During clinical trials a single 400 mg dose of Ecalta was inadvertently administered as a loading dose. No clinical adverse events were reported. In a study of 10 healthy subjects administered a loading dose of 260 mg followed by 130 mg daily, Ecalta was generally well tolerated; 3 of the 10 subjects experienced transient, asymptomatic transaminase elevations (≤3 x ULN).
Anidulafungin is not dialyzable.
The maximum non-lethal dose of anidulafungin in rats was 50 mg/kg, a dose which is equivalent to 10 times the recommended daily dose for esophageal candidiasis (50 mg/day) or equivalent to 5 times the recommended daily dose for candidemia and other Candida infections (100 mg/day), based on relative body surface area comparisons.
Ecalta is contraindicated in persons with known hypersensitivity to anidulafungin, any component of Ecalta, or other echinocandins.
The most serious adverse reactions reported with Ecalta are:
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.
The safety of Ecalta 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 Ecalta at daily doses of either 50 mg or 100 mg. A total of 481 patients received Ecalta for ≥14 days.
Candidemia/Other Candida InfectionsThree studies (one comparative vs. fluconazole, two non-comparative) assessed the efficacy and safety of Ecalta (100 mg) in patients with candidemia and other Candida infections.
The data described below reflect exposure to Ecalta 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 Ecalta to that of fluconazole. In Ecalta-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 Ecalta (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 Ecalta arm and 21.6% in the fluconazole arm. The most common adverse reactions leading to study drug discontinuation were multi-organ failure and systemic Candida infection in the Ecalta arm.
Table 2 presents adverse reactions that were reported in ≥5% of subjects receiving Ecalta or fluconazole therapy in this trial.
Table 2: Adverse Reactions Reported in ≥5% of Subjects Receiving Ecalta or Fluconazole Therapy for Candidemia/other Candida Infections*, **
| Ecalta 100 mg N=131 N (%) | Fluconazole 400 mg N=125 N (%) | |
| Subjects with a least one adverse reaction | 130 (99) | 122 (98) |
| Infections and infestations | 82 (63) | 80 (64) |
| Bacteremia | 23 (18) | 23 (18) |
| Urinary tract infection | 19 (15) | 22 (18) |
| Sepsis | 9 (7) | 11 (9) |
| Pneumonia | 8 (6) | 19 (15) |
| 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) |
| *A patient who experienced multiple reactions with a System Organ Class (SOC) 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 Ecalta for the adverse reactions reported in this table. |
The data described below reflect exposure to Ecalta and fluconazole in 300 and 301 patients, respectively, with esophageal candidiasis in a randomized trial comparing the efficacy and safety of Ecalta to that of oral fluconazole. In Ecalta-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 Ecalta (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 Ecalta arm and 36 (12%) patients in the fluconazole arm had adverse reactions leading to discontinuation of study medication. The most common adverse reactions leading to study drug discontinuation were maculopapular rash for the Ecalta arm. The most common adverse reactions leading to discontinuation were rash and increased AST for the fluconazole arm.
Table 3 presents adverse reactions that were reported in ≥5% of subjects receiving Ecalta therapy.
Table 3 : Adverse Reactions Reported in ≥5% of Subjects Receiving Ecalta or Fluconazole Therapy for Esophageal Candidiasis*, **
| Ecalta 50 mg N=300 N (%) | Fluconazole 100 mg N=301 N (%) | |
| Subjects with a least one adverse reactions | 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) |
| *A patient who experienced multiple reactions with a System Organ Class (SOC) 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 Ecalta for the adverse reactions reported in this table. |
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, gammaglutamyl 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
Post-marketing ExperienceThe 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.
ImmuneAnaphylactic shock, anaphylactic reaction, bronchospasm.
Ecalta is indicated for use in adults for the treatment of the following fungal infections listed below. 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 known. However, once these results become available, antifungal therapy should be adjusted accordingly.
Candidemia And Other Forms Of Candida Infections (Intra-abdominal Abscess And Peritonitis)Ecalta is indicated for the treatment of candidemia and the following Candida infections: intra-abdominal abscess and peritonitis.
Esophageal CandidiasisEcalta is indicated for the treatment of esophageal candidiasis.
Limitation Of UseEcalta has not been studied in 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 pharmacokinetics of anidulafungin following intravenous (IV) administration have been characterized in healthy subjects, special populations and patients. Systemic exposures of anidulafungin are dose-proportional and have low intersubject variability (coefficient of variation <25%) as shown in Table 4. 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 4: Mean (%CV) Steady State Pharmacokinetic Parameters of Anidulafungin Following IV Administration of Anidulafungin Once Daily for 10 Days in Healthy Adult Subjects
| PK Parametera | Anidulafungin IV Dosing Regimen (LD/MD, mg)b | ||
| 70/35c,d (N=6) | 200/100 (N=10) | 260/130de (N=10) | |
| Cmax, 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) |
| t½[h] | 43.2 (17.7) | 52.0 (11.7) | 50.3 (9.7) |
| a Parameters were obtained from separate studies b LD/MD: loading dose/maintenance dose once daily c Data were collected on Day 7 d Safety and efficacy of these doses has not been established e See OVERDOSAGE Cmax, ss = the steady state peak concentration AUCss = the steady state area under concentration vs. time curve CL = clearance t½ = the terminal elimination half-life |
The clearance of anidulafungin is about 1 L/h and anidulafungin has a terminal elimination half-life of 40-50 hours.
