1.1 Heavy Menstrual Bleeding Associated with Uterine Leiomyomas

MYFEMBREE is indicated for the management of heavy menstrual bleeding associated with uterine leiomyomas (fibroids) in premenopausal women [see Clinical Studies (14)].

1.2 Moderate to Severe Pain Associated with Endometriosis

MYFEMBREE is indicated for the management of moderate to severe pain associated with endometriosis in premenopausal women [see Clinical Studies (14)].

1.3 Limitations of Use

Use of MYFEMBREE should be limited to 24 months due to the risk of continued bone loss that may not be reversible [see Warnings and Precautions (5.2) and Adverse Reactions (6)].

2.1 Prior to Initiation of MYFEMBREE

• Exclude pregnancy [see Contraindications (4)].
• Discontinue hormonal contraceptives [see Warnings and Precautions (5.8)].

2.2 Recommended Dosage

• Take one tablet of MYFEMBREE orally once daily at approximately the same time, with or without food [see Clinical Pharmacology (12.3)].
• Start MYFEMBREE as early as possible after the onset of menses but no later than seven days after menses has started [see Clinical Studies (14)].
• The recommended total duration of treatment with MYFEMBREE is 24 months [see Indications and Usage (1.3), Warnings and Precautions (5.2), and Adverse Reactions (6)].

2.3 Missed Dose

Take the missed dose of MYFEMBREE as soon as possible the same day and then resume regular dosing the next day at the usual time.

2.4 Dosage Modification for Concomitant Use with P-gp Inhibitors

Avoid concomitant use of MYFEMBREE with oral P-gp inhibitors. If concomitant use is unavoidable, take MYFEMBREE first and separate dosing by at least 6 hours [see Drug Interactions (7.1) and Clinical Pharmacology (12.3)].

5.1 Thromboembolic Disorders and Vascular Events

MYFEMBREE 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)].

Discontinue MYFEMBREE immediately if an arterial or venous thrombotic, cardiovascular, or cerebrovascular event occurs or is suspected. Discontinue MYFEMBREE at least 4 to 6 weeks before surgery of the type associated with an increased risk of thromboembolism, or during periods of prolonged immobilization, if feasible.

Discontinue MYFEMBREE 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.

Estrogen and progestin combinations, including the estradiol/norethindrone acetate component of MYFEMBREE, 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.

Two thromboembolic events (DVT and PE) occurred in one woman treated for 38 days with MYFEMBREE for moderate to severe pain associated with endometriosis.

5.2 Bone Loss

MYFEMBREE is contraindicated in women with known osteoporosis [see Contraindications (4)]. Consider the benefits and risks of MYFEMBREE treatment in patients with a history of a low trauma fracture or risk factors for osteoporosis or bone loss, including taking medications that may decrease bone mineral density (BMD) (e.g., systemic or chronic inhaled corticosteroids, anticonvulsants, or chronic use of proton pump inhibitors).

Assessment of BMD by dual-energy X-ray absorptiometry (DXA) is recommended at baseline. In women with heavy menstrual bleeding associated with uterine fibroids, periodic DXA during treatment with MYFEMBREE is recommended. In women with moderate to severe pain associated with endometriosis, annual DXA is recommended while taking MYFEMBREE. Consider discontinuing MYFEMBREE if the risk associated with bone loss exceeds the potential benefit of treatment. Although the effect of supplementation with calcium and vitamin D was not studied, such supplementation for patients with inadequate dietary intake may be beneficial. MYFEMBREE may cause a decrease in BMD in some patients. BMD loss may be greater with increasing duration of use and may not be completely reversible after stopping treatment [see Adverse Reactions (6.1)]. The impact of BMD decreases on long-term bone health and future fracture risk in premenopausal women is unknown.

5.3 Hormone-Sensitive Malignancies

MYFEMBREE is contraindicated in women with current or a history of hormone-sensitive malignancies (e.g., breast cancer) and in women at increased risk for hormone-sensitive malignancies [see Contraindications (4)]. Discontinue MYFEMBREE if a hormone-sensitive malignancy is diagnosed.

Surveillance measures in accordance with standard of care, such as breast examinations and mammography, are recommended. The use of estrogen alone or estrogen plus progestin has been reported to result in an increase in abnormal mammograms requiring further evaluation.

