Zejula niraparib 300 mg Tablet, Film Coated, 30-count — NDC 0173-0915-13 (Billing 00173-0915-13)

12 CLINICAL PHARMACOLOGY

12.1Mechanism of Action Niraparib is an inhibitor of PARP enzymes, including PARP-1 and PARP-2, that play a role in DNA repair. In vitro studies have shown that niraparib-induced cytotoxicity may involve inhibition of PARP enzymatic activity and increased formation of PARP-DNA complexes resulting in DNA damage, apoptosis, and cell death. Increased niraparib‑induced cytotoxicity was observed in tumor cell lines with or without deficiencies in BRCA1/2 .

Niraparib decreased tumor growth in mouse xenograft models of human cancer cell lines with deficiencies in BRCA1/2 and in human patient-derived xenograft tumor models with homologous recombination deficiency (HRD) that had either mutated or wild-type BRCA1/2 .

12.2Pharmacodynamics The pharmacodynamic response of niraparib has not been characterized. Hypertension and Cardiovascular Effects Niraparib has the potential to cause effects on pulse rate and blood pressure in patients receiving the recommended dose, which may be related to pharmacological inhibition of the dopamine transporter, norepinephrine transporter, and serotonin transporter [see Nonclinical Toxicology ( 13.2 )] . In PRIMA, mean pulse rate and blood pressure increased over baseline in the niraparib arm relative to the placebo arm at most on-study assessments.

Mean greatest increases from baseline in pulse rate on treatment were 22.4 and 14.0 beats/min in the niraparib and placebo arms, respectively. Mean greatest increases from baseline in systolic blood pressure on treatment were 24.4 and 19.6 mmHg in the niraparib and placebo arms, respectively. Mean greatest increases from baseline in diastolic blood pressure on treatment were 15.9 and 13.9 mmHg in the niraparib and placebo arms, respectively.

In NOVA, mean pulse rate and blood pressure increased over baseline in the niraparib arm relative to the placebo arm at all on-study assessments. Mean greatest increases from baseline in pulse rate on treatment were 24.1 and 15.8 beats/min in the niraparib and placebo arms, respectively. Mean greatest increases from baseline in systolic blood pressure on treatment were 24.5 and 18.3 mmHg in the niraparib and placebo arms, respectively.

Mean greatest increases from baseline in diastolic blood pressure on treatment were 16.5 and 11.6 mmHg in the niraparib and placebo arms, respectively. Cardiac Electrophysiology At the approved maximum recommended dose, a mean increase in the QTc interval >20 ms was not observed.

12.3Pharmacokinetics Niraparib mean (±SD) maximum plasma concentration (C max ) is 603 (±343) ng/mL at the approved maximum recommended dose of 300 mg. Niraparib steady-state C max and AUC increased in a dose-proportional manner with daily doses ranging from 30 mg (0.15 times the approved minimum recommended dose) to 400 mg (1.3 times the approved maximum recommended dose). The accumulation of niraparib exposure is approximately 2-fold at the approved recommended doses.

Absorption The absolute bioavailability of niraparib is approximately 73%. Time to maximum plasma concentration (T max ) is reached within 5 hours. Food Effect: Niraparib C max increased by 11% and AUC by 28%, following administration with a high-fat meal (800 to 1,000 calories, 50% fat).

Distribution Niraparib is 83% bound to human plasma proteins. Niraparib mean (±SD) apparent (oral) volume of distribution (Vd/F) is 1,220 (±1,114) L. Elimination Niraparib apparent (oral) total clearance (CL/F) is 15.9 (±3.8) L/h and mean half-life (t 1/2 ) is 50 (±15) hours.

Metabolism: Niraparib is metabolized by carboxylesterases to form a major inactive metabolite M1, which subsequently undergoes glucuronidation. Excretion: Following administration of a single oral dose of radio-labeled niraparib 300 mg, 48% of the dose was recovered in urine (11% unchanged) and 39% in feces (19% unchanged). Specific Populations No clinically significant differences in the pharmacokinetics of niraparib were observed based on age (18 to 65 years), race… [Excerpted — this section continues on DailyMed.]

