- 1. NAME OF THE MEDICINAL PRODUCT
- 2. QUALITATIVE AND QUANTITATIVE COMPOSITION
- 3. PHARMACEUTICAL FORM
- 4. CLINICAL PARTICULARS
- 4.1 Therapeutic indications
- 4.2 Posology and method of administration
- 4.3 Contraindications
- 4.4 Special warnings and precautions for use
- 4.5 Interaction with other medicinal products and other forms of interaction
- 4.6 Fertility, pregnancy and lactation
- 4.7 Effects on ability to drive and use machines
- 4.8 Undesirable effects
- 4.9 Overdose
- 5. PHARMACOLOGICAL PROPERTIES
- 6. PHARMACEUTICAL PARTICULARS
- 7. MARKETING AUTHORISATION HOLDER
- 8. MARKETING AUTHORISATION NUMBER(S)
- 9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
- 10. DATE OF REVISION OF THE TEXT
1.NAME OF THE MEDICINAL PRODUCT
Raloxifene Teva 60 mg
2.QUALITATIVE AND QUANTITATIVE COMPOSITION
For the full list of excipients, see section 6.1.
Raloxifene is indicated for the treatment and prevention of osteoporosis in postmenopausal women. A significant reduction in the incidence of vertebral, but not hip fractures has been demonstrated.
When determining the choice of raloxifene or other therapies, including oestrogens, for an individual postmenopausal woman, consideration should be given to menopausal symptoms, effects on uterine and breast tissues, and cardiovascular risks and benefits (see section 5.1).
4.2Posology and method of administration
The recommended dose is one tablet daily.Due to the nature of this disease process, raloxifene is intended for long term use.
Generally calcium and vitamin D supplements are advised in women with a low dietary intake.
No dose adjustment is necessary for the elderly.
Patients with renal impairment:
Raloxifene should not be used in patients with severe renal impairment (see section 4.3). In patients with moderate and mild renal impairment, raloxifene should be used with caution.
Patients with hepatic impairment:
Raloxifene should not be used in patients with hepatic impairment (see section 4.3 and 4.4).
Raloxifene should not be used in children of any age. There is no relevant use of Raloxifene in the paediatric population.
Method of administration
The tablet can be taken at any time of the day without regard to meals.
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
Must not be used in women with child bearing potential.
Active or past history of venous thromboembolic events (VTE), including deep vein thrombosis, pulmonary embolism and retinal vein thrombosis.
Hepatic impairment including cholestasis.
Severe renal impairment.
Unexplained uterine bleeding.
Raloxifene should not be used in patients with signs or symptoms of endometrial cancer as safety in this patient group has not been adequately studied.
4.4Special 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
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
Limited clinical data suggest that in patients with a history of oral
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
Raloxifene is not effective in reducing vasodilatation (hot flushes), or other symptoms of the menopause associated with oestrogen deficiency.
4.5Interaction with other medicinal products and other forms of interaction
Concurrent administration of either calcium carbonate or aluminium and
Raloxifene has no effect on the pharmacokinetics of methylprednisolone given as a single dose.
Raloxifene does not affect the
The influence of concomitant medication on raloxifene plasma concentrations was evaluated in the prevention and treatment trials. Frequently
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
Peak concentrations of raloxifene are reduced with
Raloxifene modestly increases
4.6Fertility, pregnancy and lactation
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
4.7Effects 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 Raloxifen were venous thromboembolic events (see section 4.4), which occurred in less than 1% of treated patients.
b. Tabulated summary of adverse reactions
The table below gives the adverse reactions and frequencies observed in treatment and prevention studies involving over 13,000 postmenopausal women along with adverse reactions arising from postmarketing reports. The duration of the treatment in these studies ranged from 6 to 60 months. The majority of adverse reactions have not usually required cessation of therapy.
The frequencies for postmarketing reports were calculated from
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
The following convention has been used for the classification of the adverse reactions: very common
(≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000) very rare (< 1/10,000), not known (cannot be estimated from the available data).
Blood and lymphatic system disorders
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 thrombophlebitis,
Arterial thromboembolic reactionsa
Very common: Gastrointestinal symptomsa 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
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
(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
HR = 1.44,
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
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
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
11.7 % of the
Rare cases of moderate increases in AST and/or ALT have been reported where a causal relationship to raloxifene can not be excluded. A similar frequency of increases was noted among placebo patients.
In a study (RUTH) of postmenopausal women with documented coronary heart disease or at increased risk for coronary events, an additional adverse reaction of cholelithiasis occurred in 3.3 % of patients treated with raloxifene and 2.6 % of patients treated with placebo. Cholecystectomy rates for raloxifene (2.3 %) were not statistically significantly different from placebo (2.0 %).
Raloxifene (n = 317) was compared with continuous combined (n = 110) hormone replacement therapy (HRT) or cyclic (n = 205) HRT patients in some clinical trials. The incidence of breast symptoms and uterine bleeding in raloxifene treated women was significantly lower than in women treated with either form of HRT.
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.
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.
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
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
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
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
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
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 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
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
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 exten
sive. Absolute bioavailability of raloxifene is 2 %. The time to reach average maximum plasma concentration and bioavailability are functions of systemic interconversion and enterohepatic cycling of raloxifene and its glucuronide metabolites.
Raloxifene is distributed extensively in the body. The volume of distribution is not dose dependent. Raloxifene is strongly bound to plasma proteins
Raloxifene undergoes extensive first pass metabolism to the glucuronide conjugates:
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
5.3Preclinical safety data
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
6.1List of excipients
Pregelatinized starch (maize)
Colloidal anhydrous silica
Microcrystalline cellulose, silicified
Titanium dioxide (E171)
6.4Special precautions for storage
Do not store above 25°C. Store in the original package to protect from moisture.
6.5Nature and contents of container
Transparent PVC/PVdC - Aluminium blisters. Pack sizes of 14, 28 and 84 tablets. Not all pack sizes may be marketed.
6.6Special precautions for disposal
No special requirements.
7.MARKETING AUTHORISATION HOLDER
8.MARKETING AUTHORISATION NUMBER(S)
9.DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
Date of first authorisation: 29 April 2010
Date of first renewal: 06 February 2015
10.DATE OF REVISION OF THE TEXT
Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu