Activella (Estradiol/norethindrone acetate) 1.0 mg/0.5 mg is a single tablet for oral administration containing 1 mg of estradiol and 0.5 mg of norethindrone acetate and the following excipients: lactose monohydrate, starch (corn), copovidone, talc, magnesium stearate, hypromellose and triacetin.

Activella (Estradiol/norethindrone acetate) 0.5 mg/0.1 mg is a single tablet for oral administration containing 0.5 mg of estradiol and 0.1 mg of norethindrone acetate and the following excipients: lactose monohydrate, starch (corn), hydroxypropylcellulose, talc, magnesium stearate, hypromellose and triacetin.

Estradiol (E) is a white or almost white crystalline powder. Its chemical name is estra-1, 3, 5 (10)-triene-3, 17β-diol hemihydrate with the empirical formula of CHO, ½ H2O and a molecular weight of 281.4. The structural formula of E is as follows:

Norethindrone acetate (NETA) is a white or yellowish-white crystalline powder. Its chemical name is 17β-acetoxy-19-nor-17α-pregn-4-en-20-yn-3-one with the empirical formula of CHO and molecular weight of 340.5. The structural formula of NETA is as follows:

Endogenous estrogens are largely responsible for the development and maintenance of the female reproductive system and secondary sexual characteristics. Although circulating estrogens exist in a dynamic equilibrium of metabolic interconversions, estradiol is the principal intracellular human estrogen and is substantially more potent than its metabolites, estrone and estriol, at the receptor level.

The primary source of estrogen in normally cycling adult women is the ovarian follicle, which secretes 70 to 500 mcg of estradiol daily, depending on the phase of the menstrual cycle. After menopause, most endogenous estrogen is produced by conversion of androstenedione, secreted by the adrenal cortex, to estrone by peripheral tissues. Thus, estrone and the sulfate conjugated form, estrone sulfate, are the most abundant circulating estrogens in postmenopausal women.

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

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

Progestin compounds enhance cellular differentiation and generally oppose the actions of estrogens by decreasing estrogen receptor levels, increasing local metabolism of estrogens to less active metabolites, or inducing gene products that blunt cellular responses to estrogen. Progestins exert their effects in target cells by binding to specific progesterone receptors that interact with progesterone response elements in target genes. Progesterone receptors have been identified in the female reproductive tract, breast, pituitary, hypothalamus, and central nervous system. Progestins produce similar endometrial changes to those of the naturally occurring hormone progesterone.

Estradiol is well absorbed through the gastrointestinal tract. Following oral administration of Activella (Estradiol/norethindrone acetate) tablets, peak plasma estradiol concentrations are reached slowly within 5-8 hours. When given orally, estradiol is extensively metabolized (first-pass effect) to estrone sulfate, with smaller amounts of other conjugated and unconjugated estrogens. After oral administration, norethindrone acetate is rapidly absorbed and transformed to norethindrone. It undergoes first-pass metabolism in the liver and other enteric organs, and reaches a peak plasma concentration within 0.5 - 1.5 hours after the administration of Activella (Estradiol/norethindrone acetate) tablets. The oral bioavailability of estradiol and norethindrone following administration of Activella (Estradiol/norethindrone acetate) 1.0 mg/0.5 mg when compared to a combination oral solution is 53% and 100%, respectively. Administration of Activella (Estradiol/norethindrone acetate) 1.0 mg/0.5 mg with food did not modify the bioavailability of estradiol, although increases in AUC of 19% and decreases in C of 36% for norethindrone were seen.

The pharmacokinetic parameters of estradiol (E), estrone (E), and norethindrone (NET) following oral administration of 1 Activella (Estradiol/norethindrone acetate) 1.0 mg/0.5 mg or 2 Activella (Estradiol/norethindrone acetate) 0.5 mg/0.1 mg tablet(s) to healthy postmenopausal women are summarized in Table 1.

Following continuous dosing with once-daily administration of Activella (Estradiol/norethindrone acetate) 1.0 mg/0.5 mg, serum levels of estradiol, estrone, and norethindrone reached steady-state within two weeks with an accumulation of 33-47% above levels following single dose administration. Unadjusted circulating levels of E, E, and NET during Activella (Estradiol/norethindrone acetate) 1.0 mg/0.5 mg treatment at steady state (dosing at time 0) are provided in Figures 1a and 1b.

