Applies to estradiol / norethindrone / relugolix: oral tablet.

Serious side effects

Along with its needed effects, estradiol / norethindrone / relugolix may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor immediately if any of the following side effects occur while taking estradiol / norethindrone / relugolix:

More common

• Heavy non-menstrual vaginal bleeding
• longer or heavier menstrual periods
• normal menstrual bleeding occurring earlier, possibly lasting longer than expected
• unusually heavy or unexpected menstrual bleeding
• vaginal bleeding or spotting

Less common

• Anxiety
• discouragement
• feeling sad or empty
• hair loss, thinning of hair
• irritability
• lack of appetite
• loss of interest or pleasure
• mood swings
• trouble concentrating
• trouble sleeping
• unusual tiredness or weakness

Rare

• Pelvic pain
• stomach pain, bloating

Incidence not known

• Blurred vision
• chest pain or tightness
• chills
• clay-colored stools
• cough
• dark urine
• diarrhea
• dizziness or lightheadedness
• dry mouth
• fainting
• fast heartbeat
• fever
• fruit-like breath odor
• headache
• hives, itching
• increased hunger
• increased thirst
• increased urination
• loss of appetite
• loss of consciousness
• nausea and vomiting
• puffiness or swelling of the eyelids or around the eyes, face, lips, or tongue
• skin rash
• trouble breathing
• unexplained weight loss
• unpleasant breath odor
• vomiting of blood
• yellow eyes or skin

Other side effects

Some side effects of estradiol / norethindrone / relugolix may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects.

Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

More common

• Feeling of warmth
• increased sweating
• night sweats
• redness of the face, neck, arms, and occasionally, upper chest
• toothache

Less common

• Back pain
• decreased interest in sexual intercourse
• difficulty in moving
• inability to have or keep an erection
• joint pain
• loss in sexual ability, desire, drive, or performance
• muscle pain or stiffness

For Healthcare Professionals

Applies to estradiol / norethindrone / relugolix: oral tablet.

General

The most common adverse reactions have included hot flush, uterine bleeding, hyperhidrosis, night sweats, alopecia, and decreased libido.^[Ref]

Genitourinary

Very common (10% or more): Posttherapy resumption of menstruation (up to 100%)

Common (1% to 10%): Uterine bleeding/abnormal uterine bleeding (included menorrhagia, metrorrhagia, vaginal hemorrhage, polymenorrhea, menstruation irregular)

Uncommon (0.1% to 1%): Uterine myoma expulsion, uterine leiomyoma (prolapse), pelvic pain

Relugolix:

-Postmarketing reports: Uterine leiomyoma degeneration^[Ref]

Musculoskeletal

Very common (10% or more): Decline in lumbar spine bone mineral density (BMD; up to 23%)

Uncommon (0.1% to 1%): Low trauma fractures

Frequency not reported: Bone loss^[Ref]

In clinical trials, women treated with this drug for up to 52 weeks had a decline in lumbar spine BMD of 0.8%. A decline in lumbar spine BMD of greater than 3% was observed in 23% (30/132) of women who had a dual-energy x-ray absorptiometry (DXA) scan after 12 months of therapy with this drug and in 17.4% (37/213) of untreated women. A decline of greater than 8% was seen in 0.8% (1/132) of women receiving this drug who completed a DXA scan at 12 months and in 0.9% (2/213) of untreated women.^[Ref]

Other

For women with normal total cholesterol (less than 200 mg/dL) at baseline, increases to 200 to 240 mg/dL and increases to greater than 240 mg/dL were seen in 13.7% and 1.7% of patients treated with this drug, respectively. For women with LDL cholesterol less than 130 mg/dL at baseline, increases to 130 to less than 160 mg/dL, 160 to less than 190 mg/dL, and at least 190 mg/dL were seen in 9.3%, 1.5%, and 0.5% of women treated with this drug, respectively.^[Ref]

Very common (10% or more): Increased total cholesterol (up to 13.7%)

Common (1% to 10%): Increased low-density lipoprotein (LDL) cholesterol, breast cyst^[Ref]

Cardiovascular

In clinical trials in 1066 women treated with this drug for another indication, 2 thromboembolic events (DVT and PE) occurred in 1 woman with risk factors of obesity and a preceding knee injury; 1 case was reported for a woman treated with relugolix monotherapy in the postmarketing period.^[Ref]

Common (1% to 10%): Hot flush, new/worsening hypertension

Rare (0.01% to 0.1%): Thromboembolic events (deep vein thrombosis [DVT], pulmonary embolism [PE])

Relugolix:

-Postmarketing reports: Thromboembolic event^[Ref]

Dermatologic

Common (1% to 10%): Alopecia/hair loss/hair thinning, hyperhidrosis, night sweats

Relugolix:

-Postmarketing reports: Drug eruption^[Ref]

Psychiatric

Common (1% to 10%): Decreased libido (included decreased libido, loss of libido), irritability, depression (included depression, mood swings, depressed mood), anxiety

Frequency not reported: Suicidal ideation, adverse mood changes^[Ref]

Gastrointestinal

Common (1% to 10%): Dyspepsia^[Ref]

Hepatic

Uncommon (0.1% to 1%): Elevated AST, elevated ALT, cholecystitis^[Ref]

In clinical trials, elevated AST (at least 3 times the upper limit of normal [3 x ULN]: 0.8%) and ALT (at least 3 x ULN: 0.4%) occurred in women treated with this drug.^[Ref]

Hypersensitivity

Frequency not reported: Anaphylactoid reactions

Relugolix:

-Postmarketing reports: Anaphylactoid reaction^[Ref]

Respiratory

Relugolix:

-Postmarketing reports: Pulmonary embolism^[Ref]