Registrants1
Companies and organizations registered with the FDA for this drug approval, including their contact information and regulatory details.
480146015
Products1
Detailed information about drug products covered under this FDA approval, including NDC codes, dosage forms, ingredients, and administration routes.
Myfembree
Product Details
Drug Labeling Information
Complete FDA-approved labeling information including indications, dosage, warnings, contraindications, and other essential prescribing details.
PACKAGE LABEL.PRINCIPAL DISPLAY PANEL
PRINCIPAL DISPLAY PANEL - 28 Tablet Bottle Label
NDC 72974-415-01
Rx only
Myfembree ®
(relugolix, estradiol, and
norethindrone acetate) tablets
40 mg, 1 mg, 0.5 mg
28 tablets
CLINICAL PHARMACOLOGY SECTION
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
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.
12.2 Pharmacodynamics
Estradiol and norethindrone acetate (components of MYFEMBREE) may have the following effects:
- Increased thyroxin-binding globulin levels leading to [see Warnings and Precautions (5.13)]:
- Increased circulating total thyroid hormone concentrations as measured by protein-bound iodine (PBI), thyroxine (T4) levels (by column or by radioimmunoassay), or triiodothyronine (T3) concentrations by radioimmunoassay
- Decreased T3 resin uptake
- Unaltered free T4 and free T3 concentrations in women with normal thyroid function [see Warnings and Precautions (5.13)].
- Elevated corticosteroid-binding globulin (CBG) and sex hormone-binding globulin (SHBG) concentrations leading to increases in total circulating corticosteroid and sex hormone concentrations, respectively [see Warnings and Precautions (5.13)] .
- Possible decreased free testosterone concentrations.
- Possible increased other plasma proteins concentrations (angiotensinogen/renin substrate, alpha-1 antitrypsin, ceruloplasmin).
- Increased plasma high-density lipoprotein (HDL) and HDL2 cholesterol subfraction concentration, reduced low-density lipoprotein concentration, increased triglyceride concentrations.
- Accelerated prothrombin time, partial thromboplastin time, and platelet aggregation time; increased platelet count; increased factors II, VII antigen, VIII coagulant activity, IX, X, XII, VII-X complex, and beta-thromboglobulin; decreased concentrations of anti-factor Xa and antithrombin III, decreased antithrombin III activity, increased concentrations of fibrinogen and fibrinogen activity; increased plasminogen antigen and activity.
Cardiac Electrophysiology
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.
12.3 Pharmacokinetics
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 | |
|---|---|---|---|
|
Abbreviations: AUC = area under the concentration-time curve; AUC 0-inf= AUC from time 0 extrapolated to infinity; C max= maximum observed concentration; E2 = estradiol; NET = norethindrone; T max= time to maximum observed concentration. | |||
|
Notes: AUC 0-infis presented in ng∙hr/mL for relugolix, NET and in pg∙hr/mL for unconjugated E2. C maxis presented in ng/mL for relugolix, NET and in pg/mL for unconjugated E2. | |||
|
AUC 0-inf(ng∙hr/mL or pg∙hr/mL), mean (SD) |
198.1 |
818.7 |
17.5 |
|
C max(ng/mL or pg/mL), mean (SD) |
26.0 |
28.0 |
3.6 |
|
T max(hr), median (min, max) |
2.00 |
7.00 |
1.0 |
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 AUC 0-infand C maxof 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 α 1-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 (t 1/2) 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.
Specific Populations
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.
Drug Interaction Studies
Clinical Studies
- Combined P-gp and Moderate CYP3A Inhibitor:Co-administration with erythromycin (P-gp and moderate CYP3A inhibitor) increased the AUC and C maxof relugolix by 6.2-fold.
- Combined P-gp and Strong CYP3A Inducer:Co-administration with rifampin (P-gp and strong CYP3A inducer) decreased the AUC and C maxof relugolix by 55% and 23%, respectively.
- Other Drugs:No clinically significant differences in the pharmacokinetics of relugolix were observed when co-administered with voriconazole (strong CYP3A inhibitor), fluconazole (moderate CYP3A inhibitor), or atorvastatin (weak CYP3A inhibitor). No clinically significant differences in the pharmacokinetics of midazolam (sensitive CYP3A substrate) or rosuvastatin (BCRP substrate) were observed upon co-administration with relugolix.
