Anidulafungin

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 instituted before the results of the cultures and other laboratory studies are known. However, once these results become available, antifungal therapy should be adjusted accordingly.

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 mL 1.4 mL/min or 84 mL/ hour 180 min Pediatric Patients The volume of infusion solution required to deliver the dose is dependent on the weight of the child. The reconstituted solution must be further diluted to a concentration of 0.77 mg/mL for the final infusion solution. A programmable syringe or infusion pump is recommended. 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) ] . Steps for the Preparation of Pediatric Doses below 50 mg 1. Calculate pediatric patient dose and aseptically reconstitute vial(s) required according to reconstitution instructions to provide a concentration of 3.33 mg/mL (if dose is 50 mg or above, see preparation instructions for Adult Patients above ) [see Dosage and Administration (2.2 , 2.3) ] . 2. Calculate the volume (mL) of reconstituted ERAXIS required: [ Volume of reconstituted ERAXIS (mL) = Dose of ERAXIS (mg) ÷ 3.33 mg/mL] 3. Calculate the total volume of the infusion solution (mL) that contains a final concentration of 0.77 mg/mL: [ Total volume of infusion solution (mL) = Dose of ERAXIS (mg) ÷ 0.77 mg/mL] 4. Calculate the volume of diluent [5% Dextrose Injection, USP or 0.9% Sodium Chloride Injection, USP (normal saline)] required to prepare the infusion solution: [ Volume of diluent (mL) = Total volume of final infusion solution (mL) – Volume of reconstituted ERAXIS (mL)] 5. Prepare the infusion solution by aseptically transferring the required volumes (mL) of the reconstituted ERAXIS and diluent [5% Dextrose Injection, USP or 0.9% Sodium Chloride Injection, USP (normal saline)] into an infusion syringe or IV infusion bag needed for administration. Storage of the Infusion Solution ERAXIS infusion solution can be stored at temperatures up to 25°C (77°F) for up to 48 hours. Do not freeze. Chemical and physical in-use stability of the infusion solution has been demonstrated for 48 hours at 25°C (77°F). From a microbiological point of view, following good aseptic practices, the infusion solution can be utilized for up to 48 hours from preparation when stored at 25°C.

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) Leukocytosis 7 (5) 6 (5) Skin and subcutaneous tissue disorders 30 (23) 32 (26) Decubitus ulcer 7 (5) 10 (8) Nervous system disorders 27 (21) 31 (25) Headache 11 (8) 10 (8) Musculoskeletal and connective tissue disorders 27 (21) 25 (20) Back pain 7 (5) 13 (10) Esophageal Candidiasis The data described below reflect exposure to ERAXIS and fluconazole in 300 and 301 patients, respectively, with esophageal candidiasis in a randomized trial comparing the efficacy and safety of ERAXIS to that of oral fluconazole. In ERAXIS-treated patients, the age range was 18–68 years, the gender distribution was 42% male and 58% female and the race distribution was 15% White, 49% Black/African American, 15% Asian, 0.3 % Hispanic, 21% other races. Patients were randomized to receive IV ERAXIS (100 mg on day 1, followed by 50 mg per day) or oral fluconazole (200 mg on day 1, followed by 100 mg per day) for 7 days beyond resolution of symptoms (range, 14–21 days). Twenty-eight (9%) patients in the ERAXIS arm and 36 (12%) patients in the fluconazole arm had adverse reactions related to study medication. The most common adverse reactions leading to study discontinuation were maculopapular rash (1 patient) for the ERAXIS arm. The most common adverse reactions leading to discontinuation were rash (1 patient) and increased AST (1 patient) for the fluconazole arm. Table 3 presents adverse reactions that were reported in ≥5% of subjects receiving ERAXIS therapy. Table 3: Adverse Reactions Reported in ≥5% of Adult Patients Receiving ERAXIS or Fluconazole Therapy for Esophageal Candidiasis 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 50 mg N=300 Fluconazole 100 mg N=301 N (%) N (%) Subjects with a least one adverse reaction 239 (80) 227 (75) Infections and infestations 115 (38) 99 (33) Oral candidiasis 15 (5) 10 (3) Gastrointestinal disorders 106 (35) 113 (38) Diarrhea 27 (9) 26 (9) Vomiting 27 (7) 30 (10) Nausea 20 (7) 23 (8) Dyspepsia 20 (7) 21 (7) Blood and lymphatic system disorders 55 (18) 50 (17) Anemia 25 (8) 22 (7) Metabolism and nutrition disorders 50 (17) 46 (15) Hypokalemia 14 (5) 17 (6) General disorders and administration site condition 49 (16) 54 (18) Pyrexia 27 (9) 28 (9) Nervous system disorders 39 (13) 36 (12) Headache 25 (8) 20 (7) Less Common Adverse Reactions in Adult Patients with Candidemia/other Candida Infections and Esophageal Candidiasis The following selected adverse reactions occurred in <2% of patients: Blood and Lymphatic : coagulopathy, thrombocytopenia Cardiac : atrial fibrillation, bundle branch block (right), sinus arrhythmia, ventricular extrasystoles Eye : eye pain, vision blurred, visual disturbance General and Administration Site : infusion related reaction, peripheral edema, rigors Hepatobiliary : abnormal liver function tests, cholestasis, hepatic necrosis Infections : clostridial infection Investigations : amylase increased, bilirubin increased, CPK increased, electrocardiogram QT prolonged, gamma-glutamyl transferase increased, lipase increased, potassium decreased, prothrombin time prolonged, urea increased Nervous System : convulsion, dizziness Respiratory, Thoracic and Mediastinal : cough Skin and Subcutaneous Tissue : angioneurotic edema, erythema, pruritus, sweating increased, urticaria Vascular : flushing, hot flushes, thrombophlebitis superficial Clinical Trials Experience in Pediatric Patients with Candidemia/Invasive Candidiasis The safety of ERAXIS was investigated in 68 pediatric patients from 1 month to less than 18 years of age with candidemia/invasive candidiasis in a prospective, open-label, non-comparative pediatric trial [see Clinical Studies (14.1) ] . Overall, the safety profile of ERAXIS in the pediatric patients 1 month and older was similar to that of adults. Most Common Adverse Reactions The most common adverse reactions occurring in ≥5% of pediatric patients receiving ERAXIS therapy in the clinical trial are displayed by body system in Table 4. Table 4 Adverse Reactions Occurring in ≥5% of Pediatric Patients Receiving ERAXIS Therapy for Candidemia/other Candida Infections Reflects adverse reactions including those that started on or after first dose of anidulafungin through 6-week follow-up for patients who did not receive oral fluconazole, and those that started between first dose and last dose of anidulafungin for patients who received oral fluconazole. , 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". Adverse Reaction 1 month to <2 years N=19 2 to <5 years N=19 5 to <18 years N=30 Overall N=68 n (%) n (%) n (%) n (%) Subjects with a least one adverse reaction 17 (90) 14 (74) 24 (80) 55 (81) Blood and lymphatic system disorders 9 (47) 3 (16) 4 (13) 16 (24) Anemia 5 (26) 2 (11) 0 7 (10) Thrombocytopenia 2 (11) 1 (5) 1 (3) 4 (6) Gastrointestinal disorders 8 (42) 8 (42) 12 (40) 28 (41) Diarrhea 4 (21) 2 (11) 5 (17) 11 (16) Vomiting 4 (21) 5 (26) 2 (7) 11 (16) Abdominal pain Includes such terms as: abdominal pain and abdominal pain upper. 0 4 (21) 2 (7) 6 (9) General disorders and administration site condition 5 (26) 6 (32) 9 (30) 20 (29) Pyrexia 4 (21) 3 (16) 5 (17) 12 (18) Laboratory Investigations 4 (21) 4 (21) 8 (27) 16 (24) Alanine aminotransferase increased 2 (11) 2 (11) 2 (7) 6 (9) Aspartate aminotransferase increased 2 (11) 1 (5) 1 (3) 4 (6) Metabolism and nutrition disorders 3 (16) 4 (21) 6 (20) 13 (19) Hypoglycemia 1 (5) 2 (11) 1 (3) 4 (6) Respiratory, thoracic and mediastinal disorders 5 (26) 5 (26) 5 (17) 15 (22) Epistaxis 1 (5) 2 (11) 3 (10) 6 (9) Skin and subcutaneous tissue disorders 6 (32) 5 (26) 5 (17) 16 (24) Rash Includes such terms as: rash and rash generalized. 