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Name:Eraxis
Manufacturer:Roerig
Category:Prescription Marketed Drugs


ERAXIS™ (anidulafungin) FOR INJECTION

ERAXIS - anidulafungin injection, powder, lyophilized, for solution 
Roerig

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ERAXIS™ (anidulafungin) FOR INJECTION

[INTRAVENOUS INFUSION, DILUTED WITH STERILE WATER FOR INJECTION] (not for IV Bolus Injection)

DESCRIPTION

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]-4-yl]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:

50 mg/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.

100 mg/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:

Chemical Structure

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).

CLINICAL PHARMACOLOGY

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
  Anidulafungin IV Dosing Regimen (LD/MD, mg)*
PK Parameter 70/35 ,§
(N = 6)
200/100
(N = 10)
260/130 §,
(N = 10)
Cmax, ss = the steady state peak concentration
AUCss = the steady state area under concentration vs. time curve
CL = clearance
t1/2 = the terminal elimination half-life
*
LD/MD: loading dose/maintenance dose once daily
Parameters were obtained from separate studies
Data were collected on Day 7
§
Safety and efficacy of these doses has not been established
See OVERDOSAGE
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)
t1/2 [h] 43.2 (17.7) 52.0 (11.7) 50.3 (9.7)

The clearance of anidulafungin is about 1 L/h and anidulafungin has a terminal elimination half-life of 40–50 hours.

Distribution

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

Metabolism

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

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

Excretion

In a single-dose clinical study, radiolabeled (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 Parameter * Anidulafungin IV Dosing Regimen (LD/MD, mg)
100/50 200/100
*
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.
LD/MD: loading dose/daily maintenance dose
t1/2, β is the predominant elimination half-life that characterizes the majority of the concentration-time profile.
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)
t1/2, β [h] 26.5 (28.5)

Gender

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

Geriatric

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

Race

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

HIV Status

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

Hepatic Insufficiency

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 Parameter *

Anidulafungin IV Dosing Regimen
(LD/MD, mg/kg)
1.5/0.75 3.0/1.5
*
Data were collected on Day 5
LD/MD: loading dose/daily maintenance dose
Age Group 2–11 yrs
(N = 6)
12–17 yrs
(N = 6)
2–11 yrs
(N = 6)
12–17 yrs
(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)

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 co-administration. 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 fluconazole-resistant C. albicans in an oropharyngeal/esophageal infection model in immunosuppressed rabbits.

Drug Resistance

There have been reports of Candida isolates with reduced susceptibility to anidulafungin, suggesting a potential for development of drug resistance. The clinical significance of this observation is unknown.

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

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 difference *(95% CI)
*
Calculated as ERAXIS minus fluconazole
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 1/2 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 - 1/2 -
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%) -

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 ‘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 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)
*
Calculated as ERAXIS minus fluconazole
Endoscopic Response at End of Therapy
Response ERAXIS
N= 231
Fluconazole
N= 236
Treatment Difference * 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 Difference * 95% CI
Endoscopic
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.

INDICATIONS AND USAGE

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.

CONTRAINDICATIONS

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

PRECAUTIONS

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 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.

Drug Interactions

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 Interaction 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 Interaction 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 Interaction Studies).

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 laboratory's historical control 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).

ADVERSE REACTIONS

General

Possible histamine-mediated symptoms have been reported with ERAXIS, including rash, urticaria, flushing, pruritus, bronchospasm, 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 * adverse events reported in ≥2.0% of subjects receiving ERAXIS or fluconazole therapy for candidemia/other Candida infections
ERAXIS
100 mg
N = 131
Fluconazole
400 mg
N = 125
N (%) N (%)
*
Treatment-related AEs are defined as those that are possibly or probably related to study treatment, as determined by the investigator.
Maintenance dose
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)

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 * adverse events reported in ≥1.0% of subjects receiving ERAXIS or fluconazole therapy for esophageal candidiasis
ERAXIS
50 mg
N = 300
Fluconazole
100 mg
N = 301
N (%) N (%)
*
Treatment-related AEs include those that are of possible, probable, or unknown relationship to study treatment, as determined by the investigator.
Maintenance dose
Not Otherwise Specified
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 NOS 2 (0.7) 4 (1.3)

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

OVERDOSAGE

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 × 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.

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.

DOSAGE AND ADMINISTRATION

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 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 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 sterile Water for Injection to provide a concentration of 3.33 mg/mL. The reconstituted solution can be stored in a refrigerator for up to one hour at 2°C – 8°C (36°F – 46°F) prior to dilution into the infusion solution. Do not freeze.

Reconstitution 100 mg/vial

Aseptically reconstitute each 100 mg vial with 30 mL of sterile Water for Injection to provide a concentration of 3.33 mg/mL. The reconstituted solution can be stored in a refrigerator for up to one hour at 2°C – 8°C (36°F – 46°F) prior to dilution into the infusion solution. Do not freeze.

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). See Table 10 for the dilution and infusion instructions for each dose.

Table 10. Dilution Requirements For ERAXIS Administration
Dose Number of Vials Required Total Reconstituted Volume Required Infusion Volume * Total Infusion Volume Rate of Infusion Minimum Duration of Infusion
*
Either 5% Dextrose Injection, USP or 0.9% Sodium Chloride Injection, USP (normal saline)
Infusion solution concentration is 0.77 mg/mL
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

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).

If the infusion solution is not used immediately, it should be stored in a refrigerator at 2°C – 8°C (36°F – 46°F). Do not freeze. The infusion solution should be administered within 24 hours of preparation.

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.

