ERAXIS for Injection is a sterile, lyophilized product for intravenous (IV) infusion that contains anidulafungin. ERAXIS (anidulafungin) is a semi-synthetic lipopeptide synthesized from a fermentation product of Aspergillus nidulans. Anidulafungin is an echinocandin, a class of antifungal drugs that inhibits the synthesis of 1,3-β-D-glucan, an essential component of fungal cell walls.

ERAXIS (anidulafungin) is 1-[(4R,5R)-4,5-Dihydroxy-N²-[[4“-(pentyloxy)[1,1':4',1”-terphenyl]-4­yl]carbonyl]-L-ornithine]echinocandin B. Anidulafungin is a white to off-white powder that is practically insoluble in water and slightly soluble in ethanol. In addition to the active ingredient, anidulafungin, ERAXIS for Injection contains the following inactive ingredients: 

50mg/vial - fructose (50 mg), mannitol (250 mg), polysorbate 80 (125 mg), tartaric acid (5.6 mg), and sodium hydroxide and/or hydrochloric acid for pH adjustment. 
100mg/vial - fructose (100 mg), mannitol (500 mg), polysorbate 80 (250 mg), tartaric acid (11.2 mg), and sodium hydroxide and/or hydrochloric acid for pH adjustment.

The empirical formula of anidulafungin is C₅₈H₇₃N₇O₁₇ and the formula weight is 1140.3.

The structural formula is:

Prior to administration, ERAXIS for Injection requires reconstitution with sterile Water for Injection and subsequent dilution with either 5% Dextrose Injection, USP or 0.9% Sodium Chloride Injection, USP (normal saline). 

DO NOT dilute with other solutions or co-infuse with other medications or electrolytes (see DOSAGE AND ADMINISTRATION).

Last updated on RxList: 6/24/2009

ERAXIS is indicated for use in the treatment of the following fungal infections:

Candidemia and other forms of Candida infections (intra-abdominal abscess, and peritonitis) (see Clinical Studies and MICROBIOLOGY).

ERAXIS 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.

Esophageal candidiasis (see Clinical Studies, Table 7 for higher relapse rates off ERAXIS therapy).

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.

Candidemia and other Candida infections (intra-abdominal abscess, and peritonitis)

The recommended dose is a single 200 mg loading dose of ERAXIS on Day 1, followed by 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 candidiasis

The recommended dose is a single 100 mg loading dose of ERAXIS 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.

No dosing adjustments are required for patients with any degree of renal or hepatic insufficiency, patients using concomitant medications or those in other special populations (see CLINICAL PHARMACOLOGY - Special Populations and Drug Interaction Studies).

Preparation of ERAXIS for Administration

ERAXIS for Injection must be reconstituted with the companion diluent (20% (w/w) Dehydrated Alcohol in Water for Injection) and subsequently diluted with only 5% Dextrose Injection, USP or 0.9% Sodium Chloride Injection, USP (normal saline). 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.

Reconstitution 50 mg/vial

Aseptically reconstitute each 50 mg vial with 15 mL of the companion diluent (20% (w/w) Dehydrated Alcohol in Water for Injection) to provide a concentration of 3.33 mg/mL. The reconstituted solution should be stored at 25ºC (77ºF); excursions permitted to 15-30ºC (59-86ºF) (see USP Controlled Room Temperature). Do not refrigerate or freeze. The reconstituted solution must be further diluted and administered within 24 hours.

Reconstitution 100 mg/vial

Aseptically reconstitute each 100 mg vial with 30 mL of the companion diluent (20% (w/w) Dehydrated Alcohol in Water for Injection) to provide a concentration of 3.33 mg/mL. The reconstituted solution should be stored at 25ºC (77ºF); excursions permitted to 15-30ºC (59-86ºF) (see USP Controlled Room Temperature). Do not refrigerate or freeze. The reconstituted solution must be further diluted and administered within 24 hours.

Dilution and Infusion

Aseptically transfer the contents of the reconstituted vial(s) into the appropriately sized IV bag (or bottle) containing either 5% Dextrose Injection, USP or 0.9% Sodium Chloride Injection, USP (normal saline). Table 10 provides the number of Unit Packs (ERAXIS vial and companion diluent vial, see HOW SUPPLIED), volumes and infusion solution concentration for each dose.

