Caspofungin Acetate

Important Administration Instructions for All Patients ( 2.1 ):

• Administer by slow intravenous (IV) infusion over approximately 1 hour. Do not administer by intravenous (IV) bolus administration.
• Do not mix or co-infuse Caspofungin acetate for Injection with other medications. Do not use diluents containing dextrose (α- D-glucose). Dosage in Adults [18 years of age and older] ( 2.2 ):
• Administer a single 70 mg loading dose on Day 1, followed by 50 mg once daily for all indications except esophageal candidiasis.
• For esophageal candidiasis, use 50 mg once daily with no loading dose. Dosage in Pediatric Patients [3 months to 17 years of age] ( 2.3 ) :
• Dosing should be based on the patient's body surface area.
• For all indications, administer a single 70 mg/m2 loading dose on Day 1, followed by 50 mg/m2 once daily thereafter.
• Maximum loading dose and daily maintenance dose should not exceed 70 mg, regardless of the patient's calculated dose. Dosage Adjustments in Patients with Hepatic Impairment ( 2.4 ): Reduce dosage for adult patients with moderate hepatic impairment (35 mg once daily, with a 70 mg loading dose on Day 1 where appropriate). Dosage Adjustments in Patients Receiving Concomitant Inducers of Hepatic CYP Enzymes ( 2.5 ):
• Use 70 mg once daily dose for adult patients on rifampin.
• Consider dose increase to 70 mg once daily for adult patients on nevirapine, efavirenz, carbamazepine, dexamethasone, or phenytoin.
• Pediatric patients receiving these same concomitant medications may also require an increase in dose to 70 mg/m2 once daily (maximum daily dose not to exceed 70 mg).

2.1 Important Administration Instructions for Use in All Patients Administer Caspofungin acetate for Injection by slow intravenous (IV) infusion over approximately 1 hour. Do not administer Caspofungin acetate for Injection by intravenous (IV) bolus administration.

2.2 Recommended Dosage in Adult Patients [18 years of age and older] The dosage and duration of Caspofungin acetate for Injection treatment for each indication are as follows: Empirical Therapy for Presumed Fungal Infections in Febrile Neutropenic Patients Administer a single 70 mg loading dose on Day 1, followed by 50 mg once daily thereafter. Duration of treatment should be based on the patient's clinical response. Continue empirical therapy until resolution of neutropenia. In general, treat patients found to have a fungal infection for a minimum of 14 days after the last positive culture and continue treatment 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 Administer a single 70 mg loading dose 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, continue antifungal therapy for at least 14 days after the last positive culture. Patients with neutropenia 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 Administer a single 70 mg loading dose 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.

2.3 Recommended Dosing in Pediatric Patients [3 months to 17 years of age] For all indications, administer a single 70 mg/m 2 loading dose on Day 1, followed by 50 mg/m 2 once 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 2 ) x 70 mg/m 2 . The maintenance dose in milligrams should be calculated as BSA (m 2 ) x 50 mg/m 2 . 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/m 2 daily dose is well tolerated but does not provide an adequate clinical response, the daily dose can be increased to 70 mg/m 2 daily (not to exceed 70 mg). BSA Formula 2.4 Dosage Adjustments in Patients with Hepatic Impairment 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), Caspofungin acetate for Injection 35 mg once daily is recommended based upon pharmacokinetic data [see Clinical Pharmacology ( 12.3 )] with a 70 mg loading dose administered on Day 1 where appropriate. There is no clinical experience in adult patients with severe hepatic impairment (Child-Pugh score greater than 9) and in pediatric patients with any degree of hepatic impairment.

2.5 Dosage Adjustments in Patients Receiving Concomitant Inducers of Hepatic CYP Enzymes Adult Patients: Adult patients on rifampin should receive 70 mg of Caspofungin acetate for Injection once daily. When Caspofungin acetate for Injection is co-administered to adult patients with other inducers of hepatic CYP enzymes such as nevirapine, efavirenz, carbamazepine, dexamethasone, or phenytoin, administration of a daily dose of 70 mg of Caspofungin acetate for Injection should be considered [see Drug Interactions ( 7 )]. Pediatric Patients: Pediatric patients on rifampin should receive 70 mg/m 2 of Caspofungin acetate for Injection daily (not to exceed an actual daily dose of 70 mg). When Caspofungin acetate for Injection is co-administered to pediatric patients with other inducers of hepatic CYP enzymes, such as efavirenz, nevirapine, phenytoin, dexamethasone, or carbamazepine, a Caspofungin acetate for Injection dose of 70 mg/m 2 once daily (not to exceed 70 mg) should be considered [see Drug Interactions ( 7 )].

