Caspofungin Acetate Injection

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

Hypersensitivity

Anaphylaxis has been reported during administration of caspofungin.  If this occurs, discontinue caspofungin and administer appropriate treatment.

Possible 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.

Hepatic Effects

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

Elevated Liver Enzymes During Concimitant Use with Cyclosporine

 Elevated liver enzymes have occurred in patients receiving caspofungin and cyclosporine concomitantly.  Only use caspofungin and cyclosporine in those patients for whom the potential benefit outweighs the potential risk.  Patients who develop abnormal liver enzymes during concomitant therapy should be monitored and the risk/benefit of continuing therapy should be evaluated.

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

• Hypersensitivity [see Warnings and Precautions (5.1)]
• Hepatic Effects [see Warnings and Precautions (5.2)]
• Elevated Liver Enzymes During Concomitant Use with Cyclosporine [see Warnings and Precautions (5.3)]

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in clinical trials of caspofungin cannot be directly compared to rates in clinical trials of another drug and may not reflect the rates observed in practice.  

Clinical Trials Experience in Adults

The overall safety of caspofungin was assessed in 1,865 adult individuals who received single or multiple doses of caspofungin: 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 for Presumed Fungal Infections in Febrile Neutropenic Patients

In the randomized, double-blinded empirical therapy study, patients received either caspofungin 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 caspofungin and AmBisome groups, respectively.  Also reported was an isolated, serious adverse reaction of hyperbilirubinemia.  Adverse reactions occurring in 7.5% or greater of the patients in either treatment group are presented in Table 2. 

             Table 2: Adverse Reactions Among Patients with Persistent Fever and Neutropenia Incidence 7.5% or Greater for at Least One Treatment Group  

Within any system organ class, individuals may experience more than 1 adverse reaction.

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

   for 73 patients.

†3 mg/kg/day; daily dose was increased to 5 mg/kg for 74 patients.

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 caspofungin (35%) than in the group treated with AmBisome (52%).

To evaluate the effect of caspofungin and AmBisome on renal function, nephrotoxicity was defined as doubling of serum creatinine relative to baseline or an increase of greater than or equal to 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 greater than 30 mL/min, the incidence of nephrotoxicity was significantly lower in the group treated with caspofungin (3%) than in the group treated with AmBisome (12%).  

Candidemia and Other Candida Infections

In the randomized, double-blinded invasive candidiasis study, patients received either caspofungin 50 mg/day (following a 70 mg loading dose) or amphotericin B 0.6 to 1 mg/kg/day.  Adverse reactions occurring in 10% or greater of the patients in either treatment group are presented in Table 3. 

         Table 3: Adverse Reactions Among Patients with Candidemia or other Candida Infections* Incidence 10% or Greater for at Least One Treatment Group  

Within any system organ class, individuals may experience more than 1 adverse reaction.

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

† Patients received caspofungin 70 mg on Day 1, then 50 mg once daily for the remainder of their treatment.

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 caspofungin (20%) than in the group treated with amphotericin B (49%).

To evaluate the effect of caspofungin and amphotericin B on renal function, nephrotoxicity was defined as doubling of serum creatinine relative to baseline or an increase of greater than or equal to 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 greater than 30 mL/min, the incidence of nephrotoxicity was significantly lower in the group treated with caspofungin than in the group treated with amphotericin B.

In a second randomized, double-blinded invasive candidiasis study, patients received either caspofungin 50 mg/day (following a 70 mg loading dose) or caspofungin 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 reactions.  Adverse reactions occurring in 5% or greater of the patients in either treatment group are presented in Table 4. 

              Table 4: Adverse Reactions Among Patients with Candidemia or other Candida Infections* Incidence 5% or Greater for at Least One Treatment Group 

Within any system organ class, individuals may experience more than 1 adverse event.

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

† Patients received caspofungin 70 mg on Day 1, then 50 mg once daily for the remainder of their treatment.

Esophageal Candidiasis and Oropharyngeal Candidiasis

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

           Table 5: Adverse Reactions Among Patients with Esophageal and/or Oropharyngeal Candidiasis Incidence 10% or Greater for at Least One Treatment Group  

 Within any system organ class, individuals may experience more than 1 adverse reaction.

*Derived from a comparator-controlled clinical study.