12.1Mechanism of Action Niraparib is an inhibitor of PARP enzymes, including PARP-1 and PARP-2, that play a role in DNA repair. In vitro studies have shown that niraparib-induced cytotoxicity may involve inhibition of PARP enzymatic activity and increased formation of PARP-DNA complexes resulting in DNA damage, apoptosis, and cell death. Increased niraparib‑induced cytotoxicity was observed in tumor cell lines with or without deficiencies in BRCA1/2 .

Niraparib decreased tumor growth in mouse xenograft models of human cancer cell lines with deficiencies in BRCA1/2 and in human patient-derived xenograft tumor models with homologous recombination deficiency (HRD) that had either mutated or wild-type BRCA1/2 .

12.3Pharmacokinetics Niraparib mean (±SD) maximum plasma concentration (C max ) is 603 (±343) ng/mL at the approved maximum recommended dose of 300 mg. Niraparib steady-state C max and AUC increased in a dose-proportional manner with daily doses ranging from 30 mg (0.15 times the approved minimum recommended dose) to 400 mg (1.3 times the approved maximum recommended dose). The accumulation of niraparib exposure is approximately 2-fold at the approved recommended doses.

Absorption The absolute bioavailability of niraparib is approximately 73%. Time to maximum plasma concentration (T max ) is reached within 5 hours. Food Effect: Niraparib C max increased by 11% and AUC by 28%, following administration with a high-fat meal (800 to 1,000 calories, 50% fat).

Distribution Niraparib is 83% bound to human plasma proteins. Niraparib mean (±SD) apparent (oral) volume of distribution (Vd/F) is 1,220 (±1,114) L. Elimination Niraparib apparent (oral) total clearance (CL/F) is 15.9 (±3.8) L/h and mean half-life (t 1/2 ) is 50 (±15) hours.

Metabolism: Niraparib is metabolized by carboxylesterases to form a major inactive metabolite M1, which subsequently undergoes glucuronidation. Excretion: Following administration of a single oral dose of radio-labeled niraparib 300 mg, 48% of the dose was recovered in urine (11% unchanged) and 39% in feces (19% unchanged). Specific Populations No clinically significant differences in the pharmacokinetics of niraparib were observed based on age (18 to 65 years), race/ethnicity, and mild to moderate renal impairment (CLcr 30 to 90 mL/min).

The effect of severe renal impairment (CLcr <30 mL/min) or end-stage renal disease undergoing hemodialysis on the pharmacokinetics of niraparib is unknown. Hepatic Impairment: Mild hepatic impairment (total bilirubin <1.5 x ULN and any AST level or bilirubin ≤ULN and AST >ULN) had no clinically significant effect on the pharmacokinetics of niraparib. Niraparib AUC increased 1.6-fold in patients with moderate hepatic impairment (total bilirubin ≥1.5 to 3 x ULN and any AST level) with no effect on niraparib C max or protein binding.

The effect of severe hepatic impairment (total bilirubin >3 x ULN and any AST level) on the pharmacokinetics of niraparib is unknown. Drug Interaction Studies In Vitro Studies: Cytochrome P450 ( CYP) Enzymes: Niraparib and M1 did not inhibit CYP1A, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A. Niraparib and M1 do not induce CYP3A.

Uridine 5'-Diphospho-Glucuronosyltransferases (UGTs): Niraparib did not inhibit UGT1A1, UGT1A4, UGT1A9, and UGT2B7. Transporters: Niraparib inhibits BCRP, MATE1, and MATE2K, but does not inhibit P-glycoprotein (P-gp), BSEP, or MRP2. M1 did not inhibit P‑gp, BCRP, BSEP, MRP2, MATE1 or MATE2K.

