ANNEX I
SUMMARY OF PRODUCT CHARACTERISTICS
EVISTA 60 mg film coated tablets
Each film coated tablet contains 60 mg raloxifene hydrochloride, equivalent
to 56 mg raloxifene free
base.
Excipient: each tablet contains lactose (149.40 mg).
For a full list of excipients, see section 6.1.
Film coated tablet.
Elliptically shaped, white tablets imprinted with the code ’4165’.
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).
The recommended dose is one tablet daily by oral administration, which may be taken at any time of
the day without regard to meals. No dose adjustment is necessary for the elderly. 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.
Use in renal impairment
:
EVISTA should not be used in patients with severe renal impairment (see section 4.3). In patients with
moderate and mild renal impairment, EVISTA should be used with caution.
Use in hepatic impairment
:
EVISTA should not be used in patients with hepatic impairment (see section 4.3).
Hypersensitivity to the active substance or to any of the excipients.
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.
2
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.
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 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 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. Until safety and efficacy have been evaluated further in patients with hepatic
insufficiency, the use of EVISTA 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.
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.
3
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.
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 C
max
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.
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.
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).
4
It is not known whether raloxifene is excreted in human milk. Its clinical use, therefore, cannot be
recommended in breast-feeding women. EVISTA may affect the development of the baby.
Raloxifene has no known influence on the ability to drive and use machines.
In osteoporosis treatment and prevention studies involving over 13,000 postmenopausal women all
adverse reactions were recorded. 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.
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.
The adverse reactions associated with the use of raloxifene in osteoporosis clinical trials are
summarised in the table below. The following convention has been used for the classification of the
adverse reactions: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to
<1/100), rare (≥1/10,000 to <1/1,000) very rare (<1/10,000), not known (cannot be estimated from the
available data).
Vascular disorders
Very common:
Vasodilation (hot flushes)
Uncommon:
Venous thromboembolic events, including deep vein thrombosis,
pulmonary embolism, retinal vein thrombosis
Superficial vein thrombophlebitis
Musculoskeletal and connective tissue disorders
Common:
Leg cramps
General disorders and administration site conditions
Very common:
Flu syndrome
Common:
Peripheral oedema
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 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
5
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.
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 no
t
statistically
sig
nificantly 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.
The adverse reactions reported in post-marketing experience and are presented in the table below.
Blood and lymphatic system disorders
Very rare:
thrombocytopenia
Gastrointestinal disorders
Very rare:
Gastrointestinal symptoms such as nausea, vomiting, abdominal pain, dyspepsia
General disorders and administration site conditions
Rare:
peripheral oedema
Investigations
Very rare:
Increased blood pressure
Nervous system disorders
Very rare:
Headache, including migraine
Skin and subcutaneous tissue disorders
Very rare:
Rash
Reproductive system and breast disorders
Very rare:
Mild breast symptoms such as pain, enlargement and tenderness
Vascular disorders
Rare
: venous thromboembolic reaction
Very rare:
arterial thromboembolic reaction
6
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.
5.1 Pharmacodynamic properties
Pharmaco-therapeutic group: Selective Oestrogen Receptor Modulator, ATC code: G03XC01.
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.
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
7
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 4
th
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 4
th
to the 8
th
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
.
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).
8
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
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 7705 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.
9
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 %).
Metabolism
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).
Excretion
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.
10
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.
6.1 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.
11
Not all pack sizes may be marketed in all countries.
6.6 Special precautions for disposal
No special requirements.
Daiichi Sankyo Europe GmbH
Zielstattstrasse 48
D-81379 Munich
Germany
8. MARKETING AUTHORISATION NUMBERS
EU/1/98/073/001
EU/1/98/073/002
EU/1/98/073/003
EU/1/98/073/004
Date of first authorisation:
5 August 1998
Date of last renewal:
8 August 2008
12
ANNEX II
A.
MANUFACTURING AUTHORISATION HOLDERS
RESPONSIBLE FOR BATCH RELEASE
B.
