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Elagolix Tablets

TABLE OF CONTENTS

1. DESCRIPTION 8. USE IN SPECIFIC POPULATIONS
2. INDICATIONS AND USAGE 9. OVERDOSAGE
3. DOSAGE AND ADMINISTRATION 10. MECHANISM OF ACTION
4. CONTRAINDICATIONS 11. PHARMACODYNAMICS
5. WARNINGS AND PRECAUTIONS 12. PHARMACOKINETICS
6. ADVERSE REACTIONS 13. HOW SUPPLIED/STORAGE AND HANDLING
7. DRUG INTERACTIONS

 

1. DESCRIPTION

Elagolix tablets for oral administration contain elagolix sodium, the sodium salt of the active moiety elagolix. Elagolix sodium is 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-dioxo-3,6-dihydropyrimidin-1(2H)-yl]-1-phenylethyl}amino)butanoate. Elagolix sodium has the following structural formula:

Empirical formula: C32H29F5N3O5Na - Molecular weight: 653.58 g/mol (Free acid MW = 631.60 g/mol)

Elagolix sodium is a white to off white to light yellow powder and is freely soluble in water.

Elagolix 150 mg tablets are light pink, oblong, film-coated tablets with “EL 150” debossed on one side. Each tablet contains 155.2 mg of elagolix sodium (equivalent to 150 mg of elagolix) as the active ingredient and the following inactive ingredients: mannitol, sodium carbonate monohydrate, pregelatinized starch, povidone, magnesium stearate, polyvinyl alcohol, titanium dioxide, polyethylene glycol, talc, and carmine high tint.

Elagolix 200 mg tablets are light orange, oblong, film-coated tablets with “EL 200” debossed on one side. Each tablet contains 207.0 mg of elagolix sodium (equivalent to 200 mg of elagolix) as the active ingredient and the following inactive ingredients: mannitol, sodium carbonate monohydrate, pregelatinized starch, povidone, magnesium stearate, polyvinyl alcohol, titanium dioxide, polyethylene glycol, talc, and iron oxide red.

2. INDICATIONS AND USAGE

Elagolix is indicated for the management of moderate to severe pain associated with endometriosis.

3. DOSAGE AND ADMINISTRATION

3.1 Important Dosing Information

• Exclude pregnancy before starting elagolix or start elagolix within 7 days from the onset of menses.

• Take elagolix at approximately the same time each day, with or without food.

• Use the lowest effective dose, taking into account the severity of symptoms and treatment objectives [see Warnings and Precautions (5.1, 5.3, 5.4) and Clinical Studies].

• Limit the duration of use because of bone loss (Table 1) [see Warnings and Precautions (5.1)].

Table 1. Recommended Dosage and Duration of Use

3.2 Hepatic Impairment

No dosage adjustment of elagolix is required in women with mild hepatic impairment (Child-Pugh A).

Compared to women with normal liver function, those with moderate hepatic impairment had approximately 3-fold higher elagolix exposures and those with severe hepatic impairment had approximately 7-fold higher elagolix exposures. Because of these increased exposures and risk for bone loss:

• Elagolix 150 mg once daily is recommended for women with moderate hepatic impairment (Child-Pugh B) with the duration of treatment limited to 6 months. Use of elagolix 200 mg twice daily is not recommended for women with moderate hepatic impairment [see Use in Specific Populations (8.7) and Clinical Pharmacology].

• Elagolix is contraindicated in women with severe hepatic impairment (Child-Pugh C) [see Contraindications (4), Use in Specific Populations (8.7) and Clinical Pharmacology].

3.3 Missed Dose

Instruct the patient to take a missed dose of elagolix on the same day as soon as she remembers and then resume the regular dosing schedule.

• 150 mg once daily: take no more than 1 tablet each day.

• 200 mg twice daily: take no more than 2 tablets each day.

4. CONTRAINDICATIONS

Elagolix is contraindicated in women:

• Who are pregnant [see Use in Specific Populations (8.1)]. Exposure to elagolix early in pregnancy may increase the risk of early pregnancy loss.

