Activella

Name: Activella

Estradiol Norethindrone Side Effects

Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficult breathing; swelling of your face, lips, tongue, or throat.

Call your doctor at once if you have:

  • chest pain or heavy feeling, pain spreading to the jaw or shoulder, sweating, feeling short of breath, fainting;
  • sudden numbness or weakness (especially on one side of the body), sudden severe headache, slurred speech, problems with vision or balance;
  • sudden cough, wheezing, rapid breathing, coughing up blood;
  • pain, swelling, warmth, or redness in one or both legs;
  • vomiting, jaundice (yellowing of the skin or eyes);
  • unusual vaginal bleeding; or
  • a lump in your breast.

Common side effects may include:

  • nausea, bloating, stomach cramps;
  • headache, depressed mood;
  • breast pain, back pain;
  • sleep problems (insomnia);
  • hair loss, weight changes, acne; or
  • vaginal itching or discharge, breakthrough bleeding.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

Get emergency medical help if you have signs of an allergic reaction: hives; difficult breathing; swelling of your face, lips, tongue, or throat.

Call your doctor at once if you have:

  • confusion, depression, unusual thoughts or behavior;
  • unusual or heavy vaginal bleeding;
  • a lump in your breast;
  • heart attack symptoms--chest pain or pressure, pain spreading to your jaw or shoulder, nausea, sweating;
  • signs of a stroke--sudden numbness or weakness (especially on one side of the body), sudden severe headache, slurred speech, problems with vision or balance;
  • signs of a blood clot in the lung--chest pain, sudden cough, wheezing, rapid breathing, coughing up blood;
  • signs of a blood clot in your leg--pain, swelling, warmth, or redness in one or both legs; or
  • liver problems--nausea, upper stomach pain, itching, tired feeling, loss of appetite, dark urine, clay-colored stools, jaundice (yellowing of the skin or eyes).

Common side effects may include:

  • nausea, vomiting, bloating, stomach cramps;
  • light vaginal bleeding or spotting;
  • vaginal itching or discharge;
  • headache;
  • breast pain; or
  • redness or irritation where the patch is worn.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

What happens if I overdose?

Seek emergency medical attention or call the Poison Help line at 1-800-222-1222.

How do I store and/or throw out Activella?

  • Store at room temperature.
  • Store in a dry place. Do not store in a bathroom.
  • Keep all drugs in a safe place. Keep all drugs out of the reach of children and pets.
  • Check with your pharmacist about how to throw out unused drugs.

Use in specific populations

Pregnancy

Activella should not be used during pregnancy [see Contraindications (4)]. There appears to be little or no increased risk of birth defects in children born to women who have used estrogens and progestins as an oral contraceptive inadvertently during early pregnancy.

Nursing Mothers

Activella 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 estrogen and progestin have been identified in the breast milk of women receiving estrogen plus progestin therapy. Caution should be exercised when Activella is administered to a nursing woman.

Pediatric Use

Activella is not indicated in children. Clinical studies have not been conducted in the pediatric population.

Geriatric Use

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

The Women’s Health Initiative Studies

In the WHI estrogen plus progestin substudy (daily CE [0.625 mg] plus MPA [2.5 mg] versus placebo), there was a higher relative risk of nonfatal stroke and invasive breast cancer in women greater than 65 years of age [see Clinical Studies ( 14.5)].

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 [see Clinical Studies ( 14.5)].

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. It is unknown whether this finding applies to younger postmenopausal women [see Warnings and Precautions ( 5.3), and Clinical Studies ( 14.6)].

Since both ancillary studies were conducted in women 65 to 79 years of age, it is unknown whether these findings apply to younger postmenopausal women 8 [see Warnings and Precautions ( 5.3), and Clinical Studies ( 14.6)].

Renal Impairment

The effect of renal impairment on the pharmacokinetics of Activella has not been studied.

Hepatic Impairment

The effect of hepatic impairment on the pharmacokinetics of Activella has not been studied.

Activella Description

Activella 1 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  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 2), an estrogen, 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 C 18H 24O 2, ½ H 2O and a molecular weight of 281.4. The structural formula of E 2 is as follows:

Estradiol

Norethindrone acetate (NETA), a progestin, 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 C 22H 28O 3 and molecular weight of 340.5. The structural formula of NETA is as follows:

Norethindrone Acetate

Clinical Studies

Effects on Vasomotor Symptoms

In a 12-week randomized clinical trial involving 92 subjects, Activella 1 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 1 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 0.5 mg/0.1 mg, 0.5 mg E 2/0.25 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 0.5 mg/0.1 mg (see Figure 3) and 0.5 mg E 2/0.25 mg NETA groups compared to placebo.

Figure 3 Mean Number of Moderate to Severe Hot Flushes for Weeks 0 Through 12

Effects on the Endometrium

Activella 1 mg/0.5 mg reduced the incidence of estrogen-induced endometrial hyperplasia at 1 year in a randomized, controlled clinical trial. This trial enrolled 1,176 subjects who were randomized to one of 4 arms: 1 mg estradiol unopposed (n=296), 1 mg E 2 + 0.1 mg NETA (n=294), 1 mg E 2 + 0.25 mg NETA (n=291), and Activella 1 mg/0.5 mg (n=295). At the end of the study, endometrial biopsy results were available for 988 subjects. The results of the 1 mg estradiol unopposed arm compared to Activella 1 mg/0.5 mg are shown in Table 4.

TABLE 4 INCIDENCE OF ENDOMETRIAL HYPERPLASIA WITH UNOPPOSED ESTRADIOL AND Activella 1 MG/0.5 MG IN A 12-MONTH STUDY

1 mg E 2


(n=296)

Activella

1 mg E 2/0.5 mg NETA

(n=295)

1 mg E 2/0.25 mg NETA

(n=291 )

1 mg E 2/0.1 mg NETA

(n=294 )

No. of subjects with histological evaluation at the end of the study

247

241

251

249

No. (%) of subjects with endometrial hyperplasia at the end of the study

36 (14.6%)

1 (0.4%)

1 (0.4%)

2 (0.8%)

Effects on Uterine Bleeding or Spotting

During the initial months of therapy, irregular bleeding or spotting occurred with Activella 1 mg/0.5 mg treatment. However, bleeding tended to decrease over time, and after 12 months of treatment with Activella 1 mg/0.5 mg, about 86 percent of women were amenorrheic (see Figure 4).

Figure 4 Patients Treated with Activella 1 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

Note: the percentage of patients who were amenorrheic in a given cycle and through cycle 13 is shown. If data were missing, the bleeding value from the last reported day was carried forward (LOCF).

In the clinical trial with Activella 0.5 mg/0.1 mg, 88 percent of women were amenorrheic after 6 months of treatment (See Figure 5).

Figure 5

Effects on Bone Mineral Density

The results of two randomized, multicenter, calcium-supplemented (500-1000 mg per day), placebo-controlled, 2 year clinical trials have shown that Activella 1 mg/0.5 mg and estradiol 0.5 mg are effective in preventing bone loss in postmenopausal women. 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 (T-score > -2.0) 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, 0.5 mg, 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 percent and 67 percent of the randomized subjects in the two clinical trials, respectively, completed the two clinical trials. BMD was measured using dual-energy x-ray absorptiometry (DXA).

A summary of the results comparing Activella 1 mg/0.5 mg and estradiol 0.5 mg to placebo from the two prevention trials is shown in Table 5.

* While Activella 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 0.5 mg/0.1 mg should be at least as great as observed with estradiol 0.5 mg. † Significantly (p<0.001) different from placebo ‡ Significantly (p<0.007) different from placebo § Significantly (p<0.002) different from placebo

TABLE 5 PERCENTAGE CHANGE (MEAN ± SD) IN BONE MINERAL DENSITY (BMD) FOR Activella 1 MG/0.5 MG AND 0.5 MG E 2*(Intent to Treat Analysis, Last Observation Carried Forward)

US Trial

EU Trial

Placebo
(n=37)

0.5 mg E 2*

(n=31)

Activella

1 mg/0.5 mg
(n=37)

Placebo

(n=40)