CONDITIONS OF THE MARKETING AUTHORISATION
13
A. MANUFACTURING AUTHORISATION HOLDERS RESPONSIBLE FOR BATCH
RELEASE
Name and address of the manufacturers responsible for batch release
Lilly SA
Avda de la Industria 30
28108 Alcobendas
Madrid
Spain
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 OF THE MARKETING AUTHORISATION
•
Medicinal product subject to medical prescription
•
CONDITIONS OR RESTRICTIONS WITH REGARDS TO THE SAFE AND
EFFECTIVE USE OF THE MEDICINAL PRODUCT
Not applicable.
•
OTHER CONDITIONS
The Marketing Authorisation Holder will provide the PSUR at 3-yearly intervals.
14
ANNEX III
LABELLING AND PACKAGE LEAFLET
15
A. LABELLING
16
PARTICULARS TO APPEAR ON THE OUTER PACKAGING AND THE IMMEDIATE
PACKAGING
BOTTLE LABEL, BOTTLE CARTON:
1.
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.
100 film coated tablets
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
For oral use
6.
SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF THE REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight 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.
17
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
Marketing Authorisation Holder:
Daiichi Sankyo Europe GmbH
Zielstattstrasse 48
D-81379 Munich
Germany
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
18
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
BLISTER BOX FILM COATED TABLETS:
1.
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.
14 film coated tablets
28 film coated tablets
84 film coated tablets
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
For oral use
6.
SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF THE REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight 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
Marketing Authorisation Holder:
Daiichi Sankyo Europe GmbH
Zielstattstrasse 48
D-81379 Munich
Germany
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
20
MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS
BLISTER (ALL BLISTER PACKS):
1.
EVISTA 60 mg film coated tablets
raloxifene hydrochloride
2.
Daiichi Sankyo Europe GmbH
3.
EXPIRY DATE
EXP {MM/YYYY}
4.
BATCH NUMBER
Lot {number}
5.
OTHER
21
B. PACKAGE LEAFLET
22
PACKAGE LEAFLET : INFORMATION FOR THE USER
EVISTA 60 mg film coated tablets
raloxifene hydrochloride
Read all of this leaflet carefully before you start taking your medicine.
•
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. Do not pass it on to others. It may harm them, even
if their symptoms are the same as yours.
•
If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet,
please tell your doctor or pharmacist.
In this leaflet:
1.
What EVISTA is and what it is used for
2.
Before you take EVISTA
3.
How to take EVISTA
4.
Possible side effects
5.
How to store EVISTA
6.
Further information
1.
WHAT EVISTA IS AND WHAT IT IS USED FOR
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.
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.
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.
BEFORE YOU TAKE EVISTA
Do not take EVISTA:
•
If you are allergic (hypersensitive) to raloxifene or any of the ingredients of EVISTA.
•
If there is still a possibility that you can get pregnant, EVISTA 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.
•
If you have active uterine cancer, as there is insufficient experience of EVISTA use in women
with this disease.
•
If you have severe kidney problems.
23
Take special care with EVISTA
The following are reasons why this product may not be suitable for you. If any of them apply to you,
talk to your doctor before you take the medicine.
•
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 EVISTA 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.
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.
Taking other medicines
Please tell your doctor or pharmacist if you are taking or have recently taken 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.
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 known effects on driving or using machines.
Important information about some ingredients of EVISTA
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.
3.
HOW TO TAKE EVISTA
Always take this product 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.
24
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 EVISTA. The doctor may also advise
you to take calcium and vitamin D supplements.
If you stop taking EVISTA
You should talk to your doctor first.
If you have the impression that the effect of this product is too strong or too weak, talk to your doctor
or pharmacist.
If you forget to take
EVISTA
Take a tablet as soon as you remember and then continue as before.
If you take more EVISTA than you should
Tell your doctor or pharmacist.
4.
