Dosage & administration
Myfembree prescribing information
- Estrogen and progestin combinations, including MYFEMBREE, increase the risk of thrombotic or thromboembolic disorders including pulmonary embolism (PE), deep vein thrombosis (DVT), stroke and myocardial infarction (MI), especially in women at increased risk for these events[see Warnings and Precautions ()].
5.1 Thromboembolic Disorders and Vascular EventsMYFEMBREE is contraindicated in women with current or history of thrombotic or thromboembolic disorders and in women at increased risk for these events
[see Contraindications ].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.
- MYFEMBREE is contraindicated in women with current or a history of thrombotic or thromboembolic disorders and in women at increased risk for these events, including women over 35 years of age who smoke or women with uncontrolled hypertension[see Contraindications ()].
4 CONTRAINDICATIONSMYFEMBREE is contraindicated in women:
- With a high risk of arterial, venous thrombotic, or thromboembolic disorders[see Boxed Warningand Warnings and Precautions ]. 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[see Warnings and Precautions and Use in Specific Populations ].
- With known osteoporosis, because of the risk of further bone loss[see Warnings and Precautions ].
- With current or history of breast cancer or other hormone-sensitive malignancies, and with increased risk for hormone-sensitive malignancies[see Warnings and Precautions ].
- With known hepatic impairment or disease[see Warnings and Precautions ].
- 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[see Warnings and Precautions , Adverse Reactions ].
- High risk of arterial, venous thrombotic, or thromboembolic disorder.
- Pregnancy.
- Known osteoporosis.
- Current or history of breast cancer or other hormone-sensitive malignancies.
- Known hepatic impairment or disease.
- Undiagnosed abnormal uterine bleeding.
- Known hypersensitivity to components of MYFEMBREE.
- With a high risk of arterial, venous thrombotic, or thromboembolic disorders
MYFEMBREE is a combination of relugolix, a gonadotropin-releasing hormone (GnRH) receptor antagonist, estradiol, an estrogen, and norethindrone acetate, a progestin, indicated in premenopausal women for the:
- management of heavy menstrual bleeding associated with uterine leiomyomas (fibroids). (,
1.1 Heavy Menstrual Bleeding Associated with Uterine LeiomyomasMYFEMBREE is indicated for the management of heavy menstrual bleeding associated with uterine leiomyomas (fibroids) in premenopausal women [
see Clinical Studies].)14.1 Heavy Menstrual Bleeding Associated with Uterine FibroidsThe 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 LossIn 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: Proportion of Responders for Reduction in MBL Volume Over Last 35 days of Treatment in Women with Uterine Fibroids (Studies L1 and L2) Abbreviations: CI = confidence interval.
Study L1Study L2MYFEMBREE(N = 122)Placebo(N = 113)MYFEMBREE(N = 125)Placebo(N = 129)Women with MBL Volume < 80 mL and ≥50% Reduction in MBL Volume from Baseline to the Last 35 Days of Treatment72.1% 16.8% 71.2% 14.7% Difference from placebo, %95% CIp-value55.3%
(44.2%, 65.6%)
< 0.000156.5%
(46.6%, 66.5%)
< 0.0001AmenorrheaIn Studies L1 and L2, 50.0% and 50.4% of women treated with MYFEMBREE, respectively, achieved amenorrhea as compared to 6.2% and 3.1% treated with placebo, respectively, over the last 35 days of treatment.
Percent Change in MBL VolumeThe 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 weeksStudy L1Study L2
Figure 1 Figure 1 Hemoglobin LevelsFor efficacy, a hemoglobin response was defined as a hemoglobin increase > 2 g/dL from baseline to Week 24 in the subgroup of women with anemia at baseline (hemoglobin ≤ 10.5 g/dL). A statistically higher proportion treated with MYFEMBREE compared with placebo had > 2 g/dL improvement in hemoglobin levels, see Table 9.
Table 9: Proportion of Women with Baseline Hgb ≤ 10.5 and > 2 g/dL Improvement in Hemoglobin Levels from Baseline at Week 24 Abbreviation: CI = confidence interval.
n = number of patients with Hgb ≤10.5 g/dL at baseline.
N = number of patients in each treatment group.
Study L1Study L2MYFEMBREEn=43(N = 122)Placebon=29(N = 113)MYFEMBREEn=40(N = 125)Placebon=53(N = 129)% at Week 2444.2% 17.2% 55.0% 5.7% Difference from placebo, %
95% CI
p-value26.9%
(6.7%, 47.2%)
0.017749.3%
(32.7%, 66.0%)
<0.0001Recurrence of Heavy Menstrual Bleeding After Discontinuation of MYFEMBREEIn a randomized withdrawal study (L4), 229 women from the open label extension Study L3 were rerandomized to either continue blinded treatment with MYFEMBREE or withdrawal of therapy (placebo) for an additional 52 weeks. The median time to return to heavy menstrual bleeding among women randomized to placebo (treatment withdrawal) was 5.9 weeks.