• With known osteoporosis because of the risk of further bone loss [see Warnings and Precautions (5.1)]

• With severe hepatic impairment because of the risk of bone loss [see Use in Specific Populations (8.7), Clinical Pharmacology]

• With concomitant use of strong organic anion transporting polypeptide (OATP) 1B1 inhibitors (e.g., cyclosporine and gemfibrozil) [see Drug Interactions (7.2)]

5. WARNINGS AND PRECAUTIONS

5.1 Bone Loss

Elagolix causes a dose-dependent decrease in bone mineral density (BMD). BMD loss is greater with increasing duration of use and may not be completely reversible after stopping treatment [see Adverse Reactions (6.1)]. The impact of these BMD decreases on long-term bone health and future fracture risk are unknown. Consider assessment of BMD in patients with a history of a low-trauma fracture or other risk factors for osteoporosis or bone loss, and do not use in women with known osteoporosis. Limit the duration of use to reduce the extent of bone loss [see Dosage and Administration (3.2)].

Although the effect of supplementation with calcium and vitamin D was not studied, such supplementation may be beneficial for all patients.

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

Women who take elagolix may experience a reduction in the amount, intensity or duration of menstrual bleeding, which may reduce the ability to recognize the occurrence of a pregnancy in a timely manner [see Adverse Reactions (6.1)]. Perform pregnancy testing if pregnancy is suspected, and discontinue elagolix if pregnancy is confirmed.

5.3 Suicidal Ideation, Suicidal Behavior, and Exacerbation of Mood Disorders

Suicidal ideation and behavior, including one completed suicide, occurred in subjects treated with elagolix in the endometriosis clinical trials. Elagolix subjects had a higher incidence of depression and mood changes compared to placebo, and elagolix subjects with a history of suicidality or depression had a higher incidence of depression compared to subjects without such a history [see Adverse Reactions (6.1)]. Promptly evaluate patients with depressive symptoms to determine whether the risks of continued therapy outweigh the benefits [see Adverse Reactions (6.1)]. 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 elagolix if such events occur.

5.4 Hepatic Transaminase Elevations

In clinical trials, dose-dependent elevations of serum alanine aminotransferase (ALT) at least 3-times the upper limit of the reference range occurred with elagolix. Use the lowest effective dose of elagolix and instruct patients to promptly seek medical attention in case of symptoms or signs that may reflect liver injury, such as jaundice. Promptly evaluate patients with elevations in liver tests to determine whether the benefits of continued therapy outweigh the risks [see Adverse Reactions (6.1)].

5.5 Reduced Efficacy with Estrogen-Containing Contraceptives

Based on the mechanism of action of elagolix, estrogen containing contraceptives are expected to reduce the efficacy of elagolix. The effect of progestin-only contraceptives on the efficacy of elagolix is unknown. Advise women to use non-hormonal contraceptives during treatment with elagolix and for one week after discontinuing elagolix [see Use in Specific Populations (8.1, 8.3), Drug Interactions (7.3), Clinical Pharmacology].

6. ADVERSE REACTIONS

The following serious adverse reactions are discussed elsewhere in labeling:

• Bone loss [see Warnings and Precautions (5.1)]

• Change in menstrual bleeding pattern and reduced ability to recognize pregnancy [see Warnings and Precautions (5.2)]

• Suicidal ideation, suicidal behavior, and exacerbation of mood disorders [see Warnings and Precautions (5.3)]

• Hepatic transaminase elevations [see Warnings and Precautions (5.4)]

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 elagolix was evaluated in two six-month, randomized, double-blind, placebo-controlled clinical trials [EM-1 (NCT01620528) and EM-2 (NCT01931670)] in which a total of 952 adult women with moderate to severe pain associated with endometriosis were treated with elagolix (475 with 150 mg once daily and 477 with 200 mg twice daily) and 734 were treated with placebo. The population age range was 18-49 years old. Women who completed six months of treatment and met eligibility criteria continued treatment in two uncontrolled, blinded six-month extension trials [EM-3 (NCT01760954) and EM-4 (NCT02143713)], for a total treatment duration of up to 12 months.

