ADVERSE REACTIONS SECTION.

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)] 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. 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). 6.1Clinical Trials Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of 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 AdultsThe 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. total of 633 patients received ERAXIS at daily doses of either 50 mg or 100 mg. total of 481 patients received ERAXIS for >=14 days.. Candidemia/other Candida InfectionsThree 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 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 InfectionsA patient who experienced multiple reactions within 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 ReactionERAXIS100 mgN=131Fluconazole400 mgN=125N (%)N (%)Subjects with least one adverse reaction130 (99)122 (98) Gastrointestinal disorders81 (62)72 (58) Nausea32 (24)15 (12) Diarrhea24 (18)23 (18) Vomiting23 (18)12 (10) Constipation11 (8)14 (11) Abdominal pain8 (6)16 (13)General disorders and administration site conditions70 (53)76 (61) Pyrexia23 (18)23 (18) Edema peripheral14 (11)16 (13) Chest pain7 (5)6 (5)Respiratory, thoracic, and mediastinal disorders67 (51)55 (44) Dyspnea15 (12)4 (3) Pleural effusion13 (10)11 (9) Cough9 (7)7 (6) Respiratory distress8 (6)2 (2)Investigations66 (50)46 (37) Blood alkaline phosphatase increased15 (12)14 (11) White blood cell increased11 (8)3 (2) Hepatic enzyme increased7 (5)14 (11) Blood creatinine increased7 (5)1 (1)Metabolism and nutrition disorders61 (47)61 (49) Hypokalemia33 (25)24 (19) Hypomagnesemia15 (12)14 (11) Hypoglycemia9 (7)10 (8) Hyperkalemia8 (6)14 (11) Hyperglycemia8 (6)8 (6) Dehydration8 (6)2 (2)Vascular disorders50 (38)41 (33) Hypotension19 (15)18 (14) Hypertension15 (12)5 (4) Deep vein thrombosis13 (10)9 (7)Psychiatric disorders48 (37)45 (36) Insomnia20 (15)12 (10) Confusional state10 (8)10 (8) Depression8 (6)5 (4)Blood and lymphatic system disorders34 (26)36 (29) Anemia12 (9)20 (16) Thrombocythemia8 (6)1 (1) Leukocytosis7 (5)6 (5)Skin and subcutaneous tissue disorders30 (23)32 (26) Decubitus ulcer7 (5)10 (8)Nervous system disorders27 (21)31 (25) Headache11 (8)10 (8)Musculoskeletal and connective tissue disorders27 (21)25 (20) Back pain7 (5)13 (10). Esophageal CandidiasisThe data described below reflect exposure to ERAXIS and fluconazole in 300 and 301 patients, respectively, with esophageal candidiasis in 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 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 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 CandidiasisA patient who experienced multiple reactions within 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 ReactionERAXIS50 mgN=300Fluconazole100 mgN=301N (%)N (%)Subjects with least one adverse reaction239 (80)227 (75) Infections and infestations115 (38)99 (33) Oral candidiasis15 (5)10 (3)Gastrointestinal disorders106 (35)113 (38) Diarrhea27 (9)26 (9) Vomiting27 (7)30 (10) Nausea20 (7)23 (8) Dyspepsia20 (7)21 (7)Blood and lymphatic system disorders55 (18)50 (17) Anemia25 (8)22 (7)Metabolism and nutrition disorders50 (17)46 (15) Hypokalemia14 (5)17 (6)General disorders and administration site condition49 (16)54 (18) Pyrexia27 (9)28 (9)Nervous system disorders39 (13)36 (12) Headache25 (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, thrombocytopeniaCardiac: atrial fibrillation, bundle branch block (right), sinus arrhythmia, ventricular extrasystolesEye: eye pain, vision blurred, visual disturbanceGeneral and Administration Site: infusion related reaction, peripheral edema, rigorsHepatobiliary: abnormal liver function tests, cholestasis, hepatic necrosisInfections: clostridial infectionInvestigations: amylase increased, bilirubin increased, CPK increased, electrocardiogram QT prolonged, gamma-glutamyl transferase increased, lipase increased, potassium decreased, prothrombin time prolonged, urea increasedNervous System: convulsion, dizzinessRespiratory, Thoracic and Mediastinal: coughSkin and Subcutaneous Tissue: angioneurotic edema, erythema, pruritus, sweating increased, urticariaVascular: flushing, hot flushes, thrombophlebitis superficial. Clinical Trials Experience in Pediatric Patients with Candidemia/Invasive CandidiasisThe safety of ERAXIS was investigated in 68 pediatric patients from month to less than 18 years of age with candidemia/invasive candidiasis in prospective, open-label, non-comparative pediatric trial [see Clinical Studies (14.1)]. Overall, the safety profile of ERAXIS in the pediatric patients month and older was similar to that of adults.. Most Common Adverse ReactionsThe 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 4Adverse Reactions Occurring in >=5% of Pediatric Patients Receiving ERAXIS Therapy for Candidemia/other Candida InfectionsReflects 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 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 Reaction1 month to <2 yearsN=192 to <5 yearsN=195 to <18 yearsN=30OverallN=68n (%)n (%)n (%)n (%)Subjects with least one adverse reaction17 (90)14 (74)24 (80)55 (81) Blood and lymphatic system disorders9 (47)3 (16)4 (13)16 (24) Anemia5 (26)2 (11)07 (10) Thrombocytopenia2 (11)1 (5)1 (3)4 (6)Gastrointestinal disorders8 (42)8 (42)12 (40)28 (41) Diarrhea4 (21)2 (11)5 (17)11 (16) Vomiting4 (21)5 (26)2 (7)11 (16) Abdominal painIncludes such terms as: abdominal pain and abdominal pain upper. 04 (21)2 (7)6 (9)General disorders and administration site condition5 (26)6 (32)9 (30)20 (29) Pyrexia4 (21)3 (16)5 (17)12 (18)Laboratory Investigations4 (21)4 (21)8 (27)16 (24) Alanine aminotransferase increased2 (11)2 (11)2 (7)6 (9) Aspartate aminotransferase increased2 (11)1 (5)1 (3)4 (6)Metabolism and nutrition disorders3 (16)4 (21)6 (20)13 (19) Hypoglycemia1 (5)2 (11)1 (3)4 (6)Respiratory, thoracic and mediastinal disorders5 (26)5 (26)5 (17)15 (22) Epistaxis1 (5)2 (11)3 (10)6 (9)Skin and subcutaneous tissue disorders6 (32)5 (26)5 (17)16 (24) RashIncludes such terms as: rash and rash generalized. (16)1 (5)2 (7)6 (9)Other adverse reactions were reported in 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, neutropeniaEye Disorders: Periorbital edemaGastrointestinal Disorders: gastroesophageal reflux disease, abdominal distension, nausea, stomatitis, dry mouthGeneral Disorders and Administrative Site Conditions: chest pain, edema peripheralInfections and Infestations: bacteremia, device related infection, gastroenteritis, lower respiratory tract infection, upper respiratory tract infection, urinary tract infectionLaboratory Investigations: gamma-glutamyltransferase increased, transaminases increasedMetabolism and Nutrition Disorders: hypocalcemia, hypokalemia, hyponatremia, hypoproteinemiaMusculoskeletal and Connective Tissue Disorders: back pain, pain in extremityNervous System Disorders: headache, tremor, seizurePsychiatric Disorders: agitationRespiratory, Thoracic and Mediastinal Disorders: hemoptysisVascular 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 population of uncertain size, it is not always possible to reliably estimate their frequency or establish causal relationship to drug exposure.Immune: Anaphylactic shock, anaphylactic reaction, bronchospasm [see Warnings and Precautions (5.2)].

