Cancidas

Caspofungin acetate.

Before reconstitution, CANCIDAS appears to be solid, white to off-white compact powder.
After reconstitution, CANCIDAS appears to be a clear, colorless solution, leaving no visible residue as undissolved matter and free from particles of foreign matter that can be observed on visual inspection.
Therapeutic Class: CANCIDAS is a sterile, lyophilized product for intravenous infusion that contains a semi-synthetic lipopeptide (echinocandin) compound synthesized from a fermentation product of Glarea lozoyensis. CANCIDAS is the first of a new class of antifungal drugs (echinocandins) that inhibit the synthesis of β (1,3)-D-glucan, an integral component of the fungal cell wall.
CANCIDAS (caspofungin acetate) is 1-[(4R,5S)-5-[(2-aminoethyl)amino]-N²-(10,12-dimethyl-1-oxotetradecyl)-4-hydroxy-L-ornithine]-5-[(3R)-3-hydroxy-L-ornithine]pneumocandin B₀ diacetate (salt).
Caspofungin acetate is a hygroscopic, white to off-white powder. It is freely soluble in water and methanol, and slightly soluble in ethanol. The pH of a saturated aqueous solution of caspofungin acetate is approximately 6.6. The empirical formula is C₅₂H₈₈N₁₀O₁₅·2C₂H₄O₂ and the formula weight is 1213.42.
Excipients/Inactive Ingredients: In addition to the active ingredient caspofungin acetate, CANCIDAS contains the following inactive ingredients: sucrose, mannitol, acetic acid, and sodium hydroxide.

Pharmacology: Mechanism of Action: Caspofungin acetate, the active ingredient of CANCIDAS, inhibits the synthesis of β (1,3)-D-glucan, an essential component of the cell wall of many filamentous fungi and yeast. β (1,3)-D-glucan is not present in mammalian cells.
Pharmacodynamics: Activity in vitro: Caspofungin has in vitro activity against Aspergillus species (including Aspergillus fumigatus, Aspergillus flavus, Aspergillus niger, Aspergillus nidulans, Aspergillus terreus) and Aspergillus candidus and Candida species (including Candida albicans, Candida dubliniensis, Candida glabrata, Candida guilliermondii, Candida kefyr, Candida krusei, Candida lipolytica, Candida lusitaniae, Candida parapsilosis, Candida rugosa, and Candida tropicalis). Susceptibility testing was performed according to a modification of both the Clinical and Laboratory Standards Institute (CLSI, formerly known as the National Committee for Clinical Laboratory Standards [NCCLS]) method M38-A (for Aspergillus species) and method M27-A (for Candida species).
Interpretive standards (or breakpoints) for caspofungin against Candida species are applicable only to tests performed using CLSI microbroth dilution reference method M27-A3 for minimum inhibitory concentrations (MIC) read as a partial inhibition endpoint at 24 hours. The MIC values for caspofungin using CLSI microbroth dilution reference method M27-A3 should be interpreted according to the criteria provided in Table 1 as follows (CLSI M27-S3). (See Table 1.)

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There are no established breakpoints for caspofungin against Candida species using the European Committee for Antimicrobial Susceptibility Testing (EUCAST) method.
Standardized techniques for susceptibility testing have been established for yeasts by EUCAST. No standardized techniques for susceptibility testing or interpretive breakpoints have been established for Aspergillus species and other filamentous fungi using either the CLSI or EUCAST method.
Activity in vivo: Caspofungin was active when parenterally administered to immune-competent and immune-suppressed animals with disseminated infections of Aspergillus and Candida for which the endpoints were prolonged survival of infected animals (Aspergillus and Candida) and clearance of fungi from target organs (Candida). Caspofungin was also active in immunodeficient animals after disseminated infection with C. glabrata, C. krusei, C. lusitaniae, C. parapsilosis, or C. tropicalis in which the endpoint was clearance of Candida from target organs. In a lethal, rat pulmonary-infection model with A. fumigatus, caspofungin was highly active in the prevention and treatment of pulmonary aspergillosis.
Cross-resistance: Caspofungin acetate is active against strains of Candida with intrinsic or acquired resistance to fluconazole, amphotericin B, or flucytosine consistent with their different mechanisms of action.
Drug Resistance: A caspofungin MIC of ≤2 μg/mL ("Susceptible" per Table 1) using the CLSI M27-A3 method indicates that the Candida isolate is likely to be inhibited if caspofungin therapeutic concentrations are achieved. Breakthrough infections with Candida isolates requiring caspofungin concentrations >2 μg/mL for growth inhibition have developed in a mouse model of C. albicans infection. Isolates of Candida with reduced susceptibility to caspofungin have been identified in small number of patients during treatment (MICs for caspofungin ≥2 μg/mL using standardized MIC testing techniques approved by the CLSI). Some of these isolates had mutations in the FKS1/FKS2 gene. Although the incidence is rare, these cases have been routinely associated with poor clinical outcomes.
Development of in vitro resistance to caspofungin in Aspergillus species has been identified. In clinical experience, drug resistance in patients with invasive aspergillosis has been observed. The mechanism of resistance has not been established.
The incidence of drug resistance in various clinical isolates of Candida and Aspergillus species is rare.
Drug Interactions: In vitro and in vivo studies of caspofungin acetate, in combination with amphotericin B, demonstrate no antagonism of antifungal activity against either A. fumigatus or C. albicans. Results from in vitro studies suggest that there was some evidence of additive/indifferent or synergistic activity against A. fumigatus and additive/indifferent activity against C. albicans. The clinical significance of these results is unknown.
Clinical Studies: The results of the adult clinical studies are presented by each indication as follows, followed thereafter by the results of pediatric clinical trials.
Empirical Therapy in febrile, neutropenic patients: A multicenter, double-blind study enrolled 1111 febrile, neutropenic patients who were randomized to treatment with daily doses of CANCIDAS (50 mg/day following a 70-mg loading dose on Day 1) or AmBisome (amphotericin B liposome for injection, 3.0 mg/kg/day). Eligible patients had received chemotherapy for malignancy or had undergone hematopoietic stem-cell transplantation (HSCT), and presented with neutropenia (<500 cells/mm³ for 96 hours) and fever (>38.0°C) that had not responded to antibacterial therapy. Any patient known to have a documented fungal infection was excluded from entering the study. Patients were to be treated until resolution of neutropenia, with a maximum treatment duration of 28 days. However, patients found to have a documented fungal infection could be treated longer. If the drug was well tolerated but the patient's fever persisted and clinical condition deteriorated following 5 days of therapy, the dosage of study drug could be increased to 70 mg/day for CANCIDAS (13.3% of patients treated) or to 5.0 mg/kg/day for AmBisome (14.3% of patients treated).
Patients were stratified based on risk category (high-risk patients had undergone allogeneic HSCT or had relapsed acute leukemia) and on receipt of prior antifungal prophylaxis. The percentage of patients in the high-risk stratum at entry was 26.6% for the CANCIDAS group and 22.9% for the AmBisome group. In both groups a similar percentage of patients had received antifungal prophylaxis. The most frequent diagnoses were acute myelogenous leukemia, acute lymphocytic leukemia, and non-Hodgkin's lymphoma.
Patients who met the entry criteria and received at least one dose of study therapy were included in the modified intention-to-treat (MITT) population (556 treated with CANCIDAS and 539 treated with AmBisome). An overall favorable response required meeting each of 5 criteria: 1) successful treatment of any baseline fungal infection, 2) no breakthrough fungal infections during administration of study drug or within 7 days after completion of treatment, 3) survival for 7 days after completion of study therapy, 4) no discontinuation of the study drug because of drug-related toxicity or lack of efficacy, and 5) resolution of fever during the period of neutropenia.
An independent expert panel adjudicated blinded data from all patients identified as having a suspected invasive fungal infection. The panel assessed the presence of invasive fungal infection, timing of onset (baseline or breakthrough), causative pathogen, and, for baseline infections, response to study treatment. The only fungal infections considered to be present for purposes of statistical analysis were those classified by the expert panel as either probable or proven. Approximately 5% of patients were found to have baseline fungal infections, of which the majority were due to Aspergillus or Candida species.
The proportion of MITT patients with an overall favorable response and the proportion of MITT patients with favorable responses to the individual criteria are shown in Table 2. (See Table 2.)

