Orilissa Elagolix 150 mg Tablet, Film Coated, 7-count — NDC 0074-0038-07 (Billing 00074-0038-07)

12 CLINICAL PHARMACOLOGY

12.1Mechanism of Action ORILISSA is a GnRH receptor antagonist that inhibits endogenous GnRH signaling by binding competitively to GnRH receptors in the pituitary gland. Administration of ORILISSA results in dose-dependent suppression of luteinizing hormone (LH) and follicle-stimulating hormone (FSH), leading to decreased blood concentrations of the ovarian sex hormones, estradiol and progesterone.

12.2Pharmacodynamics Effect on Ovulation and Estradiol In a 3-menstrual cycle study in healthy women, ORILISSA 150 mg once daily and 200 mg twice daily resulted in an ovulation rate of approximately 50% and 32%, respectively. In the Phase 3 trials in women with endometriosis, ORILISSA caused a dose-dependent reduction in median estradiol concentrations to approximately 42 pg/mL for 150 mg once daily regimen and 12 pg/mL for the 200 mg twice daily regimen. Cardiac Electrophysiology The effect of elagolix on the QTc interval was evaluated in a randomized, placebo- and positive-controlled, open-label, single-dose, crossover thorough QTc study in 48 healthy adult premenopausal women.

Elagolix concentrations in subjects given a single dose of 1200 mg was 17-times higher than the concentration in subjects given elagolix 200 mg twice daily. There was no clinically relevant prolongation of the QTc interval.

12.3Pharmacokinetics The pharmacokinetic properties of ORILISSA in healthy subjects are summarized in Table 8 . The steady state pharmacokinetic parameters under fasting conditions are summarized in Table 9 . Table 8. Pharmacokinetic Properties of ORILISSA in Healthy Subjects Absorption T max (h)

1.0Effect of high-fat meal (relative to fasting) AUC: ↓24%, C max : ↓36% Distribution % Bound to human plasma proteins 80 Blood-to-plasma ratio

0.6Metabolism Metabolism CYP3A (major) Minor pathways include: CYP2D6, CYP2C8, and uridine glucuronosyl transferases (UGTs) Elimination Major route of elimination Hepatic metabolism Terminal phase elimination half-life (t 1/2 ) (h) 4-6 % of dose excreted in urine <3 % of dose excreted in feces 90 Table 9. Mean (%CV) Steady State Pharmacokinetic Parameters of ORILISSA Pharmacokinetic Parameter (Units) 150 mg Once Daily N = 6 200 mg Twice Daily N = 7 C max (ng/mL) 574 (29) 774 (68) AUC τ (ng●hr/mL) 1292 (31) 1725 (57) CL/F (L/hr) 123 (21) 144 (43) V dss /F 1674 (94) 881 (38) R ac 0.98 (7) 0.89 (19) CV: Coefficient of variation C max : peak concentration AUC τ : area under the plasma concentration-time curve during the dosing interval (τ) i.e., 12 hours for twice daily regimen, 24 hours for once daily regimen.

CL/F: oral clearance V dss /F: apparent volume of distribution at steady state R ac : drug accumulation ratio Specific Populations Patients with Renal Impairment Elagolix exposures (C max and AUC) are not altered by renal impairment. The mean exposures are similar for women with moderate to severe or end stage renal disease (including women on dialysis) compared to women with normal renal function. Patients with Hepatic Impairment Elagolix exposures (C max and AUC) are similar between women with normal hepatic function and women with mild hepatic impairment.

Elagolix exposures in women with moderate and severe hepatic impairment are approximately 3-fold and 7-fold, respectively, higher than exposures from women with normal hepatic function [see Use in Specific Populations ( 8.7 )] . Rac ial or Ethnic Groups No clinically meaningful difference in the pharmacokinetics of ORILISSA between White and Black subjects or between Hispanics and others was observed. There is no clinically meaningful difference in the pharmacokinetics of ORILISSA between Japanese and Han Chinese subjects.

Body weight/Body mass index Body weight or body mass index does not affect the pharmacokinetics of ORILISSA. Drug Interaction Studies Drug interaction studies were performed with ORILISSA and other drugs that are likely to be co-administered and with drugs commonly used as probes for pharmacokinetic… [Excerpted — this section continues on DailyMed.]

12.1Mechanism of Action ORILISSA is a GnRH receptor antagonist that inhibits endogenous GnRH signaling by binding competitively to GnRH receptors in the pituitary gland. Administration of ORILISSA results in dose-dependent suppression of luteinizing hormone (LH) and follicle-stimulating hormone (FSH), leading to decreased blood concentrations of the ovarian sex hormones, estradiol and progesterone.