Table 10. Dilution requirements for ERAXIS Administration

Dose	Number of Unit Packs Required	Total Reconstituted Volume Required	Infusion Volume a	Total Infusion Volume	Infusion Solution Concentration
50 mg	1-50 mg	15 mL	100 mL	115 mL	0.43 mg/mL
100 mg	2-50 mg OR 1-100 mg	30 mL	250 mL	280 mL	0.36 mg/mL
200 mg	4-50 mg OR 2-100 mg	60 mL	500 mL	560 mL	0.36 mg/mL
a Either 5% Dextrose Injection, USP or 0.9% Sodium Chloride Injection, USP (normal saline)

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 are identified, discard the solution.

The rate of infusion should not exceed 1.1 mg/minute.

The infusion solution should be stored at 25ºC (77ºF); excursions permitted to 15-30ºC (59-86ºF) (see USP Controlled Room Temperature). Do not refrigerate or freeze.

ERAXIS (anidulafungin) for Injection is supplied in a single-use vial of sterile, lyophilized, preservative-free, powder. The companion single-use diluent vial contains 20% (w/w) Dehydrated Alcohol in Water for Injection. ERAXIS (anidulafungin) is available in the following packaging configuration:

Single Use Unit Pack (containing ERAXIS 50 mg vial and 15 mL Diluent vial)

NDC 0049-1010-28 One - 50 mg vial and 15 mL diluent vial

Single Use Unit Pack (containing ERAXIS 100 mg vial and 30 mL Diluent vial)

NDC 0049-0115-28 One - 100 mg vial and 30 mL diluent vial

Storage

Unreconstituted vials

ERAXIS for Injection unreconstituted vials and companion diluent vials should be stored at 25ºC (77ºF); excursions permitted to 15-30ºC (59-86ºF) (see USP Controlled Room Temperature). Do not freeze.

Reconstituted vials

Reconstituted ERAXIS for Injection should be stored at 25ºC (77ºF); excursions permitted to 15-30ºC (59-86ºF) (see USP Controlled Room Temperature). Do not refrigerate or freeze. The reconstituted vials must be further diluted and administered within 24 hours.

Diluted Product

Diluted ERAXIS for Injection should be stored at 25ºC (77ºF); excursions permitted to 15-30ºC (59-86ºF) (see USP Controlled Room Temperature). Do not refrigerate or freeze.

Distributed by: Roerig Division of Pfizer Inc, NY, NY 10017. Revised May 2007. FDA Rev date: 11/9/2007

Last updated on RxList: 6/24/2009

General

Possible histamine-mediated symptoms have been reported with ERAXIS, including rash, urticaria, flushing, pruritus, dyspnea, and hypotension. These events are infrequent when the rate of ERAXIS infusion does not exceed 1.1 mg/minute.

Overall Eraxis Safety Experience

The safety of ERAXIS for Injection was assessed in 929 individuals, including 672 patients in clinical studies and 257 individuals in Phase 1 studies.  A total of 633 patients received ERAXIS at daily doses of either 50 or 100 mg.  A total of 481 patients received ERAXIS for ≥ 14 days.

Candidemia/Other Candida  Infections

Three studies (one comparative vs. fluconazole, two non-comparative) assessed the efficacy and safety of ERAXIS (100 mg) in patients with candidemia and other Candida infections. Table 8 presents treatment-related adverse events that were reported in ≥ 2.0% of subjects receiving ERAXIS or fluconazole therapy in the comparative candidemia study.

TABLE 8 : TREATMENT-RELATED^A ADVERSE EVENTS REPORTED IN  2.0% OF SUBJECTS RECEIVING ERAXIS OR FLUCONAZOLE THERAPY FOR CANDIDEMIA/OTHER CANDIDA INFECTIONS 

	ERAXIS 100 mgb N = 131 N (%)	Fluconazole 400 mgb N = 125 N (%)
Subjects with at least 1 treatment-related AE	32 (24.4)	33 (26.4)
Gastrointestinal System
Diarrhea	4 (3.1)	2 (1.6)
Investigations
ALT ↑	3 (2.3)	4 (3.2)
AST↑	1 (0.8)	3 (2.4)
Alkaline phosphatase ↑	2 (1.5)	5 (4.0)
Hepatic enzyme↑	2 (1.5)	9 (7.2)
Metabolic and Nutritional Systems
Hypokalemia	4 (3.1)	3 (2.4)
Vascular System
Deep vein thrombosis	1 (0.8)	3 (2.4)
a Treatment-related AEs are defined as those that are possibly or probably related to study treatment, as determined by the investigator. b Maintenance dose

Esophageal Candidiasis

A single phase 3, randomized, double-blind study compared the efficacy and safety of ERAXIS to that of fluconazole in patients with esophageal candidiasis.  Table 9 presents treatment-related adverse events that were reported in ≥ 1.0% of subjects receiving ERAXIS therapy.  (No adverse events were reported at a frequency of 2% or greater in patients with esophageal candidiasis).

