Cresemba isavuconazonium sulfate 40 mg Capsule, 35-count — NDC 0469-2860-35 (Billing 00469-2860-35)

12 CLINICAL PHARMACOLOGY

12.1Mechanism of Action Isavuconazonium sulfate is the prodrug of isavuconazole, an azole antifungal [see Microbiology ( 12.4 )] .

12.2Pharmacodynamics Pharmacokinetic/Pharmacodynamic Relationship In patients treated with CRESEMBA for invasive aspergillosis in a controlled trial, there was no significant association between plasma AUC or plasma isavuconazole concentration and efficacy. Cardiac Electrophysiology The effect on QTc interval of multiple doses of CRESEMBA capsules was evaluated. CRESEMBA was administered as 2 capsules (equivalent to 200 mg isavuconazole) three times daily on days 1 and 2 followed by either 2 capsules or 6 capsules (equivalent to 600 mg isavuconazole) once daily for 13 days in a randomized, placebo- and active-controlled (moxifloxacin 400 mg single-dose), four-treatment-arm, parallel study in 160 healthy subjects.

Isavuconazole resulted in dose-related shortening of the QTc interval. For the 2-capsule dosing regimen, the least squares mean (LSM) difference from placebo was -13.1 msec at 2 hours postdose [90% CI: -17.1, -9.1 msec]. Increasing the dose to 6 capsules resulted in an LSM difference from placebo of -24.6 msec at 2 hours postdose [90% CI: -28.7, -20.4].

CRESEMBA was not evaluated in combination with other drugs that reduce the QTc interval, so the additive effects are not known.

12.3Pharmacokinetics General Pharmacokinetics In healthy subjects, the pharmacokinetics of isavuconazole following oral administration of CRESEMBA capsules at isavuconazole equivalent doses up to 600 mg per day (6 capsules) are dose proportional ( Table 6 ). Based on a population pharmacokinetics analysis of healthy subjects and patients, the mean plasma half-life of isavuconazole was 130 hours and the mean volume of distribution (V ss ) was approximately 450 L following intravenous administration. Table 6.

Steady State Pharmacokinetic Parameters of Isavuconazole Following Administration of 186 mg CRESEMBA Capsules Parameter CRESEMBA 186 mg 2 Capsules Each capsule contains the equivalent of 100 mg of isavuconazole. (n = 37) CRESEMBA 186 mg 6 Capsules (n = 32) C max (mg/L) Mean SD CV % 7.5 1.9 25.2 20.0 3.6 17.9 t max (hr) Median Range 3.0 2.0 – 4.0 4.0 2.0 –

4.0AUC (mg•hr/L) Mean SD CV % 121.4 35.8 29.5 352.8 72.0

20.4Following oral administration of CRESEMBA capsules at an isavuconazole equivalent dose of 200 mg in 66 fasted healthy male subjects, a single dose administration of two 186 mg CRESEMBA capsules and five 74.5 mg CRESEMBA capsules exhibited a mean (SD) C max and AUC of 3.3 (0.6) mg/L and 112.2 (30.3) mg·hr/L, respectively, and 3.3 (0.6) mg/L and 118.0 (33.1) mg·hr/L, respectively. Absorption After oral administration of CRESEMBA in healthy volunteers, the active moiety, isavuconazole, generally reaches maximum plasma concentrations (C max ) 2 hours to 3 hours after single and multiple dosing.

The absolute bioavailability of isavuconazole following oral administration of CRESEMBA is 98%. No significant concentrations of the prodrug or inactive cleavage product were seen in plasma after oral administration. Following intravenous administration of CRESEMBA, maximal plasma concentrations of the prodrug and inactive cleavage product were detectable during infusion and declined rapidly following the end of administration.

The prodrug was below the level of detection by 1.25 hours after the start of a one-hour infusion. The total exposure of the prodrug based on AUC was less than 1% that of isavuconazole. The inactive cleavage product was quantifiable in some subjects up to 8 hours after the start of infusion.

The total exposure of inactive cleavage product based on AUC was approximately 1.3% that of isavuconazole. CRESEMBA given orally as an intravenous solution administered via nasogastric (NG) tube provides systemic isavuconazole exposure that is similar to the oral capsule ( Table 7 ). Table 7.

Statistical Comparison of Plasma Pharmacokinetics of Isavuconazole Following Single… [Excerpted — this section continues on DailyMed.]

12.1Mechanism of Action Isavuconazonium sulfate is the prodrug of isavuconazole, an azole antifungal [see Microbiology ( 12.4 )] .

12.3Pharmacokinetics General Pharmacokinetics In healthy subjects, the pharmacokinetics of isavuconazole following oral administration of CRESEMBA capsules at isavuconazole equivalent doses up to 600 mg per day (6 capsules) are dose proportional ( Table 6 ). Based on a population pharmacokinetics analysis of healthy subjects and patients, the mean plasma half-life of isavuconazole was 130 hours and the mean volume of distribution (V ss ) was approximately 450 L following intravenous administration. Table 6.