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Based on overall favorable response rates, CANCIDAS was as effective as AmBisome in empirical therapy of persistent febrile neutropenia. CANCIDAS had significantly higher favorable response rates than AmBisome for the following criteria: successful treatment of any baseline fungal infection (CANCIDAS 51.9%, AmBisome 25.9%) and absence of premature discontinuation from study therapy due to toxicity or lack of efficacy (CANCIDAS 89.7%, AmBisome 85.5%). CANCIDAS was comparable to AmBisome for the other criteria (absence of a breakthrough fungal infection, survival for 7 days after the end of treatment, and resolution of fever during neutropenia).
Overall favorable response rates were comparable in high-risk patients (CANCIDAS 43.2%, AmBisome 37.7%) and low-risk patients (CANCIDAS 31.0%, AmBisome 32.4%). Rates were also comparable in patients who had received prior antifungal prophylaxis (CANCIDAS 33.5%, AmBisome 32.9%) and those who had not (CANCIDAS 35.0%, AmBisome 34.5%).
The majority of baseline infections were due to Aspergillus or Candida species. Response rates to CANCIDAS and AmBisome for baseline infections caused by Aspergillus species were, respectively, 41.7% (5/12) and 8.3% (1/12), and by Candida species were 66.7% (8/12) and 41.7% (5/12).
Invasive Candidiasis: In a Phase III randomized, double-blind study, patients with a proven diagnosis of invasive candidiasis received daily doses of CANCIDAS (50 mg/day following a 70-mg loading dose on Day 1) or amphotericin B deoxycholate (0.6 to 0.7 mg/kg/day for non-neutropenic patients and 0.7 to 1.0 mg/kg/day for neutropenic patients). Patients were stratified by both neutropenic status and APACHE II score. Patients who met the entry criteria and received one or more doses of IV study therapy were included in the primary (modified intention-to-treat [MITT]) analysis of response at the end of IV study therapy. A predefined analysis to support the MITT, the evaluable-patients assessment, included patients who met entry criteria, received IV study therapy for 5 or more days and had a full efficacy evaluation at the end of IV study therapy. A favorable response required both symptom resolution and microbiological clearance of the Candida infection.
Of the 239 patients enrolled, 224 (109 treated with CANCIDAS and 115 treated with amphotericin B) met the criteria for inclusion in the MITT analysis. Of these patients, 185 (88 treated with CANCIDAS and 97 treated with amphotericin B) met the criteria for inclusion in the evaluable-patients analysis. The most frequent diagnoses were bloodstream infections (candidemia) (83%) and Candida peritonitis (10%). Most infections were caused by C. albicans (45%), followed by C. parapsilosis (19%), C. tropicalis (16%), C. glabrata (11%), and C. krusei (2%). The favorable response rates at the end of IV study therapy are shown in Table 3. (See Table 3.)

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In neutropenic patients, the favorable response rates at the end of IV study therapy in the CANCIDAS and amphotericin B groups were comparable: 50% (7/14) in the CANCIDAS group and 40% (4/10) in the amphotericin B group. In patients with high (>20) APACHE II scores at study entry, favorable response rates in the CANCIDAS and amphotericin B group were similar: 57.1% (12/21) in the CANCIDAS group and 43.5% (10/23) in the amphotericin B group. Response rates were also consistent across all identified Candida species. For all other efficacy time points (Day 10 of IV study therapy, end of all antifungal therapy, 2-week post-therapy follow-up, and 6- to 8-week post-therapy follow-up), CANCIDAS was as effective as amphotericin B. CANCIDAS was also comparable to amphotericin B with regard to relapse or survival rates.
CANCIDAS was comparable to amphotericin B in the treatment of invasive candidiasis at the end of IV study therapy in the primary (MITT) efficacy analysis. In a predefined efficacy analysis of evaluable patients to support the MITT, CANCIDAS was statistically superior to amphotericin B at the end of IV study therapy.
Candidemia: Of the 224 patients from the invasive candidiasis study who met the criteria for inclusion in the MITT analysis, 186 patients (92 treated with CANCIDAS and 94 treated with amphotericin B) had candidemia. Of these patients, 150 (71 treated with CANCIDAS and 79 treated with amphotericin B) met the criteria for inclusion in the evaluable-patients analysis. The favorable response rates at the end of IV study therapy for patients with candidemia are shown in Table 4. (See Table 4.)

