CLIMARA (Estradiol)

What is this medication?

CLIMARA (Estradiol)
Female Reproductive Hormone; Estrogen

CLIMARA (Estradiol) is indicated for the treatment of hypoestrogenism due to hypogonadism, castration, or primary ovarian failure, as well as the prevention of postmenopausal osteoporosis.

ALERT: WARNING
Endometrial cancer:
There is an increased risk of endometrial cancer in a woman with a uterus who uses unopposed estrogens. Adding a progestin to estrogen therapy has been shown to reduce the risk of endometrial hyperplasia, which may be a precursor to endometrial cancer. Use adequate diagnostic measures, including directed or random endometrial sampling when indicated, to rule out malignancy in all cases of undiagnosed persistent or recurring abnormal genital bleeding.

Cardiovascular disease:
Do not use estrogen-alone therapy for the prevention of cardiovascular disease. The Women’s Health Initiative (WHI) estrogen-alone substudy reported increased risks of stroke and deep vein thrombosis (DVT) in postmenopausal women (50 to 79 years of age) during 7.1 years of treatment with daily oral conjugated estrogens (CE) (0.625 mg) alone, relative to placebo.

Do not use estrogen plus progestin therapy for the prevention of cardiovascular disease. The WHI estrogen plus progestin substudy reported increased risks of DVT, pulmonary embolism, stroke, and myocardial infarction in postmenopausal women (50 to 79 years of age) during 5.6 years of treatment with daily oral CE (0.625 mg) combined with medroxyprogesterone acetate (MPA) (2.5 mg), relative to placebo.

Breast cancer:
The WHI estrogen plus progestin substudy demonstrated an increased risk of invasive breast cancer.

Dementia:
Do not use estrogen-alone therapy for the prevention of dementia. The WHI Memory Study (WHIMS) estrogen-alone ancillary study of the WHI reported an increased risk of developing probable dementia in postmenopausal women ≥65 years of age 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 plus progestin therapy for the prevention of dementia. The WHIMS estrogen plus progestin ancillary study of the WHI reported an increased risk of developing probable dementia in postmenopausal women ≥65 years of age 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.

Risk vs benefits:
Only daily oral CEs (0.625 mg) and daily oral CE (0.625 mg) and MPA (2.5 mg) were studied in the estrogen-alone and estrogen plus progestin substudies of the WHI, respectively. Therefore, the relevance of the WHI findings regarding the adverse cardiovascular events and dementia to lower CE doses, other routes of administration, or other estrogen alone products is not known. Likewise, the relevance of the WHI findings regarding the adverse cardiovascular events, dementia, and breast cancer to lower CE plus other MPA doses, other routes of administration, or other estrogen plus progestin products is not known. Without such data, it is not possible to definitively exclude these risks or determine the extent of the risks for other products. Discuss with your patient the benefits and risks of estrogen-alone or estrogen plus progestin therapy, taking into account her individual risk profile. Prescribe estrogens with or without progestins at the lowest effective doses and for the shortest duration consistent with treatment goals and risks for the individual woman.

How does this medication work? 

Estradiol acts like natural estradiol to support development and function of the female reproductive system, secondary sex characteristics and urogenital structures.  Estradiol inhibits the pituitary release of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) thereby inhibiting ovulation.

How should I take this medication? 

Hormone Therapy for Transgender Females (Male-to-Female)
Transdermal: Apply one patch (25mcg to 200mcg) every three to five days.  

Hypoestrogenism due to Hypogonadism
Transdermal: Apply one patch (25mcg) once weekly.

Osteoporosis Prevention (Females)
Transdermal: Apply one patch (25mcg) once weekly.

Vasomotor Symptoms (Moderate to Severe) Associated with Menopause
Transdermal: Apply one patch (25mcg) once weekly.

Vulvar and Vaginal Atrophy
Transdermal: Apply one patch (25mcg) once weekly.

*When treating symptoms of menopause, evaluate hormone therapy routinely for appropriate dose, duration, and route of administration for each individual patient based on treatment goals, risk factors, and overall health. 

How to Take: To apply the patch, start with washing and drying your hands and selected area.  Remove one patch from its pouch, using your fingers and not scissors.  Remove the protective liner from the patch.  Press the patch firmly with the palm of your hand onto the area of skin, holding it down for about 10 seconds and making sure you rub down all the edges.  The best place to apply the patch is the buttocks however the lower abdomen, hip, side, or lower back can alternatively be used.  To avoid irritation, do not apply it to the same site twice in a row.  Switch from left to right sides of your body.  If the patch falls off, try to reapply it to a different clean, dry skin area.  If it will no longer adhere, then use a new patch.  You can swim or bath with the patch on however very hot water can loosen the adhesive of the patch and should be avoided.