POSSIBLE SIDE EFFECTS
Like all medicines, EVISTA 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
Common side effects (affects 1 to 10 users in 100) are:
•
Leg cramps
•
Swelling of hands, feet and legs (peripheral oedema)
•
Gallstones
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)
Very rare side effects (affects less than 1 user in 10,000) are:
•
Rash
•
Gastrointestinal symptoms such as nausea, vomiting, abdominal pain and stomach upset
•
Increased blood pressure
•
Decrease in the number of the platelets in the blood
•
Blood clot in an artery (for example stroke)
•
Headache including migraine
•
Mild breast symptoms such as pain, enlargement and tenderness
In rare cases, blood levels of liver enzymes may increase during treatment with EVISTA.
If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please
tell your doctor or pharmacist.
25
5.
HOW TO STORE EVISTA
Keep out of the reach and sight of children.
Do not use after the expiry date which is stated on the pack.
Store in the original package. Do not freeze.
Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to
dispose of medicines no longer required. These measures will help to protect the environment.
6.
FURTHER 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 of EVISTA tablets 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
Daiichi Sankyo Europe GmbH, Zielstattstrasse 48, D-81379 Munich, Germany.
Manufacturer
- Lilly S.A., Avda. de la Industria 30, 28108 Alcobendas (Madrid), Spain.
26
For any information about this medicinal product, please contact the representative in your country:
Belgique/België/Belgien
Daiichi Sankyo Belgium N.V.-S.A
Tél/Tel: +32-(0) 10 48 95 95
Luxembourg/Luxemburg
Daiichi Sankyo Belgium N.V.-S.A
Tél/Tel: +32-(0) 10 48 95 95
България
Аришоп Фарма ЕАД
Тел.: +359 882 882 977
Magyarország
Goodwill Pharma Kft.
Tel: +36 62 443 571
Česká republika
Meda Pharma s.r.o.
Tel: +420 234 064 201
Malta
Charles de Giorgio Ltd.
Tel: +356 25600 500
Danmark
Meda AS
Tlf: +45 44 52 88 88
Nederland
Daiichi Sankyo Nederland B.V.
Tel: +31-(0) 20 4 07 20 72
Deutschland
Daiichi Sankyo Deutschland GmbH
Tel. +49-(0) 89 7808 0
Norge
Meda A/S
Tlf: +47 66 75 33 00
Eesti
Meda Pharma SIA
Tel: +372 6261 025
Österreich
Daiichi Sankyo Austria GmbH
Tel: +43-(0) 1 485 86 42 0
Ελλάδα
Φαρμασερβ-Λιλλυ Α.Ε.Β.Ε.
Τηλ: +30 210 629 4600
Polska
Meda Pharmaceuticals Sp. z o.o.
Tel.: +48 22 697 71 00
España
Daiichi Sankyo España, S.A.
Tel: +34 91 539 99 11
Portugal
Daiichi Sankyo Portugal, Lda.
Tel: +351 21 4232010
France
Daiichi Sankyo France S.A.S.
Tél: +33-(0) 1 55 62 14 60
România
Terapia SA
Tel: +40-(0) 26 45 01 502
Ireland
Daiichi Sankyo Ireland Ltd
Tel: +353-(0) 1 489 3000
Slovenija
Medis, d.o.o.
Tel: +386 1 589 69 00
Ísland
Meda AB, Svíþjóð
Simi: +46-(0) 8 630 19 00
Slovenská republika
Meda Pharma Slovakia s.r.o.
Tel: +421 2 4914 0172
Italia
Daiichi Sankyo Italia S.p.A.
Tel: +39-06 85 2551
Suomi/Finland
Meda Oy
Puh./Tel: +358 20 720 9550
Κύπρος
Phadisco Ltd.
Τηλ: +357 22 715000
Sverige
Meda AB
Tel: +46-(0) 8 630 19 00
Latvija
Meda Pharma SIA
Tel: +371 67 805 140
United Kingdom
Daiichi Sankyo UK Ltd
Tel: +44-(0) 1753 893 600
Lietuva
Meda Pharma SIA
Tel. +370 37 330 509
This leaflet was last approved in:
Detailed information on this medicine is available on the European Medicines Agency (EMEA) web
27
Source: European Medicines Agency
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