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WARNING
THROMBOEMBOLIC DISORDERS AND VASCULAR EVENTS
MYFEMBREE tablets for oral administration contain a fixed-dose combination of relugolix 40 mg, estradiol 1 mg, and norethindrone acetate 0.5 mg as active ingredients.
Relugolix is a non-peptide small molecule, GnRH receptor antagonist. It is a white to off white to slightly yellow solid and is sparingly soluble in water. The chemical name is N-(4-{1-[(2,6difluorophenyl)methyl]-5-[(dimethylamino)methyl]-3-(6-methoxypyridazin-3-yl)-2,4-dioxo-1,2,3,4 - tetrahydrothieno[2,3-d]pyrimidin-6-yl}phenyl)-N-methoxyurea with the empirical formula of C29H27F2N7O5S and a molecular weight of 623.63. The structural formula is:
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Estradiol (E2) is an estrogen with its chemical name as estra-1, 3, 5 (10)-triene-3, 17β-diol. The empirical formula of E2 is C18H24O2 and a molecular weight of 272.4. The structural formula is:
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Estradiol is present as the hemihydrate (C18H24O2•½H2O) which is a white or almost white crystalline powder.
Norethindrone acetate (NETA), a progestin, is a white or yellowish-white crystalline powder. Its chemical name is 17-Hydroxy-19-nor-17α-pregn-4-en-20-yn-3-one acetate with the empirical formula of C22H28O3 and a molecular weight of 340.5. The structural formula is:
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Each MYFEMBREE (relugolix, estradiol, and norethindrone acetate) film-coated tablet contains the following inactive ingredients: hydroxypropyl cellulose, hypromellose, iron oxide yellow, lactose monohydrate, mannitol, magnesium stearate, sodium starch glycolate, titanium dioxide, and triacetin.
The following clinically significant adverse reactions are discussed elsewhere in the labeling:
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 [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
| 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 | ||
|
1 Includes hot flush, hyperhidrosis, or night sweats. |
||||
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
| 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 | |
| Abbreviations: BMD = bone mineral density; CI = confidence interval. | ||
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
|
Number of Women |
||||
| Month 6* |
Month 12 |
|||
| Percent change from baseline* (95% CI) | -0.23 (-0.69, 0.24) |
-0.80 (-1.36, -0.25) |
||
|
Abbreviations: BMD = bone mineral density; CI = confidence interval. |
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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.
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).
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
| Adverse Reaction | MYFEMBREE (N = 418) % |
Placebo (N = 416) % |
||
| Headache | 33.0 | 26.4 | ||
| Vasomotor symptoms[1] | 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 | ||
|
1 Includes hot flush, hyperhidrosis, night sweats, and flushing. |
||||
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
| 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 | |||
|
Abbreviations: LS = least squares; BMD = bone mineral density; CI = confidence interval. |
||||
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
|
Number of Women |
||||
|
Month 6* |
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) |
|
|
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. |
||||
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 longterm 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.
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
Co-administration of MYFEMBREE with P-gp inhibitors increases the AUC and maximum concentration (Cmax) of relugolix [see Clinical Pharmacology (12.3)] 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 [see Dosage and Administration (2.4)].
Use of MYFEMBREE with combined P-gp and strong CYP3A inducers decreases the AUC and Cmax of relugolix, estradiol, and/or norethindrone [see Clinical Pharmacology (12.3)] and may decrease the therapeutic effects of MYFEMBREE. Avoid use of MYFEMBREE with combined P-gp and strong CYP3A inducers.
Included as part of the PRECAUTIONS section.
MYFEMBREE is contraindicated in women with current or history of thrombotic or thromboembolic disorders and in women at increased risk for these events [see Contraindications (4)].
Discontinue MYFEMBREE immediately if an arterial or venous thrombotic, cardiovascular, or cerebrovascular event occurs or is suspected. Discontinue MYFEMBREE at least 4 to 6 weeks before surgery of the type associated with an increased risk of thromboembolism, or during periods of prolonged immobilization, if feasible.
Discontinue MYFEMBREE immediately if there is sudden unexplained partial or complete loss of vision, proptosis, diplopia, papilledema, or retinal vascular lesions and evaluate for retinal vein thrombosis as these have been reported in patients receiving estrogens and progestins.
