Xtandi enzalutamide 80 mg Tablet, 60-count — NDC 0469-0725-60 (Billing 00469-0725-60)

12 CLINICAL PHARMACOLOGY

12.1Mechanism of Action Enzalutamide is an androgen receptor inhibitor that acts on different steps in the androgen receptor signaling pathway. Enzalutamide has been shown to competitively inhibit androgen binding to androgen receptors; and consequently, inhibits nuclear translocation of androgen receptors and their interaction with DNA. A major metabolite, N‑desmethyl enzalutamide, exhibited similar in vitro activity to enzalutamide.

Enzalutamide decreased proliferation and induced cell death of prostate cancer cells in vitro , and decreased tumor volume in a mouse prostate cancer xenograft model.

12.2Pharmacodynamics Once daily dosing of 160 mg enzalutamide in addition to ADT reduced PSA levels to undetectable levels (< 0.2 ng/mL) in 68% of patients with mCSPC (ARCHES). Based on the efficacy results of AFFIRM after once daily dosing of 160 mg enzalutamide, no exposure‑response relationship for the efficacy endpoint of overall survival could be identified. In addition, there was no clinically meaningful exposure-response relationship for adverse effects (e.g. fatigue, flushing, headache, or hypertension) within the limited exposure range for 160 mg/day.

Cardiac Electrophysiology At the recommended dosage, XTANDI does not cause large mean increases (i.e., > 20 msec) in the QT interval.

12.3Pharmacokinetics Enzalutamide achieves steady-state by Day 28 and its AUC accumulates approximately 8.3-fold relative to a single dose. At steady-state, the mean (%CV) maximum concentration (C max ) for enzalutamide and N-desmethyl enzalutamide are 16.6 µg/mL (23%) and 12.7 µg/mL (30%), respectively, and the mean (%CV) minimum concentrations (C min ) are 11.4 µg/mL (26%) and 13.0 µg/mL (30%), respectively. Enzalutamide showed approximately dose proportional pharmacokinetics over the daily dose range of 30 (0.2 times the approved recommended dosage) to 360 mg (2.25 times the approved recommended dosage).

Absorption The median T max is 1 hour (0.5 to 3 hours) following a single 160 mg dose of capsules and 2 hours (0.5 to 6 hours) following a single 160 mg dose of tablets. Effect of Food There was no clinically meaningful effect on enzalutamide or N-desmethyl enzalutamide pharmacokinetics following the administration of XTANDI with a high‑fat meal (approximately 150 calories from protein, 250 calories from carbohydrates, and 500 to 600 calories from fat). Distribution The mean (%CV) volume of distribution after a single oral dose is 110 L (29%).

Enzalutamide is 97% to 98% bound to plasma proteins, primarily albumin. N-desmethyl enzalutamide is 95% bound to plasma proteins. Elimination Enzalutamide is primarily eliminated by hepatic metabolism.

The mean apparent clearance (CL/F) of enzalutamide after a single dose is

0.56L/h (0.33 to

1.02L/h). The mean terminal half-life (t 1/2 ) for enzalutamide after a single oral dose is 5.8 days (2.8 to 10.2 days). The mean terminal t 1/2 for N‑desmethyl enzalutamide is approximately 7.8 to 8.6 days.

Metabolism Enzalutamide is metabolized by CYP2C8 and CYP3A4. CYP2C8 is primarily responsible for the formation of the active metabolite (N-desmethyl enzalutamide). Carboxylesterase 1 metabolizes N-desmethyl enzalutamide and enzalutamide to the inactive carboxylic acid metabolite.

Specific Populations No clinically meaningful differences in the pharmacokinetics of enzalutamide were observed based on age (41 to 92 years), race (White, Chinese, and Japanese), body weight (46 kg to 163 kg), mild to moderate renal impairment (CLcr ≥ 30 mL/min) and hepatic impairment (Child-Pugh A, B, and C). Severe renal impairment and end stage renal disease (CLcr < 30 mL/min) have not been studied. Drug Interaction Studies Clinical Studies Effect of CYP2C8 Inhibitors on XTANDI : The coadministration of XTANDI 160 mg with gemfibrozil (strong CYP2C8 inhibitor) increased the AUC of enzalutamide plus N-desmethyl enzalutamide by 2.2-fold with minimal effect on C max .