In Vitro Studies
- Cytochrome P450 (CYP) Enzymes: Relugolix is a substrate of CYP3A and CYP2C8. Relugolix is an inducer of CYP3A and CYP2B6, but not an inducer of CYP1A2. Relugolix is not an inhibitor of CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, or CYP3A4.
- Transporter Systems:Relugolix is a substrate of P-gp, but not a substrate of BCRP. Relugolix is an inhibitor of BCRP and P-gp, but not an inhibitor of OATP1B1, OATP1B3, OAT1, OAT3, OCT2, MATE1, MATE2-K, or BSEP.
INDICATIONS & USAGE SECTION
Highlight: 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)
- management of moderate to severe pain associated with endometriosis. ( 1.2)
Limitations of Use
Use of MYFEMBREE should be limited to 24 months due to the risk of continued bone loss which may not be reversible .( 1.3, 5.2, 6)
1 INDICATIONS AND USAGE
1.1 Heavy Menstrual Bleeding Associated with Uterine Leiomyomas
MYFEMBREE is indicated for the management of heavy menstrual bleeding associated with uterine leiomyomas (fibroids) in premenopausal women.
1.2 Moderate to Severe Pain Associated with Endometriosis
MYFEMBREE is indicated for the management of moderate to severe pain associated with endometriosis in premenopausal women.
1.3 Limitations of Use
Use of MYFEMBREE should be limited to 24 months due to the risk of continued bone loss that may not be reversible [see Warnings and Precautions (5.2)].
WARNINGS AND PRECAUTIONS SECTION
Highlight: * Thromboembolic Disorders and Vascular Events: Discontinue MYFEMBREE if an arterial or venous thrombotic, cardiovascular, or cerebrovascular event occurs. Discontinue MYFEMBREE if there is sudden unexplained partial or complete loss of vision, proptosis, diplopia, papilledema, or retinal vascular lesions and evaluate for retinal vein thrombosis immediately. ( 5.1)
- Bone Loss: Decreases in bone mineral density (BMD) may not be completely reversible. Baseline BMD assessment is recommended in all women. In women with heavy menstrual bleeding associated with uterine fibroids, periodic BMD assessments are recommended. In women with moderate to severe pain associated with endometriosis, annual BMD assessments are recommended. Assess risk-benefit for women with additional risk factors for bone loss. ( 5.2)
- Suicidal Ideation and Mood Disorders (Including Depression): Advise patients to seek medical attention for new onset or worsening depression, anxiety, or other mood changes. ( 5.4)
- Hepatic Impairment and Transaminase Elevations: Counsel patients on signs and symptoms of liver injury. ( 5.5)
- Elevated Blood Pressure: Do not use in women with uncontrolled hypertension. For women with well-controlled hypertension, continue to monitor blood pressure and stop MYFEMBREE if blood pressure rises significantly. ( 5.7)
- Change in Menstrual Bleeding Pattern and Reduced Ability to Recognize Pregnancy: Advise women to use non-hormonal contraception during treatment and for one week after discontinuing MYFEMBREE. MYFEMBREE may delay the ability to recognize pregnancy because it alters menstrual bleeding. Perform testing if pregnancy is suspected and discontinue MYFEMBREE if pregnancy is confirmed. ( 5.8)
- Risk of Early Pregnancy Loss: Can cause early pregnancy loss. Advise women to use effective non-hormonal contraception. ( 5.9)
- Uterine Fibroid Prolapse or Expulsion: Advise patients to seek medical attention for severe uterine bleeding. ( 5.10)
- Hypersensitivity Reactions: Immediately discontinue MYFEMBREE if a hypersensitivity reaction occurs. ( 5.14)
5 WARNINGS AND PRECAUTIONS
5.1 Thromboembolic Disorders and Vascular Events
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.
5.2 Bone Loss
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.
5.3 Hormone-Sensitive Malignancies
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.
5.4 Suicidal Ideation and Mood Disorders (Including Depression)
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)] .
