ERAXIS Solution for injection Ref.[10806] Active ingredients: Anidulafungin

General Pharmacokinetic Characteristics

The pharmacokinetics of anidulafungin following intravenous (IV) administration of ERAXIS have been characterized in healthy subjects, special populations and patients. Systemic exposures of anidulafungin are dose-proportional and have low inter-subject variability (coefficient of variation <25%) as shown in Table 5. The steady state was achieved on the first day after a loading dose (twice the daily maintenance dose) and the estimated plasma accumulation factor at steady state is approximately 2.

Table 5. Mean (%CV) Steady State Pharmacokinetic Parameters of Anidulafungin Following IV Administration of ERAXIS Once Daily for 10 Days in Healthy Adult Subjects:

C_max,ss = the steady state peak concentration
AUC_ss = the steady state area under concentration vs. time curve
CL = clearance
t_1/2 = the terminal elimination half-life
^* LD/MD: loading dose/maintenance dose once daily
Parameters were obtained from separate studies
^† Parameters were obtained from separate studies
^‡ Data were collected on Day 7
^§ Safety and efficacy of these doses has not been established
^¶ See OVERDOSAGE

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.

Specific Populations

Patients with fungal infections

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

The pharmacokinetics of anidulafungin in patients with fungal infections are similar to those observed in healthy subjects. The pharmacokinetic parameters of anidulafungin estimated using population pharmacokinetic modeling following IV administration of a maintenance dose of 50 mg/day or 100 mg/day (following a loading dose) of ERAXIS are presented in Table 6.

Table 6. Mean (%CV) Steady State Pharmacokinetic Parameters of Anidulafungin Following IV Administration of ERAXIS in Patients with Fungal Infections Estimated Using Population Pharmacokinetic Modeling:

^* All the parameters were estimated by population modeling using a twocompartment model with first order elimination; AUC_ss, C_max,ss and C_min,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.
^‡ t_1/2,β is the predominant elimination half-life that characterizes the majority of the concentration-time profile.

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

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 [see Use in Specific Populations (8.6)].

Renal Insufficiency

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 [see Use in Specific Populations (8.7)].

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 C_max and AUC_ss 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 7).

Table 7. Mean (%CV) Steady State Pharmacokinetic Parameters of Anidulafungin Following IV Administration of ERAXIS Once Daily in Pediatric Patients:

^* Data were collected on Day 5
^† LD/MD: loading dose/daily maintenance dose

The pharmacokinetics of anidulafungin were also investigated in 66 pediatric patients (1 month to <18 years) with candidemia/invasive candidiasis (ICC) in a prospective, open-label, non-comparative pediatric study following administration of ERAXIS of 3 mg/kg loading dose on Day 1 and followed by 1.5 mg/kg once daily maintenance dose [see Clinical Studies (14.1)]. Based on population pharmacokinetic analysis of combined data from adult and pediatric patients with ICC, the mean steady state exposure parameters (AUC_0–24,,ss C_min,,ss and C_max,ss) across age groups in the overall pediatric patients (Table 8) were comparable to those in adults receiving 200 mg loading dose and 100 mg once daily maintenance dose.

Table 8. Mean (%CV) Steady State Pharmacokinetic Parameters of Anidulafungin Following IV Administration of ERAXIS in Pediatric Patients with Candidemia/Invasive Candidiasis Estimated Using Population Pharmacokinetic Modeling:

^* LD/MD: loading dose on Day 1/once daily maintenance dose.

Drug Interactions

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) in clinically relevant concentrations. No clinically relevant drug-drug interactions were observed with drugs likely to be co-administered with anidulafungin.

Cyclosporine (CYP3A4 substrate)

In 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 C_max 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 [see Drug Interactions (7.1)].

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 C_max and AUC of anidulafungin and voriconazole were not significantly altered by co-administration [see Drug Interactions (7.2)].

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 C_max and AUC of anidulafungin and tacrolimus were not significantly altered by co-administration [see Drug Interactions (7.3)].

Rifampin (potent CYP450 inducer)

The pharmacokinetics of anidulafungin were examined in 27 patients that were co-administered anidulafungin and rifampin. The population pharmacokinetic analysis showed that when compared to data from patients that did not receive rifampin, the pharmacokinetics of anidulafungin were not significantly altered by co-administration with rifampin [see Drug Interactions (7.4)].

Amphotericin B liposome for injection

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 [see Drug Interactions (7.5)].

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.

Resistance

Echinocandin resistance is due to point mutations within the genes (FKS1 and FKS2) encoding for subunits in the glucan synthase enzyme complex. There have been reports of Candida isolates with reduced susceptibility to anidulafungin, suggesting a potential for development of drug resistance. The clinical significance of this observation is not fully understood.

