EVISTA 60mg tablets medication leaflet

Evista 60 mg film coated tablets

Each film coated tablet contains 60 mg raloxifene hydrochloride, equivalent to 56 mg raloxifene freebase.

Each tablet contains lactose (149.40 mg).

For the full list of excipients, see section 6.1.

Film coated tablet.

Elliptically shaped, white tablets.

Evista is indicated for the treatment and prevention of osteoporosis in postmenopausal women. Asignificant reduction in the incidence of vertebral, but not hip fractures has been demonstrated.

When determining the choice of Evista or other therapies, including oestrogens, for an individualpostmenopausal woman, consideration should be given to menopausal symptoms, effects on uterineand breast tissues, and cardiovascular risks and benefits (see section 5.1).

The recommended dose is one tablet daily by oral administration, which may be taken at any time ofthe day without regard to meals. Due to the nature of this disease process, Evista is intended for longterm use.

Generally calcium and vitamin D supplements are advised in women with a low dietary intake.

No dose adjustment is necessary for the elderly.

Evista should not be used in patients with severe renal impairment (see section 4.3). In patients withmoderate and mild renal impairment, Evista should be used with caution.

Evista should not be used in patients with hepatic impairment (see section 4.3 and 4.4).

Evista should not be used in children of any age. There is no relevant use of Evista in the paediatricpopulation.

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Must not be used in women with child bearing potential (see section 4.6).

Active or past history of venous thromboembolic events (VTE), including deep vein thrombosis,pulmonary embolism and retinal vein thrombosis.

Hepatic impairment including cholestasis.

Unexplained uterine bleeding.

Evista should not be used in patients with signs or symptoms of endometrial cancer as safety in thispatient group has not been adequately studied.

Raloxifene is associated with an increased risk for venous thromboembolic events that is similar to thereported risk associated with current use of hormone replacement therapy. The risk-benefit balanceshould be considered in patients at risk of venous thromboembolic events of any aetiology. Evistashould be discontinued in the event of an illness or a condition leading to a prolonged period ofimmobilisation. Discontinuation should happen as soon as possible in case of the illness, or from 3days before the immobilisation occurs. Therapy should not be restarted until the initiating conditionhas resolved and the patient is fully mobile.

In a study of postmenopausal women with documented coronary heart disease or at increased risk forcoronary events, raloxifene did not affect the incidence of myocardial infarction, hospitalized acutecoronary syndrome, overall mortality, including overall cardiovascular mortality, or stroke, comparedto 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 1000 women per year for raloxifene versus 1.5 per 1000women per year for placebo (see section 4.8). This finding should be considered when prescribingraloxifene for postmenopausal women with a history of stroke or other significant stroke risk factors,such as transient ischemic attack or atrial fibrillation.

There is no evidence of endometrial proliferation. Any uterine bleeding during Evista therapy isunexpected and should be fully investigated by a specialist. The two most frequent diagnosesassociated with uterine bleeding during raloxifene treatment were endometrial atrophy and benignendometrial polyps. In postmenopausal women who received raloxifene treatment for 4 years, benignendometrial polyps were reported in 0.9 % compared to 0.3 % in women who received placebotreatment.

Raloxifene is metabolised primarily in the liver. Single doses of raloxifene given to patients withcirrhosis and mild hepatic impairment (Child-Pugh class A) produced plasma concentrations ofraloxifene which were approximately 2.5 times the controls. The increase correlated with totalbilirubin concentrations. Therefore Evista is not recommended to be used in patients with hepaticinsufficiency. Serum total bilirubin, gamma-glutamyl transferase, alkaline phosphatase, ALT and ASTshould be closely monitored during treatment if elevated values are observed.

Limited clinical data suggest that in patients with a history of oral oestrogen-inducedhypertriglyceridemia (>5.6 mmol/l), raloxifene may be associated with a marked increase in serumtriglycerides. Patients with this medical history should have serum triglycerides monitored whentaking raloxifene.

The safety of Evista in patients with breast cancer has not been adequately studied. No data areavailable on the concomitant use of Evista and agents used in the treatment of early or advanced breastcancer. Therefore, Evista should be used for osteoporosis treatment and prevention only after thetreatment of breast cancer, including adjuvant therapy, has been completed.