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. Anidulafungin is an anti-fungal drug [see Microbiology (12.4)]. 12.3 Pharmacokinetics. General Pharmacokinetic CharacteristicsThe 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 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 SubjectsAnidulafungin IV Dosing Regimen (LD/MD, mg)LD/MD: loading dose/maintenance dose once daily PK ParameterParameters were obtained from separate studies 70/35Data were collected on Day , Safety and efficacy of these doses has not been established (N=6)200/100(N=10)260/130 See OVERDOSAGE (N=10)Cmax, ss the steady state peak concentrationAUCss the steady state area under concentration vs. time curveCL clearancet1/2 the terminal elimination half-lifeCmax, ss [mg/L]3.55 (13.2)8.6 (16.2)10.9 (11.7)AUCss [mgh/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)t1/2 [h]43.2 (17.7)52.0 (11.7)50.3 (9.7)The clearance of anidulafungin is about L/h and anidulafungin has terminal elimination half-life of 40-50 hours.. DistributionThe pharmacokinetics of anidulafungin following IV administration are characterized by short distribution half-life (0.5-1 hour) and volume of distribution of 30-50 that is similar to total body fluid volume. Anidulafungin is extensively bound (>99%) to human plasma proteins.. MetabolismHepatic metabolism of anidulafungin has not been observed. Anidulafungin is not 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 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.. ExcretionIn single-dose clinical study, radiolabeled (14C) anidulafungin was administered to healthy subjects. Approximately 30% of the administered radioactive dose was eliminated in the feces over 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 days post-dose. Negligible amounts of drug-derived radioactivity were recovered in blood, urine, and feces weeks post-dose.. Specific Populations Patients with fungal infectionsPopulation 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 maintenance dose of 50 mg/day or 100 mg/day (following 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 ModelingPK ParameterAll the parameters were estimated by population modeling using two-compartment model with first order elimination; AUCss, Cmax,ss and Cmin,ss (steady state trough plasma concentration) were estimated using individual PK parameters and infusion rate of 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. 100/50200/100Cmax, ss [mg/L]4.2 (22.4)7.2 (23.3)Cmin, ss [mg/L]1.6 (42.1)3.3 (41.8)AUCss [mgh/L]55.2 (32.5)110.3 (32.5)CL [L/h]1.0 (33.5)t1/2, [h] t1/2, is the predominant elimination half-life that characterizes the majority of the concentration-time profile. 26.5 (28.5). GenderDosage 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.. GeriatricDosage 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.. RaceDosage adjustments are not required based on race. Anidulafungin pharmacokinetics were similar among Whites, Blacks, Asians, and Hispanics.. HIV StatusDosage adjustments are not required based on HIV status, irrespective of concomitant anti-retroviral therapy.. Hepatic InsufficiencyAnidulafungin is not hepatically metabolized. Anidulafungin pharmacokinetics were examined in subjects with Child-Pugh class A, or hepatic insufficiency. Anidulafungin concentrations were not increased in subjects with any degree of hepatic insufficiency. Though slight decrease in AUC was observed in patients with Child-Pugh hepatic insufficiency, it was within the range of population estimates noted for healthy subjects [see Use in Specific Populations (8.6)].. Renal InsufficiencyAnidulafungin has negligible renal clearance. In 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)].. PediatricThe 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 Cmax and AUCss increased in 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 PatientsPK ParameterData were collected on Day 5ERAXIS IV Dosing Regimen(LD/MD, mg/kg)LD/MD: loading dose/daily maintenance dose 1.5/0.753.0/1.5Age Group2-11 years(N 6)12-17 years(N 6)2-11 years(N 6)12-17 years(N 6)Cmax, ss [mg/L]3.32 (50.0)4.35 (22.5)7.57 (34.2)6.88 (24.3)AUCss [mgh/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 prospective, open-label, non-comparative pediatric study following administration of ERAXIS of mg/kg loading dose on Day 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 (AUC0-24,,ss Cmin,,ss and Cmax,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 ModelingPK ParameterERAXIS IV Dosing Regimen (3 mg/kg LD/1.5 mg/kg MD)LD/MD: loading dose on Day 1/ once daily maintenance dose. Age Group1 month to <2 years(N 17)2 to 5 years(N 19)5 to <18 years(N 30)Cmax, ss [mg/L]6.7 (28.3)7.1 (39.4)6.5 (29.2)Cmin, ss [mg/L]2.0 (29)2.5 (44)2.5 (38.4)AUCss [mgh/L]69.9 (25.3)82.8 (38.5)86.8 (35.8). Drug InteractionsIn 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 study in which 12 healthy adult subjects received 100 mg/day maintenance dose of anidulafungin following 200 mg loading dose (on Days to 8) and in combination with 1.25 mg/kg oral cyclosporine twice daily (on Days to 8), the steady state Cmax of anidulafungin was not significantly altered by cyclosporine; the steady state AUC of anidulafungin was increased by 22%. 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 study in which 17 healthy subjects received 100 mg/day maintenance dose of anidulafungin following 200 mg loading dose, 200 mg twice daily oral voriconazole (following two 400 mg loading doses) and both in combination, the steady state Cmax and AUC of anidulafungin and voriconazole were not significantly altered by co-administration [see Drug Interactions (7.2)].. Tacrolimus (CYP3A4 substrate)In study in which 35 healthy subjects received single oral dose of mg tacrolimus (on Day 1), 100 mg/day maintenance dose of anidulafungin following 200 mg loading dose (on Days to 12) and both in combination (on Day 13), the steady state Cmax 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 liposome for injectionThe 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 [see Drug Interactions (7.5)].. 