Prefest Information
Prefest (Estradiol)
Prefest (Estradiol) Description:
The Prefest (Estradiol) regimen provides for a single oral tablet to be taken once daily. The peach tablet containing 1 mg estradiol is taken on days one through three of therapy; the white tablet containing 1 mg estradiol and 0.09 mg norgestimate is taken on days four through six of therapy. This pattern is then repeated continuously to produce the constant estrogen/intermittent progestogen regimen of Prefest (Estradiol) .
The estrogenic component of Prefest (Estradiol) is estradiol, USP. It is a white, crystalline solid, chemically described as estra-1,3,5(10)-triene-3,17β-diol. The structural formula is as follows:
The progestational component of Prefest (Estradiol) is micronized norgestimate, a white powder which is chemically described as 18,19-dinor-17-pregn-4-en-20-yn-3-one, 17-(acetyloxy)-13-ethyl-,oxime,(17α)-(+)-. The structural formula is as follows:
Each tablet for oral administration contains 1 mg estradiol alone or 1 mg estradiol and 0.09 mg of norgestimate. The inactive ingredients are as follows:
The estradiol tablet contains anhydrous lactose, croscarmellose sodium, FD&C yellow no. 6 aluminum lake, magnesium stearate and microcrystalline cellulose.
The estradiol and norgestimate tablet contains anhydrous lactose, croscarmellose sodium, magnesium stearate and microcrystalline cellulose.
Prefest (Estradiol) Clinical Pharmacology:
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.
Norgestimate is a derivative of 19-nortestosterone and binds to androgen and progestogen receptors, similar to that of the natural hormone progesterone; it does not bind to estrogen receptors. Progestins counter the estrogenic effects by decreasing the number of nuclear estradiol receptors and suppressing epithelial DNA synthesis in endometrial tissue.
Prefest (Estradiol) Clinical Studies:
The effect of the estrogen component of Prefest (Estradiol) on vasomotor symptoms was confirmed in a 12-week placebo-controlled trial of 168 healthy postmenopausal women between 28 and 66 years of age (87% Caucasian) with moderate to severe vasomotor symptoms (MSVS). The addition of norgestimate to estrogen (i.e., the Prefest (Estradiol) regimen) was studied in two 12-month trials in 1212 healthy postmenopausal women between 40 and 65 years of age (85% Caucasian) for endometrial protection. Results from a subset population (n=119) of these 12-month trials (women with MSVS) are shown in Table 2.
The effects of the addition of norgestimate on steady state estrogen levels and the clinical relevance thereof have been discussed in (see ).
The effect of Prefest (Estradiol) on the endometrium was evaluated in two 12-month trials. The combined results are shown in Table 4.
In another 12-month controlled clinical trial for endometrial protection an additional 190 postmenopausal women were treated with Prefest (Estradiol) . No subject had a diagnosis of endometrial hyperplasia after treatment.
The effects of Prefest (Estradiol) on uterine bleeding or spotting, as recorded on daily diary cards, were evaluated in two 12-month trials. Combined results are shown in Figure 1.
Prefest (Estradiol) Indications And Usage:
Prefest (Estradiol) is indicated in women who have a uterus for the:
The mainstays for decreasing the risk of postmenopausal osteoporosis are weight bearing exercise, adequate calcium and vitamin D intake, and when indicated, pharmacologic therapy. Postmenopausal women require an average of 1500 mg/day of elemental calcium. Therefore, when not contraindicated, calcium supplementation may be helpful for women with suboptimal dietary intake. Vitamin D supplementation of 400-800 IU/day may also be required to ensure adequate daily intake in postmenopausal women.
Prefest (Estradiol) Contraindications:
Prefest (Estradiol) should not be used in women with any of the following conditions:
Prefest (Estradiol) Warnings:
See .