DistributionThe 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.
MetabolismHepatic 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.
ExcretionIn a 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 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.
Included as part of the PRECAUTIONS section.
PRECAUTIONS Hepatic EffectsLaboratory abnormalities in liver function tests have been seen in healthy volunteers and patients treated with Ecalta. In some patients with serious underlying medical conditions who were receiving multiple concomitant medications along with Ecalta, clinically significant hepatic abnormalities have occurred. Isolated cases of significant hepatic dysfunction, hepatitis, or hepatic failure have been reported in patients; a causal relationship to Ecalta has not been established. Patients who develop abnormal liver function tests during Ecalta therapy should be monitored for evidence of worsening hepatic function and evaluated for risk/benefit of continuing Ecalta therapy.
HypersensitivityAnaphylactic reactions, including shock were reported with the use of Ecalta. If these reactions occur, Ecalta should be discontinued and appropriate treatment administered.
Infusion-related adverse reactions, possibly histamine-mediated, have been reported with Ecalta, including rash, urticaria, flushing, pruritus, bronchospasm, dyspnea, and hypotension. To reduce occurrence of these reactions, do not exceed a rate of Ecalta infusion of 1.1 mg/minute.
Nonclinical Toxicology Carcinogenesis, Mutagenesis, Impairment Of FertilityLong-term animal carcinogenicity studies of anidulafungin have not been conducted.
Anidulafungin was not genotoxic in the following in vitro studies: bacterial reverse mutation assays, a chromosome aberration assay with Chinese hamster ovary cells, and a forward gene mutation assay with mouse lymphoma cells. Anidulafungin was not genotoxic in mice using the in vivo micronucleus assay.
Anidulafungin produced no adverse effects on fertility in male or female rats at intravenous doses of 20 mg/kg/day (equivalent to 2 times the proposed therapeutic maintenance dose of 100 mg/day on the basis of relative body surface area).
Use In Specific Populations Pregnancy Risk SummaryBased on findings from animal studies, Ecalta can cause fetal harm when administered to a pregnant woman. There are no available human data on the use of Ecalta in pregnant women to inform a 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 4 times the proposed therapeutic maintenance dose of 100 mg/day on the basis of relative body surface area. 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. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20% respectively.
DataAnimal Data
In a combined fertility and embryo-fetal development study in rats dosed with anidulafungin for 4 weeks prior to cohabitation and through cohabitation for males or for 2 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 2 times the proposed therapeutic maintenance dose of 100 mg/day on the basis of relative body surface area).
In a rabbit embryo-fetal development study, intravenous administration of anidulafungin (0, 5, 10, and 20 mg/kg/day) from gestation day 7 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 4 times the proposed therapeutic maintenance dose of 100 mg/day on the basis of relative body surface area).
In a pre-and postnatal development study, pregnant rats were intravenously administered anidulafungin at doses of 2, 6, or 20 mg/kg/day from gestation day 7 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.
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. Anidulafungin was found in the milk of lactating rats. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for Ecalta and any potential adverse effects on the breastfed child from Ecalta or from the underlying maternal condition.
DataAnimal Data
Pregnant rats were intravenously administered anidulafungin at doses of 2, 6, or 20 mg/kg/day from gestation day 7 through lactation day 20. Milk samples were collected from 5 rats per group on lactation day 14 at approximately 1 hours post dose. Approximately dose-proportional anidulafungin concentrations were found in the milk of lactating rats.
Pediatric UseThe safety and effectiveness of Ecalta in patients ≤16 years old has not been established.
Geriatric UseDosage adjustments are not required for geriatric patients.
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.
Hepatic InsufficiencyNo 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, 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.
Renal InsufficiencyDosage adjustments are not required for patients with any degree of renal insufficiency including those on hemodialysis. Anidulafungin has negligible (<1%) 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.
The recommended dose is a single 200 mg loading dose of Ecalta on Day 1, followed by 100 mg daily 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 CandidiasisThe recommended dose is a single 100 mg loading dose of Ecalta on Day 1, followed by 50 mg daily 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 infections, suppressive antifungal therapy may be considered after a course of treatment.
Preparation For AdministrationEcalta 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). The compatibility of reconstituted Ecalta 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.
Reconstitution 50 mg/vialAseptically reconstitute each 50 mg vial with 15 mL of sterile Water for Injection to provide a concentration of 3.33 mg/mL. The reconstituted solution can be stored for up to 24 hours at temperatures up to 25°C (77°F) prior to dilution into the infusion solution.
Reconstitution 100 mg/vialAseptically reconstitute each 100 mg vial with 30 mL of sterile Water for Injection to provide a concentration of 3.33 mg/mL. The reconstituted solution can be stored for up to 24 hours at temperatures up to 25°C (77°F) prior to dilution into the infusion solution.
Dilution And InfusionAseptically 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 and infusion instructions for each dose.
Table 1: Dilution Requirements for Ecalta Administration
| Dose | Number of Vials Required | Total Reconstituted Volume Required | Infusion Volume a | Total Infusion Volume b | 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 |
| a Either 5% Dextrose Injection, USP or 0.9% Sodium Chloride Injection, USP (normal saline) b Infusion solution concentration is 0.77 mg/mL |
Caution: 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).
The infusion solution may be stored for up to 48 hours at temperatures up to 25°C (77°F), or stored frozen for at least 72 hours prior to administration.
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.