Serious Adverse Events

Overall, the most common serious adverse events reported for subjects treated with elagolix in the two placebo-controlled clinical trials (Studies EM-1 and EM-2) included appendicitis (0.3%), abdominal pain (0.2%), and back pain (0.2%). In these trials, 0.2% of subjects treated with elagolix 150 mg once daily and 0.2% of subjects treated with elagolix 200 mg twice daily discontinued therapy due to serious adverse reactions compared to 0.5% of those given placebo.

Adverse Reactions Leading to Study Discontinuation

In the two placebo-controlled clinical trials (Studies EM-1 and EM-2), 5.5% of subjects treated with elagolix 150 mg once daily and 9.6% of subjects treated with elagolix 200 mg twice daily discontinued therapy due to adverse reactions compared to 6.0% of those given placebo. Discontinuations were most commonly due to hot flushes or night sweats (1.1% with 150 mg once daily and 2.5% with 200 mg twice daily) and nausea (0.8% with 150 mg once daily and 1.5% with 200 mg twice daily) and were dose-related. The majority of discontinuations due to hot flushes or night sweats (10 of 17, 59%) and nausea (7 of 11, 64%) occurred within the first 2 months of therapy.

In the two extension trials (Studies EM-3 and EM-4), discontinuations were most commonly due to decreased BMD and were dose-related. In these trials, 0.3% of subjects treated with elagolix 150 mg once daily and 3.6% of subjects treated with elagolix 200 mg twice daily discontinued therapy due to decreased BMD.

Common Adverse Reactions

Adverse reactions reported in ≥ 5% of women in the two placebo-controlled trials in either elagolix dose group and at a greater frequency than placebo are noted in the following table.

Table 2. Percentage of Subjects in Studies EM-1 and EM-2 with Treatment-Emergent Adverse Reactions Occurring in at Least 5% of Subjects (either Elagolix Dose Group) and at a Greater Incidence than with Placebo

Less Common Adverse Reactions

In Study EM-1 and Study EM-2, adverse reactions reported in ≥ 3% and < 5% in either elagolix dose group and greater than placebo included: decreased libido, diarrhea, abdominal pain, weight gain, dizziness, constipation and irritability.

The most commonly reported adverse reactions in the extension trials (EM-3 and EM-4) were similar to those in the placebo-controlled trials.

Bone Loss

The effect of elagolix on BMD was assessed by dual-energy X-ray absorptiometry (DXA).

In Studies EM-1 and EM-2, there was a dose-dependent decrease in BMD in elagolix-treated subjects compared to an increase in placebo-treated subjects.

In Study EM-1, compared to placebo, the mean change from baseline in lumbar spine BMD at 6 months was -0.9% (95% CI: -1.3, -0.4) with ORLISSA 150 mg once daily and -3.1% (95% CI: -3.6, -2.6) with elagolix 200 mg twice daily (Table 3). The percentage of subjects with greater than 8% BMD decrease in lumbar spine, total hip or femoral neck at any time point during the placebo-controlled treatment period was 2% with elagolix 150 mg once daily, 7% with elagolix 200 mg twice daily and < 1% with placebo. In the blinded extension Study EM-3, continued bone loss was observed with 12 months of continuous treatment with elagolix. The percentage of subjects with greater than 8% BMD decrease in lumbar spine, total hip or femoral neck at any time point during the extension treatment period was 8% with continuous elagolix 150 mg once daily and 21% with continuous elagolix 200 mg twice daily.

In Study EM-2, compared to placebo, the mean change from baseline in lumbar spine BMD at 6 months was -1.3% (95% CI: -1.8, -0.8) with ORLISSA 150 mg once daily and -3.0% (95% CI: -3.5, -2.6) with elagolix 200 mg twice daily (Table 3). The percentage of subjects with greater than 8% BMD decrease in lumbar spine, total hip or femoral neck at any time point during the placebo-controlled treatment period was < 1% with elagolix 150 mg once daily, 6% with elagolix 200 mg twice daily and 0% with placebo. In the blinded extension Study EM-4, continued bone loss was observed with 12 months of continuous treatment with elagolix. The percentage of subjects with greater than 8% BMD decrease in lumbar spine, total hip or femoral neck at any time point during the extension treatment period was 2% with continuous elagolix 150 mg once daily and 21% with continuous elagolix 200 mg twice daily.