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In both the MITT and evaluable-patients efficacy analyses, CANCIDAS was comparable to amphotericin B in the treatment of candidemia at the end of IV study therapy.
Esophageal Candidiasis: Three comparative studies were conducted to evaluate the efficacy of CANCIDAS for the treatment of esophageal candidiasis. One study compared CANCIDAS to IV fluconazole. In addition, two dose-ranging studies compared different doses of CANCIDAS to amphotericin B. A total of 393 patients with esophageal candidiasis were enrolled in these 3 studies (CANCIDAS, n=222; fluconazole, n=94; amphotericin B, n=77). In all 3 studies, patients were required to have symptoms and microbiological documentation of esophageal candidiasis; and most patients had advanced AIDS (with CD4 counts <50/mm³). Disease severity was determined by esophagoscopy (endoscopy).
In the randomized, double-blind study comparing CANCIDAS 50 mg/day versus IV fluconazole 200 mg/day for the treatment of esophageal candidiasis, patients were treated for 7 to 21 days. A favorable overall response required both complete resolution of symptoms and significant endoscopic improvement 5 to 7 days following discontinuation of study therapy. The definition of endoscopic response was based on severity of disease at baseline using a 4 grade scale and required at least a two grade reduction from baseline endoscopic score or reduction to grade 0 for patients with a baseline score of 2 or less. The proportion of patients with a favorable overall response with CANCIDAS was comparable to that seen with fluconazole (81.5% and 85.1%, respectively). The proportion of patients with a favorable symptom response was also comparable (90.1% and 89.4% for CANCIDAS and fluconazole, respectively). In addition, the proportion of patients with a favorable endoscopic response (85.2% and 86.2% for CANCIDAS and fluconazole, respectively) was comparable.
Two double-blind, comparative dose-ranging studies evaluated 3 different doses of CANCIDAS (35, 50, 70 mg/day) and amphotericin B (0.5 mg/kg/day). The proportion of patients with a favorable overall response in the group receiving CANCIDAS 50 mg/day was 34/46 (73.9%) for study 1, and 18/20 (90.0%) for study 2; the proportion of patients with a favorable overall response in the group receiving amphotericin B was 34/54 (63.0%) for study 1 and 14/23 (60.9%) for study 2. Doses of CANCIDAS above 50 mg daily provided no additional benefit in esophageal candidiasis.
Oropharyngeal Candidiasis: Evidence to support the efficacy of CANCIDAS for the treatment of oropharyngeal candidiasis was derived from two groups of patients enrolled in the 3 comparative studies described previously. The first group, derived from the patients in these comparative studies, had both oropharyngeal and esophageal disease (n=173); the second group had only oropharyngeal disease (n=52). A favorable response was defined as complete resolution of all symptoms of oropharyngeal disease and all visible oropharyngeal lesions.
Of the fifty-two patients who had only oropharyngeal disease and who were treated for 7 to 10 days, 14 patients received CANCIDAS at the recommended dose of 50 mg/day. The favorable response rates were 92.9% (13/14) for CANCIDAS and 66.7% (8/12) for amphotericin B dosed at 0.5 mg/kg/day.
Results from patients with both oropharyngeal and esophageal disease provide additional evidence that CANCIDAS (50 mg/day; n=67) is effective for the treatment of oropharyngeal candidiasis, with results comparable to amphotericin B or fluconazole. Doses of CANCIDAS above 50 mg daily provided no additional benefit in oropharyngeal candidiasis.
Invasive Aspergillosis: Sixty-nine patients between the ages of 18 and 80 with invasive aspergillosis were enrolled in an open-label, non-comparative study to evaluate the safety, tolerability, and efficacy of CANCIDAS. Enrolled patients had previously been refractory to or intolerant of other antifungal therapy(ies). Refractory patients were classified as those who had disease progression or failed to improve despite therapy for 7 days or more with amphotericin B, lipid formulations of amphotericin B, itraconazole, or an investigational azole with reported activity against Aspergillus. Intolerance to previous therapy was defined as a doubling of creatinine (or creatinine of 2.5 mg/dL or more while on therapy), other acute reactions, or infusion-related toxicity. To be included in the study, patients with pulmonary disease must have had invasive aspergillosis classified as definite (positive tissue histopathology or positive culture from tissue obtained by an invasive procedure) or probable (positive radiographic or computed tomographic evidence with supporting culture from bronchoalveolar lavage or sputum, galactomannan enzyme-linked immunosorbent assay, and/or polymerase chain reaction). Patients with extrapulmonary disease had to have definite invasive aspergillosis.
The definitions were modeled after the Mycoses Study Group Criteria². Patients were administered a single 70-mg loading dose of CANCIDAS and subsequently dosed with 50 mg daily. The mean duration of therapy was 33.7 days, with a range of 1 to 162 days.
An independent expert panel evaluated patient data, including diagnosis of invasive aspergillosis, response and tolerability to previous antifungal therapy, treatment course on CANCIDAS, and clinical outcome.
A favorable response was defined as either complete resolution (complete response) or clinically meaningful improvement (partial response) of all signs and symptoms and attributable radiographic findings. Stable, nonprogressive disease was considered to be an unfavorable response.
Among the 69 patients enrolled in the study, 63 met entry diagnostic criteria and had outcome data; and of these, 52 patients received treatment for greater than 7 days. Fifty-three (84%) were refractory to previous antifungal therapy and 10 (16%) were intolerant. Forty-five patients had pulmonary disease and 18 had extrapulmonary disease. Underlying conditions were hematologic malignancy (N=24), allogeneic bone marrow transplant or stem cell transplant (N=18), organ transplant (N=8), solid tumor (N=3), or other conditions (N=10). All patients in the study received concomitant therapies for their other underlying conditions. Eighteen patients received tacrolimus and CANCIDAS concomitantly, of whom 8 also received mycophenolate mofetil.
Overall the expert panel determined that 41% (26/63) of patients receiving at least one dose of CANCIDAS had a favorable response. For those patients who received greater than 7 days of therapy with CANCIDAS, 50% (26/52) had a favorable response. The favorable response rates for patients who were either refractory to or intolerant of previous therapies were 36% (19/53) and 70% (7/10) respectively. The response rates among patients with pulmonary disease and extrapulmonary disease were 47% (21/45) and 28% (5/18), respectively. Among patients with extrapulmonary disease, 2 of 8 patients who also had definite, probable, or possible CNS involvement had a favorable response.