- management of moderate to severe pain associated with endometriosis. (,
1.2 Moderate to Severe Pain Associated with EndometriosisMYFEMBREE is indicated for the management of moderate to severe pain associated with endometriosis in premenopausal women [
see Clinical Studies].)14.2 Moderate to Severe Pain Associated with EndometriosisThe 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 ≥ 2.5or
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.
Table 10: Proportion of Dysmenorrhea and Non-Menstrual Pelvic Pain Responders at Week 24 Abbreviations: CI = confidence interval.
Responders are women with a reduction from baseline of at least 2.8 points on the NRS for dysmenorrhea or at least 2.1 points on the NRS for non-menstrual pelvic pain and no increase in analgesic use over the last 35 days of treatment.
Study S1Study S2MYFEMBREE(N = 212)Placebo(N = 212)MYFEMBREE(N = 205)Placebo(N = 200)Dysmenorrhea74.5% 26.9% 75.1% 30.5% Difference from placebo
(95% CI)
p-value47.6%
(39.3%, 56.0%)
≤ 0.0001- 44.6%
(35.9%, 53.3%)
≤ 0.0001- Non-menstrual pelvic pain58.5% 39.6% 65.9% 42.5% Difference from placebo
(95% CI) *
p-value18.9%
(9.5%, 28.2%)
≤ 0.0001- 23.4%
(13.9%, 32.8%)
≤ 0.0001- 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 ScoresWomen 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: Mean DYS NRS Scores in Study S1 and Study S2 over 24 WeeksStudy S1Study S2
Figure 3: Mean NMPP NRS Scores in Study S1 and Study S2 over 24 WeeksStudy S1Study S2
Figure 2 Figure 2 Figure 3 Figure 3 Reduction in EHP-30 Pain Domain ScoresThe 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 WeeksStudy S1Study S2
Figure 4 Figure 4 Reduction in DyspareuniaDyspareunia associated with endometriosis was evaluated in a subgroup of women who engaged in sexual activity with vaginal intercourse at baseline and during treatment (68% of enrolled women). Dyspareunia (pain during sexual intercourse) was assessed daily using an 11-point NRS ranging from 0 (“no pain”) to 10 (“pain as bad as you can imagine”). In Studies S1 and S2, women treated with MYFEMBREE had a greater reduction in dyspareunia from baseline to Week 24 compared with placebo [LS mean change in Study S1: -2.4 vs. -1.7, with a treatment difference of -0.7 (95% CI: -1.3, -0.1); in Study S2: -2.4 vs. -1.9, with a treatment difference of -0.5 (95% CI: -1.0, 0.0)].
Use of Opioid Rescue AnalgesicsThe opioid analgesics used in the studies were tramadol 50 mg, codeine 30 mg, tramadol/acetaminophen (TRM/APAP) 37.5/325 mg, codeine/APAP at strengths of 15/500 mg, 30/300 mg, and 30/500 mg, and hydrocodone/acetaminophen 5/325 mg. The opioid rescue analgesics used at baseline, Month 3, and Month 6 are shown in Table 11.
The clinical relevance of these data has not been demonstrated.
Table 11: Opioid Rescue Analgesic Use in Studies S1 and S2 Max = maximum; Min = minimum; SD = standard deviation; monthly tablets calculations are both on 28-day interval.
* = denominator is the number of subjects on opioid rescue analgesics at baseline.
#= denominator is the number of subjects off opioid rescue analgesics at baseline.
