Fem7 Combi

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Fem7 Combi uses


1 INDICATIONS AND USAGE

Fem7 Combi is an estrogen plus progestin indicated in a woman with a uterus for:

1.1 Treatment of Moderate to Severe Vasomotor Symptoms due to Menopause

1.2 Prevention of Postmenopausal Osteoporosis

Limitation of Use

When prescribing solely for the prevention of postmenopausal osteoporosis, therapy should only be considered for women at significant risk of osteoporosis and non-estrogen medication should be carefully considered.

2 DOSAGE AND ADMINISTRATION

Use of estrogen-alone, or in combination with a progestin, should be with the lowest effective dose and for the shortest duration consistent with treatment goals and risks for the individual women. Postmenopausal women should be re-evaluated periodically as clinically appropriate to determine if treatment is still necessary.

One Fem7 Combi transdermal system is available for use.

Initiation of Therapy

Women not currently using continuous estrogen-alone therapy or estrogen plus progestin therapy may start therapy with Fem7 Combi at any time. However, women currently using continuous estrogen-alone therapy or estrogen plus progestin therapy should complete the current cycle of therapy before initiating Fem7 Combi therapy. Women often experience withdrawal bleeding at the completion of the cycle. The first day of this bleeding would be an appropriate time to begin Fem7 Combi therapy.

2.1 Treatment of Moderate to Severe Vasomotor Symptoms due to Menopause

Fem7 Combi 0.045 mg per day/0.015 mg per day applied to the skin once weekly. Therapy should be started at the lowest effective dose and the shortest duration consistent with the treatment goals. Attempts to discontinue the medication should be made at 3 to 6 month intervals.

2.2 Prevention of Postmenopausal Osteoporosis

Fem7 Combi 0.045 mg per day/0.015 mg per day applied to the skin once weekly.

2.3 Application of the Transdermal System

Site Selection

Application

2.4 Removal of the Transdermal System

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3 DOSAGE FORMS AND STRENGTHS

Fem7 Combi (estradiol/levonorgestrel transdermal system) 0.045 mg/day Fem7 Combi and 0.015 mg/day levonorgestrel – each 22 cm2 system contains 4.4 mg of Fem7 Combi and 1.39 mg of levonorgestrel.

4 CONTRAINDICATIONS

Fem7 Combi is contraindicated in women with any of the following conditions:

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5 WARNINGS AND PRECAUTIONS

5.1 Cardiovascular Disorders

An increased risk of PE, DVT, stroke and MI has been reported with estrogen plus progestin therapy. An increased risk of stroke and DVT has been reported with estrogen-alone therapy. Should any of these occur or be suspected, estrogen with or without progestin therapy should be discontinued immediately.

Risk factors for arterial vascular disease (for example, hypertension, diabetes mellitus, tobacco use, hypercholesterolemia, and obesity) and/or venous thromboembolism (VTE) (for example, personal history or family history of VTE, obesity, and systemic lupus erythematosus) should be managed appropriately.

Stroke

In the WHI estrogen plus progestin substudy, a statistically significant increased risk of stroke was reported in women 50 to 79 years of age receiving daily CE plus MPA (2.5 mg) compared to women in the same age group receiving placebo (33 versus 25 per 10,000 women-years) . The increase in risk was demonstrated after the first year and persisted.1 Should a stroke occur or be suspected, estrogen plus progestin therapy should be discontinued.

In the WHI estrogen-alone substudy, a statistically significant increased risk of stroke was reported in women 50 to 79 years of age receiving daily CE (0.625 mg)-alone compared to women in the same age group receiving placebo (45 versus 33 per 10,000 women-years). The increase in risk was demonstrated in year 1 and persisted . Should a stroke occur or be suspected, estrogen-alone therapy should be discontinued immediately.

Subgroup analyses of women 50 to 59 years of age suggest no increased risk of stroke for those women receiving CE (0.625 mg)-alone versus those receiving placebo (18 versus 21 per 10,000 women-years).1

Coronary Heart Disease

In the WHI estrogen plus progestin substudy, there was a statistically non-significant increased risk of coronary heart disease (CHD) events (defined as nonfatal MI, silent MI, or CHD death) reported in women receiving daily CE (0.625 mg) plus MPA (2.5 mg) compared to women receiving placebo (41 versus 34 per 10,000 women-years).1 An increase in relative risk was demonstrated in year 1, and a trend toward decreasing relative risk was reported in years 2 through 5 .

In the WHI estrogen-alone substudy, no overall effect on CHD events was reported in women receiving estrogen-alone compared to placebo2 .

Subgroup analyses of women 50 to 59 years of age suggest a statistically non-significant reduction in CHD events (CE [0.625 mg]-alone compared to placebo) in women with less than 10 years since menopause (8 versus 16 per 10,000 women-years).1

In postmenopausal women with documented heart disease (n = 2,763), average 66.7 years of age, in a controlled clinical trial of secondary prevention of cardiovascular disease (Heart and Estrogen/Progestin Replacement Study [HERS]), treatment with daily CE (0.625 mg) plus MPA (2.5 mg) demonstrated no cardiovascular benefit. During an average follow-up of 4.1 years, treatment with CE plus 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 plus MPA-treated group than in the placebo group in year 1, but not during the subsequent years. A total of 2,321 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 plus MPA group and the placebo group in HERS, HERS II, and overall.

Venous Thromboembolism

In the WHI estrogen plus progestin substudy, a statistically significant 2-fold greater rate of VTE was reported in women receiving daily CE (0.625 mg) plus MPA (2.5 mg) compared to women receiving placebo (35 versus 17 per 10,000 women-years). Statistically significant increases in risk for both DVT (26 versus 13 per 10,000 women-years) and PE (18 versus 8 per 10,000 women-years) were also demonstrated. The increase in VTE risk was demonstrated during the first year and persisted3 [see Clinical Studies (14.5 )]. Should a VTE occur or be suspected, estrogen plus progestin therapy should be discontinued immediately.

In the WHI estrogen-alone substudy, the risk of VTE was increased for women receiving daily CE (0.625 mg)-alone compared to placebo (30 versus 22 per 10,000 women-years), although only the increased risk of DVT reached statistical significance (23 versus 15 per 10,000 women-years). The increase in VTE risk was demonstrated during the first 2 years4 . Should a VTE occur or be suspected, estrogen-alone therapy should be discontinued immediately.

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.

5.2 Malignant Neoplasms

Breast Cancer

The most important randomized clinical trial providing information about breast cancer in estrogen plus progestin users is the WHI substudy of daily CE plus MPA (2.5 mg).

After a mean follow-up of 5.6 years, the estrogen plus progestin substudy reported an increased risk of invasive breast cancer in women who took daily CE plus MPA. In this substudy, prior use of estrogen-alone or estrogen plus progestin therapy was reported by 26 percent of the women. The relative risk of invasive breast cancer was 1.24, and the absolute risk was 41 versus 33 cases per 10,000 women-years, for CE plus 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 versus 25 cases per 10,000 women-years, for CE plus 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 versus 36 cases per 10,000 women-years for CE plus MPA compared with placebo. In the same substudy, invasive breast cancers were larger, were more likely to be node positive, and were diagnosed at a more advanced stage in the CE (0.625 mg) plus MPA (2.5 mg) 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 groups5 .