Table 3. Percent Change from Baseline in Lumbar Spine BMD at Month 6

To assess for recovery, the change in lumbar spine BMD over time was analyzed for subjects who received continuous treatment with elagolix 150 mg once daily or elagolix 200 mg twice daily for up to 12 months and who were then followed after cessation of therapy for an additional 6 months. Partial recovery of BMD was seen in these subjects (Figure 1).

In Study EM-3, if a subject had BMD loss of more than 1.5% at the lumbar spine or more than 2.5% at the total hip at the end of treatment, follow-up DXA was required after 6 months off-treatment. In Study EM-4, all subjects were required to have a follow-up DXA 6 months off treatment regardless of change in BMD and if a subject had BMD loss of more than 1.5% at the lumbar spine or more than 2.5% at the total hip after 6 months off treatment, follow-up DXA was required after 12 months off-treatment. Figure 2 shows the change in lumbar spine BMD for the subjects in Study EM-2/EM-4 who completed 12 months of treatment with elagolix and who had a follow-up DXA 12-months off treatment.

Figure 1. Percent Change from Baseline in Lumbar Spine BMD in Subjects Who Received 12 Months of Elagolix and Had Follow-up BMD 6 Months off Therapy in Studies EM-2/EM-4

Figure 2. Percent Change from Baseline in Lumbar Spine BMD in Subjects Who Received 12 Months of Elagolix and Had Follow-up BMD 12 Months off Therapy in Studies EM-2/EM-4

Suicidal Ideation, Suicidal Behavior and Exacerbation of Mood Disorders

In the placebo-controlled trials (Studies EM-1 and EM-2), elagolix was associated with adverse mood changes (see Table 2 and Table 4), particularly in those with a history of depression.

Table 4. Suicidal Ideation and Suicidal Behavior in Studies EM-1 and EM-2

A 44-year-old woman received 31 days of elagolix 150 mg once daily then completed suicide 2 days after elagolix discontinuation. She had no relevant past medical history; life stressors were noted.

Among the 2090 subjects exposed to elagolix in the endometriosis Phase 2 and Phase 3 studies, there were four reports of suicidal ideation. In addition to the two subjects in Table 4, there were two additional reports of suicidal ideation: one subject in EM-3 (150 mg once daily) and one in a Phase 2 study (75 mg once daily, an unapproved dose). Three of these subjects had a history of depression. Two subjects discontinued elagolix and two completed the clinical trial treatment periods.

Hepatic Transaminase Elevations

In the placebo-controlled clinical trials (Studies EM-1 and EM-2), dose-dependent asymptomatic elevations of serum ALT to at least 3-times the upper limit of the reference range occurred during treatment with elagolix (150 mg once daily – 1/450, 0.2%; 200 mg twice daily – 5/443, 1.1%; placebo – 1/696, 0.1%). Similar increases were seen in the extension trials (Studies EM-3 and EM-4).

Changes in Lipid Parameters

Dose-dependent increases in total cholesterol, low-density lipoprotein cholesterol (LDL-C), high density lipoprotein cholesterol (HDL-C), and serum triglycerides were noted during elagolix treatment in EM-1 and EM-2. In EM-1 and EM-2, 12% and 1% of subjects with mildly elevated LDL-C (130-159 mg/dL) at baseline had an increase in LDL-C concentrations to 190 mg/dL or higher during treatment with elagolix and placebo, respectively. In EM-1 and EM-2, 4% and 1% of subjects with mildly elevated serum triglycerides (150-300 mg/dL) at baseline had an increase in serum triglycerides to at least 500 mg/dL during treatment with elagolix and placebo, respectively. The highest measured serum triglyceride concentration during treatment with elagolix was 982 mg/dL.

