Summary
Commonly reported side effects of estradiol/norethindrone include: asthenia, dysmenorrhea, menstrual disease, pharyngitis, vaginitis, back pain, and mastalgia. Other side effects include: nervousness. Continue reading for a comprehensive list of adverse effects.
Applies to estradiol / norethindrone: oral tablet. Other dosage forms:
- transdermal patch extended release
Warning
Oral route (Tablet)
Estrogen Plus Progestin TherapyCardiovascular Disorders and Probable DementiaThe Women’s Health Initiative (WHI) estrogen plus progestin substudy reported increased risks of deep vein thrombosis (DVT), pulmonary embolism (PE), stroke and myocardial infarction (MI) in postmenopausal women (50 to 79 years of age) during 5.6 years of treatment with daily oral conjugated estrogen (0.625 mg) combined with medroxyprogesterone acetate (2.5 mg), relative to placebo.The WHI Memory Study (WHIMS) estrogen plus progestin ancillary study of the WHI reported an increased risk of developing probable dementia in postmenopausal women 65 years of age or older during 4 years of treatment with daily conjugated estrogen (0.625 mg) combined with medroxyprogesterone acetate (2.5 mg), relative to placebo. It is unknown whether this finding applies to younger postmenopausal women.Do not use estrogen plus progestogen therapy for the prevention of cardiovascular disease or dementia.Breast CancerThe WHI estrogen plus progestin substudy also demonstrated an increased risk of invasive breast cancer.Only daily oral 0.625 mg CE and 2.5 mg MPA were studied in the estrogen plus progestin substudy of the WHI. Therefore the relevance of the WHI findings regarding adverse cardiovascular events, dementia and breast cancer to lower CE plus other MPA doses, other routes of administration, or other estrogen plus progestogen products is not know. Without such data, it is not possible to definitively exclude these risks or determine the extent of these risks for other products. Discuss with your patient the benefits and risks of estrogen plus progestogen therapy, taking into account her individual risk profile.Prescribe estrogens with or without progestogens at the lowest effective doses and for the shortest duration consistent with treatment goals and risks for the individual woman.Estrogen-Alone TherapyEndometrial CancerThere is an increased risk of endometrial cancer in a woman with a uterus who uses unopposed estrogens.Adding a progestogen to estrogen therapy has been shown to reduce the risk of endometrial hyperplasia, which may be a precursor to endometrial cancer.Adequate diagnostic measures, including directed or random endometrial sampling when indicated, should be undertaken to rule out malignancy in postmenopausal women with undiagnosed persistent or recurring abnormal genital bleeding. Cardiovascular Disorders and Probable DementiaThe WHI estrogen-alone substudy reported increased risks of stroke and DVT in postmenopausal women (50 to 79 years of age) during 7.1 years of treatment with daily oral conjugated estrogen (0.625 mg)-alone, relative to placebo.The WHIMS estrogen-alone ancillary study of the WHI reported an increased risk of developing probable dementia in postmenopausal women 65 years of age or older during 5.2 years of treatment with daily conjugated estrogen (0.625 mg)-alone, relative to placebo. It is unknown whether this finding applies to younger postmenopausal women.Do not use estrogen-alone therapy for the prevention of cardiovascular disease or dementia.Only daily oral 0.625 mg CE was studied in the estrogen-alone substudy of the WHI. Therefore, the relevance of the WHI findings adverse cardiovascular events and dementia to lower CE doses, other routes of administration, or other estrogen-alone products is not known. With out such data, it is not possible to definitively exclude these risks or determine the extent of these risks for other products. Discuss with your patient the benefits and risks of estrogen-alone therapy, taking into account her individual risk profile.Prescribe estrogens with or without progestogens at the lowest effective doses and for the shortest duration consistent with treatment goals and risks for the individual woman.
Serious side effects
Along with its needed effects, estradiol/norethindrone 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:
More common
- Body aches or pain
- chills or fever
- cold or flu-like symptoms
- difficulty breathing
- headache
- itching of the vagina or genital area
- non-menstrual vaginal bleeding
- pain during sexual intercourse
- thick, white vaginal discharge with no odor or with a mild odor
- unusual tiredness or weakness
Incidence not known
- Blistering, peeling, or loosening of the skin
- breast tenderness
- change in vaginal discharge
- change in vision
- chest pain, discomfort, or tightness
- clay-colored stools
- clear or bloody discharge from the nipple
- confusion
- dark urine
- difficulty speaking
- difficulty swallowing
- dizziness or lightheadedness
- double vision
- fainting
- fast heartbeat
- inability to move the arms, legs, or facial muscles
- inability to speak
- joint or muscle pain
- loss of appetite
- lump in the breast or under the arm
- nausea and vomiting
- noisy breathing
- pain in the ankles or knees
- pain or discomfort in the arms, jaw, back, or neck
- pain or feeling of pressure in the pelvis
- pain, redness, or swelling in the arm or leg
- painful, red lumps under the skin, mostly on the legs
- pains in the stomach, side, or abdomen, possibly radiating to the back
- problems with memory or speech
- puffiness or swelling of the eyelids or around the eyes, face, lips, or tongue
- red, irritated eyes
- redness or swelling of the breast
- skin rash, hives, or itching
- sores, ulcers, or white spots in the mouth or on the lips
- stomach pain
- sweating
- trouble breathing
- trouble recognizing objects
- trouble thinking and planning
- trouble walking
- unexpected or excess milk flow from the breasts
Other side effects
Some side effects of estradiol / norethindrone 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
- Back pain
- cramps
- crying
- euphoria
- mental depression
- paranoia
- quick to react or overreact emotionally
- rapidly changing moods
- trouble sleeping
- weakness
- weight gain
Incidence not known
- Changes in appetite
- changes in sexual ability, desire, drive, or performance
- excess air or gas in the stomach or intestines
- increased hair growth, especially on the face
- patchy brown or dark brown discoloration of the skin
- trouble wearing contact lenses
For Healthcare Professionals
Applies to estradiol / norethindrone: oral tablet, transdermal film extended release.
