ORILISSA

ORILISSA (elagolix) tablets for oral administration contain elagolix sodium, the sodium salt of the active moiety elagolix. Elagolix sodium is a nonpeptide small molecule, GnRH receptor antagonist. Elagolix sodium is chemically described as sodium 4-({(1 R )-2-[5-(2-fluoro-3-methoxyphenyl)-3-{[2-fluoro-6-(trifluoromethyl)phenyl]methyl}-4-methyl-2,6-dioxo-3,6-dihydropyrimidin-1(2 H )-yl]-1-phenylethyl}amino)butanoate. Elagolix sodium has a molecular formula of C 32 H 29 F 5 N 3 O 5 Na and a molecular weight of 653.58. Elagolix free acid has a molecular weight of 631.60. Elagolix sodium has the following structural formula: Elagolix sodium is a white to off white to light yellow powder and is freely soluble in water. ORILISSA 150 mg tablets are light pink, oblong, film-coated tablets with “EL 150” debossed on one side. Each tablet contains 155.2 mg of elagolix sodium (equivalent to 150 mg of elagolix) as the active ingredient and the following inactive ingredients: mannitol, sodium carbonate monohydrate, pregelatinized starch, povidone, magnesium stearate, polyvinyl alcohol, titanium dioxide, polyethylene glycol, talc, and carmine high tint. ORILISSA 200 mg tablets are light orange, oblong, film-coated tablets with “EL 200” debossed on one side. Each tablet contains 207.0 mg of elagolix sodium (equivalent to 200 mg of elagolix) as the active ingredient and the following inactive ingredients: mannitol, sodium carbonate monohydrate, pregelatinized starch, povidone, magnesium stearate, polyvinyl alcohol, titanium dioxide, polyethylene glycol, talc, and iron oxide red. Elagolix sodium has the following structural formula

ORILISSA is indicated for the management of moderate to severe pain associated with endometriosis. Limitation s of Use: Limit the duration of use based on the dose and coexisting condition (see Table 1 ) [see D osage and Administration ( 2.1 ) and Warnings and Precautions ( 5.1 ) ] . ORILISSA is a gonadotropin-releasing hormone (GnRH) receptor antagonist indicated for the management of moderate to severe pain associated with endometriosis. ( 1 ) Limitation s of Use: Limit the duration of use based on the dose and coexisting condition (see Table 1 ). ( 1 )

Normal liver function or mild hepatic impairment : 150 mg once daily for up to 24 months or 200 mg twice daily for up to 6 months. ( 2.1 ) Moderate hepatic impairment : 150 mg once daily for up to 6 months. ( 2.1 ) 2.1 Important Dosing Information Exclude pregnancy before starting ORILISSA or start ORILISSA within 7 days from the onset of menses. Take ORILISSA at approximately the same time each day, with or without food. Use the lowest effective dose, taking into account the severity of symptoms and treatment objectives [see Warnings and Precautions ( 5.1 , 5.3 , 5.4 ) and Clinical Studies ( 14 )] . Limit the duration of use because of bone loss ( Table 1 ) [see Warnings and Precautions ( 5.1 )] . Table 1. Recommended Dosage and Duration of Use Dosing Regimen Maximum Treatment Duration Coexisting Condition Initiate treatment with ORILISSA 150 mg once daily 24 months None Consider initiating treatment with ORILISSA 200 mg twice daily 6 months Dyspareunia Initiate treatment with ORILISSA 150 mg once daily. Use of 200 mg twice daily is not recommended. 6 months Moderate hepatic impairment (Child-Pugh Class B) 2.2 Hepatic Impairment No dosage adjustment of ORILISSA is required in women with mild hepatic impairment (Child-Pugh A). Compared to women with normal liver function, those with moderate hepatic impairment had approximately 3-fold higher elagolix exposures and those with severe hepatic impairment had approximately 7-fold higher elagolix exposures. Because of these increased exposures and risk for bone loss: ORILISSA 150 mg once daily is recommended for women with moderate hepatic impairment (Child-Pugh B) with the duration of treatment limited to 6 months. Use of ORILISSA 200 mg twice daily is not recommended for women with moderate hepatic impairment [see Use in Specific Populations ( 8.7 ) and Clinical Pharmacology ( 12.3 )] . ORILISSA is contraindicated in women with severe hepatic impairment (Child-Pugh C) [see Contraindications ( 4 ), Use in Specific Populations ( 8.7 ) and Clinical Pharmacology ( 12.3 )] . 2.3 Missed Dose Instruct the patient to take a missed dose of ORILISSA on the same day as soon as she remembers and then resume the regular dosing schedule. 150 mg once daily: take no more than 1 tablet each day. 200 mg twice daily: take no more than 2 tablets each day.

