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Orilissa

Generic Name: Elagolix Sodium
Class: Antigonadotropins
Chemical Name: sodium;4-[[(1R)-2-[5-(2-fluoro-3-methoxyphenyl)-3-[[2-fluoro-6-(trifluoromethyl)phenyl]methyl]-4-methyl-2,6-dioxopyrimidin-1-yl]-1-phenylethyl]amino]butanoate
Molecular Formula: C32H29F5N3O5Na
CAS Number: 832720-36-2

Medically reviewed by Drugs.com. Last updated on May 18, 2020.

Introduction

Gonadotropin-releasing hormone (GnRH, luteinizing hormone-releasing hormone [LHRH], gonadorelin) receptor antagonist.1

Uses for Orilissa

Endometriosis

Management of moderate to severe endometriosis-associated pain.1 2 3

Orilissa Dosage and Administration

General

Exclude pregnancy prior to initiation of elagolix or begin therapy ≤7 days after onset of menses.1

Administration

Oral Administration

Administer orally once or twice daily (at approximately the same time every day) without regard to meals.1

If dose is missed, take missed dose as soon as possible and resume regular dosing schedule with next dose.1 Do not exceed 1 or 2 tablets daily in patients receiving the drug in a once- or twice-daily regimen, respectively.1

Dosage

Available as elagolix sodium; dosage expressed in terms of elagolix.1

Adults

Endometriosis
Moderate to Severe Pain
Oral

Use lowest effective dosage, taking into account severity of symptoms and goals of treatment.1 Limit duration of therapy because greater loss of bone mineral density (BMD) occurs with increasing duration of use.1 (See Decreased Bone Mineral Density under Cautions.)

Recommended dosage differs depending on presence or absence of endometriosis-associated dyspareunia.1 (See Table 1.)

Table 1. Recommended Dosage and Treatment Duration of Elagolix for Management of Pain in Patients with Endometriosis.1

Dosage

Maximum Treatment Duration

Patients without concomitant dyspareunia

Initiate treatment with elagolix 150 mg once daily

24 months

Patients with concomitant dyspareunia

Consider initiating treatment with elagolix 200 mg twice daily

6 months

Special Populations

Hepatic Impairment

For dosage recommendations in patients with hepatic impairment, see Table 2.1

Table 2. Recommended Dosage and Treatment Duration of Elagolix for Management of Pain in Patients with Hepatic Impairment.1

Hepatic Impairment

Dosage

Maximum Treatment Duration

Mild hepatic impairment (Child-Pugh class A)

Initiate treatment with elagolix 150 mg once daily

24 months

Moderate hepatic impairment (Child-Pugh class B)

Initiate treatment with elagolix 150 mg once daily; use of elagolix 200 mg twice daily not recommended.

6 months

Severe hepatic impairment (Child-Pugh class C)

Contraindicated

Renal Impairment

Mild, moderate, or severe renal impairment or end-stage renal disease, including patients receiving dialysis: Dosage adjustment not needed.1

Geriatric Patients

No specific dosage recommendations at this time.1

Cautions for Orilissa

Contraindications

  • Pregnancy.1 (See Fetal/Neonatal Morbidity and Mortality and also see Pregnancy under Cautions.)

  • Known osteoporosis.1 (See Decreased Bone Mineral Density under Cautions.)

  • Severe hepatic impairment.1 (See Hepatic Effects under Cautions.)

  • Concomitant use with potent organic anion transporting polypeptide (OATP) 1B1 inhibitors.1 (See Drugs Transported by Organic Anion Transporting Polypeptide 1B1 under Interactions.)

Warnings/Precautions

Decreased Bone Mineral Density

Elagolix causes dose- and duration-dependent decreases in BMD that may not be completely reversible after discontinuance of the drug.1 Impact of elagolix loss on long-term bone health and future fracture risk unknown.1

Limit duration of therapy to reduce extent of bone loss.1 (See Dosage under Dosage and Administration.) Consider assessment of BMD in patients with history of low-trauma fracture or other risk factors for osteoporosis or bone loss.1 Supplementation with calcium and vitamin D may be beneficial; however, effect of such supplements not studied in this patient population.1 Use of elagolix contraindicated in patients with known osteoporosis because of risk of further bone loss.1

Effects on Menstrual Bleeding Pattern

Elagolix causes a dose-dependent reduction in mean number days of menstrual bleeding and spotting and bleeding intensity.1 Amenorrhea reported in clinical studies; menses resumed in most patients ≤6 months after discontinuance of elagolix.1

Elagolix-associated changes in menstrual bleeding may impair timely recognition of a pregnancy.1 Perform pregnancy testing if pregnancy suspected; discontinue if pregnancy confirmed.1 (See Pregnancy under Cautions.)

