CANCIDAS

1 INDICATIONS AND USAGE CANCIDAS 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 CANCIDAS ® 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 CANCIDAS 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: CANCIDAS has not been studied in endocarditis, osteomyelitis, and meningitis due to Candida . 1.3 Treatment of Esophageal Candidiasis CANCIDAS 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: CANCIDAS 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 CANCIDAS 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: CANCIDAS has not been studied as initial therapy for invasive aspergillosis.

2 DOSAGE AND ADMINISTRATION Important Administration Instructions for All Patients ( 2.1 ): Administer by slow intravenous (IV) infusion over approximately 1 hour. Do not administer by IV bolus administration. Do not mix or co-infuse CANCIDAS 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/m 2 loading dose on Day 1, followed by 50 mg/m 2 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 Adjustment 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/m 2 once daily (maximum daily dose not to exceed 70 mg). 2.1 Important Administration Instructions for Use in All Patients Administer CANCIDAS by slow intravenous (IV) infusion over approximately 1 hour. Do not administer CANCIDAS by IV bolus administration. 2.2 Recommended Dosage in Adult Patients [18 years of age and older] The dosage and duration of CANCIDAS 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 DOSAGE FORMS AND STRENGTHS CANCIDAS 50 mg is a white to off-white lyophilized cake or powder for reconstitution in a single-dose glass vial with a red aluminum band and a plastic cap. CANCIDAS 50-mg vial contains 50 mg of caspofungin equivalent to 55.5 mg of caspofungin acetate. CANCIDAS 70 mg is a white to off-white lyophilized cake or powder for reconstitution in a single-dose glass vial with a yellow/orange aluminum band and a plastic cap. CANCIDAS 70-mg vial contains 70 mg of caspofungin equivalent to 77.7 mg of caspofungin acetate. For Injection: 50 or 70 mg lyophilized powder (plus allowance for overfill) in a single-dose vial for reconstitution ( 3 )

4 CONTRAINDICATIONS CANCIDAS is contraindicated in patients with known hypersensitivity (e.g., anaphylaxis) to any component of this product [see Adverse Reactions (6) ] . CANCIDAS is contraindicated in patients with known hypersensitivity to any component of this product. ( 4 )

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 Merck Sharp & Dohme LLC at 1-877-888-4231 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 CANCIDAS 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 CANCIDAS was assessed in 1865 adult individuals who received single or multiple doses of CANCIDAS: 564 febrile, neutropenic patients (empirical therapy study); 382 patients with candidemia and/or intra-abdominal abscesses, peritonitis, or pleural space infections (including 4 patients with chronic disseminated candidiasis); 297 patients with esophageal and/or oropharyngeal candidiasis; 228 patients with invasive aspergillosis; and 394 individuals in phase I studies. In the empirical therapy study patients had undergone hematopoietic stem-cell transplantation or chemotherapy. In the studies involving patients with documented Candida infections, the majority of the patients had serious underlying medical conditions (e.g., hematologic or other malignancy, recent major surgery, HIV) requiring multiple concomitant medications. Patients in the noncomparative Aspergillus studies often had serious predisposing medical conditions (e.g., bone marrow or peripheral stem cell transplants, hematologic malignancy, solid tumors or organ transplants) requiring multiple concomitant medications. Empirical Therapy for Presumed Fungal Infections in Febrile Neutropenic Patients In the randomized, double-blinded empirical therapy study, patients received either CANCIDAS 50 mg/day (following a 70-mg loading dose) or AmBisome ® (amphotericin B liposome for injection, 3 mg/kg/day). In this study clinical or laboratory hepatic adverse reactions were reported in 39% and 45% of patients in the CANCIDAS and AmBisome groups, respectively. Also reported was an isolated, serious adverse reaction of hyperbilirubinemia. 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 Adverse Reactions CANCIDAS 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. N=564 (percent) AmBisome 3 mg/kg/day; daily dose was increased to 5 mg/kg for 74 patients. N=547 (percent) Within any system organ class, individuals may experience more than 1 adverse reaction. 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 …

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 CANCIDAS. CANCIDAS did not increase the plasma levels of cyclosporine. There were transient increases in liver ALT and AST when CANCIDAS and cyclosporine were co-administered . 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 CANCIDAS 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 CANCIDAS is expected to reduce the plasma concentrations of CANCIDAS. Therefore, adult patients on rifampin should receive 70 mg of CANCIDAS daily and pediatric patients on rifampin should receive 70 mg/m 2 of CANCIDAS 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 CANCIDAS 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 CANCIDAS should be considered [see Dosage and Administration (2.5) and Clinical Pharmacology (12.3) ] . Pediatric Patients: When CANCIDAS 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 CANCIDAS (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, CANCIDAS 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 CANCIDAS 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 CANCIDAS and any potential adverse effects on the breastfed child from CANCIDAS or from the underlying maternal condition. 8.4 Pediatric Use The safety and effectiveness of CANCIDAS 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 invasi …

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

11 DESCRIPTION CANCIDAS is a sterile, lyophilized product for intravenous (IV) infusion that contains a semisynthetic lipopeptide (echinocandin) compound synthesized from a fermentation product of Glarea lozoyensis. CANCIDAS is an echinocandin antifungal that inhibits the synthesis of β (1,3)-D-glucan, an integral component of the fungal cell wall. CANCIDAS (caspofungin acetate) is 1-[(4 R ,5 S )-5-[(2-aminoethyl)amino]- N 2 -(10,12-dimethyl-1-oxotetradecyl)-4-hydroxy-L-ornithine]-5-[(3 R )-3-hydroxy-L-ornithine] pneumocandin B 0 diacetate (salt). CANCIDAS 50 mg contains 50 mg of caspofungin equivalent to 55.5 mg of caspofungin acetate. CANCIDAS 50 mg also contains: 39 mg sucrose, 26 mg mannitol, 2 mg glacial acetic acid added as a buffering agent, and sodium hydroxide added as a pH adjuster ingredient. CANCIDAS 70 mg contains 70 mg of caspofungin equivalent to 77.7 mg of caspofungin acetate. CANCIDAS 70 mg also contains 54 mg sucrose, 36 mg mannitol, 2.7 mg glacial acetic acid added as a buffering agent, and sodium hydroxide added as a pH adjuster ingredient. Caspofungin acetate is a hygroscopic, white to off-white powder. It is freely soluble in water and methanol, and slightly soluble in ethanol. The pH of a saturated aqueous solution of caspofungin acetate is approximately 6.6. The empirical formula is C 52 H 88 N 10 O 15 ∙2C 2 H 4 O 2 and the formula weight is 1213.42. The structural formula is: Chemical Structure

10 OVERDOSAGE In 6 healthy subjects who received a single 210-mg dose, no significant adverse reactions were reported. Multiple doses above 150 mg daily have not been studied. Caspofungin is not dialyzable. In clinical trials, one pediatric patient (16 years of age) unintentionally received a single dose of caspofungin of 113 mg (on Day 1), followed by 80 mg daily for an additional 7 days. No clinically significant adverse reactions were reported.

16 HOW SUPPLIED/STORAGE AND HANDLING How Supplied CANCIDAS 50 mg is a lyophilized white to off-white cake or powder for intravenous infusion supplied in single-dose vials with a red aluminum band and a plastic cap. NDC 0006-3822-10 supplied as one single-dose vial. CANCIDAS 70 mg is a white to off-white powder/cake for infusion in a vial with a yellow/orange aluminum band and a plastic cap. NDC 0006-3823-10 supplied as one single-dose vial. Storage and Handling The lyophilized vials should be stored refrigerated at 2° to 8°C (36° to 46°F).