As safety information regarding co-administration of raloxifene with systemic oestrogens is limited,such use is not recommended.

Evista is not effective in reducing vasodilatation (hot flushes), or other symptoms of the menopauseassociated with oestrogen deficiency.

Evista contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapplactase deficiency or glucose-galactose malabsorption should not take this medicine.

Concurrent administration of either calcium carbonate or aluminium and magnesium-hydroxidecontaining antacids do not affect the systemic exposure of raloxifene.

Co-administration of raloxifene and warfarin does not alter the pharmacokinetics of either compound.

However, modest decreases in the prothrombin time have been observed, and if raloxifene is givenconcurrently with warfarin or other coumarin derivatives, the prothrombin time should be monitored.

Effects on prothrombin time may develop over several weeks if Evista treatment is started in patientswho are already on coumarin anticoagulant therapy.

Raloxifene has no effect on the pharmacokinetics of methylprednisolone given as a single dose.

Raloxifene does not affect the steady-state AUC of digoxin. The Cmax of digoxin increased by less than5 %.

The influence of concomitant medication on raloxifene plasma concentrations was evaluated in theprevention and treatment trials. Frequently co-administered medicinal products included: paracetamol,non-steroidal anti-inflammatory drugs (such as acetylsalicylic acid, ibuprofen, and naproxen), oralantibiotics, H1 antagonists, H2 antagonists, and benzodiazepines. No clinically relevant effects of theco-administration of the agents on raloxifene plasma concentrations were identified.

Concomitant use of vaginal oestrogen preparations was allowed in the clinical trial programme, ifnecessary to treat atrophic vaginal symptoms. Compared to placebo there was no increased use in

Evista treated patients.

In vitro, raloxifene did not interact with the binding of warfarin, phenytoin, or tamoxifen.

Raloxifene should not be co-administered with cholestyramine (or other anion exchange resins), whichsignificantly reduces the absorption and enterohepatic cycling of raloxifene.

Peak concentrations of raloxifene are reduced with co-administration with ampicillin. However, sincethe overall extent of absorption and the elimination rate of raloxifene are not affected, raloxifene canbe concurrently administered with ampicillin.

Raloxifene modestly increases hormone-binding globulin concentrations, including sex steroid bindingglobulins (SHBG), thyroxine binding globulin (TBG), and corticosteroid binding globulin (CBG),with corresponding increases in total hormone concentrations. These changes do not affectconcentrations of free hormones.

Evista is only for use in postmenopausal women.

Evista must not be taken by women of child bearing potential. Raloxifene may cause foetal harm whenadministered to a pregnant woman. If this medicinal product is used mistakenly during pregnancy orthe patient becomes pregnant while taking it, the patient should be informed of the potential hazard tothe foetus (see section 5.3).

It is unknown whether raloxifene/raloxifene metabolites are excreted in human milk. A risk to thenewborns/infants cannot be excluded. Its clinical use, therefore, cannot be recommended in breast-feeding women. Evista may affect the development of the baby.

Raloxifene has no or negligible influence on the ability to drive and use machines.

The clinically most important adverse reactions reported in postmenopausal women treated with

Evista were venous thromboembolic events (see section 4.4), which occurred in less than 1% oftreated patients.

b. Tabulated summary of adverse reactions

The table below gives the adverse reactions and frequencies observed in treatment and preventionstudies involving over 13,000 postmenopausal women along with adverse reactions arising frompostmarketing reports. The duration of treatment in these studies ranged from 6 to 60 months. Themajority 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) inpostmenopausal women with osteoporosis, or established coronary heart disease (CHD) or increasedrisk for CHD, without comparison to the frequencies of adverse events in the placebo assignmentgroups.

In the prevention population discontinuations of therapy due to any adverse reaction occurred in10.7 % of 581 Evista treated patients and 11.1 % of 584 placebo-treated patients. In the treatmentpopulation discontinuations of therapy due to any clinical adverse event occurred in 12.8 % of 2,557

Evista 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).

