Active ingredients: Raloxifene
Raloxifene Sandoz 60 mg coated tablets
Why is Raloxifene used - Generic drug? What is it for?
Raloxifene Sandoz contains the active substance raloxifene hydrochloride.
Raloxifene Sandoz is used to treat and prevent osteoporosis in postmenopausal women.
Raloxifene Sandoz reduces the risk of vertebral fractures in women with postmenopausal osteoporosis. A reduction in the risk of hip fracture has not been demonstrated.
How Raloxifene Sandoz works
Raloxifene Sandoz belongs to a group of non-hormonal medicines called Selective Estrogen Receptor Modulators (MSREs). When a woman reaches menopause, the level of estrogen, the female sex hormones, decreases. Raloxifene Sandoz reproduces some of the positive effects of estrogen after menopause.
Osteoporosis is a disease that makes your bones thin and fragile - this disease is particularly common in postmenopausal women. Although it may have no symptoms at first, osteoporosis makes it more prone to breaking bones, especially the spine. back, hips and wrists and could cause back pain, reduced height and hunched back.
Contraindications When Raloxifene should not be used - Generic drug
Do not take Raloxifene Sandoz:
- If you are being treated or have been treated for blood clots in the legs (deep vein thrombosis), lungs (pulmonary embolism) or eyes (retinal vein thrombosis).
- If you are allergic (hypersensitive) to raloxifene or any of the other ingredients of this medicine.
- If it is still possible for you to become pregnant, Raloxifene Sandoz could harm the unborn baby.
- If you have liver disease (examples of liver disease are cirrhosis, mild liver failure or cholestatic jaundice).
- If you have severe kidney problems.
- If you have unexplained vaginal bleeding. This situation must be evaluated by the doctor.
- If you have active uterine cancer, as there is insufficient experience with the use of Raloxifene Sandoz in women with this disease.
Precautions for use What you need to know before taking Raloxifene - Generic drug
Consult your doctor or pharmacist before taking Raloxifene Sandoz.
- If you have been immobilized for some time, for example if you are confined to a wheelchair, need hospitalization, or need to stay in bed to recover from an accident or unexpected illness, as these conditions can increase your risk of thrombosis (deep vein thrombosis, pulmonary embolism or retinal vein thrombosis).
- 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 disease.
- If you suffer from breast cancer, as there is insufficient experience with the use of Raloxifene Sandoz in women with this disease.
- If you are taking oral estrogen therapy.
Raloxifene Sandoz is unlikely to cause vaginal bleeding. Therefore, no vaginal bleeding is expected while taking Raloxifene Sandoz. This situation should be evaluated by your doctor.
Raloxifene Sandoz does not treat postmenopausal symptoms, such as hot flashes.
Raloxifene Sandoz lowers the level of total cholesterol and LDL ("bad") cholesterol. In general, the level of triglycerides and HDL ("good") cholesterol does not change. However, if you have taken estrogen in the past and have had an exaggerated rise in triglycerides, you should consult your doctor before taking Raloxifene Sandoz.
Raloxifene Sandoz contains lactose
If you have been told by your doctor that you have "lactose intolerance, a type of sugar, contact your doctor before taking this medicine.
Interactions Which drugs or foods can modify the effect of Raloxifene - Generic drug
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 heart medicines or blood thinners such as warfarin to thin the blood, your doctor may need to vary the dose of these medicines.
Tell your doctor if you are taking cholestyramine which is mainly used as a lipid-lowering drug as Raloxifene Sandoz may not work optimally.
Warnings It is important to know that:
Pregnancy, breastfeeding and fertility
Raloxifene Sandoz can only be taken by postmenopausal women and must not be taken by women who may still have a baby. Raloxifene Sandoz could harm the unborn baby.
Do not take Raloxifene Sandoz if you are breast-feeding as it may mix with breast milk.
Driving and using machines
Raloxifene Sandoz has no known, or negligible, effects on driving or using machines.
Dose, Method and Time of Administration How to use Raloxifene - Generic drug: Posology
Always take Raloxifene Sandoz exactly as your doctor has told you. If in doubt, consult your doctor or pharmacist.
The recommended dose is one tablet a day. It doesn't matter what time of day you take it, but always taking it at the same time will help you remember to take it. You can take it with or without food.
The tablets are for oral use.
Swallow the tablet whole. You can drink water with it if you wish. Do not break or crush the tablet before taking it. The broken or crushed tablet may taste bad and there is a possibility that you may take an incorrect dose.
Your doctor will tell you how long to continue taking Raloxifene Sandoz. Your doctor may also advise you to take calcium and vitamin D supplements.
