Myfembree (relugolix, estradiol, and norethindrone acetate) - 2 indications

Scroll down for more information on each indication:

• for the management of heavy menstrual bleeding associated with uterine fibroids premenopausal women; approved May of 2021 
• for the management of moderate to severe pain associated with endometriosis in premenopausal women; approved August of 2022

General Information

Myfembree is a combination of relugolix, a gonadotropin-releasing hormone (GnRH) receptor antagonist, estradiol, an estrogen, and norethindrone acetate, a progestin.

Myfembree is specifically indicated for:

• the management of heavy menstrual bleeding associated with uterine leiomyomas (fibroids) in premenopausal women
• the management of moderate to severe pain associated with endometriosis in premenopausal women

Myfembree is supplied as a tablet for oral administration. Exclude pregnancy and discontinue hormonal contraceptives prior to initiating Myfembree. Take one tablet orally once daily at approximately the same time, with or without food. Start Myfembree as early as possible after the onset of menses but no later than seven days after menses has started. The recommended total duration of treatment with Myfembree is 24 months

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.

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.

Side Effects

In women with heavy menstrual bleeding associated with uterine fibroids, adverse reactions may include, but are not limited to, the following:

• vasomotor symptoms
• uterine bleeding
• alopecia
• decreased libido

In women with moderate to severe pain associated with endometriosis, adverse reactions may include, but are not limited to, the following:

• headache
• vasomotor symptoms
• mood disorders
• abnormal uterine bleeding
• nausea
• toothache
• back pain
• decreased sexual desire and arousal
• arthralgia
• fatigue
• dizziness

The Myfembree drug label comes with the following Black Box 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.

Indication 1 - the management of heavy menstrual bleeding associated with uterine leiomyomas (fibroids) in premenopausal women

Approved May of 2021

Clinical Trial Results

The FDA approval of Myfembree was based on 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. Th 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. In 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.

Indication 2 - the management of moderate to severe pain associated with endometriosis in premenopausal women

Approved August of 2022

Clinical Trial Results

FDA approval was based on one-year efficacy and safety data, including 24-week data from the Phase 3 SPIRIT 1 and SPIRIT 2 trials in over 1,200 women. SPIRIT 1 and 2 each met their co-primary endpoints with 75% of women in the Myfembree group in both studies achieving a clinically meaningful reduction in dysmenorrhea compared with 27% and 30% of women in the placebo groups at Week 24, respectively. For non-menstrual pelvic pain, treatment with Myfembree demonstrated a clinically meaningful reduction in pain in 59% and 66% of women, compared with 40% and 43% of women in the placebo groups. The open-label extension study for eligible women who completed either SPIRIT 1 or SPIRIT 2 showed mean bone mineral density loss of less than 1% from baseline through one year of treatment; some patients (19.7%) had losses >3%.