5.4 Suicidal Ideation and Mood Disorders (Including Depression)

Evaluate patients with a history of suicidal ideation, depression, and mood disorders prior to initiating treatment. Monitor patients for mood changes and depressive symptoms including shortly after initiating treatment, to determine whether the risks of continuing therapy with MYFEMBREE 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. Re-evaluate the benefits and risks of continuing MYFEMBREE if such events occur.

Gonadotropin-releasing hormone receptor antagonists, including MYFEMBREE, have been associated with mood disorders (including depression) and suicidal ideation.

In Studies L1 and L2 in women with heavy menstrual bleeding associated with uterine fibroids, a greater proportion of women treated with MYFEMBREE compared with placebo reported depression (including depression, mood swings, and depressed mood) (2.4% vs. 0.8%), irritability (2.4% vs. 0%), and anxiety (1.2% vs. 0.8%) [see Adverse Reactions (6.1)].

In Studies S1 and S2 in women with moderate to severe pain associated with endometriosis, a greater proportion of women treated with MYFEMBREE as compared to placebo reported mood disorders (including depression) (9.1% vs. 7.2%). In addition, cases of suicidal ideation were reported with MYFEMBREE use. All women who reported suicidal ideation had a history of depression and/or anxiety [see Adverse Reactions (6.1)].

5.5 Hepatic Impairment and Transaminase Elevations

5.6 Gallbladder Disease or History of Cholestatic Jaundice

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

5.7 Elevated Blood Pressure

MYFEMBREE is contraindicated in women with uncontrolled hypertension [see Contraindications (4)]. For women with well-controlled hypertension, continue to monitor blood pressure and stop MYFEMBREE if blood pressure rises significantly.

In the placebo-controlled clinical trials in women with heavy menstrual bleeding associated with uterine fibroids or with moderate to severe pain associated with endometriosis, more women in one study (Study L1; uterine fibroids) experienced the adverse reaction of new or worsening hypertension with MYFEMBREE compared to placebo (7.0% vs. 0.8%).

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

Exclude pregnancy before initiating MYFEMBREE [see Dosage and Administration (2.1)]. Start MYFEMBREE as early as possible after the start of menses but no later than 7 days after menses has started. If MYFEMBREE is initiated later in the menstrual cycle, irregular and/or heavy bleeding may initially occur. Women who take MYFEMBREE may experience amenorrhea or a reduction in the amount, intensity, or duration of menstrual bleeding, which may delay the ability to recognize pregnancy. Perform pregnancy testing if pregnancy is suspected and discontinue MYFEMBREE if pregnancy is confirmed [see Use in Specific Populations (8.1, 8.3)].

Advise women of reproductive potential to use effective non-hormonal contraception during treatment with MYFEMBREE and for one week after the final dose. Avoid concomitant use of hormonal contraceptives with MYFEMBREE. The use of estrogen-containing hormonal contraceptives can increase estrogen levels which may increase the risk of estrogen-associated adverse events and decrease the efficacy of MYFEMBREE [see Use in Specific Populations (8.1, 8.3)].

5.9 Risk of Early Pregnancy Loss

MYFEMBREE is contraindicated for use in pregnancy [see Contraindications (4)]. Based on findings from animal studies and its mechanism of action, MYFEMBREE can cause early pregnancy loss. However, in both rabbits and rats, no fetal malformations were present at any dose level tested which were associated with relugolix exposures about half and approximately 300 times exposures in women at the recommended human dose [see Use in Specific Populations (8.1)].

5.10 Uterine Fibroid Prolapse or Expulsion

Advise women with known or suspected submucosal uterine fibroids about the possibility of uterine fibroid prolapse or expulsion and instruct them to contact their physician if severe bleeding and/or cramping occurs while being treated with MYFEMBREE. In Studies L1 and L2, uterine fibroid prolapse or uterine fibroid expulsion were reported in women treated with MYFEMBREE [see Adverse Reactions (6.1)].

5.11 Alopecia

Consider discontinuing MYFEMBREE if hair loss becomes a concern [see Adverse Reactions (6.1)].

In Phase 3 placebo-controlled clinical trials in women with heavy menstrual bleeding associated with uterine fibroids, 3.5% of MYFEMBREE-treated women experienced alopecia, hair loss, and hair thinning as compared to 0.8% of placebo-treated women. In 3 of the 11 affected women treated with MYFEMBREE across Studies L1 and L2, alopecia was reported as moderate. For one MYFEMBREE-treated woman in the extension trial, alopecia was a reason for discontinuing treatment. No specific pattern of hair loss was described. The majority of affected women completed the study with reported hair loss ongoing. Whether the hair loss is reversible is unknown [see Adverse Reactions (6.1)].

