ORIAHNN (elagolix, estradiol, and norethindrone acetate capsules; elagolix capsules)

ORIAHNN (elagolix, estradiol, and norethindrone acetate capsules; elagolix capsules)

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ORIAHNN

ORIAHNN consists of two capsules: one to be taken orally in the morning (AM) and one to be taken orally in the evening (PM). The AM capsule is white and yellow and contains 300 mg elagolix (equivalent to 310.4 mg of elagolix sodium), 1 mg estradiol, and 0.5 mg norethindrone acetate. The PM capsule is white and light blue and contains 300 mg of elagolix (equivalent to 310 mg of elagolix sodium).

Elagolix

Elagolix sodium is the sodium salt of the active moiety elagolix, a nonpeptide small molecule, GnRH receptor antagonist. Elagolix sodium is chemically described as sodium 4-({(1R)-2-[5-(2­ fluoro-3-methoxyphenyl)-3-{[2-fluoro-6-(trifluoromethyl)phenyl]methyl}-4-methyl-2,6-dioxo3,6-dihydropyrimidin-1(2H)-yl]-1-phenylethyl}amino)butanoate. Elagolix sodium has a molecular formula of C32H29F5N3O5Na and a molecular weight of 653.58. Elagolix free acid has a molecular formula of C32H30F5N3O5 and a molecular weight of 631.60.

Estradiol

Estradiol (E2), an estrogen, is a white or almost white crystalline powder. Its chemical name is estra-1,3,5(10)-triene-3,17β-diol with the molecular formula of C18H24O2, and molecular weight of 272.38.

Norethindrone acetate

Norethindrone acetate (NETA), a progestin, is a white or yellowish white crystalline powder. Its chemical name is 17β-acetoxy-19-nor-17α-pregn-4-en-20-yn-3-one with the molecular formula of C22H28O3 and molecular weight of 340.46.

ORIAHNN morning (AM) capsules contain the following inactive ingredients: anhydrous sodium carbonate, polyethylene glycol 3350, crospovidone, colloidal silicon dioxide, magnesium stearate, polyvinyl alcohol, titanium dioxide, polyethylene glycol, talc, purified water, lactose monohydrate, starch (corn), copovidone, talc, hypromellose, triacetin, and gelatin capsule shell. The capsule shell contains the following ingredients: FD&C Red #40, FD&C Yellow #5, FD&C Yellow #6, titanium dioxide, gelatin, and printing ink (shellac, dehydrated alcohol, isopropyl alcohol, butyl alcohol, propylene glycol, strong ammonia solution, black iron oxide, potassium hydroxide, and purified water).

ORIAHNN evening (PM) capsules contain the following inactive ingredients: anhydrous sodium carbonate, polyethylene glycol 3350, crospovidone, colloidal silicon dioxide, magnesium stearate, polyvinyl alcohol, titanium dioxide, polyethylene glycol, talc, purified water, and gelatin capsule shell. The capsule shell contains the following ingredients: FD&C Blue #2, FDA/E172 yellow iron oxide, titanium dioxide, gelatin, and printing ink (shellac, dehydrated alcohol, isopropyl alcohol, butyl alcohol, propylene glycol, strong ammonia solution, black iron oxide, potassium hydroxide, and purified water).

Indications and usage

ORIAHNN is a combination of elagolix, a gonadotropin-releasing hormone (GnRH) receptor antagonist, estradiol, an estrogen, and norethindrone acetate, a progestin, indicated for the management of heavy menstrual bleeding associated with uterine leiomyomas (fibroids) in premenopausal women.

Limitation of Use: Use of ORIAHNN should be limited to 24 months due to the risk of continued bone loss, which may not be reversible.

Dosage and administration

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.

Missed Dose Instruct the patient to take the missed dose of ORIAHNN within 4 hours of the time that it was supposed to be taken and then the next dose at the usual time. If more than 4 hours have passed since a capsule is usually taken, instruct the patient not to take the missed dose and take the next dose at the usual time. Take only one morning capsule and one evening capsule per day.

Mechanism of Action

ORIAHNN combines elagolix and estradiol/norethindrone acetate (E2/NETA), a combination of estrogen and 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.

E2 acts by binding to nuclear receptors that are expressed in estrogen-responsive tissues. As a component of ORIAHNN, 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 NETA act by binding to nuclear receptors that are expressed in progesteroneresponsive tissues. As a component of ORIAHNN, NETA may protect the uterus from the potential adverse endometrial effects of unopposed estrogen.

