ANGELIQ TABLETS provide a hormone regimen consisting of film coated tablets each containing 0.5 mg of drospirenone and 1 mg of estradiol. The inactive ingredients are lactose monohydrate NF, corn starch NF, modified starch NF, povidone 25000 USP, magnesium stearate NF, hydroxylpropylmethyl cellulose USP, macrogol 6000 NF, talc USP, titanium dioxide USP, and ferric oxide pigment NF.

Drospirenone, (6R,7R,8R,9S,10R,13S,14S,15S,16S,17S) -1,3´, 4´,6,6a,7,8,9,10,11,12,13,14,15,15a,16-hexadecahydro-10,13- dimethylspiro-[17H-dicyclopropa[6,7:15,16]cyclopenta [a]phenanthrene-17,2´(5H)-furan]-3,5´(2H)-dione (CAS) is a synthetic progestational compound and has a molecular weight of 366.5 and a molecular formula of C₂₄H₃₀O₃.

Estradiol USP, (Estra–1,3,5(10)–triene–3,17–diol,17β), has a molecular weight of 272.39 and the molecular formula is C₁₈H₂₄O₂. The structural formulas are as follows:

Last updated on RxList: 1/16/2009

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

1. Treatment of moderate to severe vasomotor symptoms associated with the menopause.
2. Treatment of moderate to severe symptoms of vulvar and vaginal atrophy associated with the menopause. When prescribing solely for the treatment of symptoms of vulvar and vaginal atrophy, topical vaginal products should be considered.

The dosage of ANGELIQ is one tablet daily. Women who are already using a product containing estrogen should stop taking that product before starting ANGELIQ .

Use of estrogen, alone or in combination with a progestin, should be limited to the lowest effective dose available 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 sections). 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.

The lowest effective dose of ANGELIQ has not been determined.

ANGELIQ TABLETS (drospirenone and estradiol) 0.5 mg/1 mg are available as round, biconvex pink film-coated tablets embossed with “CK” inside a hexagon, and supplied in the following packaging:

3 blisters of 28 tablets NDC 50419-483-03

Storage Conditions

Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F)

[See USP Controlled Room Temperature].

Manufactured for: Bayer HealthCare Pharmaceuticals Inc., Wayne, NJ 07470. Manufactured in Germany. FDA revision date: 9/28/2005

Last updated on RxList: 1/16/2009

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 are adverse events reported with ANGELIQ occurring in > 5% of subjects:

Table 4: Adverse Events Regardless of Drug Relationship Reported at a Frequency of > 5% in a 1-year Double-blind Clinical Trial

The following additional adverse reactions have been reported with estrogen and or estrogen/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 gall bladder disease, pancreatitis, enlargement of hepatic hemangiomas.

Skin

Chloasma or melasma, which 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, arthralgias, leg cramps, changes in libido, anaphylactoid/anaphylactic reactions including urticaria and angioedema, hypocalcemia, exacerbation of asthma, increased triglycerides.

Drug/Laboratory Test Interactions

1. 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 anti-factor Xa and antithrombin III, decreased antithrombin III activity; increased levels of fibrinogen and fibrinogen activity; increased plasminogen antigen and activity.
2. Increased thyroid-binding globulin (TBG) levels leading to increased circulating total thyroid hormone, as measured by proteinbound iodine (PBI), T4 levels (by column or by radio immunoassay) or T3 levels by radio immunoassay. 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.
3. Other binding proteins may be elevated in serum (i.e., corticosteroid binding globulin (CBG), sex hormone-binding globulin (SHBG)) leading to increased 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).
4. Increased plasma HDL and HDL-2 subfraction concentrations, reduced LDL cholesterol concentration, increased triglyceride levels.
5. Impaired glucose tolerance.
6. Reduced response to metyrapone test.

Last updated on RxList: 1/16/2009

ANGELIQ contains 0.5 mg of the progestin drospirenone that has antialdosterone activity, including the potential for hyperkalemia in high-risk patients.

ANGELIQ should not be used in patients with conditions that predispose to hyperkalemia (i.e. renal insufficiency, hepatic dysfunction, and adrenal insufficiency).

Use caution when prescribing ANGELIQ to women who regularly take other medications that can increase potassium, such as NSAIDs, potassium-sparing diuretics, potassium supplements, ACE inhibitors, angiotensin-II receptor antagonists, and heparin. Consider checking serum potassium levels during the first treatment cycle in high-risk patients.

See BOXED WARNINGS.

Cardiovascular disorders

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 cardiovascular 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.

Coronary heart disease and stroke

In the Women's Health Initiative study (WHI), an increase in the number of myocardial infarctions and strokes has been observed in women receiving oral CE compared to placebo. (See CLINICAL PHARMACOLOGY, Clinical Studies sections.)

In the CE/MPA substudy of WHI an increased risk of coronary heart disease (CHD) events (defined as non-fatal myocardial infarction and CHD death) was observed in women receiving CE/MPA compared to women receiving placebo (37 vs 30 per 10,000 person years). The increase in risk was observed in year one and persisted.

In the same substudy of WHI, an increased risk of stroke was observed in women receiving CE/MPA compared to women receiving placebo (29 vs 21 per 10,000 person-years). The increase in risk was observed after the first year and persisted.

In postmenopausal women with documented heart disease (n = 2,763, average age 66.7 years) a controlled clinical trial of secondary prevention of cardiovascular disease (Heart and Estrogen/Progestin Replacement Study; HERS) treatment with CE/MPA-0.625 mg/2.5 mg per day demonstrated no cardiovascular benefit. During an average follow-up of 4.1 years, treatment with CE/MPA did not reduce the overall rate of CHD events in postmenopausal women with established coronary heart disease. There were more CHD events in the CE/MPA-treated group than in the placebo group in year 1, but not during the subsequent years.