12.4 Microbiology. Mechanism of ActionAnidulafungin is semi-synthetic echinocandin with antifungal activity. Anidulafungin inhibits glucan synthase, an enzyme present in fungal, but not mammalian cells. This results in inhibition of the formation of 1,3--D-glucan, an essential component of the fungal cell wall.. ResistanceEchinocandin resistance is due to point mutations within the genes (FKS1 and FKS2) encoding for subunits in the glucan synthase enzyme complex. There have been reports of Candida isolates with reduced susceptibility to anidulafungin, suggesting potential for development of drug resistance. The clinical significance of this observation is not fully understood.. Antimicrobial ActivityAnidulafungin has been shown to be active against most isolates of the following microorganisms both in vitro and in clinical infections:Candida albicansCandida glabrataCandida parapsilosisCandida tropicalisThe following in vitro data are available, but their clinical significance is unknown. At least 90 percent of the following fungi exhibit an in vitro minimum inhibitory concentration (MIC) less than or equal to the susceptible breakpoint for anidulafungin against isolates of the following Candida species. However, the effectiveness of anidulafungin in treating clinical infections due to these fungi has not been established in adequate and well-controlled clinical trials:Candida guilliermondiiCandida krusei. Susceptibility TestingFor specific information regarding susceptibility test interpretive criteria and associated test methods and quality control standards recognized by FDA for this drug, please see: https://www.fda.gov/STIC.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. 14.1Candidemia and Other Candida Infections (Intra-abdominal Abscess and Peritonitis). Adults Candidemia and Other Candida Infections (Intra-abdominal Abscess and Peritonitis) TrialThe safety and efficacy of ERAXIS were evaluated in Phase 3, randomized, double-blind study of patients with candidemia and/or other forms of invasive candidiasis. 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). Patients were stratified by APACHE II score (<=20 and >20) and the presence or absence of neutropenia. Patients with Candida endocarditis, osteomyelitis or meningitis, or those with infection due to C. krusei, were excluded from the study. Treatment was administered for at least 14 and not more than 42 days. Patients in both study arms were permitted to switch to oral fluconazole after at least 10 days of intravenous therapy, provided that they were able to tolerate oral medication, were afebrile for at least 24 hours, and the last blood cultures were negative for Candida species.Patients who received at least one dose of study medication and who had positive culture for Candida species from normally sterile site before entry into the study (modified intent-to-treat [MITT] population) were included in the analysis of global response at the end of IV therapy. successful global response required clinical cure or improvement (significant, but incomplete resolution of signs and symptoms of the Candida infection and no additional antifungal treatment), and documented or presumed microbiological eradication. Patients with an indeterminate outcome were analyzed as failures in this population.Two hundred and fifty-six patients in the intent-to-treat (ITT) population were randomized and received at least one dose of study medication. In ERAXIS-treated patients, the age range was 16-89 years, the gender distribution was 50% male and 50% female, and the race distribution was 71% White, 20% Black/African American, 7% Hispanic, 2% other races. The median duration of IV therapy was 14 and 11 days in the ERAXIS and fluconazole arms, respectively. For those who received oral fluconazole, the median duration of oral therapy was days for the ERAXIS arm and days for the fluconazole arm.Patient disposition is presented in Table 9.Table 9: Patient Disposition and Reasons for Discontinuation in Candidemia and other Candida Infections StudyERAXISFluconazolen (%)n (%)Treated patients131125Patients completing study through week follow-up94 (72)80 (64)DISCONTINUATIONS FROM STUDY MEDICATIONTotal discontinued from study medication34 (26)48 (38) Discontinued due to adverse events12 (9)21 (17) Discontinued due to lack of efficacy11 (8)16 (13)Two hundred and forty-five patients (127 ERAXIS, 118 fluconazole) met the criteria for inclusion in the MITT population. Of these, 219 patients (116 ERAXIS, 103 fluconazole) had candidemia only. Risk factors for candidemia among patients in both treatment arms in this study were: presence of central venous catheter (78%), receipt of broad-spectrum antibiotics (69%), recent surgery (42%), recent hyperalimentation (25%), and underlying malignancy (22%). The most frequent species isolated at baseline was C. albicans (62%), followed by C. glabrata (20%), C. parapsilosis (12%) and C. tropicalis (11%). The majority (97%) of patients were non-neutropenic (ANC >500) and 81% had APACHE II scores less than or equal to 20.Global success rates in patients with candidemia and other Candida infections are summarized in Table 10.Table 10: Efficacy Analysis: Global Success in patients with Candidemia and other Candida Infections (MITT Population)Time-pointERAXIS(N=127)n (%)Fluconazole(N=118)n (%)Treatment DifferenceCalculated as ERAXIS minus fluconazole, (95% C.I.)End of IV Therapy96 (75.6)71 (60.2)15.4(3.9, 27.0)End of All Therapy33 patients in each study arm (26% ERAXIS and 29% fluconazole-treated) switched to oral fluconazole after the end of IV therapy. 