Anidulafungin

12.1 Mechanism of Action Anidulafungin is an anti-fungal drug [see Microbiology (12.4) ].

1 INDICATIONS AND USAGE ERAXIS is an echinocandin antifungal indicated for the treatment of the following infections: • Candidemia and other forms of Candida infections (intra-abdominal abscess and peritonitis) in adults and pediatric patients (1 month of age and older) ( 1.1 ) • Esophageal candidiasis in adults ( 1.2 ) Limitations of use • ERAXIS has not been studied in adult and pediatric patients with endocarditis, osteomyelitis, and meningitis due to Candida or in sufficient numbers of neutropenic patients. The dosage of ERAXIS for the treatment of Candida dissemination into the CNS and the eye has not been established. ( 1.3 , 5.3 , 8.4 ) • ERAXIS is associated with high relapse rates in esophageal candidiasis. ( 1.3 , 14.2 ) 1.1 Candidemia and Other Forms of Candida Infections (Intra-abdominal Abscess and Peritonitis) ERAXIS is indicated for the treatment of candidemia and the following Candida infections: intra-abdominal abscess and peritonitis in adults and pediatric patients 1 month of age and older [see Clinical Studies (14.1) and Microbiology (12.4) ] . 1.2 Esophageal Candidiasis ERAXIS is indicated for the treatment of esophageal candidiasis in adults [see Indications and Usage (1.3) , Clinical Studies (14.2) ] . 1.3 Limitations of Use • ERAXIS has not been studied in adult and pediatric patients with endocarditis, osteomyelitis, and meningitis due to Candida , and has not been studied in sufficient numbers of neutropenic patients to determine efficacy in this group. The dosage of ERAXIS for the treatment of Candida dissemination into the CNS and the eye has not been established [see Warning and Precautions (5.3) , Use in Specific Populations (8.4) ] . • ERAXIS is associated with high relapse rates in esophageal candidiasis [see Clinical Studies (14.2) ] . 1.4 Usage Specimens for fungal culture and other relevant laboratory studies (including histopathology) should be obtained prior to therapy to isolate and identify causative organism(s). Therapy may be

2 DOSAGE AND ADMINISTRATION Adults Pediatric Patients 1 Month of Age and Older Candidemia and other forms of Candida infections 200 mg loading dose on Day 1, followed by 100 mg once daily maintenance dose thereafter for at least 14 days after the last positive culture ( 2.1 ) 3 mg/kg (not to exceed 200 mg) loading dose on Day 1, followed by 1.5 mg/kg (not to exceed 100 mg) once daily maintenance dose thereafter for at least 14 days after the last positive culture ( 2.2 ) Esophageal candidiasis 100 mg loading dose on Day 1, followed by 50 mg once daily maintenance dose thereafter for a minimum of 14 days and for at least 7 days following resolution of symptoms ( 2.1 ) Not Approved Rate of Infusion for Adults and Pediatric Patients The rate of infusion should not exceed 1.1 mg/minute [equivalent to 1.4 mL/minute or 84 mL/hour when reconstituted and diluted per instructions] ( 2.3 , 2.4 ) 2.1 Recommended Dosage in Adults Candidemia and other Candida infections (intra-abdominal abscess and peritonitis) The recommended dose is a single 200 mg loading dose of ERAXIS on Day 1, followed by a 100 mg once daily maintenance dose thereafter. Duration of treatment should be based on the patient's clinical response. In general, antifungal therapy should continue for at least 14 days after the last positive culture. Esophageal Candidiasis The recommended dose is a single 100 mg loading dose of ERAXIS on Day 1, followed by a 50 mg once daily maintenance dose thereafter. Patients should be treated for a minimum of 14 days and for at least 7 days following resolution of symptoms. Duration of treatment should be based on the patient's clinical response. Because of the risk of relapse of esophageal candidiasis in patients with HIV infection, suppressive antifungal therapy may be considered after a course of treatment. 2.2 Recommended Dosage in Pediatric Patients (1 Month of Age and Older) Candidemia and other Candida infections (intra-abdominal abscess and peritonitis) The recommended dose is a single loading dose of 3 mg/kg (not to exceed 200 mg) of ERAXIS on Day 1, followed by a once daily maintenance dose of 1.5 mg/kg (not to exceed 100 mg) of ERAXIS thereafter. Overall antifungal treatment should continue for at least 14 days after the last positive culture. 2.3 Preparation for Administration ERAXIS for Injection must be reconstituted with sterile Water for Injection and subsequently diluted only with 5% Dextrose Injection, USP or 0.9% Sodium Chloride Injection, USP (normal saline), prior to administration. The compatibility of reconstituted ERAXIS with intravenous substances, additives, or medications other than 5% Dextrose Injection, USP or 0.9% Sodium Chloride Injection, USP (normal saline) has not been established. Do NOT dilute with other solutions or co-infuse with other medications or electrolytes . The infusion solution must not be frozen. Reconstitution of the 50 mg/vial Aseptically reconstitute each 50 mg vial with 15 mL of sterile Water for Injection to provide a concentration of 3.33 mg/mL. Reconstitution of the 100 mg/vial Aseptically reconstitute each 100 mg vial with 30 mL of sterile Water for Injection to provide a concentration of 3.33 mg/mL. Storage of the Reconstituted Solution ERAXIS reconstituted solution can be stored at 25°C (77°F) for up to 24 hours prior to dilution into the infusion solution. Chemical and physical in-use stability of the reconstituted solution has been demonstrated for 24 hours at 25°C (77°F). From a microbiological point of view, following good aseptic practices, the reconstituted solution can be utilized for up to 24 hours when stored at 25°C. 2.4 Dilution and Administration of the Infusion Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. If particulate matter or discoloration is identified, discard the solution. Adult Patients Aseptically transfer the contents of the reconstituted vial(s) into the appropriately sized IV bag (or bottle) containing either 5% Dextrose Injection, USP or 0.9% Sodium Chloride Injection, USP (normal saline). See Table 1 for the dilution to a concentration of 0.77 mg/mL for the final infusion solution and infusion instructions for each dose. The rate of infusion should not exceed 1.1 mg/minute (equivalent to 1.4 mL/minute or 84 mL/hour when reconstituted and diluted per instructions) [see Warnings and Precautions (5.2) ]. Table 1: Dilution Requirements for ERAXIS Administration Dose Number of Vials Required Total Reconstituted Volume Required Infusion Volume Either 5% Dextrose Injection, USP or 0.9% Sodium Chloride Injection, USP (normal saline) Total Infusion Volume Infusion solution concentration is 0.77 mg/mL Rate of Infusion Minimum Duration of Infusion 50 mg 1–50 mg 15 mL 50 mL 65 mL 1.4 mL/min or 84 mL/ hour 45 min 100 mg 2–50 mg or 1–100 mg 30 mL 100 mL 130 mL 1.4 mL/min or 84 mL/ hour 90 min 200 mg 4–50 mg or 2–100 mg 60 mL 200 mL 260

