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SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Ostiral 60 mg film coated tablets.

Raloxifene hydrochloride 60 mg Film-Coated Tablets

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

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

Excipient: each tablet contains lactose monohydrate (1.5 mg).

For a full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Film coated tablet.

Elliptically shaped, white tablets

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

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

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

4.2    Posology and method of administration

Posology

The 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, Ostiral 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:

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

Hepatic impairment:

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

Paediatric population:

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

paediatric

population.

4.3    Contraindications

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

•    Must not be used in women with childbearing 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.

•    Severe renal impairment.

•    Unexplained uterine bleeding.

Ostiral should not be used in patients with signs or symptoms of endometrial cancer, as safety in this patient group has not been adequately studied.

4.4    Special warnings and precautions    for    use

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

In a study of postmenopausal women with documented coronary heart disease or at increased risk for coronary events, raloxifene did not affect the incidence of myocardial infarction, hospitalised acute coronary syndrome, overall mortality, including overall cardiovascular mortality, or 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 1.5 per 1,000 women per year for placebo versus 2.2 per 1,000 women per year for raloxifene (see section 4.8). This finding should be considered when prescribing raloxifene for postmenopausal women with a history of stroke or other significant stroke risk factors, such as transient ischaemic attack or atrial fibrillation.

There is no evidence of endometrial proliferation. Any uterine bleeding during Ostiral therapy is unexpected and should be fully investigated by a specialist. The two most frequent diagnoses associated with uterine bleeding during raloxifene treatment were endometrial atrophy and benign endometrial polyps. 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.

Raloxifene is metabolised primarily in the liver. Single doses of raloxifene given to patients with cirrhosis and mild hepatic impairment (Child-Pugh class A) produced plasma concentrations of raloxifene which were approximately 2.5-times the controls. The increase correlated with total bilirubin concentrations. Therefore Ostiral is not recommended to be used in patients with hepatic

insufficiency.. Serum total bilirubin, gamma-glutamyl transferase, alkaline phosphatase, ALT and AST should be closely monitored during treatment if elevated values are observed.

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

The safety of raloxifene in patients with breast cancer has not been adequately studied. No data are available on the concomitant use of raloxifene and agents used in the treatment of early or advanced breast cancer. Therefore, Ostiral should be used for osteoporosis treatment and prevention only after the treatment 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.

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

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

4.5 Interaction with other medicinal products and other forms of interaction

Concurrent administration of either calcium carbonate or aluminium and magnesium-hydroxide containing 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 given concurrently with warfarin or other coumarin derivatives, the prothrombin time should be monitored. Effects on prothrombin time may develop over several weeks if raloxifene treatment is started in patients who 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 than 5%.

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

Concomitant use of vaginal oestrogen preparations was allowed in the clinical trial programme, if necessary to treat atrophic vaginal symptoms. Compared to placebo there was no increased use in raloxifene-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), which significantly reduces the absorption and enterohepatic cycling of raloxifene.

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

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

4.6 Pregnancy and lactation

Pregnancy

Ostiral is only for use in postmenopausal women.

Ostiral must not be taken by women of childbearing 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-feeding

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

4.7    Effects on ability to drive and use machines

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

4.8    Undesirable effects

a. Summary of the safety profile

The 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 reactions

The 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 undesirable reactions associated with the use of raloxifene in osteoporosis clinical trials are summarised in the table below. 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).

^a 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 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 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.

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 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 (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.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.

4.9 Overdose

In some clinical trials, daily doses were given up to 600mg for 8 weeks and 120mg, for 3 years. No cases of raloxifene overdose were reported during clinical trials.

In adults, symptoms of leg cramps and dizziness have been reported in patients who took more than 120mg as a single ingestion.

In accidental overdose in children younger than 2 years of age, the maximum reported dose has been 180mg. In children, symptoms of accidental overdose included ataxia, dizziness, vomiting, rash, diarrhoea, tremor, flushing, and elevation in alkaline phosphatase.

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

There is no specific antidote for raloxifene hydrochloride.

