ESTRADIOL/ NORETHINDRONE/ RELUGOLIX TAB
Clinical Criteria Summary
Document 338: Contraceptive Agents Hormonal on VA National Formulary
Criteria for Monophasic Oral Contraceptive Pills
- 20 mcg Ethinyl Estradiol (EE) Combinations: Drospirenone 3 mg; Levonorgestrel 0.1 mg; Norethindrone 1 mg. Regimen: 21 active pills; 7 inert pills.
- 30 mcg EE Combinations: Desogestrel 0.15 mg; Drospirenone 3 mg; Levonorgestrel 0.15 mg; Norethindrone 1.5 mg; Norethindrone 1 mg; Norgestimate 0.25 mg. Regimen: 21 active pills; 7 inert pills.
- 35 mcg EE Combinations: Levonorgestrel 0.05/0.075/0.125 mg; Norethindrone 0.5/0.75/1 mg; Norgestimate 0.18/0.215/0.25 mg. Regimen: 21 active pills; 7 inert pills.
Criteria for Triphasic Oral Contraceptive Pills
- Contains varying doses of levonorgestrel, norethindrone, or norgestimate across the cycle.
- Regimen: 21 active pills; 7 inert pills.
Criteria for Extended Cycle Oral Contraceptive Pills
- Levonorgestrel 0.15 mg with 30 mcg EE.
- Regimen: 84 active pills; 7 inert pills.
Criteria for Progestin-Only Oral Contraceptive Pills
- Norethindrone 0.35 mg.
- Regimen: Active pill daily continuously; no inert pills.
Criteria for Vaginal Ring
- Etonogestrel 15 mcg EE/day.
- Regimen: 1 ring inserted for 3 weeks, 1 week off.
Criteria for Transdermal Patch
- Norelgestromin 150 mcg/day with 35 mcg EE/day.
- Regimen: 1 patch weekly for 3 weeks, 1 week off.
Criteria for Injectable Contraceptives
- Intramuscular (IM): Medroxyprogesterone acetate 150 mg. Regimen: 1 injection Q3 months (13 weeks).
- Subcutaneous (SQ): Medroxyprogesterone acetate 104 mg. Regimen: 1 injection Q3 months (12 to 14 weeks).
Criteria for Emergency Contraception
- Levonorgestrel 1.5 mg or Ulipristal 30 mg.
- Regimen: 1 pill x1.
General Class-Wide Clinical Criteria & Formulary Guidance
- Highly effective in preventing pregnancy when used as directed, without significant differences between formulations.
- Combination agents differ mainly in strength of estrogen, type and strength of progestin, regimen, and route of administration.
- Nuisance side effects may be managed by adjusting the estrogen/progestin content or ratio.
- Progestin-only products may be considered for patients with contraindications to estrogen or a desire to avoid estrogen.
- Non-oral hormonal contraceptives (medroxyprogesterone depot injection, vaginal ring, transdermal patch, contraceptive implant) may be useful for patients with compliance issues who do not require daily dosing.
Prerequisites for 12-Month Dispensing of Contraceptive Agents
- Patient must be stable on the product for at least 3 months.
- Contraceptive must be on the Consolidated Mail Outpatient Pharmacy (CMOP) greater than 90-day supply list.
- Patient must accept the copay burden, if applicable.
Guidance for Self-Administration of Subcutaneous Depot Medroxyprogesterone Acetate (DMPA-SQ)
- Although package labeling states the product is intended for healthcare professional administration, self-administration is a safe and effective alternative.
- Self-administration may be offered in the context of shared decision making per CDC U.S. Selected Practice Recommendations.
Document 582: Relugolix Estradiol Norethindrone MYFEMBREE Endometriosis Criteria Mar 2024
Indication & Patient Population
- Diagnosis of endometriosis (clinical or surgical) in a premenopausal patient
- Prescribed by or in consultation with a VA/VA Community Care Gynecology or Women’s Health Provider
Exclusion Criteria
- High risk or history of arterial, venous thrombotic, or thromboembolic disorder
- Pregnancy
- Known osteoporosis
- Uncontrolled hypertension
- Current or history of breast cancer or other hormonally sensitive malignancies
- Known hepatic impairment or disease
- Undiagnosed abnormal uterine bleeding
- Concomitant use of hormonal contraceptives
- Concomitant use of P-glycoprotein (P-gp) inhibitors
- Concomitant use of combined P-gp and strong CYP3A inducers
- Any additional contraindication to receiving estrogen and/or progestin
- Known hypersensitivity to relugolix, estradiol, or norethindrone
Inclusion Criteria
- Contraindication, intolerance, or inadequate response to one alternative treatment (e.g., NSAID, estrogen-containing or progestin-only hormonal contraceptive)
- Assessed for history of suicidal ideation, depression, and mood disorders prior to starting treatment
- Assessed for risk of bone density loss
- Planned duration of treatment not to exceed a maximum of 24 months (due to risk for bone loss)
Additional Patient-Specific Requirements
- For patients who can become pregnant: Exclude pregnancy prior to receiving medication
- For patients who can become pregnant: Counseling provided on potential risks vs benefits of treatment and the use of effective nonhormonal contraception during therapy
Monitoring & Safety Requirements
- Monitor for mood changes and depressive symptoms after starting treatment
- Baseline DXA (dual-energy X-ray absorptiometry) and periodic follow-up during treatment recommended
- Consider risks and benefits of treatment in patients with history of low trauma fracture or risk factors for low bone density
