Evista Raloxifene 60 Mg 28 Tablets

Adjuncts: Lactose (149.40 mg).
See for all auxiliaries. 6.1

1. PHARMACEUTICAL FORM
Film tablet.
Oval, white tablets with 4165 code on them.

4. CLASS SPECIFICATIONS
• Therapeutic Indications
Evista;
- In the treatment of osteoporosis in postmenopausal women,
- High risk for osteoporosis and breast cancer development as described below
reduce the risk of invasive breast cancer development in postmenopausal women
Indication in use:
High risk for breast cancer development in postmenopausal women
group:
• Lobular carcinoma in situ
• Receptor positive (ER and / or PR positive) ductal carcinoma in situ
• Atypical ductal hyperplasia with breast biopsy
• 1 or more of first-degree relatives have breast cancer
Wealth
• According to the GAIL model, the risk of breast cancer development at 5 years is 1.66%
occurrences
The use of these properties for at least one year is indicated for 5 years.

4.2 Posology and application pattern
Posology / Application frequency and duration:
The recommended dose is 60 mg of EVISTA tablet once a day orally.
Due to the ill nature, EVISTA is planned as a long-term treatment.
Method of Application:
Oral is used on the road.
The tablet can be taken at any time of day, on an empty stomach or on a stomach.
Women who are low in dietary intake generally have calcium and vitamin D support
one
is recommended.
Additional information relevant to special populations:
Kidney failure:
EVISTA should not be used in patients with severe renal insufficiency (see Section 4.3
Contraindications).
EVISTA should be used with caution in mild to moderate renal insufficiency.
Liver failure:
EVISTA should not be used in patients with liver failure (see Section 4.3
Contraindications).
Pediatric population:
There is no indication of the use of EVISTA in children.
Geriatric population:
Dosage adjustment is not necessary at age.

4.3 Contraindications
• Hypersensitivity to any of the active substance or adjuvant
in which,
• In women with potential for child-rearing (see Chapter 4.6 Pregnancy and
Lactation)
• Deep venous thrombosis, including pulmonary embolism and retinal venous thrombosis,
active or transient venous thromboembolic (VTE) event
In patients
• Liver, including cholestasis (reduction or complete stop of bile flow)
failure
patients,
• In those with severe renal insufficiency,
• in patients with unexplained uterine bleeding; Contraindicated.
• Patients with signs or symptoms of endometrium cancer, this patient
Since there is no safety data for the group, they should not use this medicine
must.
• Special use warnings and precautions
Risk of venous thromboembolic event
Risk of venous thromboembolic events in patients using raloxifene, hormone replacement
the risk reported for treatment shows a similar increase. From which etiological group

risk-benefit ratio in patients with risk of venous thromboembolic events
It must be taken into attention.
Long-term inactivity
In the case of disorders or diseases that lead to long-term inactivity, raloxifene treatment
It should be discontinued. Raloxifene therapy can be used immediately or in a long-term
it must be stopped 3 days before the date on which the inactivity is expected to start. inactivity
the disorder causing the disorder and the patient becoming fully mobile
it should not be restarted.
Coronary heart disease / Paralysis
In a study conducted in postmenopausal women, patients with coronary heart disease or
are at increased risk for coronary events compared to placebo
raloxifene myocardial infarction, hospitalization due to acute coronary syndrome,
the overall mortality incidence including total cardiovascular mortality or stroke
It is etkilememis. However, in women receiving raloxifene, death increases due to paralysis
There has been. The incidence of stroke mortality is 1.5 per 1000 women per year for placebo, raloxifene
for a woman of 1000 is 2.2. Stroke story or transient ischemic attack or atrial
Postmenopausal women with significant risk factors for stroke such as fibrillation
This finding should be taken into consideration when raloxifene is prescribed.
Endometrium proliferation
There is no evidence of endometrial proliferation. EVISTA treatment
The presence of any uterine bleeding during an unexpected
must be fully investigated by the expert. The uterus during raloxifene therapy
The two most common diagnoses of hemorrhage are endometrial atrophy and benign
endometrium polyps. Postmenopausal using raloxifene for four years
In women, the manifestations of benign endometrium polyps were significantly lower than placebo (0.3%),
0.9.
Liver disorder
Raloxifene is mainly metabolised in the liver. Sirozu and light liver
When given a single dose of raloxifene in a patient with inadequate disease (Child-Pugh class A)
plasma concentrations of raloxifene were 2.5 times higher than controls
It was found. Correlation between this increase and total bilirubin concentrations
It has been examined. Safety and efficacy in patients with liver failure
Raloxifene use in this patient group, until comprehensive consideration
not recommended. If Eger values ​​increase, serum total bilirubin, gamma glutamyl
transferase, alkaline phosphatase, ALT and AST should be monitored closely during treatment.
hypertriglyceridemia
Limited clinical data, oral estrogen-induced hypertriglyceridemia (> 5.6 mmol / L)
in patients with elevated serum triglyceride levels of raloxifene treatment
it may be linked to increasingly. In patients with such a medical story,
serum triglyceride levels should be monitored during raloxifene therapy.
Breast cancer
EVISTA's safety in patients with breast cancer has not been adequately investigated.
Agents used in early or advanced breast cancer together with EVISTA
No data is available for use. For this reason, EVISTA osteoporosis treatment and
for the prevention of breast cancer, including adjuvant treatments
should be used after completion.
Systemic estrogens
Knowledge of the safety of raloxifene in combination with systemic estrogens
it is not recommended to use it on this tab.
Raloxifene is associated with vasodilatation (hot flashes) or estrogen deficiency
it is effective in reducing other symptoms of menopause.
Lactose content
EVISTA contains lactose. This is why galactose intolerance, Lapp lactase deficiency or
patients with rare hereditary problems such as glucose-galactose malabsorption
they should not use medicine.

