Short answer: In the label's trials, common Activella side effects included breast pain (24% on 1 mg/0.5 mg in the 12-month study, 21% vs 0% on placebo in the 3-month study), headache, nausea and bleeding. On the 0.5 mg/0.1 mg strength, vaginal bleeding was 26% vs 12% on placebo. Activella carries a boxed warning on blood clots, stroke, heart attack, breast cancer, probable dementia and endometrial cancer.
What Activella is approved for: Activella combines estradiol with the progestin norethindrone acetate in one daily tablet. It is approved to treat moderate to severe hot flashes and moderate to severe symptoms of vulvar and vaginal atrophy due to menopause, and to prevent postmenopausal osteoporosis (sections 1.1 to 1.3). For vaginal symptoms alone the label says to first consider vaginal products, and for bone alone, non-estrogen medicines first.
Source
ACTIVELLA (estradiol/norethindrone acetate) tablets, prescribing information and Patient Information. Amneal Pharmaceuticals. DailyMed, version published June 3, 2024. DailyMed setid d4b0c1dd-aae9-4ca2-958c-71dbe5d0fab0
WARNING: CARDIOVASCULAR DISORDERS, PROBABLE DEMENTIA, BREAST CANCER, and ENDOMETRIAL CANCER
Estrogen plus progestin therapy: in the Women's Health Initiative (WHI), daily oral conjugated estrogens (CE) 0.625 mg plus medroxyprogesterone acetate (MPA) 2.5 mg raised the risk of deep vein thrombosis, pulmonary embolism, stroke and heart attack in women 50 to 79 over 5.6 years, and of invasive breast cancer; the WHI Memory Study found a higher risk of probable dementia in women 65 and older over 4 years. Estrogen-alone therapy: a woman with a uterus who uses estrogen without a progestogen has a higher risk of endometrial cancer, and CE alone raised the risk of stroke, DVT and probable dementia. Neither is to be used to prevent heart disease or dementia. Only those oral doses were studied, so the label says the relevance to other doses, routes or products is not known and the risks cannot be definitively excluded. Estrogens are prescribed at the lowest effective dose for the shortest duration consistent with treatment goals and risks.
These are the label's own numbers from the Adverse Reactions section. Where the label compares with placebo (a dummy treatment), both columns are shown, so you can see how much more often a reaction happened on Activella.
| Adverse reaction | Activella 12-mo (n=295) | 1 mg E2 12-mo (n=296) | Activella 3-mo (n=29) | Placebo 3-mo (n=34) | Activella 2-yr (n=47) | Placebo 2-yr (n=48) |
|---|---|---|---|---|---|---|
| Back pain | 6% | 5% | 3% | 3% | 6% | 4% |
| Headache | 16% | 16% | 17% | 18% | 11% | 6% |
| Nausea | 3% | 5% | 10% | 0% | 11% | 0% |
| Gastroenteritis | 2% | 2% | 0% | 0% | 6% | 4% |
| Insomnia | 6% | 4% | 3% | 3% | 0% | 8% |
| Emotional lability | 1% | 1% | 0% | 0% | 6% | 0% |
| Upper respiratory tract infection | 18% | 15% | 10% | 6% | 15% | 19% |
| Sinusitis | 7% | 11% | 7% | 0% | 15% | 10% |
| Weight increase | 0% | 0% | 0% | 0% | 9% | 6% |
| Breast pain | 24% | 10% | 21% | 0% | 17% | 8% |
| Post-menopausal bleeding | 5% | 15% | 10% | 3% | 11% | 0% |
| Uterine fibroid | 5% | 4% | 0% | 0% | 4% | 8% |
| Ovarian cyst | 3% | 2% | 7% | 0% | 0% | 8% |
| Infection viral | 4% | 6% | 0% | 3% | 6% | 6% |
| Moniliasis genital | 4% | 7% | 0% | 0% | 6% | 0% |
| Injury accidental | 4% | 3% | 3% | 0% | 17% | 4% |
| Other events | 2% | 3% | 3% | 0% | 6% | 4% |
Three trials: a 12-month endometrial hyperplasia study (vs 1 mg estradiol alone), a 3-month hot flash study (vs placebo) and a 2-year osteoporosis study (vs placebo). Values are percent of women. Accidental injury in the osteoporosis study includes one upper extremity fracture in each group.
| Adverse reaction | Activella 0.5 mg/0.1 mg (n=194) | Placebo (n=200) |
|---|---|---|
| Back pain | 10% | 4% |
| Headache | 22% | 19% |
| Pain in extremity | 5% | 4% |
| Nausea | 5% | 4% |
| Diarrhea | 6% | 6% |
| Nasopharyngitis | 21% | 18% |
| Endometrial thickening | 10% | 4% |
| Vaginal hemorrhage | 26% | 12% |
Values are percent of women.