Invasive Aspergillosis

In an open-label, noncomparative aspergillosis study, in which 69 patients received caspofungin (70 mg loading dose on Day 1 followed by 50 mg daily), the following adverse reactions were observed with an incidence of 12.5% or greater: blood alkaline phosphatase increased (22%), hypotension (20%), respiratory failure (20%), pyrexia (17%), diarrhea (15%), nausea (15%), headache (15%), rash (13%), alanine aminotransferase increased (13%), aspartate aminotransferase increased (13%), blood bilirubin increased (13%), and blood potassium decreased (13%).  Also reported in this patient population were pulmonary edema, ARDS (adult respiratory distress syndrome), and radiographic infiltrates. 

Clinical Trials Experience in Pediatric Patients (3 months to 17 years of age)

The overall safety of caspofungin was assessed in 171 pediatric patients who received single or multiple doses of caspofungin.  The distribution among the 153 pediatric patients who were over the age of 3 months was as follows: 104 febrile, neutropenic patients; 38 patients with candidemia and/or intra-abdominal abscesses, peritonitis, or pleural space infections; 1 patient with esophageal candidiasis; and 10 patients with invasive aspergillosis.  The overall safety profile of caspofungin in pediatric patients is comparable to that in adult patients.  Table 6 shows the incidence of adverse reactions reported in 7.5% or greater of pediatric patients in clinical studies.

One patient (0.6%) receiving caspofungin, and three patients (12%) receiving AmBisome developed a serious drug-related adverse reaction.  Two patients (1%) were discontinued from caspofungin and three patients (12%) were discontinued from AmBisome due to a drug-related adverse reaction.  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 22% in the group treated with caspofungin and 35% in the group treated with AmBisome.

    Table 6: Adverse Reactions Among Pediatric Patients (0 months to 17 years of age)Incidence 7.5% or Greater for at Least One Treatment Group

Within any system organ class, individuals may experience more than 1 adverse reaction.

* 70 mg/m2 on Day 1, then 50 mg/m2 once daily for the remainder of the treatment.

Overall Safety Experience of Caspofungin in Clinical Trials

The overall safety of caspofungin was assessed in 2,036 individuals (including 1,642 adult or pediatric patients and 394 volunteers) from 34 clinical studies.  These individuals received single or multiple (once daily) doses of caspofungin, ranging from 5 mg to 210 mg.  Full safety data is available from 1,951 individuals, as the safety data from 85 patients enrolled in 2 compassionate use studies was limited solely to serious adverse reactions.  Adverse reactions which occurred in 5% or greater of all individuals who received caspofungin in these trials are shown in Table 7.

Overall, 1,665 of the 1,951 (85%) patients/volunteers who received caspofungin experienced an adverse reaction.

 Table 7: Adverse Reactions* in Patients Who Received Caspofungin in Clinical Trials†Incidence 5% or Greater for at Least One Treatment Group  

* Defined as an adverse reaction, regardless of causality, while on caspofungin or during the 14 day

   post-caspofungin follow-up period.

† Incidence for each preferred term is 5% or greater among individuals who received at least 1 dose of

   caspofungin.

‡ Within any system organ class, individuals may experience more than 1 adverse event.

Clinically significant adverse reactions, regardless of causality or incidence which occurred in less than 5% of patients are listed below.

            • Blood and lymphatic system disorders: anemia, coagulopathy, febrile neutropenia, neutropenia, thrombocytopenia

            •Cardiac disorders: arrhythmia, atrial fibrillation, bradycardia, cardiac arrest, myocardial infarction, tachycardia

            •Gastrointestinal disorders: abdominal distension, abdominal pain upper, constipation, dyspepsia

            •General disorders and administration site conditions: asthenia, fatigue, infusion site pain/pruritus/swelling, mucosal inflammation, edema

            •Hepatobiliary disorders: hepatic failure, hepatomegaly, hepatotoxicity, hyperbilirubinemia, jaundice

            •Infections and infestations: bacteremia, sepsis, urinary tract infection

            •Metabolic and nutrition disorders: anorexia, decreased appetite, fluid overload, hypomagnesemia, hypercalcemia, hyperglycemia, hypokalemia

            •Musculoskeletal, connective tissue, and bone disorders: arthralgia, back pain, pain in extremity

            •Nervous system disorders: convulsion, dizziness, somnolence, tremor

            •Psychiatric disorders: anxiety, confusional state, depression, insomnia

            •Renal and urinary disorders: hematuria, renal failure

            •Respiratory, thoracic, and mediastinal disorders: dyspnea, epistaxis, hypoxia, tachypnea

            •Skin and subcutaneous tissue disorders: erythema, petechiae, skin lesion, urticaria

            •Vascular disorders: flushing, hypertension, phlebitis

Postmarketing Experience

The following additional adverse reactions have been identified during the post-approval use of caspofungin.  Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

          • Gastrointestinal disorders: pancreatitis

          • Hepatobiliary disorders: hepatic necrosis

          • Skin and subcutaneous tissue disorders: erythema multiforme, toxic epidermal necrolysis, Stevens-Johnson syndrome, and skin exfoliation

          • Renal and urinary disorders: clinically significant renal dysfunction

          • General disorders and administration site conditions: swelling and peripheral edema

          • Laboratory abnormalities: gamma-glutamyltransferase increased

Mechanism of Action

 Caspofungin is an echinocandin antifungal drug [see Clinical Pharmacology (12.4)].

