ANNEX I
SUMMARY OF PRODUCT CHARACTERISTICS
1.
Raloxifene Teva 60 mg film-coated tablets
2.
Each film-coated tablet contains 60 mg raloxifene hydrochloride, equivalent to 56 mg raloxifene free
base.
For a full list of excipients, see section 6.1.
3.
Film-coated tablet.
White to off-white, film coated, oval shaped tablets, debossed with the number “60” on one side and
“N” on the other side of the tablet.
4.
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).
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, raloxifene 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:
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.
Use in hepatic impairment:
Raloxifene 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.
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.
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.
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.
3
Raloxifene is not effective in reducing vasodilatation (hot flushes), or other symptoms of the
menopause associated with oestrogen deficiency.
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 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
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.
Raloxifene is only for use in postmenopausal women.
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).
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
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 has not usually required cessation of therapy.
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 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).
Very common
Common
Uncommon
Venous
thromboembolic events,
including deep vein
thrombosis, pulmonary
embolism, retinal vein
thrombosis, superficial
vein thrombophlebitis
Vascular disorders
Vasodilation (hot
flushes)
Musculoskeletal and
connective tissue
disorders
Leg cramps
General disorders and
administration site
conditions
Flu syndrome
Peripheral oedema
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.
5
Another adverse reaction observed was leg cramps (5.5 % for raloxifene, 1.9 % for placebo in the
prevention population and 9.2 % for raloxifene, 6.0 % for placebo in the treatment population). In the
RUTH study, leg cramps were observed in 12.1 % of raloxifene-treated patients and 8.3 % of
placebo-treated patients.
Flu syndrome was reported by 16.2 % of raloxifene treated patients and 14.0 % of placebo treated
patients.
One further change was seen which was not statistically significant (p > 0.05), but which did show a
significant dose trend. This was peripheral oedema, which occurred in the prevention population at an
incidence of 3.1 % for raloxifene and 1.9 % for placebo; and in the treatment population occurred at an
incidence of 7.1 % for raloxifene and 6.1 % for placebo.
In the RUTH study, peripheral oedema occurred in 14.1 % of the raloxifene-treated patients and
11.7 % of the placebo-treated patients, which was statistically significant. Slightly decreased (6-10 %)
platelet counts have been reported during raloxifene treatment in placebo-controlled clinical trials of
raloxifene in osteoporosis.
Rare cases of moderate increases in AST and/or ALT have been reported where a causal relationship
to raloxifene 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.
The adverse reactions reported in post-marketing experience are presented in the table below.
Rare
Very rare
Investigations
Increased blood pressure
Blood and lymphatic system
disorders
Thrombocytopenia
Nervous system disorders
Headache, including migraine
Gastrointestinal disorders
Gastrointestinal symptoms such
as nausea, vomiting, abdominal
pain, dyspepsia
Skin and subcutaneous tissue
disorders
Rash
Vascular disorders
Venous thromboembolic
reaction
Arterial thromboembolic
reaction
General disorders and
administration site conditions
Peripheral oedema
Reproductive system and breast
disorders
Mild breast symptoms such as
pain, enlargement and
tenderness
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.
6
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.
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, 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 4
th
year alone, raloxifene
7
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. 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.
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.
8
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.
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 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.
9
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.
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
10
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.
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
6.4
Special precautions for storage
This medicinal product does not require any special storage conditions.
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.
Teva Pharma B.V.
Computerweg 10
3542 DR Utrecht
The Netherlands
11
8.
9.
Detailed information on this medicinal product is available on the website of the European Medicines
Agency http://www.ema.europa.eu
12
ANNEX II
A.
MANUFACTURING AUTHORISATION HOLDER(S)
RESPONSIBLE FOR BATCH RELEASE
B.
CONDITIONS OF THE MARKETING AUTHORISATION
13
A. MANUFACTURING AUTHORISATION HOLDER(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
TEVA Pharmaceutical Works Private Limited Company
2100 Gödöllő, Táncsics, Milály út 82
Hungary
Teva UK Ltd, Brampton Road
Hampden Park, Eastbourne
East Sussex, BN22 9AG
UK
Pharmachemie B.V.
Swensweg 5, 2031 GA, Haarlem
The Netherlands
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 REGARD TO THE SAFE AND
EFFECTIVE USE OF THE MEDICINAL PRODUCT
Not applicable
•
OTHER CONDITIONS
Pharmacovigilance system
The MAH must ensure that the system of pharmacovigilance, as described in version 7.0 dated May
2009 presented in Module 1.8.1. of the Marketing Authorisation Application, is in place and
functioning before and whilst the product is on the market.
PSURs
The PSUR submission schedule should follow the PSUR submission schedule for the reference
medicinal product.
14
ANNEX III
LABELLING AND PACKAGE LEAFLET
15
A. LABELLING
16
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
Carton
1.
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.
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 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
9.
SPECIAL STORAGE CONDITIONS
17
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
Teva Pharma B.V.
Computerweg 10
3542 DR Utrecht
The Netherlands
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
18
MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS
1.
Raloxifene Teva 60 mg film-coated tablets
raloxifene hydrochloride
2.
Teva Pharma B.V.
3.
EXPIRY DATE
EXP
4.
BATCH NUMBER
Lot
5.
OTHER
19
B. PACKAGE LEAFLET
20
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.
-
Keep this leaflet. You may need to read it again.
-
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 Raloxifene Teva is and what it is used for
2. Before you take Raloxifene Teva
3. How to take Raloxifene Teva
4. Possible side effects
5.
How to store Raloxifene Teva
6.
Further information
1.
WHAT RALOXIFENE TEVA IS AND WHAT IT IS USED FOR
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.
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.
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 RALOXIFENE TEVA
Do not take Raloxifene Teva
-
If you are allergic (hypersensitive) to raloxifene or any of the ingredients of Raloxifene Teva.
-
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.
-
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.
Take special care with Raloxifene Teva
The following are reasons why this medicine may not be suitable for you. If any of them apply to you,
talk to your doctor before you take this medicine:
21
-
If you have any further questions, ask your doctor or pharmacist.
-
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.
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
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.
Ask your doctor or pharmacist for advice before taking any medicines.
Driving and using machines
Raloxifene Teva has no known effects on driving or using machines.
3.
HOW TO TAKE RALOXIFENE TEVA
Always take Raloxifene Teva 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 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.
22
If you take more Raloxifene Teva than you should
Tell your doctor or pharmacist.
If you forget to take Raloxifene Teva
Take a tablet as soon as you remember and then continue as before.
If you stop taking Raloxifene Teva
You should talk to your doctor first.
If you have the impression that the effect of this medicine is too strong or too weak, talk to your doctor
or pharmacist.
4.
POSSIBLE SIDE EFFECTS
Like all medicines, Raloxifene Teva can cause side effects, although not everybody gets them. The
majority of side effects seen with Raloxifene Teva have been mild.
The frequency of possible side effects listed below is defined using the following convention:
very common (affects more than 1 user in 10), common (affects 1 to 10 users in 100), uncommon
(affects 1 to 10 users in 1,000), rare (affects 1 to 10 users in 10,000), very rare (affects less than 1 user
in 10,000) and not known (frequency cannot be estimated from the available data).
Very common (affects more than 1 user in 10)
•
Hot flushes (vasodilatation).
•
Flu syndrome.
Common (affects 1 to 10 users in 100)
•
Leg cramps.
•
Swelling of hands, feet and legs (peripheral oedema).
Gallstones.
•
Uncommon (affects 1 to 10 users in 1,000)
•
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).
Rare (affects 1 to 10 users in 10,000)
•
Blood clot, usually in a leg, which causes pain, swelling or redness (venous thromboembolic
reaction).