4.5. Interactions with Other Medicinal Products and Other Interaction Stages
Gastrointestinal system drugs
Containment with calcium carbonate or aluminum or magnesium hydroxide
antacid use does not affect the systemic exposure of raloxifene.
Oral anticoagulants
The simultaneous administration of raloxifene and warfarin
pharmacokinetics. However, the prothrombin time is small
decreases and eger raloxifene is defined as warfarin or another gamurin derivative
If administered together, the prothrombin time should be monitored. Protrombin on time
effects were assessed with EVISTA in patients who were already taking anticoagulation therapy with kumarin
it may also develop a few weeks after the start of treatment.
corticosteroids
Administration of raloxifene may be achieved by administering a single dose of methylprednisolone
pharmacokinetics.
Digoxin
Raloxifene does not affect the steady-state AUC value of digoxin. Cmax of Digoxin
The value increased slightly from 5%.
Other drugs used together
Preventing the effects of concomitant drugs on raloxifene plasma concentrations and
treatment studies. Among the commonly used drugs
paracetamol, acetylsalicylic acid, ibuprofen, and naproxen
anti-inflammatory drugs, oral antibiotics, H1 antagonist Raloxifene, in combination with warfarin, phenytoin or tamoxifen

cholestyramine
Cholestyramine significantly inhibits raloxifene absorption and enterohepatic circulation
(or other anion-changing resins) with raloxifene,
should not be used together.
Ampicillin and other oral antibiotics
When administered in combination with ampicillin, peak plasma concentrations of raloxifene
It decreases. However, the general absorption and elimination of raloxifene is not affected by this
, raloxifene may be co-administered with ampicillin.
Hormones
Globulin (SHBG) linked to raloxifene sex steroids, thyroxine-bound globulin
(TBG), and globulin (CBG), which binds to corticosteroids
since the concentration of globulin bound is increased moderately, total hormone
resulting in increased concentrations. These changes include free hormone
concentrations.

4.6. Pregnancy and lactation
General advice
Pregnancy category is "X".
Women with potential for child-rearing / Birth control
(Contrast) EVISTA should only be used in postmenopausal women.
EVISTA should not be used by women with a potential for childbearing.
EVISTA may cause fetal damage if administered to a pregnant woman. Pregnancy
during pregnancy is the result of wrongness EVISTA pregnancy or the use of the drug during pregnancy
, the patient is likely to be aware of possible harmful effects on the fetus.
It should be informed.
Pregnancy period
Due to the reasons stated above, EVISTA is used during pregnancy
should not be used.
Lactation period
It is not known whether raloxifene is excreted in the mother's milk. For this reason,
it is not recommended for women who suck the use. EVISTA baby development
It can affect.
Fertility / Fertility
Animal studies have shown that reproductive toxicity has occurred.

