- 1. Name of the medicinal product
- 2. Qualitative and quantitative composition
- 3. Pharmaceutical form
- 4. Clinical particulars
- 4.1 Therapeutic indications
- 4.2 Posology and method of administration
- 4.3 Contraindications
- 4.4 Special warnings and precautions for use
- 4.5 Interaction with other medicinal products and other forms of interaction
- 4.6 Fertility, pregnancy and lactation
- 4.7 Effects on ability to drive and use machines
- 4.8 Undesirable effects
- 4.9 Overdose
- 5. Pharmacological properties
- 5.1 Pharmacodynamic properties
- 5.2 Pharmacokinetic properties
- 5.3 Preclinical safety data
- 6. Pharmaceutical particulars
- 6.1 List of excipients
- 6.2 Incompatibilities
- 6.3 Shelf life
- 6.4 Special precautions for storage
- 6.5 Nature and contents of container
- 6.6 Special precautions for disposal and other handling
- 7. Marketing authorisation holder
- 8. Marketing authorisation number(s)
- 9. Date of first authorisation/renewal of the authorisation
- 10. Date of revision of the text
Excipient with known effect:Each tablet contains 123.02 mg lactose monohydrate.For the full list of excipients, see section 6.1.
PosologyThe recommended dose is one tablet daily by oral administration, which may be taken at any time of the day without regard to meals. Due to the nature of this disease process, raloxifene is intended for long term use.Generally calcium and vitamin D supplements are advised in women with a low dietary intake.
Elderly:No dose adjustment is necessary for the elderly.Renal impairment:Raloxifene should not be used in patients with severe renal impairment (see section 4.3). In patients with moderate and mild renal impairment, raloxifene should be used with caution.
Hepatic impairment:Raloxifene should not be used in patients with hepatic impairment (see section 4.3).
PregnancyRaloxifene is only for use in postmenopausal women.Raloxifene must not be taken by women of child bearing potential. Raloxifene may cause foetal harm when administered to a pregnant woman. If this medicinal product is used mistakenly during pregnancy or the patient becomes pregnant while taking it, the patient should be informed of the potential hazard to the foetus (see Section 5.3).
Breast-feedingIt is not known whether raloxifene is excreted in human milk. Its clinical use, therefore, cannot be recommended in lactating women. Raloxifene may affect the development of the baby.
a. Summary of the safety profileThe clinically most important adverse reactions reported in postmenopausal women treated with raloxifene were venous thromboembolic events (see section 4.4), which occurred in less than 1% of treated patients.
b. Tabulated summary of adverse reactionsThe table below gives the adverse reactions and frequencies observed in treatment and prevention studies involving over 13,000 postmenopausal women along with adverse reactions arising from postmarketing reports. The duration of treatment in these studies ranged from 6 to 60 months. The majority of adverse reactions have not usually required cessation of therapy. The frequencies for postmarketing reports were calculated from placebo-controlled clinical trials (comprising a total of 15,234 patients, 7,601 on raloxifene 60 mg and 7,633 on placebo) in postmenopausal women with osteoporosis, or established coronary heart disease (CHD) or increased risk for CHD, without comparison to the frequencies of adverse events in the placebo assignment groups.In the prevention population discontinuations of therapy due to any adverse 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 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).
|Blood and lymphatic system disorders Uncommon: Thrombocytopenia a|
|Nervous system disorders Common: Headache, including migraine a Uncommon: Fatal strokes|
|Vascular Disorders Very common: Vasodilation (hot flushes) Uncommon: Venous thromboembolic events, including deep vein thrombosis, pulmonary embolism, retinal vein thrombosis, superficial vein thrombophlebitis, Arterial thromoembolic reactions a|
|Gastrointestinal disorders Very common: Gastrointestinal symptoms a such as nausea, vomiting, abdominal pain, dyspepsia|
|Skin and subcutaneous tissue disorders Common: Rash a|
|Musculoskeletal and Connective Tissue Disorders Common: Leg cramps|
|Reproductive system and breast disorders Common: Mild breast symptoms a such as pain, enlargement and tenderness|
|General Disorders and Administration Site Conditions Very common: Flu syndrome Common: Peripheral oedema|
|Investigations Very common: Increased blood pressure a|
c. Description of selected adverse reactionsCompared 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 adverse reaction was most common in the first 6 months of treatment, and seldom occurred de novo after that time. In a study of 10101 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 1000 patient-years in the raloxifene group and 1.4% or 2.70 cases per 1000 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 in a frequency of 1% in the raloxifene group and 0.6% in the placebo group.In the RUTH study, raloxifene did not affect the incidence of stroke, compared to placebo. However, there was an increase in death due to stroke in women assigned to raloxifene. The incidence of stroke mortality was 2.2 per 1,000 women per year for raloxifene versus 1.5 per 1,000 women per year for placebo (see section 4.4). During an average follow-up of 5.6 years, 59 (1.2%) raloxifene-treated women died due to a stroke compared to 39 (0.8%) placebo-treated women. Another adverse 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 edema 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 can not 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 (HRT) or cyclic (n = 205) HRT 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.