2.6 Preparation for Administration Reconstitution of Caspofungin Acetate for Injection for Intravenous Infusion A. Aseptically add 10.8 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 to the vial. B. Each vial of Caspofungin acetate for Injection contains an intentional overfill of Caspofungin acetate for Injection. Thus, the drug concentration of the resulting solution is listed in Table 1 below. Table 1: Information for Preparation of Caspofungin Acetate for Injection *Reconstitution volume of diluent to be added is based on the overfill amount of caspofungin (54.6 mg and 77.2 mg, respectively). Caspofungin Acetate for Injection vial (equivalent to caspofungin) Volume of diluent to be added* Resulting Concentration following Reconstitution 50 mg 10.8 mL 5 mg/mL 70 mg 10.8 mL 7 mg/mL C. 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. D. The reconstituted solution of Caspofungin acetate for Injection in the vial may be stored for up to one hour at ≤ 25°C (≤ 77°F) prior to the preparation of the infusion solution in the intravenous bag or bottle. E. Caspofungin acetate for Injection vials are for single-dose only. Discard unused portion. Dilution of the Reconstituted Solution in the Intravenous Bag for Infusion A. Aseptically transfer the appropriate volume (mL) of reconstituted Caspofungin acetate for Injection to an intravenous (IV) bag (or bottle) containing 250 mL of 0.9%, 0.45%, or 0.225% Sodium Chloride Injection or Lactated Ringers Injection. B. Alternatively, the volume (mL) of reconstituted Caspofungin acetate for Injection 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. C. This diluted infusion solution in the intravenous bag or bottle 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). Important Reconstitution and Dilution Instructions for Pediatric Patients 3 Months of Age and Older 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.

2.7 Drug Incompatibilities Do not mix or co-infuse Caspofungin acetate for Injection with other medications, as there are no data available on the compatibility of Caspofungin acetate for Injection with other intravenous substances, additives, or medications. Do not use diluents containing dextrose (α-D-glucose), as Caspofungin acetate for Injection is not stable in diluents containing dextrose.