3 (16) 1 (5) 2 (7) 6 (9) Other adverse reactions were reported in 2 or more pediatric patients and in less than 5% of the 68 pediatric patients treated with ERAXIS in the clinical trial: Blood and Lymphatic System Disorders: pancytopenia, thrombocytosis, febrile neutropenia, leukopenia, neutropenia Eye Disorders: Periorbital edema Gastrointestinal Disorders: gastroesophageal reflux disease, abdominal distension, nausea, stomatitis, dry mouth General Disorders and Administrative Site Conditions: chest pain, edema peripheral Infections and Infestations: bacteremia, device related infection, gastroenteritis, lower respiratory tract infection, upper respiratory tract infection, urinary tract infection Laboratory Investigations: gamma-glutamyltransferase increased, transaminases increased Metabolism and Nutrition Disorders: hypocalcemia, hypokalemia, hyponatremia, hypoproteinemia Musculoskeletal and Connective Tissue Disorders: back pain, pain in extremity Nervous System Disorders: headache, tremor, seizure Psychiatric Disorders: agitation Respiratory, Thoracic and Mediastinal Disorders: hemoptysis Vascular Disorders: hypotension 6.2 Post-marketing Experience The following adverse reactions have been identified during post approval use of anidulafungin. 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. Immune : Anaphylactic shock, anaphylactic reaction, bronchospasm [see Warnings and Precautions (5.2) ] .

12.3 Pharmacokinetics General Pharmacokinetic Characteristics The pharmacokinetics of anidulafungin following intravenous (IV) administration of ERAXIS have been characterized in healthy subjects, special populations and patients. Systemic exposures of anidulafungin are dose-proportional and have low inter-subject variability (coefficient of variation <25%) as shown in Table 5. The steady state was achieved on the first day after a loading dose (twice the daily maintenance dose) and the estimated plasma accumulation factor at steady state is approximately 2. Table 5: Mean (%CV) Steady State Pharmacokinetic Parameters of Anidulafungin Following IV Administration of ERAXIS Once Daily for 10 Days in Healthy Adult Subjects C max, ss = the steady state peak concentration AUC ss = the steady state area under concentration vs. time curve CL = clearance t 1/2 = the terminal elimination half-life PK Parameter Parameters were obtained from separate studies Anidulafungin IV Dosing Regimen (LD/MD, mg) LD/MD: loading dose/maintenance dose once daily 70/35 Data were collected on Day 7 , Safety and efficacy of these doses has not been established (N=6) 200/100 (N=10) 260/130 , See OVERDOSAGE (N=10) C max, ss [mg/L] 3.55 (13.2) 8.6 (16.2) 10.9 (11.7) AUC ss [mg∙h/L] 42.3 (14.5) 111.8 (24.9) 168.9 (10.8) CL [L/h] 0.84 (13.5) 0.94 (24.0) 0.78 (11.3) t 1/2 [h] 43.2 (17.7) 52.0 (11.7) 50.3 (9.7) The clearance of anidulafungin is about 1 L/h and anidulafungin has a terminal elimination half-life of 40–50 hours. Distribution The pharmacokinetics of anidulafungin following IV administration are characterized by a short distribution half-life (0.5–1 hour) and a volume of distribution of 30–50 L that is similar to total body fluid volume. Anidulafungin is extensively bound (>99%) to human plasma proteins. Metabolism Hepatic metabolism of anidulafungin has not been observed. Anidulafungin is not a clinically relevant substrate, inducer, or inhibitor of cytochrome P450 (CYP450) isoenzymes. It is unlikely that anidulafungin will have clinically relevant effects on the metabolism of drugs metabolized by CYP450 isoenzymes. Anidulafungin undergoes slow chemical degradation at physiologic temperature and pH to a ring-opened peptide that lacks antifungal activity. The in vitro degradation half-life of anidulafungin under physiologic conditions is about 24 hours. In vivo , the ring-opened product is subsequently converted to peptidic degradants and eliminated. Excretion In a single-dose clinical study, radiolabeled ( 14 C) anidulafungin was administered to healthy subjects. Approximately 30% of the administered radioactive dose was eliminated in the feces over 9 days, of which less than 10% was intact drug. Less than 1% of the administered radioactive dose was excreted in the urine. Anidulafungin concentrations fell below the lower limits of quantitation 6 days post-dose. Negligible amounts of drug-derived radioactivity were recovered in blood, urine, and feces 8 weeks post-dose. Specific Populations Patients with fungal infections Population pharmacokinetic analyses from four