6 ADVERSE REACTIONS The following most serious adverse reactions are described elsewhere in other labeling sections: • Hepatic Adverse Reactions [see Warnings and Precautions (5.1) ] • Anaphylactic and Hypersensitivity Reactions [see Warnings and Precautions (5.2) ] Adults • Candidemia and other forms of Candida infections: Most common adverse reactions (≥15%) are hypokalemia, nausea, diarrhea, vomiting, pyrexia, insomnia, hypotension. ( 6.1 ) • Esophageal candidiasis: Most common adverse reactions (≥5%) are diarrhea, pyrexia, anemia, headache, vomiting, nausea, dyspepsia, oral candidiasis, and hypokalemia. ( 6.1 ) Pediatric Patients (1 month and older) Candidemia and other forms of Candida infections: Most common adverse reactions (≥ 5%): diarrhea, vomiting, pyrexia, abdominal pain, anemia, thrombocytopenia, alanine aminotransferase (ALT) and aspartate aminotransferase (AST) increased, hypoglycemia, epistaxis, and rash. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Pfizer Inc at 1-800-438-1985 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 the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Clinical Trials Experience in Adults The safety of ERAXIS for Injection was assessed in 929 individuals, including 257 healthy subjects and 672 patients in clinical trials of candidemia, other forms of Candida infections, and esophageal candidiasis. A total of 633 patients received ERAXIS at daily doses of either 50 mg or 100 mg. A total of 481 patients received ERAXIS for ≥14 days. Candidemia/other Candida Infections Three trials (one comparative vs. fluconazole, two non-comparative) assessed the efficacy and safety of ERAXIS (100 mg) in patients with candidemia and other Candida infections. The data described below reflect exposure to ERAXIS and fluconazole in 127 and 118 patients, respectively, with candidemia and other forms of invasive candidiasis, in the randomized, comparative trial of the efficacy and safety of ERAXIS to that of fluconazole. In ERAXIS-treated patients, the age range was 16–89 years, the gender distribution was 51% male and 49% female, and the race distribution was 72% White, 18% Black/African American, 9% other races. Patients were randomized to receive once daily IV ERAXIS (200 mg loading dose followed by 100 mg maintenance dose) or IV fluconazole (800 mg loading dose followed by 400 mg maintenance dose). Treatment was administered for at least 14 and not more than 42 days. The number of patients with adverse reactions leading to discontinuation of study medication was 11.5% in the ERAXIS arm and 21.6% in the fluconazole arm. The most common adverse reactions leading to study drug discontinuation were multi-organ failure (2.3%) and systemic Candida infection (1.5%) in the ERAXIS arm. Table 2 presents adverse reactions that were reported in ≥5% of subjects receiving ERAXIS or fluconazole therapy in this trial. Table 2: Adverse Reactions Reported in ≥5% of Adult Patients Receiving ERAXIS or Fluconazole Therapy for Candidemia/other Candida Infections A patient who experienced multiple reactions within a Body System or preferred term was counted one time for that class, one time for the preferred term and one time for "subjects with at least one adverse reaction". , This trial was not designed to support comparative claims for ERAXIS for the adverse reactions reported in this table. Adverse Reaction ERAXIS 100 mg N=131 Fluconazole 400 mg N=125 N (%) N (%) Subjects with a least one adverse reaction 130 (99) 122 (98) Gastrointestinal disorders 81 (62) 72 (58) Nausea 32 (24) 15 (12) Diarrhea 24 (18) 23 (18) Vomiting 23 (18) 12 (10) Constipation 11 (8) 14 (11) Abdominal pain 8 (6) 16 (13) General disorders and administration site conditions 70 (53) 76 (61) Pyrexia 23 (18) 23 (18) Edema peripheral 14 (11) 16 (13) Chest pain 7 (5) 6 (5) Respiratory, thoracic, and mediastinal disorders 67 (51) 55 (44) Dyspnea 15 (12) 4 (3) Pleural effusion 13 (10) 11 (9) Cough 9 (7) 7 (6) Respiratory distress 8 (6) 2 (2) Investigations 66 (50) 46 (37) Blood alkaline phosphatase increased 15 (12) 14 (11) White blood cell increased 11 (8) 3 (2) Hepatic enzyme increased 7 (5) 14 (11) Blood creatinine increased 7 (5) 1 (1) Metabolism and nutrition disorders 61 (47) 61 (49) Hypokalemia 33 (25) 24 (19) Hypomagnesemia 15 (12) 14 (11) Hypoglycemia 9 (7) 10 (8) Hyperkalemia 8 (6) 14 (11) Hyperglycemia 8 (6) 8 (6) Dehydration 8 (6) 2 (2) Vascular disorders 50 (38) 41 (33) Hypotension 19 (15) 18 (14) Hypertension 15 (12) 5 (4) Deep vein thrombosis 13 (10) 9 (7) Psychiatric disorders 48 (37) 45 (36) Insomnia 20 (15) 12 (10) Confusional state 10 (8) 10 (8) Depression 8 (6) 5 (4) Blood and lymphatic system disorders 34 (26) 36 (29) Anemia 12 (9) 20 (16) Thrombocythemia 8 (6) 1 (1) Leu