If you forget to take Raloxifene Sandoz
Take a tablet as soon as you remember and then continue as usual. Do not take a double dose to make up for a forgotten tablet.
If you stop taking Raloxifene Sandoz
You need to talk to your doctor first.
It is important that you continue to take Raloxifene Sandoz for as long as your doctor tells you.
Raloxifene Sandoz can treat or prevent osteoporosis only if you keep taking the tablets.
Overdose What to do if you have taken an overdose of Raloxifene - Generic drug
If you take more Raloxifene Sandoz than you should
Talk to your doctor or pharmacist. If you take more Raloxifene Sandoz than you should, you may experience leg cramps and dizziness.
Side Effects What are the side effects of Raloxifene - Generic drug
Like all medicines, Raloxifene Sandoz can cause side effects, although not everybody gets them. Most of the side effects seen with raloxifene were mild.
Very common side effects (may affect more than 1 in 10 patients) are:
- Hot flashes (vasodilation)
- Flu syndrome
- Gastrointestinal symptoms such as malaise (nausea), vomiting, abdominal pain and indigestion (dyspepsia)
- Increased blood pressure
Common side effects (may affect up to 1 in 10 people) are:
- Headache, including migraine
- Leg cramps
- Swelling of the hands, feet and legs (peripheral edema)
- Gallstones
- Rash
- Mild breast symptoms such as pain, enlargement and tenderness
Uncommon side effects (may affect up to 1 in 100 people) are:
- Increased risk of blood clots in the legs (deep vein thrombosis)
- Increased risk of blood clots in the lungs (pulmonary embolism)
- Increased risk of blood clots in the eye (retinal vein thrombosis)
- The skin around the vein is red and painful (superficial vein thrombophlebitis)
- Formation of a blood clot in an artery (for example stroke, including increased risk of dying from stroke)
- Reduction in blood platelets, which increases the risk of bleeding or bruising.
In rare cases (may affect up to 1 in 1,000 patients), blood levels of liver enzymes may increase during treatment with Raloxifene Sandoz.
Reporting of side effects
If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting system at www.agenziafarmaco.it/it/responsabili. By reporting side effects you can help provide more information on the safety of this medicine.
Expiry and Retention
Keep this medicine out of the sight and reach of children.
Do not use Raloxifene Sandoz after the expiry date which is stated on the pack.
Keep the blister in the outer carton to protect it from light and moisture. Do not freeze.
Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. This will help protect the environment.
Other information
What Raloxifene Sandoz contains
- The active ingredient is raloxifene hydrochloride. Each tablet contains 60 mg of raloxifene hydrochloride, equivalent to 56 mg of raloxifene.
- The other ingredients of Raloxifene Sandoz tablets are:
- Tablet core: sodium starch glycolate, citric acid monohydrate, microcrystalline cellulose, dibasic calcium phosphate, poloxamer 407, magnesium stearate
- Tablet coating: hypromellose, lactose monohydrate, titanium dioxide (E171) and macrogol / PEG 4000.
What Raloxifene Sandoz looks like and contents of the pack
Raloxifene Sandoz are white, elliptical shaped, film-coated tablets.The tablets are packed in blisters. The boxes contain blisters of 14, 28, 30, 84, or 90 tablets.
Not all pack sizes may be marketed.
Source Package Leaflet: AIFA (Italian Medicines Agency). Content published in January 2016. The information present may not be up-to-date.
To have access to the most up-to-date version, it is advisable to access the AIFA (Italian Medicines Agency) website. Disclaimer and useful information.
01.0 NAME OF THE MEDICINAL PRODUCT
RALOXIFENE SANDOZ 60 MG TABLETS COATED WITH FILM
02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each film-coated tablet contains 60 mg of raloxifene hydrochloride, equivalent to 56 mg of free raloxifene.
Excipient (s) with known effects:
Each tablet contains lactose monohydrate (1.5 mg).
For the full list of excipients see section 6.1.
03.0 PHARMACEUTICAL FORM
Film-coated tablet. White elliptical tablets.
04.0 CLINICAL INFORMATION
04.1 Therapeutic indications
Raloxifene Sandoz is indicated for the treatment and prevention of osteoporosis in postmenopausal women. It has been shown to significantly reduce the risk of osteoporotic vertebral fractures, but not hip fractures.
In determining the choice of Raloxifene Sandoz or other therapies, including estrogen, for an individual postmenopausal woman, menopausal symptoms, effects on uterine and breast tissues, cardiovascular risks and benefits should be considered (see section 5.1)
04.2 Posology and method of administration
Dosage
The recommended dose is one tablet a day for oral administration, which can be taken at any time of the day and regardless of meals. Due to the nature of this pathology, Raloxifene Sandoz is intended for long-term use.
