PREFEST^® (ESTRADIOL/NORGESTIMATE) TABLETS

Rx only

Revised DECEMBER 2006

11001165

The PREFEST 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.

The estrogenic component of PREFEST 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 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.

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.

The effect of the estrogen component of PREFEST 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 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 CLINICAL PHARMACOLOGY (see Drug Interactions).

The effect of the estrogen component of PREFEST on vulvar and vaginal atrophy was confirmed in a 12-week placebo-controlled trial of healthy postmenopausal women with moderate to severe vasomotor symptoms (MSVS). The addition of norgestimate to estrogen (i.e., the PREFEST regimen) was studied in a 12-month trial in 143 healthy postmenopausal women between 42 and 65 years of age (92% Caucasian) for endometrial protection. Results from a subset population (n=69) with paired tests for maturation index of the vaginal mucosa are shown in Table 3.

The effect of PREFEST 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. No subject had a diagnosis of endometrial hyperplasia after treatment.

The effects of PREFEST 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.

The effect of PREFEST on lipids was evaluated in a 12-month metabolic trial of healthy postmenopausal women. Results are shown in Table 5.

PREFEST is indicated in women who have a uterus for the:

• Treatment of moderate to severe vasomotor symptoms associated with the menopause.
• Treatment of moderate to severe symptoms of vulvar and vaginal atrophy associated with the menopause. When prescribed solely for the treatment of symptoms of vulvar and vaginal atrophy, topical vaginal products should be considered.
• Prevention of postmenopausal osteoporosis. When prescribing solely for the prevention of postmenopausal osteoporosis, therapy should only be considered for women at significant risk of osteoporosis and nonestrogen medications should be carefully considered.

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 helpfulfor 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 should not be used in women with any of the following conditions:

• Undiagnosed abnormal genital bleeding.
• Known, suspected, or history of cancer of the breast.
• Known or suspected estrogen-dependent neoplasia.
• Active deep vein thrombosis, pulmonary embolism or history of these conditions.
• Active or recent (e.g., within the past year) arterial thromboembolic disease (e.g., stroke, myocardial infarction).
• Liver dysfunction or disease.
• PREFEST should not be used in patients with known hypersensitivity to its ingredients.
• Known or suspected pregnancy. There is no indication for PREFEST in pregnancy. There appears to be little or no increased risk of birth defects in children born to women who have used estrogens and progestins from oral contraceptives inadvertently during early pregnancy (See PRECAUTIONS).

See BOXED WARNINGS.

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 CLINICAL PHARMACOLOGY, Clinical Studies and PRECAUTIONS, Geriatric Use.)

It is unknown whether these findings apply to estrogen alone therapy.

A 2- to 4-fold increase in the risk of gallbladder disease requiring surgery in postmenopausal women receiving estrogens has been reported.

Estrogen administration may lead to severe hypercalcemia in patients with breast cancer and bone metastases. If hypercalcemia occurs, use of the drug should be stopped and appropriate measures taken to reduce the serum calcium level.

Retinal vascular thrombosis has been reported in patients receiving estrogens. Discontinue medication pending examination if there is sudden partial or complete loss of vision, or a sudden onset of proptosis, diplopia, or migraine. If examination reveals papilledema or retinal vascular lesions, estrogens should be permanently discontinued.

• Addition of a progestin when a woman has not had 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.
  
