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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: C32H29F5N3NaO5
CAS Number: 832720-36-2

Medically reviewed on Jul 30, 2018

Introduction

Elagolix sodium is a gonadotropin-releasing hormone (GnRH) receptor antagonist.

Uses for Orilissa

Elagolix sodium has the following uses:

Elagolix sodium is a gonadotropin-releasing hormone (GnRH) receptor antagonist indicated for the management of moderate to severe pain associated with endometriosis.1

Orilissa Dosage and Administration

General

Elagolix sodium is available in the following dosage form(s) and strength(s):

Oral tablets: 150 mg and 200 mg of elagolix.1

Dosage of elagolix sodium is expressed in terms of elagolix.1

Dosage

It is essential that the manufacturer's labeling be consulted for more detailed information on dosage and administration of this drug. Dosage summary:

Adults

Dosage and Administration

Patients without coexisting conditions: 150 mg once daily for up to 24 months.1

Dyspareunia: 200 mg twice daily for up to 6 months.1

Normal liver function or mild hepatic impairment: No dosage adjustment needed.1

Moderate hepatic impairment: 150 mg once daily for up to 6 months.1 Dosages of 200 mg twice daily not recommended.1

Cautions for Orilissa

Contraindications

  • Pregnancy1

  • Known osteoporosis1

  • Severe hepatic impairment1

  • Concomitant use of strong organic anion transporting polypeptide (OATP) 1B1 inhibitors1

Warnings/Precautions

Bone Loss

Elagolix sodium causes a dose-dependent decrease in bone mineral density (BMD). BMD loss is greater with increasing duration of use and may not be completely reversible after stopping treatment. The impact of these BMD decreases on long-term bone health and future fracture risk is unknown. Consider assessment of BMD in patients with a history of a low-trauma fracture or other risk factors for osteoporosis or bone loss, and do not use in women with known osteoporosis. Limit the duration of use to reduce the extent of bone loss.1

Although the effect of supplementation with calcium and vitamin D was not studied, such supplementation may be beneficial for all patients.1

Change In Menstrual Bleeding Pattern And Reduced Ability To Recognize Pregnancy

Women who take elagolix sodium may experience a reduction in the amount, intensity or duration of menstrual bleeding, which may reduce the ability to recognize the occurrence of a pregnancy in a timely manner. Perform pregnancy testing if pregnancy is suspected, and discontinue elagolix sodium if pregnancy is confirmed.1

Suicidal Ideation, Suicidal Behavior, and Exacerbation of Mood Disorders

Suicidal ideation and behavior, including one completed suicide, occurred in subjects treated with elagolix sodium in the endometriosis clinical trials. Elagolix sodium subjects had a higher incidence of depression and mood changes compared to placebo, and elagolix sodium subjects with a history of suicidality or depression had a higher incidence of depression compared to subjects without such a history. Promptly evaluate patients with depressive symptoms to determine whether the risks of continued therapy outweigh the benefits. Patients with new or worsening depression, anxiety or other mood changes should be referred to a mental health professional, as appropriate. Advise patients to seek immediate medical attention for suicidal ideation and behavior. Reevaluate the benefits and risks of continuing elagolix sodium if such events occur.1

Hepatic Transaminase Elevations

In clinical trials, dose-dependent elevations of serum alanine aminotransferase (ALT) at least 3 times the upper limit of the reference range occurred with elagolix sodium. Use the lowest effective dose of elagolix sodium and instruct patients to promptly seek medical attention in case of symptoms or signs that may reflect liver injury, such as jaundice. Promptly evaluate patients with elevations in liver tests to determine whether the benefits of continued therapy outweigh the risks.1

Reduced Efficacy with Estrogen-containing Contraceptives

Based on the mechanism of action of elagolix sodium, estrogen-containing contraceptives are expected to reduce the efficacy of elagolix sodium. The effect of progestin-only contraceptives on the efficacy of elagolix sodium is unknown. Advise women to use non-hormonal contraceptives during treatment with elagolix sodium and for one week after discontinuing elagolix sodium.1

Specific Populations

Pregnancy

Risk Summary: Exposure to elagolix sodium early in pregnancy may increase the risk of early pregnancy loss. Use of elagolix sodium is contraindicated in pregnant women. Discontinue elagolix sodium if pregnancy occurs during treatment.1

