anidulafungin
Dosage Form: powder, lyophilized, for solution
Eraxis™ (anidulafungin) FOR INJECTION
[INTRAVENOUS INFUSION, DILUTED WITH STERILE WATER FOR INJECTION] (not for IV Bolus Injection)
Eraxis 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:
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).
Eraxis - 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.
| 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 | |||
| |||
| 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.
| PK Parameter * | Anidulafungin IV Dosing Regimen (LD/MD, mg) † | |
|---|---|---|
| 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) | |
| 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).
| PK Parameter * | Anidulafungin IV Dosing Regimen (LD/MD, mg/kg) † | |||
|---|---|---|---|---|
| 1.5/0.75 | 3.0/1.5 | |||
| ||||
| 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.
| 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.
| Timepoint | Eraxis (N=127) n (%) | Fluconazole (N=118) n (%) | Treatment Difference *, % (95% C.I.) |
|---|---|---|---|
| |||
| 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.
| Eraxis | Fluconazole | Between group difference *(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 | 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).
| |||||
| 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 for Eraxis
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.
| Eraxis 100 mg † N = 131 | Fluconazole 400 mg † N = 125 | |
|---|---|---|
| N (%) | 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) |
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).
| Eraxis 50 mg † N = 300 | Fluconazole 100 mg † N = 301 | |
|---|---|---|
| N (%) | N (%) | |
| ||
| Subjects with at least 1 treatment-related AE | 43 (14.3) | 50 (16.6) |
| Blood and lymphatic System | ||
| Neutropenia | 3 (1.0) | |
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