Raloxifene Teva

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ANNEX I 
 

SUMMARY OF PRODUCT CHARACTERISTICS 
 



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1. NAME OF THE MEDICINAL PRODUCT 
 
Raloxifene Teva 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. 
 
For the full list of excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Film-coated tablet. 
 
White to off-white, film coated, oval shaped tablets, embossed with the number “60” on one side and 
“N” on the other side of the tablet. 
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
Raloxifene 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 raloxifene 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.Due to the nature of this disease process, raloxifene is 
intended for long term use.   
 
Generally calcium and vitamin D supplements are advised in women with a low dietary intake. 
 
Elderly: 
No dose adjustment is necessary for the elderly. 
 
Patients with renal impairment: 
Raloxifene should not be used in patients with severe renal impairment (see section 4.3). In patients 
with moderate and mild renal impairment, raloxifene should be used with caution. 
 
Patients with hepatic impairment: 
Raloxifene should not be used in patients with hepatic impairment (see section 4.3 and 4.4). 
 
Paediatric population: 
Raloxifene should not be used in children of any age. There is no relevant use of Raloxifene in the 
paediatric population. 
 
Method of administration 
Oral administration.  
The tablet can be taken at any time of the day without regard to meals.  



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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. 
 
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. 
 
Raloxifene 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. Raloxifene 
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 1.5 per 1000 women per year for placebo versus 2.2 per 
1000 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 ischemic attack or atrial fibrillation. 
 
There is no evidence of endometrial proliferation. Any uterine bleeding during raloxifene 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. Until safety and efficacy have been evaluated further in patients with hepatic 
insufficiency, the use of raloxifene is not recommended in this patient population. 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 
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. 



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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, raloxifene 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. 
 
Raloxifene is not effective in reducing vasodilatation (hot flushes), or other symptoms of the 
menopause associated with oestrogen deficiency. 
 
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 Fertility, pregnancy and lactation 
 
Pregnancy 
Raloxifene is only for use in postmenopausal women. 



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Raloxifene must not be taken by women of child bearing potential. Raloxifene may cause foetal harm 
when administered to a pregnant woman. If this medicinal product is used mistakenly during 
pregnancy or the patient becomes pregnant while taking it, the patient should be informed of the 
potential hazard to the foetus (see section 5.3). 
 
Breast-feeding 
It is not known whether raloxifene is excreted in human milk. Its clinical use, therefore, cannot be 
recommended in breast-feeding women. Raloxifene 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 
Raloxifen 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 the 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 event occurred in 12.8 % of 2,557 
raloxifene treated patients and 11.1 % of 2,576 placebo treated patients. 
 
The following convention has been used for the classification of the adverse reactions: very common 
(≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to 
< 1/1,000) very rare (< 1/10,000), not known (cannot be estimated from the available data). 
 

Blood and lymphatic system disorders 
Uncommon: Thrombocytopeniaa 
Nervous system disorders 
Common: Headache, including migrainea 
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 reactionsa 
Gastrointestinal disorders 
Very common: Gastrointestinal symptomsa such as nausea, vomiting, abdominal pain, dyspepsia 
Skin and subcutaneous tissue disorders 
Common: Rasha 
Musculoskeletal and connective tissue disorders 



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Common: Leg cramps 
Reproductive system and breast disorders 
Common: Mild breast symptomsa such as pain, enlargement and tenderness 
General disorders and administration site conditions 
Very common: Flu syndrome 
Common: Peripheral oedema 
Investigations 
Very common: Increased blood pressurea 

aTerm(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 1000 patient-years in the raloxifene group and 1.4 % or 2.70 cases per 1000 
patient-years in the placebo group. The hazard ratio for all VTE events in the RUTH study was 
HR = 1.44, (1.06-1.95). Superficial vein thrombophlebitis occurred in a frequency of 1 % in the 
raloxifene group and 0.6 % in the placebo group. 
 
In the RUTH study, raloxifene did not affect the incidence of stroke, compared to placebo. However, 
there was an increase in death due to stroke in women assigned to raloxifene. The incidence of stroke 
mortality was 2.2 per 1,000 women per year for raloxifene versus 1.5 per 1,000 women per year for 
placebo (see section 4.4). During an average follow-up of 5.6 years, 59 (1.2%) raloxifene-treated 
women died due to a stroke compared to 39 (0.8%) placebo-treated women. 
 