Table 9 : Treatment-related^a adverse events reported in ≥ 1.0% of subjects receiving ERAXIS or fluconazole therapy for esophageal candidiasis

	ERAXIS 50 mgb N = 300 N (%)	Fluconazole 100 mgb N = 301 N (%)
Subjects with at least 1 treatment-related AE	43 (14.3)	50 (16.6)
Blood and lymphatic System
Neutropenia	3 (1.0)	--
Leukopenia	2 (0.7)	4 (1.3)
Gastrointestinal System
Dyspepsia aggravated	1 (0.3)	3 (1.0)
Nausea	3 (1.0)	3 (1.0)
Vomiting NOS	2 (0.7)	3 (1.0)
General Disorders and Administration Site Conditions
Pyrexia	2 (0.7)	3 (1.0)
Investigations
Gamma-glutamyl transferase ↑	4 (1.3)	4 (1.3)
ALT ↑	--	3 (1.0)
AST ↑	1 (0.3)	7 (2.3)
Nervous System
Headache	4 (1.3)	3 (1.0)
Skin and Subcutaneous Tissue
Rash	3 (1.0)	2 (0.7)
Vascular System
Phlebitis NOSc	2 (0.7)	4 (1.3)
a  Treatment-related AEs include those that are of possible, probable, or unknown relationship to study treatment, as determined by the investigator. b Maintenance dose c  Not Otherwise Specified

The following events occurred in either < 2% of patients treated for candidemia/other Candida  infections, or in < 1% of patients treated for esophageal candidiasis and were judged by investigators to be at least possibly related to ERAXIS:

Blood and Lymphatic: coagulopathy, thrombocytopenia

Cardiac: atrial fibrillation, bundle branch block (right), sinus arrhythmia, ventricular extrasystoles

Eye: eye pain, vision blurred, visual disturbance

Gastrointestinal: abdominal pain upper, constipation, diarrhea NOS, dyspepsia, fecal incontinence, nausea, vomiting

General and Administration Site: infusion related reaction, peripheral edema, rigors

Hepatobiliary: abnormal liver function tests NOS, cholestasis, hepatic necrosis

Infections: candidiasis, clostridial infection, fungemia, oral candidiasis

Investigations : amylase ↑, bilirubin ↑, CPK ↑, creatinine ↑, electrocardiogram QT prolonged, electrocardiogram early transition, gamma-glutamyl transferase ↑, lipase ↑, magnesium ↓, platelet count ↑, platelet count ↓, potassium ↓, prothrombin time prolonged, urea ↑

Metabolism and Nutrition: hypercalcemia, hyperglycemia, hyperkalemia, hypernatremia, hypomagnesemia

Musculoskeletal and Connective Tissue: back pain

Nervous System: convulsion, dizziness, headache

Respiratory, Thoracic and Mediastinal: cough

Skin and Subcutaneous Tissue: angioneurotic edema, erythema, pruritus, pruritus generalized, sweating increased, urticaria, urticaria NOS

Vascular: flushing, hot flushes, hypertension, hypotension, thrombophlebitis superficial

Pre-clinical in vitro and in vivo and clinical studies demonstrated that anidulafungin is not a clinically relevant substrate, inducer, or inhibitor of cytochrome P450 isoenzymes.  Anidulafungin has negligible renal clearance. Minimal interactions are expected from the concomitant medications (see CLINICAL PHARMACOLOGY –Drug Interactions Studies).

Drug interaction studies were performed with anidulafungin and other drugs likely to be co-administered.  When used in therapeutic doses, no dosage adjustment of either drug is recommended when anidulafungin is co-administered with voriconazole or tacrolimus, and no dosage adjustment for anidulafungin is recommended when co-administered with amphotericin B or rifampin (see CLINICAL PHARMACOLOGY – Drug Interactions Studies).