The most important randomized clinical trial providing information about breast cancer in estrogen-alone users is the WHI substudy of daily CE (0.625 mg)-alone. In the WHI estrogen-alone substudy, after an average follow-up of 7.1 years, daily CE-alone was not associated with an increased risk of invasive breast cancer [relative risk (RR) 0.80] 6 .

Consistent with the WHI clinical trials, observational studies have also reported an increased risk of breast cancer for estrogen plus progestin therapy, and a smaller increased risk for estrogen-alone therapy, after several years of use. The risk increased with duration of use, and appeared to return to baseline over about 5 years after stopping treatment (only the observational studies have substantial data on risk after stopping). Observational studies also suggest that the risk of breast cancer was greater, and became apparent earlier, with estrogen plus progestin therapy as compared to estrogen-alone therapy. However, these studies have not found significant variation in the risk of breast cancer among different estrogen plus progestin combinations, doses, or routes of administration.

The use of estrogen-alone and 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, risk factors, and prior mammogram results.

Endometrial Cancer

An increased risk of endometrial cancer has been reported with the use of unopposed estrogen therapy in a woman with a uterus. The reported endometrial cancer risk among unopposed estrogen users is about 2 to 12 times greater than in nonusers, 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 1 year. The greatest risk appears associated with prolonged use, with increased risks of 15- to 24-fold for 5 to 10 years or more. This risk has been shown to persist for at least 8 to 15 years after estrogen therapy is discontinued.

Clinical surveillance of all women using estrogen-alone or estrogen plus progestin therapy is important. Adequate diagnostic measures, including directed or random endometrial sampling when indicated, should be undertaken to rule out malignancy in postmenopausal women with undiagnosed persistent or recurring abnormal genital 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 in postmenopausal women has been shown to reduce the risk of endometrial hyperplasia, which may be a precursor to endometrial cancer.

Ovarian Cancer

The WHI estrogen plus progestin substudy reported a statistically non-significant increased risk of ovarian cancer. After an average follow-up of 5.6 years, the relative risk for ovarian cancer for CE plus MPA versus placebo was 1.58. The absolute risk for CE plus MPA versus placebo was 4 versus 3 cases per 10,000 women-years.7 A meta-analysis of 17 prospective and 35 retrospective epidemiology studies found that women who used hormonal therapy for menopausal symptoms had an increased risk for ovarian cancer. The primary analysis, using case-control comparisons, included 12,110 cancer cases from the 17 prospective studies. The relative risks associated with current use of hormonal therapy was 1.41 (95% confidence interval [CI] 1.32 to 1.50); there was no difference in the risk estimates by duration of the exposure (less than 5 years [median of 3 years]vs. greater than 5 years [median of 10 years] of use before the cancer diagnosis). The relative risk associated with combined current and recent use (discontinued use within 5 years before cancer diagnosis) was 1.37 (95% CI 1.27 to 1.48), and the elevated risk was significant for both estrogen-alone and estrogen plus progestin products. The exact duration of hormone therapy use associated with an increased risk of ovarian cancer, however, is unknown.

5.3 Probable Dementia

In the WHIMS estrogen plus progestin ancillary study of WHI, a population of 4,532 postmenopausal women 65 to 79 years of age was randomized to daily CE (0.625 mg) plus MPA (2.5 mg) or placebo.

After an average follow-up of 4 years, 40 women in the CE plus MPA group and 21 women in the placebo group were diagnosed with probable dementia. The relative risk of probable dementia for CE plus MPA versus placebo was 2.05 (95 percent CI, 1.21-3.48). The absolute risk of probable dementia for CE plus MPA versus placebo was 45 versus 22 cases per 10,000 women-years8 .

In the WHIMS estrogen-alone ancillary study of WHI, a population of 2,947 hysterectomized women 65 to 79 years of age was randomized to daily CE (0.625 mg)-alone or placebo.

After an average follow-up of 5.2 years, 28 women in the estrogen-alone group and 19 women in the placebo group were diagnosed with probable dementia. The relative risk of probable dementia for CE-alone versus placebo was 1.49 (95 percent CI, 0.83-2.66). The absolute risk of probable dementia for CE-alone versus placebo was 37 versus 25 cases per 10,000 women-years8 .

When data from the two populations in the WHIMS estrogen-alone and estrogen plus progestin ancillary studies were pooled as planned in the WHIMS protocol, the reported overall relative risk for probable dementia was 1.76 (95 percent CI, 1.19-2.60). Since both ancillary studies were conducted in women 65 to 79 years of age, it is unknown whether these findings apply to younger postmenopausal women8 .

5.4 Gallbladder Disease

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

5.5 Hypercalcemia

Estrogen administration may lead to severe hypercalcemia in women 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.

5.6 Visual Abnormalities

Retinal vascular thrombosis has been reported in women 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.

5.7 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 an increased risk of breast cancer.

5.8 Elevated Blood Pressure

In a small number of case reports, substantial increases in blood pressure have been attributed to idiosyncratic reactions to estrogens. In a large, randomized, placebo-controlled clinical trial, a generalized effect of estrogens on blood pressure was not seen.

5.9 Hypertriglyceridemia

In women with pre-existing hypertriglyceridemia, estrogen therapy may be associated with elevations of plasma triglycerides leading to pancreatitis. Consider discontinuation of treatment if pancreatitis occurs.

5.10 Hepatic Impairment and/or Past History of Cholestatic Jaundice

Estrogens may be poorly metabolized in women with impaired liver function. For women 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.

5.11 Hypothyroidism

Estrogen administration leads to increased thyroid-binding globulin levels. Women 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. Women dependent on thyroid hormone replacement therapy who are also receiving estrogens may require increased doses of their thyroid replacement therapy. These women should have their thyroid function monitored in order to maintain their free thyroid hormone levels in an acceptable range.

5.12 Fluid Retention

Estrogens plus progestins may cause some degree of fluid retention. Women with conditions that might be influenced by this factor, such as a cardiac or renal impairment, warrant careful observation when estrogens plus progestins are prescribed.

5.13 Hypocalcemia

Estrogen therapy should be used with caution in women with hypoparathyroidism as estrogen-induced hypocalcemia may occur.

5.14 Exacerbation of Endometriosis

A few cases of malignant transformation of residual endometrial implants have been reported in women treated post-hysterectomy with estrogen-alone therapy. For women known to have residual endometriosis post-hysterectomy, the addition of progestin should be considered.

5.15 Hereditary Angioedema

Exogenous estrogens may exacerbate symptoms of angioedema in women with hereditary angioedema.

5.16 Exacerbation of Other Conditions

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

5.17 Laboratory Tests

Serum follicle stimulating hormone and Fem7 Combi levels have not been shown to be useful in the management of moderate to severe vasomotor symptoms.

5.18 Drug-Laboratory Test Interactions

Accelerated prothrombin time, partial thromboplastin time, and platelet aggregation time; increased platelet count; increased factors II, VII antigen, VIII antigen, VIII coagulant activity, IX, X, XII, VII-X complex, II-VII-X complex, and beta-thromboglobulin; decreased levels of antifactor Xa and antithrombin III, decreased antithrombin III activity; increased levels of fibrinogen and fibrinogen activity; increased plasminogen antigen and activity.

