Pharmaceutical Approval Update: Estradiol Gel 0.1% (Divigel) part 2

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Venous Thromboembolism. In the estrogen-alone sub-study, the risk of VTE (DVT and pulmonary embolism), was increased for women taking conjugated estrogens compared with those receiving placebo (30 vs. 22 per 10,000 women-years), although only the increased risk of DVT reached statistical significance (23 vs. 15 per 10,000 women-years). The increased risk of VTE was demonstrated during the first two years.

In the estrogen-plus-progestin substudy, a statistically significant two-fold greater rate of VTE was reported for conjugated estrogens plus MPA compared with placebo (35 vs. 17 per 10,000 women-years). Statistically significant increases in risk for both DVT (26 vs. 13 per 10,000 women-years) and pulmonary embolism (18 vs. 8 per 10,000 women-years) were also noted. The increased VTE risk occurred during the first year and persisted.

If feasible, estrogens should be discontinued at least four to six weeks before surgery of the type that can be associated with an increased risk of thromboembolism or during periods of prolonged immobilization.
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Endometrial Cancer. The use of unopposed estrogens in women with an intact uterus has been associated with an increased risk of endometrial cancer. The reported endometrial cancer risk among women taking unopposed estrogen is about two to 12 times greater than in non-users, and it appears dependent on the duration of treatment and on the estrogen dose. Most studies show no significant increased risk associated with the use of estrogens for less than one year. The greatest risk is associated with prolonged use for five to 10 years or more (a 15-fold to 24-fold increased risk). This risk can persist for at least eight to 15 years after estrogen therapy is discontinued.

Adequate diagnostic measures, including endometrial sampling when indicated, should be undertaken to rule out malignancy in all cases of undiagnosed persistent or recurring abnormal vaginal bleeding. There is no evidence that natural estrogens have a different endometrial risk profile than synthetic estrogens of equivalent estrogen dose. Adding a pro-gestin to estrogen therapy can reduce the risk of endometrial hyperplasia, which may be a precursor to endometrial cancer.

Breast Cancer. In some studies, the use of estrogens and progestins by postmenopausal women has been reported to increase the risk of breast cancer. The most important randomized clinical trial providing information about this occurrence is the WHI. The results from observational studies are generally consistent with those of the WHI trial.

Observational studies have also reported an increased risk of breast cancer with estrogen-plus-progestin combination therapy and a smaller increased risk for estrogen-alone therapy after several years of use. For both findings, the excess risk increased with duration of use and appeared to return to the baseline risk over about five years after stopping treatment; only the observational studies have substantial data on risk after stopping. In these studies, the risk of breast cancer was greater and became apparent earlier with estrogen plus pro-gestin, compared with estrogen alone. However, these studies have not found a significant variation in the risk of breast cancer associated with different estrogens or different estro-gen-plus-progestin combinations, doses, or routes of administration.

In the estrogen-alone substudy, after an average of 7.1 years of follow-up, conjugated estrogens at doses of 0.625 mg daily were not associated with an increased risk of invasive breast cancer (risk ratio [RR], 0.80; 95% confidence interval [nCI], 0.62-1.04).

In the estrogen-plus-progestin substudy, after a mean follow-up of 5.6 years, the WHI substudy reported an increased risk of breast cancer. In this substudy, prior use of estrogen alone or estrogen/progestin combination hormone therapy was reported by 26% of the women. The RR of invasive breast cancer was 1.24 (95% nCI, 1.01-1.54); the absolute risk with estrogen plus progestin was 41 cases per 10,000 women-years compared with 33 for placebo. silagra

Among women who reported previous use of hormone therapy, the RR of invasive breast cancer was 1.86. The absolute risk was 46 cases per 10,000 women-years for estrogen plus progestin, compared with 25 for placebo.

Among women who reported no prior use of hormone therapy, the RR of invasive breast cancer was 1.09. The absolute risk was 40 cases per 10,000 women-years for estrogen plus progestin, compared with 36 for placebo.

In the WHI trial, invasive breast cancers were larger and were diagnosed at a more advanced stage with estrogen plus progestin, compared with placebo. Metastatic disease was rare, with no apparent difference between the two groups. Other prognostic factors such as histologic subtype, grade, and hormone receptor status did not differ between the groups.

The use of estrogen alone and estrogen plus progestin has been reported to result in an increased number of abnormal mammograms necessitating further evaluation.

Dementia. In the estrogen-alone WHIMS substudy, 2,947 women 65 to 79 years of age who had undergone hysterectomy were randomly assigned to receive conjugated estrogens 0.625 mg daily or placebo.

