Universal reference book for medicines
Product name: EVIANA (EVIANA)

Active substance: estradiol, norethisterone

Type: Anti-climacteric drug

Manufacturer: NOVO NORDISK (Denmark)
Composition, form of production and packaging
The tablets covered with a film shell of
white color, round, biconcave, on one side engraving "NOVO 291", on another - a symbol of the company (Bull Apis).

1 tab.

Estradiol (in the form of hemihydrate) 0.5 mg

norethisterone acetate 0.1 mg

Excipients: lactose monohydrate 37.5 mg, corn starch 37.5 mg, giprolose 3.2 mg, talc 0.8 mg, magnesium stearate 0.4 mg.

Composition of the film membrane: hypromellose 2.28 mg, triacetin 0.12 mg.

28 pcs.
- discs plastic calendar (1) - packs cardboard.
INSTRUCTION FOR THE SPECIALIST.

Description of the drug approved by the manufacturer for the printed edition of 2011.

PHARMACHOLOGIC EFFECT

Estradiol : synthetic 17? -estradiol, identical to the woman's ovarian endogenous estradiol, eliminates estrogen deficiency in postmenopausal women and softens the symptoms of menopause, and also prevents bone loss during menopause or ovariectomy.

Norethisterol : Since estrogens stimulate the growth of the endometrium, the use of exclusively estrogen increases the risk of endometrial hyperplasia and endometrial cancer.
The addition of progestogen significantly reduces estrogen-induced risk, endometrial hyperplasia in women who have not undergone hysterectomy.
Attenuation of menopausal symptoms occurs in the first weeks of treatment.
In the third week of the medication, the mean incidence of moderate and severe hot flushes was significantly lower (p <0.001) in the group of patients receiving 0.5 mg of estradiol statistically compared with that in the placebo group. This decline persisted until the end of the study (24 weeks).
Evian ® is a combined preparation for HRT that contains 17? -estradiol and norethisterone (in the form of acetate), which prevents the development of regular withdrawal bleeding associated with cyclic or sequential HRT.
In 89% of women, development of amenorrhea (absence of bleeding and spotting bleeding) was noted six months after the start of treatment. In the first 6 months of treatment bleeding and / or spotting spotting can be observed in 11-15% of women.
It is known that combined therapy with estrogens and progesterone increases the density of the mammogram, which may have a negative effect on the radiological study for the detection of breast cancer.
Six months after the start of the treatment with Eviana ®, an increase in breast density during mammography was not observed.
Deficiency of estrogen during the menopause is associated with a decrease in bone mineral density.
The effect of estrogens on the mineral density of bones depends on the dose. It is believed that this effect persists as long as the treatment continues. After the termination of HRT, the bone mass is reduced to the same extent as in women who have not undergone treatment.
Studies show that the widespread use of HRT alone estrogen or in combination with progestogen, prescribed mainly to healthy women, reduces the risk of fractures of the hip joint, spine and other fractures due to osteoporosis.
HRT can also prevent fractures in women whose bone mineral density is low and / or with diagnosed cases of osteoporosis, but the evidence supporting this assumption is limited.
The effect of estrogens on the mineral density of bones depends on the dose the effect of the Evian ® preparation may be less than that observed with higher doses of estradiol.

The effect of 17? -estradiol 0.5 mg on bone mineral density was examined in two bi-annual randomized, double-blind, placebo-controlled trials and with participation of women in menopause (n = 327, including 44 women taking 17? -estradiol 0.5 mg and n = 171 in another study, including 40 women taking 17? -estradiol 0.5 mg).All women received a calcium supplement 500-1000 mg / day.
17? -estradiol 0.5 mg significantly prevented loss of bone mass in the lumbar spine, hip joints, radius, and the whole body in patients who took 17? -estradiol 0.5 mg for 2 years in the first study (n = 327 ), the percentage of bone mineral density in the lumbar spine, in the femoral neck and femoral spit was 2.26 ± 2.76%, 0.26 ± 2.86%, and 1.74 ± 4.12% (mean ± SD), respectively. In comparison with the baseline, the percent change in bone mineral density in the second study (n = 171) in the lumbar spine, in the femoral neck and femoral spit was, respectively, -0.17 ± 3.28%, 1.76 ± 4.23%, 0.97 ± 5.71% and 0.74 ± 6.41%. The percentage of women whose bone mineral density persisted or increased in the first study (n = 327) during treatment with 17? -estradiol 0.5 mg in the lumbar spine, in the neck of the femur and femoral spit was 74%, 57%, and 67%, respectively .
In the second study (n = 171), conducted over 2 years, this percentage was 41%, 69%, 56% and 44%, respectively.

