What are the side effects of Tamoxifen (tamoxifen citrate)?

Tamoxifen Side Effects

Tamoxifen is generally well tolerated but carries specific serious risks including endometrial cancer (doubling baseline risk), venous thromboembolism, stroke, and cataracts, while the most common side effects are hot flashes and vaginal discharge. 1

Most Serious Side Effects Requiring Immediate Action

Endometrial and Uterine Cancer

• Tamoxifen doubles the risk of endometrial cancer from 1 in 1,000 to 2 in 1,000 women per year and increases uterine sarcoma risk in women with an intact uterus 1
• The relative risk is 2.4-fold (95% CI 1.5-4.0) compared to placebo, with risk primarily elevated in women ≥50 years old 2
• Most tumors are stage I adenocarcinomas successfully treated when detected early 2
• Patients must report any vaginal bleeding or bloody discharge immediately, even minimal amounts, as well as changes in menstrual bleeding patterns or pelvic pain 1
• Baseline gynecologic examination before starting tamoxifen and annual follow-up thereafter is required, with prompt evaluation of abnormal bleeding 2

Venous Thromboembolism (VTE)

• Risk of VTE increases 1.7-fold (95% CI 1.27-2.36), translating to 14 additional events per 1,000 women over median follow-up 2
• Deep vein thrombosis risk increases 1.84-fold (95% CI 1.21-2.82), with 9 additional cases per 1,000 women 2
• Pulmonary embolism risk increases 3-fold (RR 3.01; 95% CI 1.15-9.27) 2
• Blood clots can occur up to 2-3 months after discontinuing tamoxifen 1
• Warning signs include sudden chest pain, shortness of breath, coughing up blood, or leg pain/swelling/tenderness 1

Stroke

• Tamoxifen increases ischemic stroke risk 1.82-fold (95% CI 1.41-2.36), particularly in women ≥50 years 2
• Warning signs include sudden weakness, numbness, confusion, vision changes, trouble walking, or severe headache 1
• Tamoxifen is contraindicated in women with prior stroke or transient ischemic attack 2

Common Side Effects

Vasomotor Symptoms

• Hot flashes occur in 64-78% of patients, making them the most common side effect 1, 3
• Hot flashes typically increase gradually over 3 months then plateau 4
• Women with prior moderate-to-severe menopausal hot flashes and prior estrogen therapy use are at highest risk for severe symptoms requiring treatment 4
• Night sweats are also common 2

Gynecologic Effects

• Vaginal discharge occurs in 35-55% of patients (versus 34% with placebo), with a 3.44-fold increase in risk 2, 3
• Vaginal dryness affects 35% of patients 3
• Bloody vaginal discharge requires immediate evaluation as it may indicate endometrial pathology 1
• Benign endometrial changes including polyps and hyperplasia are more common 2

Ocular Effects

• Cataract risk increases 1.14-fold (95% CI 1.01-1.29), with 14 additional cases per 1,000 women 2
• Cataract surgery risk increases 1.57-fold (95% CI 1.16-2.14) 2
• Risk is particularly elevated in older women 2
• Patients should report gradual vision blurring 1

Less Common Side Effects

Musculoskeletal and Bone Health

• Tamoxifen has protective effects on bone in postmenopausal women, preserving bone mineral density and potentially reducing fracture risk 2, 5
• This contrasts with aromatase inhibitors which increase bone loss and fracture risk by 2-4% 2

Cardiovascular Effects

• Tamoxifen may reduce fatal myocardial infarction through favorable effects on serum lipids and cholesterol 5, 6
• Lower rates of hypercholesterolemia and hypertension compared to aromatase inhibitors 2

Other Effects

• Weight gain (6% of patients) 3
• Depression, irritability, or mood swings (6% of patients) 3
• Sleep problems (36% of patients) 3
• Nausea and headaches occur but are less common 2, 5
• Liver problems including jaundice are rare; signs include loss of appetite and yellowing of skin/eyes 1

Factors Predicting Side Effect Severity

Duration of Treatment

• Women on tamoxifen >12 months are significantly less likely to report side effects (OR 0.15; 95% CI 0.04-0.58) or severe side effects (OR 0.05; 95% CI 0.005-0.58) compared to those on treatment <12 months 3
• Most side effects are greatest during active treatment and decrease post-treatment 2

Age

• Women aged 60-70 years have 78% lower odds of side effects (OR 0.22; 95% CI 0.03-1.35), and women >70 years have 87% lower odds (OR 0.13; 95% CI 0.01-0.99) compared to women <50 years 3
• Younger women require closer monitoring for adherence due to higher side effect burden 3

Prior Hormone Therapy

• Women with prior postmenopausal hormone therapy use are more likely to report severe side effects and should be monitored closely 3

Endoxifen Levels

• Higher endoxifen levels (the active metabolite) correlate with increased side effects (OR 1.67; 95% CI 1.01-2.77 per standard deviation increase) 3

Absolute Contraindications

Do not prescribe tamoxifen if the patient: 1

• Is pregnant or planning pregnancy (tamoxifen may harm the fetus; requires 2 months to clear after stopping)
• Is breastfeeding
• Has history of blood clots requiring medical treatment
• Is taking warfarin or other anticoagulants
• Has limited mobility for most waking hours
• Has prior stroke or transient ischemic attack
• Has allergic reaction to tamoxifen

Drug Interactions

• Avoid concurrent use of CYP2D6 inhibitors (paroxetine, fluoxetine, bupropion) as they reduce conversion to active endoxifen metabolite, potentially decreasing efficacy 2
• If CYP2D6 inhibitors are necessary for other conditions, consider alternative endocrine therapy 2

Quality of Life Considerations

• Most patients maintain well-preserved quality of life on tamoxifen, with severity of common side effects being mild-to-moderate for the majority 2
• Serious adverse effects are rare 2
• Consider switching treatment if adverse effects are intolerable or if patients are persistently noncompliant 2