A medical chart review of 206 patients with invasive aspergillosis was also conducted to assess the response to standard (non-investigational) therapies. Patient characteristics and important risk factors in this review were similar to those patients enrolled in the open-label noncomparative study (see previous text), and the same rigorous definitions of diagnosis and outcome were used. To be included in this study, patients had to have had invasive aspergillosis and to have received at least 7 days of standard antifungal therapy. The favorable response rate from this historical control study was 17% (35/206) for standard therapy compared to the favorable response rate of 41% (26/63) for CANCIDAS in the open-label noncomparative study. The results of the multivariate analyses demonstrated an odds ratio of greater than 3 for CANCIDAS, with 95% confidence interval excluding 1, suggesting a benefit of therapy with CANCIDAS.
Pediatric Patients: The safety and efficacy of CANCIDAS was evaluated in pediatric patients 3 months to 17 years of age in two prospective, multicenter clinical trials.
The first study, which enrolled 82 patients between 2 to 17 years of age, was a randomized, double-blind study comparing CANCIDAS (50 mg/m² IV once daily following a 70-mg/m² loading dose on Day 1 [not to exceed 70 mg daily]) to AmBisome (3 mg/kg IV daily) in a 2:1 treatment fashion (56 on caspofungin, 26 on AmBisome) as empirical therapy in pediatric patients with persistent fever and neutropenia. The study design and criteria for efficacy assessment were similar to the study in adult patients (see Clinical Studies, Empirical Therapy in febrile, neutropenic patients). Patients were stratified based on risk category (high-risk patients had undergone allogeneic stem cell transplantation or had relapsed acute leukemia). Twenty-seven percent of patients in both treatment groups were high risk. The overall success rates in the MITT analysis results, adjusted by risk strata, were as follows: 46% (26/56) for CANCIDAS and 32% (8/25) for AmBisome. For those patients in the high risk category, the favorable overall response rate was 60% (9/15) in the CANCIDAS group and 0% (0/7) in the AmBisome group.
The second study was a prospective, open-label, non-comparative study estimating the safety and efficacy of caspofungin in pediatric patients (ages 3 months to 17 years) with invasive candidiasis, esophageal candidiasis, and invasive aspergillosis (as salvage therapy). The study employed diagnostic criteria which were based on established EORTC/MSG criteria of proven or probable infection; these criteria were similar to those criteria employed in the adult studies for these various indications. Similarly, the efficacy time points and endpoints used in this study were similar to those employed in the corresponding adult studies (see Clinical Studies, Invasive Candidiasis, Candidemia, Esophageal Candidiasis, Oropharyngeal Candidiasis, Invasive Aspergillosis). All patients received CANCIDAS at 50 mg/m² IV once daily following a 70-mg/m² loading dose on Day 1 (not to exceed 70 mg daily). Among the 49 enrolled patients who received CANCIDAS, 48 were included in the MITT analysis. Of these 48 patients, 37 had invasive candidiasis, 10 had invasive aspergillosis, and 1 patient had esophageal candidiasis. The favorable response rate, by indication, at the end of caspofungin therapy was as follows in the MITT analysis: 81% (30/37) in invasive candidiasis, 50% (5/10) in invasive aspergillosis, and 100% (1/1) in esophageal candidiasis.
Pharmacokinetics: Absorption: Absorption is not relevant since caspofungin acetate is administered intravenously.
Distribution: Plasma concentrations of caspofungin decline in a polyphasic manner following single 1-hour intravenous infusions. A short α-phase occurs immediately post-infusion, followed by a β-phase with a half-life of 9 to 11 hours that characterizes much of the profile and exhibits clear log-linear behavior from 6 to 48 hours post-dose, during which the plasma concentration decreases by 10 fold. An additional γ-phase also occurs (half-life 40-50 hours). Distribution, rather than excretion or biotransformation, is the dominant mechanism influencing plasma clearance. Caspofungin is extensively bound to albumin (approximately 97%), and distribution into red blood cells is minimal. Mass balance results showed that approximately 92% of the administered radioactivity was distributed to tissues by 36 to 48 hours after a single 70-mg dose of [³H] caspofungin acetate. There is little excretion or biotransformation of caspofungin during the first 30 hours after administration.
Metabolism: Caspofungin is slowly metabolized by hydrolysis and N-acetylation. Caspofungin also undergoes spontaneous chemical degradation to an open-ring peptide compound. At later time points (≥5 days postdose), there is a low level (≤7 picomoles/mg protein, or ≤1.3% of administered dose) of covalent binding of radiolabel in plasma following single-dose administration of [³H] caspofungin acetate, which may be due to two reactive intermediates formed during the chemical degradation of caspofungin. Additional metabolism involves hydrolysis into constitutive amino acids and their derivatives, including dihydroxyhomotyrosine and N-acetyl-dihydroxyhomotyrosine. These two tyrosine derivatives are found only in urine, suggesting rapid clearance of these derivatives by the kidneys.
Elimination: Two single-dose radiolabeled pharmacokinetic studies were conducted. In one study, plasma, urine, and feces were collected over 27 days, and in the second study plasma was collected over 6 months. Approximately 75% of the radioactivity was recovered: 41% in urine and 34% in feces. Plasma concentrations of radioactivity and of caspofungin were similar during the first 24 to 48 hours postdose; thereafter drug levels fell more rapidly. In plasma, caspofungin concentrations fell below the limit of quantitation after 6 to 8 days postdose, while radiolabel fell below the limit of quantitation at 22.3 weeks postdose. A small amount of caspofungin is excreted unchanged in urine (approximately 1.4% of dose). Renal clearance of parent drug is low (approximately 0.15 mL/min).
Characteristics in Patients: Gender: The plasma concentration of caspofungin was similar in healthy men and women on Day 1 following a single 70-mg dose. After 13 daily 50-mg doses, the caspofungin plasma concentration in some women was elevated approximately 20% relative to men.
Hepatic Insufficiency: Plasma concentrations of caspofungin after a single 70-mg dose in patients with mild hepatic insufficiency (Child-Pugh score 5 to 6) were increased by approximately 55% in AUC compared to healthy control subjects. In a 14-day multiple-dose study (70 mg on Day 1 followed by 50 mg daily thereafter), plasma concentrations in patients with mild hepatic insufficiency were increased modestly (19 to 25% in AUC) on Days 7 and 14 relative to healthy control subjects.
Renal Insufficiency: In a clinical study of single 70-mg doses, caspofungin pharmacokinetics were similar in volunteers with mild renal insufficiency (creatinine clearance 50 to 80 mL/min) and control subjects. Moderate (creatinine clearance 31 to 49 mL/min), advanced (creatinine clearance 5 to 30 mL/min), and end-stage (creatinine clearance <10 mL/min and dialysis dependent) renal insufficiency moderately increased caspofungin plasma concentrations after single-dose administration (range: 30 to 49% for AUC). However, in patients with invasive aspergillosis who received multiple daily doses of CANCIDAS 50 mg, there was no significant effect of mild to advanced renal impairment on caspofungin trough concentrations. No dosage adjustment is necessary for patients with renal insufficiency. Caspofungin is not dialyzable, thus supplementary dosing is not required following hemodialysis.