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 )]
• Adults : Most common adverse reactions (incidence 10% or greater) are diarrhea, pyrexia, ALT/AST increased, blood alkaline phosphatase increased, and blood potassium decreased. ( 6.1 )
• Pediatric patients : Most common adverse reactions (incidence 10% or greater) are pyrexia, diarrhea, rash, ALT/AST increased, blood potassium decreased, hypotension, and chills. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Fresenius Kabi USA, LLC at 1-800-551-7176 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in clinical trials of caspofungin acetate for injection 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 acetate for injection was assessed in 1,865 adult individuals who received single or multiple doses of caspofungin acetate for injection: 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 acetate for injection 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 acetate for injection 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. Adverse Reactions Caspofungin Acetate for Injection * N=564 (percent) AmBisome † N=547 (percent) All Systems, Any Adverse Reaction 95 97 Investigations 58 63 Alanine Aminotransferase Increased 18 20 Blood Alkaline Phosphatase Increased 15 23 Blood Potassium Decreased 15 23 Aspartate Aminotransferase Increased 14 17 Blood Bilirubin Increased 10 14 Blood Magnesium Decreased 7 9 Blood Glucose Increased 6 9 Bilirubin Conjugated Increased 5 9 Blood Urea Increased 4 8 Blood Creatinine Increased 3 11 General Disorders and Administration Site Conditions 57 63 Pyrexia 27 29 Chills 23 31 Edema Peripheral 11 12 Mucosal Inflammation 6 8 Gastrointestinal Disorders 50 55 Diarrhea 20 16 Nausea 11 20 Abdominal Pain 9 11 Vomiting 9 17 Respiratory, Thoracic and Mediastinal Disorders 47 49 Dyspnea 9 10 Skin and Subcutaneous Tissue Disorders 42 37 Rash 16 14 Nervous System Disorders 25 27 Headache 11 12 Metabolism and Nutrition Disorders 21 24 Hypokalemia 6 8 Vascular Disorders 20 23 Hypotension 6 10 Cardiac Disorders 16 19 Tachycardia 7 9 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 acetate for injection (35%) than in the group treated with AmBisome (52%). To evaluate the effect of caspofungin acetate for injection 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 acetate for injection (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 acetate for injection 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 acetate for injection 70 mg on Day 1, then 50 mg once daily for the remainder of their treatment. Adverse Reactions Caspofungin Acetate for Injection 50 mg † N=114 (percent) Amphotericin B N=125 (percent) All Systems, Any Adverse Reaction 96 99 Investigations 67 82 Blood Potassium Decreased 23 32 Blood Alkaline Phosphatase Increased 21 32 Hemoglobin Decreased 18 23 Alanine Aminotransferase Increased 16 15 Aspartate Aminotransferase Increased 16 14 Blood Bilirubin Increased 13 17 Hematocrit Decreased 13 18 Blood Creatinine Increased 11 28 Red Blood Cells Urine Positive 10 10 Blood Urea Increased 9 23 Bilirubin Conjugated Increased 8 14 Gastrointestinal Disorders 49 53 Vomiting 17 16 Diarrhea 14 10 Nausea 9 17 General Disorders and Administration Site Conditions 47 63 Pyrexia 13 33 Edema Peripheral 11 12 Chills 9 30 Respiratory, Thoracic and Mediastinal Disorders 40 54 Tachypnea 1 11 Cardiac Disorders 26 34 Tachycardia 8 12 Skin and Subcutaneous Tissue Disorders 25 28 Rash 4 10 Vascular Disorders 25 38 Hypotension 10 16 Blood and Lymphatic System Disorders 15 13 Anemia 11 9 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 acetate for injection (20%) than in the group treated with amphotericin B (49%). To evaluate the effect of caspofungin acetate for injection 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 acetate for injection than in the group treated with amphotericin B. In a second randomized, double-blinded invasive candidiasis study, patients received either caspofungin acetate for injection 50 mg/day (following a 70 mg loading dose) or caspofungin acetate for injection 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 acetate for injection 70 mg on Day 1, then 50 mg once daily for the remainder of their treatment. Adverse Reactions Caspofungin Acetate for Injection 50 mg † N=104 (percent) Caspofungin Acetate for Injection 150 mg N=100 (percent) All Systems, Any Adverse Reaction 83 83 General Disorders and Administration Site Conditions 33 27 Pyrexia 6 6 Gastrointestinal Disorders 30 33 Vomiting 11 6 Diarrhea 6 7 Nausea 5 7 Investigations 28 35 Alkaline Phosphatase Increased 12 9 Aspartate Aminotransferase Increased 6 9 Blood Potassium Decreased 6 8 Alanine Aminotransferase Increased 4 7 Vascular Disorders 19 18 Hypotension 7 3 Hypertension 5 6 