elagolix/estradiol/norethindrone

General

Pronunciation:
el-a-goe-lix/es-tra-dye-ole/nor-eth-in-drone

Trade Name(s)

Oriahnn

Ther. Class.

hemostatic agents

hormones

Pharm. Class.

gnrh antagonist

estrogens

progestins

Indications

Heavy menstrual bleeding associated with uterine fibroids in premenopausal women.

Action

Elagolix: competitively binds to and inhibits gonadotropin-releasing hormone receptors in the pituitary gland, causing a decrease in the release of estradiol and progesterone by the ovaries, reducing bleeding associated with uterine fibroids. Estradiol: binds to estrogen receptors and reduces the increase in bone resorption and potential bone loss associated with elagolix. Norethindrone: protects uterus from potential adverse endometrial effects caused by unopposed estrogen use.

Therapeutic Effect(s):

Reduced menstrual blood loss.

Pharmacokinetics

Elagolix

Absorption: Rapidly absorbed following oral administration.

Distribution: Unknown.

Metabolism and Excretion: Primarily metabolized in the liver via the CYP3A isoenzyme with some metabolism by the CYP2D6 and CYP2C8 isoenzymes as well as UGT. 90% of dose excreted in feces, <3% in urine.

Half-life: 4–6 hr.

Estradiol

Absorption: Well absorbed following oral administration.

Distribution: Widely distributed.

Protein Binding: 98%.

Metabolism and Excretion: Metabolized by the liver via the CYP3A isoenzyme; also undergoes sulfation and glucuronidation. Enterohepatic recirculation occurs, and more absorption may occur from the GI tract.

Half-life: 8–20 hr.

Norethindrone

Absorption: Rapidly absorbed following oral administration.

Distribution: Unknown.

Protein Binding: 97%.

Metabolism and Excretion: Metabolized by the liver via the CYP3A isoenzyme.

Half-life: 5–13 hr.

TIME/ACTION PROFILE (plasma concentrations)

ROUTE	ONSET	PEAK	DURATION
PO	rapid	1–2 hr	unknown

Contraindication/Precautions

Contraindicated in:

Hypersensitivity to elagolix, estradiol, or norethindrone;
History of cigarette smoking and age >35 yr (↑ risk of cardiovascular or thromboembolic phenomenon);
Thromboembolic disease (e.g., deep vein thrombosis [DVT], pulmonary embolism [PE], MI, stroke);
Cerebrovascular disease, coronary artery disease, or peripheral vascular disease;
Valvular heart disease or thrombogenic heart rhythms;
Protein C, protein S, or antithrombin deficiency or other thrombophilic disorder;
Headache with focal neurological symptoms or migraine headaches with aura in women >35 yr;
Uncontrolled hypertension;
Major surgery with extended periods of immobility;
Osteoporosis (may ↑ risk of bone loss);
Breast cancer or other hormone-sensitive malignancy;
↑ risk for hormone sensitive malignancy;
Hepatic impairment;
Undiagnosed abnormal uterine bleeding;
Concurrent use of strong organic anion transporting polypeptide (OATP) 1B1 inhibitors;
OB: Pregnancy.

Use Cautiously in:

Aspirin hypersensitivity (contains tartrazine, which may cause allergic reaction);
History of low-trauma fracture or other risk factors for osteoporosis;
History of suicidal thoughts/behaviors or depression;
Controlled hypertension;
Diabetes;
Hypertriglyceridemia (↑ risk of pancreatitis);
Lactation: Use while breastfeeding only if potential maternal benefit justifies potential risk to infant;
Rep: Women of reproductive potential;
Pedi: Safety and effectiveness not established in children.

Adverse Reactions/Side Effects

CV: ↑ BP, DVT, MI

Derm: alopecia

Endo: hot flush, hyperglycemia

GI: ↑ liver enzymes, cholelithiasis, vomiting

GU: ↓ libido, metrorrhagia

Metabolic: ↑ weight, hyperlipidemia

MS: ↓ bone density, arthralgia

Neuro: depression, headache, mood swings, STROKE, SUICIDAL THOUGHTS/BEHAVIOR

Resp: PE

Misc: fatigue, MALIGNANCY (BREAST, ENDOMETRIAL, OVARIAN)

* CAPITALS indicate life-threatening.
Underline indicate most frequent.

Interactions

Drug-Drug

Strong OATP1B1 inhibitors, including rifampin may significantly ↑ elagolix levels and risk of toxicity; concurrent use contraindicated.
Corticosteroids, anticonvulsants, and proton pump inhibitors may ↑ risk for bone loss.
Elagolix may ↓ levels of CYP3A substrates, including midazolam ; consider ↑ midazolam dose.
Elagolix may ↑ levels of CYP2C19 substrates, including omeprazole ; consider ↓ omeprazole dose when using higher doses (>40 mg/day).
Elagolix may ↑ levels of P-glycoprotein substrates, including digoxin ; closely monitor digoxin levels.
May ↓ rosuvastatin levels; consider ↑ rosuvastatin dose.
Strong CYP3A inhibitors may ↑ elagolix, estradiol, and norethindrone levels and risk of toxicity; concurrent use not recommended.
Strong CYP3A inducers may ↓ elagolix, estradiol, and norethindrone levels and effectiveness.