Table 5. Mean Change and Maximum Increase from Baseline in Serum Lipids in Studies EM-1 and EM-2

Lipid increases occurred within 1 to 2 months after the start of elagolix and remained stable thereafter over 12 months.

Hypersensitivity Reactions

In Studies EM-1 and EM-2, non-serious hypersensitivity reactions including rash occurred in 5.8% of elagolix treated-subjects and 6.1% of placebo-treated subjects. These events led to study drug discontinuation in 0.4% of elagolix-treated subjects and 0.5% of placebo-treated subjects.

Endometrial Effects

Endometrial biopsies were performed in subjects in Study EM-1 and its extension at Month 6 and Month 12. These biopsies showed a dose-dependent decrease in proliferative and secretory biopsy patterns and an increase in quiescent/minimally stimulated biopsy patterns. There were no abnormal biopsy findings on treatment, such as endometrial hyperplasia or cancer.

Based on transvaginal ultrasound, during the course of a 3-menstrual cycle study in healthy women, elagolix 150 mg once daily and 200 mg twice daily resulted in a dose-dependent decrease from baseline in mean endometrial thickness.

Effects on menstrual bleeding patterns

The effects of elagolix on menstrual bleeding were evaluated for up to 12 months using an electronic daily diary where subjects classified their flow of menstrual bleeding (if present in the last 24 hours) as spotting, light, medium, or heavy. Elagolix led to a dose-dependent reduction in mean number of bleeding and spotting days and bleeding intensity in those subjects who reported menstrual bleeding.

Table 6. Mean Bleeding/Spotting Days and Mean Intensity Scores at Month 3

a Intensity for subjects who reported at least 1 day of bleeding or spotting during 28 day interval. Scale ranges from 1 to 4, 1 = spotting, 2 = light, 3 = medium, 4 = heavy

Elagolix also demonstrated a dose-dependent increase in the percentage of women with amenorrhea (defined as no bleeding or spotting in a 56-day interval) over the treatment period. The incidence of amenorrhea during the first six months of treatment ranged from 6-17% for elagolix 150 mg once daily, 13-52% for elagolix 200 mg twice daily and less than 1% for placebo. During the second 6 months of treatment, the incidence of amenorrhea ranged from 1115% for elagolix 150 mg once daily and 46-57% for elagolix 200 mg twice daily.

After 6 months of therapy with elagolix 150 mg once daily, resumption of menses after stopping treatment was reported by 59%, 87% and 95% of women within 1, 2, and 6 months, respectively. After 6 months of therapy with elagolix 200 mg twice daily, resumption of menses after stopping treatment was reported by 60%, 88%, and 97% of women within 1, 2, and 6 months, respectively.

After 12 months of therapy with elagolix 150 mg once daily resumption of menses after stopping treatment was reported by 77%, 95% and 98% of women within 1, 2, and 6 months respectively. After 12 months of therapy with elagolix 200 mg twice daily resumption of menses after stopping treatment was reported by 55%, 91% and 96% of women within 1, 2, and 6 months respectively.

7. DRUG INTERACTIONS

7.1 Potential for Elagolix to Affect Other Drugs

Elagolix is a weak to moderate inducer of cytochrome P450 (CYP) 3A. Co-administration with elagolix may decrease plasma concentrations of drugs that are substrates of CYP3A.

Elagolix is an inhibitor of efflux transporter P-glycoprotein (P-gp). Co-administration with elagolix may increase plasma concentrations of drugs that are substrates of P-gp (e.g., digoxin).

7.2 Potential for Other Drugs to Affect Elagolix

Elagolix is a substrate of CYP3A, P-gp, and OATP1B1.

Concomitant use of elagolix 200 mg twice daily and strong CYP3A inhibitors for more than 1 month is not recommended. Limit concomitant use of elagolix 150 mg once daily and strong CYP3A inhibitors to 6 months.

Co-administration of elagolix with drugs that induce CYP3A may decrease elagolix plasma concentrations.