Two thousand three hundred and twenty one women from the original HERS trial agreed to participate in an open label extension of HERS, HERS II. Average follow-up in HERS II was an additional 2.7 years, for a total of 6.8 years overall. Rates of CHD events were comparable among women in the CE/MPA group and the placebo group in HERS, HERS II, and overall.

Large doses of estrogen (5 mg conjugated estrogens per day), comparable to those used to treat cancer of the prostate and breast, have been shown in a large prospective clinical trial in men to increase the risks of nonfatal myocardial infarction, pulmonary embolism, and thrombophlebitis.

Venous thromboembolism (VTE)

In the Women's Health Initiative study (WHI), an increase in VTE has been observed in women receiving CE compared to placebo. (See CLINICAL PHARMACOLOGY and Clinical Studies sections.)

In the CE/MPA substudy of WHI, a 2-fold greater rate of VTE, including deep venous thrombosis and pulmonary embolism, was observed in women receiving CE/MPA compared to women receiving placebo. The rate of VTE was 34 per 10,000 woman years in the CE/MPA group compared to 16 per 10,000 woman years in the placebo group. The increase in VTE risk was observed during the first year and persisted.

If feasible, estrogens should be discontinued at least 4 to 6 weeks before surgery of the type associated with an increased risk of thromboembolism, or during periods of prolonged immobilization.

Malignant neoplasms

Endometrial cancer

The use of unopposed estrogens in women with intact uteri has been associated with an increased risk of endometrial cancer. The reported endometrial cancer risk among unopposed estrogen users is about 2- to 12-fold greater than in non-users, and appears dependent on duration of treatment and on estrogen dose. Most studies show no significant increased risk associated with use of estrogens for less than one year. The greatest risk appears associated with prolonged use, with increased risks of 15- to 24-fold for five to ten years or more and this risk has been shown to persist for at least 8 to 15 years after estrogen therapy is discontinued.

Clinical surveillance of all women taking estrogen/progestin combinations is important. 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 the use of natural estrogens results in a different endometrial risk profile than synthetic estrogens of equivalent estrogen dose. Adding a progestin to estrogen therapy has been shown to reduce the risk of endometrial hyperplasia, which may be a precursor to endometrial cancer.

Breast cancer

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 issue is the Women's Health Initiative (WHI) substudy of CE/MPA (see CLINICAL PHARMACOLOGY, Clinical Studies). The results from observational studies are generally consistent with those of the WHI clinical trial and report no significant variation in the risk of breast cancer among different estrogens or progestins, doses, or routes of administration.

The CE/MPA substudy of WHI reported an increased risk of breast cancer in women who took CE/MPA for a mean follow-up of 5.6 years. Observational studies have also reported an increased risk for estrogen/progestin combination therapy, and a smaller increased risk for estrogen alone therapy, after several years of use. In the WHI trial and from observational studies, the excess risk increased with duration of use. From observational studies, the risk appeared to return to baseline in about five years after stopping treatment. In addition, observational studies suggest that the risk of breast cancer was greater, and became apparent earlier, with estrogen/progestin combination therapy as compared to estrogen alone therapy.

In the CE/MPA substudy, 26% of the women reported prior use of estrogen alone and/or estrogen/progestin combination hormone therapy. After a mean follow-up of 5.6 years during the clinical trial, the overall relative risk of invasive breast cancer was 1.24 (95% confidence interval 1.01-1.54), and the overall absolute risk was 41 vs. 33 cases per 10,000 women-years, for CE/MPA compared with placebo. Among women who reported prior use of hormone therapy, the relative risk of invasive breast cancer was 1.86, and the absolute risk was 46 vs. 25 cases per 10,000 women years, for CE/MPA compared with placebo. Among women who reported no prior use of hormone therapy, the relative risk of invasive breast cancer was 1.09, and the absolute risk was 40 vs. 36 cases per 10,000 women-years for CE/MPA compared with placebo. In the same substudy, invasive breast cancers were larger and diagnosed at a more advanced stage in the CE/MPA group compared with the placebo group. 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 plus progestin has been reported to result in an increase in abnormal mammograms requiring further evaluation. All women should receive yearly breast examinations by a healthcare provider and perform monthly breast self examinations. In addition, mammography examinations should be scheduled based on patient age, and risk factors, and prior mammogram results.

Dementia

In the estrogen alone Women's Health Initiative Memory Study (WHIMS), a substudy of WHI, 2,947 hysterectomized women aged 65 to 79 years were randomized to CE or placebo. In the estrogen plus progestin WHIMS substudy, 4,532 postmenopausal women aged 65 to 79 years were randomized to CE/MPA 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 estrogen alone versus placebo was 1.49 (95%CI 0.83-2.66). The absolute risk of probable dementia for estrogen alone versus placebo was 37 versus 25 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.)

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.)

Gallbladder disease

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

Hypercalcemia

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.

Visual abnormalities

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.

General

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 regimens. 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 estrogen therapy 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. The clearance of drospirenone was decreased in patients with moderate hepatic impairment.

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 estrogen and estrogen/progestin therapy 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.

Hyponatremia

As an aldosterone antagonist, drospirenone may increase the possibility of hyponatremia in high-risk patients.

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

Endometriosismay be exacerbated with administration of estrogens.

Exacerbation of other conditions

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

Patient Information

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

Laboratory Tests

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

Carcinogenesis, mutagenesis, and impairment of Fertility

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. (See BOXED WARNINGS, CONTRAINDICATIONS, and WARNINGS sections.)