Estrogen and progestin combinations, including the estradiol/norethindrone acetate component of MYFEMBREE, increase the risk of thrombotic or thromboembolic disorders, including pulmonary embolism, deep vein thrombosis, stroke, and myocardial infarction, especially in women at high risk for these events. In general, the risk is greatest among women over 35 years of age who smoke and women with uncontrolled hypertension, dyslipidemia, vascular disease, or obesity.
Two thromboembolic events (DVT and PE) occurred in one woman treated for 38 days with MYFEMBREE for moderate to severe pain associated with endometriosis.
MYFEMBREE is contraindicated in women with known osteoporosis [see Contraindications (4)]. Consider the benefits and risks of MYFEMBREE treatment in patients with a history of a low trauma fracture or risk factors for osteoporosis or bone loss, including taking medications that may decrease bone mineral density (BMD) (e.g., systemic or chronic inhaled corticosteroids, anticonvulsants, or chronic use of proton pump inhibitors).
Assessment of BMD by dual-energy X-ray absorptiometry (DXA) is recommended at baseline. In women with heavy menstrual bleeding associated with uterine fibroids, periodic DXA during treatment with MYFEMBREE is recommended. In women with moderate to severe pain associated with endometriosis, annual DXA is recommended while taking MYFEMBREE. Consider discontinuing MYFEMBREE if the risk associated with bone loss exceeds the potential benefit of treatment. Although the effect of supplementation with calcium and vitamin D was not studied, such supplementation for patients with inadequate dietary intake may be beneficial. MYFEMBREE may cause a decrease in BMD in some patients. BMD loss may be greater with increasing duration of use and may not be completely reversible after stopping treatment [see Adverse Reactions (6.1)]. The impact of BMD decreases on long-term bone health and future fracture risk in premenopausal women is unknown.
MYFEMBREE is contraindicated in women with current or a history of hormone-sensitive malignancies (e.g., breast cancer) and in women at increased risk for hormone-sensitive malignancies [see Contraindications (4)]. Discontinue MYFEMBREE if a hormone-sensitive malignancy is diagnosed.
Surveillance measures in accordance with standard of care, such as breast examinations and mammography, are recommended. The use of estrogen alone or estrogen plus progestin has been reported to result in an increase in abnormal mammograms requiring further evaluation.
Evaluate patients with a history of suicidal ideation, depression, and mood disorders prior to initiating treatment. Monitor patients for mood changes and depressive symptoms including shortly after initiating treatment, to determine whether the risks of continuing therapy with MYFEMBREE outweigh the benefits. Patients with new or worsening depression, anxiety, or other mood changes should be referred to a mental health professional, as appropriate. Advise patients to seek immediate medical attention for suicidal ideation and behavior. Re-evaluate the benefits and risks of continuing MYFEMBREE if such events occur.
Gonadotropin-releasing hormone receptor antagonists, including MYFEMBREE, have been associated with mood disorders (including depression) and suicidal ideation.
In Studies L1 and L2 in women with heavy menstrual bleeding associated with uterine fibroids, a greater proportion of women treated with MYFEMBREE compared with placebo reported depression (including depression, mood swings, and depressed mood) (2.4% vs. 0.8%), irritability (2.4% vs. 0%), and anxiety (1.2% vs. 0.8%) [see Adverse Reactions (6.1)].
In Studies S1 and S2 in women with moderate to severe pain associated with endometriosis, a greater proportion of women treated with MYFEMBREE as compared to placebo reported mood disorders (including depression) (9.1% vs. 7.2%). In addition, cases of suicidal ideation were reported with MYFEMBREE use. All women who reported suicidal ideation had a history of depression and/or anxiety [see Adverse Reactions (6.1)].
MYFEMBREE is contraindicated in patients with known hepatic impairment or disease [see Contraindications (4) and Use in Specific Populations (8.6)]. Steroid hormones may be poorly metabolized in patients with impaired liver function [see Clinical Pharmacology (12.3)].
Instruct 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.