General
The most common adverse events were vaginal bleeding and breast pain/tenderness. Vaginal bleeding usually occurred in the first months of treatment. Breast pain usually disappeared after a few months of therapy.[Ref]
Genitourinary
Very common (10% or more): Vaginal hemorrhage (26%), breast pain (24%), post-menopausal bleeding (11%), endometrial thickening (10%), breast tenderness, menstruation irregular
Common (1% to 10%): Ovarian cyst, uterine fibroid, breast edema, breast enlargement, uterine fibroids aggravated, uterine fibroids recurrence, uterine fibroids
Uncommon (0.1% to 1%): Endometrial hyperplasia, dysmenorrhea
Rare (less than 0.1%): Fallopian tube cysts, endocervical polyps
Postmarketing reports: Changes in vaginal bleeding pattern and abnormal withdrawal bleeding or flow, breakthrough bleeding, spotting, increase in size of uterine leiomyomata, change in amount of cervical secretion, changes in cervical ectropion, pre-menstrual-like syndrome, cystitis-like syndrome, nipple discharge, galactorrhea, fibrocystic breast changes, vulvovaginal pruritus[Ref]
Nervous system
Very common (10% or more): Headache (22%)
Common (1% to 10%): Migraine or migraine aggravated, dizziness
Rare (less than 0.1%): Paresthesia
Postmarketing reports: Dizziness, exacerbation of epilepsy, dementia, chorea, stroke[Ref]
Cardiovascular
Common (1% to 10%): Blood pressure increase
Uncommon (0.1% to 1%): Thrombophlebitis superficial, venous thromboembolism
Rare (less than 0.1%): Thrombophlebitis deep, deep venous thromboembolism
Postmarketing reports: Deep and superficial vein thrombosis, thrombophlebitis, myocardial infarction, stroke, hypertension aggravated[Ref]
Gastrointestinal
Very common (10% or more): Nausea (11%)
Common (1% to 10%): Gastroenteritis, diarrhea, abdominal pain, abdominal distention, abdominal discomfort
Uncommon (0.1% to 1%): Flatulence, bloating
Postmarketing reports: Vomiting, abdominal cramps, pancreatitis, dyspepsia[Ref]
Psychiatric
Common (1% to 10%): Insomnia, emotional lability, depression or depression aggravated
Uncommon (0.1% to 1%): Nervousness, changes in libido
Postmarketing reports: Mental depression, mood disturbances, irritability, anxiety[Ref]
Other
Very common (10% or more): Accidental injury (17%)
Common (1% to 10%): Weight increase, weight decreased, edema peripheral, pain, asthenia
Uncommon (0.1% to 1%): Drug ineffective
Postmarketing reports: Fatigue, edema[Ref]
Musculoskeletal
Very common (10% or more): Back pain (10%)
Common (1% to 10%): Pain in extremity, leg cramps[Ref]
Immunologic
Very common (10% or more): Nasopharyngitis (21%), upper respiratory tract infection (18%), sinusitis (15%)
Common (1% to 10%): Infection viral, moniliasis genital, genital candidiasis or vaginitis[Ref]
Dermatologic
Common (1% to 10%): Acne, rash, pruritus, dry skin
Uncommon (0.1% to 1%): Alopecia, hirsutism, urticaria, skin reactions, skin discoloration
Postmarketing reports: Chloasma or melasma that may persist when drug is discontinued, erythema multiforme, erythema nodosum, hemorrhagic eruption, loss of scalp hair, seborrhea, skin rash, seborrhea, angioneurotic edema[Ref]
Oncologic
Uncommon (0.1% to 1%): Breast cancer
Rare (less than 0.1%): Uterine leiomyoma
Postmarketing reports: Ovarian cancer, endometrial cancer[Ref]
Hypersensitivity
Uncommon (0.1% to 1%): Hypersensitivity
Rare (less than 0.1%): Allergic reaction
Postmarketing reports: Anaphylactoid/anaphylactic reactions[Ref]
Respiratory
Rare (less than 0.1%): Pulmonary embolism, asthma
Postmarketing reports: Exacerbation of asthma[Ref]
Hepatic
Uncommon (0.1% to 1%): Gallbladder disease, gallstones, transaminases increased
Rare (less than 0.1%): Cholelithiasis
Postmarketing reports: Cholestatic jaundice, gallbladder disease, cholelithiasis aggravated, cholelithiasis recurrence[Ref]
Metabolic
Common (1% to 10%): Fluid retention
Postmarketing reports: Changes in appetite, increased triglycerides[Ref]
Ocular
Postmarketing reports: Retinal vascular thrombosis, intolerance to contact lenses, visual disturbances[Ref]