Activella

1 mg/0.5 mg
(n=38)

Lumbar spine

-2.1 ± 2.9

2.3 ± 2.8 †

3.8 ± 3.0 †

-0.9 ± 4.0

5.4 ± 4.8 †

Femoral neck

-2.3 ± 3.4

0.3 ± 2.9 ‡

1.8 ± 4.1 †

-1.0 ± 4.6

0.7 ± 6.1

Femoral trochanter

-2.0 ± 4.3

1.7 ± 4.1 §

3.7 ± 4.3 †

0.8 ± 6.9

6.3 ± 7.6 †

US = United States, EU = European

The overall difference in mean percentage change in BMD at the lumbar spine in the US trial (1000 mg per day calcium) between Activella 1 mg/0.5 mg and placebo was 5.9 percent and between estradiol 0.5 mg and placebo was 4.4 percent. In the European trial (500 mg per day calcium), the overall difference in mean percentage change in BMD at the lumbar spine was 6.3 percent. Activella 1 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 1 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 1 mg/0.5 mg and Estradiol 0.5 mg (Intent to Treat Analysis with Last Observation Carried Forward)

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 (average 63 years of age, range 50 to 79; 83.9 percent White, 6.8 percent Black, 5.4 percent Hispanic, 3.9 percent Other) are presented in Table 6. These results reflect centrally adjudicated data after an average follow-up of 5.6 years.

Table 6: Relative and Absolute Risk Seen in the Estrogen Plus Progestin Substudy of WHI at an Average of 5.6 Years *, †
* Adapted from numerous WHI publications. WHI publications can be viewed at www.nhlbi.nih.gov/whi. † Results are based on centrally adjudicated data. ‡ Nominal confidence intervals unadjusted for multiple looks and multiple comparisons. § Not included in “global index”. ¶ Includes metastatic and non-metastatic breast cancer, with the exception of in situ breast cancer. # All deaths, except from breast or colorectal cancer, definite or probable CHD, PE or cerebrovascular disease. Þ A 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.

Event

Relative Risk
CE/MPA versus Placebo
(95% nCI ‡)

CE/MPA
n = 8,506

Placebo
n = 8,102

Absolute Risk per 10,000 Women-Years

CHD events

1.23 (0.99-1.53)

41

34

  Non-fatal MI

1.28 (1.00-1.63)

31

25

  CHD death

1.10 (0.70-1.75)

8

8

All strokes

1.31 (1.03–1.68)

33

25

Ischemic stroke

1.44 (1.09–1.90)

26

18

Deep vein thrombosis §

1.95 (1.43–2.67)

26

13

Pulmonary embolism

2.13 (1.45–3.11)

18

8

Invasive 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 Mortality #

1.00 (0.83-1.19)

52

52

Global Index Þ

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 63 years of age, 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 7.

* Adapted from numerous WHI publications. WHI publications can be viewed at www.nhlbi.nih.gov/whi. † Nominal confidence intervals unadjusted for multiple looks and multiple comparisons. ‡ Results are based on centrally adjudicated data for an average follow-up of 7.1 years. § Not included in “global index”. ¶ Results are based on an average follow-up of 6.8 years. # All deaths, except from breast or colorectal cancer, definite or probable CHD, PE or cerebrovascular disease. Þ A 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.

Table 7: Relative and Absolute Risk Seen in the Estrogen-Alone Substudy of WHI*

Event

Relative Risk
CE versus Placebo
(95% nCI †)

CE
n = 5,310

Placebo
n = 5,429

Absolute Risk per 10,000 Women-Years

CHD events ‡

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 ‡,§

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 causes ¶,#

1.08 (0.88–1.32)

53

50

Overall mortality ‡,§

1.04 (0.88–1.22)

79

75

Global Index Þ

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)].

Women’s Health Initiative Memory Study

The WHIMS estrogen plus progestin ancillary study of WHI enrolled 4,532 predominantly healthy postmenopausal women 65 years of age and older (47 percent were 65 to 69 years of age, 35 percent were 70 to 74 years of age, 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 versus placebo 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 types (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 [see Warnings and Precautions ( 5.3), and Use in Specific Populations ( 8.5)].