ORILISSA is contraindicated in women: Who are pregnant [see Use in Specific Populations ( 8.1 )] . Exposure to ORILISSA early in pregnancy may increase the risk of early pregnancy loss. With known osteoporosis because of the risk of further bone loss [see Warnings and Precautions ( 5.1 )] With severe hepatic impairment [see Use in Specific Populations ( 8.7 ), Clinical Pharmacology ( 12.3 )] Taking inhibitors of organic anion transporting polypeptide (OATP)1B1 (a hepatic uptake transporter) that are known or expected to significantly increase elagolix plasma concentrations [see Drug Interactions ( 7.2 )] With known hypersensitivity reaction to ORILISSA or any of its inactive components. Reactions have included anaphylaxis and angioedema [see Adverse Reactions ( 6.2 )] . Pregnancy ( 4 ) Known osteoporosis ( 4 ) Severe hepatic impairment ( 4 ) Organic anion transporting polypeptide (OATP) 1B1 inhibitors that significantly increase elagolix plasma concentrations ( 4 ) Hypersensitivity reactions ( 4 , 6.2 )

The following serious adverse reactions are discussed elsewhere in labeling: Bone loss [see Warnings and Precautions ( 5.1 )] Change in menstrual bleeding pattern and reduced ability to recognize pregnancy [see Warnings and Precautions ( 5.2 )] Suicidal ideation, suicidal behavior, and exacerbation of mood disorders [see Warnings and Precautions ( 5.3 )] Hepatic transaminase elevations [see Warnings and Precautions ( 5.4 )] Most common adverse reactions (>5%) in clinical trials included hot flushes and night sweats, headache, nausea, insomnia, amenorrhea, anxiety, arthralgia, depression-related adverse reactions and mood changes ( 6.1 ). To report SUSPECTED ADVERSE REACTIONS, contact AbbVie Inc. at 1-800-633-9110 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch Figure 1. Percent Change from Baseline in Lumbar Spine BMD in Subjects Who Received 12 Months of ORILISSA and Had Follow-up BMD 6 Months off Therapy in Studies EM-2/EM-4 Figure 2. Percent Change from Baseline in Lumbar Spine BMD in Subjects Who Received 12 Months of ORILISSA and Had Follow-up BMD 12 Months off Therapy in Studies EM-2/EM-4 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. The safety of ORILISSA was evaluated in two six-month, randomized, double-blind, placebo-controlled clinical trials [EM-1 (NCT01620528) and EM-2 (NCT01931670)] in which a total of 952 adult women with moderate to severe pain associated with endometriosis were treated with ORILISSA (475 with 150 mg once daily and 477 with 200 mg twice daily) and 734 were treated with placebo. The population age range was 18-49 years old. Women who completed six months of treatment and met eligibility criteria continued treatment in two uncontrolled, blinded six-month extension trials [EM-3 (NCT01760954) and EM-4 (NCT02143713)], for a total treatment duration of up to 12 months. Serious Adverse Events Overall, the most common serious adverse events reported for subjects treated with ORILISSA in the two placebo-controlled clinical trials (Studies EM-1 and EM-2) included appendicitis (0.3%), abdominal pain (0.2%), and back pain (0.2%). In these trials, 0.2% of subjects treated with ORILISSA 150 mg once daily and 0.2% of subjects treated with ORILISSA 200 mg twice daily discontinued therapy due to serious adverse reactions compared to 0.5% of those given placebo. Adverse Reactions Leading to Study Discontinuation In the two placebo-controlled clinical trials (Studies EM-1 and EM-2), 5.5% of subjects treated with ORILISSA 150 mg once daily and 9.6% of subjects treated with ORILISSA 200 mg twice daily discontinued therapy due to adverse reactions compared to 6.0% of those given placebo. Discontinuations were most commonly due to hot flushes or night sweats (1.1% with 150 mg