Estrogen and estrogen/progestin therapy has been associated with an increased risk of cardiovascular events such as myocardial infarction and stroke, as well as venous thrombosis and pulmonary embolism (venous thromboembolism or VTE). 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 Women’s Health Initiative Memory Study (WHIMS), 4,532 generally healthy postmenopausal women 65 years of age and older were studied, of whom 35% were 70 to 74 years of age and 18% were 75 or older. After an average follow-up of 4 years, 40 women being treated with CE/MPA (1.8%, n=2,229) and 21 women in the placebo group (0.9%, n=2,303) received diagnoses of probable dementia. The relative risk for CE/MPA versus placebo was 2.05 (95% confidence interval 1.21–3.48), and was similar for women with and without histories of menopausal hormone use before WHIMS. The absolute risk of probable dementia for CE/MPA versus placebo was 45 versus 22 cases per 10,000 women-years, and the absolute excess risk for CE/MPA was 23 cases per 10,000 women-years. It is unknown whether these findings apply to younger postmenopausal women. (See , and , .)
It is unknown whether these findings apply to estrogen alone therapy.
Prefest (Estradiol) Precautions:
Long-term continuous administration of estrogen, with and without progestin, in women with and without a uterus, has shown an increased risk of endometrial cancer, breast cancer, and ovarian cancer. (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 clinical studies utilizing Prefest (Estradiol) to determine whether those over 65 years of age differ from younger subjects in their response to Prefest (Estradiol) .
In the Women’s Health Initiative Memory Study, including 4,532 women 65 years of age and older, followed for an average of 4 years, 82% (n=3,729) were 65 to 74 while 18% (n=803) were 75 and over. Most women (80%) had no prior hormone therapy use. Women treated with conjugated estrogens plus medroxyprogesterone acetate were reported to have a two-fold increase in the risk of developing probable dementia. Alzheimer’s disease was the most common classification of probable dementia in both the conjugated estrogens plus medroxyprogesterone acetate group and the placebo group. Ninety percent of the cases of probable dementia occurred in the 54% of women that were older than 70. (See , .)
It is unknown whether these findings apply to estrogen alone therapy.
Prefest (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.
The following additional adverse reactions have been reported with estrogen and/or progestin therapy:
Prefest (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.
Prefest (Estradiol) Dosage And Administration:
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 reevaluated 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.
Prefest (Estradiol) regimen consists of the daily administration of a single tablet containing 1 mg estradiol (peach color) for three days followed by a single tablet of 1 mg estradiol combined with 0.09 mg norgestimate (white color) for three days. This regimen is repeated continuously without interruption.
Prefest (Estradiol) How Supplied:
Prefest (Estradiol) (estradiol 1 mg and estradiol 1mg/norgestimate 0.09 mg) tablets are packaged in cartons of six pouches.
1 mg estradiol: Peach, round, flat-faced, beveled-edge, unscored tablets, debossed with on one side and on the other side.
1 mg estradiol and 0.09 mg norgestimate: White, round, flat-faced, beveled-edge, unscored tablets, debossed with on one side and on the other side.
Each pouch consists of a blister card containing 3 peach tablets followed by 3 white tablets. This pattern of 3 peach tablets and 3 white tablets repeats for a total of 30 tablets per blister card. Each blister card contains 15 tablets of each of the two tablets. The 3-day phases are alternated continuously during treatment.
Prefest (Estradiol) Patient Information
(estradiol/norgestimate) tablets
Read this PATIENT INFORMATION before you start taking Prefest (Estradiol) and read what you get each time you refill Prefest (Estradiol) . 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.
Prefest (Estradiol) Principal Display Panel
NDC 51285-063-90
estradiol norgestimate
Cycle-Pack
Rx only
Contents: 1 compact containing 30 tablets
Each peach tablet contains 1 mg estradiol.
Each white tablet contains 1 mg estradiol and 0.09 mg norgestimate.
Dosage: One tablet daily for 30 consecutive days in the following order: 3 peach tablets followed by 3 white tablets. The 3-day phases are alternated continuously during treatment. See package insert.
Rx only
TEVA WOMEN’S HEALTH, INC.
Subsidiary of Teva Pharmaceuticals, Inc.Sellersville, PA 18960
Package not child-resistant.
Store at 20º to 25ºC (68º to 77ºF) [See USP Controlled Room Temperature].