Biochemical bone markers showed a decrease in bone resorption in both studies.

PHARMACOKINETICS

Suction

After taking Eviana ® , micronized 17? -estradiol is quickly absorbed into the gastrointestinal tract, subjected to primary metabolism in the liver and small intestine and reaches a peak plasma concentration of approximately 24 pg / ml, a coefficient of variation of 38% (after taking two Evian® tablets ), after 5-8 hours T 1/2 17? -estradiol is excreted from the body for about 15 hours. The drug circulates in the blood as a complex with albumin (61%) and globulin binding sex hormones (SHGG) (37%).
In a free form, only about 1-2% of 17? -estradiol circulates in the blood. 1-7? -estradiol is metabolized, mainly in the liver, and also outside it - in the intestine and target organs, with the formation of less active or inactive metabolites, including. estrone, catechol estrogens, as well as sulphates and glucuronides of estrogen.The bulk of estrogens is excreted as inactive metabolites by the kidneys, and also with bile, in which they undergo hydrolysis and are absorbed back (entero-hepatic, recirculation).
After taking the drug Evian ® inside norethisterone acetate is rapidly absorbed and transformed into norethisterone (NET).
The MET is subjected to primary metabolism in the liver and small intestine, and reaches a C max of about 2.4 ng / ml after about 0.5-1.5 h, the coefficient of variation is 41% (after the introduction of two Evian® tablets). The final half-life of norethisterone is about 9-11 hours. The NET makes a complex with albumin (61%) and globulin binding sex hormones SHGGG (36%). The most important metabolites are the isomers of 5-dihydro-NET and tetra-NET, which are excreted mainly with urine in the form of sulfates or conjugated glucuronides. Norethisterone does not affect the pharmacokinetic properties of estradiol. The study of the pharmacokinetics of the drug in elderly patients was not conducted.
Preclinical safety data

Estrogens have a low acute toxicity index.
In view of the significant differences between individual species of experimental animals, as well as between animals and humans, the results of preclinical studies are of limited importance for predicting efficacy in humans. Studies in animals have demonstrated that estradiol and estradiol valerate can even cause relatively low doses of fetal death, as well as the development of congenital malformations of the genitourinary tract and feminization of the male fetus.
Norethisterone, like other gestagens, causes virilization of the female fetus in rats and monkeys.
In high doses, norethisterone can cause death of the embryo. Pre-clinical data, based on data on pharmacological safety, genotoxicity and oncogeneity, did not reveal a specific risk for humans, except for those effects that are considered in other sections of the manual.
INDICATIONS

- hormone replacement therapy for symptoms of estrogen deficiency in women in the postmenopausal period, not earlier than one year after the onset of menopause.

DOSING MODE

Tablets are intended for continuous combined hormone replacement therapy of HRT in women with an unrefined uterus.
The drug is taken orally 1 tablet / day without interruption, preferably at the same time of day.
When treating the symptoms of postmenopause , the drug should be started and resumed at the lowest effective dose for short-term therapy.

If there is an insufficient response to therapy after three months, the transition to a higher-dose drug should be discussed.

Patients with amenorrhea who do not receive HRT or who take another combination drug in continuous mode can start taking Evian ® tablets on any convenient day.When transferring patients from the cyclic mode of HRT, treatment should be started immediately after the end of menstrual bleeding caused by withdrawal of the drug.

If you miss a regular tablet, the missed tablet should be taken as soon as possible within the next 12 hours. If the drug is delayed for more than 12 hours, the missed tablet should be discarded.
Skipping the next dose can cause breakthrough uterine bleeding or the appearance of spotting spotting. Unused medication should be disposed of in accordance with local regulations.
SIDE EFFECT

The most frequently reported side effects during the Evian ® clinical trials were vaginal bleeding.
According to the results of a six-month clinical study of bleeding or the appearance of spotting bleeding from the vagina, 11% of patients were registered during the first month of taking the drug, 15% at the 4th month of therapy and 11% at the end of the clinical trial. A higher frequency side effects were observed among patients receiving Eviana® treatment, compared with patients receiving placebo. Below are all the side effects that are generally believed to have a possible association with the treatment.
Very often (> 1/10 - more than 1 in 10)

Disorders from the reproductive system and mammary glands: bleeding from the vagina.