The effect of concomitant use of P-gp inhibitors or inducers on the pharmacokinetics of elagolix is unknown. Co-administration of elagolix with drugs that inhibit OATP1B1 may increase elagolix plasma concentrations. Concomitant use of elagolix and strong OATP1B1 inhibitors (e.g., cyclosporine and gemfibrozil) is contraindicated.

7.3 Drug Interactions-Examples and Clinical Management

Table 7 summarizes the effect of co-administration of elagolix on concentrations of concomitant drugs and the effect of concomitant drugs on elagolix.

Table 7. Established Drug Interactions Based on Drug Interaction Trials

See Clinical Pharmacology, Tables 8 and 9.

The direction of the arrow indicates the direction of the change in the area under the curve(AUC) (↑= increase, ↓ = decrease).

8. USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary

Exposure to elagolix early in pregnancy may increase the risk of early pregnancy loss. Use of elagolix is contraindicated in pregnant women. Discontinue elagolix 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. Although two cases of congenital malformations were reported in clinical trials with elagolix, no pattern was identified and miscarriages were reported at a similar incidence across treatment groups (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 20 times the maximum recommended human dose (MRHD). Spontaneous abortion and total litter loss was observed in rabbits at doses 7 and 12 times the MRHD. There were no structural abnormalities in the fetuses at exposures up to 40 and 12 times the MRHD for the rat and rabbit, respectively (see Data).

The background risk for major birth defects and miscarriage in the indicated population are unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Data

Human Data

There were 49 pregnancies reported in clinical trials of more than 3,500 women (of whom more than 2,000 had endometriosis) treated with elagolix for up to 12 months. These pregnancies occurred while the women were receiving elagolix or within 30 days after stopping elagolix. Among these 49 pregnancies, two major congenital malformations were reported. In one case of infant cleft palate, the mother was treated with elagolix 150 mg daily and the estimated fetal exposure to elagolix occurred during the first 30 days of pregnancy. In one case of infant tracheoesophageal fistula, the mother was treated with elagolix 150 mg daily and the estimated fetal exposure to elagolix occurred during the first 15 days of pregnancy.

Among these 49 pregnancies, there were five cases of spontaneous abortion (miscarriage) compared to five cases among the 20 pregnancies that occurred in more than 1100 women treated with placebo. Although the duration of fetal exposure was limited in elagolix clinical trials, there were no apparent decreases in birth weights associated with elagolix in comparison to placebo.

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 20 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 12 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 7 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 40 and 12 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 0.06-fold and 0.16-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 or its metabolites in human milk, the effects on the breastfed child, or the effects on milk production. There are no adequate animal data on the excretion of elagolix in milk. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for elagolix and any potential adverse effects on the breastfed child from elagolix.

Data

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, there is a risk of early pregnancy loss if elagolix is administered to a pregnant woman [see Use in Specific Populations (8.1), Clinical Pharmacology].

Pregnancy Testing

Exclude pregnancy before initiating treatment with elagolix. Perform pregnancy testing if pregnancy is suspected during treatment with elagolix [see Warnings and Precautions (5.2)].

Contraception

Advise women to use effective non-hormonal contraception during treatment with elagolix and for one week after discontinuing elagolix [see Warnings and Precautions (5.2) and Drug Interactions (7.3)].

8.4 Pediatric Use

Safety and effectiveness of elagolix in patients less than 18 years of age have not been established.

8.6 Renal Impairment

No dose adjustment of elagolix is required in women with any degree of renal impairment or end-stage renal disease (including women on dialysis) [see Clinical Pharmacology].

8.7 Hepatic Impairment

No dosage adjustment of elagolix is required for women with mild hepatic impairment (Child-Pugh A). Only the 150 mg once daily regimen is recommended for women with moderate hepatic impairment (Child-Pugh B) and the duration of treatment should be limited to 6 months.

Elagolix is contraindicated in women with severe hepatic impairment (Child-Pugh C) [see Contraindications (4), and Clinical Pharmacology].

9. OVERDOSAGE

In case of overdose, monitor the patient for any signs or symptoms of adverse reactions and initiate appropriate symptomatic treatment, as needed.