Discontinue MYFEMBREE if signs or symptoms of gallbladder disease or jaundice occur. For women with a history of cholestatic jaundice associated with past estrogen use or with pregnancy, assess the risk-benefit of continuing therapy. Studies among estrogen users suggest a small increased relative risk of developing gallbladder disease.
MYFEMBREE is contraindicated in women with uncontrolled hypertension [see Contraindications (4)]. For women with well-controlled hypertension, continue to monitor blood pressure and stop MYFEMBREE if blood pressure rises significantly.
In the placebo-controlled clinical trials in women with heavy menstrual bleeding associated with uterine fibroids or with moderate to severe pain associated with endometriosis, more women in one study (Study L1; uterine fibroids) experienced the adverse reaction of new or worsening hypertension with MYFEMBREE compared to placebo (7.0% vs. 0.8%).
Exclude pregnancy before initiating MYFEMBREE [see Dosage and Administration (2.1)]. Start MYFEMBREE as early as possible after the start of menses but no later than 7 days after menses has started. If MYFEMBREE is initiated later in the menstrual cycle, irregular and/or heavy bleeding may initially occur. Women who take MYFEMBREE may experience amenorrhea or a reduction in the amount, intensity, or duration of menstrual bleeding, which may delay the ability to recognize pregnancy. Perform pregnancy testing if pregnancy is suspected and discontinue MYFEMBREE if pregnancy is confirmed [see Use in Specific Populations (8.1, 8.3)].
Advise women of reproductive potential to use effective non-hormonal contraception during treatment with MYFEMBREE and for one week after the final dose. Avoid concomitant use of hormonal contraceptives with MYFEMBREE. The use of estrogen-containing hormonal contraceptives can increase estrogen levels which may increase the risk of estrogen-associated adverse events and decrease the efficacy of MYFEMBREE [see Use in Specific Populations (8.1, 8.3)].
MYFEMBREE is contraindicated for use in pregnancy [see Contraindications (4)]. Based on findings from animal studies and its mechanism of action, MYFEMBREE can cause early pregnancy loss. However, in both rabbits and rats, no fetal malformations were present at any dose level tested which were associated with relugolix exposures about half and approximately 300 times exposures in women at the recommended human dose [see Use in Specific Populations (8.1)].
Advise women with known or suspected submucosal uterine fibroids about the possibility of uterine fibroid prolapse or expulsion and instruct them to contact their physician if severe bleeding and/or cramping occurs while being treated with MYFEMBREE. In Studies L1 and L2, uterine fibroid prolapse or uterine fibroid expulsion were reported in women treated with MYFEMBREE [see Adverse Reactions (6.1)].
Consider discontinuing MYFEMBREE if hair loss becomes a concern [see Adverse Reactions (6.1)].
In Phase 3 placebo-controlled clinical trials in women with heavy menstrual bleeding associated with uterine fibroids, 3.5% of MYFEMBREE-treated women experienced alopecia, hair loss, and hair thinning as compared to 0.8% of placebo-treated women. In 3 of the 11 affected women treated with MYFEMBREE across Studies L1 and L2, alopecia was reported as moderate. For one MYFEMBREE-treated woman in the extension trial, alopecia was a reason for discontinuing treatment. No specific pattern of hair loss was described. The majority of affected women completed the study with reported hair loss ongoing. Whether the hair loss is reversible is unknown [see Adverse Reactions (6.1)].
More frequent monitoring in MYFEMBREE-treated women with prediabetes and diabetes may be necessary. MYFEMBREE may decrease glucose tolerance and result in increased blood glucose concentrations.
Monitor lipid levels and consider discontinuing MYFEMBREE if hypercholesterolemia or hypertriglyceridemia worsens. In women with pre-existing hypertriglyceridemia, estrogen therapy may be associated with elevations in triglycerides levels leading to pancreatitis. Use of MYFEMBREE is associated with increases in total cholesterol and low-density lipoprotein cholesterol (LDL-C) [see Adverse Reactions (6.1)].
Patients with hypothyroidism and hypoadrenalism may require higher doses of thyroid hormone or cortisol replacement therapy.
The use of estrogen and progestin combinations may raise serum concentrations of binding proteins (e.g., thyroid-binding globulin, corticosteroid-binding globulin), which may reduce free thyroid or corticosteroid hormone levels.