5.5 Hepatic Impairment and Transaminase Elevations
Contraindication in Patients with Hepatic Impairment
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)].
Transaminase Elevations
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.
5.6 Gallbladder Disease or History of Cholestatic Jaundice
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.
5.7 Elevated Blood Pressure
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%).
5.8 Change in Menstrual Bleeding Pattern and Reduced Ability to Recognize
Pregnancy
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)].
5.9 Risk of Early Pregnancy Loss
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)].
5.10 Uterine Fibroid Prolapse or Expulsion
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)] .
5.11 Alopecia
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)] .
5.12 Effects on Carbohydrate and Lipid Metabolism
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)] .
5.13 Effect on Other Laboratory Results
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)].
5.14 Hypersensitivity Reactions
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.
NONCLINICAL TOXICOLOGY SECTION
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenesis
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.
Mutagenesis
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.
Impairment of Fertility
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).
13.2 Animal Toxicology and/or Pharmacology
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 39-week 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.
INFORMATION FOR PATIENTS SECTION
17 PATIENT COUNSELING INFORMATION
Advise the patient to read the FDA-approved patient labeling (Patient Information).
Thromboembolic Disorders and Vascular Events
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)] .
Bone Loss
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)].
Suicidal Ideation and Mood Disorders (Including Depression)
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)].
Hepatic Impairment and Transaminase Elevations
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)] .
Change in Menstrual Bleeding Pattern and Reduced Ability to Recognize Pregnancy
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 non-hormonal 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)].
Alopecia
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)] .
Females of Reproductive Potential
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)].
Drug Interactions
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)].
Administration Instructions
- Advise women to begin taking MYFEMBREE as soon as possible after the start of menses but no later than 7 days after menses has started [see Dosage and Administration (2.2)].
- Advise women to take any missed dose of MYFEMBREE as soon as possible the same day and then resume regular dosing the next day at the usual time [see Dosage and Administration (2.3)].
- Advise women taking oral P-gp inhibitors to take MYFEMBREE first and separate dosing by at least 6 hours [see Dosage and Administration (2.4)].
SPL PATIENT PACKAGE INSERT SECTION
|
PATIENT INFORMATION | |
|---|---|
|
This Patient Package Insert has been approved by the U.S. Food and Drug Administration |
Approved: 08/2023 |
|
What is the most important information I should know about MYFEMBREE? *cardiovascular conditions * MYFEMBREE may increase your chances of heart attack, stroke, or blood clots, especially if you are over 35 years of age, smoke, and have uncontrolled high blood pressure.Stop taking MYFEMBREE and call your healthcare provider right away or go to the nearest hospital emergency room right away if you have: * leg pain or swelling that will not go away * sudden shortness of breath * double vision, bulging of the eyes, or sudden blindness, partial or complete * pain or pressure in your chest, arm, or jaw * sudden, severe headache unlike your usual headaches * weakness or numbness in an arm or leg, or trouble speaking *bone loss (decreased bone mineral density) * While you are taking MYFEMBREE, your estrogen levels may be low. Low estrogen levels can lead to bone mineral density loss. * If you have bone loss on MYFEMBREE, your bone density may improve after you stop taking MYFEMBREE, but complete recovery may not occur. It is unknown if these bone changes could increase your risk for broken bones as you age. For this reason,you should not take MYFEMBREE for more than 24 months. * Your healthcare provider may order an X-ray test called a DXA scan to check your bone mineral density when you start taking MYFEMBREE and periodically after you start if you have uterine fibroids or annually if you have pain associated with endometriosis. * Your healthcare provider may advise you to take vitamin D and/or calcium supplements as part of a healthy lifestyle that promotes bone health. If you are also advised to take iron supplements, they should be taken at least two hours apart from your vitamin D or calcium supplements. *effects on pregnancy *Do not takeMYFEMBREE if you are trying to become pregnant or are pregnant. It may increase the risk of early pregnancy loss. *If you think you are pregnant, stop taking MYFEMBREE right away and call your healthcare provider. * If you become pregnant while taking MYFEMBREE, you are encouraged to enroll in the Pregnancy Registry. The purpose of the pregnancy registry is to collect information about the health of you and your baby. Talk to your healthcare provider or call 1-(855) 428-0707. * MYFEMBREE can decrease your menstrual bleeding or result in no menstrual bleeding at all, making it hard to know if you are pregnant. Watch for other signs of pregnancy such as breast tenderness, weight gain and nausea. * MYFEMBREE does not prevent pregnancy. You will need to use effective methods of birth control while taking MYFEMBREE and for 1 week after you stop taking MYFEMBREE. Examples of effective methods can include condoms or spermicide, which do not contain hormones. * Do not take hormonal birth control such as birth control pills because they may increase your side effects and MYFEMBREE may not work as well. * Talk to your healthcare provider about which birth control to use during treatment with MYFEMBREE. Your healthcare provider may change the birth control you were on before you start taking MYFEMBREE. | |
|
What is MYFEMBREE?
