Applies to estradiol / levonorgestrel: transdermal patch extended release.
Warning
Transdermal route (Patch, Extended Release)
Cardiovascular Disorders, Probable Dementia, Breast Cancer, and Endometrial CancerEstrogen Plus Progestin TherapyCardiovascular Disorders and Probable DementiaEstrogens plus progestogen therapy should not be used for the prevention of cardiovascular disease or dementia.The Women's Health Initiative (WHI) estrogen plus progestin substudy reported an increased risk 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 estrogens (CE) [0.625 mg] combined with medroxyprogesterone acetate (MPA) [2.5 mg], relative to placebo.The WHI Memory Study (WHIMS) estrogen plus progestin ancillary study of 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 CE (0.625 mg) combined with MPA (2.5 mg), relative to placebo. It is unknown whether this finding applies to younger postmenopausal women.Breast CancerThe WHI estrogen plus progestin substudy demonstrated an increased risk of invasive breast cancer.Only daily oral 0.625 mg CE and 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 known. 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. Perform adequate diagnostic measures, including directed or random endometrial sampling when indicated 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 CE (0.625 mg)-alone, relative to placebo.The WHIMS estrogen-alone ancillary study of 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 CE (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 regarding adverse cardiovascular events and dementia to lower CE doses, other routes of administration, or other estrogen-alone products is not known. 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-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/levonorgestrel 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 / levonorgestrel:
Incidence not known
- Acid or sour stomach
- anxiety
- backache
- belching
- change in vaginal discharge
- chest pain, discomfort, or tightness
- clear or bloody discharge from the nipple
- confusion
- cough
- difficulty with speaking
- difficulty with swallowing
- dimpling of the breast skin
- dizziness or lightheadedness
- double vision
- fainting
- fast heartbeat
- full or bloated feeling or pressure in the stomach
- headache
- heartburn
- hives, itching, or rash
- inability to move the arms, legs, or facial muscles
- inability to speak
- indigestion
- inverted nipple
- loss of appetite
- lump in the breast or under the arm
- nausea
- 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
- persistent crusting or scaling of the nipple
- puffiness or swelling of the eyelids or around the eyes, face, lips, or tongue
- redness or swelling of the breast
- slow speech
- sore on the skin of the breast that does not heal
- stomach discomfort, upset, or pain
- sweating
- swelling of the stomach area
- trouble breathing
- unusual tiredness or weakness
- vaginal bleeding
- vomiting
Other side effects
Some side effects of estradiol / levonorgestrel 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
- body aches or pain
- breast pain
- burning, itching, redness, skin rash, swelling, or soreness at the application site
- chills
- discouragement
- ear congestion
- feeling sad or empty
- fever
- heavy nonmenstrual vaginal bleeding
- irritability
- loss of interest or pleasure
- loss of voice
- runny or stuffy nose
- sneezing
- sore throat
- trouble concentrating
- trouble sleeping
Less common
- Bladder pain
- bloody or cloudy urine
- blurred vision
- cough producing mucus
- diarrhea
- difficult, burning, or painful urination
- difficulty with moving
- dizziness
- excess air or gas in the stomach or intestines
- frequent urge to urinate
- general feeling of discomfort or illness
- itching of the vagina or genital area
- joint pain
- lower back or side pain
- muscle aches, pains, or stiffness
- pain during sexual intercourse
- pain or tenderness around the eyes and cheekbones
- passing gas
- pounding in the ears
- shivering
- slow or fast heartbeat
- weight gain
Incidence not known
- Loss or thinning of the hair
- pressure in the stomach
For Healthcare Professionals
Applies to estradiol / levonorgestrel: transdermal film extended release.
