elagolix/estradiol/norethindrone acetate (Rx)

>10%

Decreased bone mineral density (BMD) >3% (27%)

Hot flush (22%)

Increased diastolic blood pressure (BP) ≥100 mmHg (11.3%)

1-10%

Headache (9%)

Increased systolic BP ≥160 mmHg (7.1%)

Fatigue (6%)

Metrorrhagia (5%)

Alopecia (3.5%)

Depression (3%)

Decreased BMD ≥8% (1.7%)

Increased ALT/AST (1.1-1.3%)

≥3 to <5%

• Decreased libido
• Arthralgia
• Mood swings
• Influenza
• Abdominal distension
• Upper respiratory tract infection
• Vomiting
• Increased weight

Contraindications

Pregnancy

Osteoporosis

Current or history of breast cancer or other hormonally sensitive malignancies, and with increased risk for hormonally sensitive malignancies

Hepatic impairment or disease

Undiagnosed abnormal uterine bleeding

Anaphylactic reaction, angioedema, or hypersensitivity any of the drug components

OATP1B1 inhibitors

High risk of arterial, venous thrombotic, or thromboembolic disorders

• Women aged ≥35 yr who smoke
• Current or history of DVT or pulmonary embolism
• Vascular disease (eg,, cerebrovascular disease, coronary artery disease, peripheral vascular disease)
• Thrombogenic valvular or thrombogenic rhythm diseases of the heart (eg, subacute bacterial endocarditis with valvular disease, atrial fibrillation)
• Inherited or acquired hypercoagulopathies
• Uncontrolled hypertension
• Headaches with focal neurological symptoms or migraine with aura if aged ≥35 yr

Cautions

Estrogens and progestins increase risk of thromboembolism; discontinue if thrombotic event occurs or suspected; discontinue immediately if there is sudden unexplained partial or complete vision loss, proptosis, diplopia, papilledema, or retinal vascular lesions, and evaluate for retinal vein thrombosis; contraindicated with known thrombotic conditions or individuals at high risk

May decrease BMD in some patients; BMD loss is greater with increasing duration of use; contraindicated with known osteoporosis

Use of estrogen alone and estrogen plus progestin associated with increased risk for abnormal mammograms requiring further evaluation; surveillance measures, such as breast examinations and regular mammography, are recommended; discontinue drug if hormonally sensitive malignancy is diagnosed; contraindicated with current or history of breast cancer or other hormonally sensitive cancer

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

Monitor transaminases; instruct patients to seek medical attention for signs of liver injury (eg, jaundice); contraindicated with hepatic impairment or disease

Monitor BP; for women with well-controlled hypertension, continue to monitor BP and stop drug if BP increases significantly; contraindicated with uncontrolled hypertension

Small increased risk of developing gallbladder disease; assess risk with history of cholestatic jaundice; discontinue if jaundice occurs

Alopecia reported; unknown if hair loss is reversible

Contains FD&C yellow no. 5 (tartrazine), which may cause allergic-type reactions (including bronchial asthma) in susceptible persons; although incidence is low, it is frequently seen in patients who also have aspirin hypersensitivity

Menstrual bleeding pattern and reduced ability to recognize pregnancy

• May delay ability to recognize pregnancy because it may reduce intensity, duration, and amount of menstrual bleeding
• Perform pregnancy testing if pregnancy is suspected, and discontinue drug if pregnancy confirmed
• Effect of hormonal contraceptives on the efficacy of Oriahnn is unknown
• Advise women to use nonhormonal contraception during treatment and for 1 week after discontinuing

Effects on carbohydrate and lipid metabolism

• May decrease glucose tolerance and result in increased glucose levels; more frequent monitoring with prediabetes and diabetes may be needed
• Estrogen therapy may be associated with increased plasma triglycerides leading to pancreatitis; elagolix is associated with increased total cholesterol, LDL-C, HDL-C, and serum triglycerides

Laboratory results

• Estrogens and progestins may raise serum concentrations of binding proteins (eg, thyroid-binding globulin, corticosteroid-binding globulin), which may reduce free thyroid or corticosteroid hormone levels
• Patients with hypothyroidism or hypoadrenalism may require higher doses of thyroid hormone or cortisol replacement therapy, respectively
• May also affect levels of sex hormone-binding globulin, coagulation factors, lipids, and glucose