Co-administration with cyclosporine slightly increased the steady state AUC of anidulafungin by 22%.  A separate in vitro study showed that anidulafungin has no effect on the metabolism of cyclosporine. Adverse events observed in the study were consistent with adverse events observed from other studies with the administration of anidulafungin alone.  No dosage adjustment of either drug is warranted for patients on concomitant cyclosporine (see CLINICAL PHARMACOLOGY – Drug Interactions Studies).

Last updated on RxList: 6/24/2009

No information provided.

Hepatic Effects

Laboratory abnormalities in liver function tests have been seen in healthy volunteers and 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 worsening hepatic failure have been reported in patients; a causal relationship to ERAXIS has not been established.  Patients who develop abnormal liver function tests during ERAXIS therapy should be monitored for evidence of worsening hepatic function and evaluated for risk/benefit of continuing ERAXIS therapy.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Long-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).

Pregnancy

Pregnancy Category C

Embryo-fetal development studies were conducted with doses up to 20 mg/kg/day in rats and rabbits (equivalent to 2 and 4 times, respectively, the proposed therapeutic maintenance dose of 100 mg/day on the basis of relative body surface area).  Anidulafungin administration resulted in skeletal changes in rat fetuses including incomplete ossification of various bones and wavy, misaligned or misshapen ribs.  These changes were not dose-related and were within the range of the database. Developmental effects observed in rabbits (slightly reduced fetal weights) occurred in the high dose group, a dose that also produced maternal toxicity.  Anidulafungin crossed the placental barrier in rats and was detected in fetal plasma. 

There are no adequate and well-controlled studies in pregnant women.  Because animal reproduction studies are not always predictive of human response, ERAXIS should be used during pregnancy only if the potential benefit justifies the risk to the fetus.

Nursing Mothers

ERAXIS should be administered to nursing mothers only if the potential benefit justifies the risk.  Anidulafungin was found in the milk of lactating rats.  It is not known whether anidulafungin is excreted in human milk. 

Pediatric Use

Safety and effectiveness of anidulafungin in pediatric patients has not been established (see CLINICAL PHARMACOLOGY-Special Populations/Pediatric).

Last updated on RxList: 6/24/2009

During clinical trials a single 400 mg dose of ERAXIS 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, ERAXIS 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 comparison.

ERAXIS is contraindicated in persons with known hypersensitivity to anidulafungin, any component of ERAXIS, or other echinocandins.

Last updated on RxList: 6/24/2009

Pharmacokinetics

The pharmacokinetics of anidulafungin following 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 1. 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 1 : 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)	260/130d e (N = 10)
Cmax, ss [mg/L]	3.55 (13.2)	8.6 (16.2)	10.9 (11.7)
AUCss [mg•h/L]	42.3 (14.5)	111.8 (24.9)	168.9 (10.8)
CL [L/h]	0.84 (13.5)	0.94 (24.0)	0.78 (11.3)
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.

Distribution

The pharmacokinetics of anidulafungin following IV administration are characterized by a short distribution half-life (0.5-1 hour) and a volume of distribution of 30-50 L that is similar to total body fluid volume. Anidulafungin is extensively bound ( > 99%) to human plasma proteins. 

Metabolism

Hepatic metabolism of anidulafungin has not been observed. Anidulafungin is not a clinically relevant substrate, inducer, or inhibitor of cytochrome P450 (CYP450) isoenzymes.  It is unlikely that anidulafungin will have clinically relevant effects on the metabolism of drugs metabolized by CYP450 isoenzymes.

Anidulafungin undergoes slow chemical degradation at physiologic temperature and pH to a ring-opened peptide that lacks antifungal activity. The in vitro degradation half-life of anidulafungin under physiologic conditions is about 24 hours. In vivo, the ring-opened product is subsequently converted to peptidic degradants and eliminated.

Excretion

In a single-dose clinical study, radiolabeled (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.

Special Populations

Patients with fungal infections

Population pharmacokinetic analyses from four Phase 2/3 clinical studies including 107 male and 118 female patients with fungal infections showed that the pharmacokinetic parameters of anidulafungin are not affected by age, race, or the presence of concomitant medications which are known metabolic substrates, inhibitors or inducers.

The pharmacokinetics of anidulafungin in patients with fungal infections are similar to those observed in healthy subjects. The pharmacokinetic parameters of anidulafungin estimated using population pharmacokinetic modeling following IV administration of a maintenance dose of 50 mg/day or 100 mg/day (following a loading dose) are presented in Table 2.