Calcium and vitamin D supplements are generally recommended for women with reduced dietary calcium intake.
Senior citizens
No dose adjustment is necessary in elderly patients.
Kidney damage:
Raloxifene Sandoz must not be used in patients with severe renal impairment (see section 4.3). In patients with mild or moderate renal impairment, Raloxifene Sandoz should be used with caution.
Hepatic impairment:
Raloxifene Sandoz must not be used in patients with hepatic impairment (see sections 4.3 and 4.4).
Pediatric population
Raloxifene Sandoz should not be used in children of any age. There is no relevant use of Raloxifene Sandoz in the pediatric population.
04.3 Contraindications
• Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
• It must not be given to women of childbearing potential (see section 4.6).
• Previous or current venous thromboembolic episodes (VTE), including deep vein thrombosis, pulmonary embolism and retinal vein thrombosis.
• Hepatic impairment, including cholestasis.
• Severe kidney damage.
• Uterine bleeding of an unspecified nature.
Raloxifene Sandoz should not be used in patients with signs or symptoms of endometrial cancer as the safety in this patient group has not been adequately studied.
04.4 Special warnings and appropriate precautions for use
Raloxifene is associated with an increased risk of venous thromboembolic episodes which is similar to the risk found in association with existing hormone replacement therapy. In patients at risk for venous thromboembolic events of any etiology, the benefit-risk balance should be weighed. Raloxifene Sandoz should be discontinued in the presence of any disease or situation involving a prolonged period of immobilization. The suspension should take place as soon as possible in case of illness, or three days before the immobilization period begins. Therapy should not be resumed until the cause of the discontinuation has been resolved and the patient has regained complete mobility.
In a study of postmenopausal women with documented coronary heart disease or at increased risk of coronary events, raloxifene, compared to placebo, did not affect either the incidence of myocardial infarction, hospitalizations due to acute coronary syndrome, or the overall mortality, including total cardiovascular mortality, nor the number of cerebral strokes. However, in women receiving raloxifene c "there was an increase in mortality from cerebral stroke. The incidence of death from stroke was 2.2 per 1,000 women per year with raloxifene compared with 1.5 per 1,000 women per year with placebo (see section 4.8). These data should be considered if prescribing raloxifene to postmenopausal women with a history of stroke or other significant risk factors for stroke, such as transient ischemic attack or atrial fibrillation.
Endometrial proliferation has not been demonstrated. Any uterine bleeding that occurs during therapy with Raloxifene Sandoz is unexpected and must be fully investigated by a specialist. The two most frequent diagnoses associated with uterine bleeding occurring during raloxifene treatment were endometrial atrophy and benign endometrial polyps. In postmenopausal women who have received raloxifene treatment for 4 years, benign endometrial polyps were reported at an incidence of 0.9% compared with 0.3% of women who were treated with placebo.
Raloxifene is mainly metabolised in the liver. Single doses of raloxifene administered to patients with cirrhosis and moderate hepatic impairment (Child-Pugh Class A) resulted in plasma concentrations of raloxifene approximately 2.5 times higher than controls. The increase is correlated with total bilirubin concentrations. Furthermore, Raloxifene Sandoz is not recommended in patients with hepatic insufficiency. Total bilirubinemia, gammaglutamyltransferase, alkaline phosphatase, alanine transferase and aspartate transferase should be carefully monitored during treatment if elevated values are found. .
Limited clinical data suggests that in patients with previous episodes of hypertriglyceridaemia (> 5.6 mmol / L) caused by oral estrogen, raloxifene may be associated with markedly increased triglyceridaemia. In patients with this history taking raloxifene serum triglyceride values should be monitored.
The safety of raloxifene in breast cancer patients has not been adequately studied. There are no data on the concomitant use of raloxifene with agents used in the treatment of early or advanced breast cancer. Therefore Raloxifene Sandoz should only be used for the treatment and prevention of osteoporosis after the treatment of breast cancer. including adjuvant therapy, has been completed.
As there is limited safety information regarding the simultaneous administration of raloxifene and systemic estrogen, such use is not recommended.
Raloxifene Sandoz is not effective in reducing vasodilation (hot flashes) or other menopausal symptoms associated with a lack of estrogen.
Raloxifene Sandoz contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
04.5 Interactions with other medicinal products and other forms of interaction
The concomitant administration of both calcium carbonate and antacids containing magnesium and aluminum hydroxide do not affect the bioavailability of raloxifene.