Uncommon: Thrombocytopenia a

Common: Headache, including migraine a

Uncommon: Fatal strokes

Very common: Vasodilation (hot flushes)

Uncommon: Venous thromboembolic events, including deep vein thrombosis, pulmonaryembolism, retinal vein thrombosis, superficial vein thrombophlebitis, Arterialthromboembolic reactions a

Very common: Gastrointestinal symptoms a such as nausea, vomiting, abdominal pain, dyspepsia

Common: Rash a

Common: Leg cramps

Common: Mild breast symptoms a such as pain, enlargement and tenderness

Very common: Flu syndrome

Common: Peripheral oedema

Very common: Increased blood pressure aa Term(s) included based on postmarketing experience.

c. Description of selected adverse reactions

Compared with placebo-treated patients the occurrence of vasodilatation (hot flushes) was modestlyincreased in Evista patients (clinical trials for the prevention of osteoporosis, 2 to 8 yearspostmenopausal, 24.3 % Evista and 18.2 % placebo; clinical trials for the treatment of osteoporosis,mean age 66, 10.6 % for Evista and 7.1 % placebo). This adverse reaction was most common in thefirst 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 increasedrisk for coronary events (RUTH), the occurrence of vasodilatation (hot flushes) was 7.8 % in theraloxifene-treated patients and 4.7 % in the placebo-treated patients.

Across all placebo-controlled clinical trials of raloxifene in osteoporosis, venous thromboembolicevents, including deep vein thrombosis, pulmonary embolism, and retinal vein thrombosis occurred ata frequency of approximately 0.8 % or 3.22 cases per 1,000 patient years. A relative risk of 1.60 (CI0.95, 2.71) was observed in Evista treated patients compared to placebo. The risk of athromboembolic event was greatest in the first four months of therapy. Superficial veinthrombophlebitis occurred in a frequency of less than 1 %.

In the RUTH study, venous thromboembolic events occurred at a frequency of approximately 2.0 % or3.88 cases per 1,000 patient-years in the raloxifene group and 1.4 % or 2.70 cases per1,000 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 in a frequency of 1 % in theraloxifene 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 strokemortality was 2.2 per 1,000 women per year for raloxifene versus 1.5 per 1,000 women per year forplacebo (see section 4.4). During an average follow-up of 5.6 years, 59 (1.2%) raloxifene-treatedwomen died due to a stroke compared to 39 (0.8%) placebo-treated women.

Another adverse reaction observed was leg cramps (5.5 % for Evista, 1.9 % for placebo in theprevention population and 9.2 % for Evista, 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 % ofplacebo-treated patients.

Flu syndrome was reported by 16.2 % of Evista 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 asignificant dose trend. This was peripheral oedema, which occurred in the prevention population at anincidence of 3.1 % for Evista and 1.9 % for placebo; and in the treatment population occurred at anincidence of 7.1 % for Evista 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 relationshipto 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 increasedrisk for coronary events, an additional adverse reaction of cholelithiasis occurred in 3.3 % of patientstreated with raloxifene and 2.6 % of patients treated with placebo. Cholecystectomy rates forraloxifene (2.3 %) were not statistically significantly different from placebo (2.0 %).

Evista (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 anduterine bleeding in raloxifene treated women was significantly lower than in women treated witheither form of HRT.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V

In some clinical trials, daily doses were given up to 600 mg for 8 weeks and 120 mg, for 3 years. Nocases of raloxifene overdose were reported during clinical trials.

In adults, symptoms of leg cramps and dizziness have been reported in patients who took more than120 mg as a single ingestion.

In accidental overdose in children younger than 2 years of age, the maximum reported dose has been180 mg. In children, symptoms of accidental overdose included ataxia, dizziness, vomiting, rash,diarrhea, tremor, and flushing, and elevation in alkaline phosphatase.

The highest overdose has been approximately 1.5 grams. No fatalities associated with overdose havebeen reported.

There is no specific antidote for raloxifene hydrochloride.

Pharmacotherapeutic group: Selective Oestrogen Receptor Modulator, ATC code: G03XC01.

Mechanism of action and Pharmacodynamic effect

As a selective oestrogen receptor modulator (SERM), raloxifene has selective agonist or antagonistactivities on tissues responsive to oestrogen. It acts as an agonist on bone and partially on cholesterolmetabolism (decrease in total and LDL-cholesterol), but not in the hypothalamus or in the uterine orbreast tissues.

