6 ADVERSE REACTIONS

The following clinically significant adverse reactions are discussed elsewhere in the labeling:

Thromboembolic Disorders and Vascular Events [see Warnings and Precautions (5.1)]
Bone Loss [see Warnings and Precautions (5.2)]
Suicidal Ideation and Mood Disorders (Including Depression) [see Warnings and Precautions (5.4)]
Hepatic Impairment and Transaminase Elevations [see Warnings and Precautions (5.5)]
Elevated Blood Pressure [see Warnings and Precautions (5.7)]
Change in Menstrual Bleeding Pattern and Reduced Ability to Recognize Pregnancy [see Warnings and Precautions (5.8)]
Uterine Fibroid Prolapse or Expulsion [see Warnings and Precautions (5.10)]
Alopecia [see Warnings and Precautions (5.11)]
Effects on Carbohydrate and Lipid Metabolism [see Warnings and Precautions (5.12)]
Hypersensitivity Reactions [see Warnings and Precautions (5.14)]

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.

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. Additionally, 256 women received placebo for 24 weeks, and 258 women received relugolix 40-mg monotherapy once daily for 12 weeks followed by MYFEMBREE for 12 weeks [see Clinical Studies (14.1)]. 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 MYFEMBREE in Studies L1 and L2
1 Includes hot flush, hyperhidrosis, or night sweats.
2 Includes menorrhagia, metrorrhagia, vaginal hemorrhage, polymenorrhea, and menstruation irregular.
3 Includes libido decreased and loss of libido.
Adverse Reaction	MYFEMBREE (N = 254) %	Placebo (N = 256) %
Vasomotor symptoms1	10.6	6.6
Abnormal uterine bleeding2	6.3	1.2
Alopecia	3.5	0.8
Libido decreased3	3.1	0.4

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
Abbreviations: BMD = bone mineral density; CI = confidence interval.
	MYFEMBREE	Placebo
Number of subjects	254	256
Percent change from baseline (95% CI)	-0.23 (-0.64, 0.18)	0.18 (-0.21, 0.58)
Treatment difference, %	-0.42

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
Abbreviations: BMD = bone mineral density; CI = confidence interval.
* Baseline and Month 6 assessments include only those participants from Studies L1 and L2 who participated in Study L3.
	Number of Women (N = 163)
	Month 6*	Month 12
Percent change from baseline* (95% CI)	-0.23 (-0.69, 0.24)	-0.80 (-1.36, -0.25)

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 6 and 12 were 0.00 (-0.32, 0.31) and -0.41 (-0.77, -0.05), respectively.

A decline in lumbar spine BMD of > 3% was observed in 23% (30/132) of women who had a DXA scan following 12 months of MYFEMBREE treatment in Study L3 and in 17.4% (37/213) of untreated women in the Observational Uterine Fibroids Cohort. A decline of > 8% was seen in 0.8% (1/132) of women treated with MYFEMBREE who completed a DXA scan at Month 12 and in 0.9% (2/213) of untreated women in the Observational Uterine Fibroids Cohort.

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. A greater proportion of women treated with MYFEMBREE compared to 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%).

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. For these women, 100% (35/35) in Study L1 and 93.3% (28/30) in Study L2 resumed menses. 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. Among women with normal total cholesterol (< 200 mg/dL) at baseline, increases to 200 to < 240 mg/dL were seen in 13.7% of women treated with MYFEMBREE as compared to 7.7% of women treated with placebo, and increases to ≥ 240 mg/dL were seen in 1.7% and 0.6% of MYFEMBREE- and placebo-treated women, respectively. For women with LDL < 130 mg/dL at baseline, increases to 130 to < 160 mg/dL, 160 to < 190 mg/dL and ≥ 190 mg/dL were seen in 9.3%, 1.5%, and 0.5% of women treated with MYFEMBREE as compared to 6.5%, 0.5% and 0% of women treated with placebo, respectively.

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. In these trials, women received once daily one relugolix 40-mg tablet with one over-encapsulated tablet of E2 1 mg and NETA 0.5 mg (relugolix + E2/NETA), which is equivalent to one tablet of MYFEMBREE. Across the two trials, 418 women received MYFEMBREE once daily for 24 weeks, 416 women received placebo for 24 weeks, and 417 women received relugolix 40 mg monotherapy once daily for 12 weeks followed by MYFEMBREE for 12 weeks [see Clinical Studies (14)]. 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 MYFEMBREE
1 Includes hot flush, hyperhidrosis, night sweats, and flushing.
2 Includes affect lability, affective disorder, anxiety, depressed mood, depression, emotional distress, generalized anxiety disorder, irritability, mixed anxiety and depressive disorder, mood altered, mood swings, and suicidal ideation.
3 Includes menorrhagia, metrorrhagia, vaginal hemorrhage, uterine hemorrhage, polymenorrhea, and menstruation irregular.
4 Includes libido decreased, libido disorder, and female sexual arousal disorder.
Adverse Reaction	MYFEMBREE (N = 418) %	Placebo (N = 416) %
Headache	33.0	26.4
Vasomotor symptoms1	13.2	7.2
Mood disorders2	9.1	7.2
Abnormal uterine bleeding3	6.7	4.6
Nausea	6.0	4.1
Toothache	5.5	2.4
Back pain	4.8	2.9
Decreased sexual desire and arousal4	4.3	1.2
Arthralgia	3.6	2.2
Fatigue	3.1	2.4
Dizziness	3.1	1.2

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%).