In a 24 month oral carcinogenicity study in mice dosed with 10 mg/kg/day drospirenone alone or 1 + 0.01, 3 + 0.03 and 10 + 0.1 mg/kg/day of drospirenone and ethinyl estradiol, 0.24 to 10.3 times the exposure (AUC of drospirenone) of women taking a 1 mg dose, there was an increase in carcinomas of the harderian gland in the group that received the high dose of drospirenone alone. In a similar study in rats given 10 mg/kg/day drospirenone alone or 0.3 + 0.003, 3 + 0.03 and 10 + 0.1 mg/kg/day drospirenone and ethinyl estradiol, 2.3 to 51.2 times the exposure of women taking a 1 mg dose, there was an increased incidence of benign and total (benign and malignant) adrenal gland pheochromocytomas in the group receiving the high dose of drospirenone. Drospirenone was not mutagenic in a number of in vitro(Ames, Chinese Hamster Lung gene mutation and chromosomal damage in human lymphocytes) and in vivo (mouse micronucleus) genotoxicity tests. Drospirenone increased unscheduled DNA synthesis in rat hepatocytes and formed adducts with rodent liver DNA but not with human liver DNA. (See WARNINGS section.)

Pregnancy

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

Nursing Mothers

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

After administration of an oral contraceptive containing drospirenone about 0.02% of the drospirenone dose was excreted into the breast milk of postpartum women within 24 hours. This results in a maximal daily dose of about 3 mcg drospirenone in an infant.

Pediatric Use

ANGELIQ is not indicated in children.

Geriatric Use

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

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 who were older than 70. (See WARNINGS, Dementia.)

Last updated on RxList: 1/16/2009

In cases of ANGELIQ overdose, monitor serum concentrations of potassium and sodium since drospirenone has antimineralocorticoid properties.

Serious ill effects have not been reported following acute ingestion of large doses of progestin/estrogen-containing oral contraceptives by young children. Overdosage may cause nausea and withdrawal bleeding may occur in females.

Progestogens/estrogens should not be used in individuals with any of the following conditions:

1. Undiagnosed abnormal genital bleeding.
2. Known, suspected, or history of cancer of the breast.
3. Known or suspected estrogen-dependent neoplasia.
4. Active deep vein thrombosis, pulmonary embolism or history of these conditions.
5. Active or recent (e.g., within the past year) arterial thromboembolic disease (e.g., stroke, myocardial infarction).
6. Renal insufficiency.
7. Liver dysfunction or disease.
8. Adrenal insufficiency.
9. ANGELIQ should not be used in patients with known hypersensitivity to its ingredients.
10. Known or suspected pregnancy. There is no indication for ANGELIQ 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).

Last updated on RxList: 1/16/2009

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 (E2) 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 will 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.

Drospirenone (DRSP) is a synthetic progestin and spironolactone analog with antimineralocorticoid activity. In animals and in vitro, drospirenone has anti androgenic activity, but no glucocorticoid, anti glucocorticoid, estrogenic, or androgenic activity. Progestins counter estrogenic effects by decreasing the number of nuclear estradiol receptors and suppressing epithelial DNA synthesis in endometrial tissue.

Pharmacokinetics

Absorption:Serum concentrations of DRSP reach peak levels approximately 1 hour after administration of ANGELIQ and mean absolute bioavailability of DRSP ranges from 76-85%. Following oral administration, peak serum estradiol concentrations are typically reached 6-8 hours after dosing with ANGELIQ . The oral relative bioavailability of estradiol and DRSP following administration of ANGELIQ is 107% and 102%, respectively when compared to a combination oral suspension.

The pharmacokinetics of DRSP are dose proportional within the dose range of 0.5-4 mg. Following daily dosing of ANGELIQ , steady state DRSP concentrations were observed after 10 days. Mean accumulation ratios for estradiol and DRSP were 1.9 and 2.4, respectively. Mean concentrations at 2 hours for DRSP ranged between 5.9 and 6.7 ng/mL after treatment with ANGELIQ for 365 days. Mean steady state serum DRSP and E2 concentrations are shown in Figure 1, and a summary of primary pharmacokinetic parameters following the administration of 1mg E2/1mg DRSP for 28 days is presented in Table 1.

Figure 1: Mean steady state serum drospirenone and estradiol concentrations following daily oral administration of 1 mg E2/0.5 mg DRSP¹

¹DRSP levels are simulated based on data obtained after oral administration of 1 mg DRSP/1 mg Estradiol

Table 1: Mean Steady State Pharmacokinetic Parameters of Tablets Containing Drospirenone (1 mg)* and Estradiol (1 mg)

Effect of Food: The effect of food on the absorption and bioavailability of DRSP and E2 have not been investigated following the administration of ANGELIQ . However, clinical studies with different formulations containing DRSP or E2 have shown that the bioavailability of both drugs is not affected by concomitant food intake.

Distribution: The mean volume of distribution of DRSP is 4.2 L/kg. DRSP does not bind to sex hormone binding globulin (SHBG) or corticosteroid binding globulin (CBG) but binds about 97%to other serum proteins. The distribution of exogenous estrogens is similar to that of endogenous estrogens. Estrogens are widely distributed in the body and are generally found in higher concentrations in the sex hormone target organs. Estradiol circulates in the blood bound to SHBG (37%) and to albumin (61%), while only approximately 1%-2% is unbound.

Metabolism: Mean clearance of DRSP is 1.2 mL/min/kg. DRSP is extensively metabolized after oral administration. The 2 main metabolites of DRSP found in human plasma were identified to be the acid form of DRSP generated by opening of the lactone ring and the 4,5-dihydrodrospirenone-3-sulfate, both of which are formed without the involvement of the cytochrome P450 system. These metabolites were shown not to be pharmacologically active. In in vitro studies with human liver microsomes, DRSP was metabolized only to a minor extent mainly by Cytochrome P450 3A4 (CYP3A4).

Exogenous estrogens are metabolized in the same manner as endogenous estrogens. Circulating estrogens exist in a dynamic equilibrium of metabolic interconversions. These transformations take place mainly in the liver. Estradiol is converted reversibly to estrone, and both can be converted to estriol, which is the major urinary metabolite. Estrogens also undergo enterohepatic recirculation via sulfate and glucuronide conjugation in the liver, biliary secretion of conjugates into the intestine, and hydrolysis in the gut followed by reabsorption. In postmenopausal women, a significant proportion of the circulating estrogens exist as sulfate conjugates, especially estrone sulfate, which serves as a circulating reservoir for the formation of more active estrogens.

