Short answer: In the label's placebo-controlled year, the most common Prempro side effects included breast pain (26% on 0.625 mg/2.5 mg, 20% on 0.45 mg/1.5 mg and 13% on 0.3 mg/1.5 mg vs 8% on placebo), headache, abdominal pain, vaginal bleeding and breast enlargement. Prempro and Premphase carry a boxed warning on blood clots, stroke, heart attack, breast cancer, probable dementia and endometrial cancer.
What Prempro is approved for: Prempro and Premphase combine conjugated estrogens (CE) with the progestin medroxyprogesterone acetate (MPA). They are approved for a woman with a uterus to treat moderate to severe hot flashes and moderate to severe vulvar and vaginal atrophy due to menopause, and to prevent postmenopausal osteoporosis (sections 1.1 to 1.3). Prempro is one tablet daily; Premphase gives CE alone on days 1 to 14 and CE plus MPA on days 15 to 28 (section 2).
Source
PREMPRO/PREMPHASE (conjugated estrogens/medroxyprogesterone acetate tablets) prescribing information and Patient Information. Wyeth Pharmaceuticals (Pfizer). DailyMed, version published April 29, 2026. DailyMed setid fd0c0836-5d23-2183-da81-9dc7f4287052
WARNING: CARDIOVASCULAR DISORDERS, BREAST CANCER, ENDOMETRIAL CANCER and PROBABLE DEMENTIA
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; whether this applies to younger women is unknown. Estrogen-alone therapy: a woman with a uterus who uses estrogen without a progestin 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. Without comparable data, the label says these risks should be assumed to be similar for other doses and forms. Estrogens, with or without progestins, 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 Prempro.
| Adverse reaction | Prempro 0.625/2.5 (N=331) | Prempro 0.45/1.5 (N=331) | Prempro 0.3/1.5 (N=327) | Placebo (N=332) |
|---|---|---|---|---|
| Any adverse event | 214 (65) | 208 (63) | 188 (57) | 164 (49) |
| Breast pain | 87 (26) | 66 (20) | 41 (13) | 26 (8) |
| Headache | 45 (14) | 45 (14) | 57 (17) | 46 (14) |
| Abdominal pain | 38 (11) | 33 (10) | 24 (7) | 21 (6) |
| Depression | 23 (7) | 11 (3) | 11 (3) | 17 (5) |
| Vaginal hemorrhage | 18 (5) | 14 (4) | 7 (2) | 0 |
| Breast enlargement | 18 (5) | 9 (3) | 5 (2) | 3 (1) |
| Flatulence | 16 (5) | 18 (5) | 13 (4) | 8 (2) |
| Nausea | 13 (4) | 13 (4) | 16 (5) | 16 (5) |
| Leg cramps | 13 (4) | 7 (2) | 10 (3) | 4 (1) |
| Uterine spasm | 13 (4) | 11 (3) | 7 (2) | 2 (1) |
| Vaginal moniliasis | 13 (4) | 11 (3) | 8 (2) | 5 (2) |
| Dysmenorrhea | 14 (4) | 18 (5) | 9 (3) | 2 (1) |
| Leukorrhea | 7 (2) | 14 (4) | 9 (3) | 6 (2) |
| Metrorrhagia | 7 (2) | 14 (4) | 4 (1) | 1 (0) |
| Asthenia | 11 (3) | 11 (3) | 12 (4) | 3 (1) |
| Back pain | 12 (4) | 12 (4) | 8 (2) | 4 (1) |
| Dyspepsia | 10 (3) | 9 (3) | 6 (2) | 14 (4) |
| Weight gain | 9 (3) | 8 (2) | 6 (2) | 14 (4) |
| Insomnia | 8 (2) | 7 (2) | 9 (3) | 14 (4) |
| Pain | 9 (3) | 10 (3) | 17 (5) | 14 (4) |
First year of a 2-year trial of postmenopausal women aged 40 to 65; 989 took continuous Prempro and 332 took placebo. Shown are rows at 4% or more in any group; the full table also lists reactions at 1% to 3%. Cells are number of women (percent). Leukorrhea is vaginal discharge; vaginal hemorrhage is vaginal bleeding; metrorrhagia is bleeding between periods.
