18 years of age.

Side-effects
Compared to amphotericin B, caspofungin seems to have a relatively low incidence of side-effects. In clinical studies and post-marketing reports the side-effects seen in 1% or more of the patients were as follows:


 * Gastrointestinal system : nausea, vomiting, abdominal pain, and diarrhea
 * Central nervous system : headache
 * Whole body : fever, phlebitis or thrombophlebitis, complications at intravenous cannulation site (e.g. induration), unspecified pain, flu-like-syndrome, myalgia, chills, and paresthesia
 * Respiratory : dyspnea
 * Renal : increased plasma creatinine
 * Hematological : anemia
 * Electrolytes : hypokalemia
 * Liver : increased liver enzymes (asymptomatic)
 * Hypersensitivity : rash, facial edema, pruritus
 * Others : tachycardia

Additionally, infrequent cases of symptomatic liver damage, peripheral edema and swelling, and hypercalcemia have been seen. One case of anaphylaxis (severe allergic reaction) has also been noted.

Resistance
Resistance in Candida albicans has been described but is currently still rare. The mechanism is probably a point mutation in the 1→3-β- D -glucan synthase gene.

Drug interactions

 * Cyclosporine : see under Hepatic Effects
 * Tacrolimus : potential pharmacokinetic interactions
 * Other systemic antimycotic agents : with amphotericin B, itraconazole and mycophenolate no interactions have been seen
 * Inducers of drug clearance (e.g. carbamazepine, phenytoin, rifampin, dexamethason) : consider 70mg i.v. as maintenance dose instead of 50mg

Duration of treatment
The mean duration of therapy in previous studies was 34 days. Some patients were even healed by a 1-day treatment. However, a few patients were treated for as long as 162 days and tolerated the drug well, indicating that longtime use may be indicated and tolerated favourably in complicated cases of aspergillosis. Generally, the duration of treatment is dictated by the severity of the disease, the clinical response and the improvement of immunecompetence in immunecompromised patients.

Dosage
An initial dose of 70 mg by i.v.-infusion is given followed by 50 mg i.v. daily. If no response is seen or if inducers of caspofungin clearance (see above) are coadministered the daily dose may be increased to 70 mg i.v. An infusion should take approximately 1 hour.

Dosage forms

 * Cancidas® 50mg for i.v.-infusion (manufacturer Merck)
 * Cancidas® 70mg for i.v.-infusion (manufacturer Merck)
 * Brand names in countries other than the US may vary.

External references

 * AHFS Database
 * CDC on Aspergillosis
 * Swiss pharma-compendium on Caspofungin
 * Cancidas.com
 * FDA on Cancidas
 * EMEA on Cancidas