Increased TBG levels leading to increased circulating total thyroid hormone, as measured by protein-bound iodine (PBI), T4 levels (by column or by radioimmunoassay) or T3 levels by radioimmunoassay. T3 resin uptake is decreased, reflecting the elevated TBG. Free T4 and free T3 concentrations are unaltered. Women on thyroid replacement therapy may require higher doses of thyroid hormone.

Other binding proteins may be elevated in serum, for example, corticosteroid binding globulin (CBG), sex hormone-binding globulin (SHBG), leading to increased total circulating corticosteroids and sex steroids, respectively. Free hormone concentrations, such as testosterone and Fem7 Combi, may be decreased. Other plasma proteins may be increased (angiotensinogen/renin substrate, alpha-l-antitrypsin, ceruloplasmin).

Increased plasma high-density lipoprotein (HDL) and HDL2 cholesterol subfraction concentrations, reduced low-density lipoprotein (LDL) cholesterol concentration, and in oral formulations increased triglycerides levels.

Impaired glucose tolerance.

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6 ADVERSE REACTIONS

The following serious adverse reactions are discussed elsewhere in the labeling:


In a prospective, randomized, placebo-controlled, double-blind study, the most common adverse reactions ≥5 percent are: application site reaction, vaginal bleeding, breast pain, upper respiratory infection, back pain, depression, pain, headache and flu syndrome. (6.1)

To report SUSPECTED ADVERSE REACTIONS, contact 1-888-84-BAYER (1-888-842-2937) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 Clinical Trials Experience

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 data described below is from a one-year, prospective, multicenter, double blind, double dummy, randomized, controlled trial investigating the effect of three different dosage combinations of E2/LNG versus E2 alone on the development of endometrial hyperplasia. All women were postmenopausal, had a serum Fem7 Combi level of less than 20 pg/mL, and the sample included both symptomatic and asymptomatic women. The data below includes all adverse reactions reported at a frequency of >3% in the E2/LNG 0.045 / 0.015 group (the approved dosage for Fem7 Combi, N=212) and the E2 alone group (N=204).


Body System

  • Adverse Reaction

Fem7 Combi

0.045 / 0.015


E2


N N = total number of subjects in a treatment group; n = number of subjects with event. = 212


N = 204


Body as a Whole

  • Abdominal pain

9 (4.2)


11 (5.4)

  • Accidental injury

7 (3.3)


6 (2.9)

  • Back pain

13 (6.1)


12 (5.9)

  • Flu syndrome

10 (4.7)


13 (6.4)

  • Infection

7 (3.3)


10 (4.9)

  • Pain

11 (5.2)


13 (6.4)


Cardiovascular System

  • Hypertension

7 (3.3)


9 (4.4)


Digestive System

  • Flatulence

8 (3.8)


11 (5.4)


Metabolic and Nutritional

  • Edema

8 (3.8)


5 (2.5)

  • Weight gain

6 (2.8)


10 (4.9)


Musculoskeletal System

  • Arthralgia

9 (4.2)


10 (4.9)


Nervous System

  • Depression

12 (5.7)


7 (3.4)

  • Headache

11 (5.2)


14 (6.9)


Respiratory System

  • Bronchitis

9 (4.2)


7 (3.4)

  • Sinusitis

8 (3.8)


12 (5.9)

  • Upper respiratory infection

28 (13.2)


26 (12.7)


Skin and Appendages

  • Application site reaction

86 (40.6)


69 (33.8)

  • Breast pain

40 (18.9)


20 (9.8)

  • Rash

5 (2.4)


10 (4.9)


Urogenital System

  • Urinary Tract Infection

7 (3.3)


8 (3.9)

  • Vaginal Bleeding

78 (36.8)


44 (21.6)

  • Vaginitis

4 (1.9)


6 (2.9)


Irritation potential of Fem7 Combi was assessed in a 3-week irritation study. The study compared the irritation of a Fem7 Combi placebo patch (22 cm2) to a placebo (25 cm2). Visual assessments of irritation were made on Day 7 of each wear period, approximately 30 minutes after patch removal using a 7-point scale (0 = no evidence of irritation; 1 = minimal erythema, barely perceptible; 2 = definite erythema, readily visible, or minimal edema, or minimal papular response; 3–7 = erythema and papules, edema, vesicles, strong extensive reaction).

The mean irritation scores were 0.13 (week 1), 0.12 (week 2), and 0.06 (week 3) for the Fem7 Combi placebo. The mean scores for the Climara placebo were 0.2 (week 1), 0.26 (week 2), 0.12 (week 3). There were no irritation scores greater than 2 at any timepoint in any subject.

In controlled clinical trials, withdrawals due to application site reactions occurred in 6 (2.1 percent) of subjects in the 12-week symptom study and in 71 (8.5 percent) of subjects in the 1-year endometrial protection study.

6.2 Postmarketing Experience

The following adverse reactions have been identified during post-approval use of the Fem7 Combi transdermal system. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Genitourinary System

Changes in bleeding patterns

Gastrointestinal

Abdominal distension,* abdominal pain,* nausea

Skin

Alopecia, night sweats, pruritus,* Rash,* hot flush*

Central Nervous System

Dizziness, headache, insomnia

Miscellaneous

Application site reaction,* weight increased, anaphylactic reaction

* Combined two or more similar ARs

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7 DRUG INTERACTIONS

7.1 Metabolic Interactions

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 (Hypericum perforatum) preparations, 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.

Hydroxylation of levonorgestrel is a conversion step, which is mediated by cytochrome P450 enzymes. Based on in-vitro and in-vivo studies, it can be assumed that CYP3A, CYP2E and CYP2C are involved in the metabolism of levonorgestrel. Likewise, inducers or inhibitors of these enzymes may either, respectively, decrease the therapeutic effects or result in side effects.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Fem7 Combi should not be used during pregnancy . There appears to be little or no increased risk of birth defects in children born to women who have used estrogens and progestins as oral contraceptives inadvertently during early pregnancy.

8.3 Nursing Mothers

Fem7 Combi should not be used during lactation. Estrogen administration to nursing women has been shown to decrease the quantity and quality of the breast milk. Detectable amounts of estrogens and progestins have been identified in the milk of women receiving estrogen therapy. Caution should be exercised when the Fem7 Combi transdermal system is administered to a nursing woman.

8.4 Pediatric Use

Fem7 Combi is not indicated in children. Clinical studies have not been conducted in the pediatric populations.

8.5 Geriatric Use

There have not been sufficient numbers of geriatric women involved in studies utilizing Fem7 Combi to determine whether those over 65 years of age differ from younger subjects in their response to Fem7 Combi.

The Women’s Health Initiative Studies

In the WHI estrogen plus progestin substudy, there was a higher relative risk of nonfatal stroke and invasive breast cancer in women greater than 65 years of age .