Steady State Pharmacokinetic Parameters of Isavuconazole Following Administration of 186 mg CRESEMBA Capsules Parameter CRESEMBA 186 mg 2 Capsules Each capsule contains the equivalent of 100 mg of isavuconazole. (n = 37) CRESEMBA 186 mg 6 Capsules (n = 32) C max (mg/L) Mean SD CV % 7.5 1.9 25.2 20.0 3.6 17.9 t max (hr) Median Range 3.0 2.0 – 4.0 4.0 2.0 –

4.0AUC (mg•hr/L) Mean SD CV % 121.4 35.8 29.5 352.8 72.0

20.4Following oral administration of CRESEMBA capsules at an isavuconazole equivalent dose of 200 mg in 66 fasted healthy male subjects, a single dose administration of two 186 mg CRESEMBA capsules and five 74.5 mg CRESEMBA capsules exhibited a mean (SD) C max and AUC of 3.3 (0.6) mg/L and 112.2 (30.3) mg·hr/L, respectively, and 3.3 (0.6) mg/L and 118.0 (33.1) mg·hr/L, respectively. Absorption After oral administration of CRESEMBA in healthy volunteers, the active moiety, isavuconazole, generally reaches maximum plasma concentrations (C max ) 2 hours to 3 hours after single and multiple dosing.

The absolute bioavailability of isavuconazole following oral administration of CRESEMBA is 98%. No significant concentrations of the prodrug or inactive cleavage product were seen in plasma after oral administration. Following intravenous administration of CRESEMBA, maximal plasma concentrations of the prodrug and inactive cleavage product were detectable during infusion and declined rapidly following the end of administration.

The prodrug was below the level of detection by 1.25 hours after the start of a one-hour infusion. The total exposure of the prodrug based on AUC was less than 1% that of isavuconazole. The inactive cleavage product was quantifiable in some subjects up to 8 hours after the start of infusion.

The total exposure of inactive cleavage product based on AUC was approximately 1.3% that of isavuconazole. CRESEMBA given orally as an intravenous solution administered via nasogastric (NG) tube provides systemic isavuconazole exposure that is similar to the oral capsule ( Table 7 ). Table 7.

Statistical Comparison of Plasma Pharmacokinetics of Isavuconazole Following Single Oral Dose Administration of 2 Capsules of 186 mg (Equivalent to 200 mg Isavuconazole) and Single Intravenous Solution Dose Administration of 372 mg (Equivalent to 200 mg Isavuconazole) via Nasogastric (NG) Tube in Healthy Adult Subjects Under Fasted Conditions CRESEMBA IV Solution via NG Tube CRESEMBA Oral Capsules NG Tube/Oral Capsule Pharmacokinetic Parameter N Mean (%CV) N Mean (%CV) GMR (90% CI) C max (mg/L) 13 2.3 (23.6) 13 2.2 (26.7) 105.34 (89-124) AUC 0-72hr (mg·hr/L) 13 34.9 (22.1) 13 35.8 (24.6) 97.81 (93-103) AUC 0-∞ (mg·hr/L) 12 98.1 (44.5) 12 100.1 (46.8) 99.27 (93-106) GMR = Geometric least-squares mean ratio; CI = confidence interval Effect of Food Coadministration of CRESEMBA equivalent to isavuconazole 400 mg oral dose with a high-fat meal reduced isavuconazole C max by 9% and increased AUC by 9%.

CRESEMBA can be taken with or without food. Distribution Isavuconazole is extensively distributed with a mean steady state volume of distribution (V ss ) of approximately 450 L. Isavuconazole is highly protein bound (greater than 99%), predominantly to albumin.

Elimination Metabolism In in vitro studies isavuconazonium sulfate is rapidly hydrolyzed in blood to isavuconazole by esterases, predominantly by butylcholinesterase. Isavuconazole is a substrate of cytochrome P450 enzymes 3A4 and 3A5. Following single doses of [cyano 14 C] i… [Excerpted — this section continues on DailyMed.]

14 CLINICAL STUDIES

14.1Treatment of Invasive Aspergillosis Trial 1 was a randomized, double-blind, non-inferiority active controlled trial which evaluated the safety and efficacy of CRESEMBA versus voriconazole for primary treatment of invasive fungal disease caused by Aspergillus species or other filamentous fungi. Eligible patients had proven, probable, or possible invasive fungal infections per European Organisation for Research and Treatment of Cancer/Mycoses Study Group (EORTC/MSG) criteria 1 . Patients were stratified by history of allogeneic bone marrow transplant, uncontrolled malignancy at baseline, and by geographic region.

