Is Evista (raloxifene) safe for long-term use?

Is Evista (Raloxifene) Safe for Long-Term Use?

Yes, Evista (raloxifene) is safe for long-term use beyond 5 years, particularly in postmenopausal women with osteoporosis where breast cancer risk reduction becomes an additional benefit, with 8-year safety data demonstrating no increase in mortality and a favorable side-effect profile. 1

Duration of Use Recommendations

Raloxifene may be used for longer than 5 years in women with osteoporosis, in whom breast cancer risk reduction is a secondary benefit. 1

• For breast cancer risk reduction alone, the standard recommendation is 60 mg daily for 5 years 1
• Extended use beyond 5 years is explicitly supported when osteoporosis treatment is the primary indication 1
• The longest controlled trial data extends to 8 years of continuous therapy 2, 3

Long-Term Safety Evidence (8-Year Data)

The most robust long-term safety data comes from the MORE trial (4 years) followed by the CORE trial (additional 4 years), totaling 8 years of follow-up in 4,011 postmenopausal women with osteoporosis 2, 3:

Mortality and Major Outcomes:

• No difference in all-cause mortality between raloxifene and placebo groups over 8 years 2
• No difference in hospitalization rates 2
• All-cause mortality was 2.07% per year with raloxifene versus 2.25% with placebo 4

Cancer Outcomes:

• Excluding breast cancer and non-melanoma skin cancer, overall cancer incidence was actually lower with raloxifene (4.6%) versus placebo (6.3%), p=0.027 2
• No difference in uterine cancer, endometrial hyperplasia, or ovarian cancer incidence 2
• Similar incidences of endometrial and ovarian cancer between raloxifene and placebo groups 4
• The benefit for invasive breast cancer risk reduction increased with longer duration of therapy up to 8 years 3, 5

Adverse Effects Profile

Venous Thromboembolism (Most Serious Risk):

• 1.7-fold increase in venous thromboembolism risk (95% CI 0.93-3.14) 2
• Absolute risk difference of only 0.9 per 1,000 woman-years 2
• 2% incidence with raloxifene versus 1.4% with placebo in the RUTH trial 4
• Postmarketing reports include rare cases of retinal vein occlusion, stroke, and death associated with VTE 4

Common but Non-Serious Side Effects:

• Hot flashes: 7.8% with raloxifene versus 4.7% with placebo 4
• Muscle spasms/leg cramps: 12.1% with raloxifene versus 8.3% with placebo 4, 2
• Peripheral edema: 14.1% with raloxifene versus 11.7% with placebo 4
• Uterine polyps were more common with raloxifene (p=0.028) 2
• Cholelithiasis: 3.3% with raloxifene versus 2.6% with placebo 4

Cardiovascular Safety:

• No difference in myocardial infarction or stroke incidence over 8 years 2
• No excess cardiovascular risk demonstrated 2

Gynecologic Safety:

• No difference in postmenopausal bleeding between groups 2
• Raloxifene was indistinguishable from placebo regarding breast pain and tenderness 4

Absolute Contraindications

Raloxifene is contraindicated in women with: 1

• History of deep vein thrombosis (DVT)
• History of pulmonary embolism (PE)
• History of stroke or transient ischemic attack
• Prolonged immobilization (temporary contraindication)
• Premenopausal status
• Pregnancy 4

Advantages Over Tamoxifen

Raloxifene demonstrates a more favorable long-term safety profile compared to tamoxifen: 1

• Statistically significant lower risk of thromboembolic disease versus tamoxifen 1
• Lower risk of benign uterine complaints versus tamoxifen 1
• Lower risk of cataracts versus tamoxifen 1
• No increase in endometrial cancer risk (unlike tamoxifen) 2

Bone Quality with Long-Term Use

Bone biopsies after 8 years of raloxifene therapy showed: 3

• Normal bone architecture and bone cells
• Appropriate double labeling in all specimens examined
• Continued suppression of bone turnover markers to premenopausal reference intervals 3
• Continued preservation of bone mineral density with ongoing therapy 3

Clinical Monitoring Recommendations

Based on the FDA label and trial data: 4

• Monitor for signs/symptoms of venous thromboembolism, particularly during the first 4 months of therapy
• Discontinue raloxifene at least 72 hours before and during prolonged immobilization
• If used with warfarin, monitor prothrombin time more closely when starting or stopping raloxifene 4
• No routine endometrial monitoring is required (unlike with tamoxifen) 2

Key Clinical Pitfall

The most important safety consideration is the increased risk of venous thromboembolism, though the absolute risk increase is small (0.9 per 1,000 woman-years) 2. This risk must be weighed against the benefits of fracture prevention and breast cancer risk reduction, particularly in women with osteoporosis where long-term therapy is most appropriate 1.