Note: When switching from an oral to transdermal therapy, start the Climara patch one week after discontinuing oral estrogen replacement.  You can start sooner if symptoms reappear within one week. 

Patient Education

Hormone Replacement Therapy
Hormone Replacement Therapy (HRT) refers to the use of an estrogen and a progestin in post-menopausal women.  In estrogen replacement therapy (ERT) only estrogen is administered.  It is critically important to include a progestin to reduce an estrogen induced risk of endometrial hyperplasia in women.  Estrogen replacement therapy is only used in women who have had a hysterectomy and thus are not at risk for these problems.

Treatment of Menopausal Symptoms
HRT effectively relieves or eliminates vasomotor symptoms (hot flushes, sweating), sleep disturbance and poor concentration in a dose-dependent manner. 

Treatment of Urogenital Problems
HRT effectively treats post-menopausal vaginal dryness and dyspareunia with vaginal therapy being most effective.  Furthermore, there is evidence supporting the usage of vaginal estrogens in reducing the frequency of post-menopausal urinary tract infections.

Prevention and Treatment of Osteoporosis 
HRT (with or without a progestin) taken for a period of at least 5 to 10 years is estimated to reduce the risk of osteoporosis-related hip fractures by at least 25%, wrist fractures by 25% to 75% and vertebral fractures by at least 50%; the reduction in risk is directly related to the duration of use.  For optimal protection against fracture, HRT should be started within 3 to 5 years after the last menstrual period.  

Other Uses: There is limited evidence that HRT may help minimize weight gain, prevent skin wrinkling and dryness which typically occur following menopause.

Place in Therapy
Current clinical research suggests that HRT should not be used routinely and/or long-term in post-menopausal women.  Those women who are likely to experience benefits from HRT should fully understand the fully the benefits along with the risks associated with HRT and agree to regular medical examinations. Only short-term therapy is recommended due to the risks of breast cancer, thromboembolism, and coronary heart disease.

Benefits Versus Risks Associated with HRT

Effects of HRT	Oral Estrogen	Transdermal Patch	Transdermal Gel	Vaginal Ring	Vaginal Cream
Reduced hot flushes	Yes	Yes	Yes	No	No
Urogenital benefit	Yes	Yes	Yes	Yes	Yes
Osteoporosis benefit	Yes	Yes	Yes	No	No
Reduced LDL	Yes	Yes	?	No	No
Increased HDL	Yes	No	No	No	No
Increased Triglycerides	Yes	No, decreased	No	No	No
Liver protein induction	Yes	No	?	No	Yes, if conjugated
Gallbladder disease risk	Yes	Yes	?	No	No
Need progestin	Yes	Yes	Yes	No	Depends
Skin irritation	—	Common	Less common	—	—

 

Common Problems and Suggestions

Bleeding after 12 months of continuous estrogen plus continuous progestin	Most common in early menopause. Evaluate endometrium or switch to cyclic progestin or increase dose of progestin for a few months
Bloating	Usually disappears after the first few months.  If persistent, reduce the dose of estrogen or switch to a different estrogen or progestin
Breast tenderness	Usually disappears after the first few months.  If persistent, reduce the dose of estrogen or progestin
Discontinuing HRT	Withdrawal bleeding may occur.  Decrease dose slowly or dose on alternate days for several weeks
Gastrointestinal side effects	Nausea usually disappears after the first few months; if persistent then reduce the dose of estrogen or use a transdermal form
Headache with oral therapy	Try transdermal therapy
Migraine headache exacerbated	Try continuous estrogen, specifically if headache occurs during the week off estrogen
Skin irritation with patch	Try estradiol gel
Triglyceride levels high	Use a transdermal patch

 

General Dosage Considerations
Progestin must be included in HRT for women with an intact uterus to reduce the estrogenic-induced risk of endometrial hyperplasia and carcinoma.  A progestin is not needed if a woman has had a hysterectomy.  The progestin dosage depends on the estrogen dose.

Estrogen doses required to treat menopausal vasomotor symptoms should be titrated to individual response.  Younger women have been shown to need higher doses.  It is encouraged that women discontinue every three to six months to determine if estrogen is still needed.

Estrogen Dosing Considerations:
To Preserve Bone Mineralization and Prevent Bone Thinning

Oral Conjugated Estrogen: 0.625mg daily.

Oral Estradiol-17β: 1-2mg daily.

Estradiol-16β Transdermal Patch: 50mcg daily.