Excretion: DRSP serum levels are characterized by a terminal elimination half-life of approximately 36-42 hours. Excretion of DRSP was nearly complete after 10 days and amounts excreted were slightly higher in feces compared to urine. DRSP was extensively metabolized and only trace amounts of unchanged DRSP were excreted in urine and feces. At least 20 different metabolites were observed in urine and feces. About 38% to 47% of the metabolites in urine were glucuronide and sulfate conjugates. In feces, about 17% to 20% of the metabolites were excreted as glucuronides and sulfates. Estradiol, estrone, and estriol are excreted in the urine along with glucuronide and sulfate conjugates.

Special Populations

Geriatric: No pharmacokinetic studies were conducted in the geriatric population.

Pediatric: No pharmacokinetic study for ANGELIQ has been conducted in a pediatric population.

Gender: ANGELIQ is indicated for use in women only.

Race: No studies were done to determine the effect of race on the pharmacokinetics of ANGELIQ .

Patients with Hepatic Impairment: ANGELIQ is contraindicated in patients with hepatic dysfunction(also see BOLDED WARNING).

The mean exposure to DRSP in women with moderate liver impairment is approximately three times the exposure in women with normal liver function.

Patients with Renal Impairment: ANGELIQ is contraindicated in patients with renal insufficiency (also see BOLDED WARNING).

The effect of renal insufficiency on the pharmacokinetics of DRSP (3 mg daily for 14 days) and the effects of DRSP on serum potassium levels were investigated in female subjects (n = 28, age 30 - 65) with normal renal function (11 patients), and mild (10 patients) and moderate (7 patients) renal impairment. All subjects were on a low potassium diet. During the study 7 subjects continued the use of potassium-sparing drugs for the treatment of the underlying illness. On the 14th day (steady-state) of DRSP treatment, the serum DRSP levels were on average 37% higher in the group with moderate renal impairment (CLcr 30-50 mL/min) compared to those in the group with normal renal function. Serum DRSP levels in the group with mild renal impairment (creatinine clearance CLcr, 50-80 mL/min) were comparable to those in the group with normal renal function (CLcr, > 80 mL/min). DRSP treatment was well tolerated by all groups. DRSP treatment did not show any clinically significant effect on serum potassium concentration. Although hyperkalemia was not observed in the study, in 5 of the 7 subjects who continued use of potassium sparing drugs during the study, individual mean serum potassium levels increased by up to 0.33 mEq/L. Therefore, potential exists for hyperkalemia to occur in subjects with renal impairment whose serum potassium is in the upper reference range, and who are concomitantly using potassium sparing drugs.

Drug Interactions

Effects of Drospirenone on Other Drugs

Metabolic Interactions

Metabolism of DRSP and potential effects of DRSP on hepatic cytochrome P450 (CYP) enzymes have been investigated in in vitro and in vivo studies (see Metabolism). In in vitro studies, DRSP did not affect turnover of model substrates of CYP1A2 and CYP2D6, but had an inhibitory influence on the turnover of model substrates of CYP1A1, CYP2C9, CYP2C19 and CYP3A4 with CYP2C19 being the most sensitive enzyme. The potential effect of DRSP on CYP2C19 activity was investigated in a clinical pharmacokinetic study using omeprazole as a marker substrate. In the study with 24 postmenopausal women [including 12 women with homozygous (wild type) CYP2C19 genotype and 12 women with heterozygous CYP2C19 genotype] the daily oral administration of 3 mg DRSP for 14 days did not affect the systemic clearance of the CYP2C19 substrate omeprazole (40 mg) and the CYP2C19 product 5-hydroxy-omeprazole. Furthermore, no significant effect of DRSP on the systemic clearance of the CYP3A4 product omeprazole sulfone was found. These results demonstrated that DRSP did not inhibit CYP2C19 and CYP3A4 in vivo.

Two further clinical drug-drug interaction studies using simvastatin and midazolam as marker substrates for CYP3A4, were each performed in 24 healthy, postmenopausal women. The results of these studies demonstrated that pharmacokinetics of the CYP3A4 substrates were not influenced by steady-state DRSP concentrations achieved after administration of 3 mg DRSP/day.

Based on the available results of in vivo and in vitro studies, it can be concluded that, at clinical dose level, DRSP is unlikely to interact significantly with cytochrome P450 enzymes. In vitro and in vivo studies have shown that estrogens are metabolized partially by cytochrome P450 3A4 (CYP3A4). Therefore, inducers or inhibitors of CYP3A4 may affect estrogen drug metabolism.

Inducers of CYP3A4 such as St. John's Wort preparations (Hypericum perforatum), phenobarbital, carbamazepine, and rifampin may reduce plasma concentrations of estrogens, possibly resulting in a decrease in therapeutic effects and/or changes in the uterine bleeding profile. Inhibitors of CYP3A4 such as erythromycin, clarithromycin, ketoconazole, itraconazole, ritonavir and grapefruit juice may increase plasma concentrations of estrogens and may result in side effects.

Co-Administration with Drugs that Have the Potential to Increase Serum Potassium

There is a potential for an increase in serum potassium in women taking drospirenone with other drugs that may affect electrolytes, such as angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers, or non-steroidal anti-inflammatory drugs (NSAIDs).