Another adverse reaction observed was leg cramps (5.5 % for raloxifene, 1.9 % for placebo in the 
prevention population and 9.2 % for raloxifene, 6.0 % for placebo in the treatment population). In the 
RUTH study, leg cramps were observed in 12.1 % of raloxifene-treated patients and 8.3 % of 
placebo-treated patients. 
 
Flu syndrome was reported by 16.2 % of raloxifene treated patients and 14.0 % of placebo treated 
patients. 
 
One further change was seen which was not statistically significant (p > 0.05), but which did show a 
significant dose trend. This was peripheral oedema, which occurred in the prevention population at an 
incidence of 3.1 % for raloxifene and 1.9 % for placebo; and in the treatment population occurred at an 
incidence of 7.1 % for raloxifene and 6.1 % for placebo. 
 
In the RUTH study, peripheral 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. 
 



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Rare cases of moderate increases in AST and/or ALT have been reported where a causal relationship 
to raloxifene can not be excluded. A similar frequency of increases was noted among placebo patients.  
 
In a study (RUTH) of postmenopausal women with documented coronary heart disease or at increased 
risk for coronary events, an additional adverse reaction of cholelithiasis occurred in 3.3 % of patients 
treated with raloxifene and 2.6 % of patients treated with placebo. Cholecystectomy rates for 
raloxifene (2.3 %) were not statistically significantly different from placebo (2.0 %). 
 
Raloxifene (n = 317) was compared with continuous combined (n = 110) hormone replacement 
therapy (HRT) or cyclic (n = 205) HRT patients in some clinical trials. The incidence of breast 
symptoms and uterine bleeding in raloxifene treated women was significantly lower than in women 
treated with either form of HRT. 
 
 
 
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. 
 
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 
 
Pharmaco-therapeutic 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. Recent data suggests that the oestrogen 
receptor can regulate gene expression by at least two distinct pathways which are ligand-, tissue-, 
and/or gene-specific. 



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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 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 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 60 mg per day, due primarily to decreased urinary calcium losses. 
 



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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 60 mg daily dose of raloxifene significantly decreased total cholesterol (3 
to 6 %), and LDL cholesterol (4 to 10 %). Women with the highest baseline cholesterol levels had the 
greatest decreases. HDL cholesterol and triglyceride concentrations did not change significantly. After 
3 years therapy raloxifene decreased fibrinogen (6.71 %). In the osteoporosis treatment study, 
significantly fewer raloxifene-treated patients required initiation of hypolipidaemic therapy compared 
to placebo. 
 
Raloxifene therapy for 8 years did not significantly affect the risk of cardiovascular events in patients 
enrolled in the osteoporosis treatment study. Similarly, in the RUTH study, raloxifene did not affect 
the incidence of myocardial infarction, hospitalized acute coronary syndrome, stroke or overall 
mortality, including overall cardiovascular mortality, compared to placebo (for the increase in risk of 
fatal stroke see section 4.4). 
 
The relative risk of venous thromboembolic events observed during raloxifene treatment was 1.60 
(CI 0.95, 2.71) when compared to placebo, and was 1.0 (CI 0.3, 6.2) when compared to 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 5 mm increase in endometrial 
thickness, assessed with transvaginal ultrasound, was observed in 1.9 % of the 211 women treated 
with raloxifene 60 mg/day compared to 1.8 % of the 219 women who received placebo. There were no 
differences between the raloxifene and placebo groups with respect to the incidence of reported uterine 
bleeding. 
 
Endometrial biopsies taken after six months therapy with raloxifene 60 mg daily demonstrated 
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. 



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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 7705 patients), raloxifene treatment 
compared to placebo reduced the risk of total breast cancer by 62 % (RR 0.38; CI 0.21, 0.69), the risk 
of invasive breast cancer by 71 % (RR 0.29, CI 0.13, 0.58) and the risk of invasive 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 exten 
sive. 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. 



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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). 
 
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: 
Pregelatinized starch (maize) 
Magnesium stearate 
Povidone (K30) 
Colloidal anhydrous silica 
Microcrystalline cellulose, silicified  
 
Tablet coating: 
Polydextrose (E1200) 
Titanium dioxide (E171) 
Hypromellose (E464) 
Macrogol 4000 
 
6.2 Incompatibilities 
 
Not applicable 
 
6.3 Shelf life 
 
2 years  
 



12 

6.4 Special precautions for storage 
 
Do not store above 25°C.  Store in the original package to protect from moisture.  
 