Continuous Estrogen Plus Progestin (Continuous Combined Regimen)
This regimen provide relief from menopausal symptoms while avoiding withdrawal bleeding.  It is designed to induce amenorrhea, however spotting can in the first 6 to 12 months on regimens of conjugated estrogens plus progestins.  Most women develop amenorrhea within 12 months.

1. Oral conjugated estrogen 0.3mg to 1.25mg daily plus oral medroxyprogesterone 2.5mg to 5mg or micronized progesterone 100mg daily.
2. Ethinyl estradiol 5mcg plus norethindrone 1mg daily.

Continuous Estrogen Plus Cyclic Progestin
This regimen provides relief from menopausal symptoms with regular withdrawal bleeding.  It may be tolerated than continuous progestin during the first year of menopause.

1. Oral conjugated estrogen 0.3mg to 1.25mg daily (or equivalent oral or transdermal) plus oral medroxyprogesterone 5mg to 10mg daily or micronized progesterone 200mg daily for 12-14 days per months.
2. Transdermal estradiol 50mcg daily for 2 weeks then combined with norethindrone 250mcg for 2 weeks.
3. Oral conjugated estrogen 0.3mg to 1.25mg daily (or equivalent oral or transdermal) continuously with medroxyprogesterone 10mg daily for 14 days every 3 months.  With this regimen, withdrawal bleeding occurs only once every 3 months, however a minor percentage of women may have spotting and withdrawal bleeding.  

Cyclic Estrogen
Menopausal vasomotor symptoms may return during estrogen-free days.

1. Oral conjugated estrogen 0.3mg to 1.25mg daily (or equivalent oral or transdermal) for 21 to 25 days each month with medroxyprogesterone 10mg daily for the last 12-14 days of every month.

Progestin Only
Used if estrogen is contraindicated.

1. Oral medroxyprogesterone 10mg to 20mg daily on response.

Vaginal Preparations
Vaginal preparations in the form of creams, gels, ovules only treat urogenital symptoms.  Vaginal preparations can be applied daily until symptoms resolve and can be used as a maintenance therapy with creams/gels/ovules being used twice weekly or a vaginal ring. 

Available Dosage Forms

Dosage Forms	Trade Name	Source	Equivalent Dose
Oral Estrogens
Estrogen, conjugated	Premarin	Pregnant mare serum	0.625mg
Estrone sulfate	Ogen	Either soybean or Mexican yam	0.625mg
Estrone sulfate, conjugated	C.E.S.	Plant sterols	0.625mg
Estradiol-17	Estrace	Soy	1mg
Ethinyl estradiol (plus norethindrone)	FemHRT		5mcg
Transdermal Estrogens
Estradiol-17β patch	Estraderm, Vivelle (2/week)	Soy plant	50mcg
	Climara (1/week)	Soy	50mcg
Estradiol-17β (plus norethindrone) patch	Estracomb	Soy plant	50mcg
Estradiol-17β gel	Estrogel	Plant	2.5g
Vaginal Estrogens
Conjugated estrogens	Premarin	Equine
Dienestrol	Ortho Dienestrol	Synthetic
Estradiol-17	Estring Ring	Mainly soybean
Oral Progestins
Medroxyprogesterone	Provera	Soybean	5mg
Micronized progesterone	Prometrium	Plant	200mg

 

What should I watch for while using this medication? 

Do not use in women with an increased risk of invasive breast cancer.

Do not use in women to prevent or treat dementia.

Do not use unopposed estrogen in women with a uterus.

Do not use in women with endometriosis.

Use with caution in women with pre-existing hypertriglyceridemia.

Use with caution in women with ovarian cancer.

Use with caution in women with retinal vascular thrombosis.

Use with caution in asthma, carbohydrate intolerance, cardiovascular disease, fluid retention, hepatic dysfunction, hypoparathyroidism, migraines, porphyria, and system lupus erythematosus.

What if I miss a dose?

If you miss a dose of medication, try to take it as soon as possible. However, if it is almost time for your next dose, take only that scheduled dose. Do not take double or extra doses.

How should I store this medication?

Store the patches at room temperature, away from excessive heat.  Keep each patch in its protective pouch until its ready to use.

What are the possible side effects of using this medication?

Edema, headache, pain, depression, anxiety, skin rash, weight gain, abdominal pain, mastalgia, vaginal hemorrhage, breast tenderness, endometrium disease, breakthrough bleeding, abnormal bleeding, infection, fungal infection, arthralgia, back pain, nasopharyngitis, upper respiratory tract infection, flu-like symptoms, sinusitis, sinus headache.

Note this is not a complete list of side effects for CLIMARA (Estradiol), only common ones.