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. Adverse Reactions Caspofungin Acetate for Injection 50 mg * N=83 (percent) Fluconazole intravenous (IV) 200 mg * N=94 (percent) All Systems, Any Adverse Reaction 90 93 Gastrointestinal Disorders 58 50 Diarrhea 27 18 Nausea 15 15 Investigations 53 61 Hemoglobin Decreased 21 16 Hematocrit Decreased 18 16 Aspartate Aminotransferase Increased 13 19 Blood Alkaline Phosphatase Increased 13 17 Alanine Aminotransferase Increased 12 17 White Blood Cell Count Decreased 12 19 General Disorders and Administration Site Conditions 31 36 Pyrexia 21 21 Vascular Disorders 19 15 Phlebitis 18 11 Nervous System Disorders 18 17 Headache 15 9 Invasive Aspergillosis In an open-label, noncomparative aspergillosis study, in which 69 patients received caspofungin acetate for injection (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 acetate for injection was assessed in 171 pediatric patients who received single or multiple doses of caspofungin acetate for injection. 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 acetate for injection 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 acetate for injection, and three patients (12%) receiving AmBisome developed a serious drug-related adverse reaction. Two patients (1%) were discontinued from caspofungin acetate for injection 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 acetate for injection 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/m 2 on Day 1, then 50 mg/m 2 once daily for the remainder of the treatment. Adverse Reactions Noncomparative Clinical Studies Comparator-Controlled Clinical Study of Empirical Therapy Caspofungin Acetate for Injection Any Dose N=115 (percent) Caspofungin Acetate for Injection 50 mg/m 2* N=56 (percent) AmBisome 3 mg/kg N=26 (percent) All Systems, Any Adverse Reaction 95 96 89 Investigations 55 41 50 Blood Potassium Decreased 18 9 27 Aspartate Aminotransferase Increased 17 2 12 Alanine Aminotransferase Increased 14 5 12 Blood Potassium Increased 3 0 8 General Disorders and Administration Site Conditions 47 59 42 Pyrexia 29 30 23 Chills 10 13 8 Mucosal Inflammation 10 4 4 Edema 3 4 8 Gastrointestinal Disorders 42 41 35 Diarrhea 17 7 15 Vomiting 8 11 12 Abdominal Pain 7 4 12 Nausea 4 4 8 Infections and Infestations 40 30 35 Central Line Infection 1 9 0 Skin and Subcutaneous Tissue Disorders 33 41 39 Pruritus 7 6 8 Rash 6 23 8 Erythema 4 9 0 Vascular Disorders 24 21 19 Hypotension 12 9 8 Hypertension 10 9 4 Metabolism and Nutrition Disorders 22 11 23 Hypokalemia 8 5 4 Cardiac Disorders 17 13 19 Tachycardia 4 11 19 Nervous System Disorders 13 16 8 Headache 5 9 4 Musculoskeletal and Connective Tissue Disorders 11 14 12 Back Pain 4 0 8 Blood and Lymphatic System Disorders 10 2 15 Anemia 2 0 8 Overall Safety Experience of Caspofungin Acetate for Injection in Clinical Trials The overall safety of caspofungin acetate for injection 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 acetate for injection, 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 acetate for injection in these trials are shown in Table 7 . Overall, 1,665 of the 1,951 (85%) patients/volunteers who received caspofungin acetate for injection experienced an adverse reaction. Table 7: Adverse Reactions* in Patients Who Received Caspofungin Acetate for Injection in Clinical Trials † Incidence 5% or Greater for at Least One Treatment Group * Defined as an adverse reaction, regardless of causality, while on caspofungin acetate for injection 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 acetate for injection. ‡ Within any system organ class, individuals may experience more than 1 adverse event. Adverse Reactions ‡ Caspofungin Acetate for Injection (N = 1,951) N (%) All Systems, Any Adverse Reaction 1,665 (85) Investigations 901 (46) Alanine Aminotransferase Increased 258 (13) Aspartate Aminotransferase Increased 233 (12) Blood Alkaline Phosphatase Increased 232 (12) Blood Potassium Decreased 220 (11) Blood Bilirubin Increased 117 (6) General Disorders and Administration Site Conditions 843 (43) Pyrexia 381 (20) Chills 192 (10) Edema Peripheral 110 (6) Gastrointestinal Disorders 754 (39) Diarrhea 273 (14) Nausea 166 (9) Vomiting 146 (8) Abdominal Pain 112 (6) Infections and Infestations 730 (37) Pneumonia 115 (6) Respiratory, Thoracic, and Mediastinal Disorders 613 (31) Cough 111 (6) Skin and Subcutaneous Tissue Disorders 520 (27) Rash 159 (8) Erythema 98 (5) Nervous System Disorders 412 (21) Headache 193 (10) Vascular Disorders 344 (18) Hypotension 118 (6) 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 6.2 Postmarketing Experience The following additional adverse reactions have been identified during the post-approval use of caspofungin acetate for injection. 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