In the WHI estrogen-alone substudy (daily CE [0.625 mg]-alone versus placebo), there was a higher relative risk of stroke in women greater than 65 years of age

The Women’s Health Initiative Memory Study

In the WHIMS ancillary studies of postmenopausal women 65 to 79 years of age, there was an increased risk of developing probable dementia in women receiving estrogen plus progestin or estrogen-alone when compared to placebo .

Since both ancillary studies were conducted in women 65 to 79 years of age, it is unknown whether these findings apply to younger postmenopausal women8 , and Clinical Studies (14.6)].

8.6 Renal Impairment

In postmenopausal women with end stage renal disease receiving maintenance hemodialysis, total Fem7 Combi serum levels are higher than in normal subjects at baseline and following oral doses of Fem7 Combi. Therefore, conventional transdermal Fem7 Combi doses used in individuals with normal renal function may be excessive for postmenopausal women with ESRD receiving maintenance hemodialysis.

8.7 Hepatic Impairment

Estrogens may be poorly metabolized in patients with impaired liver function and should be administered with caution.

10 OVERDOSAGE

Overdosage of estrogen plus progestin may cause nausea, vomiting, breast tenderness, abdominal pain, drowsiness and fatigue, and withdrawal bleeding may occur in women. Treatment of overdose consists of discontinuation of Fem7 Combi therapy with institution of appropriate symptomatic care.

11 DESCRIPTION

Fem7 Combi (estradiol/levonorgestrel transdermal system) is an adhesive-based matrix transdermal patch designed to release both Fem7 Combi and levonorgestrel, a progestational agent, continuously upon application to intact skin. The 22 cm2 Fem7 Combi system contains 4.4 mg Fem7 Combi and 1.39 mg levonorgestrel and provides a nominal delivery rate (mg per day) of 0.045 Fem7 Combi and 0.015 levonorgestrel.

Fem7 Combi USP has a molecular weight of 272.39 and the molecular formula is C18H24O2.

Levonorgestrel USP has a molecular weight of 312.4 and a molecular formula of C21H28O2.

The structural formulas for Fem7 Combi and levonorgestrel are:

The Fem7 Combi transdermal system comprises 3 layers. Proceeding from the visible surface towards the surface attached to the skin, these layers are:


The active components of the transdermal system are Fem7 Combi and levonorgestrel. The remaining components of the transdermal system (acrylate copolymer adhesive and polyvinylpyrrolidone/vinyl acetate copolymer) are pharmacologically inactive.

Chemical structure diagram patch

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

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, Fem7 Combi 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 Fem7 Combi daily, depending on the phase of the menstrual cycle. After menopause, most endogenous estrogen is produced by conversion of androstenedione, which is secreted by the adrenal cortex, to estrone in the peripheral tissues. Thus, estrone and the sulfate conjugated form, estrone sulfate, are the most abundant circulating estrogens in postmenopausal women.

Estrogens act through binding to nuclear receptors in estrogen-responsive tissues. To date, two estrogen receptors have been identified. These vary in proportion from tissue to tissue.

Circulating estrogens modulate the pituitary secretion of the gonadotropins, luteinizing hormone and FSH, through a negative feedback mechanism. Estrogens act to reduce the elevated levels of these hormones seen in postmenopausal women.

Levonorgestrel inhibits gonadotropin production resulting in retardation of follicular growth and inhibition of ovulation.

Studies to assess the potency of progestins using estrogen-primed postmenopausal endometrial biochemistry and morphologic features have shown that levonorgestrel counteracts the proliferative effects of estrogens on the endometrium.

12.2 Pharmacodynamics

There are no pharmacodynamic data for Fem7 Combi.

12.3 Pharmacokinetics

Absorption

Transdermal administration of Fem7 Combi produces mean maximum Fem7 Combi concentrations in serum in about 2 to 2.5 days. Fem7 Combi concentrations equivalent to the normal ranges observed at the early follicular phase in premenopausal women are achieved within 12–24 hours after the first application.

In one study, steady state Fem7 Combi concentrations in serum were measured during week 4 in 44 healthy, postmenopausal women during four consecutive Fem7 Combi applications of two formulations to the abdomen (each dose was applied for four 7-day periods). Both formulations were bioequivalent in terms of Fem7 Combi and estrone Cmax and AUC parameters. A summary of Fem7 Combi single and multiple applications Fem7 Combi, estrone and levonorgestrel pharmacokinetic parameters is shown in Table 2.


Summary of Mean (± SD) Pharmacokinetic Parameters Following a Single Application

of Fem7 Combi in 24 Healthy Postmenopausal Women


Parameter


Units


Fem7 Combi


Estrone


Levonorgestrel


Single application

Week 1 Data


Cave


Pg/mL


37.7 ± 10.4


41 ± 15


136 ± 52.7


Cmax


Pg/mL


54.3 ± 18.9


43.9 ± 14.9


138 ± 51.8


Tmax


Hours


42


84


90


Cmin


Pg/mL


27.2 ± 7.66


32.6 ± 14.3


110 ± 41.7


AUC


Pg.h/mL


6340 ± 1740


6890 ± 2520


22900 ± 8860


Summary of Mean (± SD) Pharmacokinetic Parameters (Week 4) Following Four Consecutive Weekly Applications of Fem7 Combi in 44 Healthy Postmenopausal Women


Multiple application

Week 4 Data


Cave


Pg/mL


35.7 ± 11.4


45.5 ± 62.6


166 ± 97.8


Cmax


Pg/mL


50.7 ± 28.6


81.6 ± 252


194 ± 111


Tmax


Hours


36


48


48


Cmin


Pg/mL


33.8 ± 28.7


72.5 ± 253


153 ± 69.6


AUC


Pg.h/mL


6002 ± 1919


7642 ± 10518


27948 ± 16426


All mean parameters are arithmetic means except Tmax which is expressed as the median.

At steady state, Fem7 Combi maintains during the application period an average serum Fem7 Combi concentration of 35.7 pg/mL as depicted in Figure 1.

Figure 1: Mean Fem7 Combi Concentration Profile (Week 4) Following Four Consecutive Weekly Applications of Fem7 Combi

Following the application of the Fem7 Combi transdermal system, levonorgestrel concentrations are maximum in about 2.5 days. At steady state, Fem7 Combi maintains during the application period an average serum levonorgestrel concentration of 166 pg/mL as depicted in Figure 2. The mean levonorgestrel pharmacokinetic parameters of Fem7 Combi are summarized in Table 2.

Figure 2: Mean Levonorgestrel Concentration Profile (Week 4) Following Four Consecutive Weekly Applications of Fem7 Combi

figure 1 Figure 2

Adhesion

A study of the adhesion potential of Fem7 Combi was conducted in 104 healthy women of 45–75 years of age. Each woman applied a placebo patch, containing only the Fem7 Combi adhesive without active ingredient, to the upper outer abdominal areas weekly for three weeks. The adhesion assessment was done visually on Days 2, 4, 5, 6 and 7 of each of the three weeks using a four-point scale. The mean scores ranked in the highest category possible on the 0 to 4 scale demonstrating clinically acceptable adhesion performance

Excretion

Fem7 Combi, estrone, and estriol are excreted in the urine along with glucuronide and sulfate conjugates. Following patch removal, serum Fem7 Combi concentrations decline with a mean terminal half-life of 3± 0.67 hours.