Raloxifene's biological actions, like those of oestrogen, are mediated through high affinity binding tooestrogen receptors and regulation of gene expression. This binding results in differential expressionof multiple oestrogen-regulated genes in different tissues. Data suggests that the oestrogen receptorcan regulate gene expression by at least two distinct pathways which are ligand-, tissue-, and/or gene-specific.

a) Skeletal Effects

The decrease in oestrogen availability which occurs at menopause, leads to marked increases in boneresorption, bone loss and risk of fracture. Bone loss is particularly rapid for the first 10 years aftermenopause when the compensatory increase in bone formation is inadequate to keep up withresorptive losses. Other risk factors which may lead to the development of osteoporosis include earlymenopause; osteopenia (at least 1 SD below peak bone mass); thin body build; Caucasian or Asianethnic origin; and a family history of osteoporosis. Replacement therapies generally reverse theexcessive resorption of bone. In postmenopausal women with osteoporosis, Evista reduces theincidence of vertebral fractures, preserves bone mass and increases bone mineral density (BMD).

Based on these risk factors, prevention of osteoporosis with Evista is indicated for women within tenyears of menopause, with BMD of the spine between 1.0 and 2.5 SD below the mean value of anormal young population, taking into account their high lifetime risk for osteoporotic fractures.

Likewise, Evista is indicated for the treatment of osteoporosis or established osteoporosis in womenwith BMD of the spine 2.5 SD below the mean value of a normal young population and/or withvertebral fractures, irrespective of BMD.

i) Incidence of fractures. In a study of 7,705 postmenopausal women with a mean age of 66 years andwith osteoporosis or osteoporosis with an existing fracture, Evista treatment for 3 years reduced theincidence of vertebral fractures by 47 % (RR 0.53, CI 0.35, 0.79; p < 0.001) and 31 % (RR 0.69, CI0.56, 0.86; p < 0.001) respectively. Forty five women with osteoporosis or 15 women withosteoporosis with an existing fracture would need to be treated with Evista for 3 years to prevent oneor more vertebral fractures. Evista treatment for 4 years reduced the incidence of vertebral fracturesby 46 % (RR 0.54, CI 0.38, 0.75) and 32 % (RR 0.68, CI 0.56, 0.83) in patients with osteoporosis orosteoporosis with an existing fracture respectively. In the 4th year alone, Evista reduced the newvertebral fracture risk by 39 % (RR 0.61, CI 0.43, 0.88). An effect on non-vertebral fractures has notbeen demonstrated. From the 4th to the 8th year, patients were permitted the concomitant use ofbisphosphonates, calcitonin and fluorides and all patients in this study received calcium and vitamin Dsupplementation.

In the RUTH study overall clinical fractures were collected as a secondary endpoint. Evistareduced the incidence of clinical vertebral fractures by 35% compared with placebo (HR 0.65, CI 0.470.89). These results may have been confounded by baseline differences in BMD and vertebralfractures. There was no difference between treatment groups in the incidence of new nonvertebralfractures. During the whole length of the study concomitant use of other bone-active medications waspermitted.

ii) Bone Mineral Density (BMD): The efficacy of Evista once daily in postmenopausal women agedup to 60 years and with or without a uterus was established over a two-year treatment period. Thewomen were 2 to 8 years postmenopausal. Three trials included 1,764 postmenopausal women whowere treated with Evista and calcium or calcium supplemented placebo. In one of these trials thewomen had previously undergone hysterectomy. Evista produced significant increases in bone densityof hip and spine as well as total body mineral mass compared to placebo. This increase was generally a2 % increase in BMD compared to placebo. A similar increase in BMD was seen in the treatmentpopulation who received Evista for up to 7 years. In the prevention trials, the percentage of subjectsexperiencing 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. Evista and oestrogen affect bone remodelling and calcium metabolism similarly.

Evista was associated with reduced bone resorption and a mean positive shift in calcium balance of60 mg per day, due primarily to decreased urinary calcium losses.

iv) Histomorphometry (bone quality). In a study comparing Evista with oestrogen, bone from patientstreated with either medicinal product was histologically normal, with no evidence of mineralisationdefects, woven bone or marrow fibrosis.