CANCIDAS is indicated in adults and pediatric patients (12 months and older) for: Empirical therapy for presumed fungal infections in febrile, neutropenic patients.
Treatment of Invasive Candidiasis, including candidemia.
Treatment of Esophageal Candidiasis.
Treatment of Invasive aspergillosis in patients who are refractory to or intolerant of other therapies (i.e. amphotericin B, lipid formulations of amphotericin B, and/or itraconazole).
CANCIDAS has not been studied as initial therapy for invasive aspergillosis.

General Recommendations in Adult Patients: CANCIDAS should be administered in adults (≥18 years of age) by slow intravenous infusion over approximately 1 hour.
Empirical Therapy: A single 70-mg loading dose should be administered on Day 1, followed by 50 mg 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. Although an increase in efficacy with 70 mg daily has not been demonstrated, limited safety data suggest that an increase in dose to 70 mg daily is well tolerated.
Invasive Candidiasis: A single 70-mg loading dose should be administered on Day 1, followed by 50 mg daily thereafter. Duration of treatment of invasive candidiasis 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: Fifty (50) mg should be administered daily.
Invasive Aspergillosis: A single 70-mg loading dose should be administered on Day 1, followed by 50 mg daily thereafter. Duration of treatment should be based upon the severity of the patient's underlying disease, recovery from immunosuppression, and clinical response. Although there is no information to demonstrate an increase in efficacy with higher doses, available safety data suggests that an increase in dose to 70 mg daily may be considered in patients without evidence of clinical response in whom CANCIDAS has been well tolerated.
No dosage adjustment is necessary for elderly patients (65 years of age or more).
No dosage adjustment is necessary based on gender, race, or renal impairment.
When co-administering CANCIDAS in adult patients with the metabolic inducers efavirenz, nevirapine, rifampin, dexamethasone, phenytoin, or carbamazepine, use of a daily dose of 70 mg of CANCIDAS should be considered.
Patients with Hepatic Insufficiency: Adult patients with mild hepatic insufficiency (Child-Pugh score 5 to 6) do not need a dosage adjustment. For adult patients with moderate hepatic insufficiency (Child-Pugh score 7 to 9), CANCIDAS 35 mg daily is recommended based upon pharmacokinetic data. 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 insufficiency (Child-Pugh score greater than 9) and in pediatric patients with any degree of hepatic insufficiency.
Pediatric Patients: CANCIDAS should be administered in pediatric patients (12 months to 17 years of age) by slow IV infusion over approximately 1 hour. Dosing in pediatric patients (12 months to 17 years of age) should be based on the patient's body surface area (see Instructions for Use in Pediatric Patients, Mosteller Formula as follows). For all indications, a single 70-mg/m² loading dose (not to exceed an actual dose of 70 mg) should be administered on Day 1, followed by 50 mg/m² daily thereafter (not to exceed an actual dose of 70 mg daily). Duration of treatment should be individualized to the indication, as described for each indication in adults (see previously mentioned General Recommendations in Adult Patients).
If the 50-mg/m² daily dose is well tolerated but does not provide an adequate clinical response, the daily dose can be increased to 70 mg/m² daily (not to exceed an actual daily dose of 70 mg). Although an increase in efficacy with 70 mg/m² daily has not been demonstrated, limited safety data suggest that an increase in dose to 70 mg/m² daily is well tolerated.
When CANCIDAS is co-administered to pediatric patients with inducers of drug clearance, such as rifampin, efavirenz, nevirapine, phenytoin, dexamethasone, or carbamazepine, use of a CANCIDAS dose of 70-mg/m² daily (not to exceed an actual daily dose of 70 mg) should be considered.
The efficacy and safety of CANCIDAS have not been sufficiently studied in clinical trials involving neonates and infants below 12 months of age.
Reconstitution of CANCIDAS: DO NOT USE ANY DILUENTS CONTAINING DEXTROSE (α-D-GLUCOSE), as CANCIDAS is not stable in diluents containing dextrose. DO NOT MIX OR CO-INFUSE CANCIDAS WITH ANY OTHER MEDICATIONS, as there is no data available on the compatibility of CANCIDAS with other intravenous substances, additives, or medications. Visually inspect the infusion solution for particulate matter or discoloration.
Instructions for Use in Adults: Step 1 Reconstitution of vials: To reconstitute the powdered drug, bring the refrigerated vial of CANCIDAS to room temperature and aseptically add 10.5 mL of either 0.9% Sodium Chloride Injection, Sterile Water for Injection, Bacteriostatic Water for Injection with methylparaben and propylparaben, or Bacteriostatic Water for Injection with 0.9% benzyl alcohol. The concentrations of the reconstituted vials will be: 7.2 mg/mL (70 mg vial) or 5.2 mg/mL (50 mg vial).
The white to off-white compact powder will dissolve completely. Mix gently until a clear solution is obtained. Reconstituted solutions should be visually inspected for particulate matter or discoloration. This reconstituted solution may be stored for up to 24 hours at or below 25°C (77°F).
Step 2 Addition of Reconstituted CANCIDAS to patient infusion solution: Diluents for the final patient infusion solutions are: Sterile Saline for Injection, or Lactated Ringer's Solution. The standard patient infusion is prepared by aseptically adding the appropriate amount of reconstituted drug (as shown in the table as follows) to a 100 mL intravenous bag or bottle. For a 70 mg dose, withdraw two separate 5 mL aliquots of the reconstituted solution and add one aliquot to each of two separate 100 mL intravenous bags or bottles. Dilution of a 70 mg dose in a single 100 mL intravenous bag or bottle is not recommended. Do not use if the solution is cloudy or precipitated. This infusion solution must be used within 24 hours if stored at or below 25°C (77°F) or within 48 hours if stored refrigerated at 2 to 8°C (36 to 46°F). CANCIDAS should be administered by slow intravenous infusion over approximately 1 hour. For the 70 mg dose, the two intravenous bags or bottles should be infused sequentially. Each of the bags or bottles should be infused over approximately 30 minutes, for a total infusion time of approximately one hour. (See Table 5.)