• Pregnancy : Based on animal data, may cause fetal harm. ( 8.1 )
• Pediatric Use : Safety and efficacy in neonates and infants less than 3 months old have not been established. ( 8.4 )
• Hepatic Impairment : Reduce dose for adult patients with moderate hepatic impairment (35 mg once daily, with a 70 mg loading dose on Day 1 where appropriate). No data are available in adults with severe impairment or in pediatric patients with any degree of hepatic impairment. ( 2.4 , 8.6 , 12.3 )

8.1 Pregnancy Risk Summary Based on animal data, Caspofungin acetate for Injection may cause fetal harm (see Data ) . There are insufficient human data to establish whether there is a drug-associated risk for major birth defects, miscarriage, or adverse maternal or fetal outcomes with Caspofungin acetate for Injection use in pregnant women. In animal studies, caspofungin caused embryofetal toxicity, including increased resorptions, increased peri- implantation loss, and incomplete ossification at multiple fetal sites when administered intravenously to pregnant rats and rabbits during organogenesis at doses up to 0.8 and 2 times the clinical dose, respectively ( see Data ). Advise patients of the potential risk to the fetus. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Data Animal Data In animal reproduction studies, pregnant rats dosed intravenously with caspofungin during organogenesis (gestational days [GD] 6 to 20) at 0.5, 2, or 5 mg/kg/day (up to 0.8 times the clinical dose based on body surface area comparison) showed increased resorptions and peri-implantation losses at 5 mg/kg/day. Incomplete ossification of the skull and torso and increased incidences of cervical rib were noted in offspring born to pregnant rats treated at doses up to 5 mg/kg/day. In pregnant rabbits treated with intravenous caspofungin during organogenesis (GD 7 to 20) at doses of 1, 3, or 6 mg/kg/day (approximately 2 times the clinical dose based on body surface area comparison), increased fetal resorptions and increased incidence of incomplete ossification of the talus/calcaneus in offspring were observed at the highest dose tested. Caspofungin crossed the placenta in rats and rabbits and was detectable in fetal plasma. In peri- and postnatal development study in rats, intravenous caspofungin administered at 0.5, 2 or 5 mg/kg/day from Day 6 of gestation through Day 20 of lactation was not associated with any adverse effects on reproductive performance or subsequent development of first generation (F1) offspring or malformations in second generation (F2) offspring.

8.2 Lactation Risk Summary There are no data on the presence of caspofungin in human milk, the effects on the breast-fed child, or the effects on milk production. Caspofungin was found in the milk of lactating, drug-treated rats. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for Caspofungin acetate for Injection and any potential adverse effects on the breastfed child from Caspofungin acetate for Injection or from the underlying maternal condition.

8.4 Pediatric Use The safety and effectiveness of caspofungin acetate for injection in pediatric patients 3 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 3 months to 17 years of age for the following indications [see Indications and Usage ( 1 )] :

• Empirical therapy for presumed fungal infections in febrile, neutropenic patients.
• Treatment of candidemia and the following Candida infections: intra-abdominal abscesses, peritonitis, and pleural space infections.
• Treatment of esophageal candidiasis.
• Treatment of invasive aspergillosis in patients who are refractory to or intolerant of other therapies (e.g., amphotericin B, lipid formulations of amphotericin B, itraconazole). The efficacy and safety of caspofungin acetate for injection has not been adequately studied in prospective clinical trials involving neonates and infants under 3 months of age. Although limited pharmacokinetic data were collected in neonates and infants below 3 months of age, these data are insufficient to establish a safe and effective dose of caspofungin in the treatment of neonatal candidiasis. Invasive candidiasis in neonates has a higher rate of CNS and multi-organ involvement than in older patients; the ability of caspofungin acetate for injection to penetrate the blood-brain barrier and to treat patients with meningitis and endocarditis is unknown. Caspofungin acetate for injection has not been studied in pediatric patients with endocarditis, osteomyelitis, and meningitis due to Candida . Caspofungin acetate for injection has also not been studied as initial therapy for invasive aspergillosis in pediatric patients. In clinical trials, 171 pediatric patients (0 months to 17 years of age), including 18 patients who were less than 3 months of age, were given intravenous caspofungin acetate for injection. Pharmacokinetic studies enrolled a total of 66 pediatric patients, and an additional 105 pediatric patients received caspofungin acetate for injection in safety and efficacy studies [see Clinical Pharmacology ( 12.3 ) and Clinical Studies ( 14.5 )] . The majority of the pediatric patients received caspofungin acetate for injection at a once-daily maintenance dose of 50 mg/m 2 for a mean duration of 12 days (median 9, range 1 to 87 days). In all studies, safety was assessed by the investigator throughout study therapy and for 14 days following cessation of study therapy. The most common adverse reactions in pediatric patients treated with caspofungin acetate for injection were pyrexia (29%), blood potassium decreased (15%), diarrhea (14%), increased aspartate aminotransferase (12%), rash (12%), increased alanine aminotransferase (11%), hypotension (11%), and chills (11%) [see Adverse Reactions ( 6.2 )] . Postmarketing hepatobiliary adverse reactions have been reported in pediatric patients with serious underlying medical conditions [see Warnings and Precautions ( 5.3 )] .