94 (74.0)67 (56.8)17.2(2.9, 31.6)98.3% confidence intervals, adjusted post hoc for multiple comparisons of secondary time points Week Follow-up82 (64.6)58 (49.2)15.4(0.4, 30.4) Week Follow-up71 (55.9)52 (44.1)11.8(-3.4, 27.0) Table 11 presents global response by patients with candidemia or multiple sites of Candida infection and mortality data for the MITT population.Table 11: Global Response and Mortality in Candidemia and other Candida InfectionsERAXISFluconazoleBetween group difference Calculated as ERAXIS minus fluconazole (95% CI)No. of MITT patients127118Global Success (MITT) At End Of IV Therapy Candidemia88/116 (75.9%)63/103 (61.2%)14.7 (2.5, 26.9)Neutropenic 1/22/4-Non neutropenic87/114 (76.3%)61/99 (61.6%)- Multiple sites Peritoneal fluid/ intra-abdominal abscess4/65/6-Blood/ peritoneum (intra-abdominal abscess)2/20/2-Blood /bile-1/1-Blood/renal-1/1-Pancreas-0/3-Pelvic abscess-1/2-Pleural fluid1/1--Blood/ pleural fluid0/1--Blood/left thigh lesion biopsy1/1--Total8/11 (72.7%)8/15 (53.3%)-MortalityOverall study mortality29/127 (22.8 %)37/118 (31.4%)-Mortality during study therapy10/127 (7.9%)17/118 (14.4%)-Mortality attributed to Candida 2/127 (1.6%)5/118 (4.2%)-. Pediatric Candidemia/Invasive Candidiasis TrialA prospective, open-label, non-comparative, multinational trial (National Clinical Trial (NCT) number 00761267) assessed the safety and efficacy of ERAXIS in 68 pediatric patients aged month to <18 years with candidemia/invasive candidiasis. Patients were stratified by age (1 month to <2 years, to <5 years, and to <18 years) and received once daily intravenous ERAXIS (3 mg/kg loading dose on Day 1, and 1.5 mg/kg daily maintenance dose thereafter) followed by an optional switch to oral fluconazole (6-12 mg/kg/day, maximum 800 mg/day) up to Day 49. Patients were followed at and weeks after EOT.Among 68 ERAXIS-treated patients, 64 had microbiologically confirmed Candida infection and were evaluated for efficacy in the modified intent-to-treat (MITT) population. Overall, 59 patients (92.2%) had Candida isolated from blood only. The most commonly isolated pathogens were Candida albicans (25 [39.1%] patients), followed by Candida parapsilosis (17 [26.6%] patients), and Candida tropicalis (9 [14.1%] patients). successful global response was defined as having both successful clinical (cure or improvement) and microbiological (eradication or presumed eradication) response. The overall rates of successful global response in the MITT population are presented in Table 12 below.Table 12: Summary of Successful Global Response by Age Group, MITT PopulationSuccessful Global Response, (%)TimepointGlobal Response1 month to <2 years(N 16)n (n/N, %)2 to <5 years(N=18)n (n/N, %)5 to <18 years(N=30)n (n/N, %)Overall(N=64)n (n/N, %)95% CI exact 95% confidence interval for binomial proportions using Clopper-Pearson method; EOIVT end of intravenous treatment; EOT end of treatment; FU follow-up; MITT modified intent-to-treat; = number of subjects in the population; = number of subjects with responses.EOIVTSuccess11 (68.8)14 (77.8)20 (66.7)45 (70.3)95% CI(41.3, 89.0)(52.4, 93.6)(47.2, 82.7)(57.6, 81.1)EOTSuccess11 (68.8)14 (77.8)21 (70.0)46 (71.9)95% CI(41.3, 89.0)(52.4, 93.6)(50.6, 85.3)(59.2, 82.4)2-week FUSuccess11 (68.8)13 (72.2)22 (73.3)46 (71.9)95% CI(41.3, 89.0)(46.5, 90.3)(54.1, 87.7)(59.2, 82.4)6-week FUSuccess11 (68.8)12 (66.7)20 (66.7)43 (67.2)95% CI(41.3, 89.0)(41.0, 86.7)(47.2, 82.7)(54.3, 78.4). 14.2Esophageal Candidiasis. ERAXIS was evaluated in double-blind, double-dummy, randomized Phase study. Three hundred patients received ERAXIS (100 mg loading dose IV on Day followed by 50 mg/day IV) and 301 received oral fluconazole (200 mg loading dose on Day followed by 100 mg/day). Treatment duration was days beyond resolution of symptoms for minimum of 14 and maximum of 21 days.Of the 442 patients with culture confirmed esophageal candidiasis, most patients (91%) had C. albicans isolated at the baseline.Treatment groups were similar in demographic and other baseline characteristics. In ERAXIS-treated patients, the age range was 16-69 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.In this study, of 280 patients tested, 237 (84.6%) tested HIV positive. In both groups the median time to resolution of symptoms was days and the median duration of therapy was 14 days.Efficacy was assessed by endoscopic outcome at end of therapy (EOT). Patients were considered clinically evaluable if they received at least 10 days of therapy, had an EOT assessment with clinical outcome other than indeterminate, had an endoscopy at EOT, and did not have any protocol violations prior to the EOT visit that would affect an assessment of efficacy.An endoscopic success, defined as cure (endoscopic grade of on 4-point severity scale) or improvement (decrease of one or more grades from baseline), was seen in 225/231 (97.4%) ERAXIS-treated patients and 233/236 (98.7%) fluconazole-treated patients (Table 13). The majority of these patients were endoscopic cures (grade=0). Two weeks after completing therapy, the ERAXIS group had significantly more endoscopically-documented relapses than the fluconazole group, 120/225 (53.3%) vs. 45/233 (19.3%), respectively (Table 13). Table 13: Endoscopy Results in Patients with Esophageal Candidiasis (Clinically Evaluable Population)Endoscopic Response at End of TherapyResponseERAXISN=231FluconazoleN=236Treatment DifferenceCalculated as ERAXIS minus fluconazole 95% CIEndoscopic Success, (%)225 (97.4)233 (98.7)-1.3%-3.8%, 1.2%Cure204 (88.3)221 (93.6)Improvement 21 (9.1)12 (5.1)Failure, (%)6 (2.6)3 (1.3) Endoscopic Relapse Rates at Follow-Up, Weeks Post-TreatmentERAXISFluconazoleTreatment Difference95% CIEndoscopic Relapse, n/N (%)120/225 (53.3%)45/233 (19.3%)34.0%25.8%, 42.3%Clinical success (cure or improvement in clinical symptoms including odynophagia/dysphagia and retrosternal pain) occurred in 229/231 (99.1%) of the ERAXIS-treated patients and 235/236 (99.6%) of the fluconazole-treated patients at the end of therapy. For patients with C. albicans, microbiological success occurred in 142/162 (87.7%) of the ERAXIS-treated group and 157/166 (94.6%) of the fluconazole-treated group at the end of therapy. For patients with Candida species other than C. albicans, success occurred in 10/12 (83.3%) of the ERAXIS-treated group and 14/16 (87.5%) of the fluconazole-treated group.

CLINICAL TRIALS EXPERIENCE SECTION.