The limited human data with the use of elagolix sodium in pregnant women are insufficient to determine whether there is a risk for major birth defects or miscarriage. Although two cases of congenital malformations were reported in clinical trials with elagolix sodium, no pattern was identified and miscarriages were reported at a similar incidence across treatment groups.1

When pregnant rats and rabbits were orally dosed with elagolix during the period of organogenesis, postimplantation loss was observed in pregnant rats at doses 20 times the maximum recommended human dose (MRHD). Spontaneous abortion and total litter loss was observed in rabbits at doses 7 and 12 times the MRHD. There were no structural abnormalities in the fetuses at exposures up to 40 and 12 times the MRHD for the rat and rabbit, respectively.1

The background risk for major birth defects and miscarriage in the indicated population are unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.1

Human Data: There were 49 pregnancies reported in clinical trials of more than 3,500 women (of whom more than 2,000 had endometriosis) treated with elagolix sodium for up to 12 months. These pregnancies occurred while the women were receiving elagolix sodium or within 30 days after stopping elagolix sodium. Among these 49 pregnancies, two major congenital malformations were reported. In one case of infant cleft palate, the mother was treated with elagolix sodium 150 mg daily and the estimated fetal exposure to elagolix sodium occurred during the first 30 days of pregnancy. In one case of infant tracheoesophageal fistula, the mother was treated with elagolix sodium 150 mg daily and the estimated fetal exposure to elagolix sodium occurred during the first 15 days of pregnancy.1

Among these 49 pregnancies, there were five cases of spontaneous abortion (miscarriage) compared to five cases among the 20 pregnancies that occurred in more than 1100 women treated with placebo. Although the duration of fetal exposure was limited in elagolix sodium clinical trials, there were no apparent decreases in birth weights associated with elagolix sodium in comparison to placebo.1

Animal Data: Embryofetal development studies were conducted in the rat and rabbit. Elagolix was administered by oral gavage to pregnant rats (25 animals/dose) at doses of 0, 300, 600 and 1200 mg/kg/day and to rabbits (20 animals/dose) at doses of 0, 100, 150, and 200 mg/kg/day, during the period of organogenesis (gestation day 6-17 in the rat and gestation day 7-20 in the rabbit).1

In rats, maternal toxicity was present at all doses and included six deaths and decreases in body weight gain and food consumption. Increased postimplantation losses were present in the mid dose group, which was 20 times the MRHD based on AUC. In rabbits, three spontaneous abortions and a single total litter loss were observed at the highest, maternally toxic dose, which was 12 times the MRHD based on AUC. A single total litter loss occurred at a lower non-maternally toxic dose of 150 mg/kg/day, which was 7 times the MRHD.1

No fetal malformations were present at any dose level tested in either species even in the presence of maternal toxicity. At the highest doses tested, the exposure margins were 40 and 12 times the MRHD for the rat and rabbit, respectively. However, because elagolix binds poorly to the rat gonadotropin-releasing hormone (GnRH) receptor (~1000 fold less than to the human GnRH receptor), the rat study is unlikely to identify pharmacologically mediated effects of elagolix on embryofetal development. The rat study is still expected to provide information on potential non-target-related effects of elagolix.1

In a pre- and postnatal development study in rats, elagolix was given in the diet to achieve doses of 0, 100 and 300 mg/kg/day (25 per dose group) from gestation day 6 to lactation day 20. There was no evidence of maternal toxicity. At the highest dose, two dams had total litter loss, and one failed to deliver. Pup survival was decreased from birth to postnatal day 4. Pups had lower birth weights and lower body weight gains were observed throughout the pre-weaning period at 300 mg/kg/day. Smaller body size and effect on startle response were associated with lower pup weights at 300 mg/kg/day. Post-weaning growth, development and behavioral endpoints were unaffected.1

Maternal plasma concentrations in rats on lactation day 21 at 100 and 300 mg/kg/day (47 and 125 ng/mL) were 0.06-fold and 0.16-fold the maximal elagolix concentration (Cmax) in humans at the MRHD. Because the exposures achieved in rats were much lower than the human MRHD, this study is not predictive of potentially higher lactational exposure in humans.1

Lactation

There is no information on the presence of elagolix or its metabolites in human milk, the effects on the breastfed child, or the effects on milk production. There are no adequate animal data on the excretion of elagolix sodium in milk. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for elagolix sodium and any potential adverse effects on the breastfed child from elagolix sodium.1

