Myfembree Drug Information

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.

Moderate to Severe Pain Associated with Endometriosis MYFEMBREE is indicated for the management of moderate to severe pain associated with endometriosis in premenopausal women.

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.

Prior to Initiation of MYFEMBREE

Exclude pregnancy. Discontinue hormonal contraceptives.

Recommended Dosage

Take one tablet of MYFEMBREE orally once daily at approximately the same time, with or without food. Start MYFEMBREE as early as possible after the onset of menses but no later than seven days after menses has started. The recommended total duration of treatment with MYFEMBREE is 24 months.

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.

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.

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. Heavy Menstrual Bleeding Associated with Uterine Leiomyomas The safety of MYFEMBREE was evaluated in two placebo-controlled clinical trials, Study L1 (LIBERTY 1) and Study L2 (LIBERTY 2), in women with heavy menstrual bleeding associated with uterine fibroids. In these trials, women received a once daily relugolix 40-mg tablet and an over-encapsulated tablet of E2 1 mg and NETA 0.5 mg (relugolix + E2/NETA), which is equivalent to 1 tablet of MYFEMBREE.

Across the two trials, 254 women received MYFEMBREE once daily for 24 weeks. Of these, 476 women were treated with MYFEMBREE in a 28-week extension trial, Study L3 (LIBERTY Extension), for a total treatment duration of up to 12 months. Demographics were similar across the studies; approximately 43% were White, 51% were Black, and approximately 23% were of Hispanic or Latino ethnicity.

The mean age at study entry was approximately 42 years (range 19 to 51 years). Of women who completed Study L3, 229 were rerandomized to continue MYFEMBREE or withdraw from therapy (placebo) for an additional 52 weeks (Study L4). Serious Adverse Reactions In Studies L1 and L2, serious adverse reactions were reported in 3.1% of MYFEMBREE-treated women as compared to 2.3% of placebo-treated women.

In MYFEMBREE-treated women, serious adverse drug reactions included uterine myoma expulsion and menorrhagia experienced by one woman and uterine leiomyoma (prolapse), cholecystitis, and pelvic pain reported for one woman each. Adverse Reactions Leading to Study Drug Discontinuation In Studies L1 and L2, 3.9% of women treated with MYFEMBREE discontinued therapy due to adverse reactions, as compared to 4.3% receiving placebo. The most common adverse reaction leading to discontinuation of MYFEMBREE was uterine bleeding (1.2%) with an onset usually reported within the first 3 months of therapy.

Common Adverse Reactions The most common adverse reactions reported in at least 3% of women treated with MYFEMBREE for heavy menstrual bleeding associated with uterine fibroids and at an incidence greater than placebo during double-blind placebo-controlled treatment are summarized below in Table 1. Table 1: Adverse Reactions Occurring in 3% or More in Women with Heavy Menstrual Bleeding Associated with Uterine Fibroids Treated with In Study L1, more women experienced the adverse reaction of new or worsening hypertension with MYFEMBREE as compared to placebo (7.0% vs. 0.8%). The most common adverse reactions reported during the extension trial, Study L3, were similar to those reported in the placebo-controlled trials.

Less Common Adverse Reactions Adverse reactions reported in at least 2% and less than 3% of women with heavy menstrual bleeding associated with uterine fibroids in the MYFEMBREE treated group and greater incidence than placebo included irritability, dyspepsia, and breast cyst. Other important adverse reactions reported in MYFEMBREE-treated women included one serious reaction each of uterine myoma expulsion (0.4%) and uterine leiomyoma (prolapse) (0.4%). Bone Loss The effect of MYFEMBREE on BMD was assessed by DXA.

The least squares mean percent changes from baseline in lumbar spine BMD at Month 6 in Studies L1 and L2 are presented below in Table 2. Table 2: Mean Percent Change (On-Treatment) from Baseline in Lumbar Spine BMD in Women with Heavy Menstrual Bleeding Associated with Uterine Fibroids in Studies L1 and L2 at Month 6 In the open-label extension trial, Study L3, women received an additional 28 weeks of MYFEMBREE for a total of up to 52 weeks of treatment. Women from Study L3 showed continued bone loss at Months 6 and 12 when treated with up to 52 weeks of MYFEMBREE.