6.1Clinical Trials Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of 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 AdultsThe 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. total of 633 patients received ERAXIS at daily doses of either 50 mg or 100 mg. total of 481 patients received ERAXIS for >=14 days.. Candidemia/other Candida InfectionsThree 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 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 InfectionsA patient who experienced multiple reactions within 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 ReactionERAXIS100 mgN=131Fluconazole400 mgN=125N (%)N (%)Subjects with least one adverse reaction130 (99)122 (98) Gastrointestinal disorders81 (62)72 (58) Nausea32 (24)15 (12) Diarrhea24 (18)23 (18) Vomiting23 (18)12 (10) Constipation11 (8)14 (11) Abdominal pain8 (6)16 (13)General disorders and administration site conditions70 (53)76 (61) Pyrexia23 (18)23 (18) Edema peripheral14 (11)16 (13) Chest pain7 (5)6 (5)Respiratory, thoracic, and mediastinal disorders67 (51)55 (44) Dyspnea15 (12)4 (3) Pleural effusion13 (10)11 (9) Cough9 (7)7 (6) Respiratory distress8 (6)2 (2)Investigations66 (50)46 (37) Blood alkaline phosphatase increased15 (12)14 (11) White blood cell increased11 (8)3 (2) Hepatic enzyme increased7 (5)14 (11) Blood creatinine increased7 (5)1 (1)Metabolism and nutrition disorders61 (47)61 (49) Hypokalemia33 (25)24 (19) Hypomagnesemia15 (12)14 (11) Hypoglycemia9 (7)10 (8) Hyperkalemia8 (6)14 (11) Hyperglycemia8 (6)8 (6) Dehydration8 (6)2 (2)Vascular disorders50 (38)41 (33) Hypotension19 (15)18 (14) Hypertension15 (12)5 (4) Deep vein thrombosis13 (10)9 (7)Psychiatric disorders48 (37)45 (36) Insomnia20 (15)12 (10) Confusional state10 (8)10 (8) Depression8 (6)5 (4)Blood and lymphatic system disorders34 (26)36 (29) Anemia12 (9)20 (16) Thrombocythemia8 (6)1 (1) Leukocytosis7 (5)6 (5)Skin and subcutaneous tissue disorders30 (23)32 (26) Decubitus ulcer7 (5)10 (8)Nervous system disorders27 (21)31 (25) Headache11 (8)10 (8)Musculoskeletal and connective tissue disorders27 (21)25 (20) Back pain7 (5)13 (10). Esophageal CandidiasisThe data described below reflect exposure to ERAXIS and fluconazole in 300 and 301 patients, respectively, with esophageal candidiasis in 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 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 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 CandidiasisA patient who experienced multiple reactions within 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 ReactionERAXIS50 mgN=300Fluconazole100 mgN=301N (%)N (%)Subjects with least one adverse reaction239 (80)227 (75) Infections and infestations115 (38)99 (33) Oral candidiasis15 (5)10 (3)Gastrointestinal disorders106 (35)113 (38) Diarrhea27 (9)26 (9) Vomiting27 (7)30 (10) Nausea20 (7)23 (8) Dyspepsia20 (7)21 (7)Blood and lymphatic system disorders55 (18)50 (17) Anemia25 (8)22 (7)Metabolism and nutrition disorders50 (17)46 (15) Hypokalemia14 (5)17 (6)General disorders and administration site condition49 (16)54 (18) Pyrexia27 (9)28 (9)Nervous system disorders39 (13)36 (12) Headache25 (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, thrombocytopeniaCardiac: atrial fibrillation, bundle branch block (right), sinus arrhythmia, ventricular extrasystolesEye: eye pain, vision blurred, visual disturbanceGeneral and Administration Site: infusion related reaction, peripheral edema, rigorsHepatobiliary: abnormal liver function tests, cholestasis, hepatic necrosisInfections: clostridial infectionInvestigations: amylase increased, bilirubin increased, CPK increased, electrocardiogram QT prolonged, gamma-glutamyl transferase increased, lipase increased, potassium decreased, prothrombin time prolonged, urea increasedNervous System: convulsion, dizzinessRespiratory, Thoracic and Mediastinal: coughSkin and Subcutaneous Tissue: angioneurotic edema, erythema, pruritus, sweating increased, urticariaVascular: flushing, hot flushes, thrombophlebitis superficial. Clinical Trials Experience in Pediatric Patients with Candidemia/Invasive CandidiasisThe safety of ERAXIS was investigated in 68 pediatric patients from month to less than 18 years of age with candidemia/invasive candidiasis in prospective, open-label, non-comparative pediatric trial [see Clinical Studies (14.1)]. Overall, the safety profile of ERAXIS in the pediatric patients month and older was similar to that of adults.. Most Common Adverse ReactionsThe 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 4Adverse Reactions Occurring in >=5% of Pediatric Patients Receiving ERAXIS Therapy for Candidemia/other Candida InfectionsReflects 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 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 Reaction1 month to <2 yearsN=192 to <5 yearsN=195 to <18 yearsN=30OverallN=68n (%)n (%)n (%)n (%)Subjects with least one adverse reaction17 (90)14 (74)24 (80)55 (81) Blood and lymphatic system disorders9 (47)3 (16)4 (13)16 (24) Anemia5 (26)2 (11)07 (10) Thrombocytopenia2 (11)1 (5)1 (3)4 (6)Gastrointestinal disorders8 (42)8 (42)12 (40)28 (41) Diarrhea4 (21)2 (11)5 (17)11 (16) Vomiting4 (21)5 (26)2 (7)11 (16) Abdominal painIncludes such terms as: abdominal pain and abdominal pain upper. 04 (21)2 (7)6 (9)General disorders and administration site condition5 (26)6 (32)9 (30)20 (29) Pyrexia4 (21)3 (16)5 (17)12 (18)Laboratory Investigations4 (21)4 (21)8 (27)16 (24) Alanine aminotransferase increased2 (11)2 (11)2 (7)6 (9) Aspartate aminotransferase increased2 (11)1 (5)1 (3)4 (6)Metabolism and nutrition disorders3 (16)4 (21)6 (20)13 (19) Hypoglycemia1 (5)2 (11)1 (3)4 (6)Respiratory, thoracic and mediastinal disorders5 (26)5 (26)5 (17)15 (22) Epistaxis1 (5)2 (11)3 (10)6 (9)Skin and subcutaneous tissue disorders6 (32)5 (26)5 (17)16 (24) RashIncludes such terms as: rash and rash generalized. (16)1 (5)2 (7)6 (9)Other adverse reactions were reported in 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, neutropeniaEye Disorders: Periorbital edemaGastrointestinal Disorders: gastroesophageal reflux disease, abdominal distension, nausea, stomatitis, dry mouthGeneral Disorders and Administrative Site Conditions: chest pain, edema peripheralInfections and Infestations: bacteremia, device related infection, gastroenteritis, lower respiratory tract infection, upper respiratory tract infection, urinary tract infectionLaboratory Investigations: gamma-glutamyltransferase increased, transaminases increasedMetabolism and Nutrition Disorders: hypocalcemia, hypokalemia, hyponatremia, hypoproteinemiaMusculoskeletal and Connective Tissue Disorders: back pain, pain in extremityNervous System Disorders: headache, tremor, seizurePsychiatric Disorders: agitationRespiratory, Thoracic and Mediastinal Disorders: hemoptysisVascular Disorders: hypotension.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. AdultsPediatric Patients Month of Age and OlderCandidemia and other forms of Candida infections200 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 candidiasis100 mg loading dose on Day 1, followed by 50 mg once daily maintenance dose thereafter for minimum of 14 days and for at least days following resolution of symptoms (2.1)Not ApprovedRate of Infusion for Adults and Pediatric PatientsThe 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). 2.1Recommended Dosage in Adults. Candidemia and other Candida infections (intra-abdominal abscess and peritonitis)The recommended dose is single 200 mg loading dose of ERAXIS on Day 1, followed by 100 mg once daily maintenance dose thereafter. Duration of treatment should be based on the patients clinical response. In general, antifungal therapy should continue for at least 14 days after the last positive culture.. Esophageal CandidiasisThe recommended dose is single 100 mg loading dose of ERAXIS on Day 1, followed by 50 mg once daily maintenance dose thereafter. Patients should be treated for minimum of 14 days and for at least days following resolution of symptoms. Duration of treatment should be based on the patients clinical response. Because of the risk of relapse of esophageal candidiasis in patients with HIV infection, suppressive antifungal therapy may be considered after course of treatment.. 