Triksvens - instructions for use, dose, side effects, contraindications

film sheatha: hypromellose - 0.887 mg; talc - 0.444 mg; titanium dioxide E171 - 0.259 mg; blue paste (indigocarmine E132 and macrogol 400) - 0.259 mg.

1 white tablet contains:

active substances: Estradiol (in the form of estradiol hemihydrate) - 2 mg and norethisterone - 1 mg;

Excipients: lactose monohydrate - 37.4 mg; corn starch - 37.4 mg; gelatin - 1.0 mg, talc - 0.8 mg; magnesium stearate - 0.4 mg;

film sheath: hypromellose - 0.821 mg; triacetin - 0.043 mg.

1 tablet of red color contains:

active substance: Estradiol (in the form of estradiol hemihydrate) - 1 mg;

Excipients: lactose monohydrate - 38.4 mg; corn starch - 38.4 mg; gelatin - 1.0 mg, talc - 0.8 mg; magnesium stearate - 0.4 mg;

film sheath: hypromellose - 0.720 mg; talc - 0.360 mg; titanium dioxide E171 - 0.216 mg; red paste (iron oxide red E172, titanium dioxide E171 and propylene glycol) - 0.144 mg.

Description:

12 tablets, film-coated, blue, round, biconvex, engraved "NOVO 280".

10 tablets, film-coated, white, round, biconvex, engraved "NOVO 281".

6 tablets, film-coated, red, round, biconvex, engraved "NOVO 282".

Pharmacotherapeutic group:antimycotics combined (estrogen + progestogen)

ATX: & nbsp

G.03.F.B.05 Norethisterone and estrogen

Pharmacodynamics:

Combined preparation containing estrogen and progestogen for successive hormone replacement therapy (HRT).

Estradiol: synthetic 17β-Extradiol, is chemically and biologically identical to human endogenous estradiol. Eliminates estrogen deficiency in postmenopausal women and alleviates menopause symptoms, and also prevents bone loss during menopause or oophorectomy.

Norethisterone: Since estrogens stimulate the growth of the endometrium,

exclusively estrogen increases the risk of endometrial hyperplasia and endometrial cancer. The addition of progestogen significantly reduces the estrogen-induced