Mechanism of action and Pharmacodynamic effectAs a selective estrogen receptor modulator (SERM), raloxifene has selective agonist or antagonist activities on tissues responsive to estrogen. It acts as an agonist on bone and partially on cholesterol metabolism (decrease in total and LDL-cholesterol), but not in the hypothalamus or in the uterine or breast tissues.Raloxifene's biological actions, like those of estrogen, are mediated through high affinity binding to estrogen receptors and regulation of gene expression. This binding results in differential expression of multiple estrogen-regulated genes in different tissues. Recent data suggests that the estrogen receptor can regulate gene expression by at least two distinct pathways which are ligand-, tissue-, and/or gene specific.
a) Skeletal EffectsThe decrease in estrogen availability which occurs at menopause, leads to marked increases in bone resorption, bone loss and risk of fracture. Bone loss is particularly rapid for the first 10 years after menopause when the compensatory increase in bone formation is inadequate to keep up with resorptive losses. Other risk factors which may lead to the development of osteoporosis include early menopause; osteopenia (at least 1 SD below peak bone mass); thin body build; Caucasian or Asian ethnic origin; and a family history of osteoporosis. Replacement therapies generally reverse the excessive resorption of bone. In postmenopausal women with osteoporosis, raloxifene reduces the incidence of vertebral fractures, preserves bone mass and increases bone mineral density (BMD).Based on these risk factors, prevention of osteoporosis with raloxifene is indicated for women within ten years of menopause, with BMD of the spine between 1.0 and 2.5 SD below the mean value of a normal young population, taking into account their high lifetime risk for osteoporotic fractures. Likewise, raloxifene is indicated for the treatment of osteoporosis or established osteoporosis in women with BMD of the spine 2.5 SD below the mean value of a normal young population and/or with vertebral fractures, irrespective of BMD.i) Incidence of fractures. In a study of 7,705 postmenopausal women with a mean age of 66 years and with osteoporosis or osteoporosis with an existing fracture, raloxifene treatment for 3 years reduced the incidence of vertebral fractures by 47 % (RR 0.53, CI 0.35, 0.79; p < 0.001) and 31 % (RR 0.69, CI 0.56, 0.86; p < 0.001) respectively. Forty five women with osteoporosis or 15 women with osteoporosis with an existing fracture would need to be treated with raloxifene for 3 years to prevent one or more vertebral fractures. Raloxifene treatment for 4 years reduced the incidence of vertebral fractures by 46% (RR 0.54, CI 0.38, 0.75) and 32% (RR 0.68, CI 0.56, 0.83) in patients with osteoporosis or osteoporosis with an existing fracture respectively. In the 4th year alone, raloxifene reduced the new vertebral fracture risk by 39% (RR 0.61, CI 0.43, 0.88). An effect on non-vertebral fractures has not been demonstrated. From the 4th to the 8th year, patients were permitted the concomitant use of bisphosphonates, calcitonin and fluorides and all patients in this study received calcium and vitamin D supplementation. In the RUTH study overall clinical fractures were collected as a secondary endpoint. Raloxifene reduced the incidence of clinical vertebral fractures by 35% compared with placebo (HR 0.65, CI 0.47 0.89). These results may have been confounded by baseline differences in BMD and vertebral fractures. There was no difference between treatment groups in the incidence of new non-vertebral fractures. During the whole length of the study concomitant use of other bone-active medications was permitted.ii) Bone Mineral Density (BMD): The efficacy of raloxifene once daily in postmenopausal women aged up to 60 years and with or without a uterus was established over a two-year treatment period. The women were 2 to 8 years postmenopausal. Three trials included 1,764 postmenopausal women who were treated with raloxifene and calcium or calcium supplemented placebo. In one of these trials the women had previously undergone hysterectomy. Raloxifene produced significant increases in bone density of hip and spine as well as total body mineral mass compared to placebo. This increase was generally a 2 % increase in BMD compared to placebo. A similar increase in BMD was seen in the treatment population who received raloxifene for up to 7 years. In the prevention trials, the percentage of subjects experiencing an increase or decrease in BMD during raloxifene therapy was: for the spine 37 % decreased and 63 % increased; and for the total hip 29 % decreased and 71 % increased.iii) Calcium kinetics. Raloxifene and estrogen affect bone remodelling and calcium metabolism similarly. Raloxifene was associated with reduced bone resorption and a mean positive shift in calcium balance of 60 mg per day, due primarily to decreased urinary calcium losses.iv) Histomorphometry (bone quality). In a study comparing raloxifene with estrogen, bone from patients treated with either medicinal product was histologically normal, with no evidence of mineralisation defects, woven bone or marrow fibrosis. Raloxifene decreases resorption of bone; this effect on bone is manifested as reductions in the serum and urine levels of bone turnover markers, decreases in bone resorption based on radiocalcium kinetics studies, increases in BMD and decreases in the incidence of fractures.