Figure 1a: Levels of Estradiol and Estrone at Steady State During Continuous Dosing with Activella (Estradiol/norethindrone acetate) 1.0 mg/0.5 mg (n=24)
Figure 1b: Levels of Norethindrone at Steady State During Continuous Dosing with Activella (Estradiol/norethindrone acetate) 1.0 mg/0.5 mg (n=24)
Estradiol
Norethindrone Acetate
Coadministration of estradiol with norethindrone acetate did not elicit any apparent influence on the pharmacokinetics of norethindrone. Similarly, no relevant interaction of norethindrone on the pharmacokinetics of estradiol was found within the NETA dose range investigated in a single dose study.

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 result in side effects.

In a 12-week randomized clinical trial involving 92 subjects, Activella (Estradiol/norethindrone acetate) 1.0 mg/0.5 mg was compared to 1 mg of estradiol and to placebo. The mean number and intensity of hot flushes were significantly reduced from baseline to week 4 and 12 in both the Activella (Estradiol/norethindrone acetate) 1.0 mg/0.5 mg and the 1 mg estradiol group compared to placebo (see Figure 2).

Figure 2: Mean Weekly Number of Moderate and Severe Hot Flushes in a 12-Week Study
In a study conducted in Europe a total of 577 postmenopausal women were randomly assigned to either Activella (Estradiol/norethindrone acetate) 0.5 mg/0.1 mg, 0.5 mg E/0.25 mg NETA, or placebo for 24 weeks of treatment. The mean number and severity of hot flushes were significantly reduced at week 4 and week 12 in the Activella (Estradiol/norethindrone acetate) 0.5 mg/0.1 mg (see Figure 3) and 0.5 mg E/0.25 mg NETA groups compared to placebo.

 

During the initial months of therapy, irregular bleeding or spotting occurred with Activella (Estradiol/norethindrone acetate) 1.0 mg/0.5 mg treatment. However, bleeding tended to decrease over time, and after 12 months of treatment with Activella (Estradiol/norethindrone acetate) 1.0 mg/0.5 mg, about 86% of women were amenorrheic (see Figure 4).

Figure 4: Patients Treated with Activella (Estradiol/norethindrone acetate) 1.0 mg/0.5 mg with Cumulative Amenorrhea over Time Percentage of Women with no Bleeding or Spotting at any Cycle Through Cycle 13 - Intent to Treat Population, LOCF
In the clinical trial with Activella (Estradiol/norethindrone acetate) 0.5 mg/0.1 mg, 88% of women were amenorrheic after 6 months of treatment (See Figure 5).

Figure 5: Patients Treated with Activella (Estradiol/norethindrone acetate) 0.5 mg/0.1 mg with Cumulative Amenorrhea over Time Percentage of Women with no Bleeding or Spotting at any Cycle Through Cycle 6, Intent to Treat Population, LOCF
The results of two randomized, multicenter, calcium-supplemented (500-1000 mg/day), placebo-controlled, 2 year clinical trials have shown that Activella (Estradiol/norethindrone acetate) 1.0 mg/0.5 mg and estradiol 0.5 mg are effective in preventing bone loss in postmenopausal women. While Activella (Estradiol/norethindrone acetate) 0.5 mg/0.1 mg was not directly studied in these trials, the US trial showed that addition of NETA to estradiol enhances the effect on BMD, therefore the BMD changes expected from treatment with Activella (Estradiol/norethindrone acetate) 0.5 mg/0.1 mg should be at least as great as observed with estradiol 0.5 mg. A total of 462 postmenopausal women with intact uteri and baseline BMD values for lumbar spine within 2 standard deviations of the mean in healthy young women were enrolled. In a US trial, 327 postmenopausal women (mean time from menopause 2.5 to 3.1 years) with a mean age of 53 years were randomized to 7 groups (0.25 mg, 0.5mg, and 1 mg of estradiol alone, 1 mg estradiol with 0.25 mg norethindrone acetate, 1 mg estradiol with 0.5 mg norethindrone acetate, and 2 mg estradiol with 1 mg norethindrone acetate, and placebo). In a European trial (EU trial), 135 postmenopausal women (mean time from menopause 8.4 to 9.3 years) with a mean age of 58 years were randomized to 1 mg estradiol with 0.25 mg norethindrone acetate, 1 mg estradiol with 0.5 mg norethindrone acetate, and placebo. Approximately 58% and 67% of the randomized subjects in the two clinical trials, respectively, completed the two clinical trials. BMD was measured using dual-energy x-ray absorptiometry (DEXA).

A summary of the results comparing Activella (Estradiol/norethindrone acetate) 1.0 mg/0.5 mg and estradiol 0.5 mg to placebo from the two prevention trials is shown in Table 3.

