Evista - instructions for use, doses, side effects, contraindications

Active substanceRaloxifeneRaloxifene

Similar drugsTo uncover

Evista®

pills inwards

Lilly S.A. Spain

Dosage form: & nbspfilm coated tablets

Composition:

Each tablet contains:

active ingredient raloxifene hydrochloride 60 mg equivalent to the free base of raloxifene (55.71 mg);

auxiliary substances - povidone, polysorbate 80, lactose anhydrous, lactose monohydrate, crospovidone K-30, magnesium stearate, mixture of white dye YS-1-18027-A, carnauba wax, blue food grade ink.

Description:

Tablets of ellipsoid form, covered with a film coating of white color.

On the cross section, the core is from almost white to light yellow in color. On the tablets, blue ink has an identification number of 4165.

Pharmacotherapeutic group:Bone resorption inhibitor, estrogen receptor modulator

ATX: & nbsp

G.03.X.C Selective modulators of estrogen receptors

G.03.X.C.01 Raloxifene

Pharmacodynamics:

Being a selective modulator of estrogen receptors, raloxifene is a selective agonist or a selective antagonist for estrogen-sensitive tissues. As an estrogen receptor agonist, the drug acts on bone tissue and, in part, on cholesterol metabolism (lowers total cholesterol and low-density lipoprotein (LDL) levels), but not on the hypothalamus, uterus and mammary glands.The biological effect of raloxifene, as well as the effect of estrogen, is due to the high affinity for estrogen receptors and the regulation of gene expression. Binding to receptors leads to the expression of several estrogen-regulated genes in various tissues. Current data indicate that estrogen receptors are able to regulate gene expression by at least two different mechanisms that have ligand, tissue and / or gene specificity.

The decrease in the number of post-menopausal estrogens leads to a significant increase in bone resorption, loss of bone substance and an increased risk of fractures. Loss of bone substance is especially intense in the first 10 years after menopause, when the compensatory increase in the formation of bone substance does not correspond to the rates of resorption. Other risk factors for osteoporosis include early menopause, osteopenia (reduction in peak bone mass by at least 1 standard deviation (SD)), thin physique, belonging to European or Asian ethnic groups, as well as family cases of osteoporosis.Hormone replacement therapy in most cases prevents excessive resorption of bone substance. In postmenopausal women with osteoporosis, the use of the drug Evista® leads to a decrease in the frequency of vertebral fractures, contributes to the preservation of bone mass and the increase in bone mineral density (BMD).

Based on risk factors, the appointment of raloxifene for the prevention of osteoporosis is indicated in women with a menopause within 10 years, in which the spine BMD is between 1.0 and 2.5 SD below the average normal value, given the high risk of fractures due to osteoporosis. Besides, raloxifene is indicated for the treatment of osteoporosis in women with an IPC of the spine below 2.5 SD of the mean normal value and / or in the presence of vertebral fractures regardless of the values.

The appointment of raloxifene in postmenopausal women with osteoporosis or osteoporosis complicated by fractures leads to a reduction in the frequency of vertebral fractures by 47% and 31% respectively, when taking calcium and vitamin preparations D. There was no effect on the development of fractures of other bones.

Taking raloxifene with calcium preparations leads to a significant increase in the mineral density of the femur and spine, as well as the mineral density of bone tissue.

Raloxifene and estrogen have the same effect on bone remodeling and calcium metabolism. Receiving raloxifene at a dose of 60 mg per day inhibits bone resorption and moderately increases the balance of calcium, mainly due to a decrease in the excretion of calcium in the urine.

When taking raloxifene, no histological changes are observed in the bone tissue. In addition, there are no signs of formation of membranous reticulofibrous bone tissue, mineralization disorders and bone marrow fibrosis.

Reducing the intensity of bone resorption with raloxifene is manifested by a decrease in the level of markers of bone metabolism in the urine and in the blood, as well as a decrease in bone resorption from the radiological study of calcium kinetics, an increase in BMD, and a decrease in fracture frequency.

