2.1 Important Dosing Information

• Exclude pregnancy before starting ORIAHNN or start ORIAHNN within 7 days from the onset of menses [see Use in Specific Populations (8.1) and (8.3)].
  
• The recommended dosage of ORIAHNN is:
  ○ One elagolix 300 mg, estradiol 1 mg, and norethindrone acetate 0.5 mg capsule in the morning (AM), and
  ○ One elagolix 300 mg capsule in the evening (PM).
  
• Take the morning and evening capsules at approximately the same time each day, with or without food.
  
• The recommended duration of treatment with ORIAHNN is 24 months [see Warnings and Precautions (5.2)].

2.2 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.

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)]. In Studies UF-1 and UF-2, a maximum mean increase in systolic blood pressure of 5.1 mmHg [95% confidence interval (CI) 2.68, 7.59] occurred at Month 5, and a maximum mean increase in diastolic blood pressure of 2.1 mmHg (95% CI 0.43, 3.84) occurred at Month 4 in ORIAHNN-treated women, as compared to placebo-treated women [see Adverse Reactions (6.1)].

For women with well-controlled hypertension, continue to monitor blood pressure and stop ORIAHNN if blood pressure rises significantly. Monitor blood pressure in normotensive women treated with ORIAHNN.

5.7 Gallbladder Disease or History of Cholestatic Jaundice

Studies among estrogen users suggest a small increased relative risk of developing gallbladder disease. For women with a history of cholestatic jaundice associated with past estrogen use or with pregnancy, assess the risk-benefit of continuing therapy. Discontinue ORIAHNN if jaundice occurs.

5.8 Change in Menstrual Bleeding Pattern and Reduced Ability to Recognize Pregnancy

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)]. Perform pregnancy testing if pregnancy is suspected, and discontinue ORIAHNN if pregnancy is confirmed [see Use in Specific Populations (8.1, 8.3)].

The effect of hormonal contraceptives on the efficacy of ORIAHNN is unknown. Advise women to use non-hormonal contraception during treatment and for 28 days after discontinuing ORIAHNN [see Use in Specific Populations (8.1, 8.3)].

5.9 Effects on Carbohydrate and Lipid Metabolism

ORIAHNN may decrease glucose tolerance and result in increased glucose levels. More frequent monitoring in ORIAHNN-treated women with prediabetes and diabetes may be needed.

In women with pre-existing hypertriglyceridemia, estrogen therapy may be associated with elevations of plasma triglycerides leading to pancreatitis. Use of elagolix is associated with increases in total cholesterol, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and serum triglycerides. Monitor lipid levels and consider discontinuing ORIAHNN if hypercholesterolemia or hypertriglyceridemia worsens [see Adverse Reactions (6.1)].

5.10 Alopecia

In Phase 3 clinical trials (Studies UF-1 and UF-2), more women experienced alopecia, hair loss, and hair thinning with ORIAHNN (3.5%) compared to placebo (1.0%). In almost one-third (4/14) of affected ORIAHNN-treated women, alopecia was a reason for discontinuing treatment. No specific pattern was described. In the majority of affected women, hair loss was continuing when ORIAHNN was stopped. Whether the hair loss is reversible is unknown. Consider discontinuing ORIAHNN if hair loss becomes a concern [see Adverse Reactions (6.1)].

5.11 Effect on Other Laboratory Results

The use of estrogen and progestin combinations may raise serum concentrations of binding proteins (e.g., thyroid-binding globulin, corticosteroid-binding globulin), which may reduce the free thyroid or corticosteroid hormone levels. Patients with hypothyroidism and hypoadrenalism may require higher doses of thyroid hormone or cortisol replacement therapy, respectively.

The use of estrogen and progestin may also affect the levels of sex hormone-binding globulin, coagulation factors, lipids, and glucose [see Pharmacodynamics (12.2)].

5.12 Risk of Allergic Reactions Due to the Inactive Ingredient (FD&C Yellow No. 5)

ORIAHNN contains FD&C Yellow No. 5 (tartrazine), which may cause allergic-type reactions (including bronchial asthma) in certain susceptible persons. Although the overall incidence of FD&C Yellow No. 5 (tartrazine) sensitivity in the general population is low, it is frequently seen in patients who also have aspirin hypersensitivity.

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 341women 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.

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.

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.
  
• AST elevations to at least 3 times the ULN occurred in 5/379 (1.3%) in ORIAHNN-treated women and no placebo-treated women. Peak elevation of AST 6 times the ULN was reported in 1 ORIAHNN-treated woman.

Blood Pressure Elevations

There were more ORIAHNN-treated women with systolic blood pressure ≥ 160 mmHg (7.1%) and diastolic blood pressure ≥ 100 mmHg (11.3%) compared to placebo-treated women (3.7% and 6.3%, respectively). The incidence of hypertensive adverse reactions was 3.8% in ORIAHNN-treated women and 3.1% placebo-treated women. One ORIAHNN-treated woman in Study UF-1, with no prior history but with elevated cholesterol levels, had severe hypertension (BP 204/112) and chest pain. ECG was negative. Her hypertension was controlled with anti-hypertensives and she completed Study UF-3.

