In osteoporosis treatment and prevention studies involving over 13,000 postmenopausal women, all undesirable reactions were recorded. The duration of treatment in these studies ranged from 6 to 60 months. The majority of undesirable reactions have not usually required cessation of therapy.
In the prevention population, discontinuations of therapy due to any undesirable reaction occurred in 10.7% of 581 raloxifene-treated patients and 11.1% of 584 placebo-treated patients. In the treatment population, discontinuations of therapy due to any clinical adverse experience occurred in 12.8% of 2,557 raloxifene-treated patients and 11.1% of 2,576 placebo-treated patients.
The undesirable reactions associated with the use of raloxifene in osteoporosis clinical trials are summarised in the table as follows. The following convention has been used for the classification of the adverse reactions: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000), very rare (<1/10,000),not known (cannot be estimated from the available data). (See table.)
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Compared with placebo-treated patients, the occurrence of vasodilatation (hot flushes) was modestly increased in raloxifene patients (clinical trials for the prevention of osteoporosis, 2 to 8 years postmenopausal, 24.3% raloxifene and 18.2% placebo; clinical trials for the treatment of osteoporosis, mean age 66, 10.6% for raloxifene and 7.1% placebo). This undesirable reaction was most common in the first 6 months of treatment, and seldom occurred de novo after that time.
In a study of 10,101 postmenopausal women with documented coronary heart disease or at increased risk for coronary events (RUTH), the occurrence of vasodilatation (hot flushes) was 7.8% in the raloxifene-treated patients and 4.7% in the placebo-treated patients.
Across all placebo-controlled clinical trials of raloxifene in osteoporosis, venous thromboembolic events, including deep vein thrombosis, pulmonary embolism, and retinal vein thrombosis, occurred at a frequency of approximately 0.8% or 3.22 cases per 1,000 patient years. A relative risk of 1.60 (CI 0.95, 2.71) was observed in raloxifene-treated patients compared to placebo. The risk of a thromboembolic event was greatest in the first four months of therapy. Superficial vein thrombophlebitis occurred in a frequency of less than 1%.
In the RUTH study, venous thromboembolic events occurred at a frequency of approximately 2.0% or 3 .88 cases per 1,000 patient-years in the raloxifene group and 1.4% or 2.70 cases per 1,000 patient-years in the placebo group. The hazard ratio for all VTE events in the RUTH study was HR=1.44, (1.06-1.95). Superficial vein thrombophlebitis occurred at a frequency of 1% in the raloxifene group and 0.6% in the placebo group.
Another undesirable reaction observed was leg cramps (5.5% for raloxifene, 1.9% for placebo in the prevention population and 9.2% for raloxifene, 6.0% for placebo in the treatment population).
In the RUTH study, leg cramps were observed in 12.1% of raloxifene-treated patients and 8.3% of placebo-treated patients.
Flu syndrome was reported by 16.2% of raloxifene-treated patients and 14.0% of placebo treated patients.
One further change was seen which was not statistically significant (p>0.05), but which did show a significant dose trend. This was peripheral oedema, which occurred in the prevention population at an incidence of 3.1% for raloxifene and 1.9% for placebo; and in the treatment population occurred at an incidence of 7.1% for raloxifene and 6.1% for placebo.
In the RUTH study, peripheral oedema occurred in 14.1% of the raloxifene-treated patients and 11.7% of the placebo-treated patients, which was statistically significant.
Slightly decreased (6-10%) platelet counts have been reported during raloxifene treatment in placebo-controlled clinical trials of raloxifene in osteoporosis.
Rare cases of moderate increases in AST and/or ALT have been reported where a causal relationship to raloxifene cannot be excluded. A similar frequency of increases was noted among placebo patients. In a study (RUTH) of postmenopausal women with documented coronary heart disease or at increased risk for coronary events, an additional adverse reaction of cholelithiasis occurred in 3.3% of patients treated with raloxifene and 2.6% of patients treated with placebo. Cholecystectomy rates for raloxifene (2.3%) were not statistically significantly different from placebo (2.0%).
Raloxifene (n=317) was compared with continuous combined (n=110) hormone replacement therapy (HAT) or cyclic (n=205) HAT patients in some clinical trials. The incidence of breast symptoms and uterine bleeding in raloxifene treated women was significantly lower than in women treated with either form of HRT.