Niraparib and M1 did not inhibit OATP1B1, OATP1B3, OCT1, OAT1, OAT3, or OCT2. Niraparib is a substrate of P-gp and BCRP, but not of BSEP, MRP2, MATE1, MATE2K, OATP1B1, OATP1B3, OCT1, OAT1, OAT3, or OCT2. M1 is a substrate of MATE1 and MATE2K, but not of P-gp, BCRP, BSEP, MRP2, OATP1B1, OATP1B3, OCT1, OAT1, OAT3, or OCT2.

12.2Pharmacodynamics The pharmacodynamic response of niraparib has not been characterized. Hypertension and Cardiovascular Effects Niraparib has the potential to cause effects on pulse rate and blood pressure in patients receiving the recommended dose, which may be related to pharmacological inhibition of the dopamine transporter, norepinephrine transporter, and serotonin transporter [see Nonclinical Toxicology ( 13.2 )] . In PRIMA, mean pulse rate and blood pressure increased over baseline in the niraparib arm relative to the placebo arm at most on-study assessments.

Mean greatest increases from baseline in pulse rate on treatment were 22.4 and 14.0 beats/min in the niraparib and placebo arms, respectively. Mean greatest increases from baseline in systolic blood pressure on treatment were 24.4 and 19.6 mmHg in the niraparib and placebo arms, respectively. Mean greatest increases from baseline in diastolic blood pressure on treatment were 15.9 and 13.9 mmHg in the niraparib and placebo arms, respectively.

In NOVA, mean pulse rate and blood pressure increased over baseline in the niraparib arm relative to the placebo arm at all on-study assessments. Mean greatest increases from baseline in pulse rate on treatment were 24.1 and 15.8 beats/min in the niraparib and placebo arms, respectively. Mean greatest increases from baseline in systolic blood pressure on treatment were 24.5 and 18.3 mmHg in the niraparib and placebo arms, respectively.

Mean greatest increases from baseline in diastolic blood pressure on treatment were 16.5 and 11.6 mmHg in the niraparib and placebo arms, respectively. Cardiac Electrophysiology At the approved maximum recommended dose, a mean increase in the QTc interval >20 ms was not observed.

14 CLINICAL STUDIES

14.1First-Line Maintenance Treatment of HRD-Positive Advanced Ovarian Cancer PRIMA (NCT02655016) was a double-blind, placebo-controlled trial in which patients (N = 733) in complete or partial response to first-line platinum-based chemotherapy were randomized 2:1 to ZEJULA or matched placebo. Initially, the patients received a starting dosage of 300 mg once daily regardless of body weight or platelet count. The study was amended to include a starting dose of 200 mg for patients weighing <77 kg (<170 lbs) OR with a platelet count of <150,000/mcL or 300 mg for patients weighing ≥77 kg (≥170 lbs) AND who had a platelet count ≥150,000/mcL.

Patients were randomized post‑completion of first‑line platinum‑based chemotherapy plus surgery. Randomization was stratified by best response during the front‑line platinum regimen (complete response vs. partial response), neoadjuvant chemotherapy (NACT) (yes vs. no), and HRD status (positive vs. negative or not determined). HRD status was determined using Myriad MyChoice CDx assay.

HRD‑positive status included either tumor BRCA mutant (t BRCA m) or a genomic instability score (GIS) ≥42. The major efficacy outcome measure, progression-free survival (PFS), was determined by blinded independent central review (BICR) per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. In some cases, criteria other than RECIST, such as clinical signs and symptoms and increasing CA-125, were also applied.

Overall survival (OS) was an additional efficacy outcome measure. Efficacy was evaluated in 373 patients in the HRD-positive population. The median age was 58 years (range 32 to 83 years).

Eighty-seven percent of patients were White, 4.8% were Asian, 1.6% were Black or African American, 0.3% were Native Hawaiian or Other Pacific Islander, and 0.3% were American Indian or Alaska Native. Six percent of patients were Hispanic or Latino. Seventy-five percent of patients had an Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0 at trial baseline.

Approximately 47% of patients were enrolled in the U.S. or Canada. Sixty-four percent of patients had Stage III disease and 36% had Stage IV disease. Sixty-three percent of the patients received NACT.