once daily and 2.5% with 200 mg twice daily) and nausea (0.8% with 150 mg once daily and 1.5% with 200 mg twice daily) and were dose-related. The majority of discontinuations due to hot flushes or night sweats (10 of 17, 59%) and nausea (7 of 11, 64%) occurred within the first 2 months of therapy. In the two extension trials (Studies EM-3 and EM-4), discontinuations were most commonly due to decreased BMD and were dose-related. In these trials, 0.3% of subjects treated with ORILISSA 150 mg once daily and 3.6% of subjects treated with ORILISSA 200 mg twice daily discontinued therapy due to decreased BMD. Common Adverse Reactions: Adverse reactions reported in ≥ 5% of women in the two placebo-controlled trials in either ORILISSA dose group and at a greater frequency than placebo are noted in the following table. Table 2. Percentage of Subjects in Studies EM-1 and EM-2 with Treatment-Emergent Adverse Reactions Occurring in at Least 5% of Subjects (either ORILISSA Dose Group) and at a Greater Incidence than with Placebo ORILISSA 150 mg Once Daily N=475 ORILISSA 200 mg Twice Daily N=477 Placebo N=734 % % % Hot Flush 24 46 9 Headache 17 20 12 Nausea 11 16 13 Insomnia 6 9 3 Mood altered, mood swings 6 5 3 Amenorrhea 4 7 <1 Depressed mood, depression, depressive symptoms and/or tearfulness 3 6 2 Anxiety 3 5 3 Arthralgia 3 5 3 The most commonly reported adverse reactions in the extension trials (EM-3 and EM-4) were similar to those in the placebo-controlled trials. Less Common Adverse Reactions: In Study EM-1 and Study EM-2, adverse reactions reported in ≥ 3% and < 5% in either ORILISSA dose group and greater than placebo included: decreased libido, diarrhea, abdominal pain, weight gain , dizziness, constipation and irritability. Bone Loss The effect of ORILISSA on BMD was assessed by dual-energy X-ray absorptiometry (DXA). In Studies EM-1 and EM-2, there was a dose-dependent decrease in BMD in ORILISSA-treated subjects compared to an increase in placebo-treated subjects. In Study EM-1, compared to placebo, the mean change from baseline in lumbar spine BMD at 6 months was -0.9% (95% CI: -1.3, -0.4) with ORILISSA 150 mg once daily and -3.1% (95% CI: -3.6, -2.6) with ORILISSA 200 mg twice daily ( Table 3 ). The percentage of subjects with greater than 8% BMD decrease in lumbar spine, total hip or femoral neck at any time point during the placebo-controlled treatment period was 2% with ORILISSA 150 mg once daily, 7% with ORILISSA 200 mg twice daily and < 1% with placebo. In the blinded extension Study EM-3, continued bone loss was observed with 12 months of continuous treatment with ORILISSA. The percentage of subjects with greater than 8% BMD decrease in lumbar spine, total hip or femoral neck at any time point during the extension treatment period was 8% with continuous ORILISSA 150 mg once daily and 21% with continuous ORILISSA 200 mg twice daily. In Study EM-2, compared to placebo, the mean change from baseline in lumbar spine BMD at 6 months was -1.3% (95% CI: -1.8, -0.8) with ORILISSA 150 mg once daily and -3.0% (95% CI: -3.5, -2.6) with ORILISSA 200 mg twice daily ( Table 3 ). The percentage of subjects with greater than 8% BMD decrease in lumbar spine, total hip or femoral neck at any time point during the placebo-controlled treatment period was < 1% with ORILISSA 150 mg once daily, 6% with ORILISSA 200 mg twice daily and 0% with placebo. In the blinded extension Study EM-4, continued bone loss was observed with 12 months of continuous treatment with ORILISSA. The percentage of subjects with greater than 8% BMD decrease in lumbar spine, total hip or femoral neck at any time point during the extension treatment period was 2% with continuous ORILISSA 150 mg once daily and 21% with continuous ORILISSA 200 mg