  There are, however, possible risks that may be associated with the use of progestins with estrogens compared to estrogen-alone treatment. These include a possible increased risk of breast cancer.
• Elevated blood pressure.
  In a small number of case reports, substantial increases in blood pressure have been attributed to idiosyncratic reactions to estrogens. In a large, randomized, placebo-controlled clinical trial, a generalized effect of estrogens on blood pressure was not seen. Blood pressure should be monitored at regular intervals with estrogen use.
• Hypertriglyceridemia.
  In patients with pre-existing hypertriglyceridemia, estrogen therapy may be associated with elevations of plasma triglycerides leading to pancreatitis and other complications.
• Impaired liver function and past history of cholestatic jaundice.
  Estrogens may be poorly metabolized in patients with impaired liver function. For patients with a history of cholestatic jaundice associated with past estrogen use or with pregnancy, caution should be exercised and in the case of recurrence, medication should be discontinued.
• Uterine bleeding.
  Use of PREFEST, can be associated with spotting, uterine bleeding, and anemia.
• Hypothyroidism.
  Estrogen administration 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 T₄ and T₃ serum concentrations in the normal range. Patients dependent on thyroid hormone replacement therapy who are also receiving estrogens may require increased doses of their thyroid replacement therapy. These patients should have their thyroid function monitored in order to maintain their free thyroid hormone levels in an acceptable range.
• Fluid retention.
  Because estrogens and progestins may cause some degree of fluid retention, patients with conditions that might be influenced by this factor, such as a 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.
  The CE/MPA substudy of WHI reported that estrogen plus progestin increased the risk of ovarian cancer. After an average follow-up of 5.6 years, the relative risk for ovarian cancer for CE/MPA versus placebo was 1.58 (95% confidence interval 0.77 – 3.24) but was not statistically significant. The absolute risk for CE/MPA versus placebo was 4.2 versus 2.7 cases per 10,000 women-years. In some epidemiologic studies, the use of estrogen alone, in particular for ten or more years, has been associated with an increased risk of ovarian cancer. Other epidemiologic studies have not found these associations.
• Exacerbation of endometriosis.
  Endometriosis may be exacerbated with administration of estrogens.
• Exacerbation of other conditions.
  Estrogens may cause an exacerbation of asthma, diabetes mellitus, epilepsy, migraine or porphyria, systemic lupus erythematosus, and hepatic hemangiomas and should be used with caution in women with these conditions.

Physicians are advised to discuss the spans of the PATIENT INFORMATION leaflet with patients for whom they prescribe PREFEST.

Estrogen administration should be initiated at the lowest dose approved for the indication and then guided by clinical response rather than by serum hormone levels (e.g., estradiol, FSH).

• Accelerated prothrombin time, partial thromboplastin time, and platelet aggregation time; increased platelet count; increased factors II, VII antigen, VIII antigen, VIII coagulant activity, IX, X, XII, VII-X complex, II-VII-X complex, and beta-thromboglobulin; decreased levels of antifactor Xa and antithrombin III, decreased antithrombin III activity; increased levels of fibrinogen and fibrinogen activity; increased plasminogen antigen and activity.
• Increased thyroid-binding globulin (TBG) levels leading to increased circulating total thyroid hormone levels as measured by protein-bound iodine (PBI), T₄ levels (by column or by radioimmunoassay) or T₃ levels by radioimmunoassay. T₃ resin uptake is decreased, reflecting the elevated TBG. Free T₄ and free T₃ concentrations are unaltered. Patients on thyroid replacement therapy may require higher doses of thyroid hormone.
• Other binding proteins may be elevated in serum (i.e., corticosteroid binding globulin (CBG), sex hormonebinding globulin (SHBG)) leading to increased total circulating corticosteroids and sex steroids, respectively. Free hormone concentrations may be decreased. Other plasma proteins may be increased (angiotensinogen/renin substrate, alpha-1-antitrypsin, ceruloplasmin).
• Increased plasma HDL and HDL₂ cholesterol subfraction concentrations, reduced LDL cholesterol concentration, increased triglycerides levels.
• Impaired glucose tolerance.
• Reduced response to metyrapone test.

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 BOXED WARNINGS, WARNINGS and PRECAUTIONS.)

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.

PREFEST should not be used during pregnancy. (See CONTRAINDICATIONS.)

Estrogen administration to nursing mothers has been shown to decrease the quantity and quality of the milk. Detectable amounts of estrogens and progestins have been identified in the milk of mothers receiving this drug. Caution should be exercised when PREFEST is administered to a nursing mother.