Seventy-five percent of the patients had a complete response to the first-line platinum-based chemotherapy. Approximately 35% (n = 130) of patients received a starting dose of 200 or 300 mg depending on baseline body weight and platelet count. PRIMA demonstrated a statistically significant improvement in PFS for patients randomized to ZEJULA as compared with placebo in the HRD-positive population ( Table 10 and Figure 1 ).

Table 10. Efficacy Results – PRIMA HRD-Positive Population Progression-Free Survival (PFS) a HRD = Homologous Recombination Deficient; NE = Not Estimable. a Efficacy analysis was based on blinded independent central review. b Based on a stratified Cox proportional hazards model. c Based on a stratified log-rank test. ZEJULA (n = 247) Placebo (n = 126) PFS events, n (%) 81 (33) 73 (58) PFS median in months (95% CI) 21.9 (19.3, NE) 10.4 (8.1, 12.1) Hazard ratio b (95% CI) 0.43 (0.31, 0.59) P value c <0.0001 In an exploratory subgroup analysis of patients in the HRD-positive population who were administered a starting dose of ZEJULA or matched placebo based on baseline weight or platelet count (n = 130), the hazard ratio (HR) for PFS was 0.39 (95% CI: 0.22, 0.72).

Figure 1. PRIMA Progression-Free Survival – HRD-Positive Population HRD = Homologous Recombination Deficient. A final OS analysis was conducted in the HRD-positive population after 185 events were observed; the HR was 0.95 (95% CI: 0.71, 1.29) with a median OS of 71.9 months (95% CI: 55.5, NE) for patients treated with ZEJULA and 69.8 months (95% CI: 51.6, NE) for patients on placebo.

Figure 1

14.2Maintenance Treatment of Recurrent Germline BRCA -Mutated Ovarian Cancer NOVA (NCT01847274) was a double-blind, placebo-controlled trial in which patien… [Excerpted — this section continues on DailyMed.]

13 NONCLINICAL TOXICOLOGY

13.1Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenicity studies have not been conducted with niraparib. Niraparib was clastogenic in an in vitro mammalian chromosomal aberration assay and in an in vivo rat bone marrow micronucleus assay. This clastogenicity is consistent with genomic instability resulting from the primary pharmacology of niraparib and indicates potential for genotoxicity in humans.

Niraparib was not mutagenic in a bacterial reverse mutation assay (Ames) test. Fertility studies in animals have not been conducted with niraparib. In repeat-dose oral toxicity studies, niraparib was administered daily for up to 3 months’ duration in rats and dogs.

Reduced sperm, spermatids, and germ cells in epididymides and testes were observed at doses ≥10 mg/kg and ≥1.5 mg/kg in rats and dogs, respectively. These dose levels resulted in systemic exposures approximately 0.3 and 0.012 times, respectively, the human exposure (AUC 0-24h ) at the recommended dose of 300 mg daily. There was a trend toward reversibility of these findings 4 weeks after dosing was stopped.

13.2Animal Toxicology and/or Pharmacology In vitro, niraparib bound to DAT, NET, and SERT and inhibited uptake of norepinephrine and dopamine in cells with IC 50 values that were lower than the C min at steady-state in patients receiving the recommended dose. Niraparib has the potential to cause effects in patients related to inhibition of these transporters (e.g., cardiovascular, central nervous system). Intravenous administration of niraparib to vagotomized dogs over 30 minutes at 1, 3, and 10 mg/kg resulted in an increased range of arterial pressures of 13% to 20%, 18% to 27%, and 19% to 25%, respectively, and increased range of heart rates of 2% to 11%, 4% to 17%, and 12% to 21%, respectively, above pre-dose levels.

The unbound plasma concentrations of niraparib in dogs at these dose levels were approximately 0.5, 1.5, and 5.8 times the unbound C max at steady‑state in patients receiving the recommended dose. In addition, niraparib crossed the blood-brain barrier in rats and monkeys following oral administration. The cerebrospinal fluid:plasma C max ratios of niraparib administered at 10 mg/kg orally to 2 rhesus monkeys were 0.10 and 0.52.