b) Effects on lipid metabolism and cardiovascular riskClinical trials showed that a 60 mg daily dose of raloxifene significantly decreased total cholesterol (3 to 6 %), and LDL cholesterol (4 to 10 %). Women with the highest baseline cholesterol levels had the greatest decreases. HDL cholesterol and triglyceride concentrations did not change significantly. After 3 years therapy raloxifene decreased fibrinogen (6.71 %). In the osteoporosis treatment study, significantly fewer raloxifene treated patients required initiation of hypolipidaemic therapy compared to placebo.Raloxifene therapy for 8 years did not significantly affect the risk of cardiovascular events in patients enrolled in the osteoporosis treatment study. Similarly, in the RUTH study, raloxifene did not affect the incidence of myocardial infarction, hospitalized acute coronary syndrome, stroke or overall mortality, including overall cardiovascular mortality, compared to placebo (for the increase in risk of fatal stroke see section 4.4).The relative risk of venous thromboembolic events observed during raloxifene treatment was 1.60 (CI 0.95, 2.71) when compared to placebo, and was 1.0 (CI 0.3, 6.2) when compared to estrogen or hormonal replacement therapy. The risk of a thromboembolic event was greatest in the first four months of therapy.
c) Effects on the endometrium and on the pelvic floorIn clinical trials, raloxifene did not stimulate the postmenopausal uterine endometrium. Compared to placebo, raloxifene was not associated with spotting or bleeding or endometrial hyperplasia. Nearly 3,000 transvaginal ultrasound (TVUs) examinations were evaluated from 831 women in all dose groups. Raloxifene treated women consistently had an endometrial thickness which was indistinguishable from placebo. After 3 years of treatment, at least a 5 mm increase in endometrial thickness, assessed with transvaginal ultrasound, was observed in 1.9 % of the 211 women treated with raloxifene 60 mg/day compared to 1.8 % of the 219 women who received placebo. There were no differences between the raloxifene and placebo groups with respect to the incidence of reported uterine bleeding.Endometrial biopsies taken after six months therapy with raloxifene 60 mg daily demonstrated nonproliferative endometrium in all patients. In addition, in a study with 2.5 x the recommended daily dose of raloxifene there was no evidence of endometrial proliferation and no increase in uterine volume. In the osteoporosis treatment trial, endometrial thickness was evaluated annually in a subset of the study population (1,644 patients) for 4 years. Endometrial thickness measurements in raloxifene treated women were not different from baseline after 4 years of therapy. There was no difference between raloxifene and placebo treated women in the incidences of vaginal bleeding (spotting) or vaginal discharge. Fewer raloxifene treated women than placebo treated women required surgical intervention for uterine prolapse. Safety information following 3 years of raloxifene treatment suggests that raloxifene treatment does not increase pelvic floor relaxation and pelvic floor surgery.After 4 years, raloxifene did not increase the risk of endometrial or ovarian cancer. In postmenopausal women who received raloxifene treatment for 4 years, benign endometrial polyps were reported in 0.9% compared to 0.3% in women who received placebo treatment.
d) Effects on breast tissueRaloxifene does not stimulate breast tissue. Across all placebo-controlled trials, raloxifene was indistinguishable from placebo with regard to frequency and severity of breast symptoms (no swelling, tenderness and breast pain).Over the 4 years of the osteoporosis treatment trial (involving 7705 patients), raloxifene treatment compared to placebo reduced the risk of total breast cancer by 62% (RR 0.38; CI 0.21, 0.69), the risk of invasive breast cancer by 71% (RR 0.29, CI 0.13, 0.58) and the risk of invasive estrogen receptor (ER) positive breast cancer by 79% (RR 0.21, CI 0.07, 0.50). Raloxifene has no effect on the risk of ER negative breast cancers. These observations support the conclusion that raloxifene has no intrinsic estrogen agonist activity in breast tissue.
e) Effects on cognitive functionNo adverse effects on cognitive function have been seen.
Tablet Core:Lactose monohydrate Cellulose microcrystalline (E460)Crospovidone (E1202)Povidone K30 (E1201)Citric acid, anhydrous (E330)Magnesium stearate
Tablet coating:Hypromellose (E464)Macrogol 4000Lactose monohydrateTitanium dioxide (E171)
Consilient Health Ltd
No. 1 Church Road, Richmond upon Thames, Surrey, TW9 2QE, UK
+44(0)20 3751 1889
+44(0) 20 3751 1888