Elagolix, Estradiol, and Norethindrone (Monograph)

Brand name: Oriahnn
Drug class: Antigonadotropins

Introduction

Elagolix, estradiol, and norethindrone acetate (elagolix/estradiol/norethindrone) is a fixed combination of elagolix (a gonadotropin-releasing hormone [GnRH] receptor antagonist), estradiol (an estrogen), and norethindrone acetate (a progestin).

Uses for Elagolix, Estradiol, and Norethindrone

Elagolix, estradiol, and norethindrone has the following uses:

Elagolix/estradiol/norethindrone is indicated for the management of heavy menstrual bleeding associated with uterine leiomyomas (fibroids) in premenopausal women. Use of elagolix/estradiol/norethindrone should be limited to 24 months due to the risk of continued bone loss, which may not be reversible.

Elagolix, Estradiol, and Norethindrone Dosage and Administration

General

Elagolix/estradiol/norethindrone is available in the following dosage form(s) and strength(s):

• Morning (AM) capsule: elagolix 300 mg, estradiol 1 mg, norethindrone acetate 0.5 mg.

• Evening (PM) capsule: elagolix 300 mg.

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

Exclude pregnancy before starting elagolix/estradiol/norethindrone or start within 7 days from the onset of menses.

Recommended dosage is one capsule (elagolix 300 mg, estradiol 1 mg, norethindrone acetate 0.5 mg) in the morning and one capsule (elagolix 300 mg) in the evening for up to 24 months.

Cautions for Elagolix, Estradiol, and Norethindrone

Contraindications

• High risk of arterial, venous thrombotic, or thromboembolic disorder.

• Pregnancy.

• Known osteoporosis.

• Current or history of breast cancer or other hormonally-sensitive malignancies.

• Known liver impairment or disease.

• Undiagnosed abnormal uterine bleeding.

• Known hypersensitivity to ingredients of elagolix/estradiol/ norethindrone.

• Organic anion transporting polypeptide (OATP)1B1 inhibitors that are known or expected to significantly increase elagolix plasma concentrations.

Warnings/Precautions

Thromboembolic Disorders and Vascular Events

Elagolix/estradiol/norethindrone is contraindicated in women with current or history of thrombotic or thromboembolic disorders and in women at increased risk for these events. In the Phase 3 clinical trials (Studies UF-1, UF-2, and UF-3), 2 thrombotic events occurred in 453 elagolix/estradiol/norethindrone-treated women (thrombosis in the calf and pulmonary embolism). Estrogen and progestin combinations, including the estradiol/norethindrone acetate component of elagolix/estradiol/norethindrone, increase the risk of thrombotic or thromboembolic disorders, including pulmonary embolism, deep vein thrombosis, stroke, and myocardial infarction, especially in women at high risk for these events. In general, the risk is greatest among women over 35 years of age who smoke, and women with uncontrolled hypertension, dyslipidemia, vascular disease, or obesity.

Discontinue elagolix/estradiol/norethindrone if an arterial or venous thrombotic, cardiovascular, or cerebrovascular event occurs or is suspected. If feasible, discontinue elagolix/estradiol/norethindrone at least 4 to 6 weeks before surgery of the type associated with an increased risk of thromboembolism, or during periods of prolonged immobilization.

Stop elagolix/estradiol/norethindrone immediately if there is sudden unexplained partial or complete loss of vision, proptosis, diplopia, papilledema, or retinal vascular lesions and evaluate for retinal vein thrombosis as these have been reported in patients receiving estrogens and progestins.

Bone Loss

Elagolix/estradiol/norethindrone is contraindicated in women with known osteoporosis. Elagolix/estradiol/norethindrone may cause a decrease in bone mineral density (BMD) in some patients. BMD loss is greater with increasing duration of use and may not be completely reversible after stopping treatment.

In the Phase 3 clinical trials (Studies UF-1, UF-2, and UF-3), 7 out of 453 (1.5%) elagolix/estradiol/norethindrone-treated women experienced fractures, including one (0.2%) with a fragility fracture, compared to one out of 196 (0.5%) placebo-treated women (patient had a non-fragility fracture). Five of the seven elagolix/estradiol/norethindrone-treated women reported these fractures in the post-treatment follow-up period. The impact of BMD decreases on long-term bone health and future fracture risk in premenopausal women is unknown.

Consider the benefits and risks of elagolix/estradiol/norethindrone treatment in patients with a history of a low-trauma fracture or other risk factors for osteoporosis or bone loss, including taking medications that may decrease BMD (e.g., systemic or chronic inhaled corticosteroids, anticonvulsants, or proton pump inhibitors).