Suicidal Ideation/Behavior and Exacerbation of Mood Disorders

Elagolix associated with an increased incidence of adverse mood changes (e.g., altered mood, mood swings, depressed mood, depression, depressive symptoms, tearfulness), particularly in patients with a history of depression.1 Suicidal ideation and behavior, including one completed suicide, occurred in patients receiving elagolix in clinical studies.1

Advise patients to seek medical attention immediately for suicidal ideation or behavior.1 Evaluate patients experiencing depressive symptoms promptly to determine whether risks of continued therapy outweigh benefits.1 Refer patients with new or worsening depression, anxiety, or other mood changes to a mental health clinician, as appropriate.1 Reevaluate benefits and risks of continued elagolix therapy if such events occur.1

Hepatic Effects

Asymptomatic, dose-dependent increases in ALT concentrations ≥3 times the ULN occurred in patients receiving elagolix.1

Use lowest effective dosage.1 Instruct patients to seek medical attention promptly if they experience signs or symptoms suggestive of hepatic injury (e.g., jaundice, dark amber-colored urine, fatigue or exhaustion, nausea and vomiting, generalized swelling, right upper abdominal pain, easy bruising).1 Evaluate patients with elevations in liver function tests promptly to determine whether benefits of continued therapy outweigh risks.1

Interactions with Estrogen-containing Contraceptives

Efficacy of elagolix may be decreased with concomitant use of estrogen-containing contraceptives; effect of progestin-only contraceptives (e.g., injections, implants) on efficacy unknown.1 (See Specific Drugs under Interactions.)

Advise patients to use effective nonhormonal contraceptive methods (e.g., condoms, spermicide) during treatment and for 1 week following discontinuance of the drug.1

Fetal/Neonatal Morbidity and Mortality

Based on mechanism of action, risk of early pregnancy loss exists if elagolix is administered to a pregnant woman.1 Exclude pregnancy prior to initiation of therapy.1 Discontinue drug if pregnancy occurs during treatment.1 (See Contraindications and also see Pregnancy under Cautions.)

Pharmacogenomics

Disposition of elagolix depends on OATP1B1.1 Variations in the gene encoding OATP1B1 (SLCO1B1 521T>C) can affect elagolix exposure and clearance.1 8 (See Special Populations under Pharmacokinetics.) No specific dosage recommendations at this time for patients with OATP1B1 genotypic variants.1

Sensitivity Reactions

Nonserious hypersensitivity reactions (e.g., rash) occurred in about 6% of patients receiving elagolix or placebo; such reactions led to discontinuance of study drug in 0.4 or 0.5% of patients, respectively.1

Specific Populations

Pregnancy

Elagolix exposure in pregnancy may increase risk of early pregnancy loss.1 Use contraindicated in pregnant women.1

To monitor fetal outcomes of pregnant women exposed to elagolix, the manufacturer maintains a pregnancy registry.1 Encourage patients who become pregnant while receiving the drug to enroll in the registry by calling 833-782-7241.1

Insufficient data in humans to inform risk of major birth defects and miscarriage associated with use of elagolix.1 Two major congenital malformations and 5 miscarriages occurred among 49 reported pregnancies in >3500 women receiving elagolix in clinical trials.1 Evidence of early pregnancy loss observed in animal studies.1

Advise patients to use effective nonhormonal contraceptive methods (e.g., condoms, spermicide) during treatment with elagolix and for 1 week following drug discontinuance.1 Discontinue elagolix if pregnancy occurs during treatment.1

Lactation

Not known whether elagolix or its metabolites are distributed into milk; effects of drug or its metabolites on breast-fed child or milk production also unknown.1

Consider benefits of breast-feeding along with woman’s clinical need for the drug; also consider potential adverse effects on breast-fed child from the drug.1

Pediatric Use

Safety and efficacy not established in pediatric patients <18 years of age.1

Geriatric Use

Manufacturer makes no recommendations regarding use of the drug in geriatric patients.1

Hepatic Impairment

Contraindicated in patients with severe hepatic impairment.1

Increased exposure of elagolix in patients with moderate or severe hepatic impairment.1 (See Hepatic Impairment under Dosage and Administration and also see Absorption: Special Populations, under Pharmacokinetics.)