Levonorgestrel and its metabolites are primarily excreted in the urine. Mean (± SD) terminal half-life for levonorgestrel was determined to be 28 ± 6.4 hours.

Metabolism

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. Fem7 Combi is converted reversibly to estrone, and both can be converted to estriol, which is a 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 intestine 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.

The most important metabolic pathway for levonorgestrel occurs in the reduction of the Δ4- and the 3-oxo-group as well as hydroxylations at positions 2α, 1β, and 16β, followed by conjugation. Most of the metabolites that circulate in the blood are sulfates of 3α, 5β-tetrahydro-levonorgestrel, while excretion occurs predominantly in the form of glucuronides. Some of the parent levonorgestrel also circulates as the 17β-sulfate. In-vitro studies on the biotransformation of levonorgestrel in human skin did not indicate any significant metabolism of levonorgestrel during skin penetration.

Distribution

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. Estrogens circulate in the blood largely bound to SHBG and albumin.

Levonorgestrel in serum is bound to both SHBG and albumin. Following four consecutive weekly applications of Fem7 Combi mean (± SD) SHBG concentrations declined from a predose value of 47.5 (25.8) to 41.2 (22.4) nmol/L at week 4.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

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.

14 CLINICAL STUDIES

14.1 Effects on Vasomotor Symptoms

The efficacy of 0.045 mg estradiol/0.03 mg levonorgestrel administered weekly versus placebo in the relief of moderate to severe vasomotor symptoms in postmenopausal women was studied in one 12-week clinical trial. The 0.045 mg estradiol/0.03 mg levonorgestrel dosage strength was shown to be statistically better than placebo at weeks 4 and 12 for relief of both the number and severity of moderate to severe hot flushes. See Tables 3 and 4. Fem7 Combi and the 0.045 mg estradiol/0.03 mg levonorgestrel dosage strength are bioequivalent in terms of Fem7 Combi delivery .


Baseline A subject was included at baseline only if the subject had a post-baseline mean score. The post-baseline mean score required 3 days in one week.


Week 4


Week 8


Week 12


Placebo


nn = Number of subjects in a treatment group in a cycle; number of subjects varied from cycle to cycle due to missing data.


88


82


73


69


Mean (SD)SD = standard deviation


10.8

(5.803)


6.13

(4.311)


5.35

(4.095)


5.59

(4.93)


Mean Change

from baseline (SD)


NA


-4.23

(4.374)


-4.8

(4.448)


-4.55

(5.407)


0.045/.03


n


92


88


80


73


Mean (SD)


10.13

(3.945)


2.69

(4.455)


1.22

(2.804)


1.06

(3.187)


Mean Change

from baseline (SD)


NA


-7.4

(4.715)


-8.68

(4.146)


-8.82

(4.336)


p-Value p-value for comparison to placebo, adjusted by the method of Bonferroni


NA


<0.001p <0.025


NA


<0.001


BaselineA subject was included at baseline only if the subject had at least 1 post-baseline value.


Week 4

(day 7)


Week 8

(day 7)


Week 12

(day 7)


Placebo


n


89


76


68


57


Mean (SD)d


2.42

(0.282)


1.99

(0.875)


1.93

(0.955)


1.8

(1.034)


Mean Change

from baseline

(SD)SD= standard deviation Severity scores are: 1 = Mild, 2 = Moderate, 3 = Severe. Mean severity of hot flushes by day is [(2X number of moderate hot flushes) + (3X number of severe hot flushes)] / total number of moderate to severe hot flushes on that day. If no moderate to severe hot flush was indicated, the mean severity was 0.


NA


-0.4

(0.865)


-0.48

(0.922)


-0.57

(1.044)


0.045/.03


n


92


83


72


55


Mean (SD)


2.48

(0.295)


1.1

(1.191)


0.82

(1.226)


0.44

(0.96)


Mean Change

from baseline

(SD)


NA


-1.4

(1.164)


-1.67

(1.245)


-2.06

(1.005)


p-value p-value for comparison to placebo, adjusted by the method of Bonferroni


NA


<0.001 p <0.025


NA


<0.001

14.2 Effects on the Endometrium

In a 1-year clinical trial of 412 postmenopausal women (with intact uteri) treated with a continuous regimen of Fem7 Combi or with an continuous estradiol-only transdermal system, results of evaluable endometrial biopsies show that no hyperplasia was seen with Fem7 Combi. Table 5 below summarizes these results (Intent-to-Treat populations).


Fem7 Combi

E2 0.045 mg / LNG 0.015 mg


Fem7 Combi

E2 0.045 mg


nn = number of intent-to-treat subjects. = 210


na = 202


No. of Patients with Biopsies at >6 monthsDefined as at least 180 days of treatment.


124


139


No. of Patients with Biopsies at 1 yearDefined as ≥ 323 days of treatment.


102


110


No. (%) of Patients with HyperplasiaIncludes hyperplasia occurring at any time after initiation of treatment as a proportion of patients with biopsies at 1 year.


0 (0%)p < 0.0167 p-value for comparison to unopposed Fem7 Combi dose using the Fisher Exact test. P-values were adjusted by the method of Bonferroni.


19 (17.3%)


95% Confidence Interval


0-3.55%


9.75–24.79%

14.3 Effects on Uterine Bleeding or Spotting

The effects of Fem7 Combi on uterine bleeding or spotting, as recorded using an interactive voice response system, were evaluated in one 12-month clinical trial. Results are shown in Figure 3.

Figure 3: Cumulative Proportion of Subjects at Each Cycle with No Bleeding/Spotting Through the End of Cycle 13 Last Observation Carried Forward

fig 3

14.4 Effects on Bone Mineral Density

The effects on bone mineral density were studied in a randomized, double-blind, placebo-controlled clinical trial of transdermal systems (patches) containing only Fem7 Combi (E2). The patients were postmenopausal women with hysterectomies, 40–83 years of age (mean=51.4 years), and 77.3 percent Caucasian. Patients received calcium supplements if they appeared deficient on a questionnaire. Vitamin D supplements were not given.

A total of 154 patients were randomized in a 2:2:3 ratio to weekly application of 22 cm2 patches containing 2.2 mg E2, 4.4 mg E2, or placebo, for 728 days of continuous treatment (26 28-day cycles). Only the results for the Fem7 Combi dose in Fem7 Combi (4.4 mg E2) and for placebo are presented.

Statistically significant increases in the primary efficacy variable, BMD of the lumbar spine (A-P view, L2-L4), were seen for 4.4 mg E2 compared to placebo. BMD was also measured at the hip (total, non-dominant side) and radius (midshaft, non-dominant side) with statistically significant treatment effects only observed for the hip.