Electrolytes were studied in 230 postmenopausal women with hypertension and/or diabetes mellitus requiring an ACE inhibitor or angiotensin receptor blocker (ARB). Of these, 26 patients had a creatinine clearance > 50 mL/min to < 80 mL/min. Patients were given 1 mg estradiol (E2) and 3 mg drospirenone (DRSP) (n=112) or placebo (n=118) over 28 days. Non-diabetic patients also received ibuprofen 1200 mg/day for 5 days during the study. There was a single case of serum potassium > 6 mEq/L and a single case of serum sodium < 130 mEq/L on treatment, both occurring following five days of ibuprofen therapy in two women taking E2/DRSP. Serum potassium levels > 5.5 mEq/L were observed in 8 (7.3%) E2/DRSP-treated subjects (3 diabetic and 5 non-diabetic) and in 3 (2.6%) placebo-treated subjects (2 diabetic and 1 nondiabetic). After 28 days of exposure, the mean change from baseline in serum potassium was 0.11 mEq/L for the E2/DRSP group and 0.08 mEq/L for the placebo group. None of the subjects with serum potassium levels > 5.5 mEq/L had cardiovascular adverse events. A drug-drug interaction study of DRSP 3 mg/estradiol (E2) 1 mg versus placebo was performed in 24 mildly hypertensive postmenopausal women taking enalapril maleate 10 mg twice daily. Potassium levels were obtained every other day for a total of 2 weeks in all subjects. Mean serum potassium levels in the DRSP/E2 treatment group relative to baseline were 0.22 mEq/L higher than those in the placebo group. Serum potassium concentrations also were measured at multiple timepoints over 24 hours at baseline and on Day 14. On Day 14, the ratios for serum potassium Cmax and AUC in the DRSP/E2 group to those in the placebo group were 0.955 (90% CI: 0.914, 0.999) and 1.01 (90% CI: 0.944, 1.08), respectively. No patient in either treatment group developed hyperkalemia (serum potassium concentrations > 5.5 mEq/L).

Of note, occasional or chronic use of NSAID medication was not restricted in any of the ANGELIQ clinical trials.

Clinical Studies

Support for the indications: Support for treatment of vasomotor symptoms and vaginal and vulvar atrophy was shown through bio equivalence of the E2 component of the combination product with a currently marketed E2 product (Estrace® ). The multipledose

bio equivalence study evaluated the bio equivalence of E2 from a tablet containing DRSP (2 mg) and E2 (1 mg) relative to Estrace (1 mg) tablet. DRSP/E2 tablets met the criteria for bio equivalence to Estrace.

Effects on Endometrium: In a one year clinical trial of 1,142 postmenopausal subjects treated with E2 alone or E2 + 0.5, 1, 2, or 3 mg DRSP, endometrial biopsies were performed on 966 (84.6%) subjects during the treatment period. Eight subjects in the E2 monotherapy group developed endometrial hyperplasia (4 simple hyperplasia with no cytological atypia, 3 complex hyperplasia with no cytological atypia, and 1 complex hyperplasia with cytological atypia), and one subject in the 1 mg E2 + 2 mg DRSP group developed simple hyperplasia with no cytological atypia. Table 2 shows that there were no diagnoses of endometrial hyperplasia in the ANGELIQ group.

Table 2: Incidence of Endometrial Hyperplasia after up to 12 Months of Treatment

Effects on Uterine Bleeding or Spotting

In a cumulative analysis performed over 12 months in a double blind trial, the proportions of women with amenorrhea increased and at one year, 73.5% of subjects on ANGELIQ had amenorrhea. Results are shown in Figure 2.

Figure 2: Cumulative proportion of subjects with amenorrhea at a given cycle through cycle 13, LOCF

* One patient from each treatment group did not have bleeding diary information

Women's Health Initiative Studies: The Women's Health Initiative (WHI) enrolled a total of 27,000 predominantly healthy postmenopausal women to assess the risks and benefits of either the use of 0.625 mg conjugated equine estrogens (CE) per day alone or the use of 0.625 mg conjugated equine estrogens plus 2.5 mg medroxyprogesterone acetate (MPA) per day compared to placebo in the prevention of certain chronic diseases. The primary endpoint was the incidence of coronary heart disease (CHD) (nonfatal myocardial infarction and CHD death), with invasive breast cancer as the primary adverse outcome studied. A “global index” included the earliest occurrence of CHD, invasive breast cancer, stroke, pulmonary embolism (PE), endometrial cancer, colorectal cancer, hip fracture, or death due to other cause. The study did not evaluate the effects of CE or CE/MPA on menopausal symptoms.

The CE/MPA sub-study was stopped early because, according to the predefined stopping rule, the increased risk of breast cancer and cardiovascular events exceeded the specified benefits included in the “global index”. Results of the CE/MPA sub-study, which included 16,608 women (average age of 63 years, range 50 to 79; 83.9% White, 6.5% Black, 5.5% Hispanic), after an average follow up of 5.2 years are presented in Table 3 below:

Table 3: Relative and Absolute Risk Seen in the CE/MPA Substudy of WHI^a

For those outcomes included in the “global index,”absolute excess risks per 10,000 person-years in the group treated with CE/MPA were 7 more CHD events, 8 more strokes, 8 more PEs, and 8 more invasive breast cancers, while absolute risk reductions per 10,000 person-years were 6 fewer colorectal cancers and 5 fewer hip fractures.

The absolute excess risk of events included in the “global index”was 19 per 10,000 person-years. There was no difference between the groups in terms of all-cause mortality. (See BOXED WARNINGS, WARNINGS, and PRECAUTIONS.)

Women's Health Initiative Memory Study: The Women's Health Initiative Memory Study (WHIMS), a substudy of WHI, enrolled 4,532 predominantly healthy postmenopausal women 65 years of age and older (47% were age 65 to 69 years, 35% were 70 to 74 years, and 18% were 75 years of age and older) to evaluate the effects of CE/MPA (0.625 mg conjugated estrogens plus 2.5 mg medroxyprogesterone acetate) on the incidence of probable dementia (primary outcome) compared with placebo.

After an average follow-up of 4 years, 40 women in the estrogen/ progestin (45 per 10,000 women-years) and 21 in the placebo group (22 per 10,000 women-years) were diagnosed with probable dementia. The relative risk of probable dementia in the hormone therapy group was 2.05 (95% CI, 1.21 to 3.48) compared to placebo. Differences between groups became apparent in the first year of treatment. It is unknown whether these findings apply to younger postmenopausal women. (See BOXED WARNING and WARNINGS, Dementia.)

