Elagolix and Estradiol and Norethisterone

ORIAHNN is 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 [see Dosage and Administration ( 2.1 ) and Warnings and Precautions ( 5.2 ) ] . 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. ( 1 ) 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. ( 1 )

ORIAHNN consists of two capsules: The morning (AM) capsule is white and yellow, printed with “EL300 AM” containing 300 mg elagolix, 1 mg estradiol, and 0.5 mg norethindrone acetate. The evening (PM) capsule is white and light blue, printed with “EL300 PM” containing 300 mg elagolix. Morning (AM) capsule: elagolix 300 mg, estradiol 1 mg, norethindrone acetate 0.5 mg. ( 3 ) Evening (PM) capsule: elagolix 300 mg. ( 3 )

ORIAHNN is contraindicated in women: With a high risk of arterial, venous thrombotic, or thromboembolic disorders [see Boxed Warning and Warnings and Precautions ( 5.1 ) ] . 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 [see Use in Specific Populations ( 8.1 ) ] . With known osteoporosis because of the risk of further bone loss [see Warnings and Precautions ( 5.2 ) ] . With current or history of breast cancer or other hormonally-sensitive malignancies, and with increased risk for hormonally-sensitive malignancies [see Warnings and Precautions ( 5.3 ) ] . With known hepatic impairment or disease [see Warnings and Precautions ( 5.5 ) ] . 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 [see Drug Interactions ( 7.2 ) ] . High risk of arterial, venous thrombotic, or thromboembolic disorder. ( 4 ) Pregnancy. ( 4 ) Known osteoporosis. ( 4 ) Current or history of breast cancer or other hormonally-sensitive malignancies. ( 4 ) Known liver impairment or disease. ( 4 ) Undiagnosed abnormal uterine bleeding. ( 4 ) Known hypersensitivity to ingredients of ORIAHNN. ( 4 ) Organic anion transporting polypeptide (OATP)1B1 inhibitors that are known or expected to significantly increase elagolix plasma concentrations. ( 4 )

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. ( 5.1 ) 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. ( 5.2 ) 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. ( 5.4 ) Hepatic Impairment and Transaminase Elevations: Counsel patients on signs and symptoms of liver injury. ( 5.5 ) 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. ( 5.6 ) 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. ( 5.8 ) 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. ( 5.12 )

5.1 Thromboembolic Disorders and Vascular Events ORIAHNN is contraindicated in women with current or history of thrombotic or thromboembolic disorders and in women at increased risk for these events [see Contraindications ( 4 ) ] . In the Phase 3 clinical trials (Studies UF-1, UF-2, and UF-3), two thrombotic events occurred in 453 ORIAHNN-treated women (thrombosis in the calf and pulmonary embolism) [see Adverse Reactions ( 6.1 ) and Clinical Studies ( 14 ) ] . Estrogen and progestin combinations, including the estradiol/norethindrone acetate component of ORIAHNN, 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 ORIAHNN if an arterial or venous thrombotic, cardiovascular, or cerebrovascular event occurs or is suspected. If feasible, discontinue ORIAHNN 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 ORIAHNN 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.

5.2 Bone Loss ORIAHNN is contraindicated in women with known osteoporosis [see Contraindications ( 4 )] . ORIAHNN 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 [see Adverse Reactions ( 6.1 ) ] . In the Phase 3 clinical trials (Studies UF-1, UF-2, and UF-3) [see Clinical Studies ( 14 ) ] , seven out of 453 (1.5%) ORIAHNN-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 ORIAHNN-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 ORIAHNN 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 ORIAHNN 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 [see Indications and Usage ( 1 ) and Dosage and Administration ( 2.1 ) ] . Although the effect of supplementation with calcium and vitamin D was not studied, such supplementation for patients with inadequate dietary intake may be beneficial.

5.3 Hormonally-Sensitive Malignancies ORIAHNN 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 [see Contraindications ( 4 ) ] . In the Phase 3 clinical trials (Studies UF-1, UF-2, and UF-3), two (0.4%) cases of breast cancer in 453 ORIAHNN-treated women were observed. No breast cancer cases were seen in placebo-treated women [see Adverse Reactions ( 6.1 ) ] . 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 ORIAHNN if a hormonally-sensitive malignancy is diagnosed.