The least squares mean percent changes from baseline in lumbar spine BMD at Months 6 and 12 are presented below in Table 3. Table 3: Mean Percent Change (On-Treatment) from Baseline* in Lumbar Spine BMD at Month 6* and Month 12 for MYFEMBREE-Treated Women with Heavy Menstrual Bleeding Associated with Uterine Fibroids in Study L3 A separate concurrent prospective observational study enrolled 262 women with heavy menstrual bleeding associated with uterine fibroids who were age-matched to participants of Studies L1 and L2. While these women were not randomized to receive treatment for heavy menstrual bleeding associated with uterine fibroids, women were permitted to receive treatment from their provider during the clinical trials for this indication.

Women underwent DXA scans at baseline, Month 6 and Month 12 to monitor for changes in BMD. The mean percent changes from baseline (95% CI) in lumbar spine BMD at Months respectively. In Studies L1, L2, and L3, four of women treated with MYFEMBREE experienced low trauma fractures (defined as a fall from standing height or less).

Two women, one from Study L1 and one from Study L2, fractured after 117 and 166 days of treatment with MYFEMBREE. Two women in Study L3, both treated with relugolix monotherapy for 12 weeks prior to MYFEMBREE therapy, fractured after 149 and 164 days of treatment with MYFEMBREE. Depression, Mood Disorders, and Suicidal Ideation In Studies L1 and L2, MYFEMBREE was associated with adverse mood changes.

Resumption of Menstruation after Discontinuation Post study menstrual status was available for 35 women in Study L1 and 30 women in Study L2 who were treated with MYFEMBREE and prematurely discontinued the study or did not continue into the long-term extension study. The mean time from last dose to occurrence of menses was 36 days in Study L1 and 30.7 days in Study L2. Mean time to occurrence of menses was longer for women who achieved amenorrhea (40.6 days and 41.1 days in Studies L1 and L2, respectively) compared with women without amenorrhea (33.0 days and 26.6 days in Studies L1 and L2, respectively) in the last 35 days of treatment.

After 12 months of treatment with MYFEMBREE (Study L1 or Study L2, then Study L3) 93.8% (61/65) of women resumed menses. Mean time from last dose of drug to occurrence of menses was 40.5 days. Mean time to occurrence of menses was longer in women who reported amenorrhea over the last 35 days of treatment compared with women without amenorrhea over the last 35 days of treatment (45.6 days vs. 32.6 days, respectively).

Women who did not have a return to menses included those who had surgery, used alternative medications associated with amenorrhea, entered menopause, and unknown cause. Increases in Lipids Lipid levels were assessed at baseline and Week 24/End of Treatment in Studies L1 and L2. Moderate to Severe Pain Associated with Endometriosis The safety of MYFEMBREE was evaluated in two placebo-controlled clinical trials, Study S1 and Study S2, in women with moderate to severe pain associated with endometriosis.

Of these, 799 women were treated with MYFEMBREE in an 80-week extension trial, Study S3, for a total treatment duration of up to 24 months. Demographics were similar across these trials; 91% were white, 6% were Black, and 12% were of Hispanic or Latino ethnicity. The mean age at study entry was 34 years (range 18 to 50 years).

Serious Adverse Reactions In Studies S1 and S2, serious adverse reactions were reported in 2.9% of MYFEMBREE-treated women as compared to 2.2% of placebo-treated women. In MYFEMBREE-treated women, serious adverse reactions included uterine hemorrhage, suicidal ideation, cholelithiasis, and cholecystitis. Adverse Reactions Leading to Study Drug Discontinuation In Studies S1 and S2, 4.5% of MYFEMBREE-treated women discontinued therapy due to adverse reactions as compared to 2.9% of placebo-treated women.

The most common adverse reaction (1.7%) leading to discontinuation in MYFEMBREE-treated women was mood-related disorders (including depression, mood swings, altered mood, affect lability, and suicidal ideation). Common Adverse Reactions The most common adverse reactions reported in at least 3% of women treated with MYFEMBREE for moderate to severe pain associated with endometriosis and with an incidence greater than placebo during Studies S1 and S2 are summarized below in Table 4. Table 4: Adverse Reactions Occurring in 3% or More of Women with Moderate to Severe Pain Associated with Endometriosis Treated with The most common adverse reactions reported in the safety extension trial, Study S3, were similar to those reported in the placebo-controlled trials.