- If concomitant use of P-gp inhibitors is unavoidable, take the interacting medication at least 6 hours after relugolix
Document 583: Relugolix Estradiol Norethindrone MYFEMBREE Fibroid Criteria Mar 2024
Indication
- Heavy Menstrual Bleeding Associated with Uterine Leiomyomas (Fibroids)
Exclusion Criteria
- High risk or history of arterial, venous thrombotic, or thromboembolic disorder
- Pregnancy
- Known osteoporosis
- Uncontrolled hypertension
- Current or history of breast cancer or other hormonally sensitive malignancies
- Known hepatic impairment or disease
- Undiagnosed abnormal uterine bleeding
- Concomitant use of hormonal contraceptives
- Concomitant use of P-glycoprotein (P-gp) inhibitors
- Concomitant use of combined P-gp and strong CYP3A inducers
- Any additional contraindication to receiving estrogen and/or progestin
- Known hypersensitivity to relugolix, estradiol, or norethindrone
Inclusion Criteria
- Prescribed by or in consultation with a VA/VA Community Care Gynecology or Women’s Health Provider
- Confirmed diagnosis of uterine leiomyoma and heavy menstrual bleeding in a premenopausal patient
- Contraindication, intolerance, or inadequate response to one alternative treatment (e.g., estrogen-progestin hormonal contraceptives, progestin-only contraceptives, tranexamic acid, etc.)
Monitoring & Duration Requirements
- Assessed for history of suicidal ideation, depression, and mood disorders prior to starting treatment
- Assessed for risk of bone density loss
- Planned duration of treatment not to exceed a maximum of 24 months (due to risk for bone loss)
- Baseline DXA (dual-energy X-ray absorptiometry) and periodic follow-up during treatment recommended; consider risks and benefits in patients with history of low trauma fracture or risk factors for low bone density
- Monitor for mood changes and depressive symptoms after starting treatment
Counseling & Safety Precautions
- For patients who can become pregnant: Exclude pregnancy prior to receiving REN
- For patients who can become pregnant: Counseling provided on potential risks vs benefits of treatment and the use of effective nonhormonal contraception during therapy
- If concomitant P-gp inhibitor use is unavoidable, take the interacting medication at least 6 hours after REN
Document 591: MON Relugolix Estradiol Norethindrone MYFEMBREE Monograph Mar 2024
Indications
- Management of heavy menstrual bleeding (HMB) associated with uterine leiomyomas (fibroids) in premenopausal women
- Management of moderate to severe pain associated with endometriosis in premenopausal women
Patient Population
- Premenopausal women
Dosing & Administration
- Fixed-dose combination oral tablet containing 40 mg relugolix, 1 mg estradiol, and 0.5 mg norethindrone acetate
- One tablet orally daily at the same time each day
- Initiate as soon as possible and within 7 days after the start of menses
- Treatment duration limited to 24 months due to risk of bone loss that may not be reversible
Contraindications
- Pregnancy
- Known osteoporosis
- Known hepatic impairment or hepatic disease
- High risk of arterial, venous thrombotic, or thromboembolic disorder
- Current or history of breast cancer or other hormone-sensitive malignancies
- Undiagnosed abnormal uterine bleeding
- Known hypersensitivity to ingredients
- Uncontrolled hypertension
Monitoring & Precautions
- Exclude pregnancy prior to starting treatment; discontinue hormonal contraceptives before initiation
- Perform pregnancy testing during treatment if pregnancy is suspected; discontinue if confirmed
- Advise use of effective non-hormonal contraception during treatment and for one week after discontinuation
- Avoid concomitant use of estrogen-containing hormonal contraceptives
- Baseline assessment of bone mineral density (BMD) by DXA recommended; follow-up DXA annually during treatment for endometriosis and periodically during treatment for fibroids
- Monitor blood pressure; contraindicated in uncontrolled hypertension, monitor in patients with controlled hypertension
- Evaluate patients with history of mood disorders and/or suicidal ideation before initiating; monitor for mood changes and depressive symptoms after initiation
- Advise women with submucosal uterine fibroids about possible prolapse or expulsion; seek medical attention for severe bleeding or cramping
- Consider discontinuation if hair loss (alopecia) becomes a concern
- Monitor for risk of early pregnancy loss, vasomotor symptoms (hot flushes), mood disorders including depression and suicidal ideation, hypertension, abdominal pain, decreased libido, abnormal uterine bleeding, nausea, and hypersensitivity reactions (anaphylactoid reactions, urticaria, angioedema)
Source Documents
Document 338: Contraceptive Agents Hormonal on VA National Formulary
Document 582: Relugolix Estradiol Norethindrone MYFEMBREE Endometriosis Criteria Mar 2024
Document 583: Relugolix Estradiol Norethindrone MYFEMBREE Fibroid Criteria Mar 2024
Document 591: MON Relugolix Estradiol Norethindrone MYFEMBREE Monograph Mar 2024