5.4 Suicidal Ideation, Suicidal Behavior, and Exacerbation of Mood Disorders In Phase 3 placebo-controlled clinical trials (Studies UF-1 and UF-2), ORIAHNN-treated women had a higher incidence (3%) of depression, depressed mood, and/or tearfulness compared to placebo-treated women (1%) [see Adverse Reactions ( 6.1 ) ] . 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 ORIAHNN if such events occur.

5.5 Hepatic Impairment and Transaminase Elevations Contraindication in Patients with Hepatic Impairment ORIAHNN is contraindicated in women with known hepatic impairment or disease [see Contraindications ( 4 ) , Use in Specific Populations ( 8.7 ) , and Clinical Pharmacology ( 12.3 ) ] . Transaminase Elevations 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 ORIAHNN-treated patients, respectively, compared to no elevations in placebo. 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 [see Adverse Reactions ( 6.1 ) ] .

5.6 Elevated Blood Pressure ORIAHNN is contraindicated in women with uncontrolled hypertension [see Contraindications ( 4 ) ] . […]

The following serious adverse reactions are discussed elsewhere in labeling: Thromboembolic Disorders and Vascular Events [see Warnings and Precautions ( 5.1 ) ] Bone Loss [see Warnings and Precautions ( 5.2 ) ] Suicidal Ideation, Suicidal Behavior, and Exacerbation of Mood Disorders [see Warnings and Precautions ( 5.4 ) ] Hepatic Transaminase Elevations [see Warnings and Precautions ( 5.5 ) ] Elevated Blood Pressure [see Warnings and Precautions ( 5.6 ) ] Effects on Carbohydrate and Lipid Metabolism [see Warnings and Precautions ( 5.9 ) ] Alopecia [see Warnings and Precautions ( 5.10 ) ] Most common adverse reaction (>5%) in clinical trials were hot flushes, headache, fatigue, metrorrhagia. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact AbbVie Inc. at 1–800–633–9110 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch Figure 1. Mean Percent Change From Baseline in Lumbar Spine BMD in Women Who Received 12 Months of ORIAHNN (On-Treatment) and 12 Months of Follow Up (Off Treatment)