Raloxifene decreases resorption of bone; this effect on bone is manifested as reductions in the serumand urine levels of bone turnover markers, decreases in bone resorption based on radiocalcium kineticsstudies, increases in BMD and decreases in the incidence of fractures.

b) Effects on lipid metabolism and cardiovascular risk

Clinical trials showed that a 60 mg daily dose of Evista significantly decreased total cholesterol (3 to6 %), and LDL cholesterol (4 to 10 %). Women with the highest baseline cholesterol levels had thegreatest decreases. HDL cholesterol and triglyceride concentrations did not change significantly. After3 years therapy Evista decreased fibrinogen (6.71 %). In the osteoporosis treatment study, significantlyfewer Evista-treated patients required initiation of hypolipidaemic therapy compared to placebo.

Evista therapy for 8 years did not significantly affect the risk of cardiovascular events in patientsenrolled in the osteoporosis treatment study. Similarly, in the RUTH study, raloxifene did not affectthe incidence of myocardial infarction, hospitalized acute coronary syndrome, stroke or overallmortality, including overall cardiovascular mortality, compared to placebo (for the increase in risk offatal stroke see section 4.4).

The relative risk of venous thromboembolic events observed during raloxifene treatment was 1.60 (CI0.95, 2.71) when compared to placebo, and was 1.0 (CI 0.3, 6.2) when compared to oestrogen orhormonal replacement therapy. The risk of a thromboembolic event was greatest in the first fourmonths of therapy.

c) Effects on the endometrium and on the pelvic floor

In clinical trials, Evista did not stimulate the postmenopausal uterine endometrium. Compared toplacebo, raloxifene was not associated with spotting or bleeding or endometrial hyperplasia. Nearly3,000 transvaginal ultrasound (TVUs) examinations were evaluated from 831 women in all dosegroups. Raloxifene treated women consistently had an endometrial thickness which wasindistinguishable from placebo. After 3 years of treatment, at least a 5 mm increase in endometrialthickness, assessed with transvaginal ultrasound, was observed in 1.9 % of the 211 women treatedwith raloxifene 60 mg/day compared to 1.8 % of the 219 women who received placebo. There were nodifferences between the raloxifene and placebo groups with respect to the incidence of reported uterinebleeding.

Endometrial biopsies taken after six months therapy with Evista 60 mg daily demonstrated non-proliferative endometrium in all patients. In addition, in a study with 2.5 x the recommended dailydose of Evista 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 thestudy population (1,644 patients) for 4 years. Endometrial thickness measurements in Evista treatedwomen were not different from baseline after 4 years of therapy. There was no difference between

Evista and placebo treated women in the incidences of vaginal bleeding (spotting) or vaginaldischarge. Fewer Evista treated women than placebo treated women required surgical intervention foruterine prolapse. Safety information following 3 years of raloxifene treatment suggests that raloxifenetreatment 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 postmenopausalwomen who received raloxifene treatment for 4 years, benign endometrial polyps were reported in0.9 % compared to 0.3 % in women who received placebo treatment.

d) Effects on breast tissue

Evista does not stimulate breast tissue. Across all placebo-controlled trials, Evista wasindistinguishable 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 7,705 patients), Evista treatmentcompared to placebo reduced the risk of total breast cancer by 62 % (RR 0.38; CI 0.21, 0.69), the riskof invasive breast cancer by 71 % (RR 0.29, CI 0.13, 0.58) and the risk of invasive oestrogen receptor(ER) positive breast cancer by 79 % (RR 0.21, CI 0.07, 0.50). Evista has no effect on the risk of ERnegative breast cancers. These observations support the conclusion that raloxifene has no intrinsicoestrogen agonist activity in breast tissue.

e) Effects on cognitive function

No adverse effects on cognitive function have been seen.

Raloxifene is absorbed rapidly after oral administration. Approximately 60 % of an oral dose isabsorbed. Presystemic glucuronidation is extensive. Absolute bioavailability of raloxifene is 2 %. Thetime to reach average maximum plasma concentration and bioavailability are functions of systemicinterconversion and enterohepatic cycling of raloxifene and its glucuronide metabolites.

Raloxifene is distributed extensively in the body. The volume of distribution is not dose dependent.

Raloxifene is strongly bound to plasma proteins (98-99 %).