Effect of CYP3A4 and CYP2C8 Inducers on… [Excerpted — this section continues on DailyMed.]

12.1Mechanism of Action Enzalutamide is an androgen receptor inhibitor that acts on different steps in the androgen receptor signaling pathway. Enzalutamide has been shown to competitively inhibit androgen binding to androgen receptors; and consequently, inhibits nuclear translocation of androgen receptors and their interaction with DNA. A major metabolite, N‑desmethyl enzalutamide, exhibited similar in vitro activity to enzalutamide.

Enzalutamide decreased proliferation and induced cell death of prostate cancer cells in vitro , and decreased tumor volume in a mouse prostate cancer xenograft model.

12.3Pharmacokinetics Enzalutamide achieves steady-state by Day 28 and its AUC accumulates approximately 8.3-fold relative to a single dose. At steady-state, the mean (%CV) maximum concentration (C max ) for enzalutamide and N-desmethyl enzalutamide are 16.6 µg/mL (23%) and 12.7 µg/mL (30%), respectively, and the mean (%CV) minimum concentrations (C min ) are 11.4 µg/mL (26%) and 13.0 µg/mL (30%), respectively. Enzalutamide showed approximately dose proportional pharmacokinetics over the daily dose range of 30 (0.2 times the approved recommended dosage) to 360 mg (2.25 times the approved recommended dosage).

Absorption The median T max is 1 hour (0.5 to 3 hours) following a single 160 mg dose of capsules and 2 hours (0.5 to 6 hours) following a single 160 mg dose of tablets. Effect of Food There was no clinically meaningful effect on enzalutamide or N-desmethyl enzalutamide pharmacokinetics following the administration of XTANDI with a high‑fat meal (approximately 150 calories from protein, 250 calories from carbohydrates, and 500 to 600 calories from fat). Distribution The mean (%CV) volume of distribution after a single oral dose is 110 L (29%).

Enzalutamide is 97% to 98% bound to plasma proteins, primarily albumin. N-desmethyl enzalutamide is 95% bound to plasma proteins. Elimination Enzalutamide is primarily eliminated by hepatic metabolism.

The mean apparent clearance (CL/F) of enzalutamide after a single dose is

0.56L/h (0.33 to

1.02L/h). The mean terminal half-life (t 1/2 ) for enzalutamide after a single oral dose is 5.8 days (2.8 to 10.2 days). The mean terminal t 1/2 for N‑desmethyl enzalutamide is approximately 7.8 to 8.6 days.

Metabolism Enzalutamide is metabolized by CYP2C8 and CYP3A4. CYP2C8 is primarily responsible for the formation of the active metabolite (N-desmethyl enzalutamide). Carboxylesterase 1 metabolizes N-desmethyl enzalutamide and enzalutamide to the inactive carboxylic acid metabolite.

Specific Populations No clinically meaningful differences in the pharmacokinetics of enzalutamide were observed based on age (41 to 92 years), race (White, Chinese, and Japanese), body weight (46 kg to 163 kg), mild to moderate renal impairment (CLcr ≥ 30 mL/min) and hepatic impairment (Child-Pugh A, B, and C). Severe renal impairment and end stage renal disease (CLcr < 30 mL/min) have not been studied. Drug Interaction Studies Clinical Studies Effect of CYP2C8 Inhibitors on XTANDI : The coadministration of XTANDI 160 mg with gemfibrozil (strong CYP2C8 inhibitor) increased the AUC of enzalutamide plus N-desmethyl enzalutamide by 2.2-fold with minimal effect on C max .