Pharmacokinetics

Adult and pediatric pharmacokinetic parameters are presented in Table 8.

Distribution

Plasma concentrations of caspofungin decline in a polyphasic manner following single 1 hour intravenous infusions.  A short α-phase occurs immediately postinfusion, followed by a β-phase (half-life of 9 to 11 hours) that characterizes much of the profile and exhibits clear log-linear behavior from 6 to 48 hours postdose during which the plasma concentration decreases 10-fold.  An additional, longer half-life phase, y-phase, (half-life of 40 to 50 hours), also occurs.  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, L-747969.  At later time points (5 or more days postdose), there is a low level (7 or less picomoles/mg protein, or 1.3% or less of the 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 to L-747969.  Additional metabolism involves hydrolysis into constitutive amino acids and their degradates, including dihydroxyhomotyrosine and N-acetyl-dihydroxyhomotyrosine.  These two tyrosine derivatives are found only in urine, suggesting rapid clearance of these derivatives by the kidneys.

Excretion

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.  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.  After single intravenous administration of [3H] caspofungin acetate, excretion of caspofungin and its metabolites in humans was 35% of dose in feces and 41% of dose in urine.  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) and total clearance of caspofungin is 12 mL/min.

Special Populations

Renal Impairment

In a clinical study of single 70 mg doses, caspofungin pharmacokinetics were similar in healthy adult volunteers with mild renal impairment (creatinine clearance 50 to 80 mL/min) and control subjects.  Moderate (creatinine clearance 31 to 49 mL/min), severe (creatinine clearance 5 to 30 mL/min), and end-stage (creatinine clearance less than 10 mL/min and dialysis dependent) renal impairment moderately increased caspofungin plasma concentrations after single-dose administration (range: 30 to 49% for AUC).  However, in adult patients with invasive aspergillosis, candidemia, or other Candida infections (intra-abdominal abscesses, peritonitis, or pleural space infections) who received multiple daily doses of caspofungin 50 mg, there was no significant effect of mild to end-stage renal impairment on caspofungin concentrations.  No dosage adjustment is necessary for patients with renal impairment.  Caspofungin is not dialyzable, thus supplementary dosing is not required following hemodialysis.

Hepatic Impairment

Plasma concentrations of caspofungin after a single 70 mg dose in adult patients with mild hepatic impairment (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 adult patients with mild hepatic impairment were increased modestly (19 to 25% in AUC) on Days 7 and 14 relative to healthy control subjects.  No dosage adjustment is recommended for patients with mild hepatic impairment.

Adult patients with moderate hepatic impairment (Child-Pugh score 7 to 9) who received a single 70 mg dose of caspofungin had an average plasma caspofungin increase of 76% in AUC compared to control subjects.  A dosage reduction is recommended for adult patients with moderate hepatic impairment based upon these pharmacokinetic data [see Dosage and Administration (2.4)].

There is no clinical experience in adult patients with severe hepatic impairment (Child-Pugh score greater than 9) or in pediatric patients with any degree of hepatic impairment.

Gender

Plasma concentrations of caspofungin in healthy adult men and women were similar following a single 70 mg dose.  After 13 daily 50 mg doses, caspofungin plasma concentrations in women were elevated slightly (approximately 22% in area under the curve [AUC]) relative to men.  No dosage adjustment is necessary based on gender.

Race

Regression analyses of patient pharmacokinetic data indicated that no clinically significant differences in the pharmacokinetics of caspofungin were seen among Caucasians, Blacks, and Hispanics.  No dosage adjustment is necessary on the basis of race.

Geriatric Patients

Plasma concentrations of caspofungin in healthy older men and women (65 years of age and older) were increased slightly (approximately 28% AUC) compared to young healthy men after a single 70 mg dose of caspofungin.  In patients who were treated empirically or who had candidemia or other Candida infections (intra-abdominal abscesses, peritonitis, or pleural space infections), a similar modest effect of age was seen in older patients relative to younger patients.  No dosage adjustment is necessary for the elderly [see Use in Specific Populations (8.5)].

