Caspofungin

1 INDICATIONS AND USAGE Caspofungin acetate for injection is an echinocandin antifungal indicated in adults and pediatric patients (3 months of age and older) for: Empirical therapy for presumed fungal infections in febrile, neutropenic patients. ( 1 ) Treatment of candidemia and the following Candida infections: intra-abdominal abscesses, peritonitis and pleural space infections. ( 1 ) Treatment of esophageal candidiasis. ( 1 ) Treatment of invasive aspergillosis in patients who are refractory to or intolerant of other therapies. ( 1 ) 1.1 Empirical Therapy for Presumed Fungal Infections in Febrile, Neutropenic Patients Caspofungin acetate for injection is indicated as empirical therapy for presumed fungal infections in febrile, neutropenic adult and pediatric patients (3 months of age and older) [see Clinical Studies ( 14.1 , 14.5 )]. 1.2 Treatment of Candidemia and Other Candida Infections Caspofungin acetate for injection is indicated for the treatment of candidemia and the following candida infections: intra-abdominal abscesses, peritonitis, and pleural space infections in adult and pediatric patients (3 months of age and older) [see Clinical Studies ( 14.2 , 14.5 )] . Limitations of Use : Caspofungin acetate for injection has not been studied in endocarditis, osteomyelitis, and meningitis due to Candida. 1.3 Treatment of Esophageal Candidiasis Caspofungin acetate for injection is indicated for the treatment of esophageal candidiasis in adult and pediatric patients (3 months of age and older) [see Clinical Studies ( 14.3 , 14.5 )] . Limitations of Use : Caspofungin acetate for injection has not been approved for the treatment of oropharyngeal candidiasis (OPC). In the study that evaluated the efficacy of caspofungin in the treatment of esophageal candidiasis, patients with concomitant OPC had higher relapse rate of the OPC [see Clinical Studies ( 14.3 )] . 1.4 Treatment of Invasive Aspergillosis in Patients Who Are Refractory to or Intolerant of Other Therapies Caspofungin acetate for injection is indicated for the treatment of invasive aspergillosis in adult and pediatric patients (3 months of age and older) who are refractory to or intolerant of other therapies [see Clinical Studies ( 14.4 , 14.5 )] . Limitations of Use : Caspofungin acetate for injection has not been studied as initial therapy for invasive aspergillosis.

5 WARNINGS AND PRECAUTIONS Hypersensitivity : Anaphylaxis, possible histamine-mediated adverse reactions, including rash, facial swelling, angioedema, pruritus, sensation of warmth or bronchospasm, and cases of Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) have been reported with use of caspofungin. Discontinue caspofungin at the first sign or symptom of a hypersensitivity reaction and administer appropriate treatment. ( 5.1 ) Hepatic Effects : Can cause abnormalities in liver enzymes. Isolated cases of hepatic dysfunction, hepatitis, or hepatic failure have been reported. Monitor patients who develop abnormal liver enzymes for evidence of worsening hepatic function, and evaluate risk/benefit of continuing caspofungin. ( 5.2 ) Elevated Liver Enzymes During Concomitant Use with Cyclosporine : Limit use to patients for whom potential benefit outweighs potential risk. Monitor patients who develop abnormal liver function tests (LFTs) during concomitant use with caspofungin. ( 5.3 ) 5.1 Hypersensitivity Anaphylaxis and other hypersensitivity reactions have been reported during administration of caspofungin. Possible histamine-mediated adverse reactions, including rash, facial swelling, angioedema, pruritus, sensation of warmth or bronchospasm have been reported. Cases of Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), some with a fatal outcome, have been reported with use of caspofungin [see Adverse Reactions ( 6.2 )] . Discontinue caspofungin at the first sign or symptom of a hypersensitivity reaction and administer appropriate treatment. 5.2 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. 5.3 Elevated Liver Enzymes During Concomitant 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.