2.2Recommended Dosage in Pediatric Patients (1 Month of Age and Older). Candidemia and other Candida infections (intra-abdominal abscess and peritonitis)The recommended dose is single loading dose of mg/kg (not to exceed 200 mg) of ERAXIS on Day 1, followed by 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.. 2.3Preparation 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/vialAseptically reconstitute each 50 mg vial with 15 mL of sterile Water for Injection to provide concentration of 3.33 mg/mL.. Reconstitution of the 100 mg/vialAseptically reconstitute each 100 mg vial with 30 mL of sterile Water for Injection to provide concentration of 3.33 mg/mL.. Storage of the Reconstituted SolutionERAXIS reconstituted solution can be stored at 25C (77F) 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 25C (77F). From microbiological point of view, following good aseptic practices, the reconstituted solution can be utilized for up to 24 hours when stored at 25C.. 2.4Dilution 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 PatientsAseptically 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 for the dilution to 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 AdministrationDoseNumber of Vials RequiredTotal Reconstituted Volume RequiredInfusion VolumeEither 5% Dextrose Injection, USP or 0.9% Sodium Chloride Injection, USP (normal saline) Total Infusion VolumeInfusion solution concentration is 0.77 mg/mL Rate of InfusionMinimum Duration of Infusion50 mg1-50 mg15 mL50 mL65 mL1.4 mL/min or 84 mL/ hour45 min100 mg2-50 mg or 1-100 mg30 mL100 mL130 mL1.4 mL/min or 84 mL/ hour90 min200 mg4-50 mg or 2-100 mg60 mL200 mL260 mL1.4 mL/min or 84 mL/ hour180 min. Pediatric PatientsThe 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 concentration of 0.77 mg/mL for the final infusion solution. 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 mgCalculate pediatric patient dose and aseptically reconstitute vial(s) required according to reconstitution instructions to provide 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)].Calculate the volume (mL) of reconstituted ERAXIS required: [Volume of reconstituted ERAXIS (mL) Dose of ERAXIS (mg) 3.33 mg/mL] Calculate the total volume of the infusion solution (mL) that contains final concentration of 0.77 mg/mL: [Total volume of infusion solution (mL) Dose of ERAXIS (mg) 0.77 mg/mL] 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)] 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.. Calculate pediatric patient dose and aseptically reconstitute vial(s) required according to reconstitution instructions to provide 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)].. Calculate the volume (mL) of reconstituted ERAXIS required: [Volume of reconstituted ERAXIS (mL) Dose of ERAXIS (mg) 3.33 mg/mL] Calculate the total volume of the infusion solution (mL) that contains final concentration of 0.77 mg/mL: [Total volume of infusion solution (mL) Dose of ERAXIS (mg) 0.77 mg/mL] 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)] 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 SolutionERAXIS infusion solution can be stored at temperatures up to 25C (77F) 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 25C (77F). From microbiological point of view, following good aseptic practices, the infusion solution can be utilized for up to 48 hours from preparation when stored at 25C.

INDICATIONS & USAGE SECTION.

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 useERAXIS 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). 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). 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). 1.1Candidemia 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 month of age and older [see Clinical Studies (14.1) and Microbiology (12.4)].. 1.2Esophageal Candidiasis ERAXIS is indicated for the treatment of esophageal candidiasis in adults [see Indications and Usage (1.3), Clinical Studies (14.2)].. 1.3Limitations 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)]. 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)]. 1.4Usage. 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.

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. General Pharmacokinetic CharacteristicsThe 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 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 SubjectsAnidulafungin IV Dosing Regimen (LD/MD, mg)LD/MD: loading dose/maintenance dose once daily PK ParameterParameters were obtained from separate studies 70/35Data were collected on Day , Safety and efficacy of these doses has not been established (N=6)200/100(N=10)260/130 See OVERDOSAGE (N=10)Cmax, ss the steady state peak concentrationAUCss the steady state area under concentration vs. time curveCL clearancet1/2 the terminal elimination half-lifeCmax, ss [mg/L]3.55 (13.2)8.6 (16.2)10.9 (11.7)AUCss [mgh/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)t1/2 [h]43.2 (17.7)52.0 (11.7)50.3 (9.7)The clearance of anidulafungin is about L/h and anidulafungin has terminal elimination half-life of 40-50 hours.. DistributionThe pharmacokinetics of anidulafungin following IV administration are characterized by short distribution half-life (0.5-1 hour) and volume of distribution of 30-50 that is similar to total body fluid volume. Anidulafungin is extensively bound (>99%) to human plasma proteins.. MetabolismHepatic metabolism of anidulafungin has not been observed. Anidulafungin is not 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 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.. ExcretionIn single-dose clinical study, radiolabeled (14C) anidulafungin was administered to healthy subjects. Approximately 30% of the administered radioactive dose was eliminated in the feces over 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 days post-dose. Negligible amounts of drug-derived radioactivity were recovered in blood, urine, and feces weeks post-dose.. Specific Populations Patients with fungal infectionsPopulation 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 maintenance dose of 50 mg/day or 100 mg/day (following 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 ModelingPK ParameterAll the parameters were estimated by population modeling using two-compartment model with first order elimination; AUCss, Cmax,ss and Cmin,ss (steady state trough plasma concentration) were estimated using individual PK parameters and infusion rate of 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. 100/50200/100Cmax, ss [mg/L]4.2 (22.4)7.2 (23.3)Cmin, ss [mg/L]1.6 (42.1)3.3 (41.8)AUCss [mgh/L]55.2 (32.5)110.3 (32.5)CL [L/h]1.0 (33.5)t1/2, [h] t1/2, is the predominant elimination half-life that characterizes the majority of the concentration-time profile. 26.5 (28.5). GenderDosage 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.. GeriatricDosage 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.. RaceDosage adjustments are not required based on race. Anidulafungin pharmacokinetics were similar among Whites, Blacks, Asians, and Hispanics.. HIV StatusDosage adjustments are not required based on HIV status, irrespective of concomitant anti-retroviral therapy.. Hepatic InsufficiencyAnidulafungin is not hepatically metabolized. Anidulafungin pharmacokinetics were examined in subjects with Child-Pugh class A, or hepatic insufficiency. Anidulafungin concentrations were not increased in subjects with any degree of hepatic insufficiency. Though slight decrease in AUC was observed in patients with Child-Pugh hepatic insufficiency, it was within the range of population estimates noted for healthy subjects [see Use in Specific Populations (8.6)].. Renal InsufficiencyAnidulafungin has negligible renal clearance. In 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)].. PediatricThe 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 Cmax and AUCss increased in 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 PatientsPK ParameterData were collected on Day 5ERAXIS IV Dosing Regimen(LD/MD, mg/kg)LD/MD: loading dose/daily maintenance dose 1.5/0.753.0/1.5Age Group2-11 years(N 6)12-17 years(N 6)2-11 years(N 6)12-17 years(N 6)Cmax, ss [mg/L]3.32 (50.0)4.35 (22.5)7.57 (34.2)6.88 (24.3)AUCss [mgh/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 prospective, open-label, non-comparative pediatric study following administration of ERAXIS of mg/kg loading dose on Day 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 (AUC0-24,,ss Cmin,,ss and Cmax,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 ModelingPK ParameterERAXIS IV Dosing Regimen (3 mg/kg LD/1.5 mg/kg MD)LD/MD: loading dose on Day 1/ once daily maintenance dose. Age Group1 month to <2 years(N 17)2 to 5 years(N 19)5 to <18 years(N 30)Cmax, ss [mg/L]6.7 (28.3)7.1 (39.4)6.5 (29.2)Cmin, ss [mg/L]2.0 (29)2.5 (44)2.5 (38.4)AUCss [mgh/L]69.9 (25.3)82.8 (38.5)86.8 (35.8). Drug InteractionsIn 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 study in which 12 healthy adult subjects received 100 mg/day maintenance dose of anidulafungin following 200 mg loading dose (on Days to 8) and in combination with 1.25 mg/kg oral cyclosporine twice daily (on Days to 8), the steady state Cmax of anidulafungin was not significantly altered by cyclosporine; the steady state AUC of anidulafungin was increased by 22%. 