The use of estrogen and progestin may also affect the levels of sex hormone-binding globulin, and coagulation factors [see Clinical Pharmacology (12.2)].
Hypersensitivity reactions, including anaphylactoid reactions, urticaria and angioedema, have been reported with MYFEMBREE [see Adverse Reactions (6.2)]. MYFEMBREE is contraindicated in women with a history of hypersensitivity reactions to relugolix or any component of MYFEMBREE [see Contraindications (4)]. Immediately discontinue MYFEMBREE if a hypersensitivity reaction occurs.
Relugolix
Two-year carcinogenicity studies were conducted in mice at oral relugolix doses up to 100 mg/kg/day and in rats at doses up to 600 mg/kg/day. Relugolix was not carcinogenic in mice or rats at exposures up to approximately 142 or 423 times, respectively, the exposure in human females at the MRHD of 40 mg daily, based on AUC.
E2/NETA
Long-term continuous administration of natural and synthetic estrogens in certain animal species increases the frequency of carcinomas of the breast, uterus, cervix, vagina, testis, and liver.
Relugolix was not mutagenic in the in vitro bacterial reverse mutation (Ames) assay or clastogenic in the in vitro chromosomal aberration assay in Chinese hamster lung cells or the in vivo rat bone marrow micronucleus assay.
In a fertility study in rats, no effect on female fertility was observed at up to 1000 mg/kg/day (300 times the MRHD of 40 mg daily in women). In rats, the binding affinity of relugolix for GnRH receptors is greater than 1000-fold less than in humans, and this study represents an assessment of non-pharmacological targets of relugolix.
In human GnRH-receptor knock-in mice, administration of relugolix at oral doses of 100 mg/kg and above twice daily to female mice induced a constant diestrus phase and decreased ovarian and uterine weights, effects which were reversible following cessation of treatment. In male knock-in mice, oral administration of relugolix decreased prostate and seminal vesicle weights at doses 3 mg/kg and above twice daily for 28 days, effects which were reversible, except for testis weight, which did not fully recover within 28 days after drug withdrawal.
In a 39-week toxicology study in monkeys, a decrease in the frequency of menses was observed in female monkeys at 50 mg/kg/day (99 times the MRHD of 40 mg daily in women, based on AUC), which was partially reversed following a 13-week recovery period. There were no significant effects on male reproductive organs at oral relugolix doses up to 50 mg/kg/day (approximately 53 times the human exposure at a dose of 120 mg daily in men, based on AUC).
Phospholipidosis (intracellular phospholipid accumulation) was observed in multiple organs and tissues (e.g., liver, pancreas, spleen, kidney, lymph nodes, lung, bone marrow, GI tract or testes) after repeated oral administration of relugolix in rats and monkeys. In a rat 26-week toxicity study, phospholipidosis was observed at doses of 100 mg/kg (approximately 30 times the exposure at the MRHD of 40 mg daily in women based on AUC) and above. In a monkey 39week toxicity study, this effect was observed at doses of 1.5 mg/kg (approximately equal to the MRHD) and above and demonstrated evidence of reversibility after cessation of treatment. The significance of this finding in humans is unknown.
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.
MYFEMBREE is contraindicated in women:
MYFEMBREE is a combination of relugolix, estradiol (E2), and norethindrone acetate (NETA).
Relugolix is a non-peptide GnRH receptor antagonist that competitively binds to pituitary GnRH receptors, thereby reducing the release of luteinizing hormone (LH) and follicle-stimulating hormone (FSH), leading to decreased serum concentrations of the ovarian sex hormones estradiol and progesterone and reduced bleeding associated with uterine fibroids and pain associated with endometriosis.
Estradiol acts by binding to nuclear receptors that are expressed in estrogen-responsive tissues. As a component of MYFEMBREE, the addition of exogenous estradiol may reduce the increase in bone resorption and resultant bone loss that can occur due to a decrease in circulating estrogen concentrations from relugolix alone.
Progestins such as norethindrone act by binding to nuclear receptors that are expressed in progesterone-responsive tissues. As a component of MYFEMBREE, norethindrone may protect the uterus from the potential adverse endometrial effects of unopposed estrogen.
