Evista

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ANNEX I 
 

SUMMARY OF PRODUCT CHARACTERISTICS 



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1.  NAME OF THE MEDICINAL PRODUCT 
 
Evista 60 mg film coated tablets 
 
 
2.  QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
Each film coated tablet contains 60 mg raloxifene hydrochloride, equivalent to 56 mg raloxifene free 
base. 
 
Excipient with known effect:  
Each tablet contains lactose (149.40 mg). 
 
For the full list of excipients, see section 6.1. 
 
 
3.  PHARMACEUTICAL FORM 
 
Film coated tablet. 
Elliptically shaped, white tablets imprinted with the code ’4165’. 
 
 
4.  CLINICAL PARTICULARS 
 
4.1  Therapeutic indications 
 
Evista 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 Evista 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, Evista 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:  
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. 
 
Hepatic impairment:  
Evista should not be used in patients with hepatic impairment (see section 4.3 and 4.4). 
 



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Paediatric population: 
Evista should not be used in children of any age. There is no relevant use of Evista 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 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. 
 
Severe renal impairment.  
 
Unexplained uterine bleeding. 
 
Evista 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. 
Evista 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, hospitalized 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 2.2 per 1000 women per year for raloxifene versus 1.5 per 1000 
women per year for placebo (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 ischemic attack or atrial fibrillation. 
 
There is no evidence of endometrial proliferation. Any uterine bleeding during Evista 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 Evista 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. 
 



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Limited clinical data suggest that in patients with a history of oral oestrogen-induced 
hypertriglyceridemia (>5.6 mmol/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 Evista in patients with breast cancer has not been adequately studied. No data are 
available on the concomitant use of Evista and agents used in the treatment of early or advanced 
breast cancer. Therefore, Evista 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. 
 
Evista is not effective in reducing vasodilatation (hot flushes), or other symptoms of the menopause 
associated with oestrogen deficiency. 
 
Evista 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 Evista 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 
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), 
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. 
 



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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  Fertility, pregnancy and lactation 
 
Pregnancy 
 
Evista is only for use in postmenopausal women. 
 
Evista 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-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 breast-
feeding women. Evista 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 drive and use machines. 
 
4.8  Undesirable effects 
 
a. Summary of the safety profile 
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% 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 Evista treated patients and 11.1 % of 584 placebo-treated patients. In the treatment 
population 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. 
 



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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 
thromboembolic 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 
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 Evista patients (clinical trials for the prevention of osteoporosis, 2 to 8 years 
postmenopausal, 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 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 Evista 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 in a frequency of 1 % in the 
raloxifene group and 0.6 % in the placebo group. 
 



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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 Evista, 1.9 % for placebo in the 
prevention 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 % of 
placebo-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 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. 
 
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 %). 
 
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 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 national reporting system 
listed in Appendix V 
 
 
4.9  Overdose 
 
In some clinical trials, daily 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. 
 
In adults, symptoms of leg cramps and dizziness have been reported in patients who took more than 
120 mg as a single ingestion.  
 
In accidental overdose in children younger than 2 years of age, the maximum reported dose has been 
180 mg. In children, symptoms of accidental overdose included ataxia, dizziness, vomiting, rash, 
diarrhea, tremor, and flushing, and elevation in alkaline phosphatase.  
 

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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.  PHARMACOLOGICAL PROPERTIES 
 
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, Evista reduces the 
incidence 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 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, Evista 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, Evista 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 Evista for 3 years to prevent one 
or more vertebral fractures. Evista 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, 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. 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.  