6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. The safety of ORIAHNN was evaluated in two 6-month, randomized, double-blind, placebo-controlled trials (Studies UF-1 and UF-2), in which 790 premenopausal women received at least 1 dose of ORIAHNN (n=395), elagolix 300 mg twice daily (n=199), or placebo (n=196) [see Clinical Studies ( 14 )] . Women who completed 6-month treatment in either Study UF-1 or Study UF-2 and met eligibility criteria (n=433) entered a 6-month extension study (Study UF-3), receiving either ORIAHNN (n=276) or elagolix 300 mg twice daily (n=157). Elagolix 300 mg twice daily is not an approved dosage but was included as a reference arm. A total of 341 women received ORIAHNN for 6 months and 182 women received ORIAHNN for 12 months. Serious Adverse Events Serious adverse events were reported in three (0.8%) ORIAHNN-treated women in Studies UF-1 and UF-2. Two women had heavy menstrual bleeding and required blood transfusion due to anemia (0.5%) and one woman with history of bariatric surgery had a laparoscopic cholecystectomy due to cholelithiasis. In Study UF-3, two women were diagnosed with breast cancer. One woman had completed 6 months of treatment with ORIAHNN in Study UF-1 and received 34 additional days of ORIAHNN in Study UF-3 when diagnosed. The second woman had received placebo in Study UF-2 and completed 6 months of ORIAHNN in Study UF-3 when diagnosed [see Warnings and Precautions ( 5.3 ) ] . Adverse Reactions Leading to Study Discontinuation In Studies UF-1 and UF-2, the discontinuation rate due to adverse reactions was 10% among ORIAHNN-treated women and 7% among placebo-treated women. The most common adverse reactions leading to study drug discontinuation in the ORIAHNN group were nausea (1%), headache (1%), alopecia (1%), metrorrhagia (1%), menorrhagia (1%), and hot flush (1%). One event each of the following adverse reactions led to study drug discontinuation: affect lability, angina pectoris, depression, hepatic enzyme increased, homicidal ideation, hypertension, irritability, thrombosis. In women who received ORIAHNN in Studies UF-1 or UF-2 and then in Study UF-3, 4% discontinued treatment due to adverse reactions. Three women discontinued due to serious adverse events (one each for breast cancer, menorrhagia with pelvic pain, and hysterectomy). Common Adverse Reactions Adverse reactions reported in ≥5% of ORIAHNN-treated women in Studies UF-1 and UF-2 and at a greater frequency than placebo-treated women are presented in Table 1. Table 1. Adverse Reactions that Occurred in at Least 5% of Women with Uterine Fibroids Who Received ORIAHNN in Studies UF-1 and UF-2 and at a Greater Incidence Than Placebo Adverse Reaction ORIAHNN N=395 Placebo N=196 Hot flush 22% 9% Headache 9% 7% Fatigue 6% 4% Metrorrhagia 5% 1% The most commonly reported adverse reactions in the blinded extension trial (Study UF-3) were consistent with those in the placebo-controlled trials. Less Common Adverse Reactions In Studies UF-1 and UF-2, adverse reactions reported in ≥3% and <5% in the ORIAHNN group and greater incidence than the placebo group included: libido decreased, arthralgia, hypertension, alopecia, mood swings, influenza, abdominal distension, upper respiratory tract infection, menorrhagia, vomiting, and weight increased. Thromboembolic and Vascular Events In the Studies UF-1, UF-2, and UF-3, two (0.4%) thrombotic events occurred in 453 ORIAHNN-treated patients (thrombosis in the calf and pulmonary embolism) [see Warnings and Precautions ( 5.1 ) ] . One obese woman developed thrombosis in the left calf after 30 days of treatment with ORIAHNN. Another woman developed a pulmonary embolism after taking ORIAHNN for approximately 8 months. Bone Loss The effect of ORIAHNN on BMD was assessed by dual-energy X-ray absorptiometry (DXA). In Studies UF-1 and UF-2, there was a greater decrease in BMD in women treated with ORIAHNN for 6 months compared to women treated with placebo. In Study UF-3, continued bone loss was observed in some women who received ORIAHNN for 12 consecutive months. The mean percent change from baseline in lumbar spine BMD at Month 6 (Studies UF-1 and UF-2) and Month 12 (Study UF-3) is presented in Table 2. Table 2. Mean Percent Change (On-Treatment) from Baseline in Lumbar Spine BMD in Women with Fibroids at Month 6 in Studies UF-1 and UF-2 and Month 12 in Study UF-3 Studies UF-1 and UF-2 Treatment Month 6 Study UF-3 Treatment Month 12 Placebo ORIAHNN ORIAHNN Number of Subjects 150 305 175 Percent Change from Baseline -0.1 -0.7 -1.5 Treatment Difference, % (95% CI) -0.6 (-1.0, -0.1) CI: Confidence interval Following 12 months of ORIAHNN treatment in Study UF-3, a decline in lumbar spine BMD of >3% was seen in 27% (48/175) of women and a decline of ≥8% was seen in 1.7% (3/175) of women. To assess for recovery, the change in BMD over time was analyzed for women who received continuous ORIAHNN treatment for up to 12 months and were then followed after cessation of therapy for an additional 12 months in Study UF-3 (Figure 1). The LS mean percent change from baseline in BMD 12 months after cessation of therapy was -0.72 (95% CI -1.2, -0.2), -0.59 (-1.0, -0.2), and -0.95 (-1.6, -0.3) at the lumbar spine, total hip, and femoral neck, respectively. Twelve months after cessation of ORIAHNN, continued bone loss was observed at the lumbar spine, total hip, and femoral neck in 24%, 32%, and 40% of women, respectively. Partial recovery was observed in 46%, 33%, and 38% and full recovery was observed in 30%, 35%, and 22% of women at these same sites. The time to maximum recovery in women who partially recovered is unknown. Figure 1. Mean Percent Change From Baseline in Lumbar Spine BMD in Women Who Received 12 Months of ORIAHNN (On-Treatment) and 12 Months of Follow Up (Off Treatment) Suicidal Ideation, Suicidal Behavior, and Exacerbation of Mood Disorders In the placebo-controlled trials (Studies UF-1 and UF-2), ORIAHNN was associated with adverse mood changes. Depression, depressed mood, and/or tearfulness were reported in 3% of ORIAHNN-treated women compared to 1% of placebo-treated women. One woman treated with lower dose elagolix alone for another disease completed suicide 2 days after elagolix discontinuation. Hepatic Transaminase Elevations In Studies UF-1 and UF-2, elevations of serum ALT and AST with no concurrent elevations of bilirubin were reported. ALT elevations to at least 3 times the upper limit of normal (ULN) occurred in 1.1% (4/379) of ORIAHNN-treated women and no placebo-treated women. Peak elevation of ALT almost 8 times the ULN was reported in 1 ORIAHNN-treated woman. […]