Estradiol and norethindrone acetate (components of MYFEMBREE) may have the following effects:
At a dose 9 times the maximum approved recommended dose of relugolix, the QT interval was not prolonged to a clinically relevant extent.
The effect of estradiol and norethindrone acetate (two of the components of MYFEMBREE) on the QTc interval has not been studied.
The pharmacokinetic parameters of relugolix, unconjugated estradiol, and norethindrone after administration of a single dose of MYFEMBREE to healthy postmenopausal women under fasted conditions are summarized in Table 7.
Table 7: Pharmacokinetic Parameters of Relugolix, Unconjugated Estradiol, and Norethindrone After Single Dose Administration of MYFEMBREE
|
Relugolix |
Unconjugated Estradiol |
Norethindrone |
||
| AUC0-inf (ng·hr/mL or pg·hr/mL), mean (SD) | 198.1 (111.6) |
818.7 (334.4) |
17.5 (8.5) |
|
| Cmax (ng/mL or pg/mL), mean (SD) | 26.0 (18.2) |
28.0 (19.2) |
3.6 (1.4) |
|
| Tmax (hr), median (min, max) | 2.00 (0.25, 5.00) |
7.00 (0.25, 24.00) |
1.0 (0.50, 4.00) |
|
|
Abbreviations: AUC = area under the concentration-time curve; AUC0-inf = AUC from time 0 extrapolated to infinity; Cmax = maximum observed concentration; E2 = estradiol; NET = norethindrone; Tmax = time to maximum observed concentration. Notes: AUC0-inf is presented in ng·hr/mL for relugolix, NET and in pg·hr/mL for unconjugated E2. Cmax is presented in ng/mL for relugolix, NET and in pg/mL for unconjugated E2. |
||||
Relugolix exhibits greater than dose-proportional exposures at doses ranging from 1 mg to 80 mg (0.025 to 2 times the approved recommended dose) and approximately dose-proportional exposures at doses ranging from 80 mg to 360 mg (2 to 9 times the approved recommended dose). Relugolix concentrations reach steady-state within 12 days, and the degree of accumulation is approximately 2-fold, upon once daily administration.
Estradiol and norethindrone concentrations reach steady-state within 2 weeks, with an accumulation of 33% to 47% above concentrations seen after administration of a single dose, upon once daily administration.
Absorption
The mean (%CV) absolute bioavailability of relugolix is 12% (62%).
Effect of Food
The AUC0-inf and Cmax of relugolix decreased by 38% and 55%, respectively, after administration of MYFEMBREE following consumption of a high-fat, high-calorie meal (i.e., 800-1000 calorie meal in which 50% of calories are derived from fat) compared with the fasted state; however, the decrease in exposure to relugolix is considered not to be clinically meaningful. No clinically meaningful effects of food on the exposure to estradiol or norethindrone were observed.
Distribution
Plasma protein binding of relugolix is 68% to 71%, primarily to albumin and to a lesser extent to α1-acid glycoprotein. The mean blood-to-plasma ratio is 0.78. Estradiol circulates in the blood bound to SHBG (36% to 37%) and to albumin (61%), while only approximately 1% to 2% is unbound. Norethindrone also binds to a similar extent to SHBG (36%) and to albumin (61%).
Elimination
After administration of a single dose of MYFEMBREE, the mean (SD) terminal phase elimination half-life (t1/2) of relugolix, estradiol, and norethindrone are 61.5 (13.2) hours, 16.6 (7.7) hours, and 10.9 (3.1) hours, respectively.
Metabolism
Relugolix is metabolized primarily by CYP3A and to a lesser extent by CYP2C8 in vitro.
Estradiol is converted reversibly to estrone, and both can be converted to estriol, which is a major urinary metabolite. Estrogens also undergo enterohepatic recirculation due to sulfate and glucuronide conjugation in the liver, biliary secretion of conjugates into the intestine, and hydrolysis in the intestine followed by reabsorption.
Norethindrone undergoes extensive biotransformation, primarily by reduction, in addition to sulfation, glucuronidation, and oxidation, respectively, by sulfotransferases (SULTs), glucuronosyltransferases (UGTs), and CYP enzymes, including CYP3A4. The majority of metabolites in the circulation are sulfates, with glucuronides accounting for most of the urinary metabolites.