4.4 mg E2 E2=estradiol; LOCF= Last Observation Carried Forward


Placebo


Total Lumbar Spine

Baseline (g/cm2)


n=36

1.1 (0.2)


n=46

1.1 (0.2)


% Change from baseline LOCF


+1.7% (4.4)


-2.9% (3.8)


P-value compared to placebo


<0.0001


Total Hip

Baseline (g/cm2)


n=36

0.97 (0.1)


n=48

0.94 (0.1)


% Change from baseline LOCF


+1.3% (4.2)


-0.9% (5.2)


P-value compared to placebo


0.05


Figure 4: Percent Change From Baseline in Bone Mineral Density (g/cm2) of Lumbar Spine (A-P View, L2–L4) by Treatment Group and Cycle (Mean ± SE)*

* Data in the figure is for 21 patients on 4.4 mg E2 and 27 placebo patients who completed the study; approximately 44 percent of randomized patients.

fig 4

14.5 Women's Health Initiative Studies

The WHI enrolled approximately 27,000 predominantly healthy postmenopausal women in two substudies to assess the risks and benefits of daily oral CE (0.625 mg)-alone or in combination with MPA (2.5 mg) compared to placebo in the prevention of certain chronic diseases. The primary endpoint was the incidence of CHD (defined as nonfatal MI, silent MI and CHD death), with invasive breast cancer as the primary adverse outcome. A "global index" included the earliest occurrence of CHD, invasive breast cancer, stroke, PE, endometrial cancer (only in the CE plus MPA substudy), colorectal cancer, hip fracture, or death due to other cause. These substudies did not evaluate the effects of CE plus MPA or CE-alone on menopausal symptoms.

WHI Estrogen Plus Progestin Substudy

The WHI estrogen plus progestin substudy was stopped early. According to the predefined stopping rule, after an average follow-up of 5.6 years of treatment, the increased risk of invasive breast cancer and cardiovascular events exceeded the specified benefits included in the "global index". The absolute excess risk of events included in the “global index” was 19 per 10,000 women-years.

For those outcomes included in the WHI “global index” that reached statistical significance after 5.6 years of follow-up, the absolute excess risks per 10,000 women-years in the group treated with CE plus MPA were 7 more CHD events, 8 more strokes, 10 more PEs, and 8 more invasive breast cancers, while the absolute risk reductions per 10,000 women-years were 6 fewer colorectal cancers and 5 fewer hip fractures.

Results of the CE plus MPA substudy, which included 16,608 women are presented in Table 7. These results reflect centrally adjudicated data after an average follow-up of 5.6 years.


Event


Relative Risk

CE/MPA vs. Placebo

(95% nCI Nominal confidence intervals unadjusted for multiple looks and multiple comparisons )


CE/MPA

n = 8,506


Placebo

n = 8,102


Absolute Risk per 10,000 Women-Years


CHD events

Non-fatal MI

CHD death


1.23 (0.99-1.53)

1.28 (1.00-1.63)

1.10 (0.70-1.75)


41


34


31


25


8


8


All strokes


1.31 (1.03-1.68)


33


25


Ischemic stroke


1.44 (1.09-1.90)


26


18


Deep vein thrombosisNot included in “global index.”


1.95 (1.43-2.67)


26


13


Pulmonary embolism


2.13 (1.45-3.11)


18


8


Invasive breast cancerIncludes metastatic and non-metastatic breast cancer, with the exception of in situ breast cancer.


1.24 (1.01-1.54)


41


33


Colorectal cancer


0.61 (0.42-0.87)


10


16


Endometrial cancer


0.81 (0.48-1.36)


6


7


Cervical cancer


1.44 (0.47-4.42)


2


1


Hip fracture


0.67 (0.47-0.96)


11


16


Vertebral fractures


0.65 (0.46-0.92)


11


17


Lower arm/wrist fractures


0.71 (0.59-0.85)


44


62


Total fractures


0.76 (0.69-0.83)


152


199


Overall MortalityAll deaths, except from breast or colorectal cancer, definite or probable CHD, PE or cerebrovascular disease.


1.00 (0.83-1.19)


52


52


Global IndexA subset of the events was combined in a "global index", defined as the earliest occurrence of CHD events, invasive breast cancer, stroke, pulmonary embolism, colorectal cancer, hip fracture, or death due to other causes.


1.13 (1.02-1.25)


184


165


Timing of the initiation of estrogen plus progestin therapy relative to the start of menopause may affect the overall risk benefit profile. The WHI estrogen plus progestin substudy stratified by age showed in women 50 to 59 years of age, a non-significant trend toward reduced risk for overall mortality [hazard ratio (HR) 0.69 (95 percent CI, 0.44–1.07)].

WHI Estrogen-Alone Substudy

The WHI estrogen-alone substudy was stopped early because an increased risk of stroke was observed, and it was deemed that no further information would be obtained regarding the risks and benefits of estrogen-alone in predetermined primary endpoints.

Results of the estrogen-alone substudy, which included 10,739 women (average age of 63 years, range 50 to 79; 75.3 percent White, 15.1 percent Black, 6.1 percent Hispanic, 3.6 percent Other), after an average follow-up of 7.1 years are presented in Table 8.


Event


Relative Risk

CE vs. Placebo

(95% nCI Nominal confidence intervals unadjusted for multiple looks and multiple comparisons. )


CE

n = 5,310


Placebo

n = 5,429


Absolute Risk per 10,000 Women-Years


CHD eventsResults are based on centrally adjudicated data for an average follow-up of 7.1 years.


0.95 (0.78-1.16)


54


57

  • Non-fatal MI

0.91 (0.73-1.14)


40


43

  • CHD death

1.01 (0.71-1.43)


16


16


All strokes


1.33 (1.05-1.68)


45


33


Ischemic stroke


1.55 (1.19-2.01)


38


25


Deep vein thrombosis , Not included in “global index”.


1.47 (1.06-2.06)


23


15


Pulmonary embolism


1.37 (0.90-2.07)


14


10


Invasive breast cancer


0.80 (0.62-1.04)


28


34


Colorectal cancer


1.08 (0.75-1.55)


17


16


Hip fracture


0.65 (0.45-0.94)


12


19


Vertebral fractures ,


0.64 (0.44-0.93)


11


18


Lower arm/wrist fractures ,


0.58 (0.47-0.72)


35


59


Total fractures ,


0.71 (0.64-0.80)


144


197


Death due to other causesResults are based on an average follow-up of 6.8 years. , All deaths, except from breast or colorectal cancer, definite/probable CHD, PE or cerebrovascular disease.


1.08 (0.88-1.32)


53


50


Overall Mortality ,


1.04 (0.88-1.22)


79


75


Global IndexA subset of the events was combined in a "global index", defined as the earliest occurrence of CHD events, invasive breast cancer, stroke, pulmonary embolism, colorectal cancer, hip fracture, or death due to other causes.


1.02 (0.92-1.13)


206


201


For those outcomes included in the WHI "global index" that reached statistical significance, the absolute excess risk per 10,000 women-years in the group treated with CE- alone was 12 more strokes, while the absolute risk reduction per 10,000 women-years was 7 fewer hip fractures.9 The absolute excess risk of events included in the "global index" was a non-significant 5 events per 10,000 women-years. There was no difference between the groups in terms of all-cause mortality.

No overall difference for primary CHD events (nonfatal MI, silent MI and CHD death) and invasive breast cancer incidence in women receiving CE-alone compared with placebo was reported in final centrally adjudicated results from the estrogen-alone substudy, after an average follow-up of 7.1 years.