5.1 Pharmacodynamic properties

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 antagonist activities on tissues responsive to oestrogen. 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 oestrogen, are mediated through high affinity binding to oestrogen receptors and regulation of gene expression. This binding results in differential expression of multiple oestrogen-regulated genes in different tissues. Data suggests that the oestrogen receptor can 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 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 oestrogen affect bone remodelling and calcium metabolism similarly. Raloxifene was associated with reduced bone resorption and a mean positive shift in calcium balance of 60mg per day, due primarily to decreased urinary calcium losses.

iv) Histomorphometry (bone quality). In a study comparing Raloxifene with oestrogen, 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 risk

Clinical trials showed that a 60mg 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, hospitalised 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 oestrogen 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 floor

In 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 5mm increase in endometrial thickness, assessed with transvaginal ultrasound, was observed in 1.9% of the 211 women treated with raloxifene 60mg/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 60mg daily demonstrated non-proliferative 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 tissue

Raloxifene 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 7,705 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 oestrogen 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 oestrogen agonist activity in breast tissue.

e)    Effects on cognitive function

No adverse effects on cognitive function have been seen.

5.2 Pharmacokinetic properties

Absorption

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

Distribution

Raloxifene is distributed extensively in the body. The volume of distribution is not dose dependent. Raloxifene is strongly bound to plasma proteins (98-99%).

Biotransformation

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

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

Elimination

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

Special populations

Renal insufficiency - Less than 6% of the total dose is eliminated in urine. In a population pharmacokinetic study, a 47% decrease in lean body mass adjusted creatinine clearance resulted in a 17% 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 cirrhosis and 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 correlated with bilirubin concentrations.

5.3 Preclinical safety data

In a 2-year carcinogenicity study in rats, an increase in ovarian tumours of granulosa/theca cell origin was observed in high-dose females (279mg/kg/day). Systemic exposure (AUC) of raloxifene in this group was approximately 400-times that in postmenopausal women administered a 60mg dose. In a 21-month carcinogenicity study in mice, there was an increased incidence of testicular interstitial cell tumours and prostatic adenomas and adenocarcinomas in males given 41 or 210mg/kg, and prostatic leiomyoblastoma in males given 210mg/kg. In female mice, an increased incidence of ovarian tumours in animals given 9 to 242mg/kg (0.3 to 32-times the AUC in humans) included benign and malignant tumours of granulosa/theca cell origin and benign tumours of epithelial cell origin. The female rodents in these studies were treated during their reproductive lives, when their ovaries were functional and highly responsive to hormonal stimulation. In contrast to the highly responsive ovaries in this rodent model, the human ovary after menopause is relatively unresponsive to reproductive hormonal 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 known pharmacological profile of raloxifene. At doses of 0.1 to 10mg/kg/day in female rats, raloxifene disrupted oestrus cycles of female rats during treatment, but did not delay fertile matings after treatment termination and only marginally reduced litter size, increased gestation length, and altered the timing of events in neonatal development. When given during the preimplantation period, raloxifene delayed and disrupted embryo implantation, resulting in prolonged gestation and reduced litter size, but development of offspring to weaning was not affected. Teratology studies were conducted in rabbits and rats. In rabbits, abortion and a low rate of ventricular septal defects (>0.1mg/kg) and hydrocephaly (>10mg/kg) were seen. In rats, retardation of foetal development, wavy ribs, and kidney cavitation occurred (>1mg/kg).

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

6 PHARMACEUTICAL PARTICULARS

List of excipients

Tablet core:

Sodium starch glycolate (Primogel)

Citric acid monohydrate Microcrystalline Cellulose Dibasic calcium phosphate Poloxamer 407 Magnesium stearate

Tablet coating:

Hypromellose Lactose monohydrate Polyethylene glycol Titanium dioxide (E171)

Macrogol/PEG 400.

6.2    Incompatibilities

Not applicable.

6.3    Shelf life

3 years.

6.4    Special precautions for storage

Keep the blister in the outer carton in order to protect from light and moisture. Do not freeze.

6.5    Nature and contents of container

Ostiral tablets are packed in a transparent PVC/PE/PVDC blister with Aluminum foil.

Blister boxes contain 14, 28, 30, 84, or 90 tablets.

Not all pack sizes may be marketed in all countries.

6.6    Special precautions for disposal

No special requirements.

7    MARKETING AUTHORISATION HOLDER

Pharmathen S.A 6 Dervenakion Street 153 51 Pallini Attiki Greece

8    MARKETING AUTHORISATION NUMBER(S)

PL 17277/0053

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

10    DATE OF REVISION OF THE TEXT

27/02/2015