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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 nonvertebral 
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 Evista 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 Evista and calcium or calcium supplemented placebo. In one of these trials the 
women had previously undergone hysterectomy. Evista 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 Evista 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. 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 of 
60 mg per day, due primarily to decreased urinary calcium losses.  
 
iv) Histomorphometry (bone quality). In a study comparing Evista 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 60 mg daily dose of Evista 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 Evista decreased fibrinogen (6.71 %). In the osteoporosis treatment study, 
significantly fewer 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 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 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, Evista 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 



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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 Evista 60 mg daily demonstrated non-
proliferative endometrium in all patients. In addition, in a study with 2.5 x the recommended daily 
dose 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 the 
study population (1,644 patients) for 4 years. Endometrial thickness measurements in Evista treated 
women 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 vaginal 
discharge. Fewer Evista 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 
 
Evista does not stimulate breast tissue. Across all placebo-controlled trials, Evista 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), Evista 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). Evista 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 %). 
 



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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 tumors of granulosa/theca cell origin 
was observed in high-dose females (279 mg/kg/day). Systemic exposure (AUC) of raloxifene in this 
group was approximately 400 times that in postmenopausal women administered a 60 mg 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 210 mg/kg, and prostatic 
leiomyoblastoma in males given 210 mg/kg. In female mice, an increased incidence of ovarian 
tumours in animals given 9 to 242 mg/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 10 mg/kg/day in female rats, raloxifene 
disrupted estrous 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 
(≥ 0.1 mg/kg) and hydrocephaly (≥ 10 mg/kg) were seen. In rats retardation of foetal development, 
wavy ribs and kidney cavitation occurred (≥ 1 mg/kg). 
 



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Raloxifene is a potent antioestrogen in the rat uterus and prevented growth of oestrogen-dependent 
mammary tumours in rats and mice. 
 
 
6.  PHARMACEUTICAL PARTICULARS 
 
6.1  List of excipients 
 
Tablet core:  
Povidone 
Polysorbate 80 
Anhydrous lactose 
Lactose monohydrate 
Crospovidone 
Magnesium stearate 
 
Tablet coating:  
Titanium dioxide (E 171) 
Polysorbate 80 
Hypromellose 
Macrogol 400 
Carnauba wax 
 
Ink:  
Shellac 
Propylene glycol 
Indigo carmine (E 132) 
 
 
6.2  Incompatibilities 
 
Not applicable. 
 
 
6.3  Shelf-life 
 
3 years. 
 
 
6.4  Special precautions for storage 
 
Store in the original package. Do not freeze.  
 
 
6.5  Nature and content of container 
 
Evista tablets are packed either in PVC/PE/PCTFE blisters or in high density polyethylene bottles. 
Blister boxes contain 14, 28, or 84 tablets. Bottles contain 100 tablets.  
 
Not all pack sizes may be marketed in all countries. 
 



13 

 
6.6   Special precautions for disposal 
 
No special requirements. 
 
 
7.  MARKETING AUTHORISATION HOLDER 
 
SUBSTIPHARM 
24 rue Erlanger 
75016 Paris 
France 
 
 
8.  MARKETING AUTHORISATION NUMBERS 
 
EU/1/98/073/001 
EU/1/98/073/002 
EU/1/98/073/003 
EU/1/98/073/004 
 
 
9.  DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION  
 
Date of first authorisation: 5 August 1998 
Date of latest renewal: 8 August 2008 
 
 
10.  DATE OF REVISION OF THE TEXT 
 
DD month YYYY 
 
Detailed information on this medicinal product is available on the website of the European Medicines 
Agency http://www.ema.europa.eu. 



14 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX II 
 

A. MANUFACTURER RESPONSIBLE FOR BATCH RELEASE 
 
B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY 

AND USE 
 

C. OTHER CONDITIONS AND REQUIREMENTS OF THE 
MARKETING AUTHORISATION 
 

 



15 

A. MANUFACTURER RESPONSIBLE FOR BATCH RELEASE 

 
Name and address of the manufacturer responsible for batch release 
 
Lilly SA 
Avda de la Industria 30 
28108 Alcobendas 
Madrid 
Spain 
 
 

B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE 

 
 
• Medicinal product subject to medical prescription 
 

C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 
AUTHORISATION 

 
 
• Periodic Safety Update Reports 
 
The requirements for submission of periodic safety update reports for this medicinal product are set 
out in the list of Union reference dates (EURD list) provided for under Article 107c(7) of Directive 
2001/83/EC and any subsequent updates published on the European medicines web-portal. 
 



