Divigel Information
Divigel (Estradiol)
Divigel (Estradiol)
Divigel (Estradiol) Description
Divigel (Estradiol) (estradiol gel) 0.1% is a clear, colorless gel, which is odorless when dry. It is designed to deliver sustained circulating concentrations of estradiol when applied once daily to the skin. The gel is applied to a small area (200 cm) of the thigh in a thin, quick-drying layer. Divigel (Estradiol) is available in three doses of 0.25, 0.5, and 1.0 g for topical application (corresponding to 0.25, 0.5, and 1.0 mg estradiol, respectively).
The active component of the topical gel is estradiol.
Estradiol is a white crystalline powder, chemically described as estra-1,3,5(10)-triene-3,17β-diol. It has an empirical formula of CHO and molecular weight of 272.39. The structural formula is:
The remaining components of the gel (carbomer, ethanol, propylene glycol, purified water, and triethanolamine) are pharmacologically inactive.
Divigel (Estradiol) Clinical Pharmacology
Divigel (Estradiol) provides estrogen therapy by delivering estradiol, the major estrogenic hormone secreted by the human ovary, to the systemic circulation following topical application.
Endogenous estrogens are largely responsible for the development and maintenance of the female reproductive system and secondary sexual characteristics. Although circulating estrogens exist in a dynamic equilibrium of metabolic interconversions, estradiol is the principal intracellular human estrogen and is substantially more potent than its metabolites, estrone and estriol, at the receptor level.
The primary source of estrogen in normally cycling adult women is the ovarian follicle, which secretes 70 to 500 mcg of estradiol daily, depending on the phase of the menstrual cycle. After menopause, most endogenous estrogen is produced by conversion of androstenedione, secreted by the adrenal cortex, to estrone by peripheral tissues. Thus, estrone and the sulfate conjugated form, estrone sulfate, are the most abundant circulating estrogens in postmenopausal women.
Estrogens act through binding to nuclear receptors in estrogen-responsive tissues. To date, two estrogen receptors have been identified. These vary in proportion from tissue to tissue.
Circulating estrogens modulate the pituitary secretion of the gonadotropins, luteinizing hormone (LH) and follicle-stimulating hormone (FSH), through a negative feedback mechanism. Estrogens act to reduce the elevated levels of these hormones seen in postmenopausal women.
Divigel (Estradiol) Indications And Usage
Divigel (Estradiol) (estradiol gel) 0.1% is indicated in the treatment of moderate to severe vasomotor symptoms associated with menopause.
Divigel (Estradiol) Contraindications
Estrogen products, including Divigel (Estradiol) (estradiol gel) 0.1%, should not be used in women with any of the following conditions:
Divigel (Estradiol) Warnings
See .
Estrogen-alone therapy has been associated with an increased risk of stroke and deep vein thrombosis (DVT).
Estrogen-plus progestin therapy has been associated with an increased risk of myocardial infarction as well as stroke, venous thrombosis and pulmonary embolism.
Should any of these occur or be suspected, estrogens should be discontinued immediately.
Risk factors for arterial vascular disease (e.g., hypertension, diabetes mellitus, tobacco use, hypercholesterolemia, and obesity) and/or venous thromboembolism (e.g., personal history or family history of VTE, obesity, and systemic lupus erythematosus) should be managed appropriately.
In the estrogen-alone Women's Health Initiative Memory Study (WHIMS), a substudy of WHI, a population of 2,947 hysterectomized women aged 65 to 79 years was randomized to CE (0.625 mg daily) or placebo. In the estrogen-plus-progestin WHIMS, a population of 4,532 postmenopausal women aged 65 to 79 years was randomized to CE/MPA (0.625 mg/2.5 mg daily) or placebo.
In the estrogen-alone substudy, after an average follow-up of 5.2 years, 28 women in the estrogen-alone group and 19 women in the placebo group were diagnosed with probable dementia. The relative risk of probable dementia for CE alone versus placebo was 1.49 (95% CI, 0.83-2.66). The absolute risk of probable dementia for CE alone versus placebo was 37 versus 25 cases per 10,000 women-years.
In the estrogen-plus-progestin substudy, after an average follow-up of 4 years, 40 women in the estrogen-plus-progestin group and 21 women in the placebo group were diagnosed with probable dementia. The relative risk 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 CE/MPA versus placebo was 45 versus 22 cases per 10,000 women-years.
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). Since both substudies were conducted in women aged 65 to 79 years, it is unknown whether these findings apply to younger postmenopausal women. (see and and .)
Divigel (Estradiol) Precautions
See and .