clinical trials including 107 male and 118 female patients with fungal infections showed that the pharmacokinetic parameters of anidulafungin are not affected by age, race, or the presence of concomitant medications which are known metabolic substrates, inhibitors or inducers. The pharmacokinetics of anidulafungin in patients with fungal infections are similar to those observed in healthy subjects. The pharmacokinetic parameters of anidulafungin estimated using population pharmacokinetic modeling following IV administration of a maintenance dose of 50 mg/day or 100 mg/day (following a loading dose) of ERAXIS are presented in Table 6. Table 6: Mean (%CV) Steady State Pharmacokinetic Parameters of Anidulafungin Following IV Administration of ERAXIS in Patients with Fungal Infections Estimated Using Population Pharmacokinetic Modeling PK Parameter All the parameters were estimated by population modeling using a two-compartment model with first order elimination; AUC ss , C max,ss and C min,ss (steady state trough plasma concentration) were estimated using individual PK parameters and infusion rate of 1 mg/min to administer recommended doses of 50 and 100 mg/day. ERAXIS IV Dosing Regimen (LD/MD, mg) LD/MD: loading dose/daily maintenance dose. 100/50 200/100 C max, ss [mg/L] 4.2 (22.4) 7.2 (23.3) C min, ss [mg/L] 1.6 (42.1) 3.3 (41.8) AUC ss [mg∙h/L] 55.2 (32.5) 110.3 (32.5) CL [L/h] 1.0 (33.5) t 1/2, β [h] t 1/2, β is the predominant elimination half-life that characterizes the majority of the concentration-time profile. 26.5 (28.5) Gender Dosage adjustments are not required based on gender. Plasma concentrations of anidulafungin in healthy men and women were similar. In multiple-dose patient studies, drug clearance was slightly faster (approximately 22%) in men. Geriatric Dosage adjustments are not required for geriatric patients. The population pharmacokinetic analysis showed that median clearance differed slightly between the elderly group (patients ≥65, median CL=1.07 L/h) and the non-elderly group (patients <65, median CL=1.22 L/h) and the range of clearance was similar. Race Dosage adjustments are not required based on race. Anidulafungin pharmacokinetics were similar among Whites, Blacks, Asians, and Hispanics. HIV Status Dosage adjustments are not required based on HIV status, irrespective of concomitant anti-retroviral therapy. Hepatic Insufficiency Anidulafungin is not hepatically metabolized. Anidulafungin pharmacokinetics were examined in subjects with Child-Pugh class A, B or C hepatic insufficiency. Anidulafungin concentrations were not increased in subjects with any degree of hepatic insufficiency. Though a slight decrease in AUC was observed in patients with Child-Pugh C hepatic insufficiency, it was within the range of population estimates noted for healthy subjects [see Use in Specific Populations (8.6) ] . Renal Insufficiency Anidulafungin has negligible renal clearance. In a clinical study of subjects with mild, moderate, severe or end stage (dialysis-dependent) renal insufficiency, anidulafungin pharmacokinetics were similar to those observed in subjects with normal renal function. Anidulafungin is not dialyzable and may be administered without regard to the timing of hemodialysis [see Use in Specific Populations (8.7) ] . Pediatric The pharmacokinetics of anidulafungin after daily doses were investigated in immunocompromised pediatric (2 through 11 years) and adolescent (12 through 17 years) patients with neutropenia. The steady state was achieved on the first day after administration of the loading dose (twice the maintenance dose), and the C max and AUC ss increased in a dose-proportional manner. Concentrations and exposures following administration of maintenance doses of 0.75 and 1.5 mg/kg/day in this population were similar to those observed in adults following maintenance doses of 50 and 100 mg/day, respectively (as shown in Table 7) . Table 7: Mean (%CV) Steady State Pharmacokinetic Parameters of Anidulafungin Following IV Administration of ERAXIS Once Daily in Pediatric Patients PK Parameter Data were collected on Day 5 ERAXIS IV Dosing Regimen (LD/MD, mg/kg) LD/MD: loading dose/daily