4.7. Effects on Vehicle and Machine Usage

EVISTA has the right to use any known vehicle
there is no effect.
8.4. Unwanted Affects
Over 13,000 postmenopausal women participated in osteoporosis treatment and
all the undesirable effects of the prevention work have been recorded. These studies
the duration of treatment varies from 6 to 60 months. If the unwanted reactions are
most of them require the cessation of treatment.
In the prevention population, 10.7% of 581 patients treated with EVISTA,
due to any undesirable effect in 11.1% of 584 placebo-treated patients
treatment has been terminated. The treatment population was treated with 2.557
12.8% of the patients, 11.1% of the 2,576 placebo-treated patients,
treatment was terminated due to adverse experience.
The undesirable association of raloxifene with osteoporosis clinical trials
The effects are summarized in the table below. Frequency rate is defined as: Very
common (1/10); Common (1/100 to <1/10); Uncommon (1 / 1,000 to <1/100); Rare
(1 / 10,000 to & lt; 1 / 1,000); Very rare (<1 / 10,000), not known
can not be predicted by action).
Vascular diseases
Very common: Vasodilatation (hot flashes)
Uncommon: deep vein thrombosis, pulmonary embolism, retinal venous thrombosis
venous thromboembolic events,
Superficial vein thrombophlebitis
Musculoskeletal and connective tissue diseases
Common: Leg cramps
Common disorders and related diseases
Very common: flu syndrome
Common: Peripheral edema
Compared with placebo-treated patients, patients with EVISTA
vasodilatation (hot flashes) increased moderately. (2-8 years
in postmenopausal osteoporosis prevention studies with EVISTA, 24.3%
18.2% with placebo; mean 66 years old osteoporosis treatment studies EVISTA
10.6% for placebo, 7.1% for placebo). During the first 6 months of this adverse reaction treatment,
and has rarely come to the scene again.
If coronary heart disease is detected or the risk of coronary events is increased, 10101
In a postmenopausal study (RUTH), vasodilatation (hot
rate) was 7.8% in patients treated with raloxifene, with placebo
and 4.7% in treated patients.
Placebo-controlled clinical trials have included deep vein thrombosis, pulmonary embolism,
venous thromboembolic events including retinal vein thrombosis were reported in 0.8%
or approximately 3.22 cases per 1000 patient years. in EVISTA
, a relative risk of 1.60 (CI 0.95, 2.71) was observed compared to placebo.The risk of thromboembolic events was highest in the first 4 months of treatment. Superficial
Thrombophlebitis is seen less frequently than 1%.
In the RUTH study, venous thromboembolic events occurred in approximately 2.0% of the raloxifene group
(or 3.88 cases per 1000 patient-years), whereas in the placebo group
rate was 1.4% (or 2.70 cases per 1000 patient-years). RUTH
, the hazard ratio for all VTE events is HR = 1.44, (1.06 - 1.95)
It has been examined. Superficial vein thrombophlebitis occurred in 1% of raloxifene group, placebo
and 0.6% in the group.
The other undesirable effect was leg cramps (%
5.5%, 1.9% for placebo, 9.2% for EVISTA and 6.0% for placebo in the treatment group).
In the RUTH study, 12.1% of the raloxifene group was treated with placebo
and leg cramps were observed in 8.3% of the group.
16.2% of patients treated with influenza EVISTA and treated with placebo
have been reported by 14.0% of the patients.
? statistically not significant (p> 0.05) but showing a significant dose tendency
Another change is more visible. This means that in the prevention population EVISTA
3.1% in users and 1.9% in placebo users, in the treatment population
7.1% in EVISTA users and 6.1% in placebo users
peripheral edema.
In the RUTH study, 14.1% of patients treated with raloxifene were treated with placebo
peripheral edema was observed in 11.7% of the treated patients; this is statistical
it was found to be meaningful from the perspective.
In placebo-controlled raloxifene clinical trials in osteoporotic patients
(6-10%) during raloxifene therapy.
The relationship of causality with raloxifene in AST and / or ALT levels
a rare number of cases have been reported in which moderate elevations have been seen.
A similar increase was reported in patients using placebo.
If coronary heart disease is detected or the risk of coronary events is increased
In a postmenopausal women study (RUTH), raloxifene-treated
an additional adverse reaction was observed in 3.3% of patients and 2.6% of patients treated with placebo
Biliary stones were observed as a reaction. Cholecystectomy in the raloxifene group
(2.3%) and the ratio at the placebo (2.0%) was statistically significant
It is not.
In some clinical studies, EVISTA (n = 317) consistently combined (n = 110) hormones
(HRT) or cyclic (n = 205) HRT were compared. With breast
related symptoms and the frequency of uterine bleeding treated with raloxifene
compared to women treated with HRT (any form) in women
it is lower.
The events reported in post-marketing experience are presented in the table below.
Blood and Lymphatic System Diseases
Very rare: thrombocytopenia
Gastrointestinal Diseases
Very rare: gastrointestinal symptoms such as nausea, vomiting, abdominal pain, indigestion
Common Disorders and Licensed Diseases in the Implementation Region
Rare: Peripheral edema
research studies
Very rare: Increase in blood pressure
Nervous System Diseases
Very rare: bass pain including migraine
Skin and Subcutaneous Tissue Diseases
Very rare: Rash
Reproductive system and Breast-related Diseases
Very rare: mild breast symptoms such as agitation, growth and tenderness
Vascular Diseases
Rare: venous thromboembolic reaction
Very rare: Arterial thromboembolic reaction

