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

The overall safety of caspofungin was assessed in 1440 individuals who received single or multiple doses of caspofungin acetate: 564 febrile, neutropenic patients (empirical therapy study); 125 patients with candidemia and/or intra-abdominal abscesses, peritonitis, or pleural space infections (including 4 patients with chronic disseminated candidiasis); 285 patients with esophageal and/or oropharyngeal candidiasis; 72 patients with invasive aspergillosis; and 394 individuals in phase I studies. In the empirical therapy study patients had undergone hematopoietic stem-cell transplantation or chemotherapy. In the studies involving patients with documented Candida infections, the majority of the patients had serious underlying medical conditions (e.g., hematologic or other malignancy, recent major surgery, HIV) requiring multiple concomitant medications. Patients in the noncomparative Aspergillus study often had serious predisposing medical conditions (e.g., bone marrow or peripheral stem cell transplants, hematologic malignancy, solid tumors or organ transplants) requiring multiple concomitant medications.

In the randomized, double-blinded empirical therapy study, patients received either CANCIDAS 50 mg/day (following a 70-mg loading dose) or AmBisome (3.0 mg/kg/day). In this study clinical or laboratory hepatic adverse events were reported in 39% and 45% of patients in the CANCIDAS and AmBisome groups, respectively, regardless of causality. Also reported was an isolated, serious adverse experience of hyperbilirubinemia considered possibly related to CANCIDAS. Drug-related clinical adverse experiences occurring in ≥2% of the patients in either treatment group are presented in Table 8.

Incidence ≥2% for at least one treatment group by Body System

* Determined by the investigator to be possibly, probably, or definitely drug-related.

** 70 mg on Day 1, then 50 mg daily for the remainder of treatment; daily dose was increased to 70 mg for 73 patients.

*** 3.0 mg/kg/day; daily dose was increased to 5.0 mg/kg for 74 patients.

The proportion of patients who experienced an infusion-related adverse event was significantly lower in the group treated with CANCIDAS (35.1%) than in the group treated with AmBisome (51.6%).

Drug-related laboratory adverse experiences occurring in ≥2% of the patients in either treatment group are presented in Table 9.

Incidence ≥2% for at least one treatment group by Laboratory Test Category

* Determined by the investigator to be possibly, probably, or definitely drug-related.

** 70 mg on Day 1, then 50 mg daily for the remainder of treatment; daily dose was increased to 70 mg for 73 patients.

*** 3.0 mg/kg/day; daily dose was increased to 5.0 mg/kg for 74 patients.

The percentage of patients with either a drug-related clinical or a drug-related laboratory adverse experience was significantly lower among patients receiving CANCIDAS (54.4%) than among patients receiving AmBisome (69.3%). Furthermore, the incidence of discontinuation due to a drug-related clinical or laboratory adverse experience was significantly lower among patients treated with CANCIDAS (5.0%) than among patients treated with AmBisome (8.0%).

To evaluate the effect of CANCIDAS and AmBisome on renal function, nephrotoxicity was defined as doubling of serum creatinine relative to baseline or an increase of ≥1 mg/dL in serum creatinine if baseline serum creatinine was above the upper limit of the normal range. Among patients whose baseline creatinine clearance was >30 mL/min, the incidence of nephrotoxicity was significantly lower in the group treated with CANCIDAS (2.6%) than in the group treated with AmBisome (11.5%). Serious clinical renal events, regardless of causality, were similar between CANCIDAS (11/564, 2.0%) and AmBisome (12/547, 2.2%).

Candidemia and other Candida infections (see CLINICAL STUDIES)

In the randomized, double-blinded invasive candidiasis study, patients received either CANCIDAS 50 mg/day (following a 70-mg loading dose) or amphotericin B 0.6 to 1.0 mg/kg/day. Drug-related clinical adverse experiences occurring in ≥2% of the patients in either treatment group are presented in Table 10.

Incidence ≥2% for at least one treatment group by Body System

* Determined by the investigator to be possibly, probably, or definitely drug-related.

** Intra-abdominal abscesses, peritonitis and pleural space infections

*** Patients received CANCIDAS 70 mg on Day 1, then 50 mg daily for the remainder of their treatment.

The incidence of drug-related clinical adverse experiences was significantly lower among patients treated with CANCIDAS (28.9%) than among patients treated with amphotericin B (58.4%). Also, the proportion of patients who experienced an infusion-related adverse event was significantly lower in the group treated with CANCIDAS (20.2%) than in the group treated with amphotericin B (48.8%).

Drug-related laboratory adverse experiences occurring in ≥2% of the patients in either treatment group are presented in Table 11.

Incidence ≥2% for at least one treatment group by Laboratory Test Category

* Determined by the investigator to be possibly, probably, or definitely drug-related.

** Intra-abdominal abscesses, peritonitis and pleural space infections

*** Patients received CANCIDAS 70 mg on Day 1, then 50 mg daily for the remainder of their treatment.

The incidence of drug-related laboratory adverse experiences was significantly lower among patients receiving CANCIDAS (24.3%) than among patients receiving amphotericin B (54.0%).

The percentage of patients with either a drug-related clinical adverse experience or a drug-related laboratory adverse experience was significantly lower among patients receiving CANCIDAS (42.1%) than among patients receiving amphotericin B (75.2%). Furthermore, a significant difference between the two treatment groups was observed with regard to incidence of discontinuation due to drug-related clinical or laboratory adverse experience; incidences were 3/114 (2.6%) in the group treated with CANCIDAS and 29/125 (23.2%) in the group treated with amphotericin B.