| |
|
Do not take MYFEMBREE if you:
| |
|
Before you take MYFEMBREE, tell your healthcare provider about all of your medical conditions including if you:
**Tell your healthcare provider about all the medicines you take,**including
prescription, over-the-counter medicines, vitamins, and herbal supplements. | |
|
How should I take MYFEMBREE?
| |
|
What are the possible side effects of MYFEMBREE? *See "What is the most important information I should know about MYFEMBREE?" *suicidal thoughts, suicidal behavior, and worsening of mood. Call your healthcare provider or get emergency medical help right away if you have any of these symptoms, especially if they are new, worse, or bother you: * thoughts about suicide or dying * attempts to commit suicide * new or worse depression * new or worse anxiety * other unusual changes in behavior or mood Pay attention to any changes, especially sudden changes in your mood, behaviors, thoughts, or feelings. *abnormal liver tests. Call your healthcare provider right away if you have any of these signs and symptoms of liver problems: * jaundice * dark, amber-colored urine * feeling tired (fatigue or exhaustion) * nausea and vomiting * generalized swelling * right upper stomach area (abdomen) pain * bruising easily *gallbladder problems(cholestasis), especially if you had cholestasis of pregnancy. ***high blood pressure.**See your healthcare provider to check your blood pressure regularly. ***uterine fibroid prolapse or expulsion.**Fibroids can come out completely or partially through the vagina. Call your healthcare provider right away if you have increased bleeding from the vagina, which can be serious, or cramping, while taking MYFEMBREE. ***hair loss (alopecia).**In women with uterine fibroids, hair loss and hair thinning can happen while taking MYFEMBREE. It is not known if this hair loss or hair thinning stops after you stop taking MYFEMBREE or is reversible. Talk to your healthcare provider if this is a concern for you. *increases in the blood sugar, cholesterol and fat (triglycerides) levels in your blood. *changes in laboratory testsincluding thyroid, steroid, hormone, cholesterol, and blood clotting tests. The most common side effects of MYFEMBREE in women that have heavy bleeding with uterine fibroids include:
The most common side effects of MYFEMBREE in women that have moderate to severe pain with endometriosis include:
These are not all the possible side effects of MYFEMBREE. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. | |
|
How should I store MYFEMBREE?
| |
|
General information about the safe and effective use of MYFEMBREE. | |
|
What are the ingredients of MYFEMBREE? |
214846 MS 003
HOW SUPPLIED SECTION
16 HOW SUPPLIED/STORAGE AND HANDLING
16.1 How Supplied
MYFEMBREE film-coated tablets contain relugolix 40 mg, estradiol (E2) 1 mg, and norethindrone acetate (NETA) 0.5 mg. The tablets are light yellow to yellow, round film-coated tablet with "MVT" on one side and "415" on the other side.
MYFEMBREE is supplied in a white, opaque, high-density polyethylene bottle containing 28 tablets with desiccant and closed with an induction-sealed child-resistant cap (NDC Code 72974-415-01).
16.2 Storage and Handling
Store at 15°C to 30°C (59°F to 86°F).
Dispose unused medication via a take-back option if available. Otherwise, follow FDA instructions for disposing medication in the household trash, www.fda.gov/drugdisposal. Do NOT flush down the toilet.