6.5 Nature and contents of container 
 
Transparent PVC/PVdC - Aluminium blisters.  Pack sizes of 14, 28 and 84 tablets.   
 
Not all pack sizes may be marketed. 
 
6.6 Special precautions for disposal  
 
No special requirements.   
 
 
7. MARKETING AUTHORISATION HOLDER 
 
 
Teva B.V. 
Swensweg 5 
2031GA Haarlem 
The Netherlands 
 
 
 
8. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/10/627/001-003 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation: 29 April 2010 
Date of first renewal: 06 February 2015 
 
10. DATE OF REVISION OF THE TEXT 
 
 
Detailed information on this medicinal product is available on the website of the European Medicines 
Agency http://www.ema.europa.eu  
 
 
 

 
 
 
 
 
 
 
 
 
 
 
 
 
 



13 

 
 
 
 
 

ANNEX II 
 

A. MANUFACTURER(S) RESPONSIBLE FOR BATCH 
RELEASE 

 
B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY 

AND USE 
 
C. OTHER CONDITIONS AND REQUIREMENTS OF THE 

MARKETING AUTHORISATION 
 
D. CONDITIONS OR RESTRICTIONS WITH REGARD TO 

THE SAFE AND EFFECTIVE USE OF THE MEDICINAL 
PRODUCT 

 
 



14 

A. MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE 
 
Name and address of the manufacturer(s) responsible for batch release 
 
TEVA Pharmaceutical Works Private Limited Company 
Pallagi ùt 13, 4042 Debrecen 
Hungary 
 
Pharmachemie B.V. 
Swensweg 5, 2031 GA, Haarlem 
The Netherlands 
 
Merckle GmbH  
Ludwig-Merckle-Straße 3 
89143 Blaubeuren 
Germany 
 
The printed package leaflet of the medicinal product must state the name and address of the manufacturer 
responsible for the release of the concerned batch. 
 
 
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 PSUR submission schedule for Raloxifene Teva should follow PSUR submission schedule for the 
reference medicinal product. 
 
D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 

EFFECTIVE USE OF THE MEDICINAL PRODUCT  
 

• Risk Management Plan (RMP)  
 
Not applicable 
 
 
  



15 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX III 
 

LABELLING AND PACKAGE LEAFLET 
  



16 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

A. LABELLING 
  



17 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
CARTON 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Raloxifene Teva 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 free 
base.   
 
 
3. LIST OF EXCIPIENTS 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Film-coated tablet 
 
14 film-coated tablets 
28 film-coated tablets 
84 film-coated tablets 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Swallow tablets whole.   
Read the package leaflet before use. 
Oral 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  
 
 
9. SPECIAL STORAGE CONDITIONS 
 
Do not store above 25°C.  Store in the original package to protect from moisture. 
 
 



18 

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 
 
Teva B.V. 
Swensweg 5 
2031GA Haarlem 
The Netherlands 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/10/627/001 14 film coated tablets 
EU/1/10/627/002 28 film coated tablets 
EU/1/10/627/003 84 film coated tablets 
 
 
13. BATCH NUMBER 
 
Lot  
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
Medicinal product subject to medical prescription 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Raloxifene Teva 60 mg  
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
18. UNIQUE IDENTIFIER – HUMAN READABLE DATA 
 
PC: 
SN: 
NN: 
 
  



19 

MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 
 
 

 
 

1. NAME OF THE MEDICINAL PRODUCT 
 
Raloxifene Teva 60 mg film-coated tablets 
raloxifene hydrochloride 
 
 

2. NAME OF THE MARKETING AUTHORISATION HOLDER 
 
Teva B.V. 
 
 

3. EXPIRY DATE 
 
EXP 
 
 

4. BATCH NUMBER 
 
Lot 
 
 

5. OTHER 
 
 
  



20 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

B. PACKAGE LEAFLET 
 



21 

Package leaflet: Information for the user 
 

Raloxifene Teva 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 Raloxifene Teva is and what it is used for 
2. What you need to know before you take Raloxifene Teva 
3. How to take Raloxifene Teva 
4. Possible side effects 
5. How to store Raloxifene Teva 
6. Contents of the pack and other information 
 
 
1. What Raloxifene Teva is and what it is used for 
 
 
Raloxifene Teva is used to treat and prevent osteoporosis in postmenopausal women. Raloxifene Teva 
reduces the risk of vertebral fractures in women with postmenopausal osteoporosis. A reduction in the 
risk of hip fractures has not been shown.   
 