See full prescribing information for a list of clinically important drug interactions. ( 7 )

7.1 Potential for ORIAHNN to Affect Other Drugs Elagolix (a component of ORIAHNN) is: A weak to moderate inducer of cytochrome P450 (CYP3A). Co-administration with ORIAHNN may decrease plasma concentrations of drugs that are substrates of CYP3A. A weak inhibitor of CYP2C19. Co-administration with ORIAHNN may increase plasma concentrations of drugs that are substrates of CYP2C19 (see Table 3). An inhibitor of efflux transporter P-glycoprotein (P-gp). Co-administration with ORIAHNN may increase plasma concentrations of drugs that are substrates of P-gp (see Table 3). The effects of co-administration of ORIAHNN on concentrations of concomitant drugs and the clinical recommendations for these drug interactions are summarized in Table 3. Table 3. Drug Interactions: Effects of ORIAHNN on Other Drugs Concomitant Drug Class: Drug Name Effect on Plasma Exposure of Concomitant Drug Clinical Recommendations Cardiac glycosides: digoxin ↑ digoxin Increase monitoring of digoxin concentrations and potential signs and symptoms of clinical toxicity when initiating ORIAHNN in patients who are taking digoxin. If ORIAHNN is discontinued, increase monitoring of digoxin concentrations. Benzodiazepines: oral midazolam ↓ midazolam Consider increasing the dose of midazolam by no more than 2-fold and individualize midazolam therapy based on the patient’s response. Statins: rosuvastatin ↓ rosuvastatin Monitor lipid levels and adjust the dose of rosuvastatin, if necessary. Proton pump inhibitors: omeprazole ↑ omeprazole No dose adjustment needed for omeprazole 40 mg once daily when co-administered with ORIAHNN. When ORIAHNN is used concomitantly with higher doses of omeprazole, consider dosage reduction of omeprazole. See Tables 6 and 7 [see Clinical Pharmacology ( 12.3 ) ] . The direction of the arrow indicates the direction of the change in the area under the curve (AUC) (↑= increase, ↓ = decrease).

7.2 Potential for Other Drugs to Affect ORIAHNN Elagolix (a component of ORIAHNN) is a substrate of CYP3A, P-gp, and OATP1B1; estradiol and norethindrone acetate are metabolized partially by CYP3A [see Clinical Pharmacology ( 12.3 ) ] . Concomitant use of ORIAHNN with: Strong CYP3A inducers may decrease elagolix, estradiol, and norethindrone plasma concentrations and may result in a decrease of the therapeutic effects of ORIAHNN. Rifampin is not recommended. The concomitant use of rifampin increased plasma concentrations of elagolix [see Clinical Pharmacology ( 12.3 ) ] . Strong CYP3A inhibitors are not recommended. Concomitant use of ORIAHNN with strong CYP3A inhibitors may increase elagolix, estradiol, and norethindrone plasma concentrations and increase the risk of adverse reactions. OATP1B1 inhibitors that are known or expected to significantly increase elagolix plasma concentrations is contraindicated due to increased risk of elagolix-associated adverse reactions [see Contraindications ( 4 ) ] .