Bone Loss

The effect of MYFEMBREE on BMD was assessed by DXA. 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
Abbreviations: LS = least squares; BMD = bone mineral density; CI = confidence interval.
	Treatment Month 6
	MYFEMBREE	Placebo
Number of subjects	418	416
Percent change from baseline (95% CI)	-0.72 (-1.06, -0.38)	0.12 (-0.22, 0.47)
Treatment difference, %	-0.84

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. The least squares (LS) mean percent changes from baseline in lumbar spine BMD at Months 6, 12, and 24 for women treated with MYFEMBREE in Studies S1 and S2 and then continued MYFEMBREE for an additional 80 weeks in Study S3 are presented below in Table 6.

Table 6: LS Mean Percent Change (On-Treatment) from Baseline* in Lumbar Spine BMD at Months 6*, 12, and 24 for Women with Moderate to Severe Pain Associated with Endometriosis Treated with MYFEMBREE in Study S3
Abbreviations: LS = least squares; BMD = bone mineral density; CI = confidence interval; N = number of subjects who received continuous MYFEMBREE treatment throughout Studies S1/S2 and S3; n = number of subjects who had BMD assessments.
* Baseline and Month 6 assessments include only those participants from Studies S1 and S2 who also participated in Study S3.
	Number of Women (N = 277)
	Month 6* (n=264)	Month 12 (n=228)	Month 24 (n=163)
Percent change from baseline* (95% CI)	-0.91 (-1.30, -0.53)	-0.81 (-1.26, -0.36)	-0.45 (-1.03, 0.13)

Changes in bone mineral density with MYFEMBREE treatment beyond 24 months have not been elucidated.

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. Women underwent DXA scans at baseline and Months 6 and 12 to monitor for changes in BMD. The mean percent changes from baseline (95% CI) in lumbar spine BMD at Months 6 and 12 were 0.35 (0.13, 0.57) and 0.53 (0.24, 0.83), respectively.

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. A decline of > 7% to ≤ 8% from pre-treatment baseline was seen in 0.9% (2/228) of women treated with MYFEMBREE who completed a DXA scan at Month 12 in Study S3 and in 0.6% (2/320) of untreated women in the Observational Endometriosis Cohort.

Following 24 months of MYFEMBREE treatment in Study S3, a decline in lumbar spine BMD of > 3% from pre-treatment baseline occurred in 20.2% (33/163) of women and a decline of > 7% from pre-treatment baseline occurred in 2.5% (4/163) of women. At the femoral neck, a decline in BMD of >7% was observed in 1.8% (3/163) women, one of whom (0.6%) also had a decline in BMD of > 7% at the total hip. The maximum percent decline from pre-treatment baseline at the lumbar spine, femoral neck and total hip at Month 24 was 9.1%, 8.8% and 7.0%, 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. For these women, 83.6% (46/55) in Study S1 and 84.7% (50/59) in Study S2 resumed menses. 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. Mean time from last dose of drug to occurrence of menses was 36.7 days.

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. Among women with normal total cholesterol (< 200 mg/dL) at baseline, increases to ≥ 200 to < 240 mg/dL were seen in 13.6% (41/302) of MYFEMBREE- treated women as compared to 9.3% (27/289) of placebo-treated women, and increases to ≥ 240 mg/dL were seen in 0.7% (2/302) of MYFEMBREE-treated women as compared to 1.0% (3/289) of placebo-treated women. For women with LDL < 130 mg/dL at baseline, increases to 130 to < 160 mg/dL, 160 to < 190 mg/dL and ≥ 190 mg/dL were seen in 8.0%, 0.3%, and 0% of MYFEMBREE-treated women as compared to 7.6%, 0% and 0% of placebo-treated women. Among women with normal HDL at baseline (≥ 60 mg/dL), declines to 40 to < 60 mg/dL occurred in 22.2% (49/221) of MYFEMBREE-treated women as compared to 12.2% (27/221) of placebo-treated women.

6.2 Postmarketing Experience

The following adverse reactions have been identified during post-approval use of MYFEMBREE, as well as post-approval use of relugolix monotherapy outside of the United States. 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