16 

 
 
 
 
 
 
 
 
 
 
 
 

ANNEX III 
 

LABELLING AND PACKAGE LEAFLET 



17 

 
 
 
 
 
 
 
 
 
 
 
 

A. LABELLING 



18 

 
PARTICULARS TO APPEAR ON THE OUTER PACKAGING AND THE IMMEDIATE 
PACKAGING 
 
BOTTLE LABEL, BOTTLE CARTON: 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
EVISTA 60 mg film coated tablets 
raloxifene hydrochloride 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each film coated tablet contains 60 mg raloxifene hydrochloride, equivalent to 56 mg raloxifene 
 
 
3. LIST OF EXCIPIENTS 
 
Also includes lactose 
 
See leaflet for further information 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
100 film coated tablets 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
For oral use 
Read the package leaflet before use. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP {MM/YYYY}  
 
 
9. SPECIAL STORAGE CONDITIONS 
 
Store in the original package. 
Do not freeze.  
 



19 

 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
SUBSTIPHARM 
24 rue Erlanger 
75016 Paris 
France 
 
 
12. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/98/073/004 
 
 
13. BATCH NUMBER 
 
Batch {number} 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
Medicinal product subject to medical prescription. 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Evista 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC:  
SN: 
NN:  



20 

 
PARTICULARS TO APPEAR ON THE OUTER PACKAGING  
 
BLISTER BOX FILM COATED TABLETS: 

 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
EVISTA 60 mg film coated tablets 
raloxifene hydrochloride 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each film coated tablet contains 60 mg raloxifene hydrochloride, equivalent to 56 mg raloxifene 
 
 
3. LIST OF EXCIPIENTS 
 
Also includes lactose 
 
See leaflet for further information 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
14 film coated tablets 
28 film coated tablets 
84 film coated tablets 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
For oral use 
Read the package leaflet before use. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP {MM/YYYY}  
 
 
9. SPECIAL STORAGE CONDITIONS 
 
Store in the original package. Do not freeze.  



21 

 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
SUBSTIPHARM 
24 rue Erlanger 
75016 Paris 
France 
 
 
12. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/98/073/001 14 film coated tablets 
EU/1/98/073/002 28 film coated tablets 
EU/1/98/073/003 84 film coated tablets 
 
 
13. BATCH NUMBER 
 
Batch {number} 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
Medicinal product subject to medical prescription. 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Evista 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC:  
SN: 
NN:  



22 

 
MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 
 
BLISTER (ALL BLISTER PACKS): 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
EVISTA 60 mg film coated tablets 
raloxifene hydrochloride 
 
 
2. NAME OF THE MARKETING AUTHORISATION HOLDER 
 
SUBSTIPHARM 
 
 
3. EXPIRY DATE 
 
EXP {MM/YYYY}  
 
 
4. BATCH NUMBER 
 
Lot {number} 
 
 
5. OTHER 
 
 



23 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

B. PACKAGE LEAFLET 

 



24 

Package leaflet: Information for the user 
 

Evista 60 mg film coated tablets 
raloxifene hydrochloride 

 
Read all of this leaflet carefully before you start taking this medicine because it contains 
important information for you. 
• Keep this leaflet. You may need to read it again. 
• If you have any further questions, ask your doctor or pharmacist. 
• This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, 

even if their signs of illness are the same as yours. 
• If you get any side effects talk to your doctor or pharmacist. This includes any possible side 

effects not listed in this leaflet. See section 4. 
 
What is in this leaflet 
1. What Evista is and what it is used for 
2. What you need to know before you take Evista 
3. How to take Evista 
4. Possible side effects 
5. How to store Evista 
6. Contents of the pack and other information 
 
 
1. What Evista is and what it is used for 
 
Evista contains the active substance raloxifene hydrochloride. 
 