The WHIMS estrogen-alone ancillary study of WHI study enrolled 2,947 predominantly healthy hysterectomized postmenopausal women 65 to 79 years of age (45 percent were 65 to 69 years of age, 36 percent were 70 to 74 years of age, 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 AD, VaD and mixed types (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 [see Warnings and Precautions ( 5.3), and Use in Specific Populations ( 8.5)] .

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 [see Warnings and Precautions ( 5.3), and Use in Specific Populations ( 8.5)].

Patient Counseling Information

See FDA-approved patient labeling (Patient Information)

Abnormal Vaginal Bleeding

Inform postmenopausal women of the importance of reporting abnormal vaginal bleeding to their healthcare provider as soon as possible [see Warnings and Precautions ( 5.2)] .

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 [see Warnings and Precautions ( 5.1, 5.2, 5.3)].

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.

Date of Issue: 04/2016

Rx Only

Manufactured by:

Novo Nordisk A/S

2880 Bagsvaerd, Denmark

Distributed by:

Gemini Laboratories, LLC

Bridgewater, NJ 08807 USA

Manufacturer

  • Amneal Pharmaceuticals, LLC

Activella Food Interactions

Grapefruit and grapefruit juice may interact with Activella and lead to potentially dangerous effects. Discuss the use of grapefruit products with your doctor.

Activella Overdose

If you take too much Activella, call your healthcare provider or local Poison Control Center, or seek emergency medical attention right away.

 

Other Requirements

  • Store Activella at room temperature between 68°F to 77°F (20°C to 25°C).
  • Store Activella in a dry place protected from light.
  • Keep this and all medications out of the reach of children. 

Activella FDA Warning

Warning: Cardiovascular disorders, breast cancer, endometrial cancer, and probable dementia

Estrogen Plus Progestin Therapy

Cardiovascular Disorders and Probable Dementia

Estrogen plus progestin therapy should not be used for the prevention of cardiovascular disease or dementia.

The Women’s Health Initiative (WHI) estrogen plus progestin substudy reported increased risks of deep vein thrombosis (DVT), pulmonary embolism (PE), stroke and myocardial infarction (MI) in postmenopausal women (50 to 79 years of age) during 5.6 years of treatment with daily oral conjugated estrogen (CE) [0.625 mg] combined with medroxyprogesterone acetate (MPA) [2.5 mg], relative to placebo.

The WHI Memory Study (WHIMS) estrogen plus progestin ancillary study of the WHI reported an increased risk of developing probable dementia in postmenopausal women 65 years of age or older during 4 years of treatment with daily CE (0.625 mg) combined with MPA (2.5 mg), relative to placebo. It is unknown whether this finding applies to younger postmenopausal women.

Breast Cancer

The WHI estrogen plus progestin substudy also demonstrated an increased risk of invasive breast cancer.

In the absence of comparable data, these risks should be assumed to be similar for other doses of CE and MPA and other combinations and dosage forms of estrogens and progestins.

Estrogens with or without progestins should be prescribed at the lowest effective doses and for the shortest duration consistent with treatment goals and risks for the individual woman.

Estrogen-Alone Therapy

Endometrial Cancer

There is an increased risk of endometrial cancer in a woman with a uterus who uses unopposed estrogens. Adding a progestin to estrogen therapy has been shown to reduce the risk of endometrial hyperplasia, which may be a precursor to endometrial cancer. 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.

Cardiovascular Disorders and Probable Dementia

Estrogen-alone therapy should not be used for the prevention of cardiovascular disease or dementia.

The WHI estrogen-alone substudy reported increased risks of stroke and DVT in postmenopausal women (50 to 79 years of age) during 7.1 years of treatment with daily oral CE (0.625 mg)-alone, relative to placebo.

The WHIMS estrogen-alone ancillary study of the WHI reported an increased risk of developing probable dementia in postmenopausal women 65 years of age or older during 5.2 years of treatment with daily CE (0.625 mg)-alone, relative to placebo. It is unknown whether this finding applies to younger postmenopausal women.

