These highlights do not include all the information needed to use CANCIDAS safely and effectively. See full prescribing information for CANCIDAS. CANCIDAS (caspofungin acetate) for injection, for intravenous useInitial U.S. Approval: 2001

CANCIDAS is indicated in adults and pediatric patients (3 months and older) for:

CANCIDAS should be administered by slow intravenous (IV) infusion over approximately 1 hour. CANCIDAS should not be administered by IV bolus administration.

Do not mix or co-infuse CANCIDAS with other medications, as there are no data available on the compatibility of CANCIDAS with other intravenous substances, additives, or medications. DO NOT USE DILUENTS CONTAINING DEXTROSE (α-D-GLUCOSE), as CANCIDAS is not stable in diluents containing dextrose.

The usual dose is 50 mg once daily (following a 70-mg loading dose for most indications). The safety and efficacy of a dose of 150 mg daily (range: 1 to 51 days; median: 14 days) have been studied in 100 adult patients with candidemia and other Candida infections. The efficacy of CANCIDAS at this higher dose was not significantly better than the efficacy of the 50-mg daily dose of CANCIDAS. The efficacy of doses higher than 50 mg daily in the other adult patients for whom CANCIDAS is indicated is not known [see Clinical Studies (14.2)].

Empirical Therapy

A single 70-mg loading dose should be administered on Day 1, followed by 50 mg once daily thereafter. Duration of treatment should be based on the patient’s clinical response. Empirical therapy should be continued until resolution of neutropenia. Patients found to have a fungal infection should be treated for a minimum of 14 days; treatment should continue for at least 7 days after both neutropenia and clinical symptoms are resolved. If the 50-mg dose is well tolerated but does not provide an adequate clinical response, the daily dose can be increased to 70 mg.

Candidemia and Other Candida Infections [see Clinical Studies (14.2)]

A single 70-mg loading dose should be administered on Day 1, followed by 50 mg once daily thereafter. Duration of treatment should be dictated by the patient’s clinical and microbiological response. In general, antifungal therapy should continue for at least 14 days after the last positive culture. Patients who remain persistently neutropenic may warrant a longer course of therapy pending resolution of the neutropenia.

Esophageal Candidiasis

The dose is 50 mg once daily for 7 to 14 days after symptom resolution. A 70-mg loading dose has not been studied for this indication. Because of the risk of relapse of oropharyngeal candidiasis in patients with HIV infections, suppressive oral therapy could be considered [see Clinical Studies (14.3)].

Invasive Aspergillosis

A single 70-mg loading dose should be administered on Day 1, followed by 50 mg once daily thereafter. Duration of treatment should be based upon the severity of the patient’s underlying disease, recovery from immunosuppression, and clinical response.

For all indications, a single 70-mg/m loading dose should be administered on Day 1, followed by 50 mg/monce daily thereafter. The maximum loading dose and the daily maintenance dose should not exceed 70 mg, regardless of the patient's calculated dose. Dosing in pediatric patients (3 months to 17 years of age) should be based on the patient’s body surface area (BSA) as calculated by the Mosteller Formula [see References (15)]:

Following calculation of the patient’s BSA, the loading dose in milligrams should be calculated as BSA (m) X 70 mg/m. The maintenance dose in milligrams should be calculated as BSA (m) X 50 mg/m.

Duration of treatment should be individualized to the indication, as described for each indication in adults [see Dosage and Administration (2.2)]. If the 50-mg/mdaily dose is well tolerated but does not provide an adequate clinical response, the daily dose can be increased to 70 mg/m daily (not to exceed 70 mg).

Adult patients with mild hepatic impairment (Child-Pugh score 5 to 6) do not need a dosage adjustment. For adult patients with moderate hepatic impairment (Child-Pugh score 7 to 9), CANCIDAS 35 mg once daily is recommended based upon pharmacokinetic data [see Clinical Pharmacology (12.3)]. However, where recommended, a 70-mg loading dose should still be administered on Day 1. There is no clinical experience in adult patients with severe hepatic impairment (Child-Pugh score >9) and in pediatric patients with any degree of hepatic impairment.

Adult patients on rifampin should receive 70 mg of CANCIDAS once daily. Adult patients on nevirapine, efavirenz, carbamazepine, dexamethasone, or phenytoin may require an increase in dose to 70 mg of CANCIDAS once daily [see Drug Interactions (7)].