Table 2 : Mean (%CV) Steady State Pharmacokinetic Parameters of Anidulafungin Following IV Administration of Anidulafungin in Patients with Fungal Infections Estimated Using Population Pharmacokinetic Modeling

PK Parametera	Anidulafungin IV Dosing Regimen (LD/MD, mg)c
	100/50	200/100
Cmax, ss [mg/L]	4.2 (22.4)	7.2 (23.3)
Cmin, ss [mg/L]	1.6 (42.1)	3.3 (41.8)
AUCss [mg•h/L]	55.2 (32.5)	110.3 (32.5)
CL [L/h]	1.0 (33.5)
t½,β[h] b	26.5 (28.5)
a All the parameters were estimated by population modeling using  a 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 1 mg/min to administer recommended doses of 50 and 100 mg/day. b  t½, β  is the predominant elimination half-life that characterizes the majority of the concentration-time profile.  c LD/MD: loading dose/daily maintenance dose

Gender 

Dosage adjustments are not required based on gender.  Plasma concentrations of anidulafungin in healthy men and women were similar. In multiple-dose patient studies, drug clearance was slightly faster (approximately 22%) in men. 

Geriatric 

Dosage adjustments are not required for geriatric patients. The population pharmacokinetic analysis showed that median clearance differed slightly between the elderly group (patients   65, median CL = 1.07 L/h) and the non-elderly group (patients < 65, median CL = 1.22 L/h) and the range of clearance was similar.   

Race

Dosage adjustments are not required based on race. Anidulafungin pharmacokinetics were similar among Whites, Blacks, Asians, and Hispanics.

HIV Status

Dosage adjustments are not required based on HIV status, irrespective of concomitant anti-retroviral therapy.

Hepatic Insufficiency

Dosage adjustments are not required on the basis of mild, moderate or severe 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 Insufficiency

Dosage adjustments are not required for patients with any degree of renal insufficiency including those on hemodialysis.  Anidulafungin has negligible renal clearance.  In a clinical study of subjects with mild, moderate, severe or end stage (dialysis-dependent) renal insufficiency, anidulafungin pharmacokinetics were similar to those observed in subjects with normal renal function.  Anidulafungin is not dialyzable and may be administered without regard to the timing of hemodialysis. 

Pediatric 

The pharmacokinetics of anidulafungin after daily doses were investigated in immunocompromised pediatric (2 through 11 years) and adolescent (12 through 17 years) patients with neutropenia.  The steady state was achieved on the first day after administration of the loading dose (twice the maintenance dose), and the Cmax and AUCss increased in a dose-proportional manner.  Concentrations and exposures following administration of maintenance doses of 0.75 and 1.5 mg/kg/day in this population were similar to those observed in adults following maintenance doses of 50 and 100 mg/day, respectively (as shown in Table 3) (see PRECAUTIONS, Pediatric use).

Table 3 :  Mean (%CV) Steady State Pharmacokinetic Parameters of Anidulafungin Following IV Administration of Anidulafungin Once Daily in Pediatric Subjects

PK Parametera	Anidulafungin IV Dosing Regimen (LD/MD, mg/kg)b
	1.5/0.75		3.0/1.5
Age Group	2-11 yrs	12-17 yrs	2-11 yrs	12-17 yrs
	(N = 6)	(N = 6)	(N = 6)	(N = 6)
Cmax, ss[mg/L]	3.32 (50.0)	4.35 (22.5)	7.57 (34.2)	6.88 (24.3)
AUCss[mg•h/L]	41.1 (38.4)	56.2 (27.8)	96.1 (39.5)	102.9 (28.2)
a Data were collected on Day 5 b  LD/MD: loading dose/daily maintenance dose

Drug Interaction Studies

In vitro studies showed that anidulafungin is not metabolized by human cytochrome P450 or by isolated human hepatocytes, and does not significantly inhibit the activities of human CYP isoforms (1A2, 2B6, 2C8, 2C9, 2C19, 2D6 and 3A) at clinically relevant concentrations. No clinically relevant drug-drug interactions were observed with drugs likely to be co-administered with anidulafungin.