Less Common Adverse Reactions Adverse reactions reported in at least 2% and less than 3% of women with moderate to severe pain associated with endometriosis in the MYFEMBREE group and with a greater incidence than placebo included diarrhea (2.4%), peripheral edema (2.2%), and vulvovaginal dryness (2.2%). The least squares (LS) mean percent changes from baseline in lumbar spine BMD at Month 6 and for women with moderate to severe pain associated with endometriosis in Studies S1 and S2 are presented in Table 5. Table 5: LS Mean Percent Change (On-Treatment) from Baseline in Lumbar Spine BMD in Women with Moderate to Severe Pain Associated with Endometriosis at Month 6 in Studies S1 and S2 In the open-label extension, Study S3, women received an additional 80 weeks of MYFEMBREE for a total of up to 24 months of treatment.

A separate concurrent prospective observational study enrolled 452 women with moderate to severe pain associated with endometriosis who were age-matched to participants of Studies S1 and S2. While these women were not randomized to receive treatment for moderate to severe pain associated with endometriosis, women were permitted to receive treatment from their provider for this indication. In women with moderate to severe pain associated with endometriosis, a decline in lumbar spine BMD of > 3% from pre-treatment baseline was observed in 19.7% (45/228) of women who had a DXA scan following 12 months of MYFEMBREE treatment in Study S3 and in 9.1% (29/320) of untreated women in the Observational Endometriosis Cohort.

The maximum percent decline from pre-treatment baseline at the lumbar spine, femoral neck and total hip at Month respectively. BMD loss may not be completely reversible after stopping treatment. In Study S3, two women sustained fractures after falling.

One woman, who was treated for almost 24 weeks with MYFEMBREE following 12 weeks of relugolix monotherapy, sustained a tibia/fibula fracture and one who was treated for 104 weeks with MYFEMBREE, sustained a wrist fracture 144 days after she discontinued MYFEMBREE. The impact of BMD loss on long-term bone health and future fracture risk in premenopausal women is unknown. Suicidal Ideation and Mood Disorders (Including Depression) In Studies S1 and S2, a greater proportion of women treated with MYFEMBREE compared with placebo reported mood disorders (including depression) (9.1% vs. 7.2%).

In addition, cases of suicidal ideation were reported in the safety extension trial, Study S3. Resumption of Menstruation after Discontinuation Post-study menstrual status was available for 55 women in Study S1 and 59 women in Study S2 who were treated with MYFEMBREE and either prematurely discontinued the study or did not continue into the extension study. The mean time from last dose to occurrence of menses was 27.1 days in Study S1 and 39.2 days in Study S2.

Mean time to occurrence of menses was longer for women who achieved amenorrhea (34.3 days and 42.8 days in Studies S1 and S2, respectively) compared with women without amenorrhea (21.0 days and 32.1 days in Studies S1 and S2, respectively) in the last 28 days of treatment. After 12 months of treatment with MYFEMBREE (Study S1 or Study S2, then Study S3), 97.9% (46/47) of women resumed menses. Women who did not have a return to menses included those who had surgery, used alternative medications associated with amenorrhea, or became pregnant.

Increases in Lipids Lipid levels were assessed at baseline and Week 24/End of Treatment in Studies S1 and S2. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Immune system disorders: anaphylactoid reaction Skin and subcutaneous tissue disorders: drug eruption, angioedema, urticaria Neoplasms (benign, malignant, and unspecified): uterine leiomyoma degeneration

Effect of Other Drugs on MYFEMBREE P-gp Inhibitors Co-administration of MYFEMBREE with P-gp inhibitors increases the AUC and maximum concentration (C max ) of relugolix and may increase the risk of adverse reactions associated with MYFEMBREE. Avoid use of MYFEMBREE with oral P-gp inhibitors. If use is unavoidable, take MYFEMBREE first, separate dosing by at least 6 hours, and monitor patients for adverse reactions.

Combined P-gp and Strong CYP3A Inducers Use of MYFEMBREE with combined P-gp and strong CYP3A inducers decreases the AUC and C max of relugolix, estradiol, and/or norethindrone and may decrease the therapeutic effects of MYFEMBREE.

Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to MYFEMBREE during pregnancy. Pregnant females exposed to MYFEMBREE and healthcare providers are encouraged to call the MYFEMBREE Pregnancy Exposure Registry at 1-855-428-0707. Risk Summary MYFEMBREE is contraindicated in pregnancy.