5.12 Effects on Carbohydrate and Lipid Metabolism

More frequent monitoring in MYFEMBREE-treated women with prediabetes and diabetes may be necessary. MYFEMBREE may decrease glucose tolerance and result in increased blood glucose concentrations.

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

5.13 Effect on Other Laboratory Results

Patients with hypothyroidism and hypoadrenalism may require higher doses of thyroid hormone or cortisol replacement therapy.

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 free thyroid or corticosteroid hormone levels.

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

5.14 Hypersensitivity Reactions

Hypersensitivity reactions, including anaphylactoid reactions, urticaria and angioedema, have been reported with MYFEMBREE [see Adverse Reactions (6.2)]. MYFEMBREE is contraindicated in women with a history of hypersensitivity reactions to relugolix or any component of MYFEMBREE [see Contraindications (4)]. Immediately discontinue MYFEMBREE if a hypersensitivity reaction occurs.

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.

7.1 Effect of Other Drugs on MYFEMBREE

8.1 Pregnancy

8.2 Lactation

8.3 Females and Males of Reproductive Potential

Based on animal data and the mechanism of action, MYFEMBREE can cause early pregnancy loss if MYFEMBREE is administered to pregnant women [see Use in Specific Populations (8.1)].

8.4 Pediatric Use

Safety and effectiveness of MYFEMBREE in pediatric patients have not been established.

8.6 Hepatic Impairment

MYFEMBREE is contraindicated in women with hepatic impairment or disease [see Contraindications (4)]. The use of E2 (a component of MYFEMBREE) in patients with hepatic impairment is expected to increase the exposure to E2 and increase the risk of E2-associated adverse reactions [see Clinical Pharmacology (12.3)].

12.1 Mechanism of Action

MYFEMBREE is a combination of relugolix, estradiol (E2), and norethindrone acetate (NETA).

Relugolix is a non-peptide GnRH receptor antagonist that competitively binds to pituitary GnRH receptors, thereby reducing the release of luteinizing hormone (LH) and follicle-stimulating hormone (FSH), leading to decreased serum concentrations of the ovarian sex hormones estradiol and progesterone and reduced bleeding associated with uterine fibroids and pain associated with endometriosis.

Estradiol acts by binding to nuclear receptors that are expressed in estrogen-responsive tissues. As a component of MYFEMBREE, 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 concentrations from relugolix alone.

Progestins such as norethindrone act by binding to nuclear receptors that are expressed in progesterone-responsive tissues. As a component of MYFEMBREE, norethindrone may protect the uterus from the potential adverse endometrial effects of unopposed estrogen.

12.2 Pharmacodynamics

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

• Increased thyroxin-binding globulin levels leading to [see Warnings and Precautions (5.13)]:
  • Increased circulating total thyroid hormone concentrations as measured by protein-bound iodine (PBI), thyroxine (T4) levels (by column or by radioimmunoassay), or triiodothyronine (T3) concentrations by radioimmunoassay
  • Decreased T3 resin uptake
  • Unaltered free T4 and free T3 concentrations in women with normal thyroid function [see Warnings and Precautions (5.13)].
• Elevated corticosteroid-binding globulin (CBG) and sex hormone-binding globulin (SHBG) concentrations leading to increases in total circulating corticosteroid and sex hormone concentrations, respectively [see Warnings and Precautions (5.13)].
• 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 concentrations.
• 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 concentrations of anti-factor Xa and antithrombin III, decreased antithrombin III activity, increased concentrations of fibrinogen and fibrinogen activity; increased plasminogen antigen and activity.

12.3 Pharmacokinetics

The pharmacokinetic parameters of relugolix, unconjugated estradiol, and norethindrone after administration of a single dose of MYFEMBREE to healthy postmenopausal women under fasted conditions are summarized in Table 7.

Relugolix exhibits greater than dose-proportional exposures at doses ranging from 1 mg to 80 mg (0.025 to 2 times the approved recommended dose) and approximately dose-proportional exposures at doses ranging from 80 mg to 360 mg (2 to 9 times the approved recommended dose). Relugolix concentrations reach steady-state within 12 days, and the degree of accumulation is approximately 2-fold, upon once daily administration.