General
The most common adverse events were application site reactions, which usually disappeared 2 to 3 days after patch removal.[Ref]
Cardiovascular
Cardiovascular disorders described as an increase risk of PE, DVT, stroke, and MI have been reported in the WHI (Women's Health Initiative) estrogen plus progestin substudy. Postmenopausal women 50 to 79 years of age receiving oral conjugated estrogens (0.625 mg) combined with medroxyprogesterone (2.5 mg) showed an increased risk of stroke compared to placebo (33 versus 25 per 10,000 women-years); coronary heart disease defined as nonfatal MI, silent MI or coronary heart disease death (41 versus 34 per 10,000 women-years); venous thromboembolism (35 versus 17 per 10,000 women-years).[Ref]
Estrogen plus Progestin:
Frequency not reported: Cardiovascular disorders
Estradiol / levonorgestrel
Common (1% to 10%): Hypertension[Ref]
Oncologic
Estrogen plus Progestin:
Frequency not reported: Malignant neoplasms[Ref]
The Women's Health Initiative (WHI) has shown, after a mean follow-up of 5.6 years, estrogen (0.625 mg) plus progestin (2.5 mg) use increased risk of invasive breast cancer. The relative risk (RR) of invasive breast cancer was reported at 1.24 (absolute risk 41 versus 33 cases per 10,000 women-years) compared with placebo. For women with a prior history of hormone therapy, RR was 1.86 (absolute risk 46 versus 25 cases per 10,000 women-years) compared with placebo. In the same substudy, invasive breast cancers were larger, more likely to be node positive, and diagnosed at a more advanced stage.
Endometrial Cancer has been reported with the use of unopposed estrogen therapy in woman with a uterus; risk is about 2 to 12 times greater without progestin. Most studies show the greatest risk appears associated with prolonged use. Risk has been shown to persist for 8 to 15 years after estrogen therapy is discontinued. Adding a progestin to estrogen therapy in postmenopausal women has been shown to reduce the risk of endometrial hyperplasia, which may be a precursor to endometrial cancer
A meta-analysis of 17 prospective and 35 retrospective epidemiology studies found that women using hormonal therapy for menopausal symptoms had an increased risk for ovarian cancer. Relative risks associated with current use was calculated at 1.41 (95% confidence interval [CI] 1.32 to 1.50). The relative risk associated with combined current and recent use (discontinued use within 5 years) were comparable and elevated risk was significant for both estrogen-alone and estrogen plus progestin products. It is not possible to determine the exact duration of hormone use associated with an increased risk of ovarian cancer.[Ref]
Nervous system
Uncommon (0.1% to 1%): Migraine
Postmarketing reports: Dizziness, headache[Ref]
Local
Very common (10% or more): Application site reaction (40.6%)[Ref]
Dermatologic
Common (1% to 10%): Rash
Postmarketing reports: Alopecia, night sweats, pruritus[Ref]
Gastrointestinal
Common (1% to 10%): Abdominal pain, flatulence, nausea, vomiting
Uncommon (0.1% to 1%): Bloating, abdominal cramps
Postmarketing reports: Abdominal distension[Ref]
Genitourinary
Very common (10% or more): Vaginal bleeding (36.8%)
Common (1% to 10%): Urinary tract infection, vaginitis, mastodynia
Uncommon (0.1% to 1%): Dysmenorrhea, endometrial hyperplasia
Rare (less than 0.1%): Increase in size of uterine fibrosis
Postmarketing reports: Changes in bleeding patterns[Ref]
Musculoskeletal
Common (1% to 10%): Back pain, arthralgia
Uncommon (0.1% to 1%): Leg cramps[Ref]
Psychiatric
Common (1% to 10%): Depression, increase/decrease in libido
Postmarketing reports: Insomnia[Ref]
Respiratory
Very common (10% or more): Upper respiratory infection (13.2%)
Common (1% to 10%): Sinusitis, bronchitis[Ref]
Metabolic
Uncommon (0.1% to 1%): Fluid retention
Postmarketing reports: Increased weight[Ref]
Hypersensitivity
Postmarketing reports: Anaphylactic reaction[Ref]
Other
Common (1% to 10%): Accidental injury, flu syndrome, pain, edema, weight gain
Uncommon (0.1% to 1%): Weight loss, fatigue
Postmarketing reports: Hot flush[Ref]
