What are the side effects of tamoxifen (Selective Estrogen Receptor Modulator)?

Side Effects of Tamoxifen

Tamoxifen causes serious side effects including endometrial cancer (doubling baseline risk), venous thromboembolism, stroke, and common symptoms like hot flashes and vaginal discharge, but most adverse effects are mild-to-moderate and rarely require treatment discontinuation. 1

Serious Side Effects

Endometrial and Uterine Cancer

• Tamoxifen doubles the risk of endometrial cancer (RR 2.4; 95% CI 1.5-4.0) compared to placebo, with risk primarily elevated in women ≥50 years old. 1, 2
• The absolute risk increases from 1 per 1,000 women per year to 2 per 1,000 women per year in high-risk women with intact uterus. 3
• Uterine sarcomas occur at increased rates, though less frequently than endometrial cancer. 3
• Most uterine cancers are stage I adenocarcinomas that are successfully treated; endometrioid, mucinous, clear-cell, and uterine sarcoma subtypes have also been reported. 1
• Risk of endometrial cancer is limited to the active treatment period in trials with longer follow-up (IBIS-I and Royal Marsden trials). 1

Thromboembolic Events

• Venous thromboembolism risk increases 1.7-fold (95% CI 1.27-2.36), resulting in 14 additional events per 1,000 women. 2
• Deep vein thrombosis risk is 1-2% higher with tamoxifen compared to aromatase inhibitors. 1
• Pulmonary embolism occurs at increased rates and can be fatal. 1, 3
• Blood clots may occur up to 2-3 months after stopping tamoxifen. 3
• Women at highest risk include those who are immobilized in the prior 3 months and/or have BMI ≥25 kg/m². 1

Stroke

• Ischemic stroke risk increases 1.82-fold (95% CI 1.41-2.36), particularly in women ≥50 years. 2
• Data on relative incidence of stroke with tamoxifen versus aromatase inhibitors remain inconclusive and require longer follow-up. 1
• Tamoxifen is contraindicated in women with prior stroke or transient ischemic attack. 2

Common Side Effects

Vasomotor Symptoms

• Hot flashes are the most common side effect of tamoxifen, occurring in 64% of treated women versus 48% on placebo. 1, 3
• Night sweats are commonly reported. 1
• Hot flashes appear less frequent with tamoxifen compared to aromatase inhibitors in some trials (ATAC, MA.17), though the IES trial showed similar rates. 1

Gynecologic Effects

• Vaginal discharge occurs in 30-55% of patients, representing a 3.44-fold increase in risk (30% vs 15% on placebo). 2, 3
• Vaginal dryness is reported, though some trials (ATAC, MA.17) showed lower incidence with tamoxifen compared to aromatase inhibitors. 1
• Irregular menses occur in 25% of tamoxifen users versus 19% on placebo. 3
• Benign endometrial pathology including bleeding, polyps, and hyperplasia occurs at increased rates. 1
• Hysterectomy rates are higher among tamoxifen users. 1

Other Common Effects

• Nausea occurs in 26% of patients versus 24% on placebo. 3
• Fluid retention/edema affects 32% versus 30% on placebo. 3
• Weight loss (>5%) occurs in 23% versus 18% on placebo. 3

Less Common Side Effects

Ocular Effects

• Cataract risk increases 1.14-fold (95% CI 1.01-1.29), with 14 additional cases per 1,000 women. 2
• Increased need for cataract surgery is documented. 1
• Rarely, ocular toxicity occurs. 4

Musculoskeletal and Bone Health

• Tamoxifen has protective effects on bone in postmenopausal women, preserving bone mineral density and potentially reducing fracture risk (in contrast to aromatase inhibitors which increase fracture risk by 2-4%). 1, 2
• Increased bone pain may occur, particularly at treatment initiation, sometimes associated with good tumor response and requiring additional analgesics. 3

Cardiovascular Effects

• Tamoxifen may reduce fatal myocardial infarction through favorable effects on serum lipids and cholesterol. 2
• Lower rates of hypercholesterolemia and hypertension compared to aromatase inhibitors. 1, 2
• Data suggest aromatase inhibitors are associated with increased cardiovascular disease compared to tamoxifen, though absolute differences are believed to be small. 1

Hepatic Effects

• Rarely, hepatotoxicity and liver problems including jaundice occur. 3, 4
• Signs include lack of appetite and yellowing of skin or whites of eyes. 3
• Increased SGOT (5% vs 3%) and increased bilirubin (2% vs 1%) compared to placebo. 3

Hematologic Effects

• Thrombocytopenia occurs in 2% of patients versus 1% on placebo. 3

Other Effects

• Depression, dizziness, lightheadedness, and headache are reported infrequently. 3
• Hair thinning and/or partial hair loss occurs. 3
• Skin changes occur in 19% versus 15% on placebo. 3
• Pruritus vulvae and distaste for food are infrequent. 3

Disease Flare

• Local disease flare may occur shortly after starting tamoxifen, sometimes associated with good tumor response. 3
• Patients with soft tissue disease may have sudden increases in preexisting lesion size, sometimes with marked erythema within and surrounding lesions and/or development of new lesions. 3
• These effects generally subside rapidly. 3

Special Populations

Premenopausal Women

• Amenorrhea occurs in 16% of premenopausal women on tamoxifen. 3
• Altered menses (13%), oligomenorrhea (9%), and menstrual disorders (6%) are reported. 3
• Ovarian cysts develop at increased rates (3% vs 2%). 3
• Tamoxifen has antagonistic effects on the endometrium in premenopausal women, and these patients have no known increased risk of uterine cancer, requiring no additional monitoring beyond routine gynecologic care. 5

Male Patients

• Loss of libido and impotence have resulted in discontinuation of tamoxifen therapy in male patients. 3
• In oligospermic males, LH, FSH, testosterone, and estrogen levels are elevated, though no significant clinical changes were reported. 3

Drug Interactions

• Concurrent use of CYP2D6 inhibitors (paroxetine, fluoxetine, bupropion) should be avoided, as they reduce conversion to active endoxifen metabolite, potentially decreasing efficacy. 2
• If CYP2D6 inhibitors are necessary, consider alternative endocrine therapy. 2

Monitoring and Management

Gynecologic Surveillance

• Patients on tamoxifen should have baseline gynecologic examination before starting treatment and annual follow-up thereafter, continuing post-treatment. 1, 2
• Prompt evaluation is required for any abnormal vaginal bleeding, bloody discharge, staining, or spotting. 3, 5
• Routine endometrial biopsy is not needed in the absence of abnormal vaginal bleeding. 1
• Women with abnormalities on endometrial biopsy performed due to abnormal bleeding may consider stopping tamoxifen in consultation with their gynecologist or primary care physician. 1
• Unless the patient is at high risk of endometrial cancer, routine endometrial surveillance has not proved effective in increasing early detection and is not recommended. 5

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. 1, 2
• Serious adverse effects are rare. 1
• Clinicians should consider recommending that patients change treatment if adverse effects are intolerable or if patients are persistently noncompliant with therapy. 1, 2

Contraindications

• Pregnancy or planning pregnancy during treatment or within 2 months after stopping (tamoxifen may harm unborn baby). 3
• Breastfeeding. 3
• History of allergic reaction to tamoxifen or its inactive ingredients. 3
• History of blood clots requiring medical treatment. 3
• Current use of blood thinners like warfarin. 3
• Limited mobility for most waking hours. 3
• High risk for blood clots. 3