12.3Pharmacokinetics The pharmacokinetic properties of ORILISSA in healthy subjects are summarized in Table 8 . The steady state pharmacokinetic parameters under fasting conditions are summarized in Table 9 . Table 8. Pharmacokinetic Properties of ORILISSA in Healthy Subjects Absorption T max (h)

1.0Effect of high-fat meal (relative to fasting) AUC: ↓24%, C max : ↓36% Distribution % Bound to human plasma proteins 80 Blood-to-plasma ratio

0.6Metabolism Metabolism CYP3A (major) Minor pathways include: CYP2D6, CYP2C8, and uridine glucuronosyl transferases (UGTs) Elimination Major route of elimination Hepatic metabolism Terminal phase elimination half-life (t 1/2 ) (h) 4-6 % of dose excreted in urine <3 % of dose excreted in feces 90 Table 9. Mean (%CV) Steady State Pharmacokinetic Parameters of ORILISSA Pharmacokinetic Parameter (Units) 150 mg Once Daily N = 6 200 mg Twice Daily N = 7 C max (ng/mL) 574 (29) 774 (68) AUC τ (ng●hr/mL) 1292 (31) 1725 (57) CL/F (L/hr) 123 (21) 144 (43) V dss /F 1674 (94) 881 (38) R ac 0.98 (7) 0.89 (19) CV: Coefficient of variation C max : peak concentration AUC τ : area under the plasma concentration-time curve during the dosing interval (τ) i.e., 12 hours for twice daily regimen, 24 hours for once daily regimen.

CL/F: oral clearance V dss /F: apparent volume of distribution at steady state R ac : drug accumulation ratio Specific Populations Patients with Renal Impairment Elagolix exposures (C max and AUC) are not altered by renal impairment. The mean exposures are similar for women with moderate to severe or end stage renal disease (including women on dialysis) compared to women with normal renal function. Patients with Hepatic Impairment Elagolix exposures (C max and AUC) are similar between women with normal hepatic function and women with mild hepatic impairment.

Elagolix exposures in women with moderate and severe hepatic impairment are approximately 3-fold and 7-fold, respectively, higher than exposures from women with normal hepatic function [see Use in Specific Populations ( 8.7 )] . Rac ial or Ethnic Groups No clinically meaningful difference in the pharmacokinetics of ORILISSA between White and Black subjects or between Hispanics and others was observed. There is no clinically meaningful difference in the pharmacokinetics of ORILISSA between Japanese and Han Chinese subjects.

Body weight/Body mass index Body weight or body mass index does not affect the pharmacokinetics of ORILISSA. Drug Interaction Studies Drug interaction studies were performed with ORILISSA and other drugs that are likely to be co-administered and with drugs commonly used as probes for pharmacokinetic interactions. Tables 10 and 11 summarize the pharmacokinetic effects when elagolix was co-administered with these drugs.

Table 10. Drug Interactions: Change in Pharmacokinetics of Elagolix in the Presence of Co-administered Drugs Co- administered Drug Regimen of Co- administered Drug Regimen of Elagolix N Ratio (90% CI)* Ketoconazole 400 mg once daily 150 mg single dose 11 C max AUC 1.77 (1.48 – 2.12) 2.20 (1.98 – 2.44) Rifampin # 600 mg single dose 150 mg single dose 12 4.37 (3.62 – 5.28) 5.58 (4.88 – 6.37) 600 mg once daily 2.00 (1.66 – 2.41) 1.65 (1.45 – 1.89) CI: Confidence interval *ratios for C max and AUC compare co-administration of the medication with elagolix vs. administration of elagolix alone. # A single dose of 600 mg rifampin inhibits OATP1B1; 600 mg once daily dose of rifampin inhibits OATP1B1 and induces CYP3A.

No clinically significant changes in elagolix exposures were observed when co-administered with rosuvastatin (20 mg once daily), sertraline (25 mg once daily) or fluconazole (200 mg single dose). Table 11. Drug Interactions: Change in Pharmacokinetics of Co-administered Drug in the Presence of Elagolix Co- administered Drug Regimen of Co- administered Drug Regimen of Elagolix N Ratio (90% CI)* Digoxin 0.5 mg single dose 200 mg twice daily x 10 days 11 C max AUC 1.71 (1.53 – 1.91) 1.26 (1.17 – 1.3… [Excerpted — this section continues on DailyMed.]

12.2Pharmacodynamics Effect on Ovulation and Estradiol In a 3-menstrual cycle study in healthy women, ORILISSA 150 mg once daily and 200 mg twice daily resulted in an ovulation rate of approximately 50% and 32%, respectively. In the Phase 3 trials in women with endometriosis, ORILISSA caused a dose-dependent reduction in median estradiol concentrations to approximately 42 pg/mL for 150 mg once daily regimen and 12 pg/mL for the 200 mg twice daily regimen. Cardiac Electrophysiology The effect of elagolix on the QTc interval was evaluated in a randomized, placebo- and positive-controlled, open-label, single-dose, crossover thorough QTc study in 48 healthy adult premenopausal women.

Elagolix concentrations in subjects given a single dose of 1200 mg was 17-times higher than the concentration in subjects given elagolix 200 mg twice daily. There was no clinically relevant prolongation of the QTc interval.