7 DRUG INTERACTIONS 7.1 Cyclosporine Administration of multiple doses of anidulafungin and cyclosporine to healthy subjects resulted in no significant alteration in the steady state pharmacokinetics of either drug. No dosage adjustment of cyclosporine or anidulafungin is needed when the two drugs are co-administered [see Clinical Pharmacology (12.3) ] . 7.2 Voriconazole Administration of multiple doses of anidulafungin and voriconazole to healthy subjects resulted in no significant alteration in the steady state pharmacokinetics of either drug. No dosage adjustment of voriconazole or anidulafungin is needed when the two drugs are co-administered [see Clinical Pharmacology (12.3) ] . 7.3 Tacrolimus Administration of multiple doses of anidulafungin and a single-dose of tacrolimus to healthy subjects resulted in no significant alteration in the steady state pharmacokinetics of either drug. No dosage adjustment of tacrolimus or anidulafungin is needed when the two drugs are co-administered [see Clinical Pharmacology (12.3) ] . 7.4 Rifampin Administration of multiple doses of anidulafungin and rifampin to patients resulted in no significant alteration in the steady state pharmacokinetics of anidulafungin. No dosage adjustment of anidulafungin is needed when it is co-administered with rifampin [see Clinical Pharmacology (12.3) ] . 7.5 Amphotericin B Liposome for Injection Administration of multiple doses of anidulafungin and liposomal amphotericin B to patients resulted in no significant alteration in the steady state pharmacokinetics of anidulafungin. No dosage adjustment of anidulafungin is needed when it is co-administered with liposomal amphotericin B [see Clinical Pharmacology (12.3) ] .