In the absence of comparable data, these risks should be assumed to be similar for other doses of CE and other dosage forms of estrogens.

Estrogens with or without progestins should be prescribed at the lowest effective doses and for the shortest duration consistent with treatment

For the Consumer

Applies to conjugated estrogens / medroxyprogesterone: oral tablet

Along with its needed effects, conjugated estrogens / medroxyprogesterone may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor immediately if any of the following side effects occur while taking conjugated estrogens / medroxyprogesterone:

Less common
  • Bloating or swelling of the face, arms, hands, lower legs, or feet
  • blood in the urine
  • blurred vision
  • chest pain
  • clear or bloody discharge from the nipple
  • cough or hoarseness
  • dimpling of the breast skin
  • dizziness
  • fast, irregular, pounding, or racing heartbeat or pulse
  • feeling faint, dizzy, or lightheaded
  • feeling of warmth or heat
  • fever or chills
  • flushing or redness of the skin, especially on the face and neck
  • headache
  • inverted nipple
  • lower back or side pain
  • lump in the breast or under the arm
  • nervousness
  • pain during sexual intercourse
  • painful or difficult urination
  • persistent crusting or scaling of the nipple
  • pounding in the ears
  • redness or swelling of the breast
  • severe cramping of the uterus
  • sore on the skin of the breast that does not heal
  • sweating
  • thick, white vaginal discharge with no odor or with a mild odor
  • tingling of the hands or feet
  • unusual weight gain or loss
  • vaginal bleeding that is unusual and heavy
  • vaginal or genital itching
  • vaginal yeast infection
Incidence not known
  • Absent, missed, or irregular menstrual periods
  • acid or sour stomach
  • anxiety
  • backache
  • breast pain or tenderness
  • confusion
  • constipation
  • darkened urine
  • decreased vision or other changes in vision
  • difficulty with speaking
  • double vision
  • fainting
  • heartburn
  • inability to move the arms, legs, or facial muscles
  • inability to speak
  • indigestion
  • loss of appetite
  • nausea
  • pain or discomfort in the arms, jaw, back, or neck
  • pain or feeling of pressure in the pelvis
  • pain, redness, or swelling in the arm or leg
  • painful or tender cysts in the breasts
  • pains in the stomach, side, or abdomen, possibly radiating to the back
  • slow speech
  • sudden shortness of breath or troubled breathing
  • unexpected or excess milk flow from the breasts
  • vomiting
  • yellow eyes or skin

Some side effects of conjugated estrogens / medroxyprogesterone may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

More common
  • Back pain
  • depression
  • excess gas in the stomach or intestines
  • lack or loss of strength
Less common
  • Blemishes on the skin
  • body aches or pain
  • congestion
  • depersonalization
  • diarrhea
  • difficulty with moving
  • dry skin
  • dryness of the vagina
  • dysphoria
  • euphoria
  • excessive muscle tone
  • feeling paranoid
  • flu-like symptoms
  • fullness or swelling of the breasts
  • hair loss or thinning of the hair
  • headache, severe and throbbing
  • leg cramps
  • loss of bladder control
  • menstrual periods that are longer or heavier
  • muscle pain or stiffness
  • pain in the joints
  • pain or tenderness around the eyes and cheekbones
  • pimples or acne
  • quick to react or overreact emotionally
  • rapidly changing moods
  • rash
  • sleeplessness
  • sore mouth or tongue
  • stuffy or runny nose
  • tender, swollen glands in the neck
  • tightness of the chest or wheezing
  • trouble with sleeping
  • trouble with swallowing
  • vaginal discharge that is clear or white
  • voice changes
  • white patches in the mouth or on the tongue
Incidence not known
  • Changes in appetite
  • hives or welts
  • inability to have or keep an erection
  • increased hair growth, especially on the face
  • increased interest in sexual intercourse
  • irritability
  • loss in sexual ability, desire, drive, or performance
  • loss of scalp hair
  • pain in the ankles or knees
  • painful, red lumps under the skin, mostly on the legs
  • patchy brown or dark brown discoloration of the skin
  • redness of the skin
  • weight changes

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