twice daily. Table 3. Percent Change from Baseline in Lumbar Spine BMD at Month 6 ORILISSA 150 mg Once Daily ORILISSA 200 mg Twice Daily Placebo EM-1 N 183 180 277 Percent Change from Baseline, % -0.3 -2.6 0.5 Treatment Difference, % (95% CI) -0.9 (-1.3, -0.4) -3.1 (-3.6, -2.6) EM-2 N 174 183 271 Percent Change from Baseline, % -0.7 -2.5 0.6 Treatment Difference, % (95% CI) -1.3 (-1.8, -0.8) -3.0 (-3.5, -2.6) To assess for recovery, the change in lumbar spine BMD over time was analyzed for subjects who received continuous treatment with ORILISSA 150 mg once daily or ORILISSA 200 mg twice daily for up to 12 months and who were then followed after cessation of therapy for an additional 6 months. Partial recovery of BMD was seen in these subjects (Figure 1). In Study EM-3, if a subject had BMD loss of more than 1.5% at the lumbar spine or more than 2.5% at the total hip at the end of treatment, follow-up DXA was required after 6 months off-treatment. In Study EM-4, all subjects were required to have a follow-up DXA 6 months off treatment regardless of change in BMD and if a subject had BMD loss of more than 1.5% at the lumbar spine or more than 2.5% at the total hip after 6 months off treatment, follow-up DXA was required after 12 months off-treatment. Figure 2 shows the change in lumbar spine BMD for the subjects in Study EM-2/EM-4 who completed 12 months of treatment with ORILISSA and who had a follow-up DXA 12-months off treatment. Figure 1. Percent Change from Baseline in Lumbar Spine BMD in Subjects Who Received 12 Months of ORILISSA and Had Follow-up BMD 6 Months off Therapy in Studies EM-2/EM-4 Figure 2. Percent Change from Baseline in Lumbar Spine BMD in Subjects Who Received 12 Months of ORILISSA and Had Follow-up BMD 12 Months off Therapy in Studies EM-2/EM-4 Suicidal Ideation, Suicidal Behavior and Exacerbation of Mood Disorders In the placebo-controlled trials (Studies EM-1 and EM-2), ORILISSA was associated with adverse mood changes (see Table 2 and Table 4), particularly in those with a history of depression. Table 4. Suicidal Ideation and Suicidal Behavior in Studies EM-1 and EM-2 Adverse Reactions ORILISSA 150 mg Once Daily (N=475) n (%) 200 mg Twice Daily (N=477) n (%) Placebo (N=734) n (%) Completed suicide 1 (0.2) 0 0 Suicidal ideation 1 (0.2) 1 (0.2) 0 A 44-year-old woman received 31 days of ORILISSA 150 mg once daily then completed suicide 2 days after ORILISSA discontinuation. She had no relevant past medical history; life stressors were noted. Among the 2090 subjects exposed to ORILISSA in the endometriosis Phase 2 and Phase 3 studies, there were four reports of suicidal ideation. In addition to the two subjects in Table 4, there were two additional reports of suicidal ideation: one subject in EM-3 (150 mg once daily) and one in a Phase 2 study (75 mg once daily, an unapproved dose). Three of these subjects had a history of depression. Two subjects discontinued ORILISSA and two completed the clinical trial treatment periods. Hepatic Transaminase Elevations In the placebo-controlled clinical trials (Studies EM-1 and EM-2), dose-dependent asymptomatic elevations of serum ALT to at least 3-times the upper limit of the reference range occurred during treatment with ORILISSA (150 mg once daily – 1/450, 0.2%; 200 mg twice daily – 5/443, 1.1%; placebo – 1/696, 0.1%). Similar increases were seen in the extension trials (Studies EM-3 and EM-4). Changes in Lipid Parameters Dose-dependent increases in total cholesterol, low-density lipoprotein cholesterol (LDL-C), high density lipoprotein cholesterol (HDL-C), and serum triglycerides were noted during ORILISSA treatment in EM-1 and EM-2. In EM-1 and EM-2, 12% and 1% of subjects with mildly elevated LDL-C (130-159 mg/dL) at baseline had an increase