Route/Dosage

PO (Adults): One capsule (elagolix 300 mg/estradiol 1 mg/norethindrone 0.5 mg) every am and elagolix 300 mg every pm. Continue for no longer than 24 mo.

Availability

Capsules: elagolix 300 mg/estradiol 1 mg/norethindrone 0.5 mg (am); elagolix 300 mg (pm)

Assessment

Monitor amount of menstrual bleeding during therapy.
Monitor for signs and symptoms of thromboembolic disorders and vascular events (pain, swelling, tenderness in extremities; headache; chest pain; blurred vision; sudden unexplained partial or complete loss of vision; proptosis; diplopia; papilledema retinal vascular lesions) during therapy. Discontinue therapy if symptoms occur or are suspected. Evaluate for retinal vein thrombosis if visual changes occur.
Assess bone mineral density by dual-energy x-ray absorptiometry (DXA) at baseline and periodically during therapy. Consider discontinuing therapy if risk associated with bone loss exceeds potential benefit of treatment. Consider calcium and vitamin D supplementation for patients with inadequate dietary intake.
Assess for new or worsening depression, anxiety, or other mood changes periodically during therapy. Consider referral to mental health professional. Reevaluate benefits and risks of therapy if such events occur.
Monitor BP prior to and periodically during therapy. Hold therapy for significant increases in BP.

Lab Test Considerations:

Verify negative pregnancy test within 7 days from onset of menses.

May cause ↑ AST and ALT.
May decrease glucose tolerance and ↑ blood glucose levels. Monitor blood glucose more frequently in women with prediabetes and diabetes.
Monitor lipid levels periodically during therapy. May cause ↑ total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, and serum triglycerides.

Implementation

PO Administer morning and evening doses at same times each day without regard to food.

Patient/Family Teaching

Instruct patient to take medication as directed at the same times each day. Take missed doses within 4 hr of time it was supposed to be taken and take next dose at usual time. If more than 4 hr since capsule is usually taken, omit dose and take next dose at usual time. Take only one morning and one evening capsule each day. Advise patient to read Medication Guide before starting therapy and with each Rx refill in case of changes.
Advise patient to stop taking medication and notify health care professional immediately if signs and symptoms of cardiovascular conditions (leg pain or swelling that will not go away; sudden shortness of breath; double vision; bulging of the eyes; sudden blindness, partial or complete; pain or pressure in chest, arm, or jaw; sudden, severe headache unlike usual headaches; weakness or numbness in an arm or leg; trouble speaking) occur.
Inform patient of risk of bone loss. Advise patient to take supplementary calcium and vitamin D and to avoid taking iron supplements at same time.
Instruct patient to pay attention to changes in mood, behaviors, thoughts, or feelings. Advise patients to notify health care professional immediately if signs and symptoms of suicidal ideation and behavior (thoughts about suicide or dying, attempts to commit suicide, new or worse depression, new or worse anxiety, other unusual changes in behavior or mood) occur.
Advise patient to notify health care professional if signs and symptoms of liver injury (jaundice, dark amber-colored urine, feeling tired, nausea and vomiting, generalized swelling, right upper stomach area pain, bruising easily) occur.
Advise patient that alopecia, hair loss, and hair thinning in no specific pattern, may occur and may not completely resolve after discontinuing therapy. Advise patient to consult health care professional with concerns about changes to hair.
Instruct patient to notify health care professional of all Rx or OTC medications, vitamins, or herbal products being taken and to avoid concurrent use of Rx, OTC, and herbal products without consulting health care professional.
Dispose unused medication via a take-back option if available. Otherwise, follow FDA instructions for disposing medication in the household trash: www.fda.gov/drugdisposal. Do NOT flush down the toilet.
Rep: Inform patient that Oriahnn may decrease menstrual bleeding or result in no menstrual bleeding, making it hard to know if you are pregnant; watch for other signs of pregnancy (breast tenderness, weight gain, nausea). May result in pregnancy loss if used in early pregnancy. Advise females of reproductive potential to use effective nonhormonal contraception during and for 1 wk after last dose. Hormonal contraceptives may decrease effectiveness of elagolix and may increase risk of thromboembolic and vascular disorders. Advise patient to notify health care professional if pregnancy is planned or suspected, or if breastfeeding. Encourage patients who become pregnant during therapy to enroll in pregnancy exposure registry to monitor pregnancy outcomes by calling 1-833-782-7241.

Evaluation/Desired Outcomes