Co-administration of raloxifene and warfarin did not alter their respective pharmacokinetics. However, modest reductions in prothrombin time have been observed, so if raloxifene is co-administered with warfarin or other coumarin derivatives, prothrombin time should be monitored. Effects on prothrombin time may occur after several weeks if raloxifene treatment is initiated in patients who are already on coumarin anticoagulants.
Raloxifene has no effect on the pharmacokinetics of methylprednisolone given as a single dose. Raloxifene does not interfere with the steady-state area under the digoxin curve. The maximum digoxin concentration is increased by less than 5%.
The influence of concomitant drug administration on plasma concentrations of raloxifene was evaluated in clinical prevention and treatment studies. Frequently co-administered medicinal products included: paracetamol, non-steroidal anti-inflammatory drugs (such as acetylsalicylic acid, ibuprofen and naproxen). ), oral antibiotics, H1 and H2 antagonists and benzodiazepines. No clinically relevant effect of the co-administration of the above drugs was found on the plasma concentrations of raloxifene.
In the clinical study plan, the simultaneous use of vaginal estrogenic preparations was allowed, if deemed appropriate to treat atrophic manifestations of the vagina. Compared to placebo, there was no increased use in patients treated with raloxifene.
In vitro, raloxifene does not interact with the binding of warfarin, phenytoin or tamoxifen.
Raloxifene should not be administered simultaneously with cholestyramine (or other anion exchange resins) which significantly reduces the absorption and entero-hepatic circulation of raloxifene.
The concomitant administration of ampicillin results in a reduction in the plasma concentration peaks of raloxifene. However, since the total amount absorbed and the elimination rate of raloxifene are not altered, raloxifene can be administered concomitantly with ampicillin.
Raloxifene modestly increases the concentrations of hormone-binding globulins, including sex steroid-binding globulins (SHBG), thyroxine-binding globulin (TBG) and corticosteroid-binding globulin (CBG), with a corresponding increase in total hormone concentrations. These alterations do not affect the concentrations of free hormones.
04.6 Pregnancy and breastfeeding
Pregnancy
Raloxifene Sandoz is for use only in postmenopausal women.
Raloxifene Sandoz must not be taken by women who are still able to have children. Raloxifene can cause fetal harm when administered to pregnant women. If this medicinal product is mistakenly administered during pregnancy or the patient becomes pregnant while taking it, the patient should be informed of the potential risk to the fetus (see section 5.3).
Feeding time
It is not known whether raloxifene or its metabolites are excreted in human milk. A risk to the newborn / infant cannot be excluded. Therefore, its clinical use in lactating women cannot be recommended. Raloxifene Sandoz can affect the development of the baby.
04.7 Effects on ability to drive and use machines
Raloxifene has no or negligible influence on the ability to drive or use machines.
04.8 Undesirable effects
a.) Summary of the safety profile
The most clinically important adverse reactions reported in postmenopausal women treated with Raloxifene Sandoz are venous thromboembolic events (see section 4.4) which occur in less than 1% of treated patients.
b.) Summary table of adverse reactions
The table below shows adverse reactions and frequencies observed in prevention and treatment studies conducted in more than 13,000 postmenopausal women together with adverse reactions from post-marketing data. The duration of treatment in these studies ranged from 6 to 60 months. Most adverse reactions did not routinely require discontinuation of therapy.
Frequencies for post-marketing data were calculated from placebo-controlled clinical trials (including a total of 15,234 patients, 7,601 on raloxifene 60 mg and 7,633 on placebo) in postmenopausal women with osteoporosis or coronary heart disease disease, CHD) manifested or increased risk of CHD, without comparison with the frequencies of adverse events of the placebo groups.
In the prevention studies, discontinuation of therapy for any adverse reactions occurred in 10.7% of 581 patients treated with raloxifene compared to 11.1% of 584 patients treated with placebo. In treatment studies, discontinuation of therapy for any adverse event occurred in 12.8% of 2,557 patients treated with raloxifene compared to 11.1% of 2,576 patients treated with placebo. The following convention is used for the classification of adverse reactions: very common (≥ 1/10), common (≥ 1/100,
a Term included based on post-marketing experience
c.) Description of selected adverse reactions
The frequency of vasodilation (hot flashes) was modestly increased in patients treated with raloxifene compared to those treated with placebo (in clinical trials for the prevention of osteoporosis, 2 to 8 years after menopause, 24.3% with raloxifene compared with 18.2% with placebo; in clinical trials for the treatment of osteoporosis, with a mean age of 66 years, 10.6% with raloxifene versus 7.1% with placebo). This adverse reaction was more common in the first 6 months of treatment, and rarely occurred for the first time after that time.
In a study of 10,101 postmenopausal women with documented coronary heart disease or at increased risk of coronary events (RUTH), the onset of vasodilation (hot flashes) occurred in 7.8% of patients treated with raloxifene and in 4, 7% of patients treated with placebo.