The mean age of patients was 51 years (range 17-87) and the majority were Caucasians (78%), male (60%), with fungal disease involving the lungs (95%). At least one Aspergillus species was identified in 30% of the subjects; A. fumigatus and A. flavus were the most common pathogens identified. There were few patients with other Aspergillus species: A. niger, A. sydowii , A. terreus, and A. westerdijkiae .

Baseline risk factors are presented in Table 9 . Table 9. Baseline Risk Factors in Intent-To-Treat (ITT ITT includes all randomized patients who received at least one dose of study drug. ) Population CRESEMBA N=258 n (%) Voriconazole N=258 n (%) Hematologic Malignancy 211 (82) 222 (86) Allogeneic Hematopoietic Stem Cell Transplant 54 (21) 51 (20) Neutropenia Neutropenia defined as less than 500 cells/mm 3 .

163 (63) 175 (68) Corticosteroid Use 48 (19) 39 (15) T-Cell Immunosuppressant Use 111 (43) 109 (42) Patients randomized to receive CRESEMBA treatment were administered a loading dose intravenously of 372 mg of isavuconazonium sulfate (equivalent to 200 mg of isavuconazole) every 8 hours for the first 48 hours. Beginning on Day 3, patients received intravenous or oral therapy of 372 mg of isavuconazonium sulfate (equivalent to 200 mg of isavuconazole) once daily. Patients randomized to receive voriconazole treatment were administered voriconazole intravenously with a loading dose of 6 mg/kg every 12 hours for the first 24 hours followed by 4 mg/kg intravenously every 12 hours for the following 24 hours.

Therapy could then be switched to an oral formulation of voriconazole at a dose of 200 mg every 12 hours. In this trial, the protocol-defined maximum treatment duration was 84 days. Mean treatment duration was 47 days for both treatment groups, of which 8 to 9 days was by an intravenous route of administration.

All-cause mortality through Day 42 in the overall population (ITT) was 18.6% in the CRESEMBA treatment group and 20.2% in the voriconazole treatment group for an adjusted treatment difference of -1.0% with 95% confidence interval of -8.0% to 5.9%. Similar results were seen in patients with proven or probable invasive aspergillosis confirmed by serology, culture or histology (see Table 10 ). Table 10.

All-Cause Mortality Through Day 42 CRESEMBA Voriconazole N All-cause Mortality n (%) N All-cause Mortality n (%) Difference Adjusted treatment difference (CRESEMBA-voriconazole) by Cochran-Mantel-Haenszel method stratified by the randomization factors. (95% CI)% ITT 258 48 (18.6) 258 52 (20.2) -1.0 (-8.0, 5.9) Proven or Probable Invasive Aspergillosis 123 23 (18.7) 108 24 (22.2) -2.7 (-13.6, 8.2) Overall success at End-of-Treatment (EOT) was assessed by a blinded, independent Data Review Committee (DRC) using pre-specified clinical, mycological, and radiological criteria.

In the subgroup of patients with proven or probable invasive aspergillosis confirmed by serology, culture or histology, overall success at EOT was seen in 35% of CRESEMBA-treated patients compared to 38.9% of voriconazole-treated patients (see Table 11 ). Table 11. Overall Response Success at End-of-Treatment CRESEMBA Voriconazole N Success n (%) N Success n (%) Difference Adjusted treatment difference (CRESEMBA-voriconazole) by Cochran-Mantel-Haenszel method stratified by the randomization factors.

(95% CI)% Proven or Proba… [Excerpted — this section continues on DailyMed.]

13 NONCLINICAL TOXICOLOGY

13.1Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis In a 2-year rat carcinogenicity study and a 2-year mouse carcinogenicity study, dose-related increases in hepatocellular adenomas and/or carcinomas were observed in male and female B6C3F1/Crl mice, and male, but not female Han Wistar rats at doses as low as 0.1 times the exposure seen in humans administered the maintenance dose. Hepatic hemangiomas were increased in female mice at 300 mg/kg, at an exposure similar to the maintenance dose. Hepatoblastoma were increased in male mice at 100 mg/kg, about 0.4 times the systemic exposures based on AUC comparisons.

Thyroid follicular cell adenomas were observed in male and female rats at doses as low as 60 mg/kg in male rats (about 0.2 times the human clinical maintenance dose). The relevance of the rat thyroid tumors to human carcinogenic risk remains unclear. A significant increase in the incidence of skin fibromas was seen in male rats at 300 mg/kg, exposures 0.8 times the human exposure at the human clinical maintenance dose.

Uterine adenocarcinomas were observed in female rats at 200 mg/kg, at systemic exposures similar to the human exposure at the human clinical maintenance dose. Mutagenesis No mutagenic or clastogenic effects were detected in the in vitro bacterial reverse mutation assay and the in vivo bone marrow micronucleus assay in rats. Impairment of Fertility Oral administration of isavuconazonium sulfate did not affect the fertility in male or female rats treated at doses up to 90 mg/kg/day (approximately 0.3 times the systemic exposure at the human clinical maintenance dose).