Estradiol and norethindrone concentrations reach steady-state within 2 weeks, with an accumulation of 33% to 47% above concentrations seen after administration of a single dose, upon once daily administration.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

13.2 Animal Toxicology and/or Pharmacology

Phospholipidosis (intracellular phospholipid accumulation) was observed in multiple organs and tissues (e.g., liver, pancreas, spleen, kidney, lymph nodes, lung, bone marrow, GI tract or testes) after repeated oral administration of relugolix in rats and monkeys. In a rat 26-week toxicity study, phospholipidosis was observed at doses of 100 mg/kg (approximately 30 times the exposure at the MRHD of 40 mg daily in women based on AUC) and above. In a monkey 39-week toxicity study, this effect was observed at doses of 1.5 mg/kg (approximately equal to the MRHD) and above and demonstrated evidence of reversibility after cessation of treatment. The significance of this finding in humans is unknown.

14.1 Heavy Menstrual Bleeding Associated with Uterine Fibroids

The efficacy and safety of MYFEMBREE were evaluated in two replicate, 24-week, multinational, randomized, double-blind, placebo-controlled studies in a total of 768 premenopausal women with heavy menstrual bleeding associated with uterine fibroids in Study L1 (NCT03049735) and Study L2 (NCT03103087).

For study inclusion, women had to have uterine fibroids confirmed by ultrasound examination in which at least one fibroid met at least one of the following criteria:

• Subserosal, intramural, or < 50% intracavitary submucosal fibroid with a diameter ≥ 2 cm, or
• Multiple small fibroids with a total uterine volume of ≥ 130cm3.

Women also had to have menstrual blood loss (MBL) volume of ≥ 80 mL per cycle for two menstrual cycles or ≥ 160 mL during one cycle quantified by the alkaline hematin method from menstrual products collected during baseline menstrual cycles to be included in the studies. Women with hemoglobin < 8.0 g/dL were excluded from the study. Iron therapy was required for women with hemoglobin ≥ 8 g/dL and ≤ 10 g/dL. Women were allowed, but not required, to take calcium and vitamin D during the study.

In Studies L1 and L2, women were randomized 1:1:1 to receive a once daily relugolix 40 mg tablet plus an over encapsulated tablet of E2 1 mg and NETA 0.5 mg (relugolix+E2/NETA), which is equivalent to 1 tablet of MYFEMBREE, for 24 weeks, placebo for 24 weeks, or relugolix 40 mg monotherapy for 12 weeks followed by MYFEMBREE for 12 weeks. Treatment was initiated within the first seven days after the onset of menses.

The primary endpoint was the proportion of women in the MYFEMBREE group compared with women in the placebo group, who achieved menstrual blood loss volume of < 80 mL and at least a 50% reduction from baseline MBL volume over the last 35 days of treatment, as measured by the alkaline hematin method. Key secondary endpoints were related to amenorrhea, MBL volume, and change in hemoglobin.

A total of 768 women were randomized and treated in Studies L1 and L2 (741 women in the efficacy population used for these studies). Of the 741 women, 247 received treatment with MYFEMBREE (122 and 125 in Studies L1 and L2, respectively), 252 received treatment with relugolix followed by MYFEMBREE (125 and 127 in Studies L1 and L2, respectively), and 242 received placebo (113 and 129 in Studies L1 and L2, respectively). The median age of women included in the efficacy analysis was 43 years (19 - 51 years), and mean body mass index was 31.6 kg/m2. Approximately 53% of study participants were Black, 41% were White, and 6% were of other races. Across studies at baseline, mean (± standard deviation) MBL volume at baseline was 231 mL (± 156). Baseline uterine size in Studies L1 and L2 ranged from normal to greater than 28 weeks gestation size (47 - 2625 cm3).

Menstrual Blood Loss

In both Study L1 and Study L2, a statistically higher proportion of women treated with MYFEMBREE achieved the primary endpoint of both an MBL volume of less than 80 mL and at least a 50% reduction from baseline in MBL volume over the last 35 days of treatment compared with placebo (Table 8).

Percent Change in MBL Volume

The mean MBL volumes in Studies L1 and L2 at baseline were 243.8 mL and 246.7 mL in the MYFEMBREE group and 223.2 mL and 211.8 mL in the placebo group, respectively. The mean reduction in MBL volume from baseline to Week 24 in the MYFEMBREE group was 82.0% in Study L1 and 84.3% in Study L2, which was greater than placebo (19.1% and 15.1%, respectively).

Reductions in MBL volume for MYFEMBREE and placebo groups are depicted in Figure 1.