Click on icon to see table/diagram/image

Instructions for Use in Pediatric Patients: Calculation of Body Surface Area (BSA) for pediatric dosing: Before preparation of infusion, calculate the body surface area (BSA) of the patient using the following formula: (Mosteller Formula). (See equation.)

Click on icon to see table/diagram/image

Preparation of the 70-mg/m² infusion for pediatric patients 12 months of age or older (using a 70-mg vial): 1. Determine the actual loading dose to be used in the pediatric patient by using the patient's BSA (as calculated previously) and the following equation: BSA (m²) X 70 mg/m² = Loading Dose
The maximum loading dose on Day 1 should not exceed 70 mg regardless of the patient's calculated dose.
2. Equilibrate the refrigerated vial of CANCIDAS to room temperature.
3. Aseptically add 10.5 mL of 0.9% Sodium Chloride Injection, Sterile Water for Injection, Bacteriostatic Water for Injection with methylparaben and propylparaben, or Bacteriostatic Water for Injection with 0.9% benzyl alcohol.^a This reconstituted solution may be stored for up to 24 hours at or below 25°C (77°F).^b This will give a final caspofungin concentration in the vial of 7.2 mg/mL.
4. Remove the volume of drug equal to the calculated loading dose (Step 1) from the vial. Aseptically transfer this volume (mL)^c of reconstituted CANCIDAS to an IV bag (or bottle) containing 250 mL of 0.9%, 0.45%, or 0.225% Sodium Chloride Injection, or Lactated Ringers Injection. Alternatively, the volume (mL)^c of reconstituted CANCIDAS can be added to a reduced volume of 0.9%, 0.45%, or 0.225% Sodium Chloride Injection or Lactated Ringers Injection, not to exceed a final concentration of 0.5 mg/mL. This infusion solution must be used within 24 hours if stored at or below 25°C (77°F) or within 48 hours if stored refrigerated at 2 to 8°C (36 to 46°F).
5. If the calculated loading dose is <50 mg, then the dose may be prepared from the 50-mg vial [follow Steps 2-4 from Preparation of the 50 mg/m² infusion for pediatric patients 12 months of age or older (using a 50-mg vial)]. The final caspofungin concentration in the 50-mg vial after reconstitution is 5.2 mg/mL.
Preparation of the 50-mg/m² infusion for pediatric patients 12 months of age or older (using a 50-mg vial): 1. Determine the daily maintenance dose to be used in the pediatric patient by using the patient's BSA (as calculated previously) and the following equation: BSA (m²) X 50 mg/m² = Daily Maintenance Dose
The daily maintenance dose should not exceed 70 mg regardless of the patient's calculated dose.
2. Equilibrate the refrigerated vial of CANCIDAS to room temperature.
3. Aseptically add 10.5 mL of 0.9% Sodium Chloride Injection, Sterile Water for Injection or Bacteriostatic Water for Injection with methylparaben and propylparaben, or Bacteriostatic Water for Injection with 0.9% benzyl alcohol.^a This reconstituted solution may be stored for up to 24 hours at or below 25°C (77°F).^b This will give a final caspofungin concentration in the vial of 5.2 mg/mL.
4. Remove the volume of drug equal to the calculated loading dose (Step 1) from the vial. Aseptically transfer this volume (mL)^c of reconstituted CANCIDAS to an IV bag (or bottle) containing 250 mL of 0.9%, 0.45%, or 0.225% Sodium Chloride Injection, or Lactated Ringers Injection. Alternatively, the volume (mL)^c of reconstituted CANCIDAS can be added to a reduced volume of 0.9%, 0.45%, or 0.225% Sodium Chloride Injection or Lactated Ringers Injection, not to exceed a final concentration of 0.5 mg/mL. This infusion solution must be used within 24 hours if stored at or below 25°C (77°F) or within 48 hours if stored refrigerated at 2 to 8°C (36 to 46°F).
5. If the actual daily maintenance dose is >50 mg, then the dose may be prepared from the 70-mg vial [follow Steps 2-4 from Preparation of the 70 mg/m² infusion for pediatric patients 12 months of age or older (using a 70-mg vial)]. The final caspofungin concentration in the 70-mg vial after reconstitution is 7.2 mg/mL.
Preparation notes: ^a. The white to off-white cake will dissolve completely. Mix gently until a clear solution is obtained.
^b. 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.
^c. CANCIDAS is formulated to provide the full labeled vial dose (70 mg or 50 mg) when 10 mL is withdrawn from the vial.