Often (> 1/100, <1/10 - more than 1 per 100, but less than 1 for 10)

Impaired nervous system: headache.

Disorders from the digestive tract: nausea, abdominal pain.

Disturbances from the musculoskeletal system and connective tissue: back pain, pain in the cervical spine, pain in the limbs.

Disorders from the reproductive system and mammary glands: endometrial hyperplasia, vulvovaginal mycoses.

Rarely: (> 1/1000, <1/100 - more than 1 per 1000, less than 1 per 100)

Impaired immune system: hypersensitivity.

Metabolic disorders: fluid retention in the body.

Mental disorders: depressive states or severe depression, increased excitability.

Disorders from the nervous system: migraine, dizziness.

Disorders from the digestive tract: bloating, dyspepsia.

Disturbances from the skin and subcutaneous fat: alopecia, acne, skin itch or urticaria.

Disturbances from the musculoskeletal system and connective tissue: cramps in the calf muscles.

Disorders from the reproductive system and mammary glands: soreness of the mammary glands, discomfort in the mammary glands.

General disorders and reactions at the site of administration: peripheral edema.

Mammary cancer

The risk of developing breast cancer among women currently taking or taking HRT in the recent past increases in proportion to the increase in HRT.

Endometrial cancer

In women with an unrefined uterus, the risk of developing hyperplasia and endometrial cancer increases with prolonged use of estrogens without the adverse effect of progestogerone.
Addition of progesterones to estrogen significantly reduces the risk of developing endometrial cancer.
Adverse reactions that occurred with other preparations containing estradiol / norethisterone acetate (1 mg / 0.5 mg):

- benign and malignant neoplasms (including cysts and polyps);

- endometrial cancer;

- mental disorders: insomnia, anxiety, decreased libido, increased libido;

- disorders of the nervous system: dizziness;

- impairment of vision; visual impairment;

- disorders of the cardiovascular system: severe arterial hypertension;

- violations of the digestive tract: dyspepsia, vomiting;

- Hepatobiliary disorders: cholecystitis, cholelithiasis, severe form of cholelithiasis, recurrence of cholelithiasis;

- violations of the skin and subcutaneous fat: seborrhea, rash, angioedema;

- violations of the reproductive system and mammary glands: endometrial hyperplasia, manifestations of vulvovaginal candidiasis;

- Other: weight loss, increased blood pressure.

Reports of the following adverse reactions have been reported in the literature in connection with the mention of hormonal replacement therapy with estrogens / progestogens:

- estrogen-dependent neoplasms - benign and malignant, incl.
endometrial cancer;
- venous thromboembolism, that is, deep vein thrombosis of the lower limbs or pelvic organs, as well as pulmonary embolism, is much more common in patients undergoing HRT than in women who did not take hormone replacement therapy;

- myocardial infarction and stroke;

- cholelithiasis;

- violations of the skin and subcutaneous fat: hyperpigmentation of the skin, erythema multiforme, erythema nodosum, vascular purpura;

- Possible dementia.

CONTRAINDICATIONS

- Breast cancer or suspected of it, as well as breast cancer in history;

- diagnosed (including in the anamnesis) estrogen-dependent malignant neoplasms (including endometrial cancer) or suspicion of them;

- bleeding (bleeding) from the vagina of an unclear etiology;

- untreated endometrial hyperplasia;

- deep vein thrombophlebitis, thrombosis, pulmonary embolism or idiopathic thromboembolism in history;

- diseases accompanied by arterial thromboembolism (including angina pectoris, myocardial infarction);

- acute liver disease or liver disease in an anamnesis, at which the liver function parameters did not normalize;

- hypersensitivity to the active substance or other components included in the preparation;

- porphyria;

- Pregnancy;

- lactation.

The experience of treating women over the age of 65 is limited.

With caution

If diagnosed early or there is currently any of the diseases listed below and / or worsened during pregnancy or previous hormonal treatment, the patient should be under close medical supervision, as such diseases can recur / aggravated during treatment with Evian ® :

- Leiomyoma or endometriosis;

- risk factors for thromboembolism or thromboembolism in history;

- risk factors for the development of estrogen-dependent tumors (eg, breast cancer in relatives of the first degree of kinship);

- arterial hypertension;

- liver disease (including liver adenoma);

- diabetes mellitus with or without vascular disease;

- cholelithiasis;

- Migraines or severe headaches;

- systemic lupus erythematosus;

- Endometrial hyperplasia in the anamnesis;

- epilepsy;

- bronchial asthma;

otosclerosis.

