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EVIREX 60MG FILM COATED TABLETS
Active substance(s): RALOXIFENE HYDROCHLORIDE
NAME OF THE MEDICINAL PRODUCT
Evirex 60 mg film coated tablets
QUALITATIVE AND QUANTITATIVE COMPOSITION
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.
Film coated tablet.
White to off-white, oval biconvex film-coated tablets with 'C' on one side and '12' on
Evirex 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 Evirex 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).
Posology and method of administration
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, Evirex is intended for long term
Generally calcium and vitamin D supplements are advised in women with a low
Evirex should not be used in children of any age. There is no relevant use of
Evirex in the paediatric population.
No dose adjustment is necessary for the elderly
Use in renal impairment:
Evirex should not be used in patients with severe renal impairment (see section 4.3).
In patients with moderate and mild renal impairment, Evirex should be used with
Use in hepatic impairment:
Evirex should not be used in patients with hepatic impairment (see section 4.3 and
Hypersensitivity to the active substance or to any of the excipients listed in 6.1
Must not be used in women with child bearing potential (see section 4.6)
Active or past history of venous thromboembolic events (VTE), including deep vein
thrombosis, pulmonary embolism and retinal vein thrombosis.
Hepatic impairment including cholestasis.
Severe renal impairment.
Unexplained uterine bleeding.
Evirex should not be used in patients with signs or symptoms of endometrial cancer
as safety in this patient group has not been adequately studied.
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. Evirex 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. Therefore Evirex is not
recommended to be used in patients with hepatic insufficiency. Serum total bilirubin,
gamma-glutamyl transferase, alkaline phosphatase, ALT and AST should be closely
monitored during treatment if elevated values are observed.
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, Evirex 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.
Interaction with other medicinal products and other forms of interaction
Concurrent administration of either calcium carbonate or aluminium and magnesiumhydroxide 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 Evirex treatment is started in patients who are
already on coumarin anticoagulant therapy.
Raloxifene has no effect on the pharmacokinetics of methylprednisolone given as a
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 Evirex treated patients.
In vitro, raloxifene did not interact with the binding of warfarin, phenytoin, or
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.
Fertility, pregnancy and lactation
Evirex is only for use in postmenopausal women.
Evirex must not be taken by women of child bearing potential. Evirex 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 Evirex is excreted in human milk. Its clinical use, therefore,
cannot be recommended in breast-feeding women. Evirex may affect the
development of the baby
Effects on ability to drive and use machines
Raloxifene has no or negligible influence on the ability to drive and use machines.
a. Summary of the safety profile
The clinically most important adverse reactions reported in postmenopausal women
treated with raloxifene were venous thromboembolic events (see section 4.4), which
occurred in less than 1% of treated patients.
b. Tabulated summary of adverse reactions
The table below gives the adverse reactions and frequencies observed in treatment
and prevention studies involving over 13,000 postmenopausal women along with
adverse reactions arising from postmarketing reports. The duration of treatment in
these studies ranged from 6 to 60 months. The majority of adverse reactions have not
usually required cessation of therapy.
The frequencies for postmarketing reports were calculated from placebo-controlled
clinical trials (comprising a total of 15,234 patients, 7,601 on raloxifene 60 mg and
7,633 on placebo) in postmenopausal women with osteoporosis, or established
coronary heart disease (CHD) or increased risk for CHD, without comparison to the
frequencies of adverse events in the placebo assignment groups.
In the prevention population discontinuations of therapy due to any adverse reaction
occurred in 10.7 % of 581 raloxifene treated patients and 11.1 % of 584 placebotreated 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)
Blood and lymphatic system disorders
Nervous system disorders
Common: Headache, including migraineª
Uncommon: Fatal strokes
Very common: Vasodilation (hot flushes)
Uncommon: Venous thromboembolic events, including deep vein thrombosis,
pulmonary embolism, retinal vein thrombosis, superficial vein
Arterial thromboembolic reactionsª
Very common: Gastrointestinal symptoms such as nausea, vomiting,
abdominal pain, dyspepsia
Skin and subcutaneous tissue disorders
Musculoskeletal and connective tissue disorders
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
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 % Evirex 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 raloxifne-treated patients and 4.7 % in the placebo-treated
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.
Rare cases of moderate increases in AST and/or ALT have been reported where a
causal relationship to raloxifene cannot 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 Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.
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
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.
Pharmaco-therapeutic group: Selective Oestrogen Receptor Modulator, ATC code:
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 LDLcholesterol), but not in the hypothalamus or in the uterine or breast tissues.
Raloxifen’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 genespecific.
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
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.
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
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.
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.
Raloxifene is distributed extensively in the body. The volume of distribution is not
dose dependent. Raloxifene is strongly bound to plasma proteins (98-99 %).
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).
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.
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
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.
List of excipients
Povidone K 30
Colloidal silicon dioxide
Titanium dioxide (E 171)
Special precautions for storage
Do not store above 25°C. Store in the original container
Nature and contents of container
Evirex tablets are packed in blisters containing 14, 28 or 84 tablets.
Not all pack sizes may be marketed in all countries.
Special precautions for disposal
No special requirements
MARKETING AUTHORISATION HOLDER
Strandhaven Limited T/A Somex Pharma
High Road Seven Kings,
MARKETING AUTHORISATION NUMBER(S)
DATE OF FIRST AUTHORISATION/RENEWAL OF THE
DATE OF REVISION OF THE TEXT