Effect of CYP3A4 and CYP2C8 Inducers on XTANDI : The coadministration of XTANDI 160 mg after multiple oral doses of rifampin (strong CYP3A4 and moderate CYP2C8 inducer) decreased the AUC of enzalutamide plus N-desmethyl enzalutamide by 37% with no effect on C max . Effect of CYP3A4 Inhibitors on XTANDI : The coadministration of XTANDI 160 mg after multiple oral doses of itraconazole (strong CYP3A4 inhibitor) increased the AUC of enzalutamide plus N-desmethyl enzalutamide by 1.3-fold with no effect on C max . Effect of XTANDI on Other Drugs: The coadministration of XTANDI 160 mg orally once daily with midazolam (a sensitive CYP3A4 substrate) decreased midazolam AUC by 86% and C max by 77%.

Coadministration of XTANDI 160 mg orally once daily with warfarin (a sensitive CYP2C9 substrate) decreased S‑warfarin AUC by 56% and C max by 17%. Coadministration of XTANDI 160 mg orally once daily with omeprazole (a sensitive CYP2C19 substrate) decreased omeprazole AUC by 72% and C max by 62%. Coadministration of XTANDI 160 mg orally once daily with digoxin (a P-glycoprotein substrate) increased digoxin AUC by 33% and C max by 17%.

No clinically meaningful changes in exposure of pioglitazone (a sensitive CYP2C8 substrate), caffeine (a sensitive CYP1A2 substrate), dextromethorphan (a sensitive CYP2D6 substrate), or rosuvastatin (a BCRP substrate) were observed follo… [Excerpted — this section continues on DailyMed.]

12.2Pharmacodynamics Once daily dosing of 160 mg enzalutamide in addition to ADT reduced PSA levels to undetectable levels (< 0.2 ng/mL) in 68% of patients with mCSPC (ARCHES). Based on the efficacy results of AFFIRM after once daily dosing of 160 mg enzalutamide, no exposure‑response relationship for the efficacy endpoint of overall survival could be identified. In addition, there was no clinically meaningful exposure-response relationship for adverse effects (e.g. fatigue, flushing, headache, or hypertension) within the limited exposure range for 160 mg/day.

Cardiac Electrophysiology At the recommended dosage, XTANDI does not cause large mean increases (i.e., > 20 msec) in the QT interval.

14 CLINICAL STUDIES The efficacy of XTANDI in patients with CRPC (N = 4692), mCSPC (N = 1150), or nmCSPC with high‑risk BCR (N = 1068) was demonstrated in six randomized, multicenter clinical trials. Patients received concomitant GnRH therapy or had prior bilateral orchiectomy, unless otherwise indicated. AFFIRM (NCT00974311): XTANDI versus Placebo in Metastatic CRPC Following Chemotherapy In AFFIRM, a total of 1199 patients who had received prior docetaxel-based chemotherapy were randomized 2:1 to receive either XTANDI orally at a dose of 160 mg once daily (N = 800) or placebo orally once daily (N = 399).

Study treatment continued until disease progression (evidence of radiographic progression, a skeletal-related event, or clinical progression), initiation of new systemic antineoplastic treatment, unacceptable toxicity, or withdrawal. Patients with a previous history of seizure, taking medicines known to decrease the seizure threshold, or with other risk factors for seizure were not eligible [see Warnings and Precautions ( 5.1 )] . The following patient demographics and baseline disease characteristics were balanced between the treatment arms.

The median age was 69 years (range 41-92) and the racial distribution was 92.7% White, 3.9% Black, 1.1% Asian, and 2.1% Other. Ninety-two percent of patients had an ECOG performance status score of 0-1 and 28% had a mean Brief Pain Inventory score of ≥ 4. Ninety-one percent of patients had metastases in bone and 23% had visceral involvement in the lung and/or liver.

Fifty-nine percent of patients had radiographic evidence of disease progression and 41% had PSA-only progression on study entry. All patients had received prior docetaxel-based therapy and 24% had received two cytotoxic chemotherapy regimens. During the trial, 48% of patients on the XTANDI arm and 46% of patients on the placebo arm received glucocorticoids.