Cyclosporine (CYP3A4 substrate): In a study in which 12 healthy adult subjects received 100 mg/day maintenance dose of anidulafungin following a 200 mg loading dose (on Days 1 to 8) and in combination with 1.25 mg/kg oral cyclosporine twice daily (on Days 5 to 8), the steady state Cmax  of anidulafungin was not significantly altered by cyclosporine; the steady state AUC of anidulafungin was increased by 22%.  A separate in vitro study showed that anidulafungin has no effect on the metabolism of cyclosporine.  No dosage adjustment of either drug is warranted when co-administered.

Voriconazole (CYP2C19, CYP2C9, CYP3A4 inhibitor and substrate):  In a study in which 17 healthy subjects received 100 mg/day maintenance dose of anidulafungin following a 200 mg loading dose, 200 mg twice daily oral voriconazole (following two 400 mg loading doses) and both in combination, the steady state Cmax  and AUC of anidulafungin and voriconazole were not significantly altered by co­administration. No dosage adjustment of either drug is warranted when co-administered.

Tacrolimus (CYP3A4 substrate):  In a study in which 35 healthy subjects received a single oral dose of 5 mg tacrolimus (on Day 1), 100 mg/day maintenance dose of anidulafungin following a 200 mg loading dose (on Days 4 to 12) and both in combination (on Day 13), the steady state Cmax and AUC of anidulafungin and tacrolimus were not significantly altered by co-administration.  No dosage adjustment of either drug is warranted when co-administered.

AmBisome® (liposomal amphotericin B): The pharmacokinetics of anidulafungin were examined in 27 patients that were co-administered liposomal amphotericin B.  The population pharmacokinetic analysis showed that when compared to data from patients that did not receive amphotericin B, the pharmacokinetics of anidulafungin were not significantly altered by co-administration with amphotericin B. No dosage adjustment of anidulafungin is warranted.

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. No dosage adjustment of anidulafungin is warranted.

Microbiology

Mechanism Of Action

Anidulafungin is a 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-β-D-glucan, an essential component of the fungal cell wall. 

Activity in vitro

Anidulafungin is active in vitro against Candida albicans, C. glabrata, C. parapsilosis, and C. tropicalis (see INDICATIONS AND USAGE, Clinical Studies).

MICs were determined according to the Clinical and Laboratory Standards Institute (CLSI) approved  standard reference method M27 for susceptibility testing of yeasts. However, no correlation between in vitro activity (MIC) as determined by this method and clinical outcome has been established.

Activity In Vivo

Parenterally administered anidulafungin was effective against Candida albicans in immunocompetent and immunosuppressed mice and rabbits with disseminated infection as measured by prolonged survival and reduction in mycological burden. Anidulafungin also reduced the mycological burden of fluconazole­resistant C. albicans in an oropharyngeal/esophageal infection model in immunosuppressed rabbits.

Drug Resistance

Emergence of resistance to anidulafungin has not been studied.

Anidulafungin was active against Candida albicans resistant to fluconazole. Cross resistance with other echinocandins has not been studied.

Clinical Studies

Candidemia and other Candida infections (intra-abdominal abscess, and peritonitis)

The safety and efficacy of ERAXIS were evaluated in a 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 a positive culture for Candida species from a normally sterile site before entry into the study (modified intent-to-treat [MITT]  population) were included in the primary analysis of global response at the end of IV therapy. A 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 were randomized and received at least one dose of study medication.  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 7 days for the ERAXIS arm and 5 days for the fluconazole arm.

Patient disposition is presented in Table 4.

Table 4 :  Patient Disposition and Reasons for Discontinuation in Candidemia and other Candida infection study

	ERAXIS n (%)	Fluconazole n (%)
Treated patients	131	125
Patients completing study through 6 week follow-up	94 (71.8)	80 (64.0)
DISCONTINUATIONS FROM STUDY MEDICATION
Total discontinued from study medication	34 (26.0)	48 (38.4)
Discontinued due to adverse events	12 (9.2)	21 (16.8)
Discontinued due to lack of efficacy	11 (8.4)	16 (12.8)

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 a 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 (61.6%), followed by C. glabrata (20.4%), C. parapsilosis (11.8%) and C. tropicalis (10.6%). 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 5.