PREFEST is not indicated for use in children.

There have not been sufficient numbers of geriatric patients involved in clinical studies utilizing PREFEST to determine whether those over 65 years of age differ from younger subjects in their response to PREFEST.

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 WARNINGS, Dementia.)

It is unknown whether these findings apply to estrogen alone therapy.

 See BOXED WARNINGS,WARNINGS, and PRECAUTIONS.

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:

• Genitourinary system.
  Changes in vaginal bleeding pattern and abnormal withdrawal bleeding or flow; breakthrough bleeding; spotting; dysmenorrhea, increase in size of uterine leiomyomata; vaginitis, including vaginal candidiasis; change in amount of cervical secretion; changes in cervical ectropion; ovarian cancer; endometrial hyperplasia; endometrial cancer.
• Breasts.
  Tenderness, enlargement, pain, nipple discharge, galactorrhea; fibrocystic breast changes; breast cancer.
• Cardiovascular.
  Deep and superficial venous thrombosis; pulmonary embolism; thrombophlebitis; myocardial infarction; stroke; increase in blood pressure.
• Gastrointestinal.
  Nausea, vomiting; abdominal cramps, bloating; cholestatic jaundice; increased incidence of gallbladder disease; pancreatitis, enlargement of hepatic hemangiomas.
• Skin.
  Chloasma or melasma, that may persist when drug is discontinued; erythema multiforme; erythema nodosum; hemorrhagic eruption; loss of scalp hair; hirsutism; pruritus, rash.
• Eyes.
  Retinal vascular thrombosis, intolerance to contact lenses.
• Central Nervous System.
  Headache; migraine; dizziness; mental depression; chorea; nervousness; mood disturbances; irritability; exacerbation of epilepsy, dementia.
• Miscellaneous.
  Increase or decrease in weight; reduced carbohydrate tolerance; aggravation of porphyria; edema; arthalgias; leg cramps; changes in libido; urticaria, angioedema, anaphylactoid/anaphylactic reactions; hypocalcemia; exacerbation of asthma; increased triglycerides.

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.

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 BOXED WARNINGS and WARNINGS). 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 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.

• For treatment of moderate to severe vasomotor symptoms and vulvar and vaginal atrophy associated with menopause, the patient should start with the first tablet in the first row, and place the weekday schedule sticker which starts with the weekday of first tablet intake in the appropriate space. After all tablets from the buler card have been used, the first tablet from a new buler card should be taken on the following day.
  This dose may not be the lowest effective dose for treatment of vasomotor symptoms and vulvar and vaginal atrophy.
  Patients should be re-evaluated at three-month to six-month intervals to determine if treatment for symptoms is still necessary.
• For prevention of postmenopausal osteoporosis, the patient should start with the first tablet in the first row, and place the weekday schedule sticker which starts with the weekday of first tablet intake in the appropriate space. After all tablets from the buler card have been used, the first tablet from a new buler card should be taken on the following day.
  This dose may not be the lowest effective dose for the prevention of postmenopausal osteoporosis.

If a tablet is missed for one or more days, therapy should be resumed with the next available tablet. The patient should continue to take only one tablet each day in sequence.

The lowest effective dose of PREFEST has not been determined.

PREFEST^® (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 P on one side and 93 on the other side.

1 mg estradiol and 0.09 mg norgestimate: White, round, flat-faced, beveled-edge, unscored tablets, debossed with P on one side and 92 on the other side.

Each pouch consists of a buler 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 buler card. Each buler card contains 15 tablets of each of the two tablets. The 3-day phases are alternated continuously during treatment.

Prefest^®

(estradiol/norgestimate) tablets

Read this PATIENT INFORMATION before you start taking PREFEST and read what you get each time you refill PREFEST. 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.

Duramed Pharmaceuticals, Inc.
Subsidiary of Barr Pharmaceuticals, Inc.
Pomona, New York 10970

Revised DECEMBER 2006 (v.3)
BR-9063