To evaluate the effect of CANCIDAS and amphotericin B on renal function, nephrotoxicity was defined as doubling of serum creatinine relative to baseline or an increase of ≥1 mg/dL in serum creatinine if baseline serum creatinine was above the upper limit of the normal range. In a subgroup of patients whose baseline creatinine clearance was >30 mL/min, the incidence of nephrotoxicity was significantly lower in the group treated with CANCIDAS than in the group treated with amphotericin B.

Drug-related clinical adverse experiences occurring in ≥2% of patients with esophageal and/or oropharyngeal candidiasis are presented in Table 12.

Incidence ≥2% for at least one treatment dose (per comparison) by Body System

*Relationship to drug was determined by the investigator to be possibly, probably or definitely drug-related.

** Derived from a Phase III comparator-controlled clinical study.

*** Derived from Phase II comparator-controlled clinical studies.

Laboratory abnormalities occurring in ≥2% of patients with esophageal and/or oropharyngeal candidiasis are presented in Table 13.

Drug-Related Laboratory Abnormalities Reported Among Patients with Esophageal and/or Oropharyngeal Candidiasis*

Incidence ≥2% (for at least one treatment dose) by Laboratory Test Category

*Relationship to drug was determined by the investigator to be possibly, probably or definitely drug-related.

** Derived from Phase II and Phase III comparator-controlled clinical studies.

*** Derived from Phase II comparator-controlled clinical studies.

In the open-label, noncomparative aspergillosis study, in which 69 patients received CANCIDAS (70-mg loading dose on Day 1 followed by 50 mg daily), the following drug-related clinical adverse experiences were observed with an incidence of ≥2%: fever (2.9%), infused-vein complications (2.9%), nausea (2.9%), vomiting (2.9%) and flushing (2.9%).

Also reported infrequently in this patient population were pulmonary edema, ARDS, and radiographic infiltrates.

Drug-related laboratory abnormalities reported with an incidence ≥2% in patients treated with CANCIDAS in the noncomparative aspergillosis study were: serum alkaline phosphatase increased (2.9%), serum potassium decreased (2.9%), eosinophils increased (3.2%), urine protein increased (4.9%), and urine RBCs increased (2.2%).

The following postmarketing adverse events have been reported:

Hepatobiliary: rare cases of clinically significant hepatic dysfunction

Cardiovascular: swelling and peripheral edema

Metabolic: hypercalcemia

In one clinical study, 3 of 4 subjects who received CANCIDAS 70 mg daily on Days 1 through 10, and also received two 3 mg/kg doses of cyclosporine 12 hours apart on Day 10, developed transient elevations of ALT on Day 11 that were 2 to 3 times the upper limit of normal (ULN). In a separate panel of subjects in the same study, 2 of 8 subjects who received CANCIDAS 35 mg daily for 3 days and cyclosporine (two 3 mg/kg doses administered 12 hours apart) on Day 1 had small increases in ALT (slightly above the ULN) on Day 2. In another clinical study, 2 of 8 healthy men developed transient ALT elevations of less than 2X ULN. In this study, cyclosporine (4 mg/kg) was administered on Days 1 and 12, and CANCIDAS was administered (70 mg) daily on Days 3 through 13. In one subject, the ALT elevation occurred on Days 7 and 9 and, in the other subject, the ALT elevation occurred on Day 19. These elevations returned to normal by Day 27. In all groups, elevations in AST paralleled ALT elevations but were of lesser magnitude. In these clinical studies, cyclosporine (one 4 mg/kg dose or two 3 mg/kg doses) increased the AUC of caspofungin by approximately 35% (see WARNINGS).

Studies in vitro show that caspofungin acetate is not an inhibitor of any enzyme in the cytochrome P450 (CYP) system. In clinical studies, caspofungin did not induce the CYP3A4 metabolism of other drugs. Caspofungin is not a substrate for P-glycoprotein and is a poor substrate for cytochrome P450 enzymes.

Clinical studies in healthy volunteers show that the pharmacokinetics of CANCIDAS are not altered by itraconazole, amphotericin B, mycophenolate, nelfinavir, or tacrolimus. CANCIDAS has no effect on the pharmacokinetics of itraconazole, amphotericin B, or the active metabolite of mycophenolate.

CANCIDAS reduced the blood AUC_0-12 of tacrolimus (FK-506, Prograf³) by approximately 20%, peak blood concentration (C_max) by 16%, and 12-hour blood concentration (C_12hr) by 26% in healthy subjects when tacrolimus (2 doses of 0.1 mg/kg 12 hours apart) was administered on the 10th day of CANCIDAS 70 mg daily, as compared to results from a control period in which tacrolimus was administered alone. For patients receiving both therapies, standard monitoring of tacrolimus blood concentrations and appropriate tacrolimus dosage adjustments are recommended.

In two clinical studies, cyclosporine (one 4 mg/kg dose or two 3 mg/kg doses) increased the AUC of caspofungin by approximately 35%. CANCIDAS did not increase the plasma levels of cyclosporine. There were transient increases in liver ALT and AST when CANCIDAS and cyclosporine were co-administered (see WARNINGS and ADVERSE REACTIONS).

A drug-drug interaction study with rifampin in healthy volunteers has shown a 30% decrease in caspofungin trough concentrations. Patients on rifampin should receive 70 mg of CANCIDAS daily. In addition, results from regression analyses of patient pharmacokinetic data suggest that co-administration of other inducers of drug clearance (efavirenz, nevirapine, phenytoin, dexamethasone, or carbamazepine) with CANCIDAS may result in clinically meaningful reductions in caspofungin concentrations. It is not known which drug clearance mechanism involved in caspofungin disposition may be inducible. When CANCIDAS is co-administered with inducers of drug clearance, such as efavirenz, nevirapine, phenytoin, dexamethasone, or carbamazepine, use of a daily dose of 70 mg of CANCIDAS should be considered.

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