reactions of OATP1B1 substrates when coadministered with voclosporin.vonoprazanSerious - Use Alternative (1)elagolix will decrease the level or effect of vonoprazan by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.vorapaxarMonitor Closely (1)elagolix decreases levels of vorapaxar by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Elagolix is a weak-to-moderate CYP3A4 inducer. Monitor CYP3A substrates if coadministered. Consider increasing CYP3A substrate dose if needed.voriconazoleMonitor Closely (4)voriconazole will increase the level or effect of estradiol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. elagolix decreases levels of voriconazole by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Elagolix is a weak-to-moderate CYP3A4 inducer. Monitor CYP3A substrates if coadministered. Consider increasing CYP3A substrate dose if needed. voriconazole will increase the level or effect of elagolix by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Coadministration of elagolix 200 mg BID with strong CYP3A inhibitors for >1 month is not recommended. Limit elagolix dose to 150 mg qDay and CYP3A inhibitor duration of use to 6 months if coadministered. elagolix will increase the level or effect of voriconazole by affecting hepatic enzyme CYP2C19 metabolism. Modify Therapy/Monitor Closely. Elagolix is a weak CYP2C19 inhibitor. Caution with sensitive CYP2C19 substrates.vortioxetineMonitor Closely (1)elagolix decreases levels of vortioxetine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Elagolix is a weak-to-moderate CYP3A4 inducer. Monitor CYP3A substrates if coadministered. Consider increasing CYP3A substrate dose if needed.voxelotorSerious - Use Alternative (4)voxelotor will increase the level or effect of estradiol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Voxelotor increases systemic exposure of sensitive CYP3A4 substrates. Avoid coadministration with sensitive CYP3A4 substrates with a narrow therapeutic index. Consider dose reduction of the sensitive CYP3A4 substrate(s) if unable to avoid. elagolix will decrease the level or effect of voxelotor by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Voxelotor is primarily metabolized by CYP3A4. Avoid coadministration with moderate or strong CYP3A4 inducers. If unable to avoid coadministration, increase voxelotor dose (see Dosage Modifications). voxelotor will increase the level or effect of elagolix by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Voxelotor increases systemic exposure of sensitive CYP3A4 substrates. Avoid coadministration with sensitive CYP3A4 substrates with a narrow therapeutic index. Consider dose reduction of the sensitive CYP3A4 substrate(s) if unable to avoid. voxelotor will increase the level or effect of norethindrone acetate by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Voxelotor increases systemic exposure of sensitive CYP3A4 substrates. Avoid coadministration with sensitive CYP3A4 substrates with a narrow therapeutic index. Consider dose reduction of the sensitive CYP3A4 substrate(s) if unable to avoid.voxilaprevirMonitor Closely (2)elagolix will increase the level or effect of voxilaprevir by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor. elagolix decreases levels of voxilaprevir by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Elagolix is a weak-to-moderate CYP3A4 inducer. Monitor CYP3A substrates if coadministered. Consider increasing CYP3A substrate dose if needed.warfarinMonitor Closely (2)estradiol increases effects of warfarin by unspecified interaction mechanism. Use Caution/Monitor. elagolix will decrease the level or effect of warfarin by Other (see comment). Use Caution/Monitor. Warfarin's less potent R-enantiomer is metabolized in part by CYP3A4 (and also CYP1A2 and CYP2C19). Monitor INR more frequently if coadministered with inducers of these isoenzymes and adjust warfarin dose if needed. zafirlukastMonitor Closely (1)zafirlukast will increase the level or effect of estradiol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.zanubrutinibSerious - Use Alternative (1)elagolix will decrease the level or effect of zanubrutinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Avoid coadministration of zanubrutinib (a CYP3A4 substrate) with moderate CYP3A4 inhibitors. If unavoidable, increase zanubrutinib dose to 320 mg PO BID. After discontinuing the CYP3A4 inhibitor, resume previous dose of zanubrutinib. zolpidemMonitor Closely (1)elagolix decreases levels of zolpidem by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Elagolix is a weak-to-moderate CYP3A4 inducer. Monitor CYP3A substrates if coadministered. Consider increasing CYP3A substrate dose if needed.zonisamideMonitor Closely (1)elagolix decreases levels of zonisamide by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Elagolix is a weak-to-moderate CYP3A4 inducer. Monitor CYP3A substrates if coadministered. Consider increasing CYP3A substrate dose if needed. >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 Black Box Warnings Estrogen and progestin combinations increase risk of thrombotic or thromboembolic disorders including pulmonary embolism (PE), deep vein thrombosis (DVT), stroke, or myocardial infarction (MI), especially in women at increased risk for these events Contraindicated in women with current or history of thrombotic or thromboembolic disorders and in women at increased risk for these events, including women aged ≥35 yr who smoke and women with uncontrolled hypertensionContraindications 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 There is a pregnancy registry that monitors pregnancy outcomes in women exposed to therapy 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 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 There is no information on presence of this drug or its metabolites in human milk, effects on breastfed child, 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 The developmental and health benefits of breastfeeding should be considered along with mother’s clinical need for therapy and any potential adverse effects on breastfed child from the drug or from underlying maternal conditionPregnancy 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