Raloxifene undergoes extensive first pass metabolism to the glucuronide conjugates: raloxifene-4'-glucuronide, raloxifene-6-glucuronide, and raloxifene-6, 4-diglucuronide. No other metabolites havebeen detected. Raloxifene comprises less than 1 % of the combined concentrations of raloxifene andthe glucuronide metabolites. Raloxifene levels are maintained by enterohepatic recycling, giving aplasma half-life of 27.7 hours.

Results from single oral doses of raloxifene predict multiple dose pharmacokinetics. Increasing dosesof raloxifene result in slightly less than proportional increase in the area under the plasma timeconcentration curve (AUC).

The majority of a dose of raloxifene and glucuronide metabolites are excreted within 5 days and arefound primarily in the faeces, with less than 6 % excreted in urine.

Renal insufficiency - Less than 6 % of the total dose is eliminated in urine. In a populationpharmacokinetic study, a 47 % decrease in lean body mass adjusted creatinine clearance resulted in a17 % decrease in raloxifene clearance and a 15 % decrease in the clearance of raloxifene conjugates.

Hepatic insufficiency - The pharmacokinetics of a single dose of raloxifene in patients with cirrhosisand mild hepatic impairment (Child-Pugh class A) have been compared to that in healthy individuals.

Plasma raloxifene concentrations were approximately 2.5-fold higher than in controls and correlatedwith bilirubin concentrations.

In a 2-year carcinogenicity study in rats, an increase in ovarian tumors of granulosa/theca cell originwas observed in high-dose females (279 mg/kg/day). Systemic exposure (AUC) of raloxifene in thisgroup was approximately 400 times that in postmenopausal women administered a 60 mg dose. In a21-month carcinogenicity study in mice, there was an increased incidence of testicular interstitial celltumours and prostatic adenomas and adenocarcinomas in males given 41 or 210 mg/kg, and prostaticleiomyoblastoma in males given 210 mg/kg. In female mice, an increased incidence of ovariantumours in animals given 9 to 242 mg/kg (0.3 to 32 times the AUC in humans) included benign andmalignant tumours of granulosa/theca cell origin and benign tumours of epithelial cell origin. Thefemale rodents in these studies were treated during their reproductive lives, when their ovaries werefunctional and highly responsive to hormonal stimulation. In contrast to the highly responsive ovariesin this rodent model, the human ovary after menopause is relatively unresponsive to reproductivehormonal stimulation.

Raloxifene was not genotoxic in any of the extensive battery of test systems applied.

The reproductive and developmental effects observed in animals are consistent with the knownpharmacological profile of raloxifene. At doses of 0.1 to 10 mg/kg/day in female rats, raloxifenedisrupted estrous cycles of female rats during treatment, but did not delay fertile matings aftertreatment termination and only marginally reduced litter size, increased gestation length, and alteredthe timing of events in neonatal development. When given during the preimplantation period,raloxifene delayed and disrupted embryo implantation resulting in prolonged gestation and reducedlitter size but development of offspring to weaning was not affected. Teratology studies wereconducted in rabbits and rats. In rabbits, abortion and a low rate of ventricular septal defects( 0.1 mg/kg) and hydrocephaly ( 10 mg/kg) were seen. In rats retardation of foetal development,wavy ribs and kidney cavitation occurred ( 1 mg/kg).

Raloxifene is a potent antioestrogen in the rat uterus and prevented growth of oestrogen-dependentmammary tumours in rats and mice.

Povidone

Polysorbate 80

Anhydrous lactose

Lactose monohydrate

Crospovidone

Magnesium stearate

Titanium dioxide (E 171)

Polysorbate 80

Hypromellose

Macrogol 400

Not applicable.

3 years.

Store in the original package. Do not freeze.

Evista tablets are packed either in PVC/PVDC blisters or in high density polyethylene bottles. Blisterboxes contain 14, 28, or 84 tablets. Bottles contain 100 tablets.

Not all pack sizes may be marketed in all countries.

No special requirements.

SUBSTIPHARM24 rue Erlanger75016 Paris

France

EU/1/98/073/001

EU/1/98/073/002

EU/1/98/073/003

EU/1/98/073/004

Date of first authorisation: 5 August 1998

Date of latest renewal: 8 August 2008

DD month YYYY

Detailed information on this medicinal product is available on the website of the European Medicines

Agency http://www.ema.europa.eu.