Based on findings from animal studies and its mechanism of action, MYFEMBREE may cause early pregnancy loss. Discontinue MYFEMBREE if pregnancy occurs during treatment. The limited human data with the use of MYFEMBREE in pregnant women are insufficient to evaluate for a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes.

In animal reproduction studies, oral administration of relugolix in pregnant rabbits during organogenesis resulted in spontaneous abortion and total litter loss at relugolix exposures about half those at the maximum recommended human dose (MRHD) of 40 mg. 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 MRHD, respectively. Epidemiologic studies and meta-analyses have not found an increased risk of genital or non-genital birth defects (including cardiac anomalies and limb-reduction defects) following exposure to estrogens and progestins before conception or during early pregnancy.

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. There are insufficient data to conclude whether the presence of uterine fibroids or endometriosis reduces the likelihood of achieving pregnancy or increases the risk of adverse pregnancy outcomes. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes.

In the United States general population, the estimated background risks of major birth defects and miscarriage in clinically recognized pregnancies are respectively. Data Animal Data In an embryo-fetal development study, oral administration of relugolix to pregnant rabbits during the period of organogenesis (Days 6 to 18 of gestation) resulted in abortion, total litter loss, or decreased number of live fetuses at a dose of 9 mg/kg/day (about half the human exposure at the maximum recommended human dose of 40 mg daily, based on AUC). No treatment related malformations were observed in surviving fetuses.

No treatment related effects were observed at 3 mg/kg/day (about 0.1-fold the MRHD) or lower. The binding affinity of relugolix for rabbit GnRH receptors is unknown. In a similar embryo-fetal development study, oral administration of relugolix to pregnant rats during the period of organogenesis (Days 6 to 17 of gestation) did not affect pregnancy status or fetal endpoints at doses up to 1000 mg/kg/day (300 times the MRHD), a dose at which maternal toxicity (decreased body weight gain and food consumption) was observed.

A no observed adverse effect level (NOAEL) for maternal toxicity was 200 mg/kg/day (86 times the MRHD). In rats, the binding affinity of relugolix for GnRH receptors is more than 1000-fold lower than that in humans, and this study represents an assessment of non-pharmacological targets of relugolix during pregnancy. No treatment related malformations were observed up to 1000 mg/kg/day.

In a pre- and postnatal developmental study in pregnant and lactating rats, oral administration of relugolix to rats during late pregnancy and lactation (Day 6 of gestation to Day 20 of lactation) had no effects on pre- and postnatal development at doses up to 1000 mg/kg/day (300 times the MRHD), a dose in which maternal toxicity was observed (effects on body weight gain). A NOAEL for maternal toxicity was 100 mg/kg/day (34 times the MRHD).

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

MYFEMBREE is contraindicated in women: With a high risk of arterial, venous thrombotic, or thromboembolic disorders. Examples include women over 35 years of age who smoke and women who are known to have: current or history of deep vein thrombosis or pulmonary embolism vascular disease (e.g., cerebrovascular disease, coronary artery disease, peripheral vascular disease) thrombogenic valvular or thrombogenic rhythm diseases of the heart (e.g., subacute bacterial endocarditis with valvular disease, or atrial fibrillation) inherited or acquired hypercoagulopathies uncontrolled hypertension headaches with focal neurological symptoms or migraine headaches with aura if over 35 years of age Who are pregnant. Exposure to MYFEMBREE early in pregnancy may increase the risk of early pregnancy loss.

With known osteoporosis, because of the risk of further bone loss. With current or history of breast cancer or other hormone-sensitive malignancies, and with increased risk for hormone-sensitive malignancies. With known hepatic impairment or disease.

With undiagnosed abnormal uterine bleeding. With known anaphylactic reaction, angioedema, or hypersensitivity to MYFEMBREE or any of its components. Anaphylactoid reactions, urticaria, and angioedema have been reported.

High risk of arterial, venous thrombotic, or thromboembolic disorder. Pregnancy. Known osteoporosis.

Undiagnosed abnormal uterine bleeding. Known hypersensitivity to components of MYFEMBREE.

Overdosage of estrogen plus progestin may cause nausea, vomiting, breast tenderness, abdominal pain, drowsiness, fatigue, and withdrawal bleeding. Supportive care is recommended if an overdose occurs. The amount of relugolix, estradiol, or norethindrone removed by hemodialysis is unknown.