Long-term continuous administration of natural and synthetic estrogens in certain animal species increases the frequency of carcinomas of the breast, uterus, cervix, vagina, testis and liver.
There have not been sufficient numbers of geriatric patients involved in studies utilizing Divigel (Estradiol) to determine whether those over 65 years of age differ from younger subjects in their response to Divigel (Estradiol) .
Of the total number of subjects in the estrogen-alone substudy of the Women's Health Initiative (WHI), 46% (n=4,943) were 65 years and older, while 7.1% (n=767) were 75 years and older. There was a higher relative risk (CE versus placebo) of stroke in women less than 75 years of age compared to women 75 years and older.
In the estrogen-alone substudy of the Women's Health Initiative Memory Study (WHIMS), a substudy of WHI, a population of 2,947 hysterectomized women, aged 65 to 79 years, was randomized to CE (0.625 mg per day) or placebo. After an average follow-up of 5.2 years, the relative risk (CE versus placebo) of probable dementia was 1.49 (95% CI, 0.83-2.66). The absolute risk of developing probable dementia with estrogen alone was 37 vs. 25 cases per 10,000 women-years with placebo.
Of the total number of subjects in the estrogen-plus-progestin substudy of the WHI, 44% (n=7,320) were 65 years and older, while 6.6% (n=1,095) were 75 years and older. There was a higher relative risk (CE/MPA versus placebo) of stroke and invasive breast cancer in women 75 and older compared to women less than 75 years of age. In women greater than 75, the increased risk of non-fatal stroke and invasive breast cancer observed in the estrogen-plus-progestin combination group compared to the placebo group was 75 vs. 24 per 10,000 women-years and 52 vs. 12 per 10,000 women years, respectively.
In the estrogen-plus-progestin substudy of WHIMS, a population of 4,532 postmenopausal women, aged 65 to 79 years, was randomized to CE/MPA (CE 0.625 mg/2.5 mg daily) or placebo. In the estrogen-plus-progestin group, after an average follow-up of 4 years, the relative risk (CE/MPA versus placebo) of probable dementia was 2.05 (95% CI, 1.21-3.48). The absolute risk of developing probable dementia with CE/MPA was 45 vs. 22 cases per 10,000 women-years with placebo.
Seventy-nine percent of the cases of probable dementia occurred in women that were older than 70 for the CE group, and 82 percent of the cases of probable dementia occurred in women who were older than 70 in the CE/MPA group. The most common classification of probable dementia in both the treatment groups and placebo groups was Alzheimer's disease.
When data from the two populations were pooled as planned in the WHIMS protocol, the reported overall risk of probable dementia was 1.76 (95% CI, 1.19-2.60). Since both substudies were conducted in women aged 65 to 79 years, it is unknown whether these findings apply to younger postmenopausal women. (See and .)
Divigel (Estradiol) Adverse Reactions
See and .
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The adverse reaction information from clinical trials does, however, provide a basis for identifying the adverse events that appear to be related to drug use and for approximating rates.
Divigel (Estradiol) was studied at doses of 0.25, 0.5 and 1.0 g/day in a 12-week, double-blind, placebo-controlled study that included a total of 495 postmenopausal women (86.5% Caucasian). The adverse events that occurred at a rate greater than 5% in any of the treatment groups are summarized in .
In a 12-week placebo-controlled study of Divigel (Estradiol) , application site reactions were seen in
The following additional adverse reactions have been reported with estrogen and/or progestin therapy.
Divigel (Estradiol) Overdosage
Serious ill effects have not been reported following acute ingestion of large doses of estrogen-containing drug products by young children. Overdosage of estrogen may cause nausea and vomiting, and withdrawal bleeding may occur in females.
Divigel (Estradiol) Dosage And Administration
When estrogen is prescribed for a postmenopausal woman with a uterus, a progestin should also be initiated to reduce the risk of endometrial cancer. A woman without a uterus does not need progestin. Use of estrogen, alone or in combination with a progestin, should be with the lowest effective dose and for the shortest duration consistent with treatment goals and risks for the individual woman. Patients should be re-evaluated periodically as clinically appropriate (e.g., 3-month to 6-month intervals) to determine if treatment is still necessary (see and ). For women who have a uterus, adequate diagnostic measures, such as endometrial sampling, when indicated, should be undertaken to rule out malignancy in cases of undiagnosed persistent or recurring abnormal vaginal bleeding.
Divigel (Estradiol) (estradiol gel) 0.1%, at doses of 0.25, 0.5, and 1.0 g/day, is indicated for topical use in the treatment of moderate to severe vasomotor symptoms associated with menopause. Each gram of Divigel (Estradiol) contains 1 mg of estradiol.