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 study in which 17 healthy subjects received 100 mg/day maintenance dose of anidulafungin following 200 mg loading dose, 200 mg twice daily oral voriconazole (following two 400 mg loading doses) and both in combination, the steady state Cmax and AUC of anidulafungin and voriconazole were not significantly altered by co-administration [see Drug Interactions (7.2)].. Tacrolimus (CYP3A4 substrate)In study in which 35 healthy subjects received single oral dose of mg tacrolimus (on Day 1), 100 mg/day maintenance dose of anidulafungin following 200 mg loading dose (on Days to 12) and both in combination (on Day 13), the steady state Cmax 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 liposome for injectionThe 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 [see Drug Interactions (7.5)].

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. Pregnancy: Based on findings from animal studies, ERAXIS can cause fetal harm when administered to pregnant woman. Inform pregnant woman of the risk to the fetus. (8.1)Pediatric Use: The safety and effectiveness in patients younger than month of age has not been established. (8.4). Pregnancy: Based on findings from animal studies, ERAXIS can cause fetal harm when administered to pregnant woman. Inform pregnant woman of the risk to the fetus. (8.1). Pediatric Use: The safety and effectiveness in patients younger than month of age has not been established. (8.4). 8.1 Pregnancy. Risk SummaryBased on findings from animal studies, ERAXIS can cause fetal harm when administered to pregnant woman. There are no available human data on the use of ERAXIS in pregnant women to inform drug-associated risk of adverse developmental outcomes. In animal reproduction studies fetal toxicity was observed in the presence of maternal toxicity when anidulafungin was administered to pregnant rabbits during organogenesis at times the proposed therapeutic maintenance dose of 100 mg/day on the basis of relative body surface area (see Data). Inform pregnant woman of the risk to the fetus.The estimated background risk of major birth defects and miscarriage for the indicated populations are unknown. All pregnancies have 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 to 4% and 15 to 20% respectively.. Data. Animal DataIn combined fertility and embryo-fetal development study in rats dosed with anidulafungin for weeks prior to cohabitation and through cohabitation for males or for weeks prior to cohabitation and continuing through gestation day 19 for females, there was no maternal or embryo-fetal toxicity at intravenous doses up to 20 mg/kg/day (equivalent to times the proposed therapeutic maintenance dose of 100 mg/day on the basis of relative body surface area).In rabbit embryo-fetal development study, intravenous administration of anidulafungin (0, 5, 10, and 20 mg/kg/day) from gestation day through 19, resulted in reduced fetal weights and incomplete ossification in the presence of maternal toxicity (decreased body weight gain) at 20 mg/kg/day (equivalent to times the proposed therapeutic maintenance dose of 100 mg/day on the basis of relative body surface area).In pre- and postnatal development study, pregnant rats were intravenously administered anidulafungin at doses of 2, 6, or 20 mg/kg/day from gestation day through lactation day 20. Maternal toxicity was observed at >=6 mg/kg/day (clinical signs at >=6 mg/kg/day and reduced body weight gain and food consumption during gestation at 20 mg/kg/day group). There were no effects on the viability or growth and development of the offspring. In this study, anidulafungin was detected in fetal plasma, indicating that it crossed the placental barrier.. 8.2 Lactation. Risk SummaryThere are no data on the presence of anidulafungin in human milk, the effects on the breastfed infant or the effects on milk production. When drug is present in animal milk, it is likely that the drug will be present in human milk. Anidulafungin was found in the milk of lactating rats (see Data ).The developmental and health benefits of breastfeeding should be considered along with the mothers clinical need for ERAXIS and any potential adverse effects on the breastfed child from ERAXIS or from the underlying maternal condition.. Data. Animal DataPregnant rats were intravenously administered anidulafungin at doses of 2, 6, or 20 mg/kg/day from gestation day through lactation day 20. Milk samples were collected from rats per group on lactation day 14 at approximately hours post dose. Approximately dose-proportional anidulafungin concentrations were found in the milk of lactating rats.. 8.4 Pediatric Use. The safety and effectiveness of ERAXIS for the treatment of candidemia and the following Candida infections: intra-abdominal abscess and peritonitis, have been established in pediatric patients month of age and older. Use of ERAXIS for this indication in this age group is supported by evidence from adequate and well-controlled studies in adults with additional pharmacokinetic, safety data in pediatric patients month of age and older [see Indications and Usage (1), Adverse Reactions (6.1), Clinical Pharmacology (12.3), and Clinical Studies (14.1)]. The safety and effectiveness of ERAXIS in patients younger than month of age with candidemia/invasive candidiasis has not been established.Candidemia/invasive candidiasis in pediatric patients younger than month of age has higher rate of central nervous system (CNS) and multi-organ dissemination than in older patients. In addition, in patients younger than month of age ERAXIS carries potential risk of life-threatening toxicity associated with high doses of polysorbate 80, an inactive ingredient in ERAXIS [see Warnings and Precautions (5.3)].The safety and effectiveness of ERAXIS in pediatric patients with esophageal candidiasis has not been established.ERAXIS is contraindicated in adult and pediatric patients with HFI. Because diagnosis of HFI may not yet be established in pediatric patients, obtain careful history of HFI symptoms with fructose/sucrose exposure prior to administration of ERAXIS [see Warnings and Precautions (5.4)].. 8.5 Geriatric Use. Of the total number of subjects (N 197) in the pivotal clinical studies of anidulafungin, 35% were 65 years and over, while 18% were 75 years and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.Dosage adjustments are not required for geriatric patients [see Clinical Pharmacology (12.3)].. 8.6 Hepatic Insufficiency. No dosing adjustments are required for patients with any degree of hepatic insufficiency. Anidulafungin is not hepatically metabolized. Anidulafungin pharmacokinetics were examined in subjects with Child-Pugh class A, or hepatic insufficiency. Anidulafungin concentrations were not increased in subjects with any degree of hepatic insufficiency. Though slight decrease in AUC was observed in patients with Child-Pugh hepatic insufficiency, it was within the range of population estimates noted for healthy subjects [see Clinical Pharmacology (12.3)].. 8.7 Renal Insufficiency. Dosage adjustments are not required for patients with any degree of renal insufficiency including those on hemodialysis. Anidulafungin has negligible (<1%) renal clearance. In 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 Clinical Pharmacology (12.3)].