Changes in Lipid Parameters

Increases in total cholesterol, low-density lipoprotein cholesterol (LDL-C), serum triglycerides, and apolipoprotein B were noted during ORIAHNN treatment in Studies UF-1 and UF-2.

Of the women with Grade 0 LDL-C (<130 mg/dL) at baseline, 1/313 (0.3%) ORIAHNN-treated woman shifted to Grade 3 (≥ 190 mg/dL) compared to no placebo-treated woman. Of those with Grade 1 LDL-C (130 to <160 mg/dL) at baseline, 9/54 (16.7%) ORIAHNN-treated women shifted to Grade 3 compared to no placebo-treated woman. Of those with Grade 2 LDL-C (160 to <190 mg/dL) at baseline, 7/10 (70%) ORIAHNN-treated women shifted to Grade 3 compared to 1/5 (20%) placebo-treated woman.

Alopecia

In Phase 3 placebo-controlled clinical trials (Studies UF-1 and UF-2), 3.5% (14/395) of ORIAHNN-treated women experienced alopecia, hair loss, or hair thinning compared to 1.0% (2/196) of placebo-treated women. No specific pattern in hair loss was observed. In almost one-third (4/14) of affected ORIAHNN-treated women, alopecia was a reason for study drug discontinuation; no placebo-treated women discontinued because of alopecia. In ORIAHNN-treated women, 79% of the cases were mild and 21% were moderate in severity. Hair loss was ongoing at the end of the study for 4 out of 14 women (29%). Of these 4 women, one discontinued treatment due to hair loss, two had ongoing hair loss 12 months after discontinuing ORIAHNN, and one was lost to follow-up. In the remaining 10 women (71%), hair loss either resolved while on treatment or resolved within 24 days to approximately 9 months after discontinuing ORIAHNN.

Resumption of Menses after Discontinuation

After six months of ORIAHNN treatment, resumption of menses was reported by 39%, 68%, and 73% of women within 1, 2, and 6 months, respectively, in Study UF-1 and 39%, 85%, and 92% within 1, 2, and 6 months, respectively, in Study UF-2.

After 12 months of therapy with ORIAHNN (Study UF-1 or Study UF-2 then Study UF-3), resumption of menses was reported by 43%, 82%, and 90% of women within 1, 2, and 6 months after stopping treatment, respectively.

Whether those who did not resume having menses transitioned to a peri-postmenopausal status is unknown.

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.

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

Pregnancy Exposure Registry

There is a pregnancy registry that monitors outcomes in women who become pregnant while treated with ORIAHNN. Pregnant patients should be encouraged to enroll by calling 1-833-782-7241.

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 (Cmax) 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 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)].

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

12.2 Pharmacodynamics

Estradiol and norethindrone acetate (components of ORIAHNN) may have the following effects:

• Increased thyroxin-binding globulin levels leading to [see Warnings and Precautions (5.11)]:
  ○ Increased circulating total thyroid hormone levels as measured by protein-bound iodine (PBI), thyroxine (T4) levels (by column or by radioimmunoassay), or triiodothyronine (T3) levels by radioimmunoassay
  ○ Decreased T3 resin uptake
  ○ Unaltered free T4 and free T3 concentrations in women with normal thyroid function [see Warnings and Precautions (5.11)].
  
• Elevated corticosteroid-binding globulin (CBG) and sex hormone-binding globulin (SHBG) leading to increased total circulating corticosteroids and sex steroids, respectively [see Warnings and Precautions (5.11)].
  
• Possible decreased free testosterone concentrations.
  
• Possible increased other plasma proteins concentrations (angiotensinogen/renin substrate, alpha-1 antitrypsin, ceruloplasmin).
  
• Increased plasma high-density lipoprotein (HDL) and HDL2 cholesterol subfraction concentration, reduced low-density lipoprotein concentration, increased triglyceride levels [see Warnings and Precautions (5.9)].
  
• Accelerated prothrombin time, partial thromboplastin time, and platelet aggregation time; increased platelet count; increased factors II, VII antigen, VIII coagulant activity, IX, X, XII, VII-X complex, and beta-thromboglobulin; decreased levels of anti-factor Xa and antithrombin III, decreased antithrombin III activity, increased levels of fibrinogen and fibrinogen activity; increased plasminogen antigen and activity.

Cardiac Electrophysiology

The effect of elagolix (a component of ORIAHNN) on the QTc interval was evaluated in a randomized, placebo- and positive-controlled, open-label, single-dose, crossover thorough QTc study in 48 healthy adult premenopausal women. Elagolix concentrations in women given a single dose of 1200 mg were 9 times higher than the concentration in women given elagolix 300 mg twice daily. There was no clinically relevant prolongation of the QTc interval.