The overall difference in mean percentage change in BMD at the lumbar spine in the US trial (1000 mg/day calcium) between Activella (Estradiol/norethindrone acetate) 1.0 mg/0.5 mg and placebo was 5.9% and between estradiol 0.5 mg and placebo was 4.4%. In the European trial (500 mg/day calcium), the overall difference in mean percentage change in BMD at the lumbar spine was 6.3%. Activella (Estradiol/norethindrone acetate) 1.0 mg/0.5 mg and estradiol 0.5 mg also increased BMD at the femoral neck and femoral trochanter compared to placebo. The increase in lumbar spine BMD in the US and European clinical trials for Activella (Estradiol/norethindrone acetate) 1.0 mg/0.5 mg and estradiol 0.5 mg is displayed in Figure 6.

Figure 6: Percentage Change in Bone Mineral Density (BMD) ± SEM of the Lumbar Spine (L1-L4) for Activella (Estradiol/norethindrone acetate) 1.0 mg/0.5 mg and Estradiol 0.5 mg* (Intent to Treat Analysis with Last Observation Carried Forward)
* While Activella (Estradiol/norethindrone acetate) 0.5mg/0.1 mg was not directly studied in these trials, the US trial showed that addition of NETA to estradiol enhances the effect on BMD, therefore the BMD changes expected from treatment with Activella (Estradiol/norethindrone acetate) 0.5mg/0.1 mg should be at least as great as observed with estradiol 0.5 mg.

Activella (Estradiol/norethindrone acetate) 1.0 mg/0.5 mg reduced serum and urine markers of bone turnover with a marked decrease in bone resorption markers (e.g., urinary pyridinoline crosslinks Type 1 collagen C-telopeptide, pyridinoline, deoxypyridinoline) and to a lesser extent in bone formation markers (e.g., serum osteocalcin, bone-specific alkaline phosphatase, C-terminal propetide of type 1 collagen). The suppression of bone turnover markers was evident by 3 months and persisted throughout the 24-month treatment period.

Treatment with 0.5 mg estradiol decreased biochemical markers of bone resorption (urinary pyridinoline, urinary deoxypyridinoline) and bone formation (bone-specific alkaline phosphatase) compared to placebo. These decreases occurred by 6 months of treatment after which the levels were maintained throughout the 24 months.

The WHI enrolled a total of 27,000 predominantly healthy postmenopausal women in two substudies to assess the risks and benefits of either the use of oral conjugated estrogens (CE 0.625 mg per day) alone or the use of oral conjugated estrogens (CE 0.625 mg) plus medroxyprogesterone acetate (MPA 2.5 mg 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 (MI), silent MI 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 estrogen-plus-progestin substudy was stopped early. According to the predefined stopping rule, after an average follow-up of 5.2 years of treatment, the increased risk of 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 (RR 1.15, 95% nCI 1.03-1.28).

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/MPA were six more CHD events, seven more strokes, ten more PEs, and eight more invasive breast cancers, while the absolute risk reductions per 10,000 women-years were seven fewer colorectal cancers and five fewer hip fractures. (See , , and .)

Results of the estrogen-plus-progestin substudy, which included 16,608 women (average age of 63 years, range 50 to 79; 83.9% White, 6.8% Black, 5.4% Hispanic, 3.9% Other) are presented in Table 4 below:

The estrogen-alone substudy was also 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% White, 15.1% Black, 6.1% Hispanic, 3.6% Other), after an average follow-up of 6.8 years are presented in Table 5 below.

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 estrogen-alone was 12 more strokes, while the absolute risk reduction per 10,000 women-years was six fewer hip fractures. The absolute excess risk of events included in the “global index” was a nonsignificant two events per 10,000 women-years. There was no difference between the groups in terms of all-cause mortality. (See and .)

Final adjudicated results for CHD events from the estrogen-alone substudy, after an average follow-up of 7.1 years, reported no overall difference for primary CHD events (nonfatal MI, silent MI and CHD death) in women receiving CE alone compared with placebo (see Table 5).

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

After an average follow-up of four years, 40 women in the estrogen-plus-progestin group (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 1.21-3.48) compared to placebo. It is unknown whether these findings apply to younger postmenopausal women. (See  , , and , )

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

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

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% 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. (See , , , and , .)