Warnings and precautions

  • Thromboembolic Disorders and Vascular Events: Discontinue ORIAHNN if an arterial or venous thrombotic, cardiovascular, or cerebrovascular event occurs. Stop ORIAHNN if there is sudden unexplained partial or complete loss of vision, proptosis, diplopia, papilledema, or retinal vascular lesions and evaluate for retinal vein thrombosis immediately.
  • Bone Loss: Duration-dependent decreases in bone mineral density (BMD) that may not be completely reversible. Baseline and periodic BMD assessments are recommended. Assess risk-benefit for women with additional risk factors for bone loss.
  • Suicidal Ideation and Mood Disorders: Advise patients to seek medical attention for suicidal ideation, suicidal behavior, new onset or worsening depression, anxiety, or other mood changes.
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  • Hepatic Impairment and Transaminase Elevations: Counsel patients on signs and symptoms of liver injury.
  • Elevated Blood Pressure: Do not use in women with uncontrolled hypertension. For women with well-controlled hypertension, continue to monitor blood pressure and stop ORIAHNN if blood pressure rises significantly.
  • Change in Menstrual Bleeding Pattern and Reduced Ability to Recognize Pregnancy: Advise women to use non-hormonal contraception during treatment and for 28 days after discontinuing ORIAHNN. ORIAHNN may delay the ability to recognize the occurrence of a pregnancy because it alters menstrual bleeding. Perform pregnancy testing if pregnancy is suspected and discontinue ORIAHNN if pregnancy is confirmed.

Risk of Allergic Reactions Due to the Inactive Ingredient (FD&C Yellow No 5): This product contains FD&C Yellow No. 5 (tartrazine), which may cause allergic-type reactions (including bronchial asthma) in certain susceptible persons.

Contraindications

ORIAHNN is contraindicated in women:

With a high risk of arterial, venous thrombotic, or thromboembolic disorders. Examples include women over 35 years of age who smoke, and women who are known to have:

  • current or history of deep vein thrombosis or pulmonary embolism
  • vascular disease (e.g., cerebrovascular disease, coronary artery disease, peripheral vascular disease)
  • thrombogenic valvular or thrombogenic rhythm diseases of the heart (for example, subacute bacterial endocarditis with valvular disease, or atrial fibrillation)
  • inherited or acquired hypercoagulopathies
  • uncontrolled hypertension
  • headaches with focal neurological symptoms or have migraine headaches with aura if over age 35

Who are pregnant. Exposure to ORIAHNN early in pregnancy may increase the risk of early pregnancy loss

With known osteoporosis because of the risk of further bone loss .

With current or history of breast cancer or other hormonally-sensitive malignancies, and with increased risk for hormonally-sensitive malignancies

With known hepatic impairment or disease

With undiagnosed abnormal uterine bleeding.

With known anaphylactic reaction, angioedema, or hypersensitivity to ORIAHNN or any of its components.

Taking inhibitors of organic anion transporting polypeptide (OATP)1B1 (a hepatic uptake transporter) that are known or expected to significantly increase elagolix plasma concentrations.

Use in specific populations

Pregnancy: Use of ORIAHNN is contraindicated in pregnant women. Exposure to elagolix early in pregnancy may increase the risk of early pregnancy loss. Discontinue ORIAHNNif 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.

Lactation: There is no information on the presence of elagolix 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 nonhormonal 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 ORIAHNN and any potential adverse effects on the breast-fed child from ORIAHNN or from the underlying maternal condition

Pediatric Use: Safety and effectiveness of ORIAHNN in pediatric patients have not been established.

Renal Impairment: No dose adjustment of ORIAHNN is required in women with any degree of renal impairment or end-stage renal disease (including women on dialysis)

Hepatic Impairment: ORIAHNN is contraindicated in women with any hepatic impairment or disease. The use of estradiol (a component of ORIAHNN) 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.

Overdosage

Overdosage of estrogen and progestin combination products may cause nausea, vomiting, breast tenderness, abdominal pain, drowsiness, fatigue, and withdrawal bleeding. In case of ORIAHNN overdose, monitor the patient for any signs or symptoms of adverse reactions and initiate appropriate symptomatic treatment, as needed.

Storage and handling

Store at 20°C to 25°C (68°F to 77°F), excursions permitted to 15˚C to 30˚C (59˚F to 86˚F). [See USP Controlled Room Temperature].

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.

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