Introduction
Raloxifene hydrochloride is a selective estrogen receptor modulator (SERM) approved by the FDA in 1997. It represents a class of medications that act as estrogen agonists in some tissues while functioning as estrogen antagonists in others. Originally developed as a breast cancer treatment, raloxifene has found its primary therapeutic role in the management of osteoporosis and reduction of breast cancer risk in postmenopausal women.
Mechanism of Action
Raloxifene exerts tissue-specific estrogenic and antiestrogenic effects through selective binding to estrogen receptors. In bone tissue, it acts as an estrogen agonist, reducing bone resorption by decreasing osteoclast activity and increasing bone mineral density. In breast tissue, it functions as an estrogen antagonist, blocking estrogen-mediated proliferation of breast epithelial cells. Unlike estrogen, raloxifene has minimal effects on uterine tissue and does not stimulate endometrial proliferation.
The drug's molecular mechanism involves binding to estrogen receptors, resulting in conformational changes that differ from those induced by estradiol. This altered conformation affects the receptor's interaction with coactivators and corepressors, leading to tissue-specific transcriptional responses.
Indications
1. Treatment and prevention of osteoporosis in postmenopausal women 2. Reduction of risk of invasive breast cancer in postmenopausal women with osteoporosis 3. Reduction of risk of invasive breast cancer in postmenopausal women at high risk for breast cancer
Dosage and Administration
Standard dosage: 60 mg orally once daily, with or without food Administration considerations:- No dosage adjustment required for renal impairment
- No dosage adjustment required for mild to moderate hepatic impairment
- Use with caution in patients with severe hepatic impairment
- Not recommended for use in premenopausal women
- Should be taken with adequate calcium (1000-1500 mg/day) and vitamin D (400-800 IU/day) supplementation
Pharmacokinetics
Absorption: Rapidly absorbed after oral administration with approximately 60% absolute bioavailability. Extensive first-pass metabolism results in low systemic availability. Distribution: Extensive distribution throughout the body. Volume of distribution is 2348 L/kg. Highly bound to plasma proteins (>95%), primarily albumin and α1-acid glycoprotein. Metabolism: Extensive hepatic metabolism via glucuronide conjugation. No cytochrome P450-mediated metabolism. The drug undergoes enterohepatic cycling. Elimination: Primarily excreted in feces (≥90%) with less than 0.2% excreted unchanged in urine. Elimination half-life is approximately 27.7-32.5 hours.Contraindications
1. History of venous thromboembolic events (deep vein thrombosis, pulmonary embolism, retinal vein thrombosis) 2. Pregnancy or women who may become pregnant 3. Nursing mothers 4. Hypersensitivity to raloxifene or any component of the formulation 5. Active or past history of venous thromboembolism
Warnings and Precautions
Venous Thromboembolism: Significantly increased risk of deep vein thrombosis and pulmonary embolism. Discontinue at least 72 hours prior to and during prolonged immobilization. Cardiovascular Considerations: No cardioprotective effect demonstrated. Increased risk of death from stroke in women with documented coronary heart disease or at increased risk for major coronary events. Hepatic Impairment: Use with caution in patients with hepatic impairment. Not studied in patients with severe hepatic impairment. Renal Impairment: Use with caution in patients with moderate or severe renal impairment. Endometrial Effects: Unlike tamoxifen, does not stimulate endometrial proliferation.Drug Interactions
Warfarin: Minor decrease in prothrombin time (approximately 10%). Monitor prothrombin time more frequently when starting or stopping raloxifene. Cholestyramine: Reduces enterohepatic cycling and absorption of raloxifene. Avoid concomitant use. Highly Protein-Bound Drugs: Potential for displacement interactions with other highly protein-bound drugs such as diazepam, diazoxide, and nonsteroidal anti-inflammatory drugs. Systemic Estrogens: Not recommended for concomitant use.Adverse Effects
Common adverse effects (≥5%):- Hot flashes (24.6%)
- Leg cramps (5.9%)
- Peripheral edema (5.2%)
- Arthralgia (10.7%)
- Flu syndrome (14.6%)
- Sweating (8.6%)
- Venous thromboembolism (1-2%)
- Stroke mortality increase in certain populations
- Fatal stroke (0.7% increase in women with cardiovascular risk factors)
Monitoring Parameters
1. Bone mineral density: Baseline and follow-up DEXA scans every 1-2 years 2. Venous thromboembolism signs: Monitor for symptoms of DVT/PE 3. Lipid profile: Periodic assessment may be considered 4. Hepatic function: Baseline and periodic assessment in patients with hepatic impairment 5. Breast cancer screening: Continue routine mammography per guidelines 6. Calcium and vitamin D status: Ensure adequate supplementation
Patient Education
- Take medication exactly as prescribed, typically 60 mg daily
- Report any signs of blood clots immediately: leg pain/swelling, chest pain, shortness of breath
- Continue calcium and vitamin D supplementation as recommended
- Regular weight-bearing exercise is important for bone health
- Do not use if pregnant or planning to become pregnant
- Regular follow-up with healthcare provider for monitoring
- Continue regular breast cancer screening and gynecologic care
- Report any unusual muscle pain or weakness
- Inform all healthcare providers about raloxifene use before any surgical procedures
References
1. FDA Prescribing Information: Evista (raloxifene hydrochloride) tablets 2. Cummings SR, et al. The effect of raloxifene on risk of breast cancer in postmenopausal women: results from the MORE randomized trial. JAMA. 1999;281(23):2189-2197. 3. Ettinger B, et al. Reduction of vertebral fracture risk in postmenopausal women with osteoporosis treated with raloxifene: results from a 3-year randomized clinical trial. JAMA. 1999;282(7):637-645. 4. Barrett-Connor E, et al. Effects of raloxifene on cardiovascular events and breast cancer in postmenopausal women. N Engl J Med. 2006;355(2):125-137. 5. Vogel VG, et al. Effects of tamoxifen vs raloxifene on the risk of developing invasive breast cancer and other disease outcomes: the NSABP Study of Tamoxifen and Raloxifene (STAR) P-2 trial. JAMA. 2006;295(23):2727-2741. 6. Delmas PD, et al. Efficacy of raloxifene on vertebral fracture risk reduction in postmenopausal women with osteoporosis: four-year results from a randomized clinical trial. J Clin Endocrinol Metab. 2002;87(8):3609-3617.