drospirenone 0.5 MG / Ethinyl Estradiol 1 MG 28 Oral Tablet Pack

Details

WARNINGS

Warnings 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 a.

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-0.625mg/2.5mg 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 a.

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 , I.

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 proba ble 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 , I.

GERIATRIC USE .) 4.

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.

DRUG INTERACTIONS

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 3mg 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 >6.0 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 non-diabetic).

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 1.010 (90% CI: 0.944, 1.080), 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.

OVERDOSAGE

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.

DESCRIPTION

Description 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 C 24 H 30 O 3 .

Estradiol USP, (Estra-1,3,5(10)-triene-3,17-diol,17ß), has a molecular weight of 272.39 and the molecular formula is C 18 H 24 O 2 .

The structural formulas are as follows: structural formula

CLINICAL STUDIES

Clinical Studies Support for the indications Support for treatment of vasomotor symptoms and vaginal and vulvar atrophy was shown through bioequivalence of the E2 component of the combination product with a currently marketed E2 product (Estrace®).

The multiple-dose bioequivalence study evaluated the bioequivalence 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 bioequivalence 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 E2 1 mg ANGELIQ Total No.

Subjects 226 227 Total No.

of On-Treatment Biopsies 197 (87.2%) 191 (84.1%) Hyperplasia 8 (4.0%) 0 (0%) 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 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 Event c Relative Risk CE/MPA vs placebo at 5.2 Years (95% CI) Placebo n = 8102 CE/MPA n = 8506 Absolute Risk per 10,000 Person-years CHD events Non-fatal MI CHD death 1.29 (1.02 – 1.63) 1.32 (1.02 – 1.72) 1.18 (0.70 – 1.97) 30 23 6 37 30 7 Invasive breast cancer 1.26 (1.00 – 1.59) 30 38 Stroke 1.41 (1.07 – 1.85) 21 29 Pulmonary embolism 2.13 (1.39 – 3.25) 8 16 Colorectal cancer 0.63 (0.43 – 0.92) 16 10 Endometrial cancer 0.83 (0.47 – 1.47) 6 5 Hip fracture 0.66 (0.45 – 0.98) 15 10 Death due to causes other than the events above 0.92 (0.74 – 1.14) 40 37 Global Index 1.15 (1.03 – 1.28) 151 170 Deep vein thrombosis not included in Global Index 2.07 (1.49 – 2.87) 13 26 Vertebral fractures 0.66 (0.44 – 0.98) 15 9 Other osteoporotic fractures 0.77 (0.69 – 0.86) 170 131 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 Warnings and Warnings , 3.

Dementia .)

HOW SUPPLIED

How Supplied 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: 1 blisters of 28 tablets NDC 54868-6184-0 Storage Conditions Store at 25° C (77° F); excursions permitted to 15 – 30° C (59 – 86° F) [See USP Controlled Room Temperature].

REFERENCES FURNISHED UPON REQUEST

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 , 3.

Dementia .)

INDICATIONS AND USAGE

Indications and Usage ANGELIQ is indicated in women who have a uterus for the: 1.

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 prescribing solely for the treatment of symptoms of vulvar and vaginal atrophy, topical vaginal products should be considered.

PEDIATRIC USE

ANGELIQ is not indicated in children.

PREGNANCY

ANGELIQ should not be used during pregnancy.

(See Contraindications .)

NUSRING MOTHERS

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.

BOXED WARNING

Boxed Warnings Estrogens with or without progestins should not be used for the prevention of cardiovascular disease or dementia.

(See WARNINGS, Cardiovascular disorders and Dementia.) The Women’s Health Initiative (WHI) study reported increased risks of myocardial infarction, stroke, invasive breast cancer, pulmonary emboli, and deep vein thrombosis in postmenopausal women (50 to 79 years of age) during 5 years of treatment with oral conjugated equine estrogens (CE 0.625mg) combined with medroxyprogesterone acetate (MPA 2.5mg) relative to placebo (see CLINICAL PHARMACOLOGY, Clinical Studies and WARNINGS, Cardiovascular disorders and Malignant neoplasms, Breast cancer.) The Women’s Health Initiative Memory Study (WHIMS), a substudy of WHI, reported increased risk of developing probable dementia in postmenopausal women 65 years of age or older during 5.2 years of treatment with conjugated estrogens alone and during 4 years of treatment with oral conjugated estrogens plus medroxyprogesterone acetate, relative to placebo.

It is unknown whether this finding applies to younger postmenopausal women.

(See CLINICAL PHARMACOLOGY, Clinical Studies, WARNINGS, Dementia and PRECAUTIONS, Geriatric Use.) Other doses of oral conjugated estrogens with medroxyprogesterone acetate, and other combinations and dosage forms of estrogens and progestins were not studied in the WHI clinical trials, and, in the absence of comparable data, these risks should be assumed to be similar.

Because of these risks, estrogens with or without progestins should be prescribed at the lowest effective doses and for the shortest duration consistent with treatment goals and risks for the individual woman.

DOSAGE AND ADMINISTRATION

Dosage and Administration 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.