How Raloxifene Teva works 
 
Raloxifene Teva 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. Raloxifene Teva 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 Raloxifene Teva 
 
Do not take Raloxifene Teva 
- If you are allergic 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, Raloxifene Teva could harm your unborn 

child.    
- If you are being treated or have been treated for blood clots (deep vein thrombosis, pulmonary 

embolism or retinal vein thrombosis).   
- If you have liver disease (examples of liver disease include cirrhosis, mild hepatic impairment 

or cholestatic jaundice). 
- If you have any unexplained vaginal bleeding. This must be investigated by your doctor. 



22 

- If you have active uterine cancer, as there is insufficient experience of Raloxifene Teva use in 
women with this disease. 

- If you have severe kidney problems.   
 
Warnings and precautions  
 
Talk to your doctor or pharmacist before taking Raloxifene Teva: 
 
- 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. 

- If you are receiving oral oestrogen therapy. 
- If you are suffering from breast cancer, as there is insufficient experience of Raloxifene Teva 

use in women with this disease. 
- 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 problems, as there is insufficient experience in people with liver problems. If 

you do have liver problems and your doctor still recommends treatment, then you may need 
some blood tests during treatment. 

 
It is unlikely that Raloxifene Teva will cause vaginal bleeding. So any vaginal bleeding while you take 
Raloxifene Teva is unexpected. You should have this investigated by your doctor. 
 
Raloxifene Teva does not treat postmenopausal symptoms, such as hot flushes.   
 
Raloxifene Teva 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 Raloxifene Teva. 
 
Other medicines and Raloxifene Teva 
 
Tell your doctor or pharmacist if you are taking, have recently taken or might take any other 
medicines. 
 
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. 
 
Pregnancy and breast-feeding 
Raloxifene Teva is for use only by postmenopausal women and must not be taken by women who 
could still have a baby. Raloxifene Teva could harm your unborn child. 
 
Do not take Raloxifene Teva if you are breast-feeding as it might be excreted in mother's milk. 
 
If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask 
your doctor or pharmacist for advice before taking this medicines. 
 
Driving and using machines 
Raloxifene Teva has no or negligible effects on driving or using machines.   
 
3. How to take Raloxifene Teva 
 
Always take this medicine exactly as your doctor has told you. Check with your doctor or pharmacist 
if you are not sure. 
 



23 

The recommended dose is one tablet a day. It does not matter at what time of the 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. 
 
Your doctor will tell you how long you should continue to take Raloxifene Teva. The doctor may also 
advise you to take calcium and vitamin D supplements. 
 
If you take more Raloxifene Teva than you should 
Tell your doctor or pharmacist.  If you take more Raloxifene Teva than you should you could have leg 
cramps and dizziness. 
 
If you forget to take Raloxifene Teva 
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 dose. 
  
If you stop taking Raloxifene Teva 
You should talk to your doctor first. 
It is important that you continue taking Raloxifene Teva for as long as your doctor prescribes the 
medicine. 
Raloxifene Teva 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 Raloxifene Teva have been mild.   
 
 
Very common (may affect more than 1 in 10 people) 
• Hot flushes (vasodilatation). 
• Flu syndrome. 
• Gastrointestinal symptoms such as nausea, vomiting, abdominal pain and stomach upset 
• Increased blood pressure 
 
Common (may affect up to 1 in 10 people) 
• Headache including migraine 
• Leg cramps. 
• Swelling of hands, feet and legs (peripheral oedema). 
• Gallstones.   
• Rash 
• Mild breast symptoms such as pain, enlargement and tenderness 
 
Uncommon (may affect up to 1 in 100 people) 
• 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 Raloxifene Teva. 



24 

 
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 Raloxifene Teva 
 
Keep this medicine out of the sight and reach of children. 
 
Do not use this medicine after the expiry date which is stated on the outer carton or foil after EXP. The 
expiry date refers to the last day of that month. 
 
Do not store above 25°C.  Store in the original package to protect from moisture. 
 
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 to protect the environment. 
 
 
6. Contents of the pack and other information 
 
What Raloxifene Teva contains 
 
- The active substance is raloxifene hydrochloride. Each film-coated tablet contains 60 mg 

raloxifene hydrochloride, equivalent to 56 mg raloxifene. 
- The other ingredients are: 

Tablet core: pregelatinized starch (maize), magnesium stearate, povidone (K30), colloidal 
anhydrous silica and microcrystalline cellulose, silicified.   
Tablet coating: polydextrose (E1200), titanium dioxide (E171), hypromellose (E464) and 
macrogol 4000.   