Assessment of BMD by dual-energy X-ray absorptiometry (DXA) is recommended at baseline and periodically thereafter. Consider discontinuing elagolix/estradiol/norethindrone if the risk associated with bone loss exceeds the potential benefit of treatment. Limit the duration of use to 24 months to reduce the extent of bone loss.

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

Hormonally-sensitive Malignancies

Elagolix/estradiol/norethindrone is contraindicated in women with current or history of breast cancer and in women at increased risk for hormonally-sensitive malignancies, such as those with mutations in BRCA genes.

In the Phase 3 clinical trials (Studies UF-1, UF-2, and UF-3), two (0.4%) cases of breast cancer in 453 elagolix/estradiol/norethindrone-treated women were observed. No breast cancer cases were seen in placebo-treated women.

The use of estrogen alone and estrogen plus progestin has been reported to result in an increase in abnormal mammograms requiring further evaluation. Surveillance measures, such as breast examinations and regular mammography, are recommended. Discontinue elagolix/estradiol/norethindrone if a hormonally-sensitive malignancy is diagnosed.

Suicidal Ideation, Suicidal Behavior, and Exacerbation of Mood Disorders

In Phase 3 placebo-controlled clinical trials (Studies UF-1 and UF-2), elagolix/estradiol/norethindrone-treated women had a higher incidence (3%) of depression, depressed mood, and/or tearfulness compared to placebo-treated women (1%). Suicidal ideation and behavior, including a completed suicide, occurred in women treated with lower doses of elagolix in clinical trials conducted for a different indication.

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/estradiol/norethindrone if such events occur.

Hepatic Impairment and Transaminase Elevations

Elagolix/estradiol/norethindrone is contraindicated in women with known hepatic impairment or disease.

In Phase 3 placebo-controlled clinical trials (Studies UF-1 and UF-2), elevations (> 3 times the upper limit of the reference range) in alanine aminotransferase (ALT) and aspartate aminotransferase (AST) occurred in 1.1% (4/379) and 1.3% (5/379) of elagolix/estradiol/norethindrone-treated patients, respectively, compared to no elevations in placebo-treated patients. Transaminases peaked at 8 times the upper limit for ALT and 6 times the upper limit for AST. No pattern in time to onset of these liver transaminase elevations was identified. Transaminase levels returned to baseline within 4 months after peak values in these patients.

Instruct patients to promptly seek medical attention in case of symptoms or signs that may reflect liver injury, such as jaundice.

Elevated Blood Pressure

Elagolix/estradiol/norethindrone is contraindicated in women with uncontrolled hypertension. In Studies UF-1 and UF-2, a maximum mean increase in systolic blood pressure of 5.1 mmHg [95% confidence interval (CI) 2.68, 7.59] occurred at Month 5, and a maximum mean increase in diastolic blood pressure of 2.1 mmHg (95% CI 0.43, 3.84) occurred at Month 4 in elagolix/estradiol/norethindrone-treated women, as compared to placebo-treated women.

For women with well-controlled hypertension, continue to monitor blood pressure and stop elagolix/estradiol/norethindrone if blood pressure rises significantly. Monitor blood pressure in normotensive women treated with elagolix/estradiol/norethindrone.

Gallbladder Disease or History of Cholestatic Jaundice

Studies among estrogen users suggest a small increased relative risk of developing gallbladder disease. For women with a history of cholestatic jaundice associated with past estrogen use or with pregnancy, assess the risk-benefit of continuing therapy. Discontinue elagolix/estradiol/norethindrone if jaundice occurs.

Change in Menstrual Bleeding Pattern and Reduced Ability to Recognize Pregnancy

Elagolix/estradiol/norethindrone may delay the ability to recognize the occurrence of a pregnancy because it may reduce the intensity, duration, and amount of menstrual bleeding. Perform pregnancy testing if pregnancy is suspected, and discontinue elagolix/estradiol/norethindrone if pregnancy is confirmed.

The effect of hormonal contraceptives on the efficacy of elagolix/estradiol/norethindrone is unknown. Advise women to use non-hormonal contraception during treatment and for 28 days after discontinuing the combination drug.

Effects on Carbohydrate and Lipid Metabolism

Elagolix/estradiol/norethindrone may decrease glucose tolerance and result in increased glucose levels. More frequent monitoring in elagolix/estradiol/norethindrone-treated women with prediabetes and diabetes may be needed.

In women with pre-existing hypertriglyceridemia, estrogen therapy may be associated with elevations of plasma triglycerides leading to pancreatitis. Use of elagolix is associated with increases in total cholesterol, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and serum triglycerides. Monitor lipid levels and consider discontinuing elagolix/estradiol/norethindrone if hypercholesterolemia or hypertriglyceridemia worsens.

