PRODUCT MONOGRAPH INCLUDING PATIENT MEDICATION INFORMATION PrORILISSA® elagolix (as elagolix sodium) tablets 150 mg and 200 mg Gonadotropin releasing hormone (GnRH) receptor antagonist Date of Preparation: October 4, 2018 AbbVie Corporation Date of Revision: 8401 Trans-Canada Highway March 3, 2020 St-Laurent, Qc H4S 1Z1 Submission Control No: 233793 ORILISSA Product Monograph Page 1 of 40 Date of Revision: March 3, 2020 and Control No. 233793 RECENT MAJOR LABEL CHANGES Not applicable. TABLE OF CONTENTS PART I: HEALTH PROFESSIONAL INFORMATION ............................................................... 4 1. INDICATIONS ................................................................................................................ 4 1.1. Pediatrics (< 18 years of age): .................................................................................. 4 1.2. Geriatrics (> 65 years of age): .................................................................................. 4 2. CONTRAINDICATIONS ................................................................................................. 4 3. DOSAGE AND ADMINISTRATION ................................................................................ 5 3.1. Dosing Considerations ............................................................................................. 5 3.2. Recommended Dose and Dosage Adjustment ......................................................... 5 3.3. Administration .......................................................................................................... 5 3.4. Missed Dose ............................................................................................................ 6 4. OVERDOSAGE .............................................................................................................. 6 5. DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING ......................... 6 6. WARNINGS AND PRECAUTIONS ................................................................................ 7 6.1. Special Populations .................................................................................................. 9 6.1.1. Pregnant Women .................................................................................................. 9 6.1.2. Breast-feeding .....................................................................................................10 6.1.3. Pediatrics (< 18 years of age) ..............................................................................10 6.1.4. Geriatrics (> 65 years of age) ...............................................................................10 7. ADVERSE REACTIONS ...............................................................................................11 7.1. Adverse Drug Reaction Overview ............................................................................11 7.2. Clinical Trial Adverse Drug Reactions .....................................................................11 7.3. Less Common Clinical Trial Adverse Drug Reactions ..............................................13 7.4. Abnormal Laboratory Findings: Hematologic, Clinical Chemistry and Other Quantitative Data ...........................................................................................................15 7.5. Clinical Trial Adverse Reactions (Pediatrics) ...........................................................15 7.6. Post-Market Adverse Drug Reactions ......................................................................15 8. DRUG INTERACTIONS ................................................................................................16 8.1. Drug-Drug Interactions ............................................................................................16 8.2. Drug-Food Interactions ............................................................................................19 8.3. Drug-Herb Interactions ............................................................................................19 8.4. Drug-Laboratory Test Interactions ...........................................................................19 8.5. Drug-Lifestyle Interactions .......................................................................................19 9. ACTION AND CLINICAL PHARMACOLOGY ...............................................................20 9.1. Mechanism of Action ...............................................................................................20 9.2. Pharmacodynamics .................................................................................................20 9.3. Pharmacokinetics ....................................................................................................20 10. STORAGE, STABILITY AND DISPOSAL ...................................................................22 11. SPECIAL HANDLING INSTRUCTIONS .....................................................................23 PART II: SCIENTIFIC INFORMATION .....................................................................................24 12. PHARMACEUTICAL INFORMATION ........................................................................24 13. CLINICAL TRIALS .....................................................................................................25 13.1. Trial Design and Study Demographics .................................................................25 ORILISSA Product Monograph Page 2 of 40 Date of Revision: March 3, 2020 and Control No. 233793 13.2. Study Results.......................................................................................................27 13.3. Comparative Bioavailability Studies .....................................................................31 14. MICROBIOLOGY .......................................................................................................31 15. NON-CLINICAL TOXICOLOGY ..................................................................................31 16. SUPPORTING PRODUCT MONOGRAPHS ...............................................................34 PATIENT MEDICATION INFORMATION .................................................................................35 ORILISSA Product Monograph Page 3 of 40 Date of Revision: March 3, 2020 and Control No. 233793 ORILISSA® elagolix (as elagolix sodium) PART I: HEALTH PROFESSIONAL INFORMATION 1. INDICATIONS ORILISSA (elagolix) is indicated for the treatment of moderate to severe pain associated with endometriosis. 1.1. Pediatrics (< 18 years of age): Safety and effectiveness of ORILISSA in patients less than 18 years of age has not been established. 1.2. Geriatrics (> 65 years of age): ORILISSA is not indicated in postmenopausal women and has not been studied in women over 65 years of age. 2. CONTRAINDICATIONS ● Patients who are hypersensitive to this drug or to any ingredient in the formulation or component of the container. For a complete listing, see the DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING section. ● Women who are, suspected to be, or may become pregnant during the course of therapy. ● Women with undiagnosed vaginal bleeding. ● Women with known osteoporosis, due to the risk of further bone loss. ● Women with severe hepatic impairment (Child-Pugh C). See DOSAGE AND ADMINISTRATION, Recommended Dose and Dosage Adjustment. ● Concomitant use of ORILISSA and strong organic anion transporting polypeptide (OATP)1B1 inhibitors (e.g., cyclosporine and gemfibrozil), due to the risks of increased ORILISSA plasma concentrations. ORILISSA Product Monograph Page 4 of 40 Date of Revision: March 3, 2020 and Control No. 233793 3. DOSAGE AND ADMINISTRATION 3.1. Dosing Considerations ● Women should use effective methods of contraception not containing estrogen while on treatment with ORILISSA (elagolix). ● Treatment with ORILISSA should be initiated at the time of the menstrual flow to decrease the risk of an undiagnosed pregnancy. Pregnancy should be excluded before starting treatment with ORILISSA. ● Clinical studies with ORILISSA have been limited to a 12-month exposure to the drug and therefore the safety and efficacy of ORILISSA beyond 12 months have not been established. Because of the dose-dependent loss of bone mineral density (BMD) associated with ORILISSA treatment, the use of ORILISSA 200 mg twice daily should be limited to 6 months duration. 3.2. Recommended Dose and Dosage Adjustment ORILISSA is available as either 150 mg tablets (once daily) or 200 mg tablets (twice daily), to be taken orally. Based on the severity of symptoms and treatment objectives, use the lowest effective dose (see CLINICAL TRIALS). Administration of ORILISSA results in dose-dependent suppression of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) levels, leading to decreased blood levels of the ovarian sex hormones, estradiol and progesterone. LH and FSH suppression begins within hours of administration and is readily reversible upon discontinuation of ORILISSA (see ACTION AND CLINICAL PHARMACOLOGY, Mechanism of Action). Safety and effectiveness of ORILISSA in patients less than 18 years of age has not been established. ORILISSA is not indicated in postmenopausal women and has not been studied in women over 65 years of age. No dose adjustment of ORILISSA is required in women with mild hepatic impairment (Child- Pugh A). ORILISSA 150 mg once daily is the recommended dose in women with moderate hepatic impairment (Child-Pugh B), with treatment duration limited to 6 months; the 200 mg twice daily dose is not recommended. ORILISSA is contraindicated in women with severe hepatic