Excretion
After oral administration of a single 80 mg radiolabeled dose of relugolix, approximately 81% of the radioactivity was recovered in feces (4.2% as unchanged) and 4.1% in urine (2.2% as unchanged).
Estradiol is excreted in the urine as glucuronide and sulfate conjugates. Norethindrone is primarily excreted in urine as various polar metabolites.
No clinically significant differences in the pharmacokinetics of relugolix were observed based on age (19 to 53 years), race/ethnicity (Asian [49%], White [24%], Black/African American [24%]), body weight (38 to 144 kg), mild to severe renal impairment (creatinine clearance [CLcr] 15 to 89 mL/min, as estimated by the Cockcroft-Gault equation), or mild or moderate hepatic impairment (Child-Pugh A or B). The effects of severe hepatic impairment (Child-Pugh C) or end-stage renal disease with or without hemodialysis on the pharmacokinetics of relugolix have not been studied.
The effects of renal or hepatic impairment on the pharmacokinetics of estradiol or norethindrone have not been studied. However, estradiol blood concentrations are expected to be increased in patients with hepatic impairment compared to patients with normal hepatic function.
Clinical Studies
Combined P-gp and Moderate CYP3A Inhibitor: Co-administration of MYFEMBREE with erythromycin (P-gp and moderate CYP3A inhibitor) increased the AUC and Cmax of relugolix by 4.1-fold and 3.8- fold, respectively. No clinically meaningful differences in the pharmacokinetics of unconjugated estradiol, total estrone, unconjugated estrone, and norethindrone were observed.
Advise the patient to read the FDA-approved patient labeling (Patient Information).
Advise patients that use of estrogen and progestin combinations may increase the risk of venous and arterial thrombotic/thromboembolic events, especially in women at high risk for these events [see Boxed Warning, Contraindications (4) and Warnings and Precautions (5.1)].
Advise patients about the risk of bone loss. Advise patients that supplementary calcium and vitamin D may be beneficial if dietary intake of calcium and vitamin D is not adequate. Advise women that oral iron supplementation should not be taken at the same time as calcium and vitamin D [see Warnings and Precautions (5.2) and Adverse Reactions (6.1)].
Advise patients that depression, mood disorders, and suicidal ideation may occur with MYFEMBREE use. Instruct women with new onset or worsening depression, anxiety, or other mood changes to promptly seek medical attention [see Warnings and Precautions (5.4) and Adverse Reactions (6.1)].
Advise women to promptly seek medical attention in case of signs or symptoms that may reflect liver injury, such as jaundice [see Warnings and Precautions (5.5)].
Advise patients that MYFEMBREE may delay the recognition of pregnancy because it may reduce the duration and amount of menstrual bleeding. Advise patients to use effective nonhormonal contraception while taking MYFEMBREE and to discontinue MYFEMBREE if pregnancy is diagnosed [see Warnings and Precautions (5.8)]. Advise pregnant patients that there is a pregnancy registry that monitors pregnancy outcomes in women exposed to MYFEMBREE during pregnancy [see Use in Specific Populations (8.1, 8.3)].
Advise women with uterine fibroids that alopecia, hair loss, and hair thinning in no specific pattern may occur with MYFEMBREE. Advise these women that hair loss and hair thinning may not resolve completely after stopping MYFEMBREE. Advise these women to contact their healthcare provider if they have concerns about changes to their hair [see Warnings and Precautions (5.11) and Adverse Reactions (6.1)].
Advise women to use effective non-hormonal contraception while taking MYFEMBREE and for one week after discontinuing treatment and to discontinue MYFEMBREE if pregnancy is confirmed. Advise pregnant patients that there is a pregnancy registry that monitors pregnancy outcomes in women exposed to MYFEMBREE during pregnancy [see Use in Specific Populations (8.1, 8.3)].
Advise women to report their use of any other prescription or nonprescription medications or dietary supplements. Co-administration with certain drugs may decrease the therapeutic effects of MYFEMBREE [see Drug Interactions (7.1)].