Alopecia

In Phase 3 clinical trials (Studies UF-1 and UF-2), more women experienced alopecia, hair loss, and hair thinning with elagolix/estradiol/norethindrone (3.5%) compared to placebo (1.0%). In almost one-third (4/14) of affected elagolix/estradiol/norethindrone-treated women, alopecia was a reason for discontinuing treatment. No specific pattern was described. In the majority of affected women, hair loss was continuing when elagolix/estradiol/norethindrone was stopped. Whether the hair loss is reversible is unknown. Consider discontinuing the combination drug if hair loss becomes a concern.

Effect on Other Laboratory Results

The use of estrogen and progestin combinations may raise serum concentrations of binding proteins (e.g., thyroid-binding globulin, corticosteroid-binding globulin), which may reduce the free thyroid or corticosteroid hormone levels. Patients with hypothyroidism and hypoadrenalism may require higher doses of thyroid hormone or cortisol replacement therapy, respectively.

The use of estrogen and progestin may also affect the levels of sex hormone-binding globulin, coagulation factors, lipids, and glucose.

Risk of Allergic Reactions Due to the Inactive Ingredient (FD&C Yellow No. 5)

Elagolix/estradiol/norethindrone contains FD&C Yellow No. 5 (tartrazine), which may cause allergic-type reactions (including bronchial asthma) in certain susceptible persons. Although the overall incidence of FD&C Yellow No. 5 (tartrazine) sensitivity in the general population is low, it is frequently seen in patients who also have aspirin hypersensitivity.

Specific Populations

Pregnancy

There is a pregnancy registry that monitors pregnancy outcomes in women exposed to elagolix/estradiol/norethindrone during pregnancy. Healthcare providers are encouraged to register patients, or pregnant women may enroll themselves in the registry by calling 1-833-782-7241 or visiting https://www.bloompregnancyregistry.com.

Use of elagolix/estradiol/norethindrone is contraindicated in pregnant women. Exposure to elagolix early in pregnancy may increase the risk of early pregnancy loss. Discontinue elagolix/estradiol/norethindrone if pregnancy occurs during treatment.

The limited human data with the use of elagolix in pregnant women are insufficient to determine whether there is a risk for major birth defects or miscarriage.

When pregnant rats and rabbits were orally dosed with elagolix during the period of organogenesis, postimplantation loss was observed in pregnant rats at doses 12 times the maximum recommended human dose (MRHD). Spontaneous abortion and total litter loss were observed in rabbits at doses 4 and 7 times the MRHD. There were no structural abnormalities in the fetuses at exposures up to 25 and 7 times the MRHD for the rat and rabbit, respectively.

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. When estrogen and progestins are administered to lactating women, these compounds and/or their metabolites are detected in human milk and can reduce milk production in breast-feeding females. This reduction can occur at any time but is less likely to occur once breast-feeding is well established. Advise the nursing female to use non-hormonal contraception until she discontinues breast-feeding. The developmental and health benefits of breast-feeding should be considered along with the mother’s clinical need for elagolix/estradiol/norethindrone and any potential adverse effects on the breast-fed child from elagolix/estradiol/norethindrone or from the underlying maternal condition.

Females and Males of Reproductive Potential

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

Elagolix/estradiol/norethindrone may delay the ability to recognize the occurrence of a pregnancy because it may reduce the intensity, duration, and amount of menstrual bleeding. Exclude pregnancy before initiating treatment with elagolix/estradiol/norethindrone. Perform pregnancy testing if pregnancy is suspected during treatment with the combination drug and discontinue treatment if pregnancy is confirmed.

Advise women to use non-hormonal contraception during treatment with elagolix/estradiol/norethindrone and for 28 days after discontinuing the combination drug.

Pediatric Use

Safety and effectiveness of elagolix/estradiol/norethindrone in pediatric patients have not been established.

Renal Impairment

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

Hepatic Impairment

Elagolix/estradiol/norethindrone is contraindicated in women with any hepatic impairment or disease. The use of estradiol (a component of elagolix/estradiol/norethindrone) in patients with hepatic impairment, compared to patients with normal hepatic function, is expected to increase the blood levels of estradiol and increase the risk of estradiol-associated adverse reactions. Additionally, the use of elagolix (a component of elagolix/estradiol/norethindrone) in patients with moderate and severe hepatic impairment, compared to patients with normal hepatic function, increased elagolix exposures 3-fold and 7-fold, respectively, and this increases the risk of elagolix-associated adverse reactions.