A statistically significant improvement in overall survival was demonstrated at the pre-specified interim analysis at the time of 520 deaths in patients on the XTANDI arm compared to patients on the placebo arm ( Table 9 and Figure 1 ). Table 9. Overall Survival of Patients Treated with Either XTANDI or Placebo in AFFIRM NR = Not reached.

XTANDI (N = 800) Placebo (N = 399) Number of Deaths (%) 308 (38.5) 212 (53.1) Median Survival, months (95% CI) 18.4 (17.3, NR) 13.6 (11.3, 15.8) P-value P-value is derived from a log-rank test stratified by baseline ECOG performance status score (0-1 vs. 2) and mean baseline pain score (BPI‑SF score < 4 vs. ≥ 4). p < 0.0001 Hazard Ratio (95% CI) Hazard Ratio is derived from a stratified proportional hazards model. Hazard Ratio < 1 favors XTANDI.

0.63(0.53, 0.75) Figure 1. Kaplan-Meier Curves of Overall Survival in AFFIRM PREVAIL (NCT01212991): XTANDI versus Placebo in Chemotherapy-naïve Metastatic CRPC In PREVAIL, 1717 chemotherapy-naïve patients were randomized 1:1 to receive either XTANDI orally at a dose of 160 mg once daily (N = 872) or placebo orally once daily (N = 845). Patients with visceral metastases, patients with a history of mild to moderate heart failure (NYHA class I or II), and patients taking medications associated with lowering the seizure threshold were allowed.

Patients with a previous history of seizure or a condition that might predispose to seizure and patients with moderate or severe pain from prostate cancer were excluded. Study treatment continued until disease progression (evidence of radiographic progression, a skeletal-related event, or clinical progression) and the initiation of a cytotoxic chemotherapy or an investigational agent, unacceptable toxicity, or withdrawal. Overall survival and radiographic progression-free survival (rPFS) were assessed.

Radiographic progression was assessed with the use of sequential imaging and was defined by bone scan identification of 2 or more new bone lesions with confirmation (Prostate Cancer Clinical Trials Working Group 2 criteria) and/or Response Evaluation Criteria in… [Excerpted — this section continues on DailyMed.]

13 NONCLINICAL TOXICOLOGY

13.1Carcinogenesis, Mutagenesis, Impairment of Fertility A two-year carcinogenicity study was conducted in male and female rats at oral enzalutamide doses of 10, 30, and 100 mg/kg/day. Enzalutamide increased the incidence of benign Leydig cell tumors in the testes at all dose levels tested (≥ 0.3 times the human exposure based on AUC) and combined incidence of urothelial papilloma and carcinoma in the urinary bladder in male rats at 100 mg/kg/day (1.4 times the human exposure based on AUC). The findings in the testes are considered to be related to the pharmacological activity of enzalutamide.

Rats are regarded as more sensitive than humans to developing interstitial cell tumors in the testes. Administration of enzalutamide to male and female rasH2 transgenic mice by oral gavage daily for 26 weeks did not result in increased incidence of neoplasms at doses up to 20 mg/kg/day. Enzalutamide did not induce mutations in the bacterial reverse mutation (Ames) assay and was not genotoxic in either the in vitro mouse lymphoma thymidine kinase (Tk) gene mutation assay or the in vivo mouse micronucleus assay.

Based on nonclinical findings in repeat-dose toxicology studies, which were consistent with the pharmacological activity of enzalutamide, male fertility may be impaired by treatment with XTANDI. In a 26-week study in rats, atrophy of the prostate and seminal vesicles was observed at ≥ 30 mg/kg/day (equal to the human exposure based on AUC). In 4-, 13-, and 39-week studies in dogs, hypospermatogenesis and atrophy of the prostate and epididymides were observed at ≥ 4 mg/kg/day (0.3 times the human exposure based on AUC).