Myfembree - Drug Monograph

Introduction

Myfembree (relugolix 40 mg, estradiol 1 mg, and norethindrone acetate 0.5 mg) is a once-daily oral combination therapy approved for the management of heavy menstrual bleeding associated with uterine fibroids in premenopausal women. This triple-agent formulation represents a novel approach to fibroid management through simultaneous gonadotropin-releasing hormone (GnRH) receptor blockade and hormone replacement therapy.

Mechanism of Action

Myfembree combines three distinct pharmacological actions:

• Relugolix: A competitive GnRH receptor antagonist that rapidly suppresses pituitary gonadotropin secretion, leading to decreased ovarian production of estrogen and progesterone
• Estradiol: Mitigates hypoestrogenic symptoms associated with GnRH antagonism
• Norethindrone acetate: Provides endometrial protection and progestogenic activity

This combination results in controlled estrogen levels that reduce fibroid-related bleeding while minimizing vasomotor symptoms and bone mineral density loss associated with unopposed GnRH antagonism.

Indications

• Management of heavy menstrual bleeding associated with uterine fibroids in premenopausal women
• Treatment duration should be limited to 24 months due to bone density considerations

Dosage and Administration

• Standard dosage: One tablet orally once daily, with or without food
• Initiation: Begin therapy at any time, preferably when menstrual bleeding is occurring
• Duration: Limit treatment to 24 months
• Renal impairment: No dosage adjustment required for mild to moderate impairment (eGFR ≥30 mL/min/1.73 m²)
• Hepatic impairment: Not recommended in patients with moderate to severe impairment (Child-Pugh B or C)
• Missed dose: Take as soon as remembered unless almost time for next dose

Pharmacokinetics

• Absorption: Relugolix Tmax: 2-4 hours; Estradiol Tmax: 6-8 hours; Norethindrone acetate Tmax: 1-2 hours
• Distribution: All components highly protein-bound (>98%)
• Metabolism: Relugolix undergoes minimal metabolism; estradiol and norethindrone acetate undergo extensive hepatic metabolism via CYP3A4
• Elimination: Relugolix half-life: 22-25 hours; estradiol half-life: 12-20 hours; norethindrone acetate half-life: 8-11 hours
• Excretion: Primarily fecal (relugolix); urinary and fecal (estradiol and norethindrone metabolites)

Contraindications

• Pregnancy or suspected pregnancy
• Known osteoporosis
• Current or history of thrombosis or thromboembolic disorders
• Known hepatic impairment or disease
• Undiagnosed abnormal uterine bleeding
• Known hypersensitivity to any component
• Breast cancer or other hormone-sensitive malignancies

Warnings and Precautions

• Thromboembolic disorders: Increased risk of stroke, deep vein thrombosis, pulmonary embolism, and myocardial infarction
• Bone loss: Progressive loss of bone mineral density may occur; limit duration to 24 months
• Hormone-sensitive malignancies: May stimulate growth of undiagnosed hormone-sensitive tissues
• Cardiovascular risks: Carefully consider in women with cardiovascular risk factors
• Liver impairment: Discontinue if jaundice or acute liver disorder occurs
• Blood pressure monitoring: May increase blood pressure; monitor regularly
• Galactorrhea: May occur and persist after discontinuation
• Depression: Monitor patients with history of depression or mood disorders

Drug Interactions

• Strong CYP3A4 inducers (rifampin, carbamazepine, St. John's wort): May decrease efficacy
• Strong CYP3A4 inhibitors (ketoconazole, ritonavir): May increase relugolix concentrations
• P-glycoprotein inhibitors: May increase relugolix exposure
• Other hormone therapies: Avoid concomitant use
• Anticoagulants: Potential altered anticoagulant effect

Adverse Effects

• Hot flashes
• Headache
• Fatigue
• Hyperhidrosis- Constipation

• Alopecia
• Decreased libido
• Anxiety
• Arthralgia
• Depression
• Insomnia
• Nausea
• Weight gain

• Thromboembolic events
• Hepatic impairment
• Severe hypersensitivity reactions
• Significant bone mineral density loss

Monitoring Parameters

• Efficacy: Menstrual bleeding patterns, hemoglobin/hematocrit
• Safety:

- Bone mineral density at baseline and periodically (DEXA scan) - Liver function tests at baseline and as clinically indicated - Blood pressure regularly - Lipid profile periodically - Pregnancy testing before initiation

• Adverse effects: Regular assessment of vasomotor symptoms, mood changes, and thromboembolic symptoms

Patient Education

• Take one tablet daily at approximately the same time each day
• Use non-hormonal contraception during treatment and for one week after discontinuation
• Report immediately: severe headache, visual changes, chest pain, shortness of breath, leg pain or swelling
• Understand that treatment is temporary (up to 24 months) due to bone density concerns
• Regular follow-up with healthcare provider is essential
• Do not breastfeed while taking Myfembree
• Maintain adequate calcium and vitamin D intake
• Report any thoughts of depression or mood changes

References

1. FDA Prescribing Information: Myfembree (relugolix, estradiol, norethindrone acetate) tablets. 2021. 2. Al-Hendy A, et al. Treatment of uterine fibroid symptoms with relugolix combination therapy. N Engl J Med. 2021;384(7):630-642. 3. Archer DF, et al. Long-term relugolix combination therapy for uterine fibroids. Obstet Gynecol. 2022;139(2):183-194. 4. Stewart EA, et al. Safety and efficacy of relugolix combination therapy in uterine fibroids. Fertil Steril. 2022;117(3):597-606. 5. ClinicalTrials.gov: LIBERTY 1 and 2 trials (NCT03049735, NCT03103087).