Antimicrobial Activity

Anidulafungin has been shown to be active against most isolates of the following microorganisms both in vitro and in clinical infections:

Candida albicans
Candida glabrata
Candida parapsilosis
Candida tropicalis

The following in vitro data are available, but their clinical significance is unknown. At least 90 percent of the following fungi exhibit an in vitro minimum inhibitory concentration (MIC) less than or equal to the susceptible breakpoint for anidulafungin against isolates of the following Candida species. However, the effectiveness of anidulafungin in treating clinical infections due to these fungi has not been established in adequate and well-controlled clinical trials:

Candida guilliermondii
Candida krusei

Susceptibility Testing

For specific information regarding susceptibility test interpretive criteria and associated test methods and quality control standards recognized by FDA for this drug, please see: https://www.fda.gov/STIC.

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).

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.

14.1 Candidemia and Other Candida Infections (Intra-abdominal Abscess and Peritonitis)

Adults Candidemia and Other Candida Infections (Intra-abdominal Abscess and Peritonitis) Trial

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 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 in the intent-to-treat (ITT) population were randomized and received at least one dose of study medication. In ERAXIS-treated patients, the age range was 16–89 years, the gender distribution was 50% male and 50% female, and the race distribution was 71% White, 20% Black/African American, 7% Hispanic, 2% other races. The median duration of IV therapy was 14 and 11 days in the ERAXIS and fluconazole arms, respectively. For those who received oral fluconazole, the median duration of oral therapy was 7 days for the ERAXIS arm and 5 days for the fluconazole arm.

Patient disposition is presented in Table 9.

Table 9. Patient Disposition and Reasons for Discontinuation in Candidemia and other Candida Infections Study:

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 (62%), followed by C. glabrata (20%), C. parapsilosis (12%) and C. tropicalis (11%). The majority (97%) of patients were non-neutropenic (ANC >500) and 81% had APACHE II scores less than or equal to 20.

Global success rates in patients with candidemia and other Candida infections are summarized in Table 10.

Table 10. Efficacy Analysis: Global Success in patients with Candidemia and other Candida Infections (MITT Population):

^* Calculated as ERAXIS minus fluconazole
^† 33 patients in each study arm (26% ERAXIS and 29% fluconazoletreated) switched to oral fluconazole after the end of IV therapy.
^‡ 98.3% confidence intervals, adjusted post hoc for multiple comparisons of secondary time points

Table 11 presents global response by patients with candidemia or multiple sites of Candida infection and mortality data for the MITT population.

Table 11. Global Response and Mortality in Candidemia and other Candida Infections:

^* Calculated as ERAXIS minus fluconazole

Pediatric Candidemia/Invasive Candidiasis Trial

A prospective, open-label, non-comparative, multinational trial (National Clinical Trial (NCT) number 00761267) assessed the safety and efficacy of ERAXIS in 68 pediatric patients aged 1 month to <18 years with candidemia/invasive candidiasis. Patients were stratified by age (1 month to <2 years, 2 to <5 years, and 5 to <18 years) and received once daily intravenous ERAXIS (3 mg/kg loading dose on Day 1, and 1.5 mg/kg daily maintenance dose thereafter) followed by an optional switch to oral fluconazole (6–12 mg/kg/day, maximum 800 mg/day) up to Day 49. Patients were followed at 2 and 6 weeks after EOT.

Among 68 ERAXIS-treated patients, 64 had microbiologically confirmed Candida infection and were evaluated for efficacy in the modified intent-to-treat (MITT) population. Overall, 59 patients (92.2%) had Candida isolated from blood only. The most commonly isolated pathogens were Candida albicans (25 [39.1%] patients), followed by Candida parapsilosis (17 [26.6%] patients), and Candida tropicalis (9 [14.1%] patients). A successful global response was defined as having both successful clinical (cure or improvement) and microbiological (eradication or presumed eradication) response. The overall rates of successful global response in the MITT population are presented in Table 12 below.

Table 12. Summary of Successful Global Response by Age Group, MITT Population:

95% CI = exact 95% confidence interval for binomial proportions using Clopper-Pearson method; EOIVT = end of intravenous treatment; EOT = end of treatment; FU = follow-up; MITT = modified intent-to-treat; N = number of subjects in the population; n = number of subjects with responses.

14.2 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 ERAXIS-treated patients, the age range was 16–69 years, the gender distribution was 42% male and 58% female, and the race distribution was 15% White, 49% Black/African American, 15% Asian, 0.3 % Hispanic, 21% other races.

In this study, of 280 patients tested, 237 (84.6%) tested HIV positive. In both groups the median time to resolution of symptoms was 5 days and the median duration of therapy was 14 days.

Efficacy was assessed by endoscopic outcome at end of therapy (EOT). Patients were considered clinically evaluable if they received at least 10 days of therapy, had an EOT assessment with 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 13). The majority of these patients were endoscopic cures (grade=0). Two weeks after completing therapy, the ERAXIS group had significantly more endoscopically-documented relapses than the fluconazole group, 120/225 (53.3%) vs. 45/233 (19.3%), respectively (Table 13).

Table 13. Endoscopy Results in Patients with Esophageal Candidiasis (Clinically Evaluable Population):

^* 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.