Table 5 :  Efficacy Analysis: Global Success in patients with Candidemia and other Candida infections (MITT Population)      

Timepoint	ERAXIS (N=127) n (%)	Fluconazole (N=118) n (%)	Treatment Differencea, % (95% C.I.)
End of IV Therapy	96 (75.6)	71 (60.2)	15.42 (3.9, 27.0)
End of All Therapyb	94 (74.0)	67 (56.8)	17.24 (2.9, 31.6c)
2 Week Follow-up	82 (64.6)	58 (49.2)	15.41 ( 0.4, 30.4 c)
6 Week Follow-up	71 (55.9)	52 (44.1)	11.84 (-3.4, 27.0c)
a Calculated as ERAXIS minus fluconazole b 33 patients in each study arm (26% -ERAXIS and 28.8 % fluconazole-treated) switched to oral fluconazole after the end of IV therapy.  c 98.3% confidence intervals, adjusted post hoc for multiple comparisons of secondary time points

Table 6 presents outcome and mortality data for the MITT population.

Table 6 : Outcomes & Mortality in Candidemia and other Candida Infections

	ERAXIS	Fluconazole	Between group differencea ( 95% CI)
No. of MITT patients	127	118
Favorable Outcomes (MITT) At End Of IV Therapy
All MITT patients
Candidemia	88/116 (75.9%)	63/103 (61.2%)	14.7 (2.5, 26.9)
Neutropenic	½	2/4	-
Non neutropenic	87/114 (76.3%)	61/99 (61.6%)	-
Multiple sites
Peritoneal fluid/ intra-abdominal abscess	4/6	5/6	-
Blood/peritoneum (intra-abdominal abscess)	2/2	0/2	-
Blood /bile	-	1/1	-
Blood/renal	-	1/1	-
Pancreas	-	0/3	-
Pelvic abscess	-	½	-
Pleural fluid	1/1	-	-
Blood/ pleural fluid	0/1	-	-
Blood/left thigh lesion biopsy	1/1	-	-
Total	8/11 (72.7%)	8/15 (53.3%)	-
Mortality
Overall study mortality	29/127 (22.8 %)	37/118 (31.4%)	-
Mortality during study therapy	10/127 (7.9%)	17/118 (14.4%)	-
Mortality attributed to Candida	2/127 (1.6%)	5/118 (4.2%)	-
a Calculated as ERAXIS minus fluconazole

Esophageal Candidiasis

ERAXIS was evaluated in a double-blind, double-dummy, randomized Phase 3 study. Three hundred patients received ERAXIS (100 mg loading dose IV on Day 1 followed by 50 mg/day IV) and 301 received oral fluconazole (200 mg loading dose on Day 1 followed by 100 mg/day).  Treatment duration was 7 days beyond resolution of symptoms for a minimum of 14 and a 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 this study, of 280 patients tested, 237 (84.6%) tested HIV positive. In both groups the median time to resolution of symptoms was 5 days and the median duration of therapy was 14 days.

The primary endpoint was 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 a clinical outcome other than 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 0 on a 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 7).  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 7).

Table 7 : Endoscopy Results in Patients with Esophageal Candidiasis (Clinically Evaluable Population)

Endoscopic Response at End of Therapy
Response	ERAXIS N= 231	Fluconazole N= 236	Treatment Differencea	95% CI
Endoscopic Success n, (%)	225 (97.4)	233 (98.7)	-1.3%	-3.8%, 1.2%
Cure	204 (88.3)	221 (93.6)
Improvement	21 (9.1)	12 (5.1)
Failure n, (%)	6 (2.6)	3 (1.3)
ENDOSCOPIC RELAPSE RATES AT FOLLOW-UP, 2 WEEKS POST-TREATMENT
	ERAXIS	Fluconazole	Treatment Differencea	95% CI
Endoscopic Relapse, n/N (%)	120/225 (53.3%)	45/233 (19.3%)	34.0%	25.8%, 42.3%
a Calculated as ERAXIS minus fluconazole

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.

Animal Pharmacology And Toxicology

In 3 month studies, liver toxicity, including single cell hepatocellular necrosis, hepatocellular hypertrophy and increased liver weights were observed in monkeys and rats at doses equivalent to 5-6 times human exposure. For both species, hepatocellular hypertrophy was still noted one month after the end of dosing.

Last updated on RxList: 6/24/2009

No information provided. Please refer to the PRECAUTIONS section.

Last updated on RxList: 6/24/2009

IMPORTANT NOTE: This is a summary and does not contain all possible information about this product. For complete information about this product or your specific health needs, ask your health care professional. Always seek the advice of your health care professional if you have any questions about this product or your medical condition. This information is not intended as individual medical advice and does not substitute for the knowledge and judgment of your health care professional. This information does not contain any assurances that this product is safe, effective, or appropriate for you.