Evista is used to treat and prevent osteoporosis in postmenopausal women. Evista reduces the risk of 
vertebral fractures in women with postmenopausal osteoporosis. A reduction in the risk of hip 
fractures has not been shown. 
 
How Evista works 
 
Evista belongs to a group of non-hormonal medicines called Selective Oestrogen Receptor 
Modulators (SERMs). When a woman reaches the menopause, the level of the female sex hormone 
oestrogen goes down. Evista mimics some of the helpful effects of oestrogen after the menopause.  
 
Osteoporosis is a disease that causes your bones to become thin and fragile - this disease is especially 
common in women after the menopause. Although it may have no symptoms at first, osteoporosis 
makes you more likely to break bones, especially in your spine, hips and wrists and may cause back 
pain, loss of height and a curved back. 
 
 
2. What you need to know before you take Evista 
 
Do not take Evista: 
 
• If you are being treated or have been treated for blood clots in the legs (deep vein thrombosis), 

in the lungs (pulmonary embolism) or in the eyes (retinal vein thrombosis). 
• If you are allergic (hypersensitive) to raloxifene or any of the other ingredients of this medicine 

(listed in section 6). 
• If there is still a possibility that you can get pregnant, Evista could harm your unborn child. 
• If you have liver disease (examples of liver disease include cirrhosis, mild hepatic impairment 

or cholestatic jaundice). 
• If you have severe kidney problems. 



25 

• If you have any unexplained vaginal bleeding. This must be investigated by your doctor. 
• If you have active uterine cancer, as there is insufficient experience of Evista use in women 

with this disease. 
 
Warnings and precautions 
Talk to your doctor or pharmacist before you take Evista. 
 
• If you are immobilised for some time such as being wheel-chair bound, needing to be admitted 

to a hospital or having to stay in bed while recovering from an operation or an unexpected 
illness as these may increase your risk of blood clots (deep vein thrombosis, pulmonary 
embolism or retinal vein thrombosis). 

• If you have had a cerebrovascular accident (e.g. stroke), or if your doctor has told you that you 
are at high risk of having one. 

• If you have liver disease 
• If you are suffering from breast cancer, as there is insufficient experience of Evista use in 

women with this disease. 
• If you are receiving oral oestrogen therapy. 
 
It is unlikely that Evista will cause vaginal bleeding. So any vaginal bleeding while you take Evista is 
unexpected. You should have this investigated by your doctor. 
 
Evista does not treat postmenopausal symptoms, such as hot flushes. 
 
Evista lowers total cholesterol and LDL ("bad") cholesterol. In general, it does not change 
triglycerides or HDL ("good") cholesterol. However, if you have taken oestrogen in the past and had 
extreme elevations in triglycerides, you should talk to your doctor before taking Evista.   
 
Evista contains lactose 
If you have been told by your doctor that you have an intolerance to lactose, a type of sugar, contact 
your doctor before taking this medicinal product. 
 
Other medicines and Evista 
Tell your doctor or pharmacist if you are taking, have recently taken or might take any other 
medicines, including medicines obtained without a prescription. 
 
If you are taking digitalis medicines for your heart or anticoagulants like warfarin to thin your blood, 
your doctor may need to adjust your dose of these medicines. 
 
Tell your doctor if you are taking cholestyramine which is mainly used as lipid-lowering medicine, 
because Evista may not work as well. 
 
Pregnancy and breast-feeding 
Evista is for use only by postmenopausal women and must not be taken by women who could still 
have a baby. Evista could harm your unborn child. 
Do not take Evista if you are breast-feeding as it might be excreted in mother's milk. 
 
Driving and using machines 
Evista has no or negligible effects on driving or using machines. 
 
 
 



26 

3. How to take Evista 
 
Always take this medicine exactly as your doctor has told you. You should check with your doctor or 
pharmacist if you are not sure. 
 