PREGNANCY AND LACTATION

The use of Eviana ® during pregnancy and during breastfeeding is contraindicated.
In case of pregnancy on the background of treatment with Eviana ® treatment should be immediately stopped.
Limited data on the use of Eviana ® during pregnancy indicate the adverse effects of norethisterone on the fetus.
The use of hormones in doses that are used for oral contraception, HRT or higher leads to masculinization of the female fetus.
The results of most epidemiological studies on unintended effects on the fetus of combined therapy with estrogen and progesterone suggest that it has no teratogenic or fetotoxic effect.

APPLICATION FOR VIOLATIONS OF THE FUNCTION OF KIDNEYS

Contraindication:

- acute liver disease or liver disease in an anamnesis, in which the liver function parameters did not return to normal.

With caution: liver disease (including liver adenoma).

APPLICATION IN ELDERLY PATIENTS

The experience of treating women over the age of 65 is limited.

SPECIAL INSTRUCTIONS

Treatment of estrogen-dependent symptoms of postmenopausal HRT should be started only in cases of their adverse effect on the quality of life of women.
To assess the ratio of benefits and risks of treatment with the drug, every 3 to 4 months (but at least once every 6 months), taking into account the individual characteristics of the patient, to conduct a medical examination, using clinical and laboratory data. HRT should be continued only as long as the benefits exceed the risk.
Medical examination / control

Before starting / resuming HRT, you should collect an anamnesis and study the patient's medical history, conduct the necessary examination (including pelvic organs and mammary glands), read the contraindications and special precautions for using the drug.
Women should be advised to report any changes in the mammary glands to the doctor or nurse for the purpose of timely follow-up, including mammography.
Reasons for immediate withdrawal of the treatment
The treatment should be discontinued in identifying contra and the following conditions:
- jaundice or abnormal liver function;
- a significant increase in blood pressure;
- a new type of headache a migraine;
- Pregnancy.

Endometrial hyperplasia
Prolonged estrogen alone increases the risk of endometrial hyperplasia and carcinoma. To reduce the risk in women with a uterus must be non-operated combination therapy with a progestogen for at least 12 days per cycle.
During the first months of treatment may experience breakthrough bleeding and spotting. If such bleeding or discharge appeared after some time after the start of therapy, or continues after
stopping treatment to determine their causes and exclude endometrial malignancy may require a biopsy of the endometrium.
endometrial cancer
Maximum risk assessment of endometrial cancer in women not receiving HRT, calculated on the basis of epidemiological data shows that approximately 5 out of every 1,000 women aged 50-65 years old will be diagnosed with endometrial cancer. Depending on the duration of treatment and estrogen dose risk of endometrial cancer among women receiving hormone replacement therapy of estrogen without a progestogen counteracts the effect of increases in 2-12 times as compared with that among women who have hormone replacement therapy has not been evaluated.
Mammary cancer