8.5 Geriatric Use Clinical studies of caspofungin acetate for injection did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients. Although the number of elderly patients was not large enough for a statistical analysis, no overall differences in safety or efficacy were observed between these and younger patients. Plasma concentrations of caspofungin in healthy older men and women (65 years of age and older) were increased slightly (approximately 28% in AUC) compared to young healthy men. A similar effect of age on pharmacokinetics was seen in patients with candidemia or other Candida infections (intra-abdominal abscesses, peritonitis, or pleural space infections). No dose adjustment is recommended for the elderly; however, greater sensitivity of some older individuals cannot be ruled out.

8.6 Patients with Hepatic Impairment 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), Caspofungin acetate for Injection 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 [see Dosage and Administration ( 2.4 ) and Clinical Pharmacology ( 12.3 )]. There is no clinical experience in adult patients with severe hepatic impairment (Child-Pugh score greater than 9) and in pediatric patients 3 months to 17 years of age with any degree of hepatic impairment.

8.7 Patients with Renal Impairment No dosage adjustment is necessary for patients with renal impairment. Caspofungin is not dialyzable; thus, supplementary dosing is not required following hemodialysis [see Clinical Pharmacology ( 12.3 )] .

12.1 Mechanism of Action Caspofungin is an echinocandin antifungal drug [see Microbiology ( 12.4 )].

12.3 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 [ 3 H] caspofungin acetate for injection. 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 [ 3 H] caspofungin acetate for injection, 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 [ 3 H] caspofungin acetate for injection, 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 acetate for injection 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 acetate for injection 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 acetate for injection 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 acetate for injection in pediatric and adult patients are presented in Table 8 . Table 8: Pharmacokinetic Parameters Following Multiple Doses of Caspofungin Acetate for Injection in Pediatric (3 months to 17 years) and Adult Patients * Harmonic Mean ± jackknife standard deviation. † N=5 for C 1hr and AUC 0-24hr ; N=6 for C 24hr . ‡ N=117 for C 24hr ; N=119 for C 1hr . § Following an initial 70 mg loading dose on day 1. Population N Daily Dose Pharmacokinetic Parameters (Mean ±Standard Deviation) AUC 0-24hr (mcg

• hr/mL) C 1hr (mcg/mL) C 24hr (mcg/mL) t 1/2 (hr)* CI (mL/min) PEDIATRIC PATIENTS Adolescents, Aged 12 to 17 years 8 50 mg/m 2 124.9 ± 50.4 14.0 ± 6.9 2.4 ± 1.0 11.2 ± 1.7 12.6 ± 5.5 Children, Aged 2 to 11 years 9 50 mg/m 2 120.0 ± 33.4 16.1 ± 4.2 1.7 ± 0.8 8.2 ± 2.4 6.4 ± 2.6 Young Children, Aged 3 to 23 months 8 50 mg/m 2 131.2 ± 17.7 17.6 ± 3.9 1.7 ± 0.7 8.8 ± 2.1 3.2 ± 0.4 ADULT PATIENTS Adults with Esophageal Candidiasis 6 † 50 mg 87.3 ± 30.0 8.7 ± 2.1 1.7 ± 0.7 13.0 ± 1.9 10.6 ± 3.8 Adults receiving Empirical Therapy 119 ‡ 50 mg § -- 8.0 ± 3.4 1.6 ± 0.7 -- -- 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 acetate for injection did not increase the plasma levels of cyclosporine. There were transient increases in liver ALT and AST when caspofungin acetate for injection and cyclosporine were co-administered [see Warnings and Precautions ( 5.2 )]. Tacrolimus : Caspofungin acetate for injection reduced the blood AUC 0-12 of tacrolimus (FK-506, Prograf ® ) by approximately 20%, peak blood concentration (C max ) by 16%, and 12 hour blood concentration (C 12hr ) 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 acetate for injection 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 acetate for injection 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 acetate for injection 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 )] .