When CANCIDAS is co-administered to pediatric patients with inducers of drug clearance, such as rifampin, efavirenz, nevirapine, phenytoin, dexamethasone, or carbamazepine, a CANCIDAS dose of 70 mg/m once daily (not to exceed 70 mg) should be considered [see Drug Interactions (7)].

Do not mix or co-infuse CANCIDAS with other medications, as there are no data available on the compatibility of CANCIDAS with other intravenous substances, additives, or medications. DO NOT USE DILUENTS CONTAINING DEXTROSE (α-D-GLUCOSE), as CANCIDAS is not stable in diluents containing dextrose.

Preparation of CANCIDAS for Infusion

Each vial of CANCIDAS contains an intentional overfill of CANCIDAS. Thus, the drug concentration of the resulting solution is listed in Table 1 below.

The white to off-white cake will dissolve completely. Mix gently until a clear solution is obtained. Visually inspect the reconstituted solution for particulate matter or discoloration during reconstitution and prior to infusion. Do not use if the solution is cloudy or has precipitated.

The reconstituted solution may be stored for up to one hour at ≤25°C (≤77°F).

CANCIDAS vials are for single use only; the remaining solution should be discarded.

This infusion solution must be used within 24 hours if stored at ≤25°C (≤77°F) or within 48 hours if stored refrigerated at 2 to 8°C (36 to 46°F).

Special Considerations for Pediatric Patients >3 Months of Age

Follow the reconstitution procedures described above using either the 70-mg or 50-mg vial to create the reconstituted solution [see Dosage and Administration (2.3)]. From the reconstituted solution in the vial, remove the volume of drug equal to the calculated loading dose or calculated maintenance dose based on a concentration of 7 mg/mL (if reconstituted from the 70-mg vial) or a concentration of 5 mg/mL (if reconstituted from the 50-mg vial).

The choice of vial should be based on total milligram dose of drug to be administered to the pediatric patient. To help ensure accurate dosing, it is recommended for pediatric doses less than 50 mg that 50-mg vials (with a concentration of 5 mg/mL) be used if available. The 70-mg vial should be reserved for pediatric patients requiring doses greater than 50 mg.

The maximum loading dose and the daily maintenance dose should not exceed 70 mg, regardless of the patient's calculated dose.

CANCIDAS 50 mg is a white to off-white powder/cake for infusion in a vial with a red aluminum band and a plastic cap. CANCIDAS 50-mg vial contains 54.6 mg of caspofungin.

CANCIDAS 70 mg is a white to off-white powder/cake for infusion in a vial with a yellow/orange aluminum band and a plastic cap. CANCIDAS 70-mg vial contains 75.6 mg of caspofungin.

CANCIDAS is contraindicated in patients with hypersensitivity (e.g., anaphylaxis) to any component of this product [see Adverse Reactions (6)].

Concomitant use of CANCIDAS with cyclosporine should be limited to patients for whom the potential benefit outweighs the potential risk. In one clinical study, 3 of 4 healthy adult subjects who received CANCIDAS 70 mg 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 alanine transaminase (ALT) on Day 11 that were 2 to 3 times the upper limit of normal (ULN). In a separate panel of adult subjects in the same study, 2 of 8 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 both groups, elevations in aspartate transaminase (AST) paralleled ALT elevations, but were of lesser magnitude. 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%.

In a retrospective postmarketing study, 40 immunocompromised patients, including 37 transplant recipients, were treated with CANCIDAS and cyclosporine for 1 to 290 days (median 17.5 days). Fourteen patients (35%) developed transaminase elevations >5X upper limit of normal or >3X baseline during concomitant therapy or the 14-day follow-up period; five were considered possibly related to concomitant therapy. One patient had elevated bilirubin considered possibly related to concomitant therapy. No patient developed clinical evidence of hepatotoxicity or serious hepatic events. Discontinuations due to laboratory abnormalities in hepatic enzymes from any cause occurred in four patients. Of these, 2 were considered possibly related to therapy with CANCIDAS and/or cyclosporine as well as to other possible causes.

In the prospective invasive aspergillosis and compassionate use studies, there were 4 adult patients treated with CANCIDAS (50 mg/day) and cyclosporine for 2 to 56 days. None of these patients experienced increases in hepatic enzymes.