The dose is one tablet a day. It does not matter what time of day you take your tablet but taking the 
tablet at the same time each day will help you remember to take it. You may take it with or without 
food. 
 
The tablets are for oral use. 
Swallow the tablet whole. If you wish you may take a glass of water with it. Do not break or crush the 
tablet before taking it. A broken or crushed tablet may taste bad and there is a possibility that you will 
receive an incorrect dose. 
 
Your doctor will tell you how long you should continue to take Evista. The doctor may also advise 
you to take calcium and vitamin D supplements. 
 
If you take more Evista than you should 
Tell your doctor or pharmacist. If you take more Evista than you should you could have leg cramps 
and dizziness. 
 
If you forget to take Evista 
Take a tablet as soon as you remember and then continue as before. Do not take a double dose to 
make up for a forgotten tablet dose. 
 
If you stop taking Evista 
You should talk to your doctor first. 
It is important that you continue taking Evista for as long as your doctor prescribes the medicine. 
Evista can treat or prevent your osteoporosis only if you continue to take the tablets. 
 
If you have any further questions on the use of this medicine, ask your doctor or pharmacist. 
 
 
4. Possible side effects 
 
Like all medicines, this medicine can cause side effects although not everybody gets them. The 
majority of side effects seen with Evista have been mild. 
 
The most common side effects (affects more than 1 user in 10) are:  

• Hot flushes (vasodilatation) 
• Flu syndrome 
• Gastrointestinal symptoms such as nausea, vomiting, abdominal pain and stomach upset 
• Increased blood pressure 

 
Common side effects (affects 1 to 10 users in 100) are: 

• Headache including migraine 
• Leg cramps  
• Swelling of hands, feet and legs (peripheral oedema)  
• Gallstones 
• Rash 
• Mild breast symptoms such as pain, enlargement and tenderness 

 



27 

Uncommon side effects (affects 1 to 10 users in 1000) are: 
• Increased risk of blood clots in the legs (deep vein thrombosis) 
• Increased risk of blood clots in the lungs (pulmonary embolism) 
• Increased risk of blood clots in the eyes (retinal vein thrombosis) 
• Skin around the vein is red and painful (superficial vein thrombophlebitis) 
• Blood clot in an artery (for example stroke, including an increased risk of dying from stroke)  
• Decrease in the number of the platelets in the blood  

 
In rare cases, blood levels of liver enzymes may increase during treatment with Evista.  
 
Reporting of side effects 
If you get any side effects talk to your doctor or pharmacist. This includes any possible side effects 
not listed in this leaflet. You can also report side effects directly via the national reporting system 
listed in Appendix V. By reporting side effects you can help provide more information on the safety 
of this medicine. 
 
 
5. How to store Evista 
 
Keep this medicine out of the sight and reach of children. 
 
Do not use after the expiry date which is stated on the pack after EXP. The expiry date refers to the 
last day of the month. 
 
Store in the original package. Do not freeze.  
 
Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to 
throw away medicines you no longer use. These measures will help protect the environment. 
 
 
6. Contents of the pack and other information 
 
What Evista contains 
- The active substance is raloxifene hydrochloride. Each tablet contains 60 mg of raloxifene 

hydrochloride, which is equivalent to 56 mg raloxifene. 
 
- The other ingredients are: 
 
Tablet Core: Povidone, polysorbate 80, anhydrous lactose, lactose monohydrate, crospovidone, 
magnesium stearate.  
Tablet coating: Titanium dioxide (E 171), polysorbate 80, hypromellose, macrogol 400, carnauba 
wax.  
Ink: Shellac, propylene glycol, indigo carmine (E 132). 
 
What Evista looks like and contents of the pack 
Evista are white, oval, film coated tablets which are marked with the number 4165. They are packed 
in blisters or in plastic bottles. The blister boxes contain 14, 28 or 84 tablets. The bottles contain 100 
tablets. Not all pack sizes may be marketed. 
 