Figure 1: Percent Change from Baseline in Menstrual Blood Loss Over 24 weeks

Study L1	Study L2

14.2 Moderate to Severe Pain Associated with Endometriosis

The efficacy of MYFEMBREE was assessed in two 24-week, multinational, randomized, double-blind, placebo-controlled studies in pre-menopausal women with moderate to severe pain associated with endometriosis in Study S1 (NCT03204318) and Study S2 (NCT03204331).

In Studies S1 and S2, women with moderate to severe pain associated with endometriosis were randomized 1:1:1 to receive once daily treatment with a tablet of relugolix 40 mg plus an over encapsulated tablet of E2 1 mg and NETA 0.5 mg, (equivalent to one tablet of MYFEMBREE) for 24 weeks, placebo for 24 weeks, or relugolix 40 mg monotherapy for 12 weeks followed by MYFEMBREE for 12 weeks.

For study inclusion, women had to have endometriosis confirmed by direct visualization during surgery and/or histology in addition to pain associated with endometriosis during a placebo run-in period. Dysmenorrhea (DYS) and non-menstrual pelvic pain (NMPP) were assessed daily using an 11-point numerical rating scale (NRS) ranging from 0 (“no pain”) to 10 (“pain as bad as you can imagine”). Specifically, women had to have pain that met the following criteria:

• DYS NRS score ≥ 4.0 on at least 2 days AND
• Mean NMPP NRS score ≥ 2.5 or
  Mean NMPP NRS score ≥ 1.25 and NMPP NRS score ≥ 5.0 on at least 4 days

Studies S1 and S2 each had two co-primary endpoints. The first co-primary endpoint was a responder analysis where a responder was defined as a woman who achieved a reduction from baseline in dysmenorrhea (DYS) NRS of at least 2.8 points over the last 35 days of treatment, without an increase in analgesic use (nonsteroidal anti-inflammatory drug or opioid). The second co-primary endpoint was a responder analysis where a responder was defined as a woman who achieved a reduction from baseline in non-menstrual pelvic pain (NMPP) NRS score of at least 2.1 points over the last 35 days of treatment, without an increase in analgesic use (nonsteroidal anti-inflammatory drug or opioid) for pain associated with endometriosis.

In Study S1, a total of 424 women were included in the efficacy population (212 received MYFEMBREE; 212 received placebo). The median age of the efficacy population was 34 years and the mean body mass index was 26 kg/m2. Approximately 92% were White, 6% were Black, and 7% were of Hispanic or Latino descent. A total of 19% were from the United States and/or Canada. At baseline, 29% of women used an opioid rescue analgesic for moderate to severe pain associated with endometriosis.

In Study S2, a total of 405 women were included in the efficacy population (205 received MYFEMBREE; 200 received placebo). The median age of the efficacy population was 34 years and the mean body mass index was 26 kg/m2. Approximately 90% were White, 6% were Black, and 17% were of Hispanic or Latino descent. A total of 24% were from United States and none were from Canada. At baseline, 48% of women used an opioid rescue analgesic for moderate to severe pain associated with endometriosis.

The results for the co-primary efficacy endpoints as assessed at Week 24 are shown below in Table 10.

Key secondary efficacy endpoints included changes from baseline in the DYS NRS scores, NMPP NRS scores, Endometriosis Health Profile-30 (EHP-30) pain domain scores, dyspareunia NRS scores, and opioid use.

Reduction in DYS and NMPP NRS Scores

Women treated with MYFEMBREE had a greater reduction in DYS and NMPP NRS scores as compared to placebo from baseline to Week 24 in both Studies S1 and S2 (Figure 2 and Figure 3).

Figure 2: Mean DYS NRS Scores in Study S1 and Study S2 over 24 Weeks

Study S1	Study S2

Figure 3: Mean NMPP NRS Scores in Study S1 and Study S2 over 24 Weeks

Study S1	Study S2

Reduction in EHP-30 Pain Domain Scores

The impact of moderate to severe pain associated with endometriosis was evaluated using the pain domain from the Endometriosis Health Profile-30 (EHP-30), where the domain score (normalized) ranges from 0 to 100 with a higher score representing greater impact of pain on activities.