Given the limitations of these data, CANCIDAS and cyclosporine should only be used concomitantly in those patients for whom the potential benefit outweighs the potential risk. Patients who develop abnormal liver function tests during concomitant therapy should be monitored and the risk/benefit of continuing therapy should be eva luated.

Laboratory abnormalities in liver function tests have been seen in healthy volunteers and in adult and pediatric patients treated with CANCIDAS. In some adult and pediatric patients with serious underlying conditions who were receiving multiple concomitant medications with CANCIDAS, isolated cases of clinically significant hepatic dysfunction, hepatitis, and hepatic failure have been reported; a causal relationship to CANCIDAS has not been established. Patients who develop abnormal liver function tests during CANCIDAS therapy should be monitored for evidence of worsening hepatic function and eva luated for risk/benefit of continuing CANCIDAS therapy.

The following serious adverse reactions are discussed in detail in another section of the labeling:

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

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in clinical trials of CANCIDAS cannot be directly compared to rates in clinical trials of another drug and may not reflect the rates observed in practice. The adverse reaction information from clinical trials does provide a basis for identifying adverse reactions that appear to be related to drug use and for approximating rates.

The overall safety of CANCIDAS was assessed in 1865 adult individuals who received single or multiple doses of CANCIDAS: 564 febrile, neutropenic patients (empirical therapy study); 382 patients with candidemia and/or intra-abdominal abscesses, peritonitis, or pleural space infections (including 4 patients with chronic disseminated candidiasis); 297 patients with esophageal and/or oropharyngeal candidiasis; 228 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 studies 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.

Empirical Therapy

In the randomized, double-blinded empirical therapy study, patients received either CANCIDAS 50 mg/day (following a 70-mg loading dose) or AmBisome (amphotericin B liposome for injection, 3 mg/kg/day). In this study clinical or laboratory hepatic adverse reactions were reported in 39% and 45% of patients in the CANCIDAS and AmBisome groups, respectively. Also reported was an isolated, serious adverse reaction of hyperbilirubinemia considered possibly related to CANCIDAS. Adverse reactions occurring in ≥7.5% of the patients in either treatment group are presented in Table 2.

The proportion of patients who experienced an infusion-related adverse reaction (defined as a systemic event, such as pyrexia, chills, flushing, hypotension, hypertension, tachycardia, dyspnea, tachypnea, rash, or anaphylaxis, that developed during the study therapy infusion and one hour following infusion) was significantly lower in the group treated with CANCIDAS (35%) than in the group treated with AmBisome (52%).

To eva luate 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 (3%) than in the group treated with AmBisome (12%). Clinical renal events, regardless of causality, were similar between CANCIDAS (75/564, 13%) and AmBisome (85/547, 16%).

Candidemia and Other Candida Infections

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 mg/kg/day. Adverse reactions occurring in ≥10% of the patients in either treatment group are presented in Table 3.

The proportion of patients who experienced an infusion-related adverse reaction (defined as a systemic event, such as pyrexia, chills, flushing, hypotension, hypertension, tachycardia, dyspnea, tachypnea, rash, or anaphylaxis, that developed during the study therapy infusion and one hour following infusion) was significantly lower in the group treated with CANCIDAS (20%) than in the group treated with amphotericin B (49%).

To eva luate 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.

In a second randomized, double-blinded invasive candidiasis study, patients received either CANCIDAS 50 mg/day (following a 70-mg loading dose) or CANCIDAS 150 mg/day. The proportion of patients who experienced any adverse reaction was similar in the 2 treatment groups; however, this study was not large enough to detect differences in rare or unexpected adverse events. Adverse reactions occurring in ≥5% of the patients in either treatment group are presented in Table 4.

Esophageal Candidiasis and Oropharyngeal Candidiasis

Adverse reactions occurring in ≥10% of patients with esophageal and/or oropharyngeal candidiasis are presented in Table 5.

Invasive Aspergillosis

In an 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 treatment-emergent adverse reactions were observed with an incidence of ≥12.5%: blood alkaline phosphatase increased (22%), hypotension (20%), respiratory failure (20%), pyrexia (17%), diarrhea (15%), nausea (15%), headache (15%), rash (13%), aspergillosis (13%), alanine aminotransferase increased (13%), aspartate aminotransferase increased (13%), blood bilirubin increased (13%), and blood potassium decreased (13%). Also reported infrequently in this patient population were pulmonary edema, ARDS (adult respiratory distress syndrome), and radiographic infiltrates.