Patients should be treated with the lowest effective dose of Divigel (Estradiol) . Generally, women should be started at 0.25 gram Divigel (Estradiol) daily. Subsequent dosage adjustments may be made based upon the individual patient response. This dose should be periodically reassessed by the healthcare provider.
Divigel (Estradiol) 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 (approximately the size of two palm prints). The entire contents of a unit dose packet should be applied each day. To avoid potential skin irritation, Divigel (Estradiol) should be applied to the right or left upper thigh on alternating days. Divigel (Estradiol) should not be applied on the face, breasts, or irritated skin or in or around the vagina. After application, the gel should be allowed to dry before dressing. The application site should not be washed within 1 hour after applying Divigel (Estradiol) . Contact of the gel with eyes should be avoided. Hands should be washed after application.
Divigel (Estradiol) How Supplied
Divigel (Estradiol) (estradiol gel) 0.1% is a clear, colorless, smooth, opalescent gel supplied in single-dose foil packets of 0.25, 0.5, and 1.0 g, corresponding to 0.25, 0.5, and 1.0 mg estradiol, respectively.
NDC 0245-0880-30, carton of 30 packets, 0.25 mg estradiol per single-dose foil packetNDC 0245-0881-30, carton of 30 packets, 0.5 mg estradiol per single-dose foil packetNDC 0245-0882-30, carton of 30 packets, 1.0 mg estradiol per single-dose foil packet
Keep out of the reach of children.
Manufactured byOrion Corporation Orion PharmaTengströminkatu 8FI-20360 TurkuFinland
Distributed byUpsher-Smith Laboratories, Inc.Minneapolis, MN 55447
1-800-654-2299
Product of Finland
Revised June 2007
Divigel (Estradiol) Patient Information
(Updated June 2007)
(estradiol gel) 0.1%
Read this PATIENT INFORMATION leaflet before you start using Divigel (Estradiol) and read what you get each time you refill your Divigel (Estradiol) prescription. There may be new information. This information does not take the place of talking to your healthcare provider about your medical condition or your treatment.
Divigel (Estradiol) is a medicine that contains an estrogen hormone (estradiol). Divigel (Estradiol) is a clear, colorless, smooth gel that is odorless when dry.
Divigel (Estradiol) is used after menopause to:
Estrogens are hormones made by a woman's ovaries. The ovaries normally stop making estrogens when a woman is between 45 to 55 years old. This drop in body estrogen levels causes the “change of life” or menopause (the end of monthly menstrual periods). Sometimes, both ovaries are removed during an operation before natural menopause takes place. The sudden drop in estrogen levels causes “surgical menopause.”
When the estrogen levels begin dropping, some women develop very uncomfortable symptoms, such as feelings of warmth in the face, neck, and chest, or sudden strong feelings of heat and sweating (“hot flashes” or “hot flushes”). In some women, the symptoms are mild, and they will not need estrogens. In other women, symptoms can be more severe. You and your healthcare provider should talk regularly about whether you still need treatment with Divigel (Estradiol) .
Do not start using Divigel (Estradiol) if you:
Estrogens may increase the chances of getting certain types of cancers, including cancer of the breast or uterus. If you have or have had cancer, talk with your healthcare provider about whether you should use Divigel (Estradiol) .
See the next section of this leaflet for a list of ingredients in Divigel (Estradiol) .
The hormone in Divigel (Estradiol) can pass into your milk.
Your healthcare provider may need to check you more carefully if you have certain conditions, such as asthma (wheezing); epilepsy (seizures); migraine; endometriosis; lupus; problems with your heart, liver, thyroid, or kidneys; or have high calcium levels in your blood.
This includes prescription and nonprescription medicines, vitamins, and herbal supplements. Some medicines may affect how Divigel (Estradiol) works. Divigel (Estradiol) may also affect how your other medicines work.
You may need to stop using Divigel (Estradiol) .
The active ingredient in Divigel (Estradiol) is estradiol.
The inactive ingredients are carbomer, ethanol, propylene glycol, purified water, and triethanolamine.
You and your healthcare provider should talk regularly (for example, every 3 to 6 months) about the dose you are taking and whether you still need treatment with Divigel (Estradiol) .
If you miss a dose, do not double the dose on the next day to catch up. If your next dose is less than 12 hours away, it is best just to wait and apply your normal dose the next day. If it is more than 12 hours until the next dose, apply the dose you missed and resume your normal dosing the next day. Do not apply Divigel (Estradiol) more than once each day. If you accidentally spill some of the contents of a Divigel (Estradiol) packet, do not open a new packet. Wait and apply your normal dose the next day.
Once you have applied Divigel (Estradiol) , it has dried, and you have washed your hands, there is little risk of transfer to another person. If someone else is exposed to Divigel (Estradiol) by direct contact with the wet gel, that person should wash the area of contact with soap and water as soon as possible. This is especially important for men and children. The longer the gel is in contact with the skin before washing, the chance is greater that the other person will absorb some of the estrogen hormone.
If you get Divigel (Estradiol) in your eyes, flush your eyes right away with lukewarm tap water. If you have concerns, contact your healthcare provider.
Call your healthcare provider right away if you get any of these warning signs, or any other unusual symptom that concerns you.
These are not all the possible side effects of Divigel (Estradiol) . For more information, ask your healthcare provider or pharmacist.
Talk with your healthcare provider regularly about whether you should continue taking Divigel (Estradiol) . If you have a uterus, talk to your healthcare provider about whether the addition of a progestin is right for you. In general, the addition of a progestin is recommended for women with a uterus to reduce the chance of getting cancer of the uterus. See your healthcare provider right away if you get vaginal bleeding while taking Divigel (Estradiol) . Have a breast exam and mammogram (breast X-ray) every year unless your healthcare provider tells you otherwise. If members of your family have had breast cancer or if you have ever had breast lumps or an abnormal mammogram, you may need to have breast exams more often. If you have high blood pressure, high cholesterol (fat in the blood), diabetes, are overweight, or if you use tobacco, you may have higher chances of getting heart disease. Ask your healthcare provider for ways to lower your chances of getting heart disease.
Medicines are sometimes prescribed for conditions that are not mentioned in patient information leaflets. Do not use Divigel (Estradiol) for conditions for which it was not prescribed. Do not give Divigel (Estradiol) to other people, even if they have the same symptoms you have. It may harm them.
This leaflet provides a summary of the most important information about Divigel (Estradiol) . If you would like more information, talk with your healthcare provider or pharmacist. You can ask for information about Divigel (Estradiol) that is written for health professionals. You can get more information by calling the toll free number 1-800-654-2299.
Divigel (Estradiol) is supplied in individual foil packets, each one containing a single day's dose.
Manufactured byOrion Corporation Orion PharmaTengströminkatu 8FI-20360 TurkuFinland
Distributed byUpsher-Smith Laboratories, Inc.Minneapolis, MN 55447 1-800-654-2299 Product of Finland
Divigel (Estradiol) Principal Display Panel - .mg Packet - Front And Back
NDC 0245-0880-89
Divigel (Estradiol) (estradiol gel) 0.1%0.25 g gel, providing 0.25 mgof estradiol
Mfg for: Minneapolis, MN 55447
0880-66FR1205
Divigel (Estradiol) Principal Display Panel - .mg/-packet Carton
PROFESSIONAL SAMPLE: Not for SaleNDC 0245-0880-66
7 packets0.25 g gel provides 0.25 mg estradiol/packet
Divigel (Estradiol) Principal Display Panel - .mg/-packet Carton
NDC 0245-0880-30
30 packets0.25 g gel provides 0.25 mg estradiol/packet
Exp. date
Batch
Divigel (Estradiol) Principal Display Panel - .mg Packet - Front And Back
NDC 0245-0881-89
Divigel (Estradiol) (estradiol gel) 0.1%0.5 g gel, providing 0.5 mgof estradiol
Mfg for: Minneapolis, MN 55447
0881-66FR1205
Divigel (Estradiol) Principal Display Panel - .mg/-packet Carton
PROFESSIONAL SAMPLE: Not for SaleNDC 0245-0881-66
7 packets0.5 g gel provides 0.5 mg estradiol/packet
Divigel (Estradiol) Principal Display Panel - .mg/-packet Carton
NDC 0245-0881-30
30 packets0.5 g gel provides 0.5 mg estradiol/packet
Exp. date
Batch
Divigel (Estradiol) Principal Display Panel - Mg Packet - Front And Back
NDC 0245-0882-89
Divigel (Estradiol) (estradiol gel) 0.1%1 g gel, providing 1 mgof estradiol
Mfg for: Minneapolis, MN 55447
0882-66FR1205
Divigel (Estradiol) Principal Display Panel - Mg/-packet Carton
PROFESSIONAL SAMPLE: Not for SaleNDC 0245-0882-66
7 packets1 g gel provides 1 mg estradiol/packet
Divigel (Estradiol) Principal Display Panel - Mg/-packet Carton
NDC 0245-0882-30
30 packets1 g gel provides 1 mg estradiol/packet
Exp. date
Batch