In all clinical trials with raloxifene in the treatment of osteoporosis and placebo-controlled, venous thromboembolic events, including deep vein thrombosis, pulmonary embolism and retinal vein thrombosis, occurred with an approximate frequency of 0.8% or of 3.22 cases per 1,000 patients per year. A relative risk of 1.60 (Confidence Interval 0.95, 2.71) was found in patients treated with raloxifene compared to placebo. The risk of a thromboembolic event was greater in the first four months of therapy Superficial vein thrombophlebitis occurred less than 1% in frequency.
In the RUTH study, venous thromboembolic events occurred with a frequency of approximately 2.0% or 3.88 cases per 1,000 patients per year in the raloxifene group and with a frequency of 1.4% or 2. 70 cases per 1,000 patients per year in the placebo group. The risk rate for all venous thromboembolic events in the RUTH study was HR = 1.44 (1.06 - 1.95). Superficial vein thrombophlebitis occurred with 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 stroke deaths in women who took raloxifene. The incidence of stroke mortality was 2.2 per 1000 women per year in the raloxifene group versus 1.5 per 1000 women per year in the placebo group (see section 4.4). During a mean follow-up of 5.6 years, 59 (1.2%) women treated with raloxifene died from stroke, compared with 39 (0.8%) women treated with placebo.
Another observed adverse reaction was the occurrence of leg cramps (5.5% with raloxifene, 1.9% with placebo in the prevention studies and 9.2% with raloxifene, 6.0% with placebo in the treatment studies ).
In the RUTH study, the occurrence of leg cramps was observed in 12.1% of patients treated with raloxifene and 8.3% of patients treated with placebo.
Flu syndrome was found in 16.2% of patients treated with raloxifene compared with 14.0% of patients treated with placebo.
A "further statistically insignificant difference (p> 0.05), but with evident correlation to the dosage used, was the appearance of peripheral edema, which occurred with a" 3.1% incidence with raloxifene compared to "1 , 9% with placebo in the prevention studies and with a 7.1% incidence with raloxifene versus 6.1% with placebo in the treatment studies.
In the RUTH study, the onset of peripheral edema occurred in 14.1% of patients treated with raloxifene and in 11.7% of patients treated with placebo, constituting a statistically significant finding.
Slight reductions in platelet counts (6-10%) were seen during raloxifene therapy in placebo-controlled clinical trials for the treatment of osteoporosis.
There have been rare reports of modest increases in aspartate transferase and / or alanine transferase in which a causal relationship to raloxifene cannot be excluded. Increases with similar frequency were observed in patients treated with placebo.
In a study (RUTH) conducted in postmenopausal women with documented coronary heart disease or at increased risk of coronary events, an additional adverse reaction of cholelithiasis occurred in 3.3% of patients treated with raloxifene and 2.6% of patients treated with raloxifene. patients treated with placebo. The rates of cholecystectomy in raloxifene-treated patients (2.3%) were not statistically significantly different from those seen in placebo-treated patients (2.0%).
In some clinical studies, raloxifene treatment (n = 317) was compared with combined continuous (n = 110) or cyclical (n = 205) hormone replacement therapy (HRT). The incidence of breast symptoms and uterine bleeding was significantly lower in women treated with raloxifene than in women treated with both types of HRT.
Reporting of suspected adverse reactions
Reporting of suspected adverse reactions occurring after authorization of the medicinal product is important as it allows continuous 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. "address www.agenziafarmaco.gov.it/it/responsabili.
04.9 Overdose
In some clinical studies, daily doses of up to 600 mg for 8 weeks and 120 mg for 3 years have been administered. No cases of raloxifene overdose were reported during clinical trials.
Symptoms such as leg cramps and dizziness have been reported in adult patients who had taken doses greater than 120 mg in single administration.
In accidental overdose in children less than 2 years of age, the maximum reported dose was 180 mg. In children, symptoms of accidental overdose included ataxia, dizziness, vomiting, rash, diarrhea, tremor and hot flashes, as well as an increase in alkaline phosphatase.
The highest overdose was approximately 1.5 grams. No deaths associated with overdose have been reported.
There is no specific antidote for raloxifene hydrochloride.
05.0 PHARMACOLOGICAL PROPERTIES
05.1 Pharmacodynamic properties
Pharmacotherapeutic group: Selective Estrogen Receptor Modulator. ATC code: G03XC01.
Mechanism of action and pharmacodynamic effect
As a selective estrogen receptor modulator (MSRE), raloxifene performs selective agonist or antagonist activities on estrogen-sensitive tissues. It acts as an agonist on bone and partially on cholesterol metabolism (decrease in total cholesterol and LDL cholesterol). ), but not on the hypothalamus or on the breast or uterine tissues.