ANIDULAFUNGIN - INJECTION

(a-NID-you-la-fun-gin)

COMMON BRAND NAME(S): Eraxis

USES: This medication is used to treat certain fungal infections caused by the Candida fungus (e.g., candidemia, esophageal candidiasis). It works by stopping the growth of fungus.

HOW TO USE: This medication is given into a vein by a health care professional. Follow all instructions for proper mixing and dilution with the correct IV fluid (5 percent dextrose injection or 0.9 percent sodium chloride injection). Before using this product, check it visually for particles or discoloration. If either is present, do not use the liquid. If you have questions about the use of this medication, consult the pharmacist.

This medication is usually given once daily. Do not give with other medications or minerals. The rate of infusion should not be greater than 1.1 milligrams per minute.

Dosage and length of treatment is based on your medical condition and response to therapy. It is important to continue this medication for the full course of treatment, even if symptoms disappear after a few days. Stopping the medication too early may result in a return of the infection.

Inform your doctor if your condition persists or worsens.

SIDE EFFECTS: Flushing, dizziness, diarrhea, or headache may occur. If any of these effects persist or worsen, tell your doctor or pharmacist promptly.

Remember that your doctor has prescribed this medication because he or she has judged that the benefit to you is greater than the risk of side effects. Many people using this medication do not have serious side effects.

Tell your doctor immediately if any of these unlikely but serious side effects occur: swelling/pain at injection site, shortness of breath, dark urine, severe stomach/abdominal pain, yellowing eyes/skin, persistent nausea/vomiting, muscle weakness/spasm.

Tell your doctor immediately if any of these rare but very serious side effects occur: vision changes, pain/redness/swelling of arms or legs, new signs of infection (e.g., fever, persistent sore throat), easy bruising/bleeding, fast/slow/irregular heartbeat, seizures, increased urination/thirst, mental/mood changes.

A very serious allergic reaction to this drug is rare. However, seek immediate medical attention if you notice any symptoms of a serious allergic reaction, including: rash, itching, swelling, severe dizziness, trouble breathing.

This is not a complete list of possible side effects. If you notice other effects not listed above, contact your doctor or pharmacist.

Contact your doctor for medical advice about side effects. The following numbers do not provide medical advice, but in the US you may report side effects to the Food and Drug Administration (FDA) at 1-800-FDA-1088. In Canada, you may call Health Canada at 1-866-234-2345.

PRECAUTIONS: Before receiving anidulafungin, tell your doctor or pharmacist if you are allergic to it; or to other echinocandins (e.g., caspofungin); or if you have any other allergies.

Before using this medication, tell your doctor or pharmacist your medical history, especially of: liver disease.

During pregnancy, this medication should be used only when clearly needed. Discuss the risks and benefits with your doctor.

It is not known if this medication passes into breast milk. Consult your doctor before breast-feeding.

DRUG INTERACTIONS: Your doctor or pharmacist may already be aware of any possible drug interactions and may be monitoring you for them. Do not start, stop, or change the dosage of any medicine before checking with your doctor or pharmacist first.

Before using this medication, tell your doctor or pharmacist of all prescription and nonprescription/herbal products you may use.

Keep a list of all your medications with you, and share the list with your doctor and pharmacist.

OVERDOSE: If overdose is suspected, contact your local poison control center or emergency room immediately. US residents can call the US National Poison Hotline at 1-800-222-1222. Canada residents can call a provincial poison control center.

NOTES: Laboratory and/or medical tests (e.g., liver function tests) should be performed periodically to monitor your progress or check for side effects. Consult your doctor for more details.

MISSED DOSE: It is important not to miss any doses of this medication and to use each dose as scheduled. If you miss a dose, contact your doctor or pharmacist immediately to establish a new dosing schedule.

STORAGE: Store at room temperature at 77 degrees F (25 degrees C). Do not freeze. Brief storage between 59-86 degrees F (15-30 degrees C) is permitted. The mixed vial must be further diluted and given within 24 hours. Keep all medicines away from children and pets.

Do not flush medications down the toilet or pour them into a drain unless instructed to do so. Properly discard this product when it is expired or no longer needed. Consult your pharmacist or local waste disposal company for more details about how to safely discard your product.

Information last revised July 2008 Copyright(c) 2008 First DataBank, Inc.