Very rare (affects less than 1 user in 10,000)
•
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 Raloxifene Teva.
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.
23
•
Swelling of hands, feet and legs (peripheral oedema).
5.
HOW TO STORE RALOXIFENE TEVA
Keep out of the reach and sight of children.
Do not use Raloxifene Teva after the expiry date which is stated on the outer carton or foil. The expiry
date refers to the last day of that month.
This medicine does not require any special storage conditions.
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 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 debossed 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 Pharma B.V.
Computerweg 10
3542 DR Utrecht
The Netherlands
Manufacturers:
Teva Pharmaceutical Works Private Limited Company
Pallagi út 13
Debrecen H-4042
Hungary
TEVA Pharmaceutical Works Private Limited Company
H-2100 Gödöllö
Táncsics Mihály út 82
Hungary
TEVA UK Ltd
Brampton Road
Hampden Park
24
Eastbourne, East Sussex
BN22 9AG UK
Pharmachemie B.V.
Swensweg 5
2031 GA Haarlem
The Netherlands
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.
Tel/Tél: +32 3 820 73 73
Luxembourg/Luxemburg
Teva Pharma Belgium S.A.
Tél/Tel: +32 3 820 73 73
България
Тева Фармасютикълс България ЕООД
Teл: +359 2 489 95 82
Magyarország
Teva Magyarország Zrt
Tel.: +36 1 288 64 00
Česká republika
Teva Pharmaceuticals CR, s.r.o.
Tel: +420 251 007 111
Malta
Teva Ελλάς Α.Ε.
Τel: +30 210 72 79 099
Danmark
Teva Denmark A/S
Tlf: +45 44 98 55 11
Nederland
Teva Nederland B.V.
Tel: +31 (0) 800 0228400
Deutschland
Teva Generics GmbH
Tel: (49) 351 834 0
Norge
Teva Sweden AB
Tlf: (46) 42 12 11 00
Eesti
Teva Eesti esindus UAB Sicor Biotech
Eesti filiaal
Tel: +372 611 2409
Österreich
Teva Generics GmbH
Tel: (49) 351 834 0
Ελλάδα
Teva Ελλάς Α.Ε.
Τηλ: +30 210 72 79 099
Polska
Teva Pharmaceuticals Polska Sp. z o.o.
Tel.: +(48) 22 345 93 00
España
Teva Genéricos Española, S.L.U
Tél: +(34) 91 387 32 80
Portugal
Teva Pharma - Produtos Farmacêuticos Lda
Tel: (351) 214 235 910
France
Teva Santé
Tél: +(33) 1 55 91 7800
România
Teva Pharmaceuticals S.R.L
Tel: +4021 230 65 24
Ireland
Teva Pharmaceuticals Ireland
Tel: +353 (0)42 9395 892
Slovenija
Pliva Ljubljana d.o.o.
Tel: +386 1 58 90 390
Ísland
Teva UK Limited
Sími: +(44) 1323 501 111.
Slovenská republika
Teva Pharmaceuticals Slovakia s.r.o.
Tel: +(421) 2 5726 7911
25
Italia
Teva Italia S.r.l.
Tel: +(39) 0289179805
Suomi/Finland
Teva Sweden AB
Puh/Tel: +(46) 42 12 11 00
Κύπρος
Teva Ελλάς Α.Ε.
Τηλ: +30 210 72 79 099
Sverige
Teva Sweden AB
Tel: +(46) 42 12 11 00
Latvija
UAB Sicor Biotech filiāle Latvijā
Tel: +371 67 784 980
United Kingdom
Teva UK Limited
Tel: +(44) 1323 501 111
Lietuva
UAB “Sicor Biotech”
Tel: +370 5 266 02 03
This leaflet was last approved in
Detailed information on this medicine is available on the European Medicines Agency web site:
http://www.ema.europa.eu/
26
Source: European Medicines Agency
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