Renal Impairment

Exposure of elagolix unchanged in renal impairment.1 (See Absorption: Special Populations, under Pharmacokinetics.)

Common Adverse Effects

Hot flushes1 2 3 or night sweats,1 2 headache,1 2 3 nausea,1 2 3 insomnia,1 2 altered mood or mood swings,1 2 amenorrhea,1 2 depression-related adverse effects (i.e., depressed mood, depression, depressive symptoms, tearfulness),1 anxiety,1 arthralgia.1 2 3

Interactions for Orilissa

Elagolix is a substrate of CYP3A, P-glycoprotein (P-gp), and OATP1B1.1 Elagolix is principally metabolized by CYP3A, but CYP2D6, 2C8, and UGTs also play a minor role.1 Elagolix is a weak to moderate inducer of CYP3A, a weak inhibitor of CYP2C19, and a P-gp inhibitor.1

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

Concomitant use of elagolix 200 mg twice daily with potent CYP3A inhibitors for >1 month is not recommended.1 Limit duration of concomitant use of potent CYP3A inhibitors and elagolix 150 mg once daily to 6 months.1

Concomitant use of elagolix with CYP3A inducers may decrease plasma concentrations of elagolix.1

Concomitant use of elagolix with drugs that are CYP3A substrates may decrease plasma concentrations of substrate.1

Concomitant use of elagolix with drugs that are CYP2C19 substrates (e.g., omeprazole) may increase plasma concentrations of substrate drug.1

Drugs Affecting or Affected by P-glycoprotein Transport

Effects of concomitant use of elagolix and P-gp inhibitors or inducers unknown.1

Concomitant use of elagolix with P-gp substrates (e.g., digoxin) may increase plasma concentrations of substrate.1

Drugs Transported by Organic Anion Transporting Polypeptide 1B1

Elagolix is a substrate of OATP1B1.1 Concomitant use of elagolix with OATP1B1 inhibitors may increase plasma concentrations of elagolix.1 Concomitant use of elagolix with potent OATP1B1 inhibitors (e.g., cyclosporine, gemfibrozil) contraindicated.1 (See Pharmacogenomics under Cautions and also see Special Populations under Pharmacokinetics.)

Specific Drugs

Drug

Interaction

Comments

Antifungals, azoles (fluconazole, ketoconazole)

Fluconazole: No clinically important changes in exposure to either drug1

Ketoconazole: Concomitant use of single 150 mg-dose of elagolix with ketoconazole (400 mg daily) increased peak concentrations and AUC of elagolix1

Contraceptives, hormonal

Estrogen-containing contraceptives: Concomitant use may decrease efficacy of elagolix1

Progestin-only containing contraceptives (e.g., norethindrone): Concomitant use decreased peak concentrations and AUC of norethindrone;1 effects on elagolix efficacy unknown1

Triphasic estrogen-progestin combination contraceptive containing ethinyl estradiol/norgestimate: Concomitant use increased peak concentrations and AUC of ethinyl estradiol, and decreased peak concentrations and AUCs of norgestimate metabolites (i.e., norelgestromin, norgestrel)1

Estrogen-containing contraceptives: Advise patients to use effective nonhormonal methods of contraception during elagolix treatment and for 1 week after the drug discontinued1

Cyclosporine

Possible increased concentrations of elagolix1

Concomitant use contraindicated1

Digoxin

Concomitant use increased peak concentrations and AUC of digoxin1

Clinical monitoring of digoxin recommended1

Gemfibrozil

Possible increased concentrations of elagolix1

Concomitant use contraindicated1

Midazolam

Concomitant use decreased peak concentrations and AUC of midazolam1

Consider increasing dosage of oral midazolam when used concomitantly with elagolix; individualize therapy based on patient response1

Omeprazole

Concomitant use of elagolix (300 mg twice daily for 9 days) and single 40-mg dose of omeprazole increased peak concentrations and AUC of omeprazole1

No dosage adjustment of omeprazole needed if omeprazole 40 mg once daily or lower used concomitantly with elagolix; if elagolix used concomitantly with higher dosages of omeprazole, consider dosage reduction of omeprazole1

Rifampin

Concomitant use of elagolix and rifampin (in either single or multiple doses) increased peak concentrations and AUC of elagolix1

Limit concomitant use of elagolix 150 mg once daily and rifampin to 6 months; concomitant use of rifampin with elagolix 200 mg twice daily not recommended1

Rosuvastatin

Substantially decreased rosuvastatin AUC; no effect on rosuvastatin peak concentrations1

No clinically important changes in elagolix exposure1

Consider increasing dosage of rosuvastatin when used concomitantly with elagolix1

Sertraline

No clinically important changes in exposure to either drug1

Orilissa Pharmacokinetics

No clinically meaningful differences in elagolix pharmacokinetics observed between white and black individuals, Hispanic and other individuals, and Japanese and Han Chinese individuals.1 Body weight or body mass index does not affect elagolix pharmacokinetics.1 8

Absorption

Bioavailability

Rapidly absorbed following oral administration.5

Peak plasma concentrations achieved in about 1 hour.1 5 6

Onset

LH suppressed to 22–35% of baseline concentrations 4 hours following single dose of elagolix.4

FSH suppressed to 62–71% of baseline concentrations 8–10 hours following single dose of elagolix.4

Duration

LH and FSH returned to baseline concentrations 24 hours after single dose of elagolix.4

Food

Administration with high-fat meal decreased peak plasma concentrations and AUC of elagolix by 36 and 24%, respectively.1

Special Populations

Mild hepatic impairment: Peak plasma concentrations and exposure of elagolix similar to those in women with normal hepatic function.1

Moderate or severe hepatic impairment: Approximately threefold or sevenfold greater exposures, respectively, compared with women with normal hepatic function.1

Mild renal impairment: Peak plasma concentrations and exposure of elagolix unchanged.1

Moderate to severe renal impairment or end-stage renal disease (including dialysis): Mean exposures similar to those in women with normal renal function.1

Patients with 2 reduced-function alleles of SLCO1B1 521T>C encoding OATP1B1: 78% mean increase in elagolix concentrations expected compared with patients having genotype associated with normal transporter function (i.e., SLCO1B1 521T/T).1

Distribution

Extent

Not known whether elagolix or its metabolites distributed into milk.1

Plasma Protein Binding

80%.1

Elimination

Metabolism

Metabolized principally via CYP3A; CYP2D6, 2C8, and UGTs also play a minor role.1

Hepatic metabolism may be dependent on OATP1B1 transport-mediated hepatic uptake.8

Elimination Route

Hepatic.1

90% of dose excreted in feces; <3% of dose excreted in urine.1

Half-life

Biphasic;6 terminal half-life is 4–6 hours.1 6

Special Populations

Patients classified as intermediate (heterozygous for 521T>C[s5]) or poor (homozygous for the variant of 521T>C[s5]) OATP1B1 transporters: 14% lower apparent clearance of elagolix observed compared with those classified as extensive transporters (homozygous for wild-type 521T>C[s5]); difference not considered clinically meaningful.8 (See Pharmacogenomics under Cautions.)

Stability

Storage

Oral

Tablets

2–30°C.1

Dispose of unused tablets properly, preferably through a drug take-back program, if available.1 If such a program unavailable, follow FDA guidance for disposal in the household trash in an unrecognizable, closed container.1 Do not flush down the toilet.1

Actions

  • Second generation, short-acting, nonpeptide GnRH receptor antagonist.1 2 5 7

  • Inhibits endogenous GnRH signaling by competitively binding with high affinity to GnRH receptors in the pituitary gland, resulting in immediate dose-dependent suppression of LH and FSH and somewhat delayed dose-dependent decreased concentrations of estradiol and progesterone in the blood.1 4 5 6 7 8

  • Produces dose-dependent reductions in median estradiol concentrations;1 3 at dosage of 150 mg once daily, elagolix resulted in partial estrogen suppression; at dosage of 200 mg twice daily, elagolix resulted in nearly complete estrogen suppression.2 3 7

Advice to Patients

  • Importance of reading the manufacturer's patient information (medication guide) before initiating therapy.1

  • Risk of bone loss.1 Advise patients to maintain adequate intake of calcium and vitamin D during therapy with elagolix.1