Last updated on RxList: 1/16/2009

ANGELIQ® TABLETS
(drospirenone and estradiol)

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

What is ANGELIQ?

ANGELIQ is a medicine that contains two kinds of hormones, estrogen and progestin.

What is ANGELIQ used for?

ANGELIQ is used after menopause to:

• reduce moderate to severe hot flashes.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 ANGELIQ .
• treat moderate to severe dryness, itching, and burning in or around the vagina. You and your healthcare provider should talk regularly about whether you still need treatment with ANGELIQ to control these problems. If you use ANGELIQ only to treat dryness, itching, and burning in and around your vagina, talk with your healthcare provider about whether a topical vaginal product would be better for you.

Who should not use ANGELIQ?

Do not use ANGELIQ if you have had your uterus removed (hysterectomy).

ANGELIQ contains a progestin to decrease the chances of getting cancer of the uterus. If you do not have a uterus, you do not need a progestin and you should not use ANGELIQ .

Do not start taking ANGELIQ if you:

• have unusual vaginal bleeding.
• currently have or have had certain cancers. Estrogens may increase the chances of getting certain types of cancers, including cancer of the breast or uterus. If you have or had cancer, talk with your healthcare provider about whether you should take ANGELIQ .
• had a stroke or heart attack in the past year.
• currently have or have had blood clots.
• have kidney disease, liver disease, or disease of your adrenal glands.
• are allergic to ANGELIQ or any of its ingredients. See the end of this leaflet for a list of ingredients in ANGELIQ .
• think you may be pregnant.

Tell your healthcare provider:

• if you are breastfeeding. The hormone in ANGELIQ can pass into your milk.
• about all of your medical problems. Your healthcare provider may need to check you more carefully if you have certain conditions, such as asthma (wheezing), epilepsy (seizures), migraine, endometriosis, lupus, hypertension (high blood pressure) or problems with your heart, liver, thyroid, kidneys, or have high calcium levels in your blood.
• about all the medicines you take, including prescription and nonprescription medicines, vitamins, and herbal supplements. Some medicines may affect how ANGELIQ works. ANGELIQ may also affect how your other medicines work.
• if you are going to have surgery or will be on bed rest. You may need to stop taking estrogens.

How should I take ANGELIQ?

1. Take one tablet every day.
2. Estrogens should be used only as long as needed. The lowest effective dose of ANGELIQ has not been determined. You and your healthcare provider should talk regularly (for example, every 3 to 6 months) about whether you still need treatment with ANGELIQ .

What are the possible side effects of ANGELIQ?

ANGELIQ is different from other hormonal medicines for menopausal symptoms because it contains drospirenone, and drospirenone may increase the potassium or lower the sodium in your blood.

You should not take ANGELIQ if you have kidney, liver or adrenal disease because these conditions may also increase the potassium in your blood. Some other medicines also increase potassium. If you regularly take another medicine that increases potassium levels, talk with your healthcare provider about whether ANGELIQ is right for you. In some situations, your healthcare provider may recommend testing your blood for potassium.

Less common but serious side effects include the following and should be discussed with your healthcare provider to assess your personal risks:

• Breast cancer
• Cancer of the uterus
• Stroke
• Heart attack
• Blood clots
• Dementia
• Gallbladder disease
• Ovarian cancer

These are some of the warning signs of serious side effects:

• Breast lumps
• Unusual vaginal bleeding
• Dizziness and faintness
• Changes in speech
• Severe headaches
• Chest pain
• Shortness of breath
• Pains in your legs
• Changes in vision
• Vomiting

Call your healthcare provider right away if you get any of these warning signs, or any other unusual symptom that concerns you.

Common side effects include:

• Headache
• Breast pain
• Irregular vaginal bleeding or spotting
• Stomach/abdominal cramps, bloating
• Nausea and vomiting
• Hair loss

Other side effects include:

• High blood pressure
• Liver problems
• High blood sugar
• Fluid retention
• Enlargement of benign tumors of the uterus (“fibroids”)
• Vaginal yeast infection

These are not all the possible side effects of ANGELIQ . For more information, ask your healthcare provider or pharmacist.

What can I do to lower my chances of a serious side effect with ANGELIQ?

Talk with your healthcare provider regularly about whether you should continue taking ANGELIQ .

See your healthcare provider right away if you get vaginal bleeding while taking ANGELIQ .

Have a breast exam and mammogram (breast X-ray) every year unless your healthcare provider tells you something else. 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 for getting heart disease. Ask your healthcare provider for ways to lower your chances for getting heart disease.

General information about safe and effective use of ANGELIQ.

Medicines are sometimes prescribed for conditions that are not mentioned in patient information leaflets. Do not use ANGELIQ for conditions for which it was not prescribed. Do not give ANGELIQ to other people, even if they have the same symptoms you have. It may harm them.

Keep ANGELIQ out of the reach of children

This leaflet summarizes the most important information about ANGELIQ . If you would like more information, talk with your healthcare provider or pharmacist. You can ask for information about ANGELIQ that is written for health professionals. You can get more information by calling our toll free number (1-888-237-5394) or visit www.angeliq-us.com

What are the ingredients in ANGELIQ?

The active ingredients in ANGELIQ are drospirenone (a progestin) and estradiol. ANGELIQ also contains lactose monohydrate NF, corn starch NF, modified starch NF, povidone USP, magnesium stearate NF, hydroxylpropylmethyl cellulose USP, macrogol NF, talc USP, titanium dioxide USP, and ferric oxide pigment NF.

Do not store above 86°F (30°C).