HOW SUPPLIED

ERAXIS (anidulafungin) for Injection is supplied in a single-use vial of sterile, lyophilized, preservative-free, powder. ERAXIS (anidulafungin) is available in the following packaging configuration:

Single Use Vial of ERAXIS 50 mg
NDC 0049-0114-28    One - 50 mg vial

Single Use Vial of ERAXIS 100 mg)
NDC 0049-0116-28    One - 100 mg vial

STORAGE

Unreconstituted vials

ERAXIS unreconstituted vials should be stored in a refrigerator at 2°C – 8°C (36°F – 46°F). Do not freeze.

Reconstituted solution

ERAXIS reconstituted solution can be stored in a refrigerator at 2°C – 8°C (36°F – 46°F) for up to one hour. Do not freeze.

Chemical and physical in-use stability of the reconstituted solution has been demonstrated for 1 hour at 5°C (41°F). .

Infusion solution

ERAXIS infusion solution can be stored in a refrigerator at 2°C – 8°C (36°F – 46°F ), but should be administered within 24 hours. Do not freeze.

Chemical and physical in-use stability of the infusion solution has been demonstrated for 24 hours at 5°C (41°F).

Rx only

Logo

LAB-0336-7.0
November 2010

PRINCIPAL DISPLAY PANEL - 50 mg vial label

1 Sterile Single-use Vial
Rx only

Eraxis®
(anidulafungin)
for Injection

50 mg/vial

For Intravenous Infusion Only

Pfizer

Distributed by:
Roerig
Division of Pfizer Inc, NY, NY 10017

PRINCIPAL DISPLAY PANEL - 50 mg vial label

PRINCIPAL DISPLAY PANEL - 50 mg Carton Label

NDC 0049-0114-28

Rx only

Unit Pack Contains:
1 Sterile Single-use Vial Eraxis® 50 mg

Eraxis®
(anidulafungin)
for Injection

50 mg/vial

For Intravenous Infusion Only

Store Vial in Refrigerator
at 2 - 8° C (36 - 46° F).
Do Not Freeze.
Reconstitute with Sterile Water
for Injection.

Pfizer

Distributed by:
Roerig
Division of Pfizer Inc, NY, NY 10017

PRINCIPAL DISPLAY PANEL - 50 mg Carton Label

PRINCIPAL DISPLAY PANELPANEL - 100 mg vial label

1 Sterile Single-use Vial
Rx only

Eraxis®
(anidulafungin)
for Injection

100 mg/vial

For Intravenous Infusion Only

Pfizer

Distributed by:
Roerig
Division of Pfizer Inc, NY, NY 10017

PRINCIPAL DISPLAY PANELPANEL - 100 mg vial label

PRINCIPAL DISPLAY PANEL - 100 mg Carton Label

NDC 0049-0116-28

Rx only

Unit Pack Contains:
1 Sterile Single-use Vial Eraxis® 100 mg

Eraxis®
(anidulafungin)
for Injection

100 mg/vial

For Intravenous Infusion Only

Store Vial in Refrigerator
at 2 - 8° C (36 - 46° F).
Do Not Freeze.
Reconstitute with Sterile Water
for Injection.

Pfizer

Distributed by:
Roerig
Division of Pfizer Inc, NY, NY 10017

PRINCIPAL DISPLAY PANEL - 100 mg Carton Label

ERAXIS 
anidulafungin injection, powder, lyophilized, for solution
Product Information
Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:0049-0114
Route of Administration INTRAVENOUS DEA Schedule     
Active Ingredient/Active Moiety
Ingredient Name Basis of Strength Strength
anidulafungin (anidulafungin) anidulafungin 50 mg  in 15 mL
Inactive Ingredients
Ingredient Name Strength
fructose 50 mg  in 15 mL
mannitol 250 mg  in 15 mL
polysorbate 80 125 mg  in 15 mL
tartaric acid 5.6 mg  in 15 mL
sodium hydroxide  
hydrochloric acid  
Product Characteristics
Color      Score     
Shape Size
Flavor Imprint Code
Contains     
Packaging
# Item Code Package Description Multilevel Packaging
1 NDC:0049-0114-28 15 mL in 1 VIAL, SINGLE-USE None

Marketing Information
Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
NDA NDA021632 02/17/2006

ERAXIS 
anidulafungin injection, powder, lyophilized, for solution
Product Information
Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:0049-0116
Route of Administration INTRAVENOUS DEA Schedule     
Active Ingredient/Active Moiety
Ingredient Name Basis of Strength Strength
anidulafungin (anidulafungin) anidulafungin 100 mg  in 30 mL
Inactive Ingredients
Ingredient Name Strength
fructose 100 mg  in 30 mL
mannitol 500 mg  in 30 mL
polysorbate 80 250 mg  in 30 mL
tartaric acid 11.2 mg  in 30 mL
sodium hydroxide  
hydrochloric acid  
Product Characteristics
Color      Score     
Shape Size
Flavor Imprint Code
Contains     
Packaging
# Item Code Package Description Multilevel Packaging
1 NDC:0049-0116-28 30 mL in 1 VIAL, SINGLE-USE None

Marketing Information
Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
NDA NDA021632 02/17/2006

Labeler - Roerig (829076996)
Establishment
Name Address ID/FEI Operations
Pharmacia and UpJohn 829076566 MANUFACTURE
Establishment
Name Address ID/FEI Operations
Ben Venue Laboratories 004327953 MANUFACTURE

Revised: 11/2010 Roerig



Source: http://dailymed.nlm.nih.gov
Reproduced with permission of U.S. National Library of Medicine


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