8.1 Pregnancy Risk Summary Use of ORIAHNN is contraindicated in pregnant women. Exposure to elagolix early in pregnancy may increase the risk of early pregnancy loss. Discontinue ORIAHNN 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 [see Data ]. 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 [see Data ] . Data Human Data There was one pregnancy reported in the 453 women who received ORIAHNN in the Phase 3 uterine fibroids clinical trials. The pregnancy resulted in a spontaneous abortion and the estimated fetal exposure to ORIAHNN occurred during the first 18 days of pregnancy. Animal Data Embryofetal development studies were conducted in the rat and rabbit. Elagolix was administered by oral gavage to pregnant rats (25 animals/dose) at doses of 0, 300, 600, and 1200 mg/kg/day and to rabbits (20 animals/dose) at doses of 0, 100, 150, and 200 mg/kg/day during the period of organogenesis (gestation day 6-17 in the rat and gestation day 7-20 in the rabbit). In rats, maternal toxicity was present at all doses and included six deaths and decreases in body weight gain and food consumption. Increased postimplantation losses were present in the mid dose group, which was 12 times the MRHD based on AUC. In rabbits, three spontaneous abortions and a single total litter loss were observed at the highest maternally toxic dose, which was 7 times the MRHD based on AUC. A single total litter loss occurred at a lower non-maternally toxic dose of 150 mg/kg/day, which was 4 times the MRHD. No fetal malformations were present at any dose level tested in either species even in the presence of maternal toxicity. At the highest doses tested, the exposure margins were 25 and 7 times the MRHD for the rat and rabbit, respectively. However, because elagolix binds poorly to the rat gonadotropin-releasing hormone (GnRH) receptor (~1000 fold less than to the human GnRH receptor), the rat study is unlikely to identify pharmacologically mediated effects of elagolix on embryofetal development. The rat study is still expected to provide information on potential non-target-related effects of elagolix. In a pre- and postnatal development study in rats, elagolix was given in the diet to achieve doses of 0, 100, and 300 mg/kg/day (25 per dose group) from gestation day 6 to lactation day 20. There was no evidence of maternal toxicity. At the highest dose, two dams had total litter loss, and one failed to deliver. Pup survival was decreased from birth to postnatal day 4. Pups had lower birth weights, and lower body weight gains were observed throughout the pre-weaning period at 300 mg/kg/day. Smaller body size and effect on startle response were associated with lower pup weights at 300 mg/kg/day. Post-weaning growth, development, and behavioral endpoints were unaffected. Maternal plasma concentrations in rats on lactation day 21 at 100 and 300 mg/kg/day (47 and 125 ng/mL) were 0.04-fold and 0.1-fold the maximal elagolix concentration (C max ) in humans at the MRHD. Because the exposures achieved in rats were much lower than the human MRHD, this study is not predictive of potentially higher lactational exposure in humans.

8.2 Lactation Risk Summary 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 ORIAHNN and any potential adverse effects on the breast-fed child from ORIAHNN or from the underlying maternal condition [see Data ] . Data 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. Estrogen administration to nursing women has been shown to decrease the quantity and quality of the breast milk. Detectable amounts of estrogen and progestin have been identified in the breast milk of women receiving estrogen and progestin combinations. There are no adequate animal data on excretion of elagolix in milk.

8.3 Females and Males of Reproductive Potential Based on the mechanism of action of elagolix, there is a risk of early pregnancy loss if ORIAHNN is administered to a pregnant woman [see Use in Specific Populations ( 8.1 ) , Clinical Pharmacology ( 12.1 ) ] . Pregnancy Testing ORIAHNN may delay the ability to recognize the occurrence of a pregnancy because it may reduce the intensity, duration, and amount of menstrual bleeding [see Adverse Reactions ( 6.1 ) ] . Exclude pregnancy before initiating treatment with ORIAHNN. Perform pregnancy testing if pregnancy is suspected during treatment with ORIAHNN and discontinue treatment if pregnancy is confirmed [see Contraindications ( 4 ) and Warnings and Precautions ( 5.8 ) ] . Contraception Advise women to use non-hormonal contraception during treatment with ORIAHNN and for 28 days after discontinuing ORIAHNN [see Warnings and Precautions ( 5.8 ) ] .

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

8.6 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) [see Clinical Pharmacology ( 12.3 ) ] .

8.7 Hepatic Impairment ORIAHNN is contraindicated in women with any hepatic impairment or disease [see Contraindications ( 4 ) ] . 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. Additionally, the use of elagolix (a component of ORIAHNN) 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 [see Clinical Pharmacology ( 12.3 ) ] .

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 progesterone-responsive tissues. As a component of ORIAHNN, NETA may protect the uterus from the potential adverse endometrial effects of unopposed estrogen.