The effect of estradiol and norethindrone acetate (two components of ORIAHNN) on the QTc interval has not been studied.

12.3 Pharmacokinetics

The pharmacokinetic properties of ORIAHNN in healthy subjects are summarized in Table 4.

The pharmacokinetic parameters under fasting conditions are summarized in Table 5.

Specific Populations

Patients with Renal Impairment

Elagolix exposures (Cmax and AUC) were not altered by renal impairment. The elagolix mean plasma exposures were similar for women with moderate to severe or end-stage renal disease (including women on dialysis) compared to women with normal renal function.

The effect of renal impairment on the pharmacokinetics of E2/NETA has not been studied.

Patients with Hepatic Impairment

Elagolix exposures (Cmax and AUC) were similar between women with normal hepatic function and women with mild hepatic impairment. Elagolix exposures in women with moderate and severe hepatic impairment were approximately 3-fold and 7-fold, respectively, higher than exposures from women with normal hepatic function.

The use of estradiol in patients with hepatic impairment, compared to patients with normal hepatic function, is expected to increase the estradiol blood levels [see Warnings and Precautions (5.5) and Use in Specific Populations (8.7)].

Racial or Ethnic Groups

No clinically meaningful difference in the pharmacokinetics of elagolix between White and Black subjects or between Hispanics and others was observed. There is no clinically meaningful difference in the pharmacokinetics of elagolix between Japanese and Han Chinese subjects. The effect of race/ethnicity on the pharmacokinetics of E2/NETA has not been studied.

Body Weight/Body Mass Index

Body weight or body mass index does not affect the pharmacokinetics of elagolix.

The effect of body weight/body mass index on the pharmacokinetics of E2/NETA has not been studied.

Drug Interaction Studies

Drug interaction studies were performed with elagolix and other drugs likely to be co-administered and with drugs commonly used as probes for pharmacokinetic interactions. Tables 6 and 7 summarize the pharmacokinetic effects when elagolix was co-administered with these drugs.

No clinically significant changes in elagolix exposures were observed when elagolix 300 mg twice daily was co-administered with rosuvastatin (20 mg once daily), sertraline (25 mg once daily), or fluconazole (200 mg single dose). The effect of co-administered rosuvastatin, sertraline, or fluconazole on E2/NETA has not been studied.

No clinically significant changes in sertraline, fluconazole, bupropion, or transdermal patch E2/NETA 0.51/4.8 mg exposures were observed when co-administered with elagolix 300 mg twice daily.

12.5 Pharmacogenomics

Hepatic uptake of elagolix (a component of ORIAHNN) involves the OATP1B1 transporter protein. Higher plasma concentrations of elagolix have been observed in patients who have two reduced function alleles of the gene that encodes OATP1B1 (SLCO1B1 521T>C) (these patients are likely to have reduced hepatic uptake of elagolix and thus, higher plasma elagolix concentrations). The frequency of the SLCO1B1 521C/C genotype is generally less than 5% in most racial/ethnic groups. Women with this genotype are expected to have approximately 2-fold higher elagolix mean concentrations compared to women with normal transporter function (i.e., SLCO1B1 521T/T genotype). Adverse effects of elagolix have not been fully evaluated in subjects who have two reduced function alleles of the gene that encodes OATP1B1 (SLCO1B1 521T>C).

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Elagolix

Two-year carcinogenicity studies conducted in mice (50, 150, or 500 mg/kg/day) and rats (150, 300, or 800 mg/kg/day) that administered elagolix by the dietary route revealed no increase in tumors in mice at up to 11.9-fold the MRHD based on AUC. In the rat, there was an increase in thyroid (male and female) and liver (males only) tumors at the high dose (7.7- to 8.1-fold the MRHD). The rat tumors were likely species-specific and of negligible relevance to humans.

Elagolix was not genotoxic or mutagenic in a battery of tests, including the in vitro bacterial reverse mutation assay, the in vitro mammalian cell forward mutation assay at the thymidine kinase (TK+/-) locus in L5178Y mouse lymphoma cells, and the in vivo mouse micronucleus assay.

In a fertility study conducted in the rat, there was no effect of elagolix on fertility at any dose (50, 150, or 300 mg/kg/day). Based on AUC, the exposure multiple for the MRHD in women compared to the highest dose of 300 mg/kg/day in female rats is approximately 2.9-fold. However, because elagolix has low affinity for the GnRH receptor in the rat [see Use in Specific Populations (8.1)], and because effects on fertility are most likely to be mediated via the GnRH receptor, these data have low relevance to humans.

E2/NETA

Long-term continuous administration of natural and synthetic estrogens in certain animal species increases the frequency of carcinomas of the breast, uterus, cervix, vagina, testis, and liver [see Warnings and Precautions (5.3)].