Marketing Authorisation Holder 
SUBSTIPHARM, 24 rue Erlanger, 75016 Paris, France. 
 
Manufacturer 
- Lilly S.A., Avda. de la Industria 30, 28108 Alcobendas (Madrid), Spain. 
 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


28 

For any information about this medicine, please contact the local representative of the Marketing 
Authorisation Holder: 
 
België/Belgique/ Belgien 
SUBSTIPHARM 
Tél/Tel: +33 (0)1 43 18 13 00 

Lietuva 
SUBSTIPHARM 
Tel: +33 (0)1 43 18 13 00 

България 
SUBSTIPHARM 
Тел.: +33 (0)1 43 18 13 00 

Luxembourg/Luxemburg 
SUBSTIPHARM 
Tél/Tel: +33 (0)1 43 18 13 00 

Česká republika 
SUBSTIPHARM 
Tel: +33 (0)1 43 18 13 00 

Magyarország 
SUBSTIPHARM 
Tel: +33 (0)1 43 18 13 00 

Danmark 
SUBSTIPHARM 
Tlf: +33 (0)1 43 18 13 00 

Malta 
SUBSTIPHARM 
Tel: +33 (0)1 43 18 13 00 

Deutschland 
SUBSTIPHARM 
Tel: +33 (0)1 43 18 13 00 

Nederland 
SUBSTIPHARM 
Tel: +33 (0)1 43 18 13 00 

Eesti 
SUBSTIPHARM 
Tel: +33 (0)1 43 18 13 00 

Norge 
SUBSTIPHARM 
Tlf: +33 (0)1 43 18 13 00 

Ελλάδα 
Φαρμασερβ-Λιλλυ Α.Ε.Β.Ε.  
Τηλ: +30 210 629 4600  

Österreich 
SUBSTIPHARM 
Tel: +33 (0)1 43 18 13 00 

España 
SUBSTIPHARM 
Tel: +34 91 277 10 76 

Polska 
SUBSTIPHARM 
Tel: +33 (0)1 43 18 13 00 

France 
SUBSTIPHARM 
Tél: +33 (0)1 43 18 13 00 

Portugal 
SUBSTIPHARM 
Tel: +34 91 277 10 76 

Hrvatska 
SUBSTIPHARM 
Tel: +33 (0)1 43 18 13 00 

România 
SUBSTIPHARM 
Tel: +33 (0)1 43 18 13 00 

Ireland 
SUBSTIPHARM 
Tel: +33 (0)9 71 35 39 06 

Slovenija 
SUBSTIPHARM 
Tel: +33 (0)1 43 18 13 00 

Ísland 
SUBSTIPHARM 
Simi: +33 (0)1 43 18 13 00 

Slovenská republika 
SUBSTIPHARM 
Tel: +33 (0)1 43 18 13 00 

Italia 
SUBSTIPHARM 
Tel: +34 91 277 10 76 

Suomi/Finland 
SUBSTIPHARM 
Puh./Tel: +33 (0)1 43 18 13 00 

Κύπρος 
SUBSTIPHARM 
Τηλ: +33 (0)1 43 18 13 00 

Sverige 
SUBSTIPHARM 
Tel: +33 (0)1 43 18 13 00 

Latvija 
SUBSTIPHARM 
Tel.: +33 (0)1 43 18 13 00 

United Kingdom 
SUBSTIPHARM 
Tel: +33 (0)1 43 18 13 00 

 
This leaflet was last revised in month YYYY. 
 
Detailed information on this medicine is available on the European Medicines Agency (EMA) web 
site: http://www.ema.europa.eu 


	SUMMARY OF PRODUCT CHARACTERISTICS
	A. MANUFACTURER RESPONSIBLE FOR BATCH RELEASE
	B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE
	C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION
	A. LABELLING
	B. PACKAGE LEAFLET