6 ADVERSE REACTIONS 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%) are pyrexia, diarrhea, rash, ALT/AST increased, blood potassium decreased, hypotension, and chills. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Sagent Pharmaceuticals at 1-866-625-1618 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 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 1865 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. Adverse Reactions Caspofungin * N=564 (%) AmBisome † N=547 (%) 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 (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. Adverse Reactions Caspofungin 50 mg † N=114 (%) Amphotericin B N=125 (%) 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 (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. Adverse Reactions Caspofungin 50 mg † N=104 (%) Caspofungin 150 mg N=100 (%) 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 50 mg* N=83 (%) Fluconazole IV 200 mg* N=94 (%) 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 (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/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 Any Dose N=115 (%) Caspofungin 50 mg/m 2 * N=56 (%) AmBisome 3 mg/kg N=26 (%) 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 in Clinical Trials The overall safety of caspofungin was assessed in 2036 individuals (including 1642 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 1951 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, 1665 of the 1951 (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. Adverse Reactions ‡ Caspofungin (N=1951) n (%) All Systems, Any Adverse Reaction 1665 (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. 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

7 DRUG INTERACTIONS Cyclosporine : In two adult clinical studies, cyclosporine (one 4 mg/kg dose or two 3 mg/kg doses) increased the AUC of caspofungin. 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. Monitor patients who develop abnormal liver enzymes during concomitant therapy and evaluate the risk/benefit of continuing therapy [see Warnings and Precautions ( 5.2 ) and Clinical Pharmacology ( 12.3 )] . Tacrolimus : For patients receiving caspofungin and tacrolimus, standard monitoring of tacrolimus trough whole blood concentrations and appropriate tacrolimus dosage adjustments are recommended. Inducers of Hepatic CYP Enzymes Rifampin : Rifampin is a potent CYP3A4 inducer and concomitant administration with caspofungin is expected to reduce the plasma concentrations of caspofungin. Therefore, adult patients on rifampin should receive 70 mg of caspofungin daily and pediatric patients on rifampin should receive 70 mg/m 2 of caspofungin daily (not to exceed an actual daily dose of 70 mg) [see Dosage and Administration ( 2.5 ) and Clinical Pharmacology ( 12.3 )]. Other Inducers of Hepatic CYP Enzymes Adults : When caspofungin is co-administered to adult patients with other inducers of hepatic CYP enzymes, such as efavirenz, nevirapine, phenytoin, dexamethasone, or carbamazepine, administration of a daily dose of 70 mg of caspofungin should be considered [see Dosage and Administration ( 2.5 ) and Clinical Pharmacology ( 12.3 )] . Pediatric Patients : When caspofungin is co-administered to pediatric patients with other inducers of hepatic CYP enzymes, such as efavirenz, nevirapine, phenytoin, dexamethasone, or carbamazepine, administration of a daily dose of 70 mg/m 2 caspofungin (not to exceed an actual daily dose of 70 mg) should be considered [see Dosage and Administration ( 2.5 ) and Clinical Pharmacology ( 12.3 )] .

8 USE IN SPECIFIC POPULATIONS 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 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 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 and any potential adverse effects on the breastfed child from caspofungin or from the underlying maternal condition. 8.4 Pediatric Use The safety and effectiveness of caspofungin 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 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 to penetrate the blood-brain barrier and to treat patients with meningitis and endocarditis is unknown. Caspofungin has not been studied in pediatric patients with endocarditis, osteomyelitis, and meningitis due to Candida . Caspofungin 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. Pharmacokinetic studies enrolled a total of 66 pediatric patients, and an additional 105 pediatric patients received caspofungin in safety and efficacy studies [see Clinical Pharmacology ( 12.3 ) and Clinical Studies ( 14.5 )] . The majority of the pediatric patients received caspofungin 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 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 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 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 )].

8.1 Pregnancy Risk Summary Based on animal data, caspofungin 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 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.

8.4 Pediatric Use The safety and effectiveness of caspofungin 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 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 to penetrate the blood-brain barrier and to treat patients with meningitis and endocarditis is unknown. Caspofungin has not been studied in pediatric patients with endocarditis, osteomyelitis, and meningitis due to Candida . Caspofungin 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. Pharmacokinetic studies enrolled a total of 66 pediatric patients, and an additional 105 pediatric patients received caspofungin in safety and efficacy studies [see Clinical Pharmacology ( 12.3 ) and Clinical Studies ( 14.5 )] . The majority of the pediatric patients received caspofungin 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 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 )].