After 12 months, endometrial hyperplasia was found in 1 of 241 women (0.4%) on Activella 1 mg/0.5 mg vs 36 of 247 (14.6%) on 1 mg estradiol alone (Table 4).
Irregular bleeding or spotting occurred in the first months and tended to decrease; after 12 months on 1 mg/0.5 mg, about 86 percent of women had no bleeding. On 0.5 mg/0.1 mg, 88 percent had no bleeding after 6 months.
WHI CE plus MPA vs placebo, women 50 to 79: 33 vs 25 strokes per 10,000 women-years. CE alone: 45 vs 33 strokes per 10,000 women-years.
WHIMS, women 65 to 79 on CE plus MPA: 40 vs 21 women diagnosed with probable dementia over 4 years; relative risk 2.05, 45 vs 22 cases per 10,000 women-years.
Reported after approval: changes in bleeding pattern, breakthrough bleeding, spotting, breast tenderness and enlargement, blood clots, heart attack, stroke, raised blood pressure, nausea, gallbladder disease, melasma, hair loss, migraine, mood changes, weight change, edema and hypersensitivity.
The Warnings and Precautions part of the label lists these. Each line gives the label's heading and what it means in plain words.
Who should not use it. Women with undiagnosed abnormal genital bleeding, current or past breast cancer, estrogen-dependent cancer, current or past DVT, pulmonary embolism, stroke or heart attack, a known anaphylactic reaction, angioedema or allergy to Activella, liver impairment or disease, or protein C, protein S or antithrombin deficiency or other clotting disorders.
Blood clots, stroke and heart attack. Estrogen plus progestin raised the risk of pulmonary embolism, DVT, stroke and heart attack. Treatment is stopped right away if one occurs or is suspected. Risk factors such as high blood pressure, diabetes, smoking, high cholesterol and obesity are managed.
Breast, endometrial and ovarian cancer. The WHI found more invasive breast cancer on CE plus MPA, and hormone therapy has been linked to more abnormal mammograms. Estrogen alone raises endometrial cancer risk in women with a uterus; adding a progestogen lowers hyperplasia risk. Hormone therapy has also been linked to ovarian cancer.
Probable dementia. In WHIMS studies of women 65 to 79, probable dementia was more common on CE plus MPA and on CE alone than on placebo. Whether this applies to younger women is unknown.
Gallbladder, calcium and vision. Estrogens are linked to gallbladder disease needing surgery (5.4), severe high calcium in breast cancer spread to bone (5.5), and blood clots in the retina, with treatment stopped pending exam for sudden vision changes (5.6).
Blood pressure, triglycerides, liver and thyroid. Estrogens can raise blood pressure in rare reactions (5.8), raise triglycerides with a risk of pancreatitis (5.9), cause problems with past cholestatic jaundice (5.10), raise thyroid hormone needs (5.11) and cause fluid retention (5.12).
Other conditions. Estrogens can cause low calcium in hypoparathyroidism and worsen endometriosis, hereditary angioedema, asthma, diabetes, epilepsy, migraine, porphyria, lupus and liver hemangiomas (sections 5.13 to 5.16).
From the Patient Information that comes with Activella:
Dose Track has a side-effect log. Each entry records the symptom, a severity (none, mild, moderate, severe or life-threatening), the date and an optional note, and can be tied to a specific dose or logged on its own. The history screen shows what you logged over time, which makes it easier to tell your prescriber when a reaction started and whether it is easing. The app records what you enter; it does not judge whether a symptom is serious. For anything on the label's call-your-doctor list, call your doctor.
This page is what the FDA label says, in plain words. It is not medical advice. Follow your prescriber, and ask them or your pharmacist about anything here.