Short answer: In the label's 12-week placebo-controlled trials, the most common Osphena side effects were hot flush (6.5% vs 2.6% on placebo), vaginal discharge (3.8% vs 0.4%), muscle spasms (1.8% vs 0.6%) and excess sweating (1.1% vs 0.2%). Over up to 52 weeks, hot flush was 12.2% vs 4.2%. The boxed warning covers endometrial cancer and stroke and blood clot risk.
What Osphena is approved for: Osphena is an estrogen agonist/antagonist approved to treat moderate to severe dyspareunia (pain during sex) and moderate to severe vaginal dryness, both symptoms of vulvar and vaginal atrophy due to menopause (sections 1.1, 1.2). It acts like estrogen in the lining of the uterus but can act differently in other tissues (section 5.2).
Source
OSPHENA (ospemifene) tablets, for oral use, prescribing information and Patient Information. Duchesnay USA. DailyMed, version published February 17, 2025. DailyMed setid 9accbcc9-78ee-4f84-9b7e-704f2ab1c413
WARNING: ENDOMETRIAL CANCER and CARDIOVASCULAR DISORDERS
Osphena acts like estrogen in the lining of the uterus. A woman with a uterus who uses estrogen without a progestin has a higher risk of endometrial cancer, so undiagnosed, persistent or recurring abnormal genital bleeding after menopause is checked, including with endometrial sampling when indicated. In Osphena trials of up to 15 months, thromboembolic and hemorrhagic stroke rates were 1.13 and 3.39 per thousand women-years on Osphena 60 mg vs 3.15 and 0 on placebo, and DVT was 2.26 per thousand women-years (2 cases) vs 3.15 (1 case). In the WHI, oral conjugated estrogens 0.625 mg alone raised stroke and DVT risk in women 50 to 79 over 7.1 years. Osphena is prescribed 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 Osphena.
| Adverse reaction | Ospemifene 60 mg (N=1459) | Placebo (N=1136) |
|---|---|---|
| Hot flush | 6.5 | 2.6 |
| Vaginal discharge | 3.8 | 0.4 |
| Muscle spasms | 1.8 | 0.6 |
| Hyperhidrosis (excess sweating) | 1.1 | 0.2 |
Values are percent of women.
| Adverse reaction | Ospemifene 60 mg all trials (N=847) | Placebo (N=165) |
|---|---|---|
| Headaches | 2.8 | 2.4 |
| Hot flush | 12.2 | 4.2 |
| Muscle spasms | 4.5 | 2.4 |
| Hyperhidrosis | 2.5 | 1.8 |
| Night sweats | 1.2 | 0.0 |
| Vaginal discharge | 6.0 | 0.6 |
| Vaginal hemorrhage | 1.3 | 0.0 |
Values are percent of women.
Stroke in the trials: 1 thromboembolic stroke (1.13 per thousand women-years) and 3 hemorrhagic strokes (3.39) on Osphena 60 mg, vs 1 thromboembolic stroke (3.15) and none hemorrhagic on placebo. DVT: 2 cases among 1459 women on Osphena 60 mg vs 1 among 1136 on placebo.
Two heart attacks occurred in women taking ospemifene 60 mg in the clinical trials.
Up to 52 weeks, no endometrial cancer was seen on Osphena 60 mg; there was one case of simple hyperplasia without atypia. Endometrial thickening of 5 mm or more was 101.4 per thousand women vs 20.9 on placebo, proliferative endometrium 26.3 vs 0, and uterine polyps 19.6 vs 8.3.
Fluconazole raises ospemifene exposure 2.7-fold and ketoconazole 1.4-fold; rifampin lowers it by 58% (sections 7.2 to 7.4).
Reported after approval: endometrial hyperplasia, endometrial cancer, allergic reactions including angioedema, headache, DVT, thrombosis, pulmonary embolism, rash, itching and hives.
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, estrogen-dependent cancer, current or past DVT, pulmonary embolism, stroke or heart attack, allergy to Osphena (such as angioedema, hives, rash or itching), or who are or may become pregnant.
Stroke, blood clots and heart attack. Osphena is stopped right away if a stroke or blood clot occurs or is suspected. If feasible, it is stopped at least 4 to 6 weeks before surgery linked to clots or during long immobilization. Risk factors such as high blood pressure, diabetes, smoking, high cholesterol and obesity are managed.
Endometrial cancer. Osphena has estrogen-like effects on the uterine lining. Using a progestin with Osphena was not studied. Abnormal genital bleeding after menopause is checked for cancer.
Breast cancer. Osphena has not been adequately studied in women with breast cancer, so it is not used with known or suspected breast cancer or a history of it. Yearly breast exams and monthly self-exams are advised.
Severe liver impairment. Osphena is not used in women with severe liver impairment (Child-Pugh Class C). No dose change is needed for mild or moderate liver impairment or for kidney impairment (sections 8.6, 8.7).
Medicines not used with it. Osphena is not used with estrogens or other estrogen agonist/antagonists, with fluconazole, or with rifampin (sections 7.1 to 7.3).
From the Patient Information that comes with Osphena:
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.