These randomized, placebo-controlled study of the Initiative "Women's Health" (WHI), and epidemiological studies, including large-scale Women's Health Research "Million Women" (MWS), indicate an increased risk of developing breast cancer in women who for several years conducted HRT estrogen, estrogen in combination with progestogen and tibolone. The degree of additional risk becomes apparent within a few years of HRT and increases with increasing duration of treatment. However, increased risk of falls to the initial level after several years (in most cases, after 5 years) after stopping treatment.
In women receiving substitution monotherapy with estrogens values of the relative risk (RR) of developing breast cancer obtained by reanalysis 51 epidemiological studies (in which> 80% of patients as HRT only received estrogens) and the results of epidemiological studies "Million Women" ( MWS), and comparable amount to 1.35 (95% CI: 1.21 - 1.49) and 1.30 (95% CI: 1.21 - 1.40), respectively.
According to several epidemiological studies, the overall risk of developing breast higher with combination HRT cancer estrogen and progestogen than in the estrogen monotherapy.
Supervisory findings "Million Women" (MWS) show that when comparing women who sometimes not received HRT patient receiving HRT various kinds of combined estrogen and progestogen are at higher risk of breast cancer development (OR = 2.00, 95% CI: 1.88 - 2.12) than women receiving estrogen monotherapy (oR = 1.30, 95% CI 1.21 - 1.40) or tibolone (RR = 1.45; 95% CI: 1 , 25-1,68).
According to research "Million Women" (MWS) value of the risk of breast cancer after 5.6 years of combined estrogen and progestogen hormone replacement therapy (CLE + IPA) is comparable to the placebo group, and is 1.24 (95% CI: 1.01 -1 54).
The magnitude of the absolute risk of developing breast cancer, calculated according to the study "Million Women" (MWS), and the project "Women's Health" (WHI), are as follows:
According to the study "Million Women" (MWS), starting from the known average incidence of cancer breast cancer in women in developed economies:
The expected incidence of breast cancer among women aged 50-64 years who are not taking HRT, will be 32 out of every 1,000 women.
! Women taking HRT now or in the recent past, the number of additional cases of breast cancer, based on 1,000 women for opredelosh first period will be:
Among patients receiving estrogen replacement therapy only:
- 0-3sluchaev per 1,000 women (average 1.5) for the duration of substitution therapy, 5 years;
- 3-7sluchaev per 1,000 women (mean 5) duration of therapy 10 years of age;
- among the patients who received the combined HRT of estrogen and progestogen 5-7sluchaev 1000 women (average 6) with a duration of 5 years replacement therapy;
- 18-20 cases per 1,000 women (average 19) for the duration of therapy for 10 years.
According to the study "Women's Health" (the WHI), after 5.6 years, the number of additional cases of invasive cancer of the breast in women aged 50 - 79 years who received combined estrogen and progestogen hormone replacement therapy (KLE- ± -MPA) was 8 cases per each 10 000 patient-years.
Based on clinical trial data, it was calculated that:
Out of every 1,000 women in the placebo group:
- 5 years approximately 16 women will be diagnosed with invasive breast cancer.
From each 1,000 women who received the combined HRT of estrogen and progestogen (CLE + MPA), the number of additional cases of breast cancer will be:
- 0-9sluchaev (average 4) replacement therapy duration of 5 years.
The MWS study relative risk of breast cancer was higher when added to the therapy of conjugated equine estrogens (CLE) or estradiol (E2), is adopted as a cyclic since in a continuous mode, a progestogen, and not dependent on the type of progestogen.
Evidence for a significant difference in the incidence of breast cancer depending on the method of administration, no.
The WHI study found that in breast cancer development in continuous replacement therapy background combined preparation containing conjugated equine estrogens and medroxyprogesterone acetate (CLE + IPA), neoplasm has a slightly larger size and more often metastasizes to regional lymph nodes when compared with the group placebo.
HRT, especially in combination therapy oestrogens and progestogens may increase mammographic image density (mammogram), which may conflict with radiological signs of breast cancer. In general, the number of additional cases of breast cancer in women aged 45-60 years, who take combined HRT cancer, is comparable with that of the women who are just starting HRT, and does not depend on the age at which HRT is started.
venous thromboembolism
HRT is associated with a higher relative risk of venous thromboembolism (VTE) - deep vein thrombosis or pulmonary embolism. The study found that 2-3-fold increase in risk of VTE during use of HRT. It was found that over the 5-year period does not have to undergo such treatment of patients the incidence of VTE is about 3 per 1000 women aged 50-59 years and 8 per 1000 - at the age of 60-69 years. According to a rough estimate, in healthy women who have 5 years of HRT, the number of additional cases of VTE over 5 years 2-6 (mean 4) per 1000 women aged 50-59 years and 5-15 (mean 9) per 1000 women aged 60-69 years. Greater likelihood of VTE during the first year of HRT than later. Usually,a risk factor for venous thromboembolism include cases of VTE history (including those in the immediate family) and the corresponding changes in coagulogram, significant obesity (body mass index> 30 kg / m2), Systemic lupus erythematosus. There is no consensus about the possible role of varicose veins in VTE development. HRT may increase the degree of such risk. It is necessary to analyze all cases of thromboembolism and / or miscarriages occurred in a personal or family history, in order to avoid