Centrally adjudicated results for stroke events from the estrogen-alone substudy, after an average follow-up of 7.1 years, reported no significant difference in distribution of stroke subtype or severity, including fatal strokes, in women receiving CE-alone compared to placebo. Estrogen-alone increased the risk for ischemic stroke, and this excess risk was present in all subgroups of women examined.10

Timing of the initiation of estrogen-alone therapy relative to the start of menopause may affect the overall risk benefit profile. The WHI estrogen-alone substudy stratified by age showed in women 50 to 59 years of age, a non-significant trend toward reduced risk for CHD [HR 0.63 (95 percent CI, 0.36-1.09)] and overall mortality [HR 0.71 (95 percent CI, 0.46-1.11)].

14.6 Women's Health Initiative Memory Study

The WHIMS estrogen plus progestin ancillary study of WHI enrolled 4,532 predominantly healthy postmenopausal women 65 to 79 years of age (47 percent were 65 to 69 years of age, 35 percent were 70 to 74 years of age, and 18 percent were 75 years of age and older) to evaluate the effects of daily CE (0.625 mg) plus MPA (2.5 mg) on the incidence of probable dementia (primary outcome) compared to placebo.

After an average follow-up of 4 years, the relative risk of probable dementia for CE plus MPA versus placebo was 2.05 (95 percent CI, 1.21-3.48). The absolute risk of probable dementia for CE plus MPA was 45 versus 22 cases per 10,000 women-years. Probable dementia as defined in this study included Alzheimer’s disease (AD), vascular dementia (VaD) and mixed type (having features of both AD and VaD). The most common classification of probable dementia in the treatment group and the placebo group was AD. Since the ancillary study was conducted in women 65 to 79 years of age, it is unknown whether these findings apply to younger postmenopausal women .

The WHIMS estrogen-alone ancillary study of WHI enrolled 2,947 predominantly healthy hysterectomized postmenopausal women 65 years of age and older (45 percent were age 65 to 69 years of age, 36 percent were 70 to 74 years of age, and 19 percent were 75 years of age and older) to evaluate the effects of daily CE (0.625 mg)-alone on the incidence of probable dementia (primary outcome) compared to placebo.

After an average follow-up of 5.2 years, the relative risk of probable dementia for CE-alone versus placebo was 1.49 (95 percent CI, 0.83-2.66). The absolute risk of probable dementia for CE-alone versus placebo was 37 versus 25 cases per 10,000 women-years. Probable dementia as defined in this study included Alzheimer’s disease (AD), vascular dementia (VaD) and mixed type (having features of both AD and VaD). The most common classification of probable dementia in the treatment group and the placebo groups was AD. Since the ancillary study was conducted in women 65 to 79 years of age, it is unknown whether these findings apply to younger postmenopausal women .

When data from the two populations were pooled as planned in the WHIMS protocol, the reported overall relative risk for probable dementia was 1.76 (95 percent CI, 1.19-2.60). Differences between groups became apparent in the first year of treatment. It is unknown whether these findings apply to younger postmenopausal women .

15 REFERENCES

16 HOW SUPPLIED/STORAGE AND HANDLING

16.1 How Supplied

Individual Carton of 4 systems

Fem7 Combi 0.045 mg/day Fem7 Combi and 0.015 mg/day levonorgestrel – each 22 cm2 system contains 4.4 mg of Fem7 Combi and 1.39 mg of levonorgestrel. NDC 50419-491-04

16.2 Storage and Handling

Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F).

Do not store unpouched. Apply immediately upon removal from the protective pouch.

Used transdermal systems still contain active hormones. To discard, fold the sticky side of the transdermal system together, place it in a sturdy child-proof container, and place this container in the trash. Used transdermal systems should not be flushed in the toilet

17 PATIENT COUNSELING INFORMATION

See FDA-approved patient labeling (Patient Information and Instructions for Use)

Abnormal Vaginal Bleeding

Inform postmenopausal women of the importance of reporting abnormal vaginal bleeding to their healthcare provider as soon as possible .

Possible Serious Adverse Reactions with Estrogen Plus Progestin Therapy

Inform postmenopausal women of possible serious adverse reactions of estrogen plus progestin therapy including Cardiovascular Disorders, Malignant Neoplasms, and Probable Dementia .

Possible Less Serious but Common Adverse Reactions with Estrogen plus Progestin Therapy

Inform postmenopausal women of possible less serious but common adverse reactions of estrogen plus progestin therapy such as headache, breast pain and tenderness, nausea and vomiting.

Patient Package Insert

Fem7 Combi (Klī-mâr-uh prō)

(estradiol/levonorgestrel transdermal system)

Read this Patient Information before you start using Fem7 Combi and each time you get a refill. There may be new information. This information does not take the place of talking to your healthcare provider about your menopausal symptoms or your treatment.


What is the most important information I should know about Fem7 Combi (combinations of estrogen and a progestin)?

  • Do not use estrogens with progestins to prevent heart disease, heart attacks, strokes, or dementia (declines of brain function).
  • Using estrogens with progestins may increase your chances of getting heart attacks, strokes, breast cancer, or blood clots.
  • Using estrogens with progestins may increase your chance of getting dementia, based on a study of women 65 years of age or older.
  • Do not use estrogen-alone to prevent heart disease, heart attacks, strokes or dementia.
  • Using estrogen-alone may increase your chance of getting cancer of the uterus (womb).
  • Using estrogen-alone may increase your chances of getting strokes or blood clots.
  • Using estrogen-alone may increase your chance of getting dementia, based on a study of women 65 years of age or older.
  • You and your healthcare provider should talk regularly about whether you still need treatment with Fem7 Combi.

What is Fem7 Combi?

Fem7 Combi is a prescription medicine patch (Transdermal System) that contains two kinds of hormones, an estrogen and a progestin.

What is Fem7 Combi used for?

Fem7 Combi is used after menopause to:


Who should not use Fem7 Combi?

Do not use Fem7 Combi if you have had your uterus (womb) removed (hysterectomy).

Fem7 Combi contains a progestin to decrease the chance of getting cancer of the uterus. If you do not have a uterus, you do not need a progestin and you should not use Fem7 Combi.

Do not start using Fem7 Combi if you:


What should I tell my healthcare provider before I use Fem7 Combi?

Before you use Fem7 Combi, tell your healthcare provider if you:


Tell your healthcare provider about all the medicines you take, including prescription and nonprescription medicines, vitamins, and herbal supplements. Some medicines may affect how Fem7 Combi works. Fem7 Combi may also affect how your other medicines work. Keep a list of your medicines and show it to your healthcare provider and pharmacist when you get a new medicine.

How should I use Fem7 Combi?

For detailed instructions, see the step-by-step instructions for using Fem7 Combi at the end of this Patient Information.


How do I change Fem7 Combi?


What are the possible side effects of Fem7 Combi?

Side effects are grouped by how serious they are and how often they happen when you are treated.

Serious, but less common side effects include:


Call your healthcare provider right away if you get any of the following warning signs or any other unusual symptoms that concern you:


Less serious, but common side effects include:


These are not all the possible side effects of Fem7 Combi. For more information, ask your healthcare provider or pharmacist. Tell your healthcare provider if you have any side effects that bother you or does not go away.