The biological actions of raloxifene, like those of estrogen, are mediated by a high affinity binding to estrogen receptors and by the regulation of gene expression. In different tissues this binding involves differentiated expressions of the multiple genes regulated by estrogen. The data suggest that the estrogen receptor can regulate gene expression through at least two distinct pathways which are binding-, tissue- and / or gene-specific.
a) Effects on the skeletal system
The reduced estrogen availability that occurs at menopause leads to a marked increase in bone resorption, bone loss and the risk of fracture. Bone loss is particularly rapid in the first 10 years after menopause when the compensatory increase in new bone formation is inadequate to balance the losses due to resorption. Other risk factors that can lead to the development of osteoporosis include: early menopause; presence of osteopenia (at least one standard deviation below peak bone mass values); slender constitution; Caucasian or Asian race; familiarity with osteoporosis. In general, replacement therapies prevent excessive bone resorption. In postmenopausal women with osteoporosis, raloxifene reduces the incidence of vertebral fractures, maintains bone mass and increases bone mineral density (BMD).
Based on these risk factors, the prevention of osteoporosis with raloxifene is indicated in women within 10 years of menopause, with BMD of the spine between 1.0 and 2.5 SD below the mean value of the normal young population, considering the high risk of osteoporotic fractures over their lifetime. Similarly, raloxifene is indicated for the treatment of osteoporosis or stabilized osteoporosis in women with BMD of the spine with 2.5 standard deviation below the value average young population normal and / or with vertebral fractures, without taking into account 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 associated with the presence of a fracture, treatment for 3 years with raloxifene reduced the incidence of vertebral fractures by 47%, respectively ( Relative Risk 0.53, Confidence Interval 0.35, 0.79, p vertebral fracture of 39% (Relative Risk 0.61, Confidence Interval 0.43, 0.88). No effect on non-vertebral fractures has been demonstrated. From year 4 to 8, patients were authorized for concomitant use of bisphosphonates, calcitonin and fluorides and in this study all patients received a calcium and vitamin D supplement.
In the RUTH study, all clinical fractures were recorded as a secondary endpoint. Raloxifene reduced the incidence of clinical vertebral fractures by 35% compared to placebo (HR 0.65, Confidence Interval 0.47, 0.89). These results may have been influenced by baseline differences in BMD and vertebral fractures. There was no difference between treatment groups in the incidence of new non-vertebral fractures. The simultaneous use of other bone-active treatments was allowed throughout the study period.
ii) Bone Mineral Density (BMD). The efficacy of raloxifene given once daily to postmenopausal women up to 60 years of age and with or without a uterus was demonstrated over a two-year treatment period. The women were postmenopausal for a period of time ranging from 2 to 8 years.
Three clinical trials included 1,764 postmenopausal women who were treated with raloxifene and calcium or calcium supplemented placebo. In one of these studies, the women had previously undergone hysterectomy. raloxifene resulted in a significant increase in bone mineral density at the proximal femur and spine as well as a significant increase in bone mass of the entire skeleton compared to placebo. This increase in BMD was generally 2% compared to placebo. A similar increase in BMD was seen in the treatment population that received raloxifene for up to 7 years. In the prevention studies, the percentage of subjects who demonstrated an increase or decrease in BMD during raloxifene therapy was: in the spine 37% with decrease and 63% with increase; at the level of the total proximal femur 29% with decrease and 71% with increase.
iii) Calcium kinetics data. Raloxifene and estrogen act on bone remodeling and calcium metabolism in a similar way. Raloxifene was associated with a reduced bone resorption and a positive change in the calcium balance equal to 60 mg per day, essentially due to a reduction in urinary calcium losses.
iv) Histomorphometry (bone quality). In a study comparing raloxifene and estrogens, the bone tissue of patients treated with the "one or" other medicinal product was histologically normal, with no signs of mineralization defects, of bone not lamellar or medullary fibrosis.
Raloxifene reduces bone resorption. This effect on bone is revealed by reductions in serum and urinary levels of bone turnover markers, decreases in bone resorption assessed by radioactive calcium kinetic studies, increases in BMD and reduction in the incidence of fractures.
b) Effects on lipid metabolism and cardiovascular risk
Clinical studies have shown that a daily dose of 60 mg of raloxifene significantly reduces total cholesterol (3 to 6%) and LDL cholesterol (4 to 10%). Patients with the highest baseline cholesterol levels had the greatest reductions. HDL cholesterol and triglyceride concentrations did not change significantly. After 3 years of therapy, raloxifene reduced fibrinogen (6.71%). In an osteoporosis treatment study, significantly fewer patients treated with raloxifene than those treated with placebo required initiation of lipid-lowering therapy.