In clinical studies, the highest dose was 210 mg, which was administered as a single dose to 6 adult healthy subjects, and was generally well tolerated. In addition, 100 mg once daily for 21 days has been administered to 15 adult healthy subjects and was generally well tolerated. Caspofungin is not dialyzable.

CANCIDAS is contraindicated in patients with hypersensitivity to any component of this product.

Anaphylaxis has been reported during administration of CANCIDAS. If this occurs, CANCIDAS should be discontinued and appropriate treatment administered. Possibly histamine-mediated adverse reactions, including rash, facial swelling, angioedema, pruritus, sensation of warmth, or bronchospasm have been reported and may require discontinuation and/or administration of appropriate treatment.
Cases of Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) have been reported after post marketing use of caspofungin. Caution should apply in patients with history of allergic skin reactions.
Concomitant use of CANCIDAS with cyclosporine has been evaluated in adult healthy volunteers and in adult patients. Some healthy adult subjects who received two 3 mg/kg doses of cyclosporine with caspofungin showed transient increases in alanine transaminase (ALT) and aspartate transaminase (AST) of less than or equal to 3-fold the upper limit of normal (ULN) that resolved with discontinuation of the drugs. There was also an increase of approximately 35% in the area under the curve (AUC) of caspofungin when CANCIDAS and cyclosporine were co-administered; blood levels of cyclosporine remained unchanged. In a retrospective study of 40 patients treated during marketed use with CANCIDAS and cyclosporine for 1 to 290 days (median 17.5 days), no serious hepatic adverse events were noted. As expected in patients with allogeneic hematopoietic stem cell transplants or solid organ transplants, hepatic enzyme abnormalities occurred commonly; however, no patients had elevations in ALT that were considered drug related. Elevations in AST considered at least possibly related to therapy with CANCIDAS and/or cyclosporine occurred in 5 patients, but all were less than 3.6 times the ULN. Discontinuation due to laboratory abnormalities in hepatic enzymes from any cause occurred in 4 patients. Of these, 2 were considered possibly related to therapy with CANCIDAS and/or cyclosporine as well as other possible causes. In the prospective invasive aspergillosis and compassionate use studies, there were 6 adult patients treated with CANCIDAS and cyclosporine for 2 to 56 days; none of these patients experienced increases in hepatic enzymes. These data suggest that CANCIDAS can be used in patients receiving cyclosporine when the potential benefit outweighs the potential risk.
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 evaluated for risk/benefit of continuing CANCIDAS therapy.
General: The efficacy of a 70-mg dose regimen in patients with invasive aspergillosis who are not clinically responding to the 50 mg daily dose is not known. Limited safety data suggest that an increase in dose to 70 mg daily is well tolerated. For candidiasis, see Pharmacology: Pharmacodynamics: Clinical Studies under Actions. The safety and efficacy of doses above 70 mg have not been adequately studied.
The safety information on treatment durations longer than 2 weeks is limited; however, available data suggest that CANCIDAS continues to be well tolerated with longer courses of therapy (112 patients received from 15 to 60 days of therapy; 14 patients received from 61 to 162 days of therapy).
Carcinogenesis, Mutagenesis, and Impairment of Fertility: No long-term studies in animals have been performed to evaluate the carcinogenic potential of caspofungin.
Use in Children: The safety and effectiveness of CANCIDAS in pediatric patients 12 months to 17 years of age are supported by evidence from adequate and well-controlled studies in adults, pharmacokinetic data in pediatric patients, and additional data from prospective studies in pediatric patients 12 months to 17 years of age for the following indications (see Indications/Uses): Empirical therapy for presumed fungal infections in febrile, neutropenic patients; Treatment of invasive candidiasis, including candidemia; Treatment of esophageal candidiasis; Treatment of invasive aspergillosis in patients who are refractory to or intolerant of other therapies (i.e. amphotericin B, lipid formulations of amphotericin B, and/or itraconazole).
The efficacy and safety of CANCIDAS have not been adequately studied in prospective clinical trials involving neonates and infants under 3 months of age.
CANCIDAS has not been studied in pediatric patients with endocarditis, osteomyelitis, and meningitis due to Candida. CANCIDAS has also not been studied as initial therapy for invasive aspergillosis in pediatric patients.
Use in the Elderly: The plasma concentration of caspofungin in healthy older men and women (65 years of age or more) was increased slightly (approximately 28% in AUC) compared to young healthy males. In patients who were treated empirically or who had invasive candidiasis, a similar modest effect of age was seen in older patients relative to younger patients. No dosage adjustment is necessary for elderly patients (65 years of age or more).

Pregnancy: There is no clinical experience involving pregnant women. In rats, caspofungin caused decreases in fetal body weights and an increase in the incidence of incomplete ossification of the skull and torso, at a maternally toxic dose of 5 mg/kg/day. In addition, at this same maternally toxic dose, there was an increase in the incidence of cervical rib in rats. Caspofungin has been shown to cross the placental barrier in animal studies.
CANCIDAS should not be used during pregnancy unless clearly necessary.
Nursing Mothers: It is not known whether this drug is excreted in human milk; therefore, women receiving CANCIDAS should not breast-feed.