Influence on lipid metabolism and risk of cardiovascular disorders Taking raloxifene at a dose of 60 mg per day leads to a significant reduction in total cholesterol and LDL.Women who have a higher initial level of cholesterol, there is a more pronounced decrease. HDL and triglyceride concentrations are not significantly altered. Against the background of a long reception (for 3 years) raloxifene reduces the level of fibrinogen. The maximum risk of thromboembolism is noted in the first four months of treatment.

Influence on the endometrium

According to transvaginal ultrasound examinations, there was no stimulating effect of raloxifene on the endometrium in women in the postmenopausal period. Raloxifene does not increase the incidence of spotting, uterine bleeding or endometrial hyperplasia. The biopsy results showed no proliferation of the endometrium and an increase in the volume of the uterus on the background of raloxifene therapy.

Long-term use of raloxifene does not increase the risk of developing endometrial cancer or ovarian cancer, nor does it increase the incidence of benign endometrial polyps.

Influence on mammary glands

Raloxifene does not have a stimulating effect on the mammary glands (there was no swelling and soreness of the mammary glands).

The administration of raloxifene reduces the relative risk of new cases of breast cancer in postmenopausal women by 64%. The overall risk of developing estrogen-positive invasive breast cancer is reduced by 80%. The administration of raloxifene does not affect the risk of developing estrogen-negative breast carcinomas.

The distant effect of raloxifene on the development of breast cancer has not been studied.

Influence on cognitive functions

No side effects were observed with respect to cognitive functions.

Pharmacokinetics:

Suction

Raloxifene is rapidly absorbed after oral administration (approximately 60% of the orally taken dose of the drug is absorbed). The absolute bioavailability of raloxifene is 2%. The time to reach the mean maximum plasma concentration and bioavailability indicators are due to systemic transformations and enterohepatic recirculation of raloxifene and its compounds with glucuronic acid. Distribution

Raloxifene is well distributed in the body and the volume of distribution does not depend on the dose of the drug. Raloxifene is bound by plasma proteins by 98 to 99%.

Metabolism

When you first pass through the liver raloxifene is subjected to intensive conjugation with glucuronic acid with the formation of the following metabolites: raloxifene-4'-glucoronide, raloxifene-6-glucoronide and raloxifene-4 ', 6-glucoronide. On raloxifene less than 1% of the total concentration of raloxifene and its glucuronide metabolites. The level of raloxifene is supported by intestinal hepatic recycling, thanks to which the half-life of the drug from the plasma is 27.7 hours.

An increase in the dose of raloxifene leads to an almost proportional increase in the area under the concentration-time curve.

Excretion

Most of the accepted dose of raloxifene and its metabolites is excreted mainly with feces for 5 days, with urine output less than 6% of the dose taken.

Special patient groups

Liver failure.

The concentration of raloxifene in plasma in patients suffering from cirrhosis and mild liver failure increases approximately 2.5-fold and correlates with the concentration of bilirubin.

Indications:

Osteoporosis in the postmenopausal period (treatment and prevention);
Prevention of breast cancer in women with osteoporosis in postmenopausal period.

Contraindications:

hypersensitivity to raloxifene or other substances in the formulation;
abnormal liver function, including cholestasis;
childbearing age;
vein thrombosis (including in anamnesis), including deep vein thrombosis, pulmonary vein thromboembolism, and retinal vein thrombosis;
severe renal dysfunction;
uterine bleeding of unknown etiology;
endometrial cancer;
pregnancy, lactation;
prolonged immobilization.

Pregnancy and lactation:

Use during pregnancy and lactation

The drug EVISTA ® should be given only to women in the postmenopausal period.

Women who are able to have children should not take EVISTA®. The drug may have harmful effects on the fetus when given to pregnant women. If this medication was mistakenly taken during pregnancy or if the pregnancy occurred during the period of taking the drug, the patient should be advised of the possible harmful effects on the fetus.

