NOTE:

This SPC has been re-formatted/revised in its entirety due to Evista licence renewal.

2.             QUALITATIVE AND QUANTITATIVE COMPOSITION

Added (bolt text):

Excipient: each tablet contains lactose (149.40 mg)

4.             CLINICAL PARTICULARS

4.2          Posology and method of administration

Added:

Use in renal impairment:

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

Use in hepatic impairment:

EVISTA should not be used in patients with hepatic impairment (see section 4.3).

4.4          Special warnings and precautions for use

Added:

Evista contains lactose.

4.6          Pregnancy and lactation

Amended (bold/strikethrough):

It is not known whether raloxifene is excreted in human milk. Its clinical use, therefore, cannot be recommended in breast-feedinglactating women.

4.7          Effects on ability to drive and use machines

Amended:

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

4.8          Undesirable effects

Amended throughout section:

Undesirable  adverse

Deleted:

The following convention has been used for the classification of the adverse reactions: very common (¡Ý1/10), common (¡Ý1/100 to <1/10), uncommon (¡Ý1/1,000 to <1/100), rare (¡Ý1/10,000 to <1/1,000) very rare (<1/10,000), not known (cannot be estimated from the available data).

4.9          Overdose

Amended:

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

9.             DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Changed:

Date of last renewal:                                         08 August 2008

10.          DATE OF REVISION OF THE TEXT

New date

08 August 2008

6.             PHARMACEUTICAL PARTICULARS

6.3          Shelf-life

Change of shelf-life from 2 to 3 years.

9.             DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Changes in bold text

Date of first authorisation:                              5 August 1998

Date of last renewal:                                         5 August 2003

10.          DATE OF REVISION OF THE TEXT

New date

4 May 2007

4.             CLINICAL PARTICULARS

4.8          Undesirable effects

Additions in bold text

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.

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

The following statement added above the clinical trial and post-marketing adverse event tables and as such the frequency classifications of adverse events deleted from within the tables.

The following convention has been used for the classification of the adverse reactions: very common ( ³1/10), common ( ³1/100 to <1/10), uncommon ( ³1/1,000 to <1/100), rare ( ³1/10,000 to <1/1,000), very rare ( <1/10,000), not known (cannot be estimated from the available data).

Added following paragraph

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.

Changes to the following paragraph, shown in bold text

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.

Added following paragraphs

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, leg cramps were observed in 12.1% of raloxifene-treated patients and 8.3% of placebo-treated patients.

Changes shown in bold text

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 Evista and 1.9% for placebo; and in the treatment population occurred at an incidence 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.

Added following paragraph

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%).

Deletions shown in strikethrough text and changes in bold text

The following events have been reported in post-marketing experience are presented in the table below.

5.             PHARMACOLOGICAL PROPERTIES

5.1          Pharmacodynamic properties

a)            Skeletal effects

Deletions shown in strikethrough text and additions in bold text

Evista 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.  During From the 4^th to the 8^th year, patients were permitted the concomitant use of bisphosphonates, calcitonin, and fluorides. An effect on extravertebral fractures has not been demonstrated 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.  Evista 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.

A similar increase in BMD was seen in the treatment population who received Evista for up to 7 years.

b)            Effects on lipid metabolism and cardiovascular risk

Additions in bold text

Evista 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).

d)            Effects on breast tissue

Deleted

The effect of Evista on breast cancer beyond 4 years is unknown.

9.             DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Deletions shown in strikethrough text

Date of first authorisation:                              5 August 1998

Date of last renewal of the authorisation:    28 July 2003

10.          DATE OF REVISION OF THE TEXT

New date:

27 March 2007

4.             CLINICAL PARTICULARS

4.4          Special warnings and precautions for use

Added:

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.  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.

Added:

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

Removed:

As there is no experience with co-administration of systemic oestrogens, such use is not recommended.

4.8                Undesirable effects

Added to post-marketing events table:

4.9                Overdose

Added:

In clinical trials, daily doses of 600mg for 8 weeks and 120mg for 3 years were well tolerated.

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.

Removed:

Incidents of overdose in humans have not been reported.  Daily doses of 600mg, administered during an 8 week study, and 120mg, used in clinical trials in more than 2,500 postmenopausal women for 3 years, were well tolerated.

10.          DATE OF REVISION OF THE TEXT

New date:

22 November 2006

2.             QUALITATIVE AND QUANTITATIVE COMPOSITION

Added:

Excipient: Lactose (149.40mg).

Re-worded:

For a full list of excipients, see section 6.1.

4.             CLINICAL PARTICULARS

4.4          Special warnings and precautions for use

Addition of warnings regarding the use of Evista in patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency, or glucose-galactose malabsorption.

6.             PHARMACEUTICAL PARTICULARS

6.4          Special precautions for storage

Removed:

Do not store above 30°C.

6.5          Nature and content of container

Removal of PVC blisters.

10.          DATE OF REVISION OF THE TEXT

New date (12 April 2006).