MYFEMBREE SIDE EFFECTS

Last updated on MDtodate: 10/8/2022

SIDE EFFECTS

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

• Thromboembolic Disorders and Vascular Events
• Bone Loss
• Depression, Mood Disorders, and Suicidal Ideation
• Hepatic Impairment and Transaminase Elevation
• Elevated Blood Pressure
• Uterine Fibroid Prolapse or Expulsion
• Alopecia
• Effects on Carbohydrate and Lipid Metabolism
• Hypersensitivity Reactions

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 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 the Phase 3 studies, women received 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. Across the two studies, 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. 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).

Serious Adverse Reactions

Serious adverse reactions were reported in 3.1% of MYFEMBREE-treated women compared with 2.3% of placebo-treated women in Studies L1 and L2. In MYFEMBREE-treated women, serious adverse drug reactions included uterine myoma expulsion and menorrhagia experienced by one woman, uterine leiomyoma (prolapse), cholecystitis, and pelvic pain reported for one woman each.

Adverse Reactions Leading To Study Drug Discontinuation

In the two placebo-controlled clinical trials (Study L1 and Study L2), 3.9% of women treated with MYFEMBREE discontinued therapy due to adverse reactions, compared with 4.3% receiving placebo. The most common adverse reaction leading to discontinuation of MYFEMBREE was uterine bleeding (1.2%) with 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 and at an incidence greater than placebo during double-blind placebo-controlled treatment are summarized in Table 1.

Table 1: Adverse Reactions Occurring in 3% or More of Women Treated with MYFEMBREE and at a Greater Incidence than Placebo in Studies L1 and L2

Adverse Reaction	MYFEMBREE (N = 254) %	Placebo (N = 256) %
Hot flush, hyperhidrosis, or night sweats	10.6	6.6
Abnormal uterine bleeding1	6.3	1.2
Alopecia	3.5	0.8
Libido decreased2	3.1	0.4
1 Includes menorrhagia, metrorrhagia, vaginal haemorrhage, polymenorrhoea, and menstruation irregular. 2 Includes libido decreased and loss of libido.

 

In one of the two Phase 3 clinical trials (Study L1), more women experienced the adverse reaction of new or worsening hypertension with MYFEMBREE as compared to placebo (7.0% vs 0.8%).

Less Common Adverse Reactions

Adverse reactions reported in at least 2% and less than 3% of women in the MYFEMBREE group and greater incidence than placebo included irritability, dyspepsia, and breast cyst. Other important adverse reactions reported in women treated with MYFEMBREE included one serious reaction each of uterine myoma expulsion (0.4%) and uterine leiomyoma (prolapse) (0.4%).

The adverse reactions most commonly reported in the extension trial, Study L3, were similar to those in the placebo-controlled trials.

Bone Loss

The effect of MYFEMBREE on BMD was assessed by dual-energy X-ray absorptiometry (DXA). The least squares mean percent change from baseline in lumbar spine BMD at Month 6 in Studies L1 and L2 is presented in Table 2.

Table 2: Mean Percent Change (On-Treatment) from Baseline in Lumbar Spine BMD in Women with Uterine Fibroids at Month 6 in Studies L1 and L2

	Studies L1 and L2 Treatment Month 6
	Placebo	MYFEMBREE
Number of Subjects	256	254
Percent Change from Baseline (95% CI*)	0.18 (-0.21, 0.58)	-0.23 (-0.64, 0.18)
Treatment Difference, %	-0.42
*Confidence Interval

 

In the open-label extension Study L3, continued bone loss was observed with 12 months of continuous treatment with MYFEMBREE. The least squares mean percent change from baseline in lumbar spine BMD at Month 6 and Month 12 for women treated with MYFEMBREE in Studies L1 or L2 and then continued on MYFEMBREE for an additional 28 weeks in Study L3 is presented in Table 3, below.

Table 3: Mean Percent Change (On-Treatment) from Baseline in Lumbar Spine BMD at Month 6 in Studies 1 and 2 and Month 12 in Study 3 in Women with Uterine Fibroids treated with MYFEMBREE

	Study L3 (N =163)
	Month 6*	Month 12
Percent Change from Baseline* (95% CI**)	-0.23 (-0.69, 0.24)	-0.80 (-1.36, -0.25)
*Baseline and Month 6 assessments include only those participants from Studies L1 and L2 who participated in Study L3. **CI = confidence interval.

 

A separate concurrent prospective observational study enrolled 262 women with uterine fibroids who were age-matched to participants of Studies L1 and L2. These women did not receive treatment for uterine fibroids and underwent DXA scans at Month 6 and Month 12 to monitor for changes in BMD. Mean percent change from baseline (95% CI) in BMD at the lumbar spine at Month 6 and Month 12 was 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 Cohort. A decline of > 8% was seen in 1% (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 Cohort.

In Studies L1, L2, and L3, 0.6% (4/634) women treated with MYFEMBREE experienced low trauma fractures (defined as a fall from standing height or less). Two of these women were treated with relugolix monotherapy for 12 weeks prior to MYFEMBREE therapy.

Depression, Mood Disorders, And Suicidal Ideation

In the Phase 3, placebo-controlled trials (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%).

Suicidal ideation was reported for women treated with MYFEMBREE in placebo-controlled clinical trials conducted for a different indication.

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 Study L1 and Study L2. Of the women with normal total cholesterol (< 200 mg/dL) at baseline, increases to > 200-240 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.

Postmarketing Experience

The following adverse reactions have been identified during 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

Neoplasms, benign, malignant and unspecified: uterine leiomyoma degeneration

Respiratory, thoracic and mediastinal disorders: pulmonary embolism