4.9 Dose Asymmetry and Treatment
Clinical studies have shown that 600 mg for 8 weeks and 120 mg for 3 years
daily doses are well tolerated.
In adult patients who are using a dose of more than 120 mg in one place, leg cramps and
binge turn symptoms have been reported.
Dose cases occurring in children who are younger than 2 years old,
the maximum dose is 180 mg. Dose-numbing symptoms that occur in children
ataxia, dizziness, vomiting, rash, diarrhea, tremor, "flushing" (face and neck
flush) and alkaline phosphatase.
The maximum overdose is about 1.5 grams. Death-related death case
It has been reported.
There is no specific antidote for raloxifene hydrochloride.

5. PHARMACOLOGICAL CHARACTERISTICS
• Pharmacodynamic Properties
Pharmacotherapeutic group: Selective Estrogen Receptor Modulator (SERM)
ATC code: G03XC01
Raloxifene, a selective estrogen receptor modulator (SERM), estrogen response
selective agonist and antagonist activity. Bone
and partly as an agonist on cholesterol metabolism
(reduction in total and LDL-cholesterol levels) but not in the hypothalamus, uterus or breast
there is no such effect in the tissues.
The biological effects of raloxifene are similar to those of estrogen,
receptors by high affinity binding and gene expression regulation It is shaped. This attachment is very different from estrogen in different tissues
the number of genders causes different levels of expression. New data estrogen
receptors in the ligand, tissue and / or gene-specific at least 2 different
way.
a) Skeletal Effects
The reduction in the presence of estrogen in the menopausal state, in bone resorption,
leading to a significant increase in risk of loss and fracture. Bone formation
If the loss caused by resorption is not at a level to meet, especially menopausal
Bone loss is rapid in the first 10 years. What can cause osteoporosis
other risk factors include early menopause; osteopenia (at least 1 SD low peak bone mass);
thin body structure; white or Asian ethnic origin and family osteoporosis story
comprising. Replacement treatments are usually reversed to bone resorption
It is turned. In postmenopausal women with osteoporosis, the EVISTA vertebra
reduces the incidence of fractures, protects bone mass and reduces bone mineral density
(BMD) increases.
Based on these risk factors and the risk of lifetime high osteoporotic fractures
, the mean value of the vertebrate BMD in the normal young population
Women who are between 1.0 and 2.5 SD according to menopause in the next 10 years
is indicated in the prevention of osteoporosis by EVISTA. In addition, EVISTA,
in the treatment of osteoporosis, the average of the normal young population with vertebra BMD
2.5 SD low by osteoporosis and / or independent of BMD
The vertebra is indicated in women with a chord.
i) Fracture incidence: A mean age of 66 with osteoporosis or an existing fracture
in a study involving 7,705 postmenopausal women with osteoporosis 3
year-old EVISTA treatment resulted in a 47% incidence of vertebral fracture (RR
0.53, CI 0.35, 0.79; p <0.001) and 31% (RR 0.69, CI 0.56, 0.86; p <0.001).
Forty-five women with osteoporosis or 15 with osteoporosis with an existing fracture
3 years for the prevention of one or more vertebral fractures in women EVISTA
need to use. Osteoporosis or osteoporosis with an existing fracture
In patients with EVISTA treatment for 4 years, the incidence of vertebral fracture
46% (RR 0.54, CI 0.38, 0.75) and 32% (RR 0.68, CI 0.56, 0.83). Only 4.
year, EVISTA reduced the risk of new vertebrae fracture by 39% (RR 0.61, CI 0.43, 0.88).
No effects on vertebral fractures have been shown. From the 4th to the 8th
all patients are allowed to use bisphosphonate, calcitonin and fluoride simultaneously
It is given. All patients in this study received additional calcium and vitamin D supplementation.
In the RUTH study, general clinical fractures were examined as secondary end point.
EVISTA reduced the incidence of clinical vertebral fractures by 35% compared to placebo
(HR 0.65, CI 0.47, 0.89). These findings suggest that BMD and vertebral fractures
may have been affected by differences that exist. Therapeutic groups of vertebrae
there is no difference between the incidence of fractures. Throughout the study
allowing the simultaneous use of other drugs on the bone.
ii) Bone Mineral Density (BMD): a period of two years of treatment.