In the estrogen-plus-progestin WHIMS substudy, 4,532 post-menopausal women 65 to 79 years of age received conjugated estrogens plus MPA 0.625 mg/2.5 mg daily or placebo.

In the estrogen-alone substudy, after an average follow-up of 5.2 years, probable dementia was diagnosed in 28 women using estrogen alone and in 19 women receiving placebo. The RR of probable dementia for conjugated estrogens alone versus placebo was 1.49 (95% CI, 0.83-2.66). The absolute risk of probable dementia for conjugated estrogens alone was 37 cases per 10,000 women-years, compared with 25 for placebo. buy antibiotics in canada

In the estrogen-plus-progestin substudy, after an average follow-up of four years, probable dementia was diagnosed in 40 women taking estrogen plus progestin and in 21 women taking placebo. The RR of probable dementia for estrogen-plus-progestin versus placebo was 2.05 (95% CI, 1.21-3.48). The absolute risk of probable dementia for conjugated estrogens plus MPA was 45 cases per 10,000 women-years, compared with 22 for placebo.

When data from the two populations were pooled as planned in the WHIMS protocol, the reported overall relative risk for probable dementia was 1.76 (95% CI, 1.19-2.60). Because both substudies were conducted in women 65 to 79 years of age, it is unknown whether these findings apply to younger post-menopausal women.

Gallbladder Disease. A two-fold to four-fold increase in the risk of gallbladder disease requiring surgery has been reported in postmenopausal women receiving estrogens.

Hypercalcemia. Estrogens can lead to severe hypercal-cemia in patients with breast cancer and bone metastases. If hypercalcemia occurs, estrogens should be stopped and appropriate measures should be taken to reduce serum calcium levels.

Visual Abnormalities. Retinal vascular thrombosis has been reported in patients receiving estrogens. Medication should be discontinued pending examination if the patient experiences a sudden partial or complete loss of vision or a sudden onset of proptosis, diplopia, or migraine. If the examination reveals papilledema or retinal vascular lesions, estrogens should be permanently discontinued.

Precautions:

Addition of a Progestin (in Women without a Hysterectomy). Studies of the addition of a progestin for 10 or more days of a cycle of estrogen administration, or daily with estrogen in a continuous regimen, have reported a lowered incidence of endometrial hyperplasia than would be induced by estrogen treatment alone. Endometrial hyperplasia may be a precursor to endometrial cancer; however, risks may be associated with the use of progestins with estrogens, compared with estrogen-alone regimens. These include a possible increased risk of breast cancer, adverse effects on lipoprotein metabolism (lower high-density lipoprotein levels and elevated low-density lipo-protein levels), and impaired glucose tolerance.

Hypertension. In a small number of case reports, substantial increases in blood pressure have been attributed to idiosyncratic reactions to estrogens. Although a large, randomized, placebo-controlled clinical trial showed no generalized effect of estrogens on blood pressure, blood pressure should be monitored at regular intervals with estrogen use.

Hypertriglyceridemia. In patients with pre-existing hyper-triglyceridemia, estrogen therapy has been associated with elevated plasma triglyceride levels, leading to pancreatitis and other complications.

Impaired Liver Function and History of Cholestatic Jaundice. Estrogens may be poorly metabolized in patients with impaired liver function. For patients with a history of cho-lestatic jaundice associated with prior estrogen use or with pregnancy, caution should be exercised. In the case of recurrence, estrogens should be discontinued.

Hypothyroidism. Estrogen leads to increased thyroid-binding globulin (TBG) levels. Patients with normal thyroid function can compensate for the increased TBG by making more thyroid hormone, thus maintaining free thyroxine and tri-iodothyronine serum concentrations in the normal range. Patients dependent on thyroid hormone replacement who are also receiving estrogens may require increased doses of thyroid hormone. Monitoring of thyroid function is recommended for these patients to maintain acceptable free thyroid hormone levels.

Fluid Retention. Estrogens may cause some degree of fluid retention. Because of this, patients who have conditions that might be influenced by this factor (cardiac or renal dysfunction) warrant careful observation when estrogens are prescribed.

Hypocalcemia. Estrogens should be used with caution in individuals with severe hypocalcemia.

Ovarian Cancer. In the estrogen-plus-progestin substudy of the WHI, after an average follow-up of 5.6 years, the RR for ovarian cancer for this regimen, compared with placebo, was 1.58 (95% nCI, 0.77-3.24) but was not statistically significant. The absolute risk for estrogen-plus-progestin therapy was 4.2 cases per 10,000 women-years and 2.7 for placebo. In some studies, estrogen-only products, especially for 10 or more years, were associated with an increased risk of ovarian cancer. Other epidemiological studies have not found these associations.