Hypersensitivity reactions have been reported (see Precautions).
Adult Patients: In clinical studies, 1440 adult individuals received single or multiple doses of CANCIDAS: 564 febrile, neutropenic patients (empirical therapy study), 125 patients with invasive 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 received chemotherapy for malignancy or had undergone hematopoietic stem cell transplantation. 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.
Reported drug-related clinical and laboratory abnormalities among all adult patients treated with CANCIDAS (total 989) were typically mild and rarely led to discontinuation.
Common (>1/100): General: Fever, headache, abdominal pain, pain, chills.
GI: Nausea, diarrhea, vomiting.
Liver: Elevated liver enzyme levels (AST, ALT, alkaline phosphatase, direct and total bilirubin).
Kidney: Increased serum creatinine.
Blood: Anemia (decreased hemoglobin and hematocrit).
Cardiac: Tachycardia.
Peripheral Vascular: Phlebitis/thrombophlebitis, infused-vein complication, flushing.
Respiratory: Dyspnea.
Skin: Rash, pruritus.
Pediatric Patients: In clinical studies, 171 pediatric patients received single or multiple doses of CANCIDAS: 104 febrile, neutropenic patients; 56 patients with invasive candidiasis; 1 patient with esophageal candidiasis; and 10 patients with invasive aspergillosis. The overall clinical safety profile of CANCIDAS in pediatric patients is comparable to that in adult patients.
Reported drug-related clinical and laboratory abnormalities among all pediatric patients treated with CANCIDAS (total 171) were typically mild and rarely led to discontinuation.
Common (>1/100): General: Fever, headache, chills.
Liver: Elevated liver enzyme levels (AST, ALT).
Cardiac: Tachycardia.
Peripheral Vascular: Catheter site pain, flushing, hypotension.
Skin: Rash, pruritus.
Post-Marketing Experience: The following post-marketing adverse events have been reported: Hepatobiliary: rare cases of hepatic dysfunction.
Skin and subcutaneous tissue disorders: toxic epidermal necrolysis and Stevens-Johnson syndrome.
Cardiovascular: swelling and peripheral edema.
Laboratory abnormalities: hypercalcemia; gamma-glutamyltransferase increased.
Laboratory Test Findings: Adult Patients: Other drug-related laboratory abnormalities reported in adult patients were low albumin, low potassium, hypomagnesemia, decreased white blood cells, increased eosinophils, low platelets, decreased neutrophils, increased urinary red blood cells, increased partial thromboplastin time, decreased total serum protein, increased urinary protein, increased prothrombin time, low sodium, increased urinary white blood cells, and low calcium.
Pediatric Patients: Other drug-related laboratory abnormalities reported in pediatric patients were decreased potassium, hypomagnesemia, increased glucose, decreased phosphorus, increased phosphorus, and increased eosinophils.

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.
In two adult clinical studies, cyclosporine (one 4 mg/kg dose or two 3 mg/kg doses) increased the AUC of caspofungin by approximately 35%. These AUC increases are probably due to reduced uptake of caspofungin by the liver. 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. In a retrospective study of 40 patients treated during marketed use with CANCIDAS and/or cyclosporine for 1 to 290 days (median 17.5 days), no serious hepatic adverse events were noted (see Precautions).
Clinical studies in adult 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, rifampin or the active metabolite of mycophenolate.
CANCIDAS reduced the 12-hour blood concentration (C_12hr) of tacrolimus (FK-506) by 26% in healthy adult volunteers. For patients receiving both therapies, standard monitoring of tacrolimus blood concentrations and appropriate tacrolimus dosage adjustments are recommended.
Results from two clinical drug interaction studies in healthy adult volunteers indicate that rifampin both induces and inhibits caspofungin disposition with net induction at steady state. In one study, rifampin and caspofungin were co-administered for 14 days with both therapies initiated on the same day. In the second study, rifampin was administered alone for 14 days to allow the induction effect to reach steady state, and then rifampin and caspofungin were co-administered for an additional 14 days. When the induction effect of rifampin was at steady state, there was little change in caspofungin AUC or end-of-infusion concentration, but caspofungin trough concentrations were reduced by approximately 30%. The inhibitory effect of rifampin was demonstrated when rifampin and caspofungin treatments were initiated on the same day, and a transient elevation in caspofungin plasma concentrations occurred on Day 1 (approximately 60% increase in AUC). This inhibitory effect was not seen when caspofungin was added to preexisting rifampin therapy, and no elevation in caspofungin concentrations occurred. In addition, results from population pharmacokinetic screening in adults suggest that co-administration of other inducers of drug clearance (efavirenz, nevirapine, phenytoin, dexamethasone, or carbamazepine) with CANCIDAS may also result in clinically meaningful reductions in caspofungin concentrations. Available data suggest that the inducible drug clearance mechanism involved in caspofungin disposition is likely an uptake transport process, rather than metabolism. Therefore, when CANCIDAS is co-administered to adult patients with inducers of drug clearance, such as efavirenz, nevirapine, rifampin, dexamethasone, phenytoin, or carbamazepine, use of a daily dose of 70 mg of CANCIDAS should be considered (see Dosage & Administration).
In pediatric patients, results from regression analyses of pharmacokinetic data suggest that co-administration of dexamethasone with CANCIDAS may result in clinically meaningful reductions in caspofungin trough concentrations. This finding may indicate that pediatric patients will have similar reductions with inducers as seen in adults. 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/m² daily (not to exceed an actual daily dose of 70 mg) should be considered.

Storage of unopened vials: The lyophilized compact powder in vials should be stored at 2 to 8°C (36 to 46°F).
Storage of reconstituted CANCIDAS in vials: Reconstituted CANCIDAS may be stored at or below 25°C (77°F) for up to 24 hours prior to the preparation of the patient infusion solution.
Storage of diluted product for infusion: The final patient infusion solution in the intravenous bag or bottle can be stored at or below 25°C (77°F) for up to 24 hours, or for up to 48 hours when refrigerated at 2 to 8°C (36 to 46°F).

Antifungals

J02AX04 - caspofungin ; Belongs to the class of other systemic antimycotics.

B