Last updated on RxList: 1/16/2009

IMPORTANT NOTE: This is a summary and does not contain all possible information about this product. For complete information about this product or your specific health needs, ask your health care professional. Always seek the advice of your health care professional if you have any questions about this product or your medical condition. This information is not intended as individual medical advice and does not substitute for the knowledge and judgment of your health care professional. This information does not contain any assurances that this product is safe, effective, or appropriate for you.

DROSPIRENONE/ESTRADIOL - ORAL

(droh-SPYE-re-none/ess-truh-DYE-all)

COMMON BRAND NAME(S): Angeliq

WARNING: Rarely, very serious side effects have occurred when estrogen-only and combination hormone replacement therapies (estrogen and progestin HRT) are used after menopause. Discuss the risks and benefits of hormone treatment and your personal health history with your doctor.

Combination HRT should not be used to prevent heart disease or dementia. Combination HRT can rarely cause heart disease (e.g., heart attacks), stroke, serious blood clots (pulmonary embolism and deep venous thrombosis), dementia, and breast cancer. The risk for stroke and breast cancer increases with age, especially for women older than 75. Estrogens may also increase the risk of cancer of the ovaries. Some of these risks appear to depend on the length of time this drug is used and the amount of estrogen per dose. Therefore, this medication should be used for the shortest possible length of time at the lowest effective dose, so you can obtain the benefits and minimize the chance of serious side effects from long-term treatment. Discuss the details with your doctor and check with him/her regularly (e.g., every 3-6 months) to see if you still need to take this medication.

If you use this drug for an extended time, you should have a complete physical exam at regular intervals (e.g., once a year) or as directed by your doctor. See Notes section.

USES: This medication is used to reduce menopause symptoms. It helps reduce episodes of flushing and sweating of the upper body and face, commonly called hot flashes. It also helps treat dryness, itching, and burning around the vagina. These symptoms occur when a woman's body no longer makes the usual amount of female hormone (estrogen). This medication is a combination of 2 types of female hormones: an estrogen (estradiol) and a progestin (drospirenone). A progestin is added to estrogen replacement therapy to reduce the risk of cancer of the uterus. A woman who has had her uterus removed does not need progestin and should not be treated with this combination medication.

If you need treatment only for vaginal menopause symptoms, products applied directly inside the vagina should be considered before medications that are taken by mouth, absorbed through the skin, or injected.

OTHER USES: This section contains uses of this drug that are not listed in the approved professional labeling for the drug but that may be prescribed by your health care professional. Use this drug for a condition that is listed in this section only if it has been so prescribed by your health care professional.

Certain combination HRT products may also be used to prevent bone loss (osteoporosis) in people at high risk who cannot take other drugs that are safe and effective to prevent or treat bone loss (e.g., raloxifene, bisphosphonates such as alendronate). These medicines should be considered for use before estrogen/progestin HRT therapy for osteoporosis.

HOW TO USE: Read the Patient Information Leaflet provided by your pharmacist before you start using this medication and each time you get a refill. If you have any questions, consult your doctor or pharmacist.

Take this medication by mouth, usually once daily or as directed by your doctor. Take this medication regularly to get the most benefit from it. To help you remember, take it at the same time each day.

Inform your doctor if your condition does not improve or if it worsens.

SIDE EFFECTS: Dizziness, lightheadedness, headache, stomach upset, bloating, irritability, changes in sleep patterns, nausea, weight changes, increased/decreased interest in sex, change in vaginal discharge, or breast tenderness may occur. If any of these persist or worsen, tell your doctor promptly.

Remember that your doctor has prescribed this medication because he or she has judged that the benefit to you is greater than the risk of side effects. Many people using this medication do not have serious side effects.

Tell your doctor immediately if any of these unlikely but serious side effects occur: mental/mood changes (e.g., depression, memory loss), breast lumps, nipple discharge, swelling of the hands/feet, unusual vaginal bleeding (e.g., spotting, breakthrough bleeding, prolonged/returning bleeding), yellowing eyes/skin, stomach/abdominal pain, worsening of a seizure condition, muscle weakness, signs of worsening diabetes control (e.g., increased thirst and urination).

This medication may rarely cause very serious problems such as heart attacks, stroke, and blood clots. Seek immediate medical attention if you experience any of the following: chest/jaw/left arm pain, sudden severe headache, weakness on one side of the body, confusion, slurred speech, sudden vision changes (e.g., double vision, loss of vision), pain/redness/swelling/weakness of the arms/legs, calf pain/swelling that is warm to the touch, trouble breathing, coughing up blood, sudden dizziness/fainting.

A very serious allergic reaction to this drug is rare. However, seek immediate medical attention if you notice any symptoms of a serious allergic reaction, including: rash, itching, swelling, severe dizziness, trouble breathing.

This is not a complete list of possible side effects. If you notice other effects not listed above, contact your doctor or pharmacist.

Contact your doctor for medical advice about side effects. The following numbers do not provide medical advice, but in the US you may report side effects to the Food and Drug Administration (FDA) at 1-800-FDA-1088. In Canada, you may call Health Canada at 1-866-234-2345.

PRECAUTIONS: Before taking this medication, tell your doctor or pharmacist if you are allergic to drospirenone or estradiol; or to spironolactone; or if you have any other allergies.

This medication should not be used if you have certain medical conditions. Before using this medicine, consult your doctor or pharmacist if you have: vaginal bleeding of unknown cause, certain types of cancer (breast, ovary, uterus), blood clots, recent stroke or heart attack (within 1 year), liver disease, kidney disease, adrenal gland problems.

Before using this medication, tell your doctor or pharmacist your medical history, especially of: family medical history (including blood clots, breast lumps/cancer), asthma, diabetes, seizures, migraine headaches, heart disease (e.g., high blood pressure, heart attacks, congestive heart failure), past strokes, underactive thyroid (hypothyroidism), mineral imbalance (high or low calcium blood level, high potassium blood level, low sodium blood level), mental/mood disorders (e.g., depression, memory loss), high blood pressure during pregnancy (toxemia), yellowing eyes/skin (cholestatic jaundice) during pregnancy or with past estrogen use, uterus problems (e.g., uterine fibroids, endometriosis), high blood cholesterol/fat (triglyceride) levels, gallbladder disease, obesity, a certain metabolic disorder (porphyria), lupus.