Exacerbation of Endometriosis. Endometriosis may be exacerbated with estrogen administration. Malignant transformations of residual endometrial implants have been re­ported in women treated with estrogen alone after hysterectomy. For patients with residual post-hysterectomy en-dometriosis, the addition of progestin should be considered.

Exacerbation of Other Conditions. Estrogens may cause an exacerbation of asthma, diabetes mellitus, epilepsy, migraine or porphyria, systemic lupus erythematosus, and hepatic hemangiomas. Estrogens should be used with caution in women with these conditions.

Photosensitivity and Photoallergy. The effects of direct sun exposure to estradiol gel 0.1% application sites have not been evaluated in clinical trials. Nonclinical studies in guinea pigs showed no phototoxicity or photosensitivity. The gel absorbs light primarily at wavelengths below 290 nm and is not considered to have photosensitizing potential.

Sunscreens. Studies of other topical estrogen gel products have shown that sunscreens have the potential for changing the systemic exposure of topically applied estrogen gels. The effect of applying sunscreen plus estradiol gel 0.1% to the same site has not been clinically evaluated.

Alcohol-Based Gels. Gels with an alcohol base are flammable. Patients should avoid fire, flame, or smoking until the gel has dried. Occluding the area where the topical drug product is applied with clothing or other barriers is not recommended until the gel is completely dried.

Potential for Estradiol Transfer. There is a potential for the drug to be transferred from one individual to another following physical contact of application sites. In a study that evaluated transferability to males from their female contacts, estradiol levels were somewhat elevated over baseline values in the males, but the degree of transferability was inconclusive. Patients are advised to avoid skin contact with other people until the gel is completely dried. The site should be covered with clothing after drying.

Effects of Washing. Washing the application site with soap and water one hour after gel application resulted in a 30% to 38% decrease in the mean total 24-hour exposure to estradiol. Patients should refrain from washing the application site for at least one hour after the gel is applied.

Dosage and Administration:

Topical estradiol gel 0.1% is available in strengths of 0.25, 0.5, and 1.0 g/day. Each gram of the gel product contains 1 mg of estradiol. The usual initial dose is 0.25 g daily. Dosage adjustments may vary according to individual patient response. Health care providers should periodically reassess the dose.

The gel should be applied once daily on the skin of either the right or left upper thigh. The application surface area should be about 5 by 7 inches (the size of two palm prints). The entire contents of a unit dose packet should be applied each day. To avoid potential skin irritation, patients should apply the gel to the right or left upper thigh on alternating days. They should not apply the gel to the face, breasts, or irritated skin or in or around the vagina. After the gel is applied, it should be allowed to dry. The application site should not be washed within one hour after application. Patients should avoid contact of the gel with the eyes, and they should wash their hands after applying the gel.

When estrogen is prescribed for postmenopausal women with a uterus, a progestin should also be given to reduce the risk of endometrial cancer. Women without a uterus do not need progestin. The use of estrogen, alone or with a progestin, should be with the lowest effective dose and for the shortest duration. Patients should be re-evaluated periodically as appropriate (at three-month to six-month intervals) to determine whether treatment is still necessary.
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For women with a uterus, endometrial sampling should be undertaken to rule out malignancy if there is undiagnosed persistent or recurring abnormal vaginal bleeding.

Commentary: The most common menopause-related discomfort is a vasomotor symptom commonly called hot flashes (or flushes). Although the exact cause is unclear, they are thought to be the result of changes in the hypothalamus, which regulates the body’s temperature. If the hypothalamus mistakenly senses that a woman is too warm, it starts a chain of events to cool her down. Blood vessels near the surface of the skin begin to dilate, increasing blood flow to the surface in an attempt to dissipate body heat. This produces a red, flushed look to the face and neck in light-skinned women. Women may also perspire to cool the body down. An increased pulse rate and a sensation of rapid heartbeat may also occur. Hot flashes are often followed by a cold chill; some women experience only the chill.

The best treatment depends on how severe the symptoms are, how much they interfere with quality of life, the woman’s personal preferences, and her health profile. If treatment is needed, hot flashes can usually be reduced or eliminated with lifestyle changes or nonprescription or prescription therapies. Some older oral estrogen therapies contain conjugated estrogens. Now that estradiol gel 0.1% is available, systemic estrogen therapy might not be necessary.

In clinical trials with estradiol gel 1%, women experienced a low incidence of adverse events and a decrease in the frequency and severity of hot flashes as early as two weeks from the start of therapy. This product provides the lowest approved dose of estradiol therapy on the market to treat hot flashes, although a boxed warning is associated with the gel.