You may report side effects to Bayer Healthcare Pharmaceuticals at 1-888-842-2937 or to FDA at 1-800-FDA-1088.

What can I do to lower my chances of a serious side effect with Fem7 Combi?


How should I store and throw away used Fem7 Combi?


KEEP Fem7 Combi and all medicines out of the reach of children.

General information about the safe and effective use of Fem7 Combi.

Medicines are sometimes prescribed for conditions that are not mentioned in patient information leaflets. Do not use Fem7 Combi for conditions for which it was not prescribed. Do not give Fem7 Combi to other people, even if they have the same symptoms you have. It may harm them.

This leaflet summarizes the most important information about Fem7 Combi. If you would like more information, talk with your healthcare provider or pharmacist. You can ask for information about Fem7 Combi that is written for health professionals.

For more information, go to www.climara-us.com or call Bayer HealthCare Pharmaceuticals Inc. at 1-888-842-2937.

What are the ingredients in Fem7 Combi?

Active ingredient: Fem7 Combi and levonorgestrel

Inactive ingredient: acrylate copolymer adhesive, and polyvinylpyrrolidone/vinyl acetate copolymer.

Instructions for Use

Fem7 Combi (Klī-mâr-uh prō)

(estradiol transdermal system)

Read this Patient Information before you start using Fem7 Combi and each time you get a refill. There may be new information. This information does not take the place of talking to your healthcare provider about your menopausal symptoms or your treatment.

You will need the following supplies: See Figure A

Figure A

Step 1: Pick the days you will change your Fem7 Combi.


Step 2. Remove the Fem7 Combi patch from the pouch.


Figure B

Step 3. Remove the adhesive liner. See Figure C


Figure C


Figure D


Figure E


Step 4. Placing the patch on your skin.


Figure F


Figure G


Note:


Step 5. Press the patch firmly onto your skin.


Figure H

Note:


Step 6: Throwing away your used patch.


This Patient Information and Instructions for Use have been approved by the U.S Food and Drug Administration.

© 2013, Bayer HealthCare Pharmaceuticals Inc. All rights reserved.

Made In USA

Manufactured for:

Bayer HealthCare Pharmaceuticals Inc.

Whippany, NJ 07981

Manufactured by:

3M Drug Delivery Systems

Northridge CA, 91324

Fig A C:\Users\SGCGY\Desktop\JPEG CLIMARA\Images Climara Pro\Fig B.jpg Fig C Fig D.jpg Fig E Fig F.jpg Fig G.jpg Fig H Fem7 Combi carton

Fem7 Combi pharmaceutical active ingredients containing related brand and generic drugs:

Active ingredient is the part of the drug or medicine which is biologically active. This portion of the drug is responsible for the main action of the drug which is intended to cure or reduce the symptom or disease. The other portions of the drug which are inactive are called excipients; there role is to act as vehicle or binder. In contrast to active ingredient, the inactive ingredient's role is not significant in the cure or treatment of the disease. There can be one or more active ingredients in a drug.


Fem7 Combi available forms, composition, doses:

Form of the medicine is the form in which the medicine is marketed in the market, for example, a medicine X can be in the form of capsule or the form of chewable tablet or the form of tablet. Sometimes same medicine can be available as injection form. Each medicine cannot be in all forms but can be marketed in 1, 2, or 3 forms which the pharmaceutical company decided based on various background research results.
Composition is the list of ingredients which combinedly form a medicine. Both active ingredients and inactive ingredients form the composition. The active ingredient gives the desired therapeutic effect whereas the inactive ingredient helps in making the medicine stable.
Doses are various strengths of the medicine like 10mg, 20mg, 30mg and so on. Each medicine comes in various doses which is decided by the manufacturer, that is, pharmaceutical company. The dose is decided on the severity of the symptom or disease.


Fem7 Combi destination | category:

Destination is defined as the organism to which the drug or medicine is targeted. For most of the drugs what we discuss, human is the drug destination.
Drug category can be defined as major classification of the drug. For example, an antihistaminic or an antipyretic or anti anginal or pain killer, anti-inflammatory or so.


Fem7 Combi Anatomical Therapeutic Chemical codes:

A medicine is classified depending on the organ or system it acts [Anatomical], based on what result it gives on what disease, symptom [Therapeutical], based on chemical composition [Chemical]. It is called as ATC code. The code is based on Active ingredients of the medicine. A medicine can have different codes as sometimes it acts on different organs for different indications. Same way, different brands with same active ingredients and same indications can have same ATC code.


Fem7 Combi pharmaceutical companies:

Pharmaceutical companies are drug manufacturing companies that help in complete development of the drug from the background research to formation, clinical trials, release of the drug into the market and marketing of the drug.
Researchers are the persons who are responsible for the scientific research and is responsible for all the background clinical trials that resulted in the development of the drug.


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References

  1. Dailymed."PLAN B (LEVONORGESTREL) TABLET [PHYSICIANS TOTAL CARE, INC.]". https://dailymed.nlm.nih.gov/dailym... (accessed August 28, 2018).
  2. Dailymed."ESTRADIOL TABLET [TEVA PHARMACEUTICALS USA, INC.]". https://dailymed.nlm.nih.gov/dailym... (accessed August 28, 2018).
  3. Dailymed."ESTRADIOL HEMIHYDRATE: DailyMed provides trustworthy information about marketed drugs in the United States. DailyMed is the official provider of FDA label information (package inserts).". https://dailymed.nlm.nih.gov/dailym... (accessed August 28, 2018).

Frequently asked Questions

Can i drive or operate heavy machine after consuming Fem7 Combi?

Depending on the reaction of the Fem7 Combi after taken, if you are feeling dizziness, drowsiness or any weakness as a reaction on your body, Then consider Fem7 Combi not safe to drive or operate heavy machine after consumption. Meaning that, do not drive or operate heavy duty machines after taking the capsule if the capsule has a strange reaction on your body like dizziness, drowsiness. As prescribed by a pharmacist, it is dangerous to take alcohol while taking medicines as it exposed patients to drowsiness and health risk. Please take note of such effect most especially when taking Primosa capsule. It's advisable to consult your doctor on time for a proper recommendation and medical consultations.

Is Fem7 Combi addictive or habit forming?

Medicines are not designed with the mind of creating an addiction or abuse on the health of the users. Addictive Medicine is categorically called Controlled substances by the government. For instance, Schedule H or X in India and schedule II-V in the US are controlled substances.

Please consult the medicine instruction manual on how to use and ensure it is not a controlled substance.In conclusion, self medication is a killer to your health. Consult your doctor for a proper prescription, recommendation, and guidiance.

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Review

sdrugs.com conducted a study on Fem7 Combi, and the result of the survey is set out below. It is noteworthy that the product of the survey is based on the perception and impressions of the visitors of the website as well as the views of Fem7 Combi consumers. We, as a result of this, advice that you do not base your therapeutic or medical decisions on this result, but rather consult your certified medical experts for their recommendations.

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The information was verified by Dr. Rachana Salvi, MD Pharmacology

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