Drug interaction overview

• CYP3A substrates

  • Elagolix is a weak-to-moderate inducer of CYP3A
  • Coadministration may decrease plasma concentrations of drugs that are CYP3A substrates

• CYP2C19 substrates

  • Elagolix is a weak inhibitor of CYP2C19
  • Coadministration may increase plasma concentrations of drugs that are CYP2C19 substrates

• P-gp substrates

  • Elagolix inhibits efflux transporter P-glycoprotein (P-gp)
  • Coadministration may increase plasma concentrations of drugs that are P-gp substrates

• Effect of other drugs on Oriahnn

  • Elagolix is a substrate of CYP3A, P-gp, and OATP1B1
  • Estradiol and norethindrone acetate are metabolized partially by CYP3A
  • Strong CYP3A inducers may decrease elagolix, estradiol, and norethindrone plasma concentrations and may result in decreased therapeutic effects
  • Strong CYP3A inhibitors are not recommended; coadministration may increase elagolix, estradiol, and norethindrone plasma concentrations and risk of adverse effects
  • OATP1B1 inhibitors (eg, rifampin) that are known or expected to significantly increase elagolix plasma concentrations and are contraindicated

Pregnancy

Contraindicated in pregnant women

Exposure early in pregnancy may increase risk of early pregnancy loss

Discontinue drug if pregnancy occurs during treatment

Pregnancy registry monitoring outcomes in women who become pregnant during treatment: 1-833-782-7241

Animal studies

• When pregnant rats and rabbits were dosed with elagolix during 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

Contraception

• Advise women to use nonhormonal contraception during treatment and for 1 week after discontinuing

Lactation

Data are not available on the presence of elagolix in human milk, the effects on breastfed infants, or 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 breastfeeding females; this reduction can occur at any time, but is less likely to occur once breastfeeding is well established

Advise nursing females to use nonhormonal contraception until breastfeeding discontinued

Pregnancy Categories

A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA: Information not available.

Mechanism of Action

Elagolix

• Gonadotropin-releasing hormone antagonists (GnRH); inhibits endogenous GnRH signaling by binding competitively to GnRH receptors in the pituitary gland
• Results in dose-dependent suppression of luteinizing hormone and follicle-stimulating hormone, 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
• 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

Norethindrone acetate

• Acts by binding to nuclear receptors that are expressed in progesterone-responsive tissues
• May protect uterus from potential adverse endometrial effects of unopposed estrogen

Absorption

Peak plasma time

• Elagolix: 1.5 hr
• Estradiol: 2 hr
• Norethindrone: 1 hr

Peak plasma concentration

• Elagolix: 1200 ng/mL
• Estradiol: 0.06 ng/mL
• Norethindrone: 6.1 ng/mL

AUC

• Elagolix: 2826 ng⋅hr/mL
• Estradiol: 0.86 ng⋅hr/mL
• Norethindrone: 23.8 ng⋅hr/mL

Distribution

Protein bound

• Elagolix: 80%
• Estradiol: 98%
• Norethindrone: 97%

Metabolism

Elagolix: CYP3A (major); minor pathways include CYP2D6, CYP2C8, and UGTs

Estradiol: CYP3A (partial); other pathways include sulfation and glucuronidation

Norethindrone: CYP3A (partial)

Elimination

Excretion (elagolix): Urine (<3%); feces (90%)

Half-life

• Elagolix: 5.9 hr
• Estradiol: 14.5 hr
• Norethindrone: 9.2 hr

Oral Administration

Take the morning and evening capsules at approximately the same time each day, with or without food

Missed dose

• Within 4 hr of missed dose: Take missed dose and then the next dose at the usual time
• >4 hr past missed dose: Do not to take missed dose; take next dose at the usual time
• Take only 1 morning capsule and 1 evening capsule per day

Storage

Store at 20-25ºC (68-77ºF), excursions permitted to 15-30ºC (59-86ºF)

Dispose of unused medication via a take-back program (or local pharmacy) if available

Otherwise, do not flush down toilet; follow FDA instructions for disposing medication in household trash