Tamoxifen - Drug Monograph

Introduction

Tamoxifen is a selective estrogen receptor modulator (SERM) that has been a cornerstone in the treatment of hormone receptor-positive breast cancer for over four decades. As the first FDA-approved targeted therapy for breast cancer, it represents a major advancement in endocrine therapy and continues to be widely used in both early and advanced breast cancer management, as well as for breast cancer risk reduction in high-risk populations.

Mechanism of Action

Tamoxifen functions as a competitive antagonist of estrogen at estrogen receptor sites in breast tissue. It binds to estrogen receptors, forming a complex that recruits corepressors rather than coactivators, resulting in altered DNA transcription and inhibition of estrogen-mediated cell proliferation. In other tissues, particularly bone and endometrium, tamoxifen demonstrates partial agonist activity, which accounts for some of its side effect profile.

Indications

• Adjuvant treatment of breast cancer in women with estrogen receptor-positive early breast cancer
• Treatment of metastatic breast cancer in women and men with estrogen receptor-positive disease
• Risk reduction in women at high risk for developing breast cancer
• Ductal carcinoma in situ (DCIS) after surgery and radiation to reduce risk of invasive breast cancer
• Off-label uses: Infertility treatment, gynecomastia prevention, and McCune-Albright syndrome

Dosage and Administration

• Breast cancer treatment: 20-40 mg daily, typically 20 mg once daily
• DCIS: 20 mg daily for 5 years
• Risk reduction: 20 mg daily for 5 years

• Hepatic impairment: Use with caution; consider dose reduction
• Renal impairment: No dosage adjustment necessary
• Elderly: No dosage adjustment required
• Pediatrics: Safety and effectiveness not established

Pharmacokinetics

• Absorption: Well absorbed orally with peak concentrations within 4-7 hours
• Distribution: Extensive tissue distribution, highly protein-bound (>99%)
• Metabolism: Extensive hepatic metabolism via CYP2D6, CYP3A4, and CYP2C9 to active metabolites (endoxifen and 4-hydroxytamoxifen)
• Elimination: Primarily fecal excretion with terminal half-life of 5-7 days
• Steady-state: Achieved after approximately 4 weeks of dosing

Contraindications

• Hypersensitivity to tamoxifen or any component of the formulation
• Pregnancy or women who may become pregnant
• Concomitant use with anastrozole therapy
• History of deep vein thrombosis or pulmonary embolism
• Women requiring concomitant coumarin-type anticoagulant therapy

Warnings and Precautions

• Increased risk of uterine malignancies, stroke, and pulmonary embolism
• Serious and life-threatening events requiring immediate evaluation

• Regular gynecological examinations due to increased endometrial cancer risk
• Monitoring for vision changes (retinopathy, corneal changes)
• Increased risk of thromboembolic events
• Potential for hepatotoxicity (elevated liver enzymes, fatty liver, hepatitis)
• Hypertriglyceridemia in patients with pre-existing hyperlipidemia
• Bone mineral density changes (both protective and potentially detrimental effects)

Drug Interactions

• CYP2D6 inhibitors (fluoxetine, paroxetine, bupropion): May reduce efficacy by inhibiting conversion to active metabolites
• Warfarin: Increased anticoagulant effect and risk of bleeding
• Aromatase inhibitors: Antagonistic effects
• CYP3A4 inducers (rifampin, carbamazepine): May decrease tamoxifen concentrations
• CYP3A4 inhibitors (ketoconazole, erythromycin): May increase tamoxifen concentrations

Adverse Effects

• Hot flashes (up to 80%)
• Fatigue (30-40%)
• Nausea (20-25%)
• Vaginal discharge/dryness (15-20%)
• Mood changes (15-20%)

• Endometrial cancer (2-4x increased risk)
• Thromboembolic events (DVT, PE)
• Stroke (1.5-2x increased risk)
• Cataracts and visual disturbances
• Hepatotoxicity (elevated transaminases, rare hepatitis)
• Bone pain and arthralgia
• Reduced platelet counts

Monitoring Parameters

• Regular breast examinations and mammograms
• Annual gynecological examinations with endometrial sampling for any abnormal bleeding
• Liver function tests at baseline and periodically
• Regular ophthalmologic examinations
• Monitoring for signs/symptoms of thromboembolism
• Lipid profile monitoring in patients with hyperlipidemia
• Bone mineral density in appropriate patients
• Complete blood count periodically

Patient Education

• Importance of adherence to prescribed regimen despite side effects
• Report any unusual vaginal bleeding or discharge immediately
• Seek immediate medical attention for signs of blood clots (leg pain/swelling, chest pain, shortness of breath)
• Regular follow-up appointments are essential
• Use effective non-hormonal contraception during treatment
• Notify all healthcare providers of tamoxifen use, especially before new medications
• Management of common side effects: cool environment for hot flashes, lubricants for vaginal dryness
• Do not stop medication without consulting healthcare provider

References

1. National Comprehensive Cancer Network. (2023). Breast Cancer Guidelines Version 4.2023. 2. Fisher B, et al. Tamoxifen for prevention of breast cancer: report of the National Surgical Adjuvant Breast and Bowel Project P-1 Study. J Natl Cancer Inst. 1998;90(18):1371-1388. 3. Early Breast Cancer Trialists' Collaborative Group. Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials. Lancet. 2005;365(9472):1687-1717. 4. Tamoxifen citrate [package insert]. North Wales, PA: Teva Pharmaceuticals USA; 2022. 5. Jin Y, et al. CYP2D6 genotype, antidepressant use, and tamoxifen metabolism. J Clin Oncol. 2005;23(36):9312-9318. 6. American Society of Clinical Oncology. (2022). Adjuvant Endocrine Therapy for Women With Hormone Receptor-Positive Breast Cancer Guideline. 7. FDA prescribing information for tamoxifen citrate. Accessed October 2023.