8-year raloxifene therapy 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, hospitalizations. due to acute coronary syndrome, stroke or overall mortality, including total cardiovascular mortality, compared to placebo (for the increased risk of fatal stroke, see section 4.4).
The relative risk of venous thromboembolic events observed during raloxifene therapy was 1.60 (Confidence Interval 0.95, 2.71) compared to placebo, and 1.0 (Confidence Interval 0.3, 6.2) compared to estrogen or hormone replacement therapy. The risk of a thromboembolic event was greatest in the first four months of therapy.
c) Effects on the endometrium and pelvic floor
In clinical trials, raloxifene did not stimulate the postmenopausal uterine endometrium. Compared to placebo, raloxifene was not associated with endometrial discharge, bleeding, or hyperplasia. Nearly 3,000 transvaginal ultrasound scans (TVUs) were considered on 831 women across all dose groups. Women treated with raloxifene consistently had endometrial thickness indistinguishable from that found in women treated with placebo. After 3 years of treatment, an increase of at least 5 mm in endometrial thickness, ascertained with transvaginal ultrasound, was observed in 1.9% of 211 women treated with 60 mg per day of raloxifene compared to 1.8% in 219. women who received placebo. There were no differences between the two raloxifene and placebo groups in the incidence of reported uterine bleeding.
Endometrial biopsies performed after six months of therapy with raloxifene 60 mg per day demonstrated a non-proliferative endometrium in all patients. In addition, in a study using dosages of raloxifene 2.5 times the recommended daily dose, there was no evidence of endometrial proliferation and no increase in uterine volume.
In the osteoporosis treatment study, endometrial thickness was assessed annually over a 4-year period in a subset of the population study (1,644 patients). After 4 years of therapy, endometrial thickness measurements in women treated with raloxifene did not differ from baseline. There was no difference between women treated with raloxifene and those treated with placebo in the incidences of vaginal bleeding (spotting) or vaginal discharge. Fewer women treated with raloxifene than those treated with placebo had to resort to "surgery for uterine prolapse. After 3 years of treatment with raloxifene the safety profile of the product indicates that treatment with raloxifene does not increase the relaxation of the pelvic floor or the" 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 at an incidence of 0.9% compared with 0.3% of women who were treated with placebo.
d) Effects on breast tissue
Raloxifene does not stimulate breast tissue. In all placebo-controlled clinical trials, raloxifene was indistinguishable from placebo with regard to the frequency and severity of breast symptoms (no breast enlargement, tenderness and pain).
At the end of the 4-year osteoporosis treatment study (comprising 7,705 patients), raloxifene treatment reduced the risk of total breast cancer by 62% compared to placebo (Relative Risk 0.38, Confidence Interval 0.21, 0.69), the 71% risk of invasive breast cancer (Relative Risk 0.29, Confidence Interval 0.13, 0.58) and the risk of estrogen receptor positive (ER) invasive breast cancer of 79% (Relative Risk 0.21, Confidence Interval 0.07, 0.50). Raloxifene has no effect on the risk of ER negative breast cancers. These observations support the conclusion that raloxifene does not possess "intrinsic estrogen agonist activity on breast tissue.
e) Effects on cognitive function
No adverse effects were observed on cognitive function.
05.2 Pharmacokinetic properties
Absorption
Raloxifene is rapidly absorbed after oral administration. Approximately, 60% of an oral dose is absorbed. Pre-systemic glucuronidation is extensive. The absolute bioavailability of raloxifene is 2%. The time to reach mean maximum plasma concentration and bioavailability depend on the systemic conversion and entero-hepatic circulation of raloxifene and its glucuronide metabolites.
Distribution
Raloxifene is widely distributed throughout the body. The volume of distribution is not dose dependent. Raloxifene is strongly bound to plasma proteins (98 - 99%).
Biotransformation
Raloxifene undergoes a marked first pass metabolic process to the following glucuronide conjugates: raloxifene-4 "-glucuronide, raloxifene-6-glucuronide and raloxifene-6.4" -diglucuronide. No other metabolites were discovered. Raloxifene comprises less than 1% of the combined concentrations of raloxifene and glucuronide metabolites. Levels of raloxifene are maintained by enterohepatic recirculation, with a plasma half-life of 27.7 hours.
The results of single oral doses of raloxifene are predictive of the pharmacokinetic profiles induced by multiple dosing. Increasing raloxifene doses results in an almost proportional increase in the area under the curve (AUC) plasma concentration / time.