Activella (Estradiol/norethindrone acetate) 1.0 mg/0.5 mg and 0.5 mg/0.1 mg are indicated in women who have a uterus for the:

1. Treatment of moderate to severe vasomotor symptoms associated with menopause.

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

The mainstays for decreasing the risk of postmenopausal osteoporosis are weight bearing exercise, adequate calcium and vitamin D intake, and when indicated, pharmacologic therapy. Postmenopausal women require an average of 1500 mg/day of elemental calcium. Therefore, when not contraindicated, calcium supplementation may be helpful for women with suboptimal dietary intake. Vitamin D supplementation of 400-800 IU/day may also be required to ensure adequate daily intake in postmenopausal women.

Activella (Estradiol/norethindrone acetate) 1.0 mg/0.5 mg is also indicated in women who have a uterus for the:

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

Activella (Estradiol/norethindrone acetate) should not be used in women with any of the following conditions:

1. Undiagnosed abnormal genital bleeding.

2. Known, suspected, or history of cancer of the breast.

3. Known or suspected estrogen-dependent neoplasia.

4. Active deep vein thrombosis, pulmonary embolism, or history of these conditions.

5. Active or recent (e.g., within the past year) arterial thromboembolic disease (e.g., stroke, myocardial infarction).

6. Liver dysfunction or disease.

7. Known hypersensitivity to the ingredients of Activella (Estradiol/norethindrone acetate) 1.0 mg/0.5 mg or Activella (Estradiol/norethindrone acetate) 0.5 mg/0.1 mg.

8. Known or suspected pregnancy. There is no indication for Activella (Estradiol/norethindrone acetate) in pregnancy. There appears to be little or no increased risk of birth defects in children born to women who have used estrogens and progestins from oral contraceptives inadvertently during early pregnancy. ( See .)

See

Estrogen-plus-progestin therapy has been associated with an increased risk of myocardial infarction as well as stroke, venous thrombosis and pulmonary embolism.

Estrogen-alone therapy has been associated with an increased risk of stroke and deep vein thrombosis (DVT). Should any of these events occur or be suspected, estrogens should be discontinued immediately.

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

In the estrogen-plus-progestin Women's Health Initiative Memory Study (WHIMS), a substudy of WHI, a population of 4,532 postmenopausal women aged 65 to 79 years was randomized to CE/MPA (0.625 mg/2.5 mg daily) or placebo. In the estrogen-alone WHIMS substudy, a population of 2,947 hysterectomized women, aged 65 to 79 years, was randomized to CE (0.625 mg daily) or placebo.

In the estrogen-plus-progestin substudy, after an average follow-up of four years, 40 women in the estrogen-plus-progestin group and 21 women in the placebo group were diagnosed with probable dementia. The relative risk of probable dementia for estrogen plus progestin vs. placebo was 2.05 (95% CI 1.21-3.48). The absolute risk of probable dementia for CE/MPA vs. placebo was 45 vs. 22 cases per 10,000 women-years.

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 CE alone vs. placebo was 1.49 (95% CI 0.83-2.66). The absolute risk of probable dementia for CE alone vs. placebo was 37 vs. 25 cases per 10,000 women-years.

When data from the two populations were pooled as planned in the WHIMS protocol, the reported overall relative risk of probable dementia was 1.76 (95% CI 1.19-2.60). Since both substudies were conducted in women ages 65 to 79, it is unknown whether these findings apply to younger postmenopausal women. (See and , .)

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

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

3. Other binding proteins may be elevated in serum (i.e., corticosteroid binding globulin (CBG), SHBG) leading to increased total circulating corticosteroids and sex steroids, respectively. Free hormone concentrations may be decreased. Other plasma proteins may be increased (angiotensinogen/rennin substrate, alpha-1 antitrypsin, ceruloplasmin).

4. Increased plasma HDL and HDL cholesterol subfraction concentration, reduced LDL cholesterol concentration, increased triglyceride levels.

5. Impaired glucose tolerance.

6. Reduced response to metyrapone test.

Long-term continuous administration of estrogen, with or without progestin, in women with or without a uterus, has shown an increased risk of endometrial cancer, breast cancer, and ovarian cancer. (See , , and .)

Long-term continuous administration of natural and synthetic estrogens in certain animal species increases the frequency of carcinomas of the breast, uterus, cervix, vagina, testis, and liver.

Clinical studies of Activella (Estradiol/norethindrone acetate) did not include sufficient number of subjects aged 65 and over to determine if they responded differently from younger subjects.