| Adverse reaction | Prempro 0.625/2.5 continuous (n=340) | Prempro 0.625/5 continuous (n=338) | Premphase 0.625/5 sequential (n=351) |
|---|---|---|---|
| Breast pain | 110 (32%) | 123 (36%) | 109 (31%) |
| Headache | 64 (19%) | 52 (15%) | 66 (19%) |
| Abdominal pain | 35 (10%) | 51 (15%) | 58 (17%) |
| Dysmenorrhea | 26 (8%) | 18 (5%) | 44 (13%) |
| Depression | 14 (4%) | 26 (8%) | 29 (8%) |
| Nausea | 26 (8%) | 19 (6%) | 26 (7%) |
| Flatulence | 25 (7%) | 27 (8%) | 24 (7%) |
| Leukorrhea | 19 (6%) | 13 (4%) | 29 (8%) |
| Back pain | 19 (6%) | 16 (5%) | 23 (7%) |
| Pruritus | 20 (6%) | 18 (5%) | 13 (4%) |
| Asthenia | 13 (4%) | 18 (5%) | 21 (6%) |
| Pelvic pain | 11 (3%) | 13 (4%) | 16 (5%) |
1-year trial of 678 women on Prempro and 351 on Premphase, with no placebo group. Shown are rows at 5% or more in any group. Cells are number of women (percent).
After one year, endometrial hyperplasia (all focal and non-focal) was 2 of 279 evaluable biopsies (<1%) on Prempro 0.625 mg/2.5 mg, 0 of 274 on Prempro 0.625 mg/5 mg and 3 of 277 (1%) on Premphase, vs 57 of 283 (20%) on Premarin 0.625 mg alone (Table 6).
Endometrial hyperplasia, a possible precursor of endometrial cancer, has been reported at a rate of approximately 1% or less with Prempro or Premphase.
WHI CE plus MPA vs placebo, per 10,000 women-years: stroke 33 vs 25; DVT 26 vs 13; pulmonary embolism 18 vs 8; all VTE 35 vs 17; coronary heart disease 41 vs 34 (not statistically significant).
WHI invasive breast cancer on CE plus MPA: relative risk 1.24, 41 vs 33 cases per 10,000 women-years. Among women with prior hormone use, relative risk 1.86, 46 vs 25 cases.
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.
WHI CE plus MPA also had fewer colorectal cancers (10 vs 16 per 10,000 women-years) and hip fractures (11 vs 16), and total fractures of 152 vs 199 (Table 10).
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 or angioedema with Prempro/Premphase, 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 and, if feasible, at least 4 to 6 weeks before surgery linked to clots or during long immobilization.
Breast, endometrial and ovarian cancer. CE plus MPA raised invasive breast cancer risk in the WHI, and hormone therapy has been linked to more abnormal mammograms. Estrogen alone raises endometrial cancer risk in women with a uterus; adding a progestin lowers hyperplasia risk. The WHI reported a non-significant ovarian cancer relative risk of 1.58.
Probable dementia. In women 65 to 79, the relative risk of probable dementia on CE plus MPA vs placebo was 2.05. Whether this applies to younger women is unknown.
Gallbladder, calcium and vision. Estrogens are linked to a 2- to 4-fold rise in gallbladder disease needing surgery (5.4), severe high calcium in breast cancer spread to bone (5.5), and blood clots in the retina; treatment is stopped pending exam for sudden vision changes (5.6).
Blood pressure, triglycerides and liver. In a small number of case reports, large blood pressure rises were attributed to idiosyncratic reactions to estrogens (5.8). High triglycerides can rise further and cause pancreatitis (5.9). Treatment is stopped if jaundice from bile blockage returns (5.10).
Thyroid, fluid and other conditions. Women on thyroid hormone may need higher doses. Estrogens can cause fluid retention, low calcium in hypoparathyroidism, and worsen endometriosis, hereditary angioedema, asthma, diabetes, epilepsy, migraine, porphyria, lupus and liver hemangiomas (sections 5.11 to 5.17).
From the Patient Information that comes with Prempro:
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.