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. Hepatic Effects: Risk of abnormal liver tests, hepatitis, hepatic failure; monitor hepatic function during therapy. (5.1, 13.2)Hypersensitivity: Anaphylaxis, including shock has been reported. Risk of infusion-related adverse reactions, possibly histamine-mediated, including rash, urticaria, flushing, pruritus, bronchospasm, dyspnea, and hypotension; to reduce occurrence, do not exceed rate of infusion of 1.1 mg/minute. (2.4, 5.2)Risk of Neonatal Toxicity Associated with Polysorbates: ERAXIS contains polysorbate 80, an inactive ingredient. Thrombocytopenia, renal dysfunction, hepatomegaly, cholestasis, ascites, hypotension and metabolic acidosis haves been reported in low-birth weight infants receiving high doses of polysorbate. ERAXIS is not approved in pediatric patients younger than month of age. (5.3, 8.4) Hereditary Fructose Intolerance (HFI): ERAXIS contains fructose. Risk of metabolic crisis with life-threatening hypoglycemia, hypophosphatemia, lactic acidosis, and hepatic failure. Obtain history of HFI symptoms in pediatric patients before ERAXIS administration. (5.4, 8.4). Hepatic Effects: Risk of abnormal liver tests, hepatitis, hepatic failure; monitor hepatic function during therapy. (5.1, 13.2). Hypersensitivity: Anaphylaxis, including shock has been reported. Risk of infusion-related adverse reactions, possibly histamine-mediated, including rash, urticaria, flushing, pruritus, bronchospasm, dyspnea, and hypotension; to reduce occurrence, do not exceed rate of infusion of 1.1 mg/minute. (2.4, 5.2). Risk of Neonatal Toxicity Associated with Polysorbates: ERAXIS contains polysorbate 80, an inactive ingredient. Thrombocytopenia, renal dysfunction, hepatomegaly, cholestasis, ascites, hypotension and metabolic acidosis haves been reported in low-birth weight infants receiving high doses of polysorbate. ERAXIS is not approved in pediatric patients younger than month of age. (5.3, 8.4) Hereditary Fructose Intolerance (HFI): ERAXIS contains fructose. Risk of metabolic crisis with life-threatening hypoglycemia, hypophosphatemia, lactic acidosis, and hepatic failure. Obtain history of HFI symptoms in pediatric patients before ERAXIS administration. (5.4, 8.4). 5.1Hepatic Adverse Reactions. Laboratory abnormalities in liver tests have been seen in healthy volunteers and pediatric patients treated with ERAXIS. In some patients with serious underlying medical conditions who were receiving multiple concomitant medications along with ERAXIS, clinically significant hepatic abnormalities have occurred. Isolated cases of significant hepatic dysfunction, hepatitis, or hepatic failure have been reported in patients; causal relationship to ERAXIS has not been established [see Adverse Reactions (6.1) and Nonclinical Toxicology (13.2)]. Patients who develop abnormal liver tests during ERAXIS therapy should be monitored for evidence of worsening hepatic tests and evaluated for risk/benefit of continuing ERAXIS therapy.. 5.2Anaphylactic and Hypersensitivity Reactions. Anaphylactic reactions, including shock were reported with the use of ERAXIS. If these reactions occur, ERAXIS should be discontinued and appropriate treatment administered [see Adverse Reactions (6)].Infusion-related adverse reactions, possibly histamine-mediated, have been reported with ERAXIS, including rash, urticaria, flushing, pruritus, bronchospasm, dyspnea, and hypotension [see Adverse Reactions (6)]. To reduce occurrence of these reactions, do not exceed rate of ERAXIS infusion of 1.1 mg/minute [see Dosage and Administration (2.4)].. 5.3Risk of Neonatal Toxicity Associated with Polysorbates. ERAXIS contains polysorbate 80, an inactive ingredient. Thrombocytopenia, renal dysfunction, hepatomegaly, cholestasis, ascites, hypotension, and metabolic acidosis have been reported in low-birth weight infants receiving high doses of polysorbate. Polysorbate toxicity has not been reported with ERAXIS. ERAXIS is not approved in pediatric patients younger than month of age [see Indications and Usage (1.1, 1.3), Use in Specific Populations (8.4)]. 5.4Risk in Patients with Hereditary Fructose Intolerance (HFI). ERAXIS contains fructose, an inactive ingredient, and may precipitate metabolic crisis that may include, but is not limited to life-threatening hypoglycemia, hypophosphatemia, lactic acidosis, and hepatic failure in patients with HFI. Obtain careful history of HFI symptoms (nausea, vomiting, abdominal pain) with fructose/sucrose exposure prior to ERAXIS administration because diagnosis of HFI may not yet be established in pediatric patients [see Contraindications (4) and Use in Specific Populations (8.4)].