Pediatric Patients

Caspofungin has been studied in five prospective studies involving pediatric patients under 18 years of age, including three pediatric pharmacokinetic studies [initial study in adolescents (12 to 17 years of age) and children (2 to 11 years of age) followed by a study in younger patients (3 to 23 months of age) and then followed by a study in neonates and infants (less than 3 months of age)] [see Use in Specific Populations (8.4)].

Pharmacokinetic parameters following multiple doses of caspofungin in pediatric and adult patients are presented in Table 8.

Table 8: Pharmacokinetic Parameters Following Multiple Doses of Caspofungin in Pediatric (3 months to 17 years) and Adult Patients

 * Harmonic Mean ± jackknife standard deviation.

† N=5 for C1hr and AUC0-24hr; N=6 for C24hr .

‡ N=117 for C24hr; N=119 for C1hr .

§ Following an initial 70 mg loading dose on day 1.

Drug Interactions [see Drug Interactions (7)]

Studies in vitro show that caspofungin acetate is not an inhibitor of any enzyme in the cytochrome P (CYP) system.  Caspofungin is not a substrate for P-glycoprotein and is a poor substrate for CYP enzymes.

In clinical studies, caspofungin did not induce the CYP3A4 metabolism of other drugs.  Clinical studies in adult healthy volunteers also demonstrated that the pharmacokinetics of caspofungin are not altered by itraconazole, amphotericin B, mycophenolate, nelfinavir, or tacrolimus.  Caspofungin has no effect on the pharmacokinetics of itraconazole, amphotericin B, or the active metabolite of mycophenolate.

Cyclosporine: 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%.  Caspofungin did not increase the plasma levels of cyclosporine.  There were transient increases in liver ALT and AST when caspofungin and cyclosporine were co-administered [see Warnings and Precautions (5.2)].

Tacrolimus: Caspofungin reduced the blood AUC0-12 of tacrolimus (FK-506, Prograf ®) by approximately 20%, peak blood concentration (Cmax) by 16%, and 12 hour blood concentration (C12hr) by 26% in healthy adult subjects when tacrolimus (2 doses of 0.1 mg/kg 12 hours apart) was administered on the 10th day of caspofungin 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 whole blood trough concentrations and appropriate tacrolimus dosage adjustments are recommended.

Rifampin: A drug-drug interaction study with rifampin in adult healthy volunteers has shown a 30% decrease in caspofungin trough concentrations [see Dosage and Administration (2.5)].  

Other Inducers of Hepatic CYP Enzymes

Adults: Results from regression analyses of adult patient pharmacokinetic data suggest that co-administration of other hepatic CYP enzyme inducers (e.g., efavirenz, nevirapine, phenytoin, dexamethasone, or carbamazepine) with caspofungin may result in clinically meaningful reductions in caspofungin concentrations.  It is not known which drug clearance mechanism involved in caspofungin disposition may be inducible [see Dosage and Administration (2.5)].  

Pediatric patients: In pediatric patients, results from regression analyses of pharmacokinetic data suggest that co-administration of dexamethasone with caspofungin 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 [see Dosage and Administration (2.5)].  

Microbiology

Mechanism of Action

Caspofungin, an echinocandin, inhibits the synthesis of beta (1,3)-D-glucan, an essential component of the cell wall of susceptible Aspergillus species and Candida species.  Beta (1,3)-D-glucan is not present in mammalian cells.  Caspofungin has shown activity against Candida species and in regions of active cell growth of the hyphae of Aspergillus fumigatus.

Drug Resistance

There have been reports of clinical failures in patients receiving caspofungin therapy due to the development of drug resistance.  Some of these reports have identified specific mutations in the Fks subunits of the glucan synthase enzyme.  These mutations are associated with higher MICs and breakthrough infection.  Candida species that exhibit reduced susceptibility to caspofungin as a result of an increase in the chitin content of the fungal cell wall have also been identified, although the significance of this phenomenon in vivo is not well known.

Drug Interactions

Studies in vitro and in vivo of caspofungin, in combination with amphotericin B, suggest no antagonism of antifungal activity against either A. fumigatus or C. albicans.  The clinical significance of these results is unknown.