Study S1Study S2MYFEMBREE(N = 212)Placebo(N = 212)MYFEMBREE(N = 205)Placebo(N = 200)Tablets per month at baseline
Mean (SD)
Median (Min, Max)
9.1 (12.36)
4.2
(0.6, 60.7)
11.7 (11.95)
7.2
(0.5, 54.6)
9.0 (13.51)
5.6
(0.7, 106.9)
10.0 (12.82)
6.1
(0.4, 86.3)Tablets per month at Month 3
Mean (SD)
Median (Min, Max)
3.9 (7.98)
0.0
(0.0, 32.0)
8.2 (11.48)
3.2
(0.0, 40.8)
3.4 (8.26)
0.0
(0.0, 57.6)
7.5 (23.49)
2.4
(0.0, 215.2)Tablets per month at Month 6
Mean (SD)
Median (Min, Max)
4.8 (10.38)
0.0
(0.0, 45.4)
10.7 (28.93)
3.2
(0.0, 40.8)
2.4 (5.02)
0.0
(0.0, 28.0)
5.6 (14.16)
1.2
(0.0, 120.8)Number and % of subjects on any dose of opioid rescue at baseline who were off opioid at Month 3* 33/64
(51.6%)10/56
(17.9%)46/100
(46.0%)27/94
(28.7%)Number and % of subjects on any dose of opioid rescue at baseline who were off opioid at Month 6* 39/64
(60.9%)18/56
(32.1%)65/100
(65.0%)38/94
(40.4%)Number and % of subjects not on opioid rescue at baseline who were on opioid at Month 3# 4/148
(2.7%)10/156
(6.4%)6/105
(5.7%)15/106
(14.2%)Number and % of subjects not on any dose of opioid rescue at baseline who were on opioid at Month 6# 5/148
(3.4%)12/156
(7.7%)2/105
(1.9%)12/106
(11.3%)
Use of MYFEMBREE should be limited to 24 months due to the risk of continued bone loss which may not be reversible. (
Use of MYFEMBREE should be limited to 24 months due to the risk of continued bone loss that may not be reversible
MYFEMBREE is contraindicated in women with known osteoporosis
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
The following clinically significant adverse reactions are discussed elsewhere in the labeling:
- Thromboembolic Disorders and Vascular Events[see Warnings and Precautions ]
- Bone Loss[see Warnings and Precautions ]
- Suicidal Ideation and Mood Disorders (Including Depression)[see Warnings and Precautions ]
- Hepatic Impairment and Transaminase Elevations[see Warnings and Precautions ]
- Elevated Blood Pressure[see Warnings and Precautions ]
- Change in Menstrual Bleeding Pattern and Reduced Ability to Recognize Pregnancy[see Warnings and Precautions ]
- Uterine Fibroid Prolapse or Expulsion[see Warnings and Precautions ]
- Alopecia[see Warnings and Precautions ]
- Effects on Carbohydrate and Lipid Metabolism[see Warnings and Precautions ]
- Hypersensitivity Reactions[see Warnings and Precautions ]
In women with heavy menstrual bleeding associated with uterine fibroids, most common adverse reactions (incidence ≥ 3%) are vasomotor symptoms, uterine bleeding, alopecia, and decreased libido.
In women with moderate to severe pain associated with endometriosis, most common adverse reactions (incidence ≥ 3%) are headache, vasomotor symptoms, mood disorders, abnormal uterine bleeding, nausea, toothache, back pain, decreased sexual desire and arousal, arthralgia, fatigue, and dizziness.
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 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
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.
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.
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.
1Includes hot flush, hyperhidrosis, or night sweats. | ||
2Includes menorrhagia, metrorrhagia, vaginal hemorrhage, polymenorrhea, and menstruation irregular. | ||
3Includes 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.
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%).
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.
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.
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.
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%).
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.
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.
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
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.
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).
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.
1Includes hot flush, hyperhidrosis, night sweats, and flushing. | ||
2Includes 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. | ||
3Includes menorrhagia, metrorrhagia, vaginal hemorrhage, uterine hemorrhage, polymenorrhea, and menstruation irregular. | ||
4Includes 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.
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 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.
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.
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.
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.
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.
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.
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.
- Exclude pregnancy and discontinue hormonal contraceptives prior to MYFEMBREE initiation. ()
2.1 Prior to Initiation of MYFEMBREE- Exclude pregnancy[see Contraindications ].
- Discontinue hormonal contraceptives[see Warnings and Precautions ].
- Exclude pregnancy
- Take one tablet orally once daily. ()
2.2 Recommended Dosage- Take one tablet of MYFEMBREE orally once daily at approximately the same time, with or without food[see Clinical Pharmacology ].
- Start MYFEMBREE as early as possible after the onset of menses but no later than seven days after menses has started [see Clinical Studies].
- The recommended total duration of treatment with MYFEMBREE is 24 months[see Indications and Usage , Warnings and Precautions , and Adverse Reactions ].
- Take one tablet of MYFEMBREE orally once daily at approximately the same time, with or without food
- 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. ()
2.3 Missed DoseTake the missed dose of MYFEMBREE as soon as possible the same day and then resume regular dosing the next day at the usual time.
- If concomitant use of oral P-gp inhibitors is unavoidable, take MYFEMBREE at least 6 hours before taking the P-gp inhibitor ()
2.4 Dosage Modification for Concomitant Use with P-gp InhibitorsAvoid 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 and Clinical Pharmacology ].
Tablets: Each tablet of MYFEMBREE contains a fixed-dose combination of relugolix 40 mg, estradiol (E2) 1 mg, and norethindrone acetate (NETA) 0.5 mg. The tablets are light yellow to yellow, round, film-coated, and debossed with “MVT” on one side and “415” on the other side.
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.