10. MECHANISM OF ACTION

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.

11. PHARMACODYNAMICS

Effect on Ovulation and Estradiol

In a 3-menstrual cycle study in healthy women, elagolix 150 mg once daily and 200 mg twice daily resulted in an ovulation rate of approximately 50% and 32%, respectively. In the Phase 3 trials in women with endometriosis, elagolix caused a dose-dependent reduction in median estradiol concentrations to approximately 42 pg/mL for 150 mg once daily regimen and 12 pg/mL for the 200 mg twice daily regimen.

Cardiac Electrophysiology

The effect of elagolix 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 subjects given a single dose of 1200 mg was 17-times higher than the concentration in subjects given elagolix 200 mg twice daily. There was no clinically relevant prolongation of the QTc interval.

12. PHARMACOKINETICS

The pharmacokinetic properties of elagolix in healthy subjects are summarized in Table 8. The steady state pharmacokinetic parameters under fasting conditions are summarized in Table 9.

Table 8. Pharmacokinetic Properties of Elagolix in Healthy Subjects

Table 9. Mean (%CV) Steady State Pharmacokinetic Parameters of Elagolix

CV: Coefficient of variation

Cmax: peak concentration

AUCτ: area under the plasma concentration-time curve during the dosing interval (τ) i.e., 12 hours for twice daily regimen, 24 hours for once daily regimen.

CL/F: oral clearance

Vdss/F: apparent volume of distribution at steady state

Rac: drug accumulation ratio

Specific Populations

Renal Impairment

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

Hepatic Impairment

Elagolix exposures (Cmax and AUC) are similar between women with normal hepatic function and women with mild hepatic impairment. Elagolix exposures in women with moderate and severe hepatic impairment are approximately 3-fold and 7-fold, respectively, higher than exposures from women with normal hepatic function [see Use in Specific Populations (8.7)].

Race/Ethnicity

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.

Body weight/Body mass index

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

Drug Interaction Studies

Drug interaction studies were performed with elagolix and other drugs that are likely to be co-administered and with drugs commonly used as probes for pharmacokinetic interactions. Tables 10 and 11 summarize the pharmacokinetic effects when elagolix was co-administered with these drugs.

Table 10. Drug Interactions: Change in Pharmacokinetics of Elagolix in the Presence of Co-administered Drugs

CI: Confidence interval

* ratios for Cmax and AUC compare co-administration of the medication with elagolix vs. administration of elagolix alone.

No clinically significant changes in elagolix exposures were observed when co-administered with rosuvastatin (20 mg once daily), sertraline (25 mg once daily) or fluconazole (200 mg single dose).

Table 11. Drug Interactions: Change in Pharmacokinetics of Co-administered Drug in the Presence of Elagolix

CI: Confidence interval

* ratios for Cmax and AUC compare co-administration of the medication with elagolix vs.administration of the medication alone.

a metabolite of norgestimate

No clinically significant changes in sertraline or fluconazole exposures were observed when co-administered with elagolix.

13. HOW SUPPLIED/STORAGE AND HANDLING

How Supplied:

ORILISSA tablets are available in two strengths: 150 mg and 200 mg, which are equivalent to 155.2 mg and 207.0 mg of elagolix sodium, respectively.

ORILISSA 150 mg tablets are light pink, oblong, film-coated tablets with “EL 150” debossed on one side. ORILISSA 150 mg tablets are packaged in weekly blister packs. Each blister pack contains 7 tablets supplying the drug product for one week. Four blister packs (a total of 28 tablets) are packaged into a carton that provides the drug product for 4 weeks (NDC 0074-003828).

ORILISSA 200 mg tablets are light orange, oblong, film-coated tablets with “EL 200” debossed on one side. The 200 mg tablets are packaged in weekly blister packs. Each blister pack contains 14 tablets supplying the drug product for one week. Four blister packs (a total of 56 tablets) are packaged in a carton that provides the drug product for 4 weeks (NDC 0074-0039-56).

Storage and Handling:

Store at 2°C to 30°C (36°F to 86°F).

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.

Rx only

Rev 07/18