This drug may make you dizzy or lightheaded. Use caution while driving, using machinery, or doing any activity that requires alertness. Limit alcoholic beverages.

If you are nearsighted or wear contact lenses, you may develop vision problems or trouble wearing your contact lenses. Consult your eye doctor if these problems occur.

This drug may cause a patchy darkening of the skin on the face (melasma). Sunlight may worsen this darkening. Avoid prolonged sun exposure, tanning booths, and sunlamps. Use a sunscreen and wear protective clothing when outdoors.

Do not smoke cigarettes or use tobacco. Smoking/using tobacco while taking this medication further increase your risk for stroke, blood clots, high blood pressure, and heart attacks, especially in women older than 35.

If you will be having surgery or will be confined to a chair or bed for a long time (e.g., a long plane flight), tell your doctor beforehand. Special precautions may need to be taken in these circumstances while you are taking this drug because of the increased risk for blood clots.

This medication must not be used during pregnancy. If you become pregnant or think you may be pregnant, tell your doctor immediately.

This medication is not effective for preventing a miscarriage and should not be used for this purpose.

Small amounts of this medication pass into breast milk. This drug may reduce the quality and amount of breast milk. Consult your doctor before breast-feeding.

DRUG INTERACTIONS: Your doctor or pharmacist may already be aware of any possible drug interactions and may be monitoring you for them. Do not start, stop, or change the dosage of any medicine before checking with your doctor or pharmacist first.

This drug should not be used with the following medications because very serious interactions may occur: aromatase inhibitors (e.g., anastrozole, exemestane).

If you are currently using any of these medications listed above, tell your doctor or pharmacist before starting drospirenone/estradiol.

Before using this medication, tell your doctor or pharmacist of all prescription and nonprescription products you may use, especially of: corticosteroids (e.g., prednisone), raloxifene, tamoxifen, tizanidine, warfarin, drugs affecting liver enzymes that remove estrogens from your body (such as azole antifungals including itraconazole, macrolide antibiotics including erythromycin, rifamycins including rifabutin, St. John's wort, certain anti-seizure medications including carbamazepine, phenobarbital, phenytoin).

Drospirenone may increase the level of potassium in your blood. Before taking drospirenone/estradiol, tell your doctor or pharmacist if you are taking other medications that can raise potassium blood levels. A potassium level in the blood that is too high may cause serious side effects. Follow your doctor's instructions carefully, and continue taking medications for your condition as directed. Keep all medical/laboratory appointments so your doctor can monitor your potassium levels. Check with your doctor or pharmacist if you are taking any of the following: ACE inhibitors (e.g., benazepril, lisinopril), angiotensin receptor blockers (e.g., losartan, valsartan), heparin, nonsteroidal anti-inflammatory drugs (NSAIDs such as ibuprofen, naproxen), potassium supplements (e.g., potassium chloride), salt substitutes that contain potassium, certain "water pills" (potassium-sparing diuretics such as amiloride, eplerenone, spironolactone, triamterene).

This product can affect the results of certain lab tests. Make sure laboratory personnel and all your doctors know you use this drug.

This document does not contain all possible interactions. Therefore, before using this product, tell your doctor or pharmacist of all the products you use. Keep a list of all your medications with you, and share the list with your doctor and pharmacist.

OVERDOSE: If overdose is suspected, contact your local poison control center or emergency room immediately. US residents can call the US National Poison Hotline at 1-800-222-1222. Canada residents can call a provincial poison control center. Symptoms of overdose may include: severe nausea/vomiting, unusual vaginal bleeding in females.

NOTES: Do not share this medication with others. Keep all medical and laboratory appointments. You should have a complete physical examination that includes blood pressure measurements and breast/pelvic examinations at regular intervals (e.g., once a year) or as directed by your doctor. Follow your doctor's instructions on how to examine your own breasts and report any lumps immediately. You should also be regularly screened for cervical cancer (e.g., Pap test) and have periodic mammograms as determined by your doctor. Consult your doctor for more details.

Lifestyle changes that help promote healthy bones include increasing weight-bearing exercise, stopping smoking, limiting alcohol, and eating well-balanced meals that contain adequate calcium and vitamin D. Since you may also need to take calcium and vitamin D supplements and make lifestyle changes, consult your doctor for specific advice.

Additional lifestyle changes (e.g., reducing stress, eating a low fat/low salt diet, losing weight if you are overweight) to control or prevent high blood pressure, high cholesterol, and diabetes help to prevent heart disease and strokes. Keep your mind active with mental exercises to help prevent dementia. Discuss with your doctor lifestyle changes that might benefit you.

You can also manage hot flashes by keeping a cool body temperature (e.g., using a fan, drinking cool beverages, dressing lightly/in layers, avoiding hot/spicy foods). Limiting caffeine and alcohol, exercising regularly, and learning relaxation techniques may help reduce hot flashes. Vaginal lubricants can help lessen discomfort during intercourse.

MISSED DOSE: If you miss a dose, take it as soon as you remember. If it is near the time of the next dose, skip the missed dose and resume your usual dosing schedule. Do not double the dose to catch up.

STORAGE: Store at room temperature at 77 degrees F (25 degrees C) away from light and moisture. Brief storage between 59-86 degrees F (15-30 degrees C) is permitted. Do not store in the bathroom. Keep all medicines away from children and pets.

Do not flush medications down the toilet or pour them into a drain unless instructed to do so. Properly discard this product when it is expired or no longer needed. Consult your pharmacist or local waste disposal company for more details about how to safely discard your product.

Information last revised July 2008 Copyright(c) 2008 First DataBank, Inc.