Women taking MYFEMBREE reported an improvement from baseline in EHP-30 pain domain score compared to placebo at Week 24 in both Studies S1 and S2 (Study S1: -33.8 vs. -18.7 with a treatment difference of -15.1 [95% CI: -19.7, -10.5] and Study S2: -32.2 vs. -20.0 with a treatment difference of -12.3 [95% CI: -16.7, -7.8]). Least squares mean changes in EHP-30 pain domain scores over time are shown in Figure 4.

Figure 4: Mean Change in EHP-30 Pain Domain Scores in Studies S1 and S2 over 24 Weeks

Study S1	Study S2

16.1 How Supplied

MYFEMBREE film-coated tablets contain relugolix 40 mg, estradiol (E2) 1 mg, and norethindrone acetate (NETA) 0.5 mg. The tablets are light yellow to yellow, round film-coated tablet with “MVT” on one side and “415” on the other side.

MYFEMBREE is supplied in a white, opaque, high-density polyethylene bottle containing 28 tablets with desiccant and closed with an induction-sealed child-resistant cap (NDC Code 72974-415-01).

16.2 Storage and Handling

Store at 15ºC to 30ºC (59ºF to 86ºF).

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.

Thromboembolic Disorders and Vascular Events

Advise patients that use of estrogen and progestin combinations may increase the risk of venous and arterial thrombotic/thromboembolic events, especially in women at high risk for these events [see Boxed Warning, Contraindications (4) and Warnings and Precautions (5.1)].

Bone Loss

Advise patients about the risk of bone loss. Advise patients that supplementary calcium and vitamin D may be beneficial if dietary intake of calcium and vitamin D is not adequate. Advise women that oral iron supplementation should not be taken at the same time as calcium and vitamin D [see Warnings and Precautions (5.2) and Adverse Reactions (6.1)].

Suicidal Ideation and Mood Disorders (Including Depression)

Advise patients that depression, mood disorders, and suicidal ideation may occur with MYFEMBREE use. Instruct women with new onset or worsening depression, anxiety, or other mood changes to promptly seek medical attention [see Warnings and Precautions (5.4) and Adverse Reactions (6.1)].

Hepatic Impairment and Transaminase Elevations

Advise women to promptly seek medical attention in case of signs or symptoms that may reflect liver injury, such as jaundice [see Warnings and Precautions (5.5)].

Change in Menstrual Bleeding Pattern and Reduced Ability to Recognize Pregnancy

Advise patients that MYFEMBREE may delay the recognition of pregnancy because it may reduce the duration and amount of menstrual bleeding. Advise patients to use effective non-hormonal contraception while taking MYFEMBREE and to discontinue MYFEMBREE if pregnancy is diagnosed [see Warnings and Precautions (5.8)]. Advise pregnant patients that there is a pregnancy registry that monitors pregnancy outcomes in women exposed to MYFEMBREE during pregnancy [see Use in Specific Populations (8.1, 8.3)].

Alopecia

Advise women with uterine fibroids that alopecia, hair loss, and hair thinning in no specific pattern may occur with MYFEMBREE. Advise these women that hair loss and hair thinning may not resolve completely after stopping MYFEMBREE. Advise these women to contact their healthcare provider if they have concerns about changes to their hair [see Warnings and Precautions (5.11) and Adverse Reactions (6.1)].

Females of Reproductive Potential

Advise women to use effective non-hormonal contraception while taking MYFEMBREE and for one week after discontinuing treatment and to discontinue MYFEMBREE if pregnancy is confirmed. Advise pregnant patients that there is a pregnancy registry that monitors pregnancy outcomes in women exposed to MYFEMBREE during pregnancy [see Use in Specific Populations (8.1, 8.3)].

Drug Interactions

Advise women to report their use of any other prescription or nonprescription medications or dietary supplements. Co-administration with certain drugs may decrease the therapeutic effects of MYFEMBREE [see Drug Interactions (7.1)].

Administration Instructions

• Advise women to begin taking MYFEMBREE as soon as possible after the start of menses but no later than 7 days after menses has started [see Dosage and Administration (2.2)].
• Advise women to take any missed dose of MYFEMBREE as soon as possible the same day and then resume regular dosing the next day at the usual time [see Dosage and Administration (2.3)].
• Advise women taking oral P-gp inhibitors to take MYFEMBREE first and separate dosing by at least 6 hours [see Dosage and Administration (2.4)].

Manufactured by Patheon Inc., 2100 Syntex Court, Mississauga, Ontario L5N 7K9, Canada

Distributed by: Sumitomo Pharma America, Inc., 84 Waterford Drive, Marlborough, MA 01752

214846 MS 006