(Elagolix) Tablet / Gonadotropin- Releasing Hormone

Drug Monograph

Drug/Drug OrilissaTM (elagolix) tablet / Gonadotropin- Class: releasing hormone (GnRH) receptor antagonist Prepared for: MO HealthNet Prepared by: Conduent

New Criteria Revision of Existing Criteria

Executive Summary

The purpose of this monograph is to provide a review of new therapy to determine whether the reviewed drug should be made available on an open Purpose: access basis to prescribers, require a clinical edit or require prior authorization for use.

OrilissaTM is available as 150 mg and 200 mg film-coated tablets. Dosage Forms & Manufacturer: Manufactured by: AbbVie Inc., North Chicago, IL 60064

The safety and efficacy of OrilissaTM was assessed in two randomized, double-blind, placebo-controlled multi-national phase III trials in patients with moderate to severe pain associated with endometriosis. There were Summary of meaningful reductions in dysmenorrhea pain reported by about 44% of Findings: the150 mg daily group, 74% of the 200 mg twice daily group, and 21% of the placebo group at month 3. Non-menstrual pelvic pain was decreased in 50% of the 150 mg daily group, 56% of the 200 mg twice daily group, and 36% of the placebo group at month 3.

Status Prior Authorization (PA) Required Open Access Recommendation: Clinical Edit PDL

Type of PA Increased Risk of ADE Non-Preferred Agent Criteria: Appropriate Indications No PA Required

Purpose The purpose of this monograph is to provide a review of new therapy to determine whether the reviewed drug should be considered a prior authorization drug, a clinical edit drug or an open access drug. While prescription expenditures are increasing at double-digit rates, payers are evaluating ways to control these costs by influencing prescriber behavior and guide appropriate medication usage. This review will assist in the achievement of qualitative and economic goals related to health care resource utilization. Restricting the use of certain medications can reduce costs by requiring documentation of appropriate indications for use, and where appropriate, encourage the use of less expensive agents within a drug class.

Introduction (2) Endometriosis is the result of the attachment and spread of endometrial-like tissue outside of the uterus. There is an estimated 4 to 10 million women in the United States between the ages of 18 to 50 years old with endometriosis, with peak prevalence between 25 to 35 years of age. Endometriosis can produce varying severity of pain by causing menstrual pain, non-menstrual pelvic pain, and/or pain during intercourse.

Dosage Form (1) OrilissaTM is available as 150 mg and 200 mg film-coated oral tablets.

Manufacturer (1) Manufactured by: AbbVie Inc., North Chicago, IL 60064

Indication(s) (1,3) OrilissaTM is an FDA approved gonadotropin-releasing hormone (GnRH) receptor antagonist indicated for the management of moderate to severe pain associated with endometriosis.

Clinical Efficacy (1) (mechanism of action/pharmacology, comparative efficacy)

Pharmacokinetics: OrilissaTM Protein Binding 80% plasma proteins, blood to plasma ratio 0.6 Tmax (h) 1.0 Metabolism Hepatic, Primarily CYP3A Excretion (Renal) Urine, < 3% Feces, 90% Half-life 4 to 6 hours

Efficacy and Safety of OrilissaTM

STUDY DESIGN 2 multi-national, randomized, double-blind, placebo-controlled phase III trials (N=1686)

INCLUSION Adult patients, over 18 years old, premenopausal women with moderate to severe pain associated with endometriosis, composite pelvic signs and

CRITERIA symptoms score (CPSSS) total of at least 6, with a score of at least 2 for dysmenorrhea and at least 2 for non-menstrual pelvic pain for at least 4 days in the preceding calendar month (defined as 35 days)

EXCLUSION Patients not meeting the inclusion criteria. CRITERIA

TREATMENT Patients were randomized to receive Orlissa™ 150 mg once daily (N=469), REGIMEN Orlissa™ 200 mg twice daily (N=469), or placebo (N=726). Primary efficacy endpoints: proportion of patients whose dysmenorrhea responded to treatment at month 3 and the proportion of patients whose pelvic pain not related to menses responded to treatment at month 3.

RESULTS In both Orlissa™ treatment groups, women reported significantly reduced symptoms at month 3 of treatment. There were also meaningful reductions in dysmenorrhea pain reported by about 44% of patients in the150mg daily group, 74% of the patients in the 200 mg twice daily group, and 21% of placebo at 3 months. Non-menstrual pelvic pain was decreased in 50% of patients in the 150 mg daily group, 56% of patients in the 200 mg twice daily group, and 36% of placebo. Both trials showed a dose-dependent decrease in bone mass density (BMD) in Orlissa™ treated subjects compared to an increase in BMD in placebo treated subjects.

SAFETY Not specified.

Contraindications (1)  Pregnancy  Known osteoporosis  Severe hepatic impairment  Strong organic anion transporting polypeptide (OATP) 1B1 inhibitor (e.g., cyclosporine and gemfibrozil)

Warnings and Precautions (1,3)  Bone Loss: Dose- and duration-dependent decreases in bone mineral density (BMD) that may not be completely reversible. Assess BMD in women with additional risk factors for bone loss  Reduced Ability to Recognize Pregnancy: OrilissaTM may alter menstrual bleeding, which may reduce the ability to recognize pregnancy. Perform testing if pregnancy is suspected. Discontinue if pregnancy is confirmed  Suicidal Ideation and Mood Disorders: Advise patients to seek medical attention for suicidal ideation, suicidal behavior, new onset or worsening depression, anxiety, or other mood changes  Hepatic Transaminase Elevations: Dose-dependent elevations in serum alanine

aminotransferase (ALT). Counsel patients on signs and symptoms of liver injury  Potential for Reduced Efficacy with Estrogen-Containing Contraceptives: Use non- hormonal contraception during treatment and for one week after discontinuing OrilissaTM Adverse Effects (1)

Most common, ≥ 5% OrilissaTM 150 mg OrilissaTM 200 mg Placebo Once Daily Twice Daily (N=734) % (n=475) % (n=477) % Hot Flash or Night 24 46 9 Sweats Headache 17 20 12

Nausea 11 16 13

Insomnia 6 9 3

Mood altered, Mood 6 5 3 swings Amenorrhea 4 7 <1

Depressed mood, 3 6 2 depression, depressive symptoms and/or tearfulness Anxiety 3 5 3

Arthralgia 3 5 3

Drug Interactions (1,3)  Orlissa™ is a weak to moderate inducer of CYP450 3A, may decrease plasma concentrations of medications that are substrates of CYP450 3A.  Orlissa™ is an inhibitor of efflux transporter P-glycoprotein (P-gp), may increase plasma concentrations of drugs that are substrates of P-gp, some of these medications include digoxin, midazolam, rosuvastatin, rifampin.  Use of Orlissa™ with cyclosporine and gemfibrozil is contraindicated.

Dosage and Administration (1) Dosing Regimen Maximum Treatment Coexisting Condition Duration Initiate treatment with ORILISSATM 24 months None 150 mg once daily Consider initiating treatment with 6 months Dyspareunia ORILISSA TM 200 mg twice daily Initiate treatment with ORILISSATM 6 months Moderate hepatic impairment 150 mg once daily. Use of 200 mg (Child-Pugh Class B) twice daily is not recommended.

Cost Generic Name Brand Name Manufacturer Dose Cost/Month*

Elagolix OrilissaTM AbbVie Inc. 150 mg once daily $ 905.10

Elagolix OrilissaTM AbbVie Inc. 200 mg twice daily $ 904.80

* Wholesale Acquisition Cost

Conclusion (1,3) OrilissaTM is an oral gonadotropin-releasing hormone receptor antagonist approved for the treatment of moderate to severe pain due to endometriosis in women 18 years of age and older. This is the first medication to be approved for endometriosis in over ten years. In phase III trials, both OrilissaTM treatment groups showed statistically significantly greater mean decreases from baseline compared to placebo in dysmenorrhea and non-menstrual pelvic pain scores at month 3. In OrilissaTM treated subjects, there was a dose dependent decrease in bone mass density (BMD) noted in OrilissaTM treated subjects in the studies at lumbar spine, femoral neck and total hip. The BMD loss was dose-dependent and may not be reversible.

Recommendation The Division recommends adding this drug as a new Clinical Edit.

References 1) Product Information: OrilissaTM (elagolix) AbbVie Inc. North Chicago, IL 60064 7/2018. 2) Smith, Howard R MD, Diamond, Herbert S MD et al. Rheumatoid Arthritis: Practice Essentials, Background, Pathophysiology. June 6 2018 Medscape article 331715. 3) IPD Analytics Rx Insights_New Drug Approval Review_Orilissa_07 2018.pdf

Prepared by: Jennifer Anderson PharmD Date: November 8, 2018