Elimination
Most of a dose of raloxifene and glucuronide metabolites are eliminated within 5 days, essentially being found in the faeces, while less than 6% is eliminated in the urine. Special populations
Renal insufficiency - Less than 6% of the total dose is excreted in the urine. In a population pharmacokinetic study, a 47% reduction in creatinine clearance corrected for lean body mass resulted in a 17% and 15% reduction in raloxifene and conjugate clearance, respectively.
Hepatic impairment - The kinetics of a single dose of raloxifene in patients with cirrhosis and moderate hepatic impairment (Child-Pugh class A) were compared with those of healthy subjects. Plasma concentrations of raloxifene were 2.5 times higher than controls and correlated with bilirubin concentrations.
05.3 Preclinical safety data
In a two-year carcinogenicity study in rats, an increase in ovarian tumors of granulosa / theca cell origin was observed in female specimens treated with high doses (279 mg / kg per day). In this group, the total absorption (AUC) of raloxifene was approximately 400 times that of postmenopausal women treated with a 60 mg dose. In a 21-month carcinogenicity study in mice, an "increased incidence of interstitial cell tumors of the testis, prostate adenomas and adenocarcinomas was observed in male specimens administered 41 or 210 mg / kg. , and prostatic leiomyoblastomas in male specimens that received 210 mg / kg.In female mice, an "increased incidence of ovarian tumors was found in animals that received 9 to 242 mg / kg (0.3 to 32 times the AUC in humans), including benign and malignant tumors of granulosa / theca cell origin and benign tumors of epithelial cell origin. In these studies, female rodents were treated during their reproductive life when their ovaries were functional and highly sensitive to hormonal stimulation. high sensitivity of the ovaries in this rodent model, the human ovary after menopause is relatively insensitive to stimulation with sex hormones.
Raloxifene was not genotoxic in any of the numerous tests performed.
The effects on reproduction and development observed in animals are in agreement with the known pharmacological profile of raloxifene. At doses ranging from 0.1 to 10 mg / kg per day administered to female rats, raloxifene interrupted their estrus cycles during the treatment period, but did not delay the fertile mating periods after discontinuation of treatment and only marginally it caused a reduction in offspring, an extension of gestation, and altered the duration of events in neonatal development. When administered in the pre-nesting period, raloxifene delayed and interrupted embryo nesting resulting in prolonged gestation and reduced offspring but did not affect the development of the offspring at weaning. Teratological studies were performed in rabbits. and rats. In rabbits, abortion and a low rate of ventricular septal defects (≥ 0.1 mg / kg) and hydrocephalus (≥ 10 mg / kg) were observed. Fetal developmental delay, malformations occurred in rats. ribs and renal cysts (≥ 1 mg / kg).
Raloxifene is a potent anti-estrogen on the rat uterus and has been shown to prevent the growth of estrogen-dependent mammary tumors in rats and mice.
06.0 PHARMACEUTICAL INFORMATION
06.1 Excipients
Core of the tablet:
Sodium starch glycolate (Primogel)
Citric acid monohydrate
Microcrystalline cellulose
Dibasic calcium phosphate
Poloxamer 407
Magnesium stearate
Tablet coating: Hypromellose
Lactose monohydrate
Titanium dioxide (E171)
Macrogol / PEG 4000.
06.2 Incompatibility
Not relevant.
06.3 Period of validity
3 years
06.4 Special precautions for storage
Keep the blister in the original package in order to protect it from light and moisture. Do not freeze.
06.5 Nature of the immediate packaging and contents of the package
Raloxifene Sandoz tablets are packed in a clear PVC / PE / PVDC blister with aluminum foil.
The boxes contain 14, 28, 30, 84, or 90 tablets.
Not all pack sizes may be marketed.
06.6 Instructions for use and handling
No special instructions
07.0 MARKETING AUTHORIZATION HOLDER
Sandoz S.p.A., L.go U. Boccioni 1, 21040 Origgio (VA)
08.0 MARKETING AUTHORIZATION NUMBER
"60 mg film-coated tablets" 14 tablets in PVC / PE / PVDC / AL blister - AIC n. 040742013 /
"60 mg film-coated tablets" 28 tablets in PVC / PE / PVDC / AL blister - AIC n. 040742025 /
"60 mg film-coated tablets" 30 tablets in PVC / PE / PVDC / AL blister - AIC n. 040742037 /
"60 mg film-coated tablets" 84 tablets in PVC / PE / PVDC / AL blister - AIC n. 040742049 /
"60 mg film-coated tablets" 90 tablets in PVC / PE / PVDC / AL blister - AIC n. 040742052 /
09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION
18/04/2013