in LDL-C concentrations to 190 mg/dL or higher during treatment with ORILISSA and placebo, respectively. In EM-1 and EM-2, 4% and 1% of subjects with mildly elevated serum triglycerides (150-300 mg/dL) at baseline had an increase in serum triglycerides to at least 500 mg/dL during treatment with ORILISSA and placebo, respectively. The highest measured serum triglyceride concentration during treatment with ORILISSA was 982 mg/dL. Table 5. Mean Change and Maximum Increase from Baseline in Serum Lipids in Studies EM-1 and EM-2 ORILISSA 150 mg Once Daily N=475 ORILISSA 200 mg Twice Daily N=477 Placebo N=734 LDL-C (mg/dL) Mean change at Month 6 5 13 -3 Maximum increase during Treatment Period 137 107 122 HDL-C (mg/dL) Mean change at Month 6 2 4 1 Maximum increase during Treatment Period 43 52 45 Triglycerides (mg/dL) Mean change at Month 6 <1 11 -3 Maximum increase during Treatment Period 624 484 440 Lipid increases occurred within 1 to 2 months after the start of ORILISSA and remained stable thereafter over 12 months. Hypersensitivity Reactions In Studies EM-1 and EM-2, non-serious hypersensitivity reactions including rash occurred in 5.8% of ORILISSA treated-subjects and 6.1% of placebo-treated subjects. These events led to study drug discontinuation in 0.4% of ORILISSA-treated subjects and 0.5% of placebo-treated subjects. Effects on M enstrual B leeding P atterns The effects of ORILISSA on menstrual bleeding were evaluated for up to 12 months using an electronic daily diary where subjects classified their flow of menstrual bleeding (if present in the last 24 hours) as spotting, light, medium, or heavy. ORILISSA led to a dose-dependent reduction in mean number of bleeding and spotting days and bleeding intensity in those subjects who reported menstrual bleeding. Table 6. Mean Bleeding/Spotting Days and Mean Intensity Scores at Month 3 ORILISSA 150mg Once Daily ORILISSA 200mg Twice Daily Placebo Baseline Month 3 Baseline Month 3 Baseline Month 3 Mean bleeding/ spotting days in prior 28 days 5.3 2.8 5.7 0.8 5.4 4.6 Mean Intensity score a 2.6 2.2 2.5 2.0 2.6 2.4 a Intensity for subjects who reported at least 1 day of bleeding or spotting during 28 day interval. Scale ranges from 1 to 4, 1 = spotting, 2 = light, 3 = medium, 4 = heavy ORILISSA also demonstrated a dose-dependent increase in the percentage of women with amenorrhea (defined as no bleeding or spotting in a 56-day interval) over the treatment period. The incidence of amenorrhea during the first six months of treatment ranged from 6-17% for ORILISSA 150 mg once daily, 13-52% for ORILISSA 200 mg twice daily and less than 1% for placebo. During the second 6 months of treatment, the incidence of amenorrhea ranged from 11-15% for ORILISSA 150 mg once daily and 46-57% for ORILISSA 200 mg twice daily. After 6 months of therapy with ORILISSA 150 mg once daily, resumption of menses after stopping treatment was reported by 59%, 87% and 95% of women within 1, 2, and 6 months, respectively. After 6 months of therapy with ORILISSA 200 mg twice daily, resumption of menses after stopping treatment was reported by 60%, 88%, and 97% of women within 1, 2, and 6 months, respectively. After 12 months of therapy with ORILISSA 150 mg once daily resumption of menses after stopping treatment was reported by 77%, 95% and 98% of women within 1, 2, and 6 months respectively. After 12 months of therapy with ORILISSA 200 mg twice daily resumption of menses after stopping treatment was reported by 55%, 91% and 96% of women within 1, 2, and 6 months respectively. 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of ORILISSA. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Immune system disorders: hypersensitivity reactions (including anaphylaxis, angioedema, and urticaria).

See full prescribing information for a list of clinically important drug interactions ( 7 ). 7.1 Potential for ORILISSA to Affect Other Drugs Elagolix is: A weak to moderate inducer of cytochrome P450 (CYP) 3A. Co-administration with ORILISSA may decrease plasma concentrations of drugs that are substrates of CYP3A (see Table 7). A weak inhibitor of CYP 2C19. Co-administration with ORILISSA may increase plasma concentrations of drugs that are substrates of CYP2C19 (see Table 7). An inhibitor of efflux transporter P-glycoprotein (P-gp). Co-administration with ORILISSA may increase plasma concentrations of drugs that are substrates of P-gp (see Table 7). The effects of co-administration of ORILISSA on concentrations of concomitant drugs and the clinical recommendations for these drug interactions are summarized in Table 7. Table 7. Drug Interactions: Effects of ORILISSA on Other Drugs Concomitant Drug Class: Drug Name Effect on Plasma Exposure of Concomitant Drug Clinical Recommendations Cardiac glycosides: digoxin ↑ digoxin Increase monitoring of digoxin concentrations and potential signs and symptoms of clinical toxicity when initiating ORILISSA in patients who are taking digoxin. If ORILISSA is discontinued, increase monitoring of digoxin concentrations. Benzodiazepines: oral midazolam ↓ midazolam Consider increasing the dose of midazolam by no more than 2-fold and individualize midazolam therapy based on the patient’s response. Statins: rosuvastatin ↓ rosuvastatin Monitor lipid levels and adjust the dose of rosuvastatin, if necessary. Proton pump inhibitors: omeprazole ↑ omeprazole No dose adjustment needed for omeprazole 40 mg once daily when co-administered with ORILISSA. When ORILISSA is used concomitantly with higher doses of omeprazole, consider dosage reduction of omeprazole. Combined hormonal contraceptives: oral ethinyl estradiol/levonorgestrel ↑ethinyl estradiol ↓levonorgestrel Advise women to use effective non-hormonal contraception during treatment with ORILISSA and for 28 days after discontinuing ORILISSA. See Tables 10 and 11 [ see Clinical Pharmacology ( 12.3 )] . The direction of the arrow indicates the direction of the change in the area under the curve (AUC) (↑= increase, ↓ = decrease). 7.2 Potential for Other Drugs to Affect ORILISSA Elagolix is a substrate of CYP3A, P-gp, and OATP1B1. Concomitant use of ORILISSA 200 mg twice daily and strong CYP3A inhibitors for more than 1 month is not recommended. Limit concomitant use of ORILISSA 150 mg once daily and strong CYP3A inhibitors to 6 months. Co-administration of ORILISSA with strong CYP3A inducers may decrease elagolix plasma concentrations and may result in a decrease of the therapeutic effects of ORILISSA. Concomitant use of ORILISSA 200 mg twice daily and rifampin is not recommended. Limit concomitant use of ORILISSA 150 mg once daily and rifampin to 6 months. The effect of concomitant use of P-gp inhibitors or inducers on the pharmacokinetics of ORILISSA is unknown. OATP1B1 inhibitors that are known or expected to significantly increase elagolix plasma concentrations are contraindicated due to increased risk of elagolix-associated adverse reactions [see Contraindications ( 4 )].