It is not known whether raloxifene with milk. However, it is not recommended to prescribe this drug to women during lactation, since it is impossible to exclude the effect of the drug EVISTA® for the development of the child.

Dosing and Administration:

The recommended dose of the drug is one tablet a day, orally. The drug can be taken at any time of the day, regardless of food intake. When prescribing the drug to elderly patients, dose adjustment is not required. Peculiarities of the course of the disease cause the need for a prolonged intake of EVISTA.

Usually women who receive inadequate amounts of calcium and vitamin A D, additional assignment of these substances is necessary.

Side effects:

The administration of raloxifene is accompanied by a low incidence of side effects:

thromboembolism; thrombosis of deep and superficial veins, retinal veins, embolism of pulmonary veins in less than 1% of cases;
"hot flashes" (more often observed in the first 6 months of taking the drug);
cramps in the muscles of the lower limbs;
peripheral edema;
insignificant (by 6 - 10%) decrease in the number of platelets;
level up ACT (aspartame aminotransferase) and / or ALT

(alanine aminotransferase).

Very rarely (<1/10000) the following side effects are observed:

disruption of the gastrointestinal tract (nausea, vomiting, abdominal pain and dyspeptic disorders);
rash;
increased blood pressure;
headaches, including migraines;
influenza and syndrome;
cholelithiasis

Overdose:

To date, no drug overdose has been observed. When using the drug in the amount of 600 mg / day during 2 months of clinical investigation, there were no cases of overdose. According to post-marketing observations, cases of overdose were reported rarely (less than one case per 10,000 [<0.01%] people). The maximum overdose was 1.5 g.

Lethal outcomes associated with overdose of the drug are not described. In patients taking more than 120 mg of raloxifene once, the spasms of the muscles of the lower limbs and dizziness are described. In some cases, an overdose was not accompanied by the development of adverse events.

The cases of taking 180 mg of raloxifene by children younger than 2 years are described. Symptoms of overdose in children included ataxia, dizziness, nausea, skin rashes, diarrhea, tremor, "hot flashes", and an increase in the level of alkaline phosphatase. There is no specific antidote for raloxifene hydrochloride.

Interaction:

Co-administration with antacids containing calcium or aluminum carbonate and magnesium hydroxide does not affect the systemic action of raloxifene.

The joint administration of raloxifene to warfarin does not affect the pharmacokinetics of any of the drugs. However, there was a slight reduction in prothrombin time. In this regard, when raloxifene is administered in combination with warfarin or other coumarin derivatives, the change in prothrombin time should be monitored. If patients who take anticoagulant preparations of coumarin, begin to take EVISTA®, then the effect on prothrombin time can develop for several weeks.

Reception of Evista® does not affect the pharmacokinetics of a single-dose methylprednisolone.

Raloxifene does not affect the equilibrium concentration of digoxin. When taking raloxifene, Stach (maximum concentration) of digoxin increases by less than 5%.

Joint reception of EVISTA® with the following drugs: nonsteroidal

anti-inflammatory drugs (paracetamol, acetylsalicylic acid, ibuprofen and naproxen), antibiotics for oral administration, I1 antagonists, H2 antagonists, as well as benzodiazepines, have no clinically significant effect on plasma raloxifene concentration.

A joint prescription with estrogen-containing drugs for vaginal application is possible if necessary to treat atrophy of the vaginal mucosa. However, the frequency of use of estrogen-containing drugs does not increase.

In vitro raloxifene had no effect on the binding of warfarin, phenytoin and tamoxifen to plasma proteins.

Do not assign raloxifene together with cholestyramine (and other anion-exchange resins), which significantly reduces the absorption and intestinal-hepatic recycling of raloxifene.

The maximum concentration of raloxifene is reduced when the drug is taken together with ampicillin. However, due to the fact that ampicillin does not affect the absorption and the rate of elimination of raloxifene, the drugs can be taken together.