14 CLINICAL STUDIES The efficacy of ORILISSA 150 mg once daily and 200 mg twice daily for the management of moderate to severe pain associated with endometriosis was demonstrated in two multinational double-blind, placebo-controlled trials in 1686 premenopausal women [Study EM-1 (NCT01620528) and Study EM-2 (NCT01931670)]. The median age of women in the trials was 32 years; 88% were White, 9% were Black or African American and 3% were other races. Each placebo-controlled trial assessed the reduction in endometriosis-associated pain over 6 months of treatment.

Moderate to severe pain associated with endometriosis was required for entry into the trials and was assessed during screening using the composite pelvic signs and symptoms score (CPSSS) and other baseline criteria. The CPSSS is based on a modified Biberoglu and Behrman scale with five elements: three responses reported by study subjects (dysmenorrhea, dyspareunia, and non-menstrual pelvic pain) and two findings based on investigator assessment during physical examination (rating of pelvic tenderness and induration).

Each element is scored from 0 (absent) to 3 (severe) for a maximum total score of 15. A total score of at least 6, with a score of at least 2 for dysmenorrhea and at least 2 for non-menstrual pelvic pain was required to qualify for randomization. Subjects were also required to have non-menstrual pelvic pain for at least four days in the preceding calendar month, defined as 35 days.

Other criteria to determine eligibility for randomization included subject responses in a daily electronic diary (Endometriosis Daily Pain Impact Scale, described below) for both dysmenorrhea and non-menstrual pelvic pain in the 35 days prior to randomization. Dysmenorrhea and Non-Menstrual Pelvic Pain The co-primary efficacy endpoints were (1) the proportion of subjects whose dysmenorrhea responded to treatment at Month 3 and (2) the proportion of subjects whose pelvic pain not related to menses (also known as non-menstrual pelvic pain) responded to treatment at Month 3.

Dysmenorrhea and non-menstrual pelvic pain were evaluated daily using the Endometriosis Daily Pain Impact Scale that asked subjects to rate their pain severity and its impact on daily activities during the prior 24 hours as none, mild, moderate or severe (correlating with a score of 0 to 3, respectively, where higher scores indicated greater severity). Scores at baseline and at each month were averaged over a 35-day interval. Women were defined as responders if they experienced a reduction in dysmenorrhea and non-menstrual pelvic pain as defined in Table 12 with no increase in analgesic use (nonsteroidal anti-inflammatory drug or opioid) for endometriosis-associated pain.

The threshold for defining responders was based on a receiver operating characteristic (ROC) analysis using the patient global impression of change as an anchor. A higher proportion of women treated with ORILISSA 150 mg once daily or 200 mg twice daily were responders for dysmenorrhea and non-menstrual pelvic pain compared to placebo in a dose-dependent manner at Month 3 [see Table 12 ] . Table 12.

Proportion of Responders † for Dysmenorrhea and Non-Menstrual Pelvic Pain at Month 3 in Studies EM-1 and EM-2, Using the Endometriosis Daily Pain Impact Scale Study EM-1 Study EM-2 ORILISSA Placebo ORILISSA Placebo 150 mg Once Daily N=248 200 mg Twice Daily N=244 N=373 150 mg Once Daily N=221 200 mg Twice Daily N=225 N=353 Dysmenorrhea Difference from placebo 46% 27%** 76% 56%** 20% 43% 21%** 72% 50%** 23% Non-Menstrual Pelvic Pain Difference from placebo 50% 14%** 55% 18%** 36% 50% 13%* 58% 21%** 37% † Study EM-1-Dysmenorrhea responder threshold: at least 0.81 point decrease from baseline in dysmenorrhea score; Non-Menstrual Pelvic Pain responder threshold: at least 0.36 point decrease from baseline in Non-Menstrual Pelvic Pain score Study EM-2 - Dysmenorrhea responder threshold: at least 0.85 point decrease from baseline in dysmenorrhea score; Non-Me… [Excerpted — this section continues on DailyMed.]

13 NONCLINICAL TOXICOLOGY

13.1Carcinogenesis, Mutagenesis, Impairment of Fertility Two-year carcinogenicity studies conducted in mice (50, 150, or 500 mg/kg/day) and rats (150, 300, or 800 mg/kg/day) that administered elagolix by the dietary route revealed no increase in tumors in mice at up to 19-fold the MRHD based on AUC. In the rat, there was an increase in thyroid (male and female) and liver (males only) tumors at the high dose (12 to 13-fold the MRHD). The rat tumors were likely species-specific and of negligible relevance to humans.

Elagolix was not genotoxic or mutagenic in a battery of tests, including the in vitro bacterial reverse mutation assay, the in vitro mammalian cell forward mutation assay at the thymidine kinase (TK+/-) locus in L5178Y mouse lymphoma cells, and the in vivo mouse micronucleus assay. In a fertility study conducted in the rat, there was no effect of elagolix on fertility at any dose (50, 150, or 300 mg/kg/day). Based on AUC, the exposure multiple for the MRHD in women compared to the highest dose of 300 mg/kg/day in female rats is approximately 5-fold.

However, because elagolix has low affinity for the GnRH receptor in the rat [see Use in Specific Populations ( 8.1 )] , and because effects on fertility are most likely to be mediated via the GnRH receptor, these data have low relevance to humans.