Activity in Vitro and in Clinical Infections

Caspofungin has been shown to be active bothin vitro and in clinical infections against most strains of the following microorganisms:

   Aspergillus fumigatus

   Aspergillus flavus

   Aspergillus terreus

   Candida albicans

   Candida glabrata

   Candida guilliermondii

   Candida krusei

   Candida parapsilosis

   Candida tropicalis

Susceptibility Testing Methods

The interpretive standards for caspofungin against Candida species are applicable only to tests performed using Clinical Laboratory and Standards Institute (CLSI) microbroth dilution reference methods2,3 for MIC (partial inhibition endpoint) read at 24 hours.  No interpretive criteria have been established for Aspergillus species or other filamentous fungi.

When available, the clinical microbiology laboratory should provide the results of in vitro susceptibility test results for antimicrobial drug products used in resident hospitals to the physician as periodic reports that describe the susceptibility profile of pathogens.  These reports should aid the physician in selecting an antifungal drug product for treatment.  The techniques for Broth Microdilution are described below.

Broth Microdilution Techniques

Quantitative methods are used to determine antifungal minimum inhibitory concentrations (MICs).  These MICs provide estimates of the susceptibility of Candida spp. to antifungal agents.  MICs should be determined using a standardized procedure at 24 hours2,3.  Standardized procedures are based on a microdilution method (broth) with standardized inoculum concentrations and standardized concentrations of caspofungin powder.  The MIC values should be interpreted according to the criteria provided in Table 9. 

Table 9: Susceptibility Interpretive Criteria for Caspofungin

* A report of “Susceptible” indicates that the pathogen is likely to be inhibited

   if the antimicrobial compound in the blood reaches the concentrations usually  

   achievable.

Quality Control

Standardized susceptibility test procedures require the use of quality control organisms to control the technical aspects of the test procedures.  Standard caspofungin powder should provide the following range of values noted in Table 103.  Quality control microorganisms are specific strains of organisms with intrinsic biological properties relating to resistance mechanisms and their genetic expression within fungi; the specific strains used for microbiological control are not clinically significant. 

Table 10: Acceptable Quality Control Ranges for Caspofungin to be used in 
                             Validation of Susceptibility Test Results

* The MIC for caspofungin is the lowest concentration at which a score of 2 (prominent

   decrease in turbidity [greater than 50% inhibition of growth as compared to the growth control];
see CLSI document M27-A32, Section 7.6.3) is observed after 24 hours of incubation.

Carcinogenesis, Mutagenesis, Impairment of Fertility

No long-term studies in animals have been performed to evaluate the carcinogenic potential of caspofungin.

Caspofungin did not show evidence of mutagenic or genotoxic potential when evaluated in the following in vitro assays: bacterial (Ames) and mammalian cell (V79 Chinese hamster lung fibroblasts) mutagenesis assays, the alkaline elution/rat hepatocyte DNA strand break test, and the chromosome aberration assay in Chinese hamster ovary cells.  Caspofungin was not genotoxic when assessed in the mouse bone marrow chromosomal test at doses up to 12.5 mg/kg (equivalent to a human dose of 1 mg/kg based on body surface area comparisons), administered intravenously.

Fertility and reproductive performance were not affected by the intravenous administration of caspofungin to rats at doses up to 5 mg/kg.  At 5 mg/kg exposures were similar to those seen in patients treated with the 70 mg dose.

Animal Toxicology and/or Pharmacology

In one 5 week study in monkeys at doses which produced exposures approximately 4 to 6 times those seen in adult patients treated with a 70 mg dose, scattered small foci of subcapsular necrosis were observed microscopically in the livers of some animals (2/8 monkeys at 5 mg/kg and 4/8 monkeys at 8 mg/kg); however, this histopathological finding was not seen in another study of 27 weeks duration at similar doses.

No treatment-related findings were seen in a 5 week study in infant monkeys at doses which produced exposures approximately 3 times those achieved in pediatric patients receiving a maintenance dose of 50 mg/m2 daily.

How Supplied

Caspofungin acetate for injection is a lyophilized white to off-white cake or powder for intravenous infusion, supplied in single dose vials with a rubber stopper and an aluminum seal as follows:

Storage and Handling

The lyophilized vials should be stored at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature].

Reconstituted Concentrate

Reconstituted caspofungin acetate for injection in the vial may be stored at ≤ 25°C (≤ 77°F) for one hour prior to the preparation of the patient infusion solution.

Diluted Product

The final patient infusion solution in the intravenous bag or bottle can be stored at ≤ 25°C (≤ 77°F) for 24 hours or at 2° to 8°C (36° to 46°F) for 48 hours. 

The container closure is not made with natural rubber latex.