MYFEMBREE is contraindicated in women:
- With a high risk of arterial, venous thrombotic, or thromboembolic disorders [see. Examples include women over 35 years of age who smoke and women who are known to have:and Warnings and Precautions (
WARNING: THROMBOEMBOLIC DISORDERS AND VASCULAR EVENTS- Estrogen and progestin combinations, including MYFEMBREE, increase the risk of thrombotic or thromboembolic disorders including pulmonary embolism (PE), deep vein thrombosis (DVT), stroke and myocardial infarction (MI), especially in women at increased risk for these events[see Warnings and Precautions ].
- MYFEMBREE is contraindicated in women with current or a history of thrombotic or thromboembolic disorders and in women at increased risk for these events, including women over 35 years of age who smoke or women with uncontrolled hypertension[see Contraindications ].
WARNING: THROMBOEMBOLIC DISORDERS AND VASCULAR EVENTSSee full prescribing information for complete boxed warning- Estrogen and progestin combinations, including MYFEMBREE, increase the risk of thrombotic or thromboembolic disorders, especially in women at increased risk for these events.
- MYFEMBREE is contraindicated in women with current or a history of thrombotic or thromboembolic disorders and in women at increased risk for these events, including women over 35 years of age who smoke or women with uncontrolled hypertension.
)]5.1 Thromboembolic Disorders and Vascular EventsMYFEMBREE is contraindicated in women with current or history of thrombotic or thromboembolic disorders and in women at increased risk for these events
[see Contraindications ].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.
- 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 [see Warnings and Precautions (.) and Use in Specific Populations (
5.9 Risk of Early Pregnancy LossMYFEMBREE is contraindicated for use in pregnancy
[see Contraindications ].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 PregnancyPregnancy Exposure RegistryThere 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 SummaryMYFEMBREE is contraindicated in pregnancy
[see Contraindications and Warnings and Precautions ].Based on findings from animal studies and its mechanism of action, MYFEMBREE may cause early pregnancy loss. Discontinue MYFEMBREE if pregnancy occurs during treatment[see Warnings and Precautions and Clinical Pharmacology ].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
[see Data].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
[see Data].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 2% to 4% and 15% to 20%, respectively.
DataAnimal DataIn 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 [MRHD] 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).
- With known osteoporosis, because of the risk of further bone loss [see Warnings and Precautions ()].
5.2 Bone LossMYFEMBREE is contraindicated in women with known osteoporosis
[see Contraindications ].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 ]. The impact of BMD decreases on long-term bone health and future fracture risk in premenopausal women is unknown. - With current or history of breast cancer or other hormone-sensitive malignancies, and with increased risk for hormone-sensitive malignancies [see Warnings and Precautions (.)]
5.3 Hormone-Sensitive MalignanciesMYFEMBREE 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 ]. 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.
- With known hepatic impairment or disease [see Warnings and Precautions (.)]
5.5 Hepatic Impairment and Transaminase ElevationsContraindication in Patients with Hepatic ImpairmentMYFEMBREE is contraindicated in patients with known hepatic impairment or disease
[see Contraindications and Use in Specific Populations ]. Steroid hormones may be poorly metabolized in patients with impaired liver function[see Clinical Pharmacology ].Transaminase ElevationsInstruct women to promptly seek medical attention for symptoms or signs that may reflect liver injury, such as jaundice or right upper abdominal pain. Acute liver test abnormalities may necessitate the discontinuation of MYFEMBREE use until the liver tests return to normal and MYFEMBREE causation has been excluded.
In placebo-controlled clinical trials, in women with uterine fibroids or endometriosis, elevations (≥ 3 times the upper limit of the normal [ULN] of reference range) in alanine aminotransferase (ALT) occurred in 0.4% (1/254) and 0.7% (3/418) of MYFEMBREE-treated women, respectively, as compared to 0% (0/256) and 0.5% (2/416) of placebo-treated women, respectively; moreover, elevations (≥ 3 times ULN of reference range) in aspartate aminotransferase (AST) occurred in 0.8% (2/254) and 0.2% (1/418) of MYFEMBREE-treated women, respectively, as compared to 0.4% (1/256) and 0.5% (2/416) of placebo-treated women, respectively. No patterns in time to onset of these liver transaminase elevations were identified.
- 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 [see Warnings and Precautions (), Adverse Reactions (
5.14 Hypersensitivity ReactionsHypersensitivity reactions, including anaphylactoid reactions, urticaria and angioedema, have been reported with MYFEMBREE[see Adverse Reactions ].MYFEMBREE is contraindicated in women with a history of hypersensitivity reactions to relugolix or any component of MYFEMBREE[see Contraindications ].Immediately discontinue MYFEMBREE if a hypersensitivity reaction occurs.)].6.2 Postmarketing ExperienceThe 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 reactionSkin and subcutaneous tissue disorders:drug eruption, angioedema, urticariaNeoplasms (benign, malignant, and unspecified):uterine leiomyoma degeneration