 
What Raloxifene Teva looks like and contents of the pack 
 
The film-coated tablets are white to off-white, oval shaped and embossed with the number “60” on one 
side and “N” on the other side. 
 
Raloxifene Teva 60 mg is available in pack sizes of 14, 28 and 84 film-coated tablets.  
 
Not all pack sizes may be marketed. 
 
Marketing Authorisation Holder and Manufacturer 
 
Marketing Authorisation Holder: 
Teva B.V. 
Swensweg 5 
2031GA Haarlem 
The Netherlands 
 
Manufacturers: 
Teva Pharmaceutical Works Private Limited Company 
Pallagi út 13 
Debrecen H-4042 
Hungary 
 
Pharmachemie B.V. 



25 

Swensweg 5 
2031 GA Haarlem 
The Netherlands 
 
Merckle GmbH  
Ludwig-Merckle-Straße 3 
89143 Blaubeuren 
Germany 
 
For any information about this medicine, please contact the local representative of the Marketing 
Authorisation Holder 
 

België/Belgique/Belgien  
Teva Pharma Belgium N.V./S.A./AG  
Tél/Tel: +32 38207373  
 

Lietuva 
UAB Teva Baltics 
Tel: +370 52660203 

България  
Тева Фарма ЕАД 
Тел: +359 24899585 
  

Luxembourg/Luxemburg  
Teva Pharma Belgium N.V./S.A./AG 
Belgique/Belgien 
Tél/Tel: +32 38207373 
  

Česká republika  
Teva Pharmaceuticals CR, s.r.o.  
Tel: +420 251007111  

Magyarország  
Teva Gyógyszergyár Zrt.  
Tel: +36 12886400  
 

Danmark  
Teva Denmark A/S  
Tlf: +45 44985511  

Malta  
Teva Pharmaceuticals Ireland 
L-Irlanda 
Tel: +353 19127700 
 

Deutschland 
TEVA GmbH 
Tel: +49 73140208 
 

Nederland  
Teva Nederland B.V. 
Tel: +31 8000228400  
 

Eesti 
UAB Teva Baltics Eesti filiaal 
Tel: +372 6610801 
 

Norge 
Teva Norway AS 
Tlf: +47 66775590  

Ελλάδα 
Specifar A.B.E.E. 
Τηλ: +30 2118805000 
 

Österreich 
ratiopharm Arzneimittel Vertriebs-GmbH 
Tel: +43 1970070 
 

España 
Teva Pharma, S.L.U. 
Tel: +34 913873280   
 

Polska 
Teva Pharmaceuticals Polska Sp. z o.o. 
Tel: +48 223459300 

France 
Teva Santé 
Tél: +33 155917800 

Portugal 
Teva Pharma - Produtos Farmacêuticos, 
Lda. 
Tel: +351 214767550 
 

Hrvatska 
Pliva Hrvatska d.o.o. 
Tel: +385 13720000 
 

România 
Teva Pharmaceuticals S.R.L. 
Tel: +40 212306524 
 



26 

Ireland 
Teva Pharmaceuticals Ireland 
Tel: +353 19127700 

Slovenija 
Pliva Ljubljana d.o.o. 
Tel: +386 15890390 
 

Ísland 
Teva Finland Oy 
Finnland 
Sími: +358 201805900 
 

Slovenská republika 
TEVA Pharmaceuticals Slovakia s.r.o. 
Tel: +421 257267911 
 

Italia 
Teva Italia S.r.l. 
Tel: +39 028917981 

Suomi/Finland 
Teva Finland Oy 
Puh/Tel: +358 201805900 
 

Κύπρος 
Specifar A.B.E.E. 
Ελλάδα 
Τηλ: +30 2118805000 
 

Sverige 
Teva Sweden AB 
Tel: +46 42121100 
 

Latvija 
UAB Teva Baltics filiāle Latvijā 
Tel: +371 67323666 

United Kingdom 
Teva UK Limited 
Tel: +44 1977628500 

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


	SUMMARY OF PRODUCT CHARACTERISTICS
	A. MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE
	B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE
	C.  OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION
	D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT 
	A. LABELLING
	B. PACKAGE LEAFLET