maintenance dose 1.5/0.75 3.0/1.5 Age Group 2–11 years (N = 6) 12–17 years (N = 6) 2–11 years (N = 6) 12–17 years (N = 6) C max, ss [mg/L] 3.32 (50.0) 4.35 (22.5) 7.57 (34.2) 6.88 (24.3) AUC ss [mg∙h/L] 41.1 (38.4) 56.2 (27.8) 96.1 (39.5) 102.9 (28.2) The pharmacokinetics of anidulafungin were also investigated in 66 pediatric patients (1 month to <18 years) with candidemia/invasive candidiasis (ICC) in a prospective, open-label, non-comparative pediatric study following administration of ERAXIS of 3 mg/kg loading dose on Day 1 and followed by 1.5 mg/kg once daily maintenance dose [see Clinical Studies (14.1) ] . Based on population pharmacokinetic analysis of combined data from adult and pediatric patients with ICC, the mean steady state exposure parameters (AUC 0–24,,ss C min,,ss and C max,ss ) across age groups in the overall pediatric patients (Table 8) were comparable to those in adults receiving 200 mg loading dose and 100 mg once daily maintenance dose. Table 8: Mean (%CV) Steady State Pharmacokinetic Parameters of Anidulafungin Following IV Administration of ERAXIS in Pediatric Patients with Candidemia/Invasive Candidiasis Estimated Using Population Pharmacokinetic Modeling PK Parameter ERAXIS IV Dosing Regimen (3 mg/kg LD/1.5 mg/kg MD) LD/MD: loading dose on Day 1/ once daily maintenance dose. Age Group 1 month to <2 years (N = 17) 2 to < 5 years (N = 19) 5 to <18 years (N = 30) C max, ss [mg/L] 6.7 (28.3) 7.1 (39.4) 6.5 (29.2) C min, ss [mg/L] 2.0 (29) 2.5 (44) 2.5 (38.4) AUC ss [mg∙h/L] 69.9 (25.3) 82.8 (38.5) 86.8 (35.8) Drug Interactions In vitro studies showed that anidulafungin is not metabolized by human cytochrome P450 or by isolated human hepatocytes and does not significantly inhibit the activities of human CYP isoforms (1A2, 2B6, 2C8, 2C9, 2C19, 2D6 and 3A) in clinically relevant concentrations. No clinically relevant drug-drug interactions were observed with drugs likely to be co-administered with anidulafungin. Cyclosporine (CYP3A4 substrate) In a study in which 12 healthy adult subjects received 100 mg/day maintenance dose of anidulafungin following a 200 mg loading dose (on Days 1 to 8) and in combination with 1.25 mg/kg oral cyclosporine twice daily (on Days 5 to 8), the steady state C max of anidulafungin was not significantly altered by cyclosporine; the steady state AUC of anidulafungin was increased by 22%. A separate in vitro study showed that anidulafungin has no effect on the metabolism of cyclosporine [see Drug Interactions (7.1) ] . Voriconazole (CYP2C19, CYP2C9, CYP3A4 inhibitor and substrate) In a study in which 17 healthy subjects received 100 mg/day maintenance dose of anidulafungin following a 200 mg loading dose, 200 mg twice daily oral voriconazole (following two 400 mg loading doses) and both in combination, the steady state C max and AUC of anidulafungin and voriconazole were not significantly altered by co-administration [see Drug Interactions (7.2) ] . Tacrolimus (CYP3A4 substrate) In a study in which 35 healthy subjects received a single oral dose of 5 mg tacrolimus (on Day 1), 100 mg/day maintenance dose of anidulafungin following a 200 mg loading dose (on Days 4 to 12) and both in combination (on Day 13), the steady state C max and AUC of anidulafungin and tacrolimus were not significantly altered by co-administration [see Drug Interactions (7.3) ] . Rifampin (potent CYP450 inducer) The pharmacokinetics of anidulafungin were examined in 27 patients that were co-administered anidulafungin and rifampin. The population pharmacokinetic analysis showed that when compared to data from patients that did not receive rifampin, the pharmacokinetics of anidulafungin were not significantly altered by co-administration with rifampin [see Drug Interactions (7.4) ] . Amphotericin B liposome for injection The pharmacokinetics of anidulafungin were examined in 27 patients that were co-administered liposomal amphotericin B. The population pharmacokinetic analysis showed that when compared to data from patients that did not receive amphotericin B, the pharmacokinetics of anidulafungin were not significantly altered by co-administration with amphotericin B [see Drug Interactions (7.5) ] .