Of the total number of subjects in the estrogen-plus-progestin substudy of the Women's Health Initiative (WHI) study, 44% (n=7,320) were 65-74 years of age, while 6.6% (n=1,095) were 75 years and over. There was a higher relative risk (CE/MPA vs. placebo) of non-fatal stroke and invasive breast cancer in women 75 and over compared to women less than 75 years of age. In women greater than 75, the increased risk of non-fatal stroke and invasive breast cancer observed in the estrogen-plus-progestin combination group compared to the placebo group was 75 vs. 24 per 10,000 women-years and 52 vs. 12 per 10,000 women-years, respectively.

In the estrogen-plus-progestin Women's Health Initiative Memory Study (WHIMS), a substudy of WHI, a population of 4,532 hysterectomized women, aged 65 to 79 years, was randomized to CE/MPA (0.625 mg/2.5 mg daily) or placebo. In the estrogen-plus-progestin group, after an average follow-up of four years, the relative risk (CE/MPA vs. placebo) of probable dementia was 2.05 (95% CI 1.21-3.48). The absolute risk of developing probable dementia with CE/MPA was 45 vs. 22 cases per 10,000 women-years with placebo.

Of the total number of subjects in the estrogen-alone substudy of WHI, 46% (n=4,943) were 65 years and over, while 7.1% (n=767) were 75 years and over. There was a higher relative risk (CE vs. placebo) of stroke in women less than 75 years of age compared to women 75 years and over. In the estrogen-alone WHIMS substudy, a population of 2,947 hysterectomized women, aged 65 to 79 years, was randomized to CE (0.625 mg daily) or placebo. After an average follow-up of 5.2 years, the relative risk (CE vs. placebo) of probable dementia was 1.49 (95% CI 0.83-2.66). The absolute risk of developing probable dementia with estrogen alone was 37 vs. 25 cases per 10,000 women-years with placebo.

Seventy-nine percent of the cases of probable dementia occurred in women that were older than 70 for the CE-alone group, and 82 percent of the cases of probable dementia occurred in women who were older than 70 in the CE/MPA group. The most common classification of probable dementia in both the treatment groups and placebo groups was Alzheimer's disease.

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% CI 1.19-2.60). Since both substudies were conducted in women aged 65 to 79 years, it is unknown whether these findings apply to younger postmenopausal women. (See and , .)

See ,   and .

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The adverse reaction information from clinical trials does, however, provide a basis for identifying the adverse events that appear to be related to drug use and for approximating rates.

Adverse events reported with Activella (Estradiol/norethindrone acetate) 1.0 mg/0.5 mg by investigators in the Phase 3 studies regardless of causality assessment are shown in Table 6.

Adverse events reported with Activella (Estradiol/norethindrone acetate) 0.5 mg/0.1 mg by investigators during the Phase 3 study regardless of causality assessment are shown in Table 7.

The following adverse reactions have been reported with estrogen and/or progestin therapy:

Serious ill effects have not been reported following acute ingestion of large doses of estrogen-containing drug products by young children. Overdosage of estrogen may cause nausea and vomiting, and withdrawal bleeding may occur in females.

Use of estrogen, alone or in combination with a progestin, should be with the lowest effective dose and for the shortest duration consistent with treatment goals and risks for the individual woman. Patients should be re-evaluated periodically as clinically appropriate (e.g., 3 to 6 month intervals) to determine if treatment is still necessary (See and ). For women who have a uterus, adequate diagnostic measures, such as endometrial sampling, when indicated, should be undertaken to rule out malignancy in cases of undiagnosed persistent or recurring abnormal vaginal bleeding.

Activella (Estradiol/norethindrone acetate) therapy consists of a single tablet to be taken once daily.

1. For the treatment of moderate to severe vasomotor symptoms associated with menopause, and the prevention of postmenopausal osteoporosis. When prescribing solely for the prevention of postmenopausal osteoporosis, therapy should only be considered for women at significant risk of osteoporosis and non-estrogen medications should be carefully considered.

2. For the treatment of moderate to severe symptoms of vulvar and vaginal atrophy. When used solely for the treatment of symptoms of vulvar and vaginal atrophy, topical vaginal products should be considered.

Patients should be started at the lowest dose.

Store at 25°C (77°F), excursions permitted to 15-30°C (59-86°F). [See USP Controlled Room Temperature.]

© 2000-2006 Novo Nordisk Inc.

Activella (Estradiol/norethindrone acetate) is a trademark owned by Novo Nordisk FemCare AG

Revised December 2006

Version 7

Novo Nordisk Inc.

Princeton, NJ 08540

1-866-668-6336

www.novonordisk-us.com

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Novo Nordisk A/S

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