predisposition to thrombophilia. Until then, until will be a corresponding examination, HRT is contraindicated. HRT for women receiving anticoagulants, can only be based on the benefit / risk of HRT. The risk of VTE may be temporarily increased with prolonged immobilization, including as a result of trauma, surgery, postoperative period.When planning operations necessary to consider whether the cessation of HRT for 4-6 weeks before the intervention in each case. Treatment should not be reopened until the normalization of coagulation and restore mobility. If VTE develops after initiating treatment, hormone therapy should be discontinued. The patient should stop the HRT immediately and inform your doctor at occurrence of symptoms such as pain and / or swelling of the lower limbs, sudden chest pain, shortness of breath.sudden chest pain, shortness of breath.sudden chest pain, shortness of breath.
Coronary artery disease
randomized controlled trials found no reduction in the incidence of cardiovascular disease against a background of continuous combined therapy of conjugated estrogens and medroxyprogesterone acetate (MPA). Data from two large clinical trials (WH1 and HERS - "Heart and Estrogen Replacement Therapy / progesterone") showed a possible increased risk of cardiovascular disease in the first year of treatment and lack of an overall clinical benefit. For evaluation of other drugs for hormone therapy, there is a limited number of data randomized controlled issledovshshy; studying the effect on cardiovascular morbidity and mortality,. Therefore, it is unclear whether these findings also extend to other HRT products.
Harushenie cerebral krovoobrasheniya / stroke
In a large randomized clinical trial within the WHI found an increased risk of cerebral blood flow in healthy women during combined HRT (CLE + MPA). Thus, in the absence of HRT, the number of cases of cerebrovascular accidents per 1000 women for 5 years was about 3 - at the age of 50-59 years, and about 11 - at the age of 60-69 years. 1000 women using conjugated estrogens and MPA in techenie.5 years, the number of additional cases of cerebrovascular accidents ranged from 0 to 3 (mean 1) - at the age of 50-59 and 1-9 (mean 4) - at the age of 60-69. It is not known whether this increased risk extends to other HRT products.
ovarian cancer
According to some epidemiological studies, the use of estrogen alone or in combination with a progestogen for 5-10 years accompanied by an increased risk of developing ovarian cancer.
Other conditions
Estrogens can cause fluid retention, which may worsen the condition of patients with impaired cardiac or renal function. Before the drug Evian ® in ESRD circulating levels of active components increases.
Also, careful screening and monitoring during hormone replacement therapy to be a woman with a history of hypertriglyceridemia, as in the treatment of estrogen may significantly increase the content of triglycerides in plasma, leading to pancreatitis.
Estrogens increase the concentration of thyroxine-binding globulin, which leads to an increase in the total concentration of circulating thyroid hormones identified by the content of protein-bound iodine, thyroxine (by means of column chromatography or radioimmunoassay), triiodothyronine (RIAs study). The concentrations of free thyroxine and triiodothyronine remains unchanged.
May increase the concentration of other serum binding proteins, including corticoid-binding globulin and binding globulin sex hormones, which leads to increased concentrations of circulating corticosteroids and sex hormones. The concentrations of free or biologically active hormones do not change.
May increase the concentration and other plasma proteins - angiotensinogen / renin, alpha1-antitrypsin, ceruloplasmin.
There is insufficient evidence to improve cognitive function. Moreover, when the behavior of the WHI - study shows an increase in possible risk of dementia during combined (CLE + MPA) hormone replacement therapy in women older than 65 years. It is not known whether this applies to other drugs hormone replacement therapy and / or the use of HRT in younger postmenopausal women.
Evian ®It contains lactose. Before you assign the drug to patients with rare hereditary disease - congenital lactase deficiency, lactose intolerance and glucose-galactose malabsorption should carefully assess the severity of the condition. In the case of the appointment of the drug in such patients, they should be under close medical supervision.
Impact on the ability to drive vehicles and manage mechanisms

Unknown.
OVERDOSE

In case of overdose can cause nausea and vomiting.
Treatment: symptomatic.

DRUG INTERACTION

While the use of inducers of microsomal enzymes, especially cytochrome P450 enzymes, such as anticonvulsants (e.g., phenobarbital, feiitoin, carbamazepine), and anti-infective agents (e.g., rifampicin, rifabutin, nevirapine, efavirenz), possibly acceleration of metabolism of estrogen and progesterone. In contrast, ritonavir and nelfinavir, although they are strong inhibitors, while applying with steroid hormones exhibit inducing properties.
Herbal medicines, which include St. John's wort flrypericum perforatum), may stimulate the metabolism of estrogens and progestogens.
Increased metabolism of estrogens and progestogens may be manifested clinically reduce the effect of the drug and a change in the nature of uterine bleeding.
Drugs that suppress the activity of microsomal liver enzymes, including ketoconazole may increase circulating kontsontratsiyu components Evian preparation ® .
TERMS OF RELEASE FROM PHARMACY

The drug is released by prescription.

TERMS AND CONDITIONS OF STORAGE

Store at a temperature not exceeding 25 ° C.
Do not store in the refrigerator. Keep out of the reach of children.
Shelf life - 30 months.
Do not use after expiry date.
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