12.4 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 . Resistance There have been reports of clinical failures in patients receiving caspofungin therapy due to the development of drug resistant Candida or Aspergillus species. Some of these reports have identified specific mutations in the Fks subunits, encoded by the fks 1 and/or fks 2 genes, 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. Interactions With Other Antimicrobials 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. Antimicrobial Activity Caspofungin has been shown to be active against most strains of the following microorganisms both in vitro and in clinical infections [see Indications and Usage ( 1 )] : Aspergillus flavus Aspergillus fumigatus Aspergillus terreus Candida albicans Candida glabrata Candida guilliermondii Candida krusei Candida parapsilosis Candida tropicalis Susceptibility Testing For specific information regarding susceptibility test interpretive criteria and associated test methods and quality control standards recognized by FDA for this drug, please see: https://www.fda.gov/STIC.

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 [ 3 H] caspofungin acetate for injection. 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 [ 3 H] caspofungin acetate for injection, 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 [ 3 H] caspofungin acetate for injection, 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 acetate for injection 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 acetate for injection 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 acetate for injection 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 acetate for injection in pediatric and adult patients are presented in Table 8 . Table 8: Pharmacokinetic Parameters Following Multiple Doses of Caspofungin Acetate for Injection in Pediatric (3 months to 17 years) and Adult Patients * Harmonic Mean ± jackknife standard deviation. † N=5 for C 1hr and AUC 0-24hr ; N=6 for C 24hr . ‡ N=117 for C 24hr ; N=119 for C 1hr . § Following an initial 70 mg loading dose on day 1. Population N Daily Dose Pharmacokinetic Parameters (Mean ±Standard Deviation) AUC 0-24hr (mcg

• hr/mL) C 1hr (mcg/mL) C 24hr (mcg/mL) t 1/2 (hr)* CI (mL/min) PEDIATRIC PATIENTS Adolescents, Aged 12 to 17 years 8 50 mg/m 2 124.9 ± 50.4 14.0 ± 6.9 2.4 ± 1.0 11.2 ± 1.7 12.6 ± 5.5 Children, Aged 2 to 11 years 9 50 mg/m 2 120.0 ± 33.4 16.1 ± 4.2 1.7 ± 0.8 8.2 ± 2.4 6.4 ± 2.6 Young Children, Aged 3 to 23 months 8 50 mg/m 2 131.2 ± 17.7 17.6 ± 3.9 1.7 ± 0.7 8.8 ± 2.1 3.2 ± 0.4 ADULT PATIENTS Adults with Esophageal Candidiasis 6 † 50 mg 87.3 ± 30.0 8.7 ± 2.1 1.7 ± 0.7 13.0 ± 1.9 10.6 ± 3.8 Adults receiving Empirical Therapy 119 ‡ 50 mg § -- 8.0 ± 3.4 1.6 ± 0.7 -- -- 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 acetate for injection did not increase the plasma levels of cyclosporine. There were transient increases in liver ALT and AST when caspofungin acetate for injection and cyclosporine were co-administered [see Warnings and Precautions ( 5.2 )]. Tacrolimus : Caspofungin acetate for injection reduced the blood AUC 0-12 of tacrolimus (FK-506, Prograf ® ) by approximately 20%, peak blood concentration (C max ) by 16%, and 12 hour blood concentration (C 12hr ) 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 acetate for injection 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 acetate for injection 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 acetate for injection 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 )] .