The administration of raloxifene leads to a slight increase in the concentration of hormone-binding globulins, including the concentration of globulins that bind the sex steroids, thyroxine-binding globulin and globulin, binding corticosteroids, which is accompanied by an increase in the total concentration of hormones. These changes do not affect the concentration of free hormones.

Special instructions:

A careful balance of the benefits and risks of using raloxifene in postmenopausal women with a history of stroke or in the presence of risk factors for stroke (such as transient ischemic cerebrovascular disorders or atrial fibrillation) is necessary. According to clinical studies, the incidence of strokes, myocardial infarction, the number of hospitalizations for acute coronary disorders, and the overall mortality and mortality from cardiovascular disease in postmenopausal women with a confirmed diagnosis of coronary artery disease or an increased risk of coronary heart disease were similar in the groups receiving raloxifene and placebo. However, against the background of raloxifene therapy, there was an increase in mortality from strokes - 2.2 deaths per 1000 women per year, compared with 1.5 deaths per 1000 women per year with placebo.

The use of raloxifene is associated with an increased risk of developing venous thrombosis, the same as with the use of modern hormone replacement drugs. The drug should be stopped for diseases or conditions accompanied by prolonged immobility of the patient.If the disease occurs, stop taking the drug as soon as possible, or 3 days before immobilization. Do not resume taking the drug until the cause that caused its cessation has been eliminated and the patient's motor activity will not be fully restored.

Raloxifene does not cause endometrial proliferation. Reception of EVISTTA® should not be accompanied by the development of uterine bleeding. If there is any uterine bleeding during the treatment with EVISTA®, a specialist consultation is necessary to establish the cause of the bleeding. The most common causes of uterine bleeding during raloxifene are endometrial atrophy and benign polyps of the endometrium.

The metabolism of raloxifene occurs mainly in the liver. With a single administration of raloxifene by patients suffering from cirrhosis and mild hepatic insufficiency, the concentration of the drug in the plasma was approximately 2.5 times higher than in the control group. The increase in raloxifene concentration correlated with the concentration of total bilirubin.As long as the safety and efficacy of the drug remain unrecognized in patients suffering from hepatic insufficiency, it is not recommended to appoint the EVISTA of this category of patients. It should be carefully monitored changes in levels of total bilirubin, Gamma glutamyltransferase, alkaline phosphatase, ALT and ACT, if during the treatment there was an increase in these indicators.

In patients who have a history of hypertriglyceridemia (> 5.6 mmol / L) due to oral estrogen preparations, taking raloxifene may lead to a further increase in the level of triglycerides. In patients with a similar history during the treatment with raloxifene, the level of triglycerides should be monitored.

The safety of taking EVISTA® by patients with breast cancer has not been adequately studied. Data on the joint use of Evista® and drugs used to treat breast cancer in early or advanced stages, are absent. In this regard, the drug Evista should be prescribed for the prevention or treatment of osteoporosis only after the completion of treatment (including adjuvant therapy) of breast cancer.

Since the experience of the joint use of raloxifene and systemic estrogens is not available, it is not recommended to prescribe these drugs at the same time.

There are no indications for taking raloxifene by men.

Evista® is not effective for tidal and other postmenopausal symptoms due to estrogen deficiency.

Effect on the ability to drive transp. cf. and fur:

There is no indication that raloxifene has an impact on the ability to drive and work with machinery.

Form release / dosage:

Film coated tablets.

Packaging:14 tablets per blister. For 1, 2 or 6 blisters, together with instructions for use, put in a pack of cardboard.

Storage conditions:

Store at a temperature of no higher than 30 ° C in a protected from light. Do not freeze.

Keep out of the reach of children.

Shelf life:

3 years. Do not use after the expiration date.

Terms of leave from pharmacies:On prescription

Registration number:П №015596 / 01

Date of registration:25.02.2011

Date of cancellation:2017-05-22

The owner of the registration certificate:Lilly S.A.Lilly S.A. Spain

Manufacturer: & nbsp

LILLY, S.A. Spain

Information update date: & nbsp22.05.2017

Illustrated instructions

Instructions

Evista® (Evista®)