once a day in postmenopausal women up to 60 years of age
The effectiveness of EVISTA has been proven. Women have been postmenopausal for 2 to 8 years
There period. Three trials were performed with EVISTA and placebo supplemented with calcium or calcium
1,764 postmenopausal women treated. One of these studies
women had previously undergone hysterectomy. Compared with placebo,
Using EVISTA, the bone density in the hip and vertebrae and the total body
have made significant increases in mineral mass. This increase usually occurs with placebo
compared to a 2% increase in BMD. For 7 years
A similar increase has been observed in BMD in the treatment population receiving EVISTA.
In prevention studies, an increase or decrease in BMD during raloxifene treatment
the percentage of patients who were living in the region was reduced: 37% for vertebrae and 63%
increase; 29% for total hip and 71% for hip.
iii) Calcium kinetics: EVISTA and estrogen, bone remodeling and
affect calcium metabolism in a similar manner. EVISTA, descending primarily
urinary calcium losses associated with a calcium balance of 60 mg per day
mean positive slippage and decreased bone resorption.
iv) Histomorphometry (bone quality): a comparison of EVISTA with estrogen
bones obtained from patients treated with both medicinal products in the study
histologically normal, mineralization defect, agar bone or bone
No evidence of fibroids was detected.
Raloxifene reduces bone resorption; this effect on bone, bone turnover
decrease in serum and urine levels of the markers, radiochemical kinetics
decrease in bone resorption based on studies and BMD increase and fracture
incidence were not associated with hyperplasia. Approximately 3,000 in 831 women in all dose groups
transvaginal ultrasonography (TVUs) were performed. Raloxifene-treated
an endometrial thickness that is always indistinguishable from the placebo in women
It has been examined. After 3 years of treatment, 211 patients treated with 60 mg raloxifene daily
In 1.9% of women, as evaluated by transvaginal ultrasound, endometrial
this increase was 1.8% in 219 women who received a placebo.
Among the raloxifene and placebo groups in terms of incidence of uterine bleeding report
it did not matter.
Endometrial biopsies taken after 6 months of treatment with 60 mg of EVISTA per day
proliferative endometrium in patients. Also,
a 2.5-fold daily dose of EVISTA was used for endometrial proliferation
there is no evidence of increased uterine volume.
In the osteoporosis treatment study, in a subgroup of study populations (1,644 patients), 4
The endometrial thickness was evaluated annually for a year. Treatment with EVISTA
endometrial thickness measurements in women after 4 years of treatment
they are different. Incidence of vaginal bleeding (spotting) or vaginal discharge
there was no difference between women treated with EVISTA and placebo.
In comparison with placebo-treated women, fewer EVISTA treated
surgical intervention for uterine prolapse is necessary. 3 years raloxifene
the safety information obtained after treatment, the pelvic floor of raloxifene treatment
and does not increase the pelvic floor surgeon.
After 4 years, raloxifene did not increase endometrial or over-cancer risk. 4 years
0.9% of postmenopausal women receiving raloxifene therapy during the course of benign
while endometrial polyps are reported, this is 0.3% in women receiving placebo.
d) Effects on breast tissue
EVISTA does not follow breast tissue. All placebo controlled studies
EVISTA, breast symptoms (lack of seismicity, sensitivity and nipple pain)
did not make a difference with placebo in terms of incidence and severity.
During the 4-year osteoporosis treatment study (involving 7705 patients), EVISTA
total breast cancer risk was 62% (RR 0.38, CI 0.21, 0.69) compared with placebo,
invasive breast cancer risk was 71% (RR 0.29, CI 0.13, 0.58) and estrogen receptor (ER)
positive invasive breast cancer risk was 79% (RR 0.21, CI 0.07, 0.50)
It is azaltmıs. EVISTA treatment has no effect on ER-negative breast cancer risk
there is no effect. These observations suggest that raloxifene is a true estrogen agonist
activity.
e) Effects on cognitive function
No adverse effects on cognitive function have been observed.

5.2 Pharmacokinetic Properties
General features
Absor