Common Adverse Effects

Most common adverse reaction (>5%) in clinical trials were hot flushes, headache, fatigue, metrorrhagia.

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:

Elagolix is a weak to moderate inducer of cytochrome P-450 (CYP) 3A. Co-administration with elagolix/estradiol/norethindrone may decrease plasma concentrations of drugs that are substrates of CYP3A.

Elagolix is a weak inhibitor of CYP2C19. Co-administration with elagolix/estradiol/norethindrone may increase plasma concentrations of drugs that are substrates of CYP2C19.

Elagolix is an inhibitor of efflux transporter P-glycoprotein (P-gp). Co-administration with elagolix/estradiol/norethindrone may increase plasma concentrations of drugs that are substrates of P-gp.

Strong CYP3A inducers may decrease elagolix/estradiol/norethindrone plasma concentrations and may result in a decrease of the therapeutic effects of elagolix/estradiol/norethindrone.

Rifampin is not recommended. The concomitant use of rifampin increased plasma concentrations of elagolix.

Strong CYP3A inhibitors are not recommended. Concomitant use of elagolix/estradiol/norethindrone with strong CYP3A inhibitors may increase elagolix/estradiol/norethindrone plasma concentrations and increase the risk of adverse reactions.

OATP1B1 inhibitors that are known or expected to significantly increase elagolix plasma concentrations are contraindicated due to increased risk of elagolix-associated adverse reaction.

Actions

Mechanism of Action

Elagolix sodium, estradiol, and norethindrone acetate (elagolix/estradiol/norethindrone) is a fixed combination of elagolix (a gonadotropin-releasing hormone [GnRH] receptor antagonist), estradiol (an estrogen), and norethindrone acetate (a progestin).

Elagolix is a GnRH receptor antagonist that inhibits endogenous GnRH signaling by binding competitively to GnRH receptors in the pituitary gland. Administration of elagolix 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 and reduces bleeding associated with uterine fibroids.

Estradiol acts by binding to nuclear receptors that are expressed in estrogen-responsive tissues. As a component of elagolix/estradiol/norethindrone, the addition of exogenous estradiol may reduce the increase in bone resorption and resultant bone loss that can occur due to a decrease in circulating estrogen from elagolix alone.

Progestins such as norethindrone act by binding to nuclear receptors that are expressed in progesterone-responsive tissues. As a component of elagolix/estradiol/norethindrone, norethindrone may protect the uterus from the potential adverse endometrial effects of unopposed estrogen.

Advice to Patients

• Advise the patient to read the FDA-approved patient labeling.

• Advise patients that use of estrogen and progestin combinations may increase the risk of thromboembolic disorders and vascular events, especially in women at high risk for these events.

• Advise patients about the risk of bone loss. Advise patients that supplementary calcium and vitamin D may be beneficial if dietary intake of calcium and vitamin D is not adequate. Advise patients that oral iron supplement should not be taken at the same time as calcium and vitamin D.

• Advise patients that suicidal ideation and exacerbation of mood disorders may occur with elagolix/estradiol/norethindrone use. Instruct patients with new onset or worsening depression, anxiety, or other mood changes to promptly seek medical attention.

• Advise patients to promptly seek medical attention in case of signs or symptoms that may reflect liver injury, such as jaundice.

• Advise patients that elagolix/estradiol/norethindrone may delay the recognition of pregnancy because it may reduce the duration and amount of menstrual bleeding. Advise patients to use effective non-hormonal contraception while taking elagolix/estradiol/norethindrone, for 28 days after discontinuation, and to discontinue the combination drug if pregnancy is diagnosed. Advise pregnant patients that there is a pregnancy registry that monitors outcomes in women who become pregnant while treated with elagolix/estradiol/norethindrone. Inform patients they can enroll by calling 1-833-782-7241 or visiting [Web].

• Advise patients that alopecia, hair loss, and hair thinning in no specific pattern, may occur with elagolix/estradiol/norethindrone use. Advise patients that hair loss and hair thinning may not resolve completely after stopping the combination drug. Advise patients to contact their healthcare provider if they have concerns about changes to their hair.

• Advise patients to inform their healthcare providers of all concomitant medications, including prescription medicines, over-the-counter (OTC) drugs, vitamins, and herbal products. Advise patients to avoid grapefruit juice while taking elagolix/estradiol/norethindrone.

• Instruct patients about what to do in the event a dose is missed. See “If you miss a dose of elagolix, estradiol, and norethindrone” section in FDA-approved Medication Guide.

• 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, [Web], and not to flush down the toilet.

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.

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