  • Risk of depression and exacerbation of mood disorders.1 Advise patients to seek immediate medical attention if suicidal ideation or behavior occurs during therapy.1 Instruct patients with new onset or worsening depression, anxiety, or other mood changes to promptly seek medical attention.1

  • Risk of hepatic injury.1 Advise patients regarding signs and symptoms of hepatic injury (e.g., jaundice, dark amber-colored urine, fatigue or exhaustion, nausea and vomiting, generalized swelling, right upper abdominal pain, easy bruising).1

  • Importance of instructing patients regarding proper disposal of unused medication preferably via a drug take-back program, if available, or in an unrecognizable, closed container via the household trash according to FDA guidance.1 Do not flush down the toilet.1

  • Importance of women informing clinicians if they are or plan to become pregnant.1 Advise women to avoid pregnancy during treatment, and if pregnancy occurs, to discontinue the drug.1 Inform patients to use effective nonhormonal contraceptive methods and that changes in menstrual bleeding may reduce the ability to recognize pregnancy in a timely manner.1 (See Fetal/Neonatal Morbidity and Mortality and also see Pregnancy under Cautions.)

  • Importance of women informing clinicians if they plan to breast-feed.1

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription (e.g., cyclosporine, gemfibrozil) and OTC drugs and dietary or herbal supplements, as well as any concomitant illnesses (e.g., osteoporosis, depression, hepatic impairment).1

  • Importance of informing patients of other important precautionary information.1 (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Elagolix Sodium

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets, film-coated

150 mg (of elagolix)

Orilissa

AbbVie

200 mg (of elagolix)

Orilissa

AbbVie

AHFS DI Essentials™. © Copyright 2020, Selected Revisions May 18, 2020. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

References

1. AbbVie Inc. Orilissa (elagolix) tablets prescribing information. North Chicago, IL; 2019 Aug.

2. Taylor HS, Giudice LC, Lessey BA et al. Treatment of Endometriosis-Associated Pain with Elagolix, an Oral GnRH Antagonist. N Engl J Med. 2017; 377:28-40. http://www.ncbi.nlm.nih.gov/pubmed/28525302?dopt=AbstractPlus

3. Surrey E, Taylor HS, Giudice L et al. Long-Term Outcomes of Elagolix in Women With Endometriosis: Results From Two Extension Studies. Obstet Gynecol. 2018; 132:147-160. http://www.ncbi.nlm.nih.gov/pubmed/29889764?dopt=AbstractPlus

4. Perricos A, Wenzl R. Efficacy of elagolix in the treatment of endometriosis. Expert Opin Pharmacother. 2017; 18:1391-1397. http://www.ncbi.nlm.nih.gov/pubmed/28737050?dopt=AbstractPlus

5. Struthers RS, Nicholls AJ, Grundy J et al. Suppression of gonadotropins and estradiol in premenopausal women by oral administration of the nonpeptide gonadotropin-releasing hormone antagonist elagolix. J Clin Endocrinol Metab. 2009; 94:545-51. http://www.ncbi.nlm.nih.gov/pubmed/19033369?dopt=AbstractPlus

6. Ng J, Chwalisz K, Carter DC et al. Dose-Dependent Suppression of Gonadotropins and Ovarian Hormones by Elagolix in Healthy Premenopausal Women. J Clin Endocrinol Metab. 2017; 102:1683-1691. http://www.ncbi.nlm.nih.gov/pubmed/28323948?dopt=AbstractPlus

7. Carr B, Dmowski WP, O'Brien C et al. Elagolix, an oral GnRH antagonist, versus subcutaneous depot medroxyprogesterone acetate for the treatment of endometriosis: effects on bone mineral density. Reprod Sci. 2014; 21:1341-51. http://www.ncbi.nlm.nih.gov/pubmed/25249568?dopt=AbstractPlus

8. Winzenborg I, Nader A, Polepally AR et al. Population Pharmacokinetics of Elagolix in Healthy Women and Women with Endometriosis. Clin Pharmacokinet. 2018; 57:1295-1306. http://www.ncbi.nlm.nih.gov/pubmed/29476499?dopt=AbstractPlus

9. Food and Drug Administration. Center for Drug Evaluation and Research. Application number: 210450Orig1s000: Multi-discipline review. From FDA website. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/210450Orig1s000MultiD.pdf

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