There are no adequate animal data on excretion of elagolix sodium in milk.1

Females And Males Of Reproductive Potential

Based on the mechanism of action, there is a risk of early pregnancy loss if elagolix sodium is administered to a pregnant woman.1

Exclude pregnancy before initiating treatment with elagolix sodium. Perform pregnancy testing if pregnancy is suspected during treatment with elagolix sodium.1

Advise women to use effective non-hormonal contraception during treatment with elagolix sodium and for one week after discontinuing elagolix sodium.1

Pediatric Use

Safety and effectiveness of elagolix sodium in patients less than 18 years of age have not been established.1

Renal Impairment

No dose adjustment of elagolix sodium is required in women with any degree of renal impairment or end-stage renal disease (including women on dialysis).1

Hepatic Impairment

No dosage adjustment of elagolix sodium is required for women with mild hepatic impairment (Child-Pugh A). Only the 150 mg once daily regimen is recommended for women with moderate hepatic impairment (Child-Pugh B) and the duration of treatment should be limited to 6 months.1

Elagolix sodium is contraindicated in women with severe hepatic impairment (Child-Pugh C).1

Common Adverse Effects

Most common adverse reactions (>5%) in clinical trials included hot flushes and night sweats, headache, nausea, insomnia, amenorrhea, anxiety, arthralgia, depression-related adverse reactions and mood changes.1

Drug Interactions

Specific Drugs

It is essential that the manufacturer's labeling be consulted for more detailed information on interactions with this drug, including possible dosage adjustments. Interaction highlights:

See full prescribing information for a list of clinically important drug interactions.1

Actions

Mechanism of Action

Elagolix sodium is a GnRH receptor antagonist that inhibits endogenous GnRH signaling by binding competitively to GnRH receptors in the pituitary gland. Administration of elagolix sodium results in dose-dependent suppression of luteinizing hormone (LH) and follicle-stimulating hormone (FSH), leading to decreased blood concentrations of the ovarian sex hormones, estradiol and progesterone.1

Pharmacogenomics

Disposition of elagolix involves the OATP 1B1 transporter protein. Higher plasma concentrations of elagolix have been observed in groups of patients who have two reduced function alleles of the gene that encodes OATP 1B1 (SLCO1B1 521T>C). The frequency of this SLCO1B1 521 C/C genotype is generally less than 5% in most racial/ethnic groups. Subjects with this genotype are expected to have a 78% mean increase in elagolix concentrations compared to subjects with normal transporter function (i.e., SLCO1B1 521T/T genotype).1

Advice to Patients

Patient Counseling Information

Advise patients to read the FDA-approved patient labeling (Medication Guide).1

  • Advise patients on contraceptive options, not to get pregnant while using elagolix sodium, to be mindful that menstrual changes could reflect pregnancy and to discontinue elagolix sodium if pregnancy occurs.1

  • Inform patients that estrogen-containing contraceptives are expected to reduce the efficacy of elagolix sodium.1

  • Inform patients about the risk of bone loss. Advise adequate intake of calcium and vitamin D.1

  • Advise patients to seek immediate medical attention for suicidal ideation and behavior. Instruct patients with new onset or worsening depression, anxiety, or other mood changes to promptly seek medical attention.1

  • Counsel patients on signs and symptoms of liver injury.1

  • Instruct patients who miss a dose of elagolix sodium to take the missed dose on the same day as soon as she remembers and then resume the regular dosing schedule:

    150 mg once daily: no more than 1 tablet each day should be taken.

    200 mg twice daily: no more than 2 tablets each day should be taken.1

  • Instruct patients to dispose of unused medication via a take-back option if available or to otherwise follow FDA instructions for disposing of medication in the household trash, and not to flush down the toilet.1

Additional Information

AHFSfirstRelease. For additional information until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the manufacturer's labeling be consulted for more detailed information on usual uses, dosage and administration, cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity.

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 Inc.

200 mg (of elagolix)

Orilissa

AbbVie Inc.

AHFS Drug Information. © Copyright 2018, Selected Revisions July 30, 2018. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

References

1. AbbVie Inc.. Orilissa (elagolix) ORAL prescribing information. 2018 Jul. http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=a86757b3-09c5-fd3b-1223-244e94f50a66

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