{"paper_id":"f66340ef-bae4-4486-ae18-f52626455f7f","body_text":"HIGHLIGHTS OF PRESCRIBING INFORMATION \nThese highlights do not include all the information needed to use \nORILISSA safely and effectively. See full prescribing information for \nORILISSA. \nORILISSA\n® (elagolix) tablets, for oral use \nInitial U.S. Approval: 2018 \nINDICATIONS AND USAGE \nORILISSA is a gonadotropin-releasing hormone (GnRH) receptor antagonist \nindicated for the management of moderate to severe pain associated with \nendometriosis. (1) \nLimitations of Use: \n• Limit the duration of use based on the dose and coexisting condition (see \nTable 1). (1) \nDOSAGE AND ADMINISTRATION \nNormal liver function or mild hepatic impairment: 150 mg once daily for up \nto 24 months or 200 mg twice daily for up to 6 months. (2.1) \nModerate hepatic impairment: 150 mg once daily for up to 6 months. (2.1) \nDOSAGE FORMS AND STRENGTHS \nOral tablets: 150 mg and 200 mg (3) \nCONTRAINDICATIONS \n• Pregnancy (4) \n• Known osteoporosis (4) \n• Severe hepatic impairment (4) \n• Organic anion transporting polypeptide (OATP) 1B1 inhibitors that \nsignificantly increase elagolix plasma concentrations (4) \n• Hypersensitivity reactions (4, 6.2) \nWARNINGS AND PRECAUTIONS \n• Bone Loss: Dose- and duration-dependent decreases in bone mineral \ndensity (BMD) that may not be completely reversible. Assess BMD in \nwomen with additional risk factors for bone loss (5.1) \n• Reduced Ability to Recognize Pregnancy: ORILISSA may alter menstrual \nbleeding, which may reduce the ability to recognize pregnancy. Perform \ntesting if pregnancy is suspected. Discontinue if pregnancy is confirmed \n(5.2) \n• Suicidal Ideation and Mood Disorders: Advise patients to seek medical \nattention for suicidal ideation, suicidal behavior, new onset or worsening \ndepression, anxiety, or other mood changes (5.3) \n• Hepatic Transaminase Elevations: Dose-dependent elevations in serum \nalanine aminotransferase (ALT). Counsel patients on signs and symptoms \nof liver injury (5.4) \n• Interactions with Hormonal Contraceptives: Use non-hormonal \ncontraception during treatment and for 28 days after discontinuing \nORILISSA. Coadministration of ORILISSA 200 mg twice daily with an \nestrogen-containing contraceptive is not recommended because of the \npotential for increased estrogen-associated risks. Coadministration of \nORILISSA with an estrogen-containing contraceptive may reduce the \nefficacy of ORILISSA. Coadministration with progestin-containing oral \ncontraceptives may reduce the efficacy of the contraceptive. (5.5) \nADVERSE REACTIONS \nMost common adverse reactions (>5%) in clinical trials included hot flushes \nand night sweats, headache, nausea, insomnia, amenorrhea, anxiety, \narthralgia, depression-related adverse reactions and mood changes (6.1). \nTo report SUSPECTED ADVERSE REACTIONS, contact AbbVie Inc. \nat 1-800-633-9110 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch \nDRUG INTERACTIONS \nSee full prescribing information for a list of clinically important drug \ninteractions (7). \nSee 17 for PATIENT COUNSELING INFORMATION and Medication \nGuide. \nRevised: 06/2023 \nFULL PRESCRIBING INFORMATION: CONTENTS* \n1 INDICATIONS AND USAGE \n2 DOSAGE AND ADMINISTRATION \n2.1 Important Dosing Information \n2.2 Hepatic Impairment \n2.3 Missed Dose \n3 DOSAGE FORMS AND STRENGTHS \n4 CONTRAINDICATIONS \n5 WARNINGS AND PRECAUTIONS \n5.1 Bone Loss \n5.2 Change in Menstrual Bleeding Pattern and Reduced Ability to Recognize \nPregnancy \n5.3 Suicidal Ideation, Suicidal Behavior, and Exacerbation of Mood \nDisorders \n5.4 Hepatic Transaminase Elevations \n5.5 Interactions with Hormonal Contraceptives \n6 ADVERSE REACTIONS \n6.1 Clinical Trials Experience \n6.2 Postmarketing Experience \n7 DRUG INTERACTIONS \n7.1 Potential for ORILISSA to Affect Other Drugs \n7.2 Potential for Other Drugs to Affect ORILISSA \n8 USE IN SPECIFIC POPULATIONS \n8.1 Pregnancy \n8.2 Lactation \n8.3 Females and Males of Reproductive Potential \n8.4 Pediatric Use \n8.6 Renal Impairment \n8.7 Hepatic Impairment \n10 OVERDOSAGE \n11 DESCRIPTION \n12 CLINICAL PHARMACOLOGY \n12.1 Mechanism of Action \n12.2 Pharmacodynamics \n12.3 Pharmacokinetics \n12.5 Pharmacogenomics \n13 NONCLINICAL TOXICOLOGY \n13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility \n14 CLINICAL STUDIES \n16 HOW SUPPLIED/STORAGE AND HANDLING \n17 PATIENT COUNSELING INFORMATION \n*Sections or subsections omitted from the full prescribing information are not \nlisted. \nReference ID: 5184902 \nThis label may not be the latest approved by FDA.  \nFor current labeling information, please visit https://www.fda.gov/drugsatfda\n \n\n \n \n  \n \n   \n   \n \n \n  \n \n  \n   \n  \n   \n \n   \n  \n \n \n \n  \n \n  \n  \n  \n \n  \n \n \n   \n  \n   \n \n \n  \nFULL PRESCRIBING INFORMATION \n1 INDICATIONS AND USAGE \nORILISSA is indicated for the management of moderate to severe pain associated with \nendometriosis.  \nLimitations of Use: \nLimit the duration of use based on the dose and coexisting condition (see Table 1) [see Dosage \nand Administration (2.1) and Warnings and Precautions (5.1)]. \n2 DOSAGE AND ADMINISTRATION \n2.1 Important Dosing Information \n• Exclude pregnancy before starting ORILISSA or start ORILISSA within 7 days from the \nonset of menses. \n• Take ORILISSA at approximately the same time each day, with or without food. \n• Use the lowest effective dose, taking into account the severity of symptoms and treatment \nobjectives [see Warnings and Precautions (5.1, 5.3, 5.4) and Clinical Studies (14)]. \n• Limit the duration of use because of bone loss (Table 1) [see Warnings and Precautions \n(5.1)]. \nTable 1. Recommended Dosage and Duration of Use \nDosing Regimen \nMaximum \nTreatment \nDuration Coexisting Condition \nInitiate treatment with \nORILISSA 150 mg once daily \n24 months None \nConsider initiating treatment with \nORILISSA 200 mg twice daily \n6 months Dyspareunia \nInitiate treatment with ORILISSA \n150 mg once daily. Use of 200 mg \ntwice daily is not recommended. \n6 months Moderate hepatic impairment \n(Child-Pugh Class B) \n2.2 Hepatic Impairment \nNo dosage adjustment of ORILISSA is required in women with mild hepatic impairment (Child-\nPugh A).  \nCompared to women with normal liver function, those with moderate hepatic impairment had \napproximately 3-fold higher elagolix exposures and those with severe hepatic impairment had \napproximately 7-fold higher elagolix exposures. Because of these increased exposures and risk \nfor bone loss: \nReference ID: 5184902 \nThis label may not be the latest approved by FDA.  \nFor current labeling information, please visit https://www.fda.gov/drugsatfda\n \n\n    \n \n \n  \n  \n \n  \n \n  \n  \n   \n   \n \n \n \n  \n \n \n  \n  \n \n   \n \n \n \n   \n \n   \n   \n     \n  \n \n \n \n \n \n• ORILISSA 150 mg once daily is recommended for women with moderate hepatic \nimpairment (Child-Pugh B) with the duration of treatment limited to 6 months. Use of \nORILISSA 200 mg twice daily is not recommended for women with moderate hepatic \nimpairment [see Use in Specific Populations (8.7) and Clinical Pharmacology (12.3)]. \n• ORILISSA is contraindicated in women with severe hepatic impairment (Child-Pugh C) [see \nContraindications (4), Use in Specific Populations (8.7) and Clinical Pharmacology (12.3)]. \n2.3 Missed Dose \nInstruct the patient to take a missed dose of ORILISSA on the same day as soon as she \nremembers and then resume the regular dosing schedule. \n• 150 mg once daily: take no more than 1 tablet each day. \n• 200 mg twice daily: take no more than 2 tablets each day. \n3 DOSAGE FORMS AND STRENGTHS \nThe 150 mg tablets are light pink, oblong, film-coated tablets with “EL 150” debossed on one \nside. Each tablet contains 155.2 mg of elagolix sodium equivalent to 150 mg of elagolix. \nThe 200 mg tablets are light orange, oblong, film-coated tablets with “EL 200” debossed on one \nside. Each tablet contains 207.0 mg of elagolix sodium equivalent to 200 mg of elagolix. \n4 CONTRAINDICATIONS \nORILISSA is contraindicated in women: \n• Who are pregnant [see Use in Specific Populations (8.1)]. Exposure to ORILISSA early in \npregnancy may increase the risk of early pregnancy loss. \n• With known osteoporosis because of the risk of further bone loss [see Warnings and \nPrecautions (5.1)] \n• With severe hepatic impairment [see Use in Specific Populations (8.7), Clinical \nPharmacology (12.3)] \n• Taking inhibitors of organic anion transporting polypeptide (OATP)1B1 (a hepatic uptake \ntransporter) that are known or expected to significantly increase elagolix plasma \nconcentrations [see Drug Interactions (7.2)] \n• With known hypersensitivity reaction to ORILISSA or any of its inactive components. \nReactions have included anaphylaxis and angioedema [see Adverse Reactions (6.2)]. \n5 WARNINGS AND PRECAUTIONS \n5.1 Bone Loss \nORILISSA causes a dose-dependent decrease in bone mineral density (BMD). BMD loss is \ngreater with increasing duration of use and may not be completely reversible after stopping \ntreatment [see Adverse Reactions (6.1)]. The impact of these BMD decreases on long-term bone \nhealth and future fracture risk are unknown. \nReference ID: 5184902 \nThis label may not be the latest approved by FDA.  \nFor current labeling information, please visit https://www.fda.gov/drugsatfda\n \n\n   \n  \n \n \n  \n  \n \n  \n \n \n \n \n \n  \n  \n  \n \n  \n \n \n \n  \n   \n \n  \n  \n  \n \n  \n  \n  \n  \n \n   \n \nORILISSA is contraindicated in women with known osteoporosis [see Contraindications (4)]. \nConsider assessment of BMD in patients with a history of a low-trauma fracture or other risk \nfactors for osteoporosis or bone loss. Limit the duration of use to reduce the extent of bone loss \n[see Dosage and Administration (2.2)]. Although the effect of supplementation with calcium and \nvitamin D was not studied, such supplementation may be beneficial for all patients.  \n5.2 Change in Menstrual Bleeding Pattern and Reduced Ability to Recognize Pregnancy \nWomen who take ORILISSA may experience a reduction in the amount, intensity or duration of \nmenstrual bleeding, which may reduce the ability to recognize the occurrence of a pregnancy in a \ntimely manner [see Adverse Reactions (6.1)]. Perform pregnancy testing if pregnancy is \nsuspected, and discontinue ORILISSA if pregnancy is confirmed. \n5.3 Suicidal Ideation, Suicidal Behavior, and Exacerbation of Mood Disorders \nSuicidal ideation and behavior, including one completed suicide, occurred in subjects treated \nwith ORILISSA in the endometriosis clinical trials. ORILISSA subjects had a higher incidence \nof depression and mood changes compared to placebo, and ORILISSA subjects with a history of \nsuicidality or depression had a higher incidence of depression compared to subjects without such \na history [see Adverse Reactions (6.1)]. Promptly evaluate patients with depressive symptoms to \ndetermine whether the risks of continued therapy outweigh the benefits [see Adverse Reactions \n(6.1)]. Patients with new or worsening depression, anxiety or other mood changes should be \nreferred to a mental health professional, as appropriate. Advise patients to seek immediate \nmedical attention for suicidal ideation and behavior. Reevaluate the benefits and risks of \ncontinuing ORILISSA if such events occur. \n5.4 Hepatic Transaminase Elevations \nIn clinical trials, dose-dependent elevations of serum alanine aminotransferase (ALT) at least 3-\ntimes the upper limit of the reference range occurred with ORILISSA. Use the lowest effective \ndose of ORILISSA and instruct patients to promptly seek medical attention in case of symptoms \nor signs that may reflect liver injury, such as jaundice. Promptly evaluate patients with elevations \nin liver tests to determine whether the benefits of continued therapy outweigh the risks [see \nAdverse Reactions (6.1)]. \n5.5 Interactions with Hormonal Contraceptives \nAdvise women to use effective non-hormonal contraceptives during treatment with ORILISSA \nand for 28 days after discontinuing ORILISSA [see Use in Specific Populations (8.1, 8.3), Drug \nInteractions (7.1), Clinical Pharmacology (12.3)]. \nIncrease in Estrogen Exposure and Potential Associated Increased Risks When ORILISSA 200 \nmg Twice Daily is Taken With Combined Hormonal Contraceptives \nCo-administration of a combined oral contraceptive (COC) (containing 20 mcg ethinyl \nestradiol/0.1 mg levonorgestrel) following administration of ORILISSA 200 mg twice daily for \n14 days increases the plasma ethinyl estradiol concentration by 2.2-fold compared to this COC \nalone. ORILISSA 200 mg twice daily co-administered with a COC containing ethinyl estradiol \nmay lead to increased risk of ethinyl estradiol-related adverse events including thromboembolic \nReference ID: 5184902 \nThis label may not be the latest approved by FDA.  \nFor current labeling information, please visit https://www.fda.gov/drugsatfda\n \n\n \n \n   \n \n  \n   \n \n \n \n \n \n \n  \n    \n \n \n  \n \n  \n  \n \n \n  \n   \n \n \n  \n \n  \n \n \n \ndisorders and vascular events and is not recommended [see Drug Interactions (7.1), Clinical \nPharmacology (12.3)]. \nPotential for Reduced Efficacy of Progestin-Containing Hormonal Contraceptives \nCo-administration of ORILISSA 200 mg twice daily and a COC containing 0.1 mg \nlevonorgestrel decreases the plasma concentrations of levonorgestrel by 27%, potentially \naffecting contraceptive efficacy. Co-administration of ORILISSA with COCs containing \nnorethindrone acetate did not show reduction in plasma concentrations of norethindrone [see \nDrug Interactions (7.1), Clinical Pharmacology (12.3)]. \nCo-administration of ORILISSA with progestin-containing intrauterine contraceptive systems \nhas not been studied. \nReduced efficacy of ORILISSA \nBased on the mechanism of action of ORILISSA, estrogen-containing contraceptives are \nexpected to reduce the efficacy of ORILISSA. The effect of progestin-only contraceptives on the \nefficacy of ORILISSA is unknown.  \n6 ADVERSE REACTIONS \nThe following serious adverse reactions are discussed elsewhere in labeling: \n• Bone loss [see Warnings and Precautions (5.1)] \n• Change in menstrual bleeding pattern and reduced ability to recognize pregnancy [see \nWarnings and Precautions (5.2)] \n• Suicidal ideation, suicidal behavior, and exacerbation of mood disorders [see Warnings and \nPrecautions (5.3)] \n• Hepatic transaminase elevations [see Warnings and Precautions (5.4)] \n6.1 Clinical Trials Experience \nBecause clinical trials are conducted under widely varying conditions, adverse reaction rates \nobserved in the clinical trials of a drug cannot be directly compared to rates in the clinical trials \nof another drug and may not reflect the rates observed in clinical practice. \nThe safety of ORILISSA was evaluated in two six-month, randomized, double-blind, placebo-\ncontrolled clinical trials [EM-1 (NCT01620528) and EM-2 (NCT01931670)] in which a total of \n952 adult women with moderate to severe pain associated with endometriosis were treated with \nORILISSA (475 with 150 mg once daily and 477 with 200 mg twice daily) and 734 were treated \nwith placebo. The population age range was 18-49 years old. Women who completed six months \nof treatment and met eligibility criteria continued treatment in two uncontrolled, blinded six-\nmonth extension trials [EM-3 (NCT01760954) and EM-4 (NCT02143713)], for a total treatment \nduration of up to 12 months.  \nSerious Adverse Events \nOverall, the most common serious adverse events reported for subjects treated with ORILISSA \nin the two placebo-controlled clinical trials (Studies EM-1 and EM-2) included appendicitis \n(0.3%), abdominal pain (0.2%), and back pain (0.2%). In these trials, 0.2% of subjects treated \nReference ID: 5184902 \nThis label may not be the latest approved by FDA.  \nFor current labeling information, please visit https://www.fda.gov/drugsatfda\n \n\n \n \n \n \n \n \n \n \n \n \n \n \n   \n  \n \n  \n  \n \n \n \n \n \n \n \n \n   \n       \n       \n       \n       \n       \n       \n    \n     \n       \n       \n \nwith ORILISSA 150 mg once daily and 0.2% of subjects treated with ORILISSA 200 mg twice \ndaily discontinued therapy due to serious adverse reactions compared to 0.5% of those given \nplacebo. \nAdverse Reactions Leading to Study Discontinuation \nIn the two placebo-controlled clinical trials (Studies EM-1 and EM-2), 5.5% of subjects treated \nwith ORILISSA 150 mg once daily and 9.6% of subjects treated with ORILISSA 200 mg twice \ndaily discontinued therapy due to adverse reactions compared to 6.0% of those given placebo. \nDiscontinuations were most commonly due to hot flushes or night sweats (1.1% with 150 mg \nonce daily and 2.5% with 200 mg twice daily) and nausea (0.8% with 150 mg once daily and \n1.5% with 200 mg twice daily) and were dose-related. The majority of discontinuations due to \nhot flushes or night sweats (10 of 17, 59%) and nausea (7 of 11, 64%) occurred within the first 2 \nmonths of therapy. \nIn the two extension trials (Studies EM-3 and EM-4), discontinuations were most commonly due \nto decreased BMD and were dose-related. In these trials, 0.3% of subjects treated with \nORILISSA 150 mg once daily and 3.6% of subjects treated with ORILISSA 200 mg twice daily \ndiscontinued therapy due to decreased BMD. \nCommon Adverse Reactions: \nAdverse reactions reported in ≥ 5% of women in the two placebo-controlled trials in either \nORILISSA dose group and at a greater frequency than placebo are noted in the following table.  \nTable 2. Percentage of Subjects in Studies EM-1 and EM-2 with Treatment-Emergent \nAdverse Reactions Occurring in at Least 5% of Subjects (either ORILISSA Dose Group) \nand at a Greater Incidence than with Placebo \nORILISSA \n150 mg Once Daily \nN=475 \nORILISSA \n200 mg Twice Daily \nN=477 \nPlacebo \nN=734 \n% % % \nHot Flush 24 46 9 \nHeadache 17 20 12 \nNausea 11 16 13 \nInsomnia 6 9 3 \nMood altered, mood swings 6 5 3 \nAmenorrhea 4 7 <1 \nDepressed mood, depression, depressive \nsymptoms and/or tearfulness 3 6 2 \nAnxiety 3 5 3 \nArthralgia 3 5 3 \nThe most commonly reported adverse reactions in the extension trials (EM-3 and EM-4) were \nsimilar to those in the placebo-controlled trials. \nReference ID: 5184902 \nThis label may not be the latest approved by FDA.  \nFor current labeling information, please visit https://www.fda.gov/drugsatfda\n \n\n  \n  \n \n  \n \n  \n \n \n \n \n  \n \n   \n  \n \n  \n \n  \n   \n  \n \n   \n \n  \n \n \n \n \n \n  \n \n    \n    \n    \n  \n \n    \n \n    \n    \nLess Common Adverse Reactions: \nIn Study EM-1 and Study EM-2, adverse reactions reported in ≥ 3% and < 5% in either \nORILISSA dose group and greater than placebo included: decreased libido, diarrhea, abdominal \npain, weight gain, dizziness, constipation and irritability. \nBone Loss \nThe effect of ORILISSA on BMD was assessed by dual-energy X-ray absorptiometry (DXA). \nIn Studies EM-1 and EM-2, there was a dose-dependent decrease in BMD in ORILISSA-treated \nsubjects compared to an increase in placebo-treated subjects.  \nIn Study EM-1, compared to placebo, the mean change from baseline in lumbar spine BMD at 6 \nmonths was -0.9% (95% CI: -1.3, -0.4) with ORILISSA 150 mg once daily and -3.1% (95% CI: -\n3.6, -2.6) with ORILISSA 200 mg twice daily (Table 3). The percentage of subjects with greater \nthan 8% BMD decrease in lumbar spine, total hip or femoral neck at any time point during the \nplacebo-controlled treatment period was 2% with ORILISSA 150 mg once daily, 7% with \nORILISSA 200 mg twice daily and < 1% with placebo. In the blinded extension Study EM-3, \ncontinued bone loss was observed with 12 months of continuous treatment with ORILISSA. The \npercentage of subjects with greater than 8% BMD decrease in lumbar spine, total hip or femoral \nneck at any time point during the extension treatment period was 8% with continuous ORILISSA \n150 mg once daily and 21% with continuous ORILISSA 200 mg twice daily.  \nIn Study EM-2, compared to placebo, the mean change from baseline in lumbar spine BMD at 6 \nmonths was -1.3% (95% CI: -1.8, -0.8) with ORILISSA 150 mg once daily and -3.0% (95% CI: -\n3.5, -2.6) with ORILISSA 200 mg twice daily (Table 3). The percentage of subjects with greater \nthan 8% BMD decrease in lumbar spine, total hip or femoral neck at any time point during the \nplacebo-controlled treatment period was < 1% with ORILISSA 150 mg once daily, 6% with \nORILISSA 200 mg twice daily and 0% with placebo. In the blinded extension Study EM-4, \ncontinued bone loss was observed with 12 months of continuous treatment with ORILISSA. The \npercentage of subjects with greater than 8% BMD decrease in lumbar spine, total hip or femoral \nneck at any time point during the extension treatment period was 2% with continuous ORILISSA \n150 mg once daily and 21% with continuous ORILISSA 200 mg twice daily.  \nTable 3. Percent Change from Baseline in Lumbar Spine BMD at Month 6 \nORILISSA \n150 mg \nOnce Daily \nORILISSA \n200 mg \nTwice Daily Placebo \nEM-1 \nN 183 180 277 \nPercent Change from Baseline, % -0.3 -2.6 0.5 \nTreatment Difference, % (95% CI) -0.9 \n(-1.3, -0.4) \n-3.1 \n(-3.6, -2.6) \nEM-2 \nN 174 183 271 \nPercent Change from Baseline, % -0.7 -2.5 0.6 \nReference ID: 5184902 \nThis label may not be the latest approved by FDA.  \nFor current labeling information, please visit https://www.fda.gov/drugsatfda\n \n\n    \n  \n \n    \n  \n \n \n  \n   \n   \n \n \n \n \n \n \nTreatment Difference, % (95% CI) -1.3 \n(-1.8, -0.8) \n-3.0 \n(-3.5, -2.6) \nTo assess for recovery, the change in lumbar spine BMD over time was analyzed for subjects \nwho received continuous treatment with ORILISSA 150 mg once daily or ORILISSA 200 mg \ntwice daily for up to 12 months and who were then followed after cessation of therapy for an \nadditional 6 months. Partial recovery of BMD was seen in these subjects (Figure 1). \nIn Study EM-3, if a subject had BMD loss of more than 1.5% at the lumbar spine or more than \n2.5% at the total hip at the end of treatment, follow-up DXA was required after 6 months off-\ntreatment. In Study EM-4, all subjects were required to have a follow-up DXA 6 months off \ntreatment regardless of change in BMD and if a subject had BMD loss of more than 1.5% at the \nlumbar spine or more than 2.5% at the total hip after 6 months off treatment, follow-up DXA \nwas required after 12 months off-treatment. Figure 2 shows the change in lumbar spine BMD for \nthe subjects in Study EM-2/EM-4 who completed 12 months of treatment with ORILISSA and \nwho had a follow-up DXA 12-months off treatment.  \nFigure 1. Percent Change from Baseline in Lumbar Spine BMD in Subjects Who Received \n12 Months of ORILISSA and Had Follow-up BMD 6 Months off Therapy in Studies EM-\n2/EM-4 \nReference ID: 5184902 \nThis label may not be the latest approved by FDA.  \nFor current labeling information, please visit https://www.fda.gov/drugsatfda\n \n\n \n \n \n \n  \n  \n \n   \n \n \n \n \n \n \n \n \n \n \n \n \n \n    \n    \n \n  \n \nFigure 2. Percent Change from Baseline in Lumbar Spine BMD in Subjects Who Received \n12 Months of ORILISSA and Had Follow-up BMD 12 Months off Therapy in Studies EM-\n2/EM-4 \nSuicidal Ideation, Suicidal Behavior and Exacerbation of Mood Disorders \nIn the placebo-controlled trials (Studies EM-1 and EM-2), ORILISSA was associated with \nadverse mood changes (see Table 2 and Table 4), particularly in those with a history of \ndepression. \nTable 4. Suicidal Ideation and Suicidal Behavior in Studies EM-1 and EM-2  \nAdverse Reactions \nORILISSA \nPlacebo \n(N=734) \nn (%) \n150 mg \nOnce Daily \n(N=475) \nn (%) \n200 mg \nTwice Daily \n(N=477) \nn (%) \nCompleted suicide 1 (0.2) 0 0 \nSuicidal ideation 1 (0.2) 1 (0.2) 0 \nA 44-year-old woman received 31 days of ORILISSA 150 mg once daily then completed suicide \n2 days after ORILISSA discontinuation. She had no relevant past medical history; life stressors \nwere noted. \nReference ID: 5184902 \nThis label may not be the latest approved by FDA.  \nFor current labeling information, please visit https://www.fda.gov/drugsatfda\n \n\n \n \n  \n \n \n \n  \n \n \n \n \n \n \n \n \n \n   \n \n  \n \n \n \n \n \n \n \n \n \n \n \n        \n     \n         \n \n        \n     \n         \n \n        \n     \n         \nAmong the 2090 subjects exposed to ORILISSA in the endometriosis Phase 2 and Phase 3 \nstudies, there were four reports of suicidal ideation. In addition to the two subjects in Table 4, \nthere were two additional reports of suicidal ideation: one subject in EM-3 (150 mg once daily) \nand one in a Phase 2 study (75 mg once daily, an unapproved dose). Three of these subjects had \na history of depression.  Two subjects discontinued ORILISSA and two completed the clinical \ntrial treatment periods. \nHepatic Transaminase Elevations \nIn the placebo-controlled clinical trials (Studies EM-1 and EM-2), dose-dependent asymptomatic \nelevations of serum ALT to at least 3-times the upper limit of the reference range occurred \nduring treatment with ORILISSA (150 mg once daily – 1/450, 0.2%; 200 mg twice daily – \n5/443, 1.1%; placebo – 1/696, 0.1%). Similar increases were seen in the extension trials (Studies \nEM-3 and EM-4). \nChanges in Lipid Parameters \nDose-dependent increases in total cholesterol, low-density lipoprotein cholesterol (LDL-C), high \ndensity lipoprotein cholesterol (HDL-C), and serum triglycerides were noted during ORILISSA \ntreatment in EM-1 and EM-2. In EM-1 and EM-2, 12% and 1% of subjects with mildly elevated \nLDL-C (130-159 mg/dL) at baseline had an increase in LDL-C concentrations to 190 mg/dL or \nhigher during treatment with ORILISSA and placebo, respectively. In EM-1 and EM-2, 4% and \n1% of subjects with mildly elevated serum triglycerides (150-300 mg/dL) at baseline had an \nincrease in serum triglycerides to at least 500 mg/dL during treatment with ORILISSA and \nplacebo, respectively. The highest measured serum triglyceride concentration during treatment \nwith ORILISSA was 982 mg/dL.  \nTable 5. Mean Change and Maximum Increase from Baseline in Serum Lipids in Studies \nEM-1 and EM-2 \nORILISSA \n150 mg \nOnce Daily \nN=475 \nORILISSA \n200 mg \nTwice Daily \nN=477 \nPlacebo \nN=734 \nLDL-C (mg/dL) \nMean change at Month 6 5 13 -3 \nMaximum increase during \nTreatment Period 137 107 122 \nHDL-C (mg/dL) \nMean change at Month 6 2 4 1 \nMaximum increase during \nTreatment Period 43 52 45 \nTriglycerides (mg/dL) \nMean change at Month 6 <1 11 -3 \nMaximum increase during \nTreatment Period 624 484 440 \nReference ID: 5184902 \nThis label may not be the latest approved by FDA.  \nFor current labeling information, please visit https://www.fda.gov/drugsatfda\n \n\n  \n \n   \n \n  \n  \n  \n \n   \n \n   \n \n \n  \n        \n \n \n  \n \n \n \n   \n \n \n  \n  \n \n \n \n \n \n \n \nLipid increases occurred within 1 to 2 months after the start of ORILISSA and remained stable \nthereafter over 12 months.  \nHypersensitivity Reactions \nIn Studies EM-1 and EM-2, non-serious hypersensitivity reactions including rash occurred in \n5.8% of ORILISSA treated-subjects and 6.1% of placebo-treated subjects. These events led to \nstudy drug discontinuation in 0.4% of ORILISSA-treated subjects and 0.5% of placebo-treated \nsubjects. \nEffects on Menstrual Bleeding Patterns \nThe effects of ORILISSA on menstrual bleeding were evaluated for up to 12 months using an \nelectronic daily diary where subjects classified their flow of menstrual bleeding (if present in the \nlast 24 hours) as spotting, light, medium, or heavy. ORILISSA led to a dose-dependent reduction \nin mean number of bleeding and spotting days and bleeding intensity in those subjects who \nreported menstrual bleeding.  \nTable 6. Mean Bleeding/Spotting Days and Mean Intensity Scores at Month 3 \nORILISSA \n150mg Once Daily \nORILISSA \n200mg Twice Daily Placebo \nBaseline Month 3 Baseline Month 3 Baseline Month 3 \nMean bleeding/ \nspotting days \nin prior 28 days \n5.3 2.8 5.7 0.8 5.4 4.6 \nMean Intensity \nscorea 2.6 2.2 2.5 2.0 2.6 2.4 \naIntensity for subjects who reported at least 1 day of bleeding or spotting during 28 day interval. \nScale ranges from 1 to 4, 1 = spotting, 2 = light, 3 = medium, 4 = heavy \nORILISSA also demonstrated a dose-dependent increase in the percentage of women with \namenorrhea (defined as no bleeding or spotting in a 56-day interval) over the treatment period. \nThe incidence of amenorrhea during the first six months of treatment ranged from 6-17% for \nORILISSA 150 mg once daily, 13-52% for ORILISSA 200 mg twice daily and less than 1% for \nplacebo. During the second 6 months of treatment, the incidence of amenorrhea ranged from 11-\n15% for ORILISSA 150 mg once daily and 46-57% for ORILISSA 200 mg twice daily. \nAfter 6 months of therapy with ORILISSA 150 mg once daily, resumption of menses after \nstopping treatment was reported by 59%, 87% and 95% of women within 1, 2, and 6 months, \nrespectively. After 6 months of therapy with ORILISSA 200 mg twice daily, resumption of \nmenses after stopping treatment was reported by 60%, 88%, and 97% of women within 1, 2, and \n6 months, respectively. \nAfter 12 months of therapy with ORILISSA 150 mg once daily resumption of menses after \nstopping treatment was reported by 77%, 95% and 98% of women within 1, 2, and 6 months \nrespectively. After 12 months of therapy with ORILISSA 200 mg twice daily resumption of \nmenses after stopping treatment was reported by 55%, 91% and 96% of women within 1, 2, and \n6 months respectively. \nReference ID: 5184902 \nThis label may not be the latest approved by FDA.  \nFor current labeling information, please visit https://www.fda.gov/drugsatfda\n \n\n \n \n \n \n \n \n \n \n \n   \n \n \n   \n  \n   \n  \n  \n \n \n   \n \n \n \n \n  \n \n \n  \n \n  \n \n \n \n \n  \n \n \n \n  \n \n \n \n \n   \n \n \n6.2 Postmarketing Experience \nThe following adverse reactions have been identified during post-approval use of ORILISSA. \nBecause these reactions are reported voluntarily from a population of uncertain size, it is not \nalways possible to reliably estimate their frequency or establish a causal relationship to drug \nexposure. \nImmune system disorders: hypersensitivity reactions (including anaphylaxis, angioedema, and \nurticaria). \n7 DRUG INTERACTIONS \n7.1 Potential for ORILISSA to Affect Other Drugs \nElagolix is: \n• A weak to moderate inducer of cytochrome P450 (CYP) 3A. Co-administration with \nORILISSA may decrease plasma concentrations of drugs that are substrates of CYP3A \n(see Table 7). \n• A weak inhibitor of CYP 2C19. Co-administration with ORILISSA may increase plasma \nconcentrations of drugs that are substrates of CYP2C19 (see Table 7). \n• An inhibitor of efflux transporter P-glycoprotein (P-gp). Co-administration with \nORILISSA may increase plasma concentrations of drugs that are substrates of P-gp (see \nTable 7). \nThe effects of co-administration of ORILISSA on concentrations of concomitant drugs and the \nclinical recommendations for these drug interactions are summarized in Table 7. \nTable 7. Drug Interactions: Effects of ORILISSA on Other Drugs \nConcomitant \nDrug Class: \nDrug Name \nEffect on Plasma \nExposure of \nConcomitant Drug \nClinical Recommendations \nCardiac glycosides: \ndigoxin \n↑ digoxin Increase monitoring of digoxin concentrations and \npotential signs and symptoms of clinical toxicity when \ninitiating ORILISSA in patients who are taking digoxin. \nIf ORILISSA is discontinued, increase monitoring of \ndigoxin concentrations. \nBenzodiazepines: \noral midazolam \n↓ midazolam Consider increasing the dose of midazolam by no more \nthan 2-fold and individualize midazolam therapy based \non the patient’s response. \nStatins: \nrosuvastatin \n↓ rosuvastatin Monitor lipid levels and adjust the dose of rosuvastatin, if \nnecessary. \nProton pump \ninhibitors: \nomeprazole \n↑ omeprazole No dose adjustment needed for omeprazole 40 mg once \ndaily when co-administered with ORILISSA. When \nORILISSA is used concomitantly with higher doses of \nomeprazole, consider dosage reduction of omeprazole. \nReference ID: 5184902 \nThis label may not be the latest approved by FDA.  \nFor current labeling information, please visit https://www.fda.gov/drugsatfda\n \n\n \n \n \n \n \n \n \n \n  \n      \n             \n  \n \n  \n  \n  \n  \n  \n  \n   \n   \n \n \n  \n \n  \n \n \n \n \n \n    \n \nCombined hormonal \ncontraceptives: \noral ethinyl \nestradiol/levonorgestrel \n↑ethinyl estradiol \n↓levonorgestrel \nAdvise women to use effective non-hormonal \ncontraception during treatment with ORILISSA and for \n28 days after discontinuing ORILISSA. \nSee Tables 10 and 11 [see Clinical Pharmacology (12.3)]. \nThe direction of the arrow indicates the direction of the change in the area under the curve (AUC) (↑= increase, ↓ = \ndecrease). \n7.2 Potential for Other Drugs to Affect ORILISSA \nElagolix is a substrate of CYP3A, P-gp, and OATP1B1. \nConcomitant use of ORILISSA 200 mg twice daily and strong CYP3A inhibitors for more than 1 \nmonth is not recommended. Limit concomitant use of ORILISSA 150 mg once daily and strong \nCYP3A inhibitors to 6 months.  \nCo-administration of ORILISSA with strong CYP3A inducers may decrease elagolix plasma \nconcentrations and may result in a decrease of the therapeutic effects of ORILISSA. \nConcomitant use of ORILISSA 200 mg twice daily and rifampin is not recommended. Limit \nconcomitant use of ORILISSA 150 mg once daily and rifampin to 6 months. \nThe effect of concomitant use of P-gp inhibitors or inducers on the pharmacokinetics of \nORILISSA is unknown. OATP1B1 inhibitors that are known or expected to significantly \nincrease elagolix plasma concentrations are contraindicated due to increased risk of elagolix-\nassociated adverse reactions [see Contraindications (4)]. \n8 USE IN SPECIFIC POPULATIONS \n8.1 Pregnancy \nPregnancy Exposure Registry \nThere is a pregnancy registry that monitors pregnancy outcomes in women exposed to \nORILISSA during pregnancy . Healthcare providers are encouraged to register patients, or \npregnant women may enroll themselves in the registry by calling 1-833-782-7241 or \nvisiting https://www.bloompregnancyregistry.com. \nRisk Summary \nUse of ORILISSA is contraindicated in pregnant women. Exposure to ORILISSA early in \npregnancy may increase the risk of early pregnancy loss. Discontinue ORILISSA if pregnancy \noccurs during treatment. \nThe limited human data with the use of ORILISSA in pregnant women are insufficient to \ndetermine whether there is a risk for major birth defects or miscarriage. Although two cases of \ncongenital malformations were reported in clinical trials with ORILISSA, no pattern was \nidentified and miscarriages were reported at a similar incidence across treatment groups (see \nData). \nReference ID: 5184902 \nThis label may not be the latest approved by FDA.  \nFor current labeling information, please visit https://www.fda.gov/drugsatfda\n \n\n \n \n \n \n \n \n \n \n \n   \n  \n \n \n  \n \n \n \n \n \n \n \n \n \n \n \n \n  \n  \n   \n \n \n \nWhen pregnant rats and rabbits were orally dosed with elagolix during the period of \norganogenesis, postimplantation loss was observed in pregnant rats at doses 20 times the \nmaximum recommended human dose (MRHD). Spontaneous abortion and total litter loss was \nobserved in rabbits at doses 7 and 12 times the MRHD. There were no structural abnormalities in \nthe fetuses at exposures up to 40 and 12 times the MRHD for the rat and rabbit, respectively (see \nData). \nData \nHuman Data \nThere were 49 pregnancies reported in clinical trials of more than 3,500 women (of whom more \nthan 2,000 had endometriosis) treated with ORILISSA for up to 12 months. These pregnancies \noccurred while the women were receiving ORILISSA or within 30 days after stopping \nORILISSA. Among these 49 pregnancies, two major congenital malformations were reported. In \none case of infant cleft palate, the mother was treated with ORILISSA 150 mg daily and the \nestimated fetal exposure to ORILISSA occurred during the first 30 days of pregnancy. In one \ncase of infant tracheoesophageal fistula, the mother was treated with ORILISSA 150 mg daily \nand the estimated fetal exposure to ORILISSA occurred during the first 15 days of pregnancy. \nAmong these 49 pregnancies, there were five cases of spontaneous abortion (miscarriage) \ncompared to five cases among the 20 pregnancies that occurred in more than 1100 women \ntreated with placebo. Although the duration of fetal exposure was limited in ORILISSA clinical \ntrials, there were no apparent decreases in birth weights associated with ORILISSA in \ncomparison to placebo. \nAnimal Data \nEmbryofetal development studies were conducted in the rat and rabbit. Elagolix was \nadministered by oral gavage to pregnant rats (25 animals/dose) at doses of 0, 300, 600 and 1200 \nmg/kg/day and to rabbits (20 animals/dose) at doses of 0, 100, 150, and 200 mg/kg/day, during \nthe period of organogenesis (gestation day 6-17 in the rat and gestation day 7-20 in the rabbit). \nIn rats, maternal toxicity was present at all doses and included six deaths and decreases in body \nweight gain and food consumption. Increased postimplantation losses were present in the mid \ndose group, which was 20 times the MRHD based on AUC. In rabbits, three spontaneous \nabortions and a single total litter loss were observed at the highest, maternally toxic dose, which \nwas 12 times the MRHD based on AUC. A single total litter loss occurred at a lower non-\nmaternally toxic dose of 150 mg/kg/day, which was 7 times the MRHD.  \nNo fetal malformations were present at any dose level tested in either species even in the \npresence of maternal toxicity. At the highest doses tested, the exposure margins were 40 and 12 \ntimes the MRHD for the rat and rabbit, respectively. However, because elagolix binds poorly to \nthe rat gonadotropin-releasing hormone (GnRH) receptor (~1000 fold less than to the human \nGnRH receptor), the rat study is unlikely to identify pharmacologically mediated effects of \nelagolix on embryofetal development. The rat study is still expected to provide information on \npotential non-target-related effects of elagolix. \nIn a pre- and postnatal development study in rats, elagolix was given in the diet to achieve doses \nof 0, 100 and 300 mg/kg/day (25 per dose group) from gestation day 6 to lactation day 20. There \nwas no evidence of maternal toxicity. At the highest dose, two dams had total litter loss, and one \nReference ID: 5184902 \nThis label may not be the latest approved by FDA.  \nFor current labeling information, please visit https://www.fda.gov/drugsatfda\n \n\n  \n \n \n \n \n \n  \n  \n   \n  \n \n \n    \n \n \n \n \n \n  \n \n \n  \n \n  \n  \n  \n \nfailed to deliver. Pup survival was decreased from birth to postnatal day 4. Pups had lower birth \nweights and lower body weight gains were observed throughout the pre-weaning period at 300 \nmg/kg/day. Smaller body size and effect on startle response were associated with lower pup \nweights at 300 mg/kg/day. Post-weaning growth, development and behavioral endpoints were \nunaffected. \nMaternal plasma concentrations in rats on lactation day 21 at 100 and 300 mg/kg/day (47 and \n125 ng/mL) were 0.06-fold and 0.16-fold the maximal elagolix concentration (C\nmax) in humans at \nthe MRHD. Because the exposures achieved in rats were much lower than the human MRHD, \nthis study is not predictive of potentially higher lactational exposure in humans.  \n8.2 Lactation \nRisk Summary \nThere is no information on the presence of elagolix or its metabolites in human milk, the effects \non the breastfed child, or the effects on milk production. There are no adequate animal data on \nthe excretion of ORILISSA in milk. The developmental and health benefits of breastfeeding \nshould be considered along with the mother’s clinical need for ORILISSA and any potential \nadverse effects on the breastfed child from ORILISSA. \nData \nThere are no adequate animal data on excretion of elagolix in milk. \n8.3 Females and Males of Reproductive Potential \nBased on the mechanism of action, there is a risk of early pregnancy loss if ORILISSA is \nadministered to a pregnant woman [see Use in Specific Populations (8.1), Clinical \nPharmacology (12.1)]. \nPregnancy Testing \nORILISSA may delay the ability to recognize the occurrence of a pregnancy because it may \nreduce the intensity, duration, and amount of menstrual bleeding. Exclude pregnancy before \ninitiating treatment with ORILISSA. Perform pregnancy testing if pregnancy is suspected during \ntreatment with ORILISSA and discontinue treatment if pregnancy is confirmed [see \nContraindications (4) and Warnings and Precautions (5.2)]. \nContraception \nAdvise women to use effective non-hormonal contraception during treatment with ORILISSA \nand for 28 days after discontinuing ORILISSA [see Warnings and Precautions (5.5)]. \n8.4 Pediatric Use \nSafety and effectiveness of ORILISSA in pediatric patients have not been established.  \n8.6 Renal Impairment \nNo dose adjustment of ORILISSA is required in women with any degree of renal impairment or \nend-stage renal disease (including women on dialysis) [see Clinical Pharmacology (12.3)]. \nReference ID: 5184902 \nThis label may not be the latest approved by FDA.  \nFor current labeling information, please visit https://www.fda.gov/drugsatfda\n \n\n \n  \n  \n  \n \n \n \n  \n \n \n \n \n  \n \n  \n \n \n  \n \n8.7 Hepatic Impairment \nNo dosage adjustment of ORILISSA is required for women with mild hepatic impairment \n(Child-Pugh A). Only the 150 mg once daily regimen is recommended for women with moderate \nhepatic impairment (Child-Pugh B) and the duration of treatment should be limited to 6 months. \nORILISSA is contraindicated in women with severe hepatic impairment (Child-Pugh C) [see \nContraindications (4), and Clinical Pharmacology (12.3)]. \n10 OVERDOSAGE \nIn case of overdose, monitor the patient for any signs or symptoms of adverse reactions and \ninitiate appropriate symptomatic treatment, as needed. \n11 DESCRIPTION \nORILISSA (elagolix) tablets for oral administration contain elagolix sodium, the sodium salt of \nthe active moiety elagolix. Elagolix sodium is a nonpeptide small molecule, GnRH receptor \nantagonist. Elagolix sodium is chemically described as sodium 4-({(1R)-2-[5-(2-fluoro-3-\nmethoxyphenyl)-3-{[2-fluoro-6-(trifluoromethyl)phenyl]methyl}-4-methyl-2,6-dioxo-3,6-\ndihydropyrimidin-1(2H)-yl]-1-phenylethyl}amino)butanoate. Elagolix sodium has a molecular \nformula of C32H29F5N3O5Na and a molecular weight of 653.58. Elagolix free acid has a \nmolecular weight of 631.60. \nElagolix sodium has the following structural formula: \nElagolix sodium is a white to off white to light yellow powder and is freely soluble in water. \nORILISSA 150 mg tablets are light pink, oblong, film-coated tablets with “EL 150” debossed on \none side. Each tablet contains 155.2 mg of elagolix sodium (equivalent to 150 mg of elagolix) as \nthe active ingredient and the following inactive ingredients: mannitol, sodium carbonate \nReference ID: 5184902 \nThis label may not be the latest approved by FDA.  \nFor current labeling information, please visit https://www.fda.gov/drugsatfda\n \n\n \n \n \n \n \n \n \n \n \n \n \n  \n \n \n \n  \n \n   \n \n  \n  \n \n \n   \n  \n \n   \n   \n \nmonohydrate, pregelatinized starch, povidone, magnesium stearate, polyvinyl alcohol, titanium \ndioxide, polyethylene glycol, talc, and carmine high tint. \nORILISSA 200 mg tablets are light orange, oblong, film-coated tablets with “EL 200” debossed \non one side. Each tablet contains 207.0 mg of elagolix sodium (equivalent to 200 mg of elagolix) \nas the active ingredient and the following inactive ingredients: mannitol, sodium carbonate \nmonohydrate, pregelatinized starch, povidone, magnesium stearate, polyvinyl alcohol, titanium \ndioxide, polyethylene glycol, talc, and iron oxide red.  \n12 CLINICAL PHARMACOLOGY \n12.1 Mechanism of Action \nORILISSA is a GnRH receptor antagonist that inhibits endogenous GnRH signaling by binding \ncompetitively to GnRH receptors in the pituitary gland. Administration of ORILISSA results in \ndose-dependent suppression of luteinizing hormone (LH) and follicle-stimulating hormone \n(FSH), leading to decreased blood concentrations of the ovarian sex hormones, estradiol and \nprogesterone. \n12.2 Pharmacodynamics \nEffect on Ovulation and Estradiol \nIn a 3-menstrual cycle study in healthy women, ORILISSA 150 mg once daily and 200 mg twice \ndaily resulted in an ovulation rate of approximately 50% and 32%, respectively. In the Phase 3 \ntrials in women with endometriosis, ORILISSA caused a dose-dependent reduction in median \nestradiol concentrations to approximately 42 pg/mL for 150 mg once daily regimen and 12 \npg/mL for the 200 mg twice daily regimen. \nCardiac Electrophysiology \nThe effect of elagolix on the QTc interval was evaluated in a randomized, placebo- and positive-\ncontrolled, open-label, single-dose, crossover thorough QTc study in 48 healthy adult \npremenopausal women. Elagolix concentrations in subjects given a single dose of 1200 mg was \n17-times higher than the concentration in subjects given elagolix 200 mg twice daily. There was \nno clinically relevant prolongation of the QTc interval.  \n12.3 Pharmacokinetics \nThe pharmacokinetic properties of ORILISSA in healthy subjects are summarized in Table 8. \nThe steady state pharmacokinetic parameters under fasting conditions are summarized in \nTable 9. \nTable 8. Pharmacokinetic Properties of ORILISSA in Healthy Subjects \nAbsorption \nTmax (h) 1.0 \nEffect of high-fat meal (relative to fasting) AUC: ↓24%, Cmax: ↓36% \nDistribution \nReference ID: 5184902 \nThis label may not be the latest approved by FDA.  \nFor current labeling information, please visit https://www.fda.gov/drugsatfda\n \n\n   \n   \n \n \n \n  \n \n    \n  \n \n  \n   \n   \n  \n \n \n \n \n \n \n    \n   \n   \n   \n   \n \n \n         \n  \n \n  \n \n \n   \n \n   \n \n% Bound to human plasma proteins 80 \nBlood-to-plasma ratio 0.6 \nMetabolism \nMetabolism \nCYP3A (major) \nMinor pathways include: CYP2D6, CYP2C8, \nand uridine glucuronosyl transferases (UGTs) \nElimination \nMajor route of elimination Hepatic metabolism \nTerminal phase elimination \nhalf-life (t1/2) (h) 4-6 \n% of dose excreted in urine <3 \n% of dose excreted in feces 90 \nTable 9. Mean (%CV) Steady State Pharmacokinetic Parameters of ORILISSA \nPharmacokinetic Parameter \n(Units) \n150 mg Once Daily \nN = 6 \n200 mg Twice Daily \nN = 7 \nCmax (ng/mL) 574 (29) 774 (68) \nAUCτ (ng●hr/mL) 1292 (31) 1725 (57) \nCL/F (L/hr) 123 (21) 144 (43) \nVdss/F 1674 (94) 881 (38) \nRac 0.98 (7) 0.89 (19) \nCV: Coefficient of variation \nCmax: peak concentration \nAUCτ: area under the plasma concentration-time curve during the dosing interval (τ) i.e., 12 hours for twice daily \nregimen, 24 hours for once daily regimen. \nCL/F: oral clearance \nVdss/F: apparent volume of distribution at steady state \nRac: drug accumulation ratio \nSpecific Populations \nPatients with Renal Impairment \nElagolix exposures (Cmax and AUC) are not altered by renal impairment. The mean exposures are \nsimilar for women with moderate to severe or end stage renal disease (including women on \ndialysis) compared to women with normal renal function.  \nPatients with Hepatic Impairment \nElagolix exposures (Cmax and AUC) are similar between women with normal hepatic function \nand women with mild hepatic impairment. Elagolix exposures in women with moderate and \nsevere hepatic impairment are approximately 3-fold and 7-fold, respectively, higher than \nexposures from women with normal hepatic function [see Use in Specific Populations (8.7)]. \nReference ID: 5184902 \nThis label may not be the latest approved by FDA.  \nFor current labeling information, please visit https://www.fda.gov/drugsatfda\n \n\n  \n   \n \n   \n  \n  \n \n  \n \n    \n   \n  \n \n \n \n \n   \n \n \n \n \n \n \n \n \n \n \n \n   \n    \n \n \n \n \n \n \n \n \n \n   \n   \n   \n  \n \n   \n \n   \n \n \n   \n   \n \n   \n \n   \n \n \n \n   \n \n   \n \n \n \n \n \nRacial or Ethnic Groups \nNo clinically meaningful difference in the pharmacokinetics of ORILISSA between White and \nBlack subjects or between Hispanics and others was observed. There is no clinically meaningful \ndifference in the pharmacokinetics of ORILISSA between Japanese and Han Chinese subjects. \nBody weight/Body mass index \nBody weight or body mass index does not affect the pharmacokinetics of ORILISSA. \nDrug Interaction Studies \nDrug interaction studies were performed with ORILISSA and other drugs that are likely to be co-\nadministered and with drugs commonly used as probes for pharmacokinetic interactions. Tables \n10 and 11 summarize the pharmacokinetic effects when elagolix was co-administered with these \ndrugs.  \nTable 10. Drug Interactions: Change in Pharmacokinetics of Elagolix in the Presence of \nCo-administered Drugs \nCo-\nadministered \nDrug \nRegimen \nof Co-\nadministered \nDrug \nRegimen \nof \nElagolix N Ratio (90% CI)* \nKetoconazole 400 mg once \ndaily  \n150 mg single \ndose 11 \nCmax AUC \n1.77 \n(1.48 – 2.12) \n2.20 \n(1.98 – 2.44) \nRifampin# \n600 mg single \ndose 150 mg single \ndose 12 \n4.37 \n(3.62 – 5.28) \n5.58 \n(4.88 – 6.37) \n600 mg once \ndaily \n2.00 \n(1.66 – 2.41) \n1.65 \n(1.45 – 1.89) \nCI: Confidence interval \n*ratios for Cmax and AUC compare co-administration of the medication with elagolix vs. \nadministration of elagolix alone. \n# A single dose of 600 mg rifampin inhibits OATP1B1; 600 mg once daily dose of rifampin \ninhibits OATP1B1 and induces CYP3A. \nNo clinically significant changes in elagolix exposures were observed when co-administered \nwith rosuvastatin (20 mg once daily), sertraline (25 mg once daily) or fluconazole (200 mg single \ndose). \nTable 11. Drug Interactions: Change in Pharmacokinetics of Co-administered Drug in the \nPresence of Elagolix \nCo-\nadministered \nDrug \nRegimen \nof Co-\nadministered \nDrug \nRegimen \nof \nElagolix N Ratio (90% CI)* \nDigoxin 11 Cmax AUC \nReference ID: 5184902 \nThis label may not be the latest approved by FDA.  \nFor current labeling information, please visit https://www.fda.gov/drugsatfda\n \n\n \n  \n \n \n  \n \n  \n \n   \n  \n \n \n \n  \n  \n  \n \n   \n   \n  \n \n \n  \n  \n  \n \n   \n \n \n  \n  \n  \n \n   \n   \n  \n \n \n  \n  \n  \n \n   \n \n \n \n  \n \n \n \n \n \n  \n \n  \n \n   \n  \n  \n \n   \n  \n  \n \n   \n \n  \n  \n   \n \n  \n \n \n \n  \n \n  \n \n \n  \n \n \n  \n  \n  \n \n \n  \n  \n  \n \n   \n \n  \n \n   \n  \n   \n \n  \n \n   \n \n  \n  \n0.5 mg single \ndose \n200 mg \ntwice daily \nx 10 days \n1.71 \n(1.53 – 1.91) \n1.26 \n(1.17 – 1.35) \nRosuvastatin 20 mg once \ndaily \n300 mg \ntwice daily \nx 7 days \n10 0.99 \n(0.73 – 1.35) \n0.60 \n(0.50 – 0.71) \nMidazolam 2 mg single \ndose \n300 mg \ntwice daily \nx 11 days \n20 0.56 \n(0.51 – 0.62) \n0.46 \n(0.41 – 0.50) \n150 mg \nonce daily \nx 13 days \n11 0.81 \n(0.74 – 0.89) \n0.65 \n(0.58 – 0.72) \nNorethindrone 0.35 mg once \ndaily x 112 days \n150 mg \nonce daily \nx 56 days \n32 0.95 \n(0.86 – 1.05) \n0.88 \n(0.79 – 0.99) \nEthinyl \nEstradiol \nEthinyl estradiol \n35 mcg and \ntriphasic \nnorgestimate \n0.18/0.215/0.25 \nmg once daily \n150 mg \nonce daily 21 \n1.15 \n(1.07 – 1.25) \n1.30 \n(1.19 – 1.42) \nNorelgestromina 0.87 \n(0.78 – 0.97) \n0.85 \n(0.78 – 0.92) \nNorgestrela 0.89 \n(0.78 – 1.00) \n0.92 \n(0.84 – 1.01) \nEthinyl \nEstradiol Ethinyl estradiol \n20 mcg/Levonorgestrel \n0.1 mg single dose \n200 mg \ntwice daily \nx 15 days \n20 \n1.36 \n(1.27 – 1.45) \n2.18 \n(1.99 – 2.39) \nLevonorgestrel \n0.97 \n(0.88 – 1.07) 0.73 \n(0.64 – 0.82) \nOmeprazole 40 mg single \ndose \n300 mg \ntwice daily \nx 9 days \n20 1.95 \n(1.50 – 2.53) \n1.78 \n(1.39 – 2.27) \nCI: Confidence interval \n*ratios for Cmax and AUC compare co-administration of the medication with elagolix vs. administration of the \nmedication alone. \na metabolite of norgestimate \nNo clinically significant changes were observed in exposures of sertraline, fluconazole, or \nbupropion when co-administered with elagolix 300 mg twice daily. \n12.5 Pharmacogenomics \nHepatic uptake of elagolix involves the OATP 1B1 transporter protein. Higher plasma \nconcentrations of elagolix have been observed in patients who have two reduced function alleles \nof the gene that encodes OATP 1B1 (SLCO1B1 521T>C) (these patients are likely to have \nreduced hepatic uptake of elagolix and thus, higher plasma elagolix concentrations). The \nfrequency of this SLCO1B1 521 C/C genotype is generally less than 5% in most racial/ethnic \ngroups. Subjects with this genotype are expected to have a 78% mean increase in elagolix \nconcentrations compared to subjects with normal transporter function (i.e., SLCO1B1 521T/T \nReference ID: 5184902 \nThis label may not be the latest approved by FDA.  \nFor current labeling information, please visit https://www.fda.gov/drugsatfda\n \n\n \n    \n \n \n  \n \n \n \n   \n  \n   \n  \n \n \n \n    \n  \n  \n \n \n \n \n \n \n  \n  \n \n  \n    \n \n \n \n    \n  \n  \n \ngenotype). Adverse effects of elagolix have not been fully evaluated in subjects who have two \nreduced function alleles of the gene that encodes OATP1B1 (SLCO1B1 521T>C). \n13 NONCLINICAL TOXICOLOGY \n13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility \nTwo-year carcinogenicity studies conducted in mice (50, 150, or 500 mg/kg/day) and rats (150, \n300, or 800 mg/kg/day) that administered elagolix by the dietary route revealed no increase in \ntumors in mice at up to 19-fold the MRHD based on AUC. In the rat, there was an increase in \nthyroid (male and female) and liver (males only) tumors at the high dose (12 to 13-fold the \nMRHD). The rat tumors were likely species-specific and of negligible relevance to humans. \nElagolix was not genotoxic or mutagenic in a battery of tests, including the in vitro bacterial \nreverse mutation assay, the in vitro mammalian cell forward mutation assay at the thymidine \nkinase (TK+/-) locus in L5178Y mouse lymphoma cells, and the in vivo mouse micronucleus \nassay. \nIn a fertility study conducted in the rat, there was no effect of elagolix on fertility at any dose \n(50, 150, or 300 mg/kg/day). Based on AUC, the exposure multiple for the MRHD in women \ncompared to the highest dose of 300 mg/kg/day in female rats is approximately 5-fold. However, \nbecause elagolix has low affinity for the GnRH receptor in the rat [see Use in Specific \nPopulations (8.1)], and because effects on fertility are most likely to be mediated via the GnRH \nreceptor, these data have low relevance to humans. \n14 CLINICAL STUDIES \nThe efficacy of ORILISSA 150 mg once daily and 200 mg twice daily for the management of \nmoderate to severe pain associated with endometriosis was demonstrated in two multinational \ndouble-blind, placebo-controlled trials in 1686 premenopausal women [Study EM-1 \n(NCT01620528) and Study EM-2 (NCT01931670)]. The median age of women in the trials was \n32 years; 88% were White, 9% were Black or African American and 3% were other races. Each \nplacebo-controlled trial assessed the reduction in endometriosis-associated pain over 6 months of \ntreatment. \nModerate to severe pain associated with endometriosis was required for entry into the trials and \nwas assessed during screening using the composite pelvic signs and symptoms score (CPSSS) \nand other baseline criteria. \nThe CPSSS is based on a modified Biberoglu and Behrman scale with five elements: three \nresponses reported by study subjects (dysmenorrhea, dyspareunia, and non-menstrual pelvic \npain) and two findings based on investigator assessment during physical examination (rating of \npelvic tenderness and induration). Each element is scored from 0 (absent) to 3 (severe) for a \nmaximum total score of 15. A total score of at least 6, with a score of at least 2 for dysmenorrhea \nand at least 2 for non-menstrual pelvic pain was required to qualify for randomization. Subjects \nwere also required to have non-menstrual pelvic pain for at least four days in the preceding \ncalendar month, defined as 35 days. Other criteria to determine eligibility for randomization \nincluded subject responses in a daily electronic diary (Endometriosis Daily Pain Impact Scale, \nReference ID: 5184902 \nThis label may not be the latest approved by FDA.  \nFor current labeling information, please visit https://www.fda.gov/drugsatfda\n \n\n \n \n  \n \n \n \n \n   \n \n \n  \n   \n  \n \n   \n \n  \n  \n  \n    \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n  \n \n \n \n \n \n \n \n  \n \n \n \n \n \n \n \n \n \n \n  \n \n \n \n \n \n \n \n \n   \n \n \n    \n  \n \n      \n      \ndescribed below) for both dysmenorrhea and non-menstrual pelvic pain in the 35 days prior to \nrandomization. \nDysmenorrhea and Non-Menstrual Pelvic Pain \nThe co-primary efficacy endpoints were (1) the proportion of subjects whose dysmenorrhea \nresponded to treatment at Month 3 and (2) the proportion of subjects whose pelvic pain not \nrelated to menses (also known as non-menstrual pelvic pain) responded to treatment at Month 3. \nDysmenorrhea and non-menstrual pelvic pain were evaluated daily using the Endometriosis \nDaily Pain Impact Scale that asked subjects to rate their pain severity and its impact on daily \nactivities during the prior 24 hours as none, mild, moderate or severe (correlating with a score of \n0 to 3, respectively, where higher scores indicated greater severity). Scores at baseline and at \neach month were averaged over a 35-day interval. \nWomen were defined as responders if they experienced a reduction in dysmenorrhea and non-\nmenstrual pelvic pain as defined in Table 12 with no increase in analgesic use (nonsteroidal anti-\ninflammatory drug or opioid) for endometriosis-associated pain. The threshold for defining \nresponders was based on a receiver operating characteristic (ROC) analysis using the patient \nglobal impression of change as an anchor. A higher proportion of women treated with \nORILISSA 150 mg once daily or 200 mg twice daily were responders for dysmenorrhea and \nnon-menstrual pelvic pain compared to placebo in a dose-dependent manner at Month 3 [see \nTable 12]. \nTable 12. Proportion of Responders\n† for Dysmenorrhea and Non-Menstrual Pelvic Pain at \nMonth 3 in Studies EM-1 and EM-2, Using the Endometriosis Daily Pain Impact Scale \nStudy EM-1 Study EM-2 \nORILISSA Placebo ORILISSA Placebo \n150 mg \nOnce Daily \nN=248 \n200 mg \nTwice \nDaily  \nN=244 \nN=373 \n150 mg \nOnce Daily \nN=221 \n200 mg \nTwice \nDaily  \nN=225 \nN=353 \nDysmenorrhea \nDifference from placebo \n46% \n27%** \n76% \n56%** \n20% 43% \n21%** \n72% \n50%** \n23% \nNon-Menstrual \nPelvic Pain \nDifference from placebo \n50% \n14%** \n55% \n18%** \n36% 50% \n13%* \n58% \n21%** \n37% \n† Study EM-1-Dysmenorrhea responder threshold: at least 0.81 point decrease from baseline in dysmenorrhea score; \nNon-Menstrual Pelvic Pain responder threshold: at least 0.36 point decrease from baseline in Non -Menstrual Pelvic \nPain score \nStudy EM-2 - Dysmenorrhea responder threshold: at least 0.85 point decrease from baseline in dysmenorrhea score; \nNon-Menstrual Pelvic Pain responder threshold: at least 0.43 point decrease from baseline in Non- Menstrual Pelvic \nPain score \n*p ≤0.01 for test of difference from placebo \n**p≤0.001 for test of difference from placebo \nReference ID: 5184902 \nThis label may not be the latest approved by FDA.  \nFor current labeling information, please visit https://www.fda.gov/drugsatfda\n \n\n \n   \n \n   \n \n \n \n \n \n  \n  \n \n   \n \n \n \n \n \n \n   \nWomen in these studies also provided a daily self-assessment of their endometriosis pain using a \nnumeric rating scale (NRS) that asked subjects to rate their endometriosis pain at its worst over \nthe last 24 hours on a scale from 0 (no pain) to 10 (worst pain ever). In Study EM-1, baseline \nNRS scores were 5.7 for ORILISSA 150 mg once daily, 5.5 for ORILISSA 200 mg twice daily \nand 5.6 for placebo. In Study EM-2, baseline NRS scores were 5.7 for ORILISSA 150 mg once \ndaily, 5.3 for ORILISSA 200 mg twice daily and 5.6 for placebo. Women taking ORILISSA 150 \nmg once daily and 200 mg twice daily reported a statistically (p <0.001) significant reduction \nfrom baseline in NRS scores compared to placebo at Month 3 in both Studies EM-1 and EM-2 \n(Study EM-1: 0.7 points for ORILISSA 150 mg once daily and 1.3 points for ORILISSA 200 mg \ntwice daily; Study EM-2: 0.6 points for ORILISSA 150 mg once daily and 1.2 points for \nORILISSA 200 mg twice daily). \nIn addition, both ORILISSA treatment groups showed statistically significantly greater mean \ndecreases from baseline compared to placebo in dysmenorrhea and non-menstrual pelvic pain \nscores at Month 6. Figures 3 through 6 show the mean scores for dysmenorrhea and non-\nmenstrual pelvic pain over time for Study EM-1 and EM-2. \nFigure 3. Mean Dysmenorrhea Pain Scoresa Figure 4. Mean Dysmenorrhea Pain Scoresa \nin Study EM-1 Over 6 Months in Study EM-2 Over 6 Months \nReference ID: 5184902 \nThis label may not be the latest approved by FDA.  \nFor current labeling information, please visit https://www.fda.gov/drugsatfda\n \n\n \n \n \n \n \n \n \n  \n \n  \n \n   \n  \n \n \n   \n \n \nFigure 5. Mean Non-Menstrual Pelvic Paina Figure 6. Mean Non-Menstrual Pelvic Paina \nScores in Study EM-1 Over 6 Months Scores in Study EM-2 Over 6 Months \nDyspareunia \nDyspareunia associated with endometriosis was evaluated as a secondary endpoint using the \nEndometriosis Daily Pain Impact Scale that asked subjects to rate their pain during sexual \nintercourse in the prior 24 hours as none, mild, moderate, severe (correlating with a score of 0 to \n3, respectively, where higher scores indicated greater severity), or not applicable. In both Studies \nEM-1 and EM-2, women treated with ORILISSA 200 mg twice daily showed statistically \nsignificantly greater reduction in dyspareunia from baseline to Month 3 than women given \nplacebo (Study EM-1: 0.2; Study EM-2: 0.3). Figures 7 and 8 show the mean scores over time \nfor Study EM-1 and EM-2.  \nFigure 7. Mean Dyspareunia Scoresa in Figure 8. Mean Dyspareunia Scoresa in \nStudy EM-1 Over 3 Months Study EM-2 Over 3 Months \nReference ID: 5184902 \nThis label may not be the latest approved by FDA.  \nFor current labeling information, please visit https://www.fda.gov/drugsatfda\n \n\n \n  \n \n \n   \n  \n  \n \n \n \n \n \n \n  \n \n \n \n \n \n \n \n  \n \n \n \n \n \n \n \n \n \n \n \n \n \n  \n \n  \n \n  \n \n \n \n  \n \n  \n \n \n  \n \n \n \n \n \n \n \n \n \n \n \n \n  \n \n  \n \n  \n \n \n \n  \n \n  \n \n \n  \n \n \n \n \n \n \n \n \n \n \n \n \n \n  \n \n  \n \n  \n \n \n \n  \n \n  \n \n \n \n \n      \n \n \n      \n \n \n \n \n      \n \n \n \n \n      \nUse of rescue pain medication \nIn EM-1 and EM-2, 59% and 60% of patients used an opioid rescue analgesic for pain at \nbaseline. The opioid rescue analgesics used at baseline were predominantly \nhydrocodone/acetaminophen (HC/APAP) and codeine/APAP at strengths of 5/300-325 mg and \n30/300-500 mg. In EM-1, of all patients on an opioid at baseline, 98% and 2% were on \nHC/APAP and codeine/APAP, respectively. In EM-2, of all patients on an opioid at baseline, \n50% were on HC/APAP and 16% were on codeine/APAP.  \nOther data related to opioid rescue analgesic use are summarized in Table 13. \nTable 13. Opioid Rescue Analgesic Use in EM-1 and EM-2 \nStudy EM-1 Study EM-2 \nORILISSA \n150 mg \nOnce Daily \nORILISSA \n200 mg \nTwice \nDaily \nPlacebo ORILISSA \n150 mg \nOnce Daily \nORILISSA \n200 mg \nTwice \nDaily \nPlacebo \nTablets per month at baseline \n(mean±SD) \n15 \n±24 \n15 \n±25 \n13 \n±21 \n13 \n±29 \n12 \n±26 \n12 \n±21 \nTablets per month at baseline \n[Median (Min, Max)] \n4 \n(0, 184) \n4 \n(0, 195) \n4 \n(0, 146) \n4 \n(0, 236) \n3 \n(0, 214) \n4 \n(0, 152) \nTablets per month at Month 3 \n(mean±SD) \n12 \n±29 \n7 \n±18 \n10 \n±17 \n8 \n±22 \n5 \n±14 \n8 \n±15 \nTablets per month at Month 3 \n[Median (Min, Max)] \n0 \n(0, 251) \n0 \n(0, 162) \n2 \n(0, 144) \n0 \n(0, 168) \n0 \n(0, 136) \n2 \n(0, 142) \nTablets per month at Month 6 \n(mean±SD) \n11 \n±26 \n7 \n±17 \n11 \n±19 \n7 \n±19 \n5 \n±14 \n8 \n±15 \nTablets per month at Month 6 \n[Median (Min, Max)] \n0 \n(0, 224) \n0 \n(0, 157) \n3 \n(0, 185) \n0 \n(0, 185) \n0 \n(0, 157) \n2 \n(0, 142) \nNumber and % of patients on \nany dose of opioid rescue at \nbaseline who were off opioid \nat Month 3* \n46/150 \n(31%) \n59/151 \n(39%) \n36/211 \n(17%) \n44/124 \n(35%) \n68/134 \n(51%) \n54/220 \n(25%) \nNumber and % of patients on \nany dose of opioid rescue at \nbaseline who were off opioid \nat Month 6* \n43/149 \n(29%) \n66/150 \n(44%) \n36/211 \n(17%) \n50/124 \n(40%) \n78/134 \n(58%) \n70/222 \n(32%) \nNumber and % of patients not \non opioid rescue at baseline \nwho were on any opioid at \nMonth 3^ \n9/98 \n(9%) \n6/93  \n(6%) \n17/162 \n(10%) \n10/97 \n(10%) \n10/91  \n(11%) \n29/133 \n(22%) \nNumber and % of patients not \non opioid rescue at baseline \nwho were on any opioid at \nMonth 6^ \n16/98 \n(16%) \n6/93 \n(6%) \n32/161 \n(20%) \n13/97 \n(13%) \n6/91 \n(7%) \n32/133 \n(24%) \nReference ID: 5184902 \nThis label may not be the latest approved by FDA.  \nFor current labeling information, please visit https://www.fda.gov/drugsatfda\n \n\n  \n  \n   \n  \n   \n   \n \n   \n \n \n \n \n \n \n \n  \n \n  \n \n \n \n  \n  \n   \n \nMin = minimum; Max = maximum; SD = standard deviation \nMonthly calculations are based on a 35-day interval. \n*Denominator is the number of subjects on opioid rescue at baseline. \n^Denominator is the number of subjects not on opioid rescue at baseline. \nThe clinical relevance of these data has not been demonstrated. \n16 HOW SUPPLIED/STORAGE AND HANDLING \nORILISSA tablets are available in two strengths: 150 mg and 200 mg, which are equivalent to \n155.2 mg and 207.0 mg of elagolix sodium, respectively.  \nORILISSA 150 mg tablets are light pink, oblong, film-coated tablets with “EL 150” debossed on \none side. ORILISSA 150 mg tablets are packaged in weekly blister packs. Each blister pack \ncontains 7 tablets supplying the drug product for one week. Four blister packs (a total of 28 \ntablets) are packaged into a carton that provides the drug product for 4 weeks (NDC 0074-0038-\n28).  \nORILISSA 200 mg tablets are light orange, oblong, film-coated tablets with “EL 200” debossed \non one side. The 200 mg tablets are packaged in weekly blister packs. Each blister pack contains \n14 tablets supplying the drug product for one week. Four blister packs (a total of 56 tablets) are \npackaged in a carton that provides the drug product for 4 weeks (NDC 0074-0039-56). \nStore at 2°C to 30°C (36°F to 86°F). \nDispose unused medication via a take-back option if available. Otherwise, follow FDA \ninstructions for disposing medication in the household trash, www.fda.gov/drugdisposal. Do \nNOT flush down the toilet.  \n17 PATIENT COUNSELING INFORMATION \nAdvise patients to read the FDA-approved patient labeling (Medication Guide). \nBone Loss \nInform patients about the risk of bone loss. Advise patients that supplementary calcium and \nvitamin D may be beneficial if dietary intake of calcium and vitamin D is not adequate [see \nWarnings and Precautions (5.1)]. \nChange in Menstrual Bleeding Pattern, Contraception and Pregnancy \nAdvise women that ORILISSA may delay the recognition of pregnancy because it may reduce \nthe amount, intensity, or duration of menstrual bleeding. Advise patients to use effective non-\nhormonal contraception while taking ORILISSA and to discontinue ORILISSA if pregnancy is \nconfirmed.  Advise pregnant women that there is a pregnancy registry that monitors outcomes in \nwomen who become pregnant while treated with ORILISSA. Inform patients they can enroll by \ncalling 1-833-782-7241 or visiting https://www.bloompregnancyregistry.com [see Warnings and \nPrecautions (5.2) and Use in Specific Populations (8.1)]. \nReference ID: 5184902 \nThis label may not be the latest approved by FDA.  \nFor current labeling information, please visit https://www.fda.gov/drugsatfda\n \n\n \n \n   \n  \n \n  \n  \n   \n  \n  \n  \n  \n \n \n \n \n  \n  \n \n  \n \n \n  \n \n \n \n \n   \n   \n  \n  \n  \n    \n  \n    \n  \n    \n  \n  \n  \nSuicidal Ideation, Suicidal Behavior, and Exacerbation of Mood Disorders \nAdvise patients that suicidal ideation and exacerbation of mood disorders may occur with \nORILISSA use. Instruct patients to seek immediate medical attention for suicidal ideation and \nbehavior and for new onset or worsening depression, anxiety, or other mood changes [see \nWarnings and Precautions (5.3)]. \nLiver Injury \nAdvise patients to promptly seek medical attention in case of signs or symptoms that may reflect \nliver injury, such as jaundice [see Warnings and Precautions (5.4)]. \nORILISSA Missed Dose Instructions \nInstruct a patient who miss a dose of ORILISSA to take the missed dose on the same day as soon \nas she remembers and then resume the regular dosing schedule: \n• 150 mg once daily: no more than 1 tablet each day should be taken. \n• 200 mg twice daily: no more than 2 tablets each day should be taken. \nORILISSA Disposal Instructions \nInstruct patients to dispose of unused medication via a take-back option if available or to \notherwise follow FDA instructions for disposing of medication in the household trash, \nwww.fda.gov/drugdisposal, and NOT to flush down the toilet.  \nManufactured by AbbVie Inc. North Chicago, IL 60064  \nORILISSA is a trademark of AbbVie Inc. \n© 2021 AbbVie Inc. All rights reserved. \n20075867 June 2023  \nMEDICATION GUIDE \nORILISSA® (awr-ah-lih-sah)\n(elagolix)\ntablets, for oral use \nWhat is the most important information I should know about ORILISSA? \nORILISSA may cause serious side effects, including: \n• bone loss (decreased bone mineral density). \n◦ While you are taking ORILISSA, your estrogen levels will be low. Low estrogen levels can lead to \nbone mineral density loss. \n◦ If you have bone loss on ORILISSA, your bone density may improve after you stop taking \nORILISSA but complete recovery may not occur. It is unknown if these bone changes could \nincrease your risk for broken bones as you age. For this reason, your healthcare provider may limit \nthe length of time you take ORILISSA. \n◦ Your healthcare provider may advise you to take vitamin D and calcium supplements as part of a \nhealthy lifestyle that promotes bone health. \n◦ If you have conditions or take other medicines that can cause bone loss, or if you have broken a \nbone with minimal or no injury, your healthcare provider may order an X-ray test c\nalled a DXA scan \nto check your bone mineral density. \n• effects on pregnancy \nReference ID: 5184902 \nThis label may not be the latest approved by FDA.  \nFor current labeling information, please visit https://www.fda.gov/drugsatfda\n \n\n     \n  \n     \n  \n \n  \n \n   \n   \n  \n \n     \n    \n    \n  \n   \n     \n    \n   \n \n  \n  \n  \n \n   \n   \n  \n    \n   \n   \n  \n   \n  \n   \n \n   \n    \n  \n    \n   \n     \n \n   \n   \n   \n \n \n   \n \n    \n     \n  \n   \n◦ Do not take ORILISSA if you are trying to become or are pregnant. It may increase the risk of early \npregnancy loss. \n◦ If you think you are pregnant, stop taking ORILISSA right away and call your healthcare provider. \n• If you become pregnant while taking ORILISSA, you are encouraged to enroll in the Pregnancy \nRegistry. The purpose of the pregnancy registry is to collect information about the health of you \nand your baby. Contact the registry as soon as you learn that you are pregnant or ask your \nhealthcare provider to contact the registry for you. You or your healthcare provider can get \ninformation and enroll you in the registry by calling 1-833-782-7241 or \nvisiting https://www.bloompregnancyregistry.com. \n◦ ORILISSA may change your menstrual periods (irregular bleeding or spotting, a decrease in \nmenstrual bleeding, or no bleeding at all), making it hard to know if you are pregnant. Watch for \nother signs of pregnancy such as breast tenderness, weight gain and nausea. \n◦ ORILISSA does not prevent pregnancy. You will need to use effective methods of birth control \nwhile taking ORILISSA and for 28 days after you stop taking ORILISSA. Examples of effective \nmethods can include condoms or spermicide, which do not contain hormones. \n◦ \nBirth control pills that contain estrogen may make ORILISSA less effective. It is not known how well \nORILISSA will work while you are taking progestin-only birth control such as injections or implants. \n◦ Talk to your healthcare provider about which birth control to use during treatment with ORILISSA. \nYour healthcare provider may change the birth control you were on before you start taking \nORILISSA. \nHow What is ORILISSA? \nORILISSA is a prescription medicine used to treat moderate to severe pain associated with endometriosis. \nIt is not known if ORILISSA is safe and effective in children. \nDo not take ORILISSA if you: \n• are pregnant \n• have osteoporosis \n• have severe liver disease \n• are taking medicines called organic anion transporting polypeptide (OATP)1B1 inhibitors that are \nknown or expected to significantly increase the blood levels of elagolix (the active ingredient in \nORILISSA). Ask your healthcare provider if you are not sure if you are taking one of these medicines. \nhave had a serious allergic reaction to ORILISSA or any of the ingredients in ORILISSA. See the end of \nthis Medication Guide for a complete list of ingredients in ORILISSA. Ask your healthcare provider if \nyou are not sure. \nBefore you take ORILISSA, tell your healthcare provider about all of your medical conditions, \nincluding if you: \n• have or have had broken bones or other conditions that may cause bone problems \n• have or have had depression, mood problems or suicidal thoughts or behavior \n• have liver problems \n• think you may be pregnant. You should avoid becoming pregnant while taking ORILISSA \n• are breastfeeding or plan to breastfeed. It is not known if ORILISSA passes into your breastmilk. Talk \nto your healthcare provider about the best way to feed your baby if you take ORILISSA. \nTell your healthcare provider about all the medicines you take, including prescription and over-the-\ncounter medicines, vitamins, and herbal supplements. \nEspecially tell your healthcare provider if you take: \n• birth control that contains hormones. Your healthcare provider may advise you to change your method \nof birth control. \nKnow the medicines you take. Keep a list of your medicines with you to show to your healthcare provider \nand pharmacist when you get a new medicine. \nHow should I take ORILISSA? \n• Take ORILISSA exactly as your healthcare provider tells you to take it. \n• Your healthcare provider will give you a pregnancy test before you start taking ORILISSA or will have \nyou start taking ORILISSA within 7 days after you start your period. \n• If your healthcare provider prescribes: \nReference ID: 5184902 \nThis label may not be the latest approved by FDA.  \nFor current labeling information, please visit https://www.fda.gov/drugsatfda\n \n\n   \n    \n    \n   \n  \n  \n     \n    \n   \n   \n \n   \n  \n   \n      \n    \n  \n   \n  \n  \n   \n  \n  \n      \n \n  \n  \n   \n  \n  \n   \n  \n    \n   \n     \n  \n   \n \n  \n      \n   \n   \n    \n      \n   \n   \n  \n \n   \n   \n \n  \n◦ ORILISSA 150 mg (a pink tablet), take it 1 time each day \n◦ ORILISSA 200 mg (an orange tablet), take it 2 times each day \n• Take ORILISSA at about the same time each day with or without food. \n• If you take too much ORILISSA, call your healthcare provider or go to the nearest hospital emergency \nroom right away. \n• If you miss a dose of ORILISSA: \n◦ 150 mg (1 time each day), take it as soon as you remember as long as it is on the same day. Do \nnot take more than 1 tablet each day. \n◦ 200 mg (2 times each day), take it as soon as you remember as long as it is on the same day. Do \nnot take more than 2 tablets each day. \nWhat are the possible side effects of ORILISSA? \nORILISSA may cause serious side effects including: \n• See “What is the most important information I should know about ORILISSA?” \n• suicidal thoughts, suicidal behavior, and worsening of mood. ORILISSA may cause suicidal \nthoughts or actions. Call your healthcare provider or get emergency medical help right away if \nyou have any of the following symptoms, especially if they are new, worse, or bother you : \n◦ thoughts about suicide or dying \n◦ attempts to commit suicide \n◦ new or worse depression \n◦ new or worse anxiety \n◦ other unusual changes in behavior or mood \nYou or your caregiver should pay attention to any changes, especially sudden changes in your mood, \nbehaviors, thoughts, or feelings. \n• abnormal liver tests. Call your healthcare provider right away if you have any of these signs and \nsymptoms of liver problems: \n◦ yellowing of the skin or the whites of the eyes (jaundice) \n◦ dark amber-colored urine \n◦ feeling tired (fatigue or exhaustion) \n◦ nausea and vomiting \n◦ generalized swelling \n◦ right upper stomach area (abdomen) pain \n◦ bruising easily \nThe most common side effects of ORILISSA include: hot flashes and night sweats, headache, nausea, \ndifficulty sleeping, absence of periods, anxiety, joint pain, depression and mood changes. \nThese are not all the possible side effects of ORILISSA. Call your healthcare provider for medical advice \nabout side effects. \nYou may report side effects to FDA at 1-800-FDA-1088. \nHow should I store ORILISSA? \n• Store ORILISSA between 36°F to 86°F (2°C to 30°C). \n• Do not keep medicine that is out of date or that you no longer need. \n• Throw away (dispose of) unused medicines through community take-back disposal programs when \navailable. If no community take-back disposal program is available go to www.fda.gov/drugdisposal \nfor more information on how to dispose of ORILISSA the right way. \n• Do not flush ORILISSA down the toilet. \n• Keep ORILISSA and all medicines out of the reach of children. \nGeneral information about the safe and effective use of ORILISSA. \nMedicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use \nORILISSA for a condition for which it was not prescribed. Do not give ORILISSA to other peop le, even if \nthey have the same symptoms that you have. It may harm them. You can ask your pharmacist or \nhealthcare provider for information about ORILISSA that is written for health professionals. \nWhat are the ingredients in ORILISSA? \nActive ingredient: elagolix \nReference ID: 5184902 \nThis label may not be the latest approved by FDA.  \nFor current labeling information, please visit https://www.fda.gov/drugsatfda\n \n\n  \n \n  \n  \n \n  \n \n  \n  \n  \n \n   \n                                                                     \n \n   \n  \nInactive ingredients 150 mg tablets: mannitol, sodium carbonate monohydrate, pregelatinized starch, \npovidone, magnesium stearate, polyvinyl alcohol, titanium dioxide, polyethylene glycol, talc, and carmine \nhigh tint. \nInactive ingredients 200 mg tablets: mannitol, sodium carbonate monohydrate, pregelatinized starch, \npovidone, magnesium stearate, polyvinyl alcohol, titanium dioxide, polyethylene glycol, talc, and iron oxide \nred. \nManufactured by \nAbbVie Inc. \nNorth Chicago, IL 60064 \n20066730 \nFor more information, go to www.orilissa.com or call 1-844-674-3676. \nThis Medication Guide has been approved by the U.S. Food and Drug Administration Revised: June 2023 \nReference ID: 5184902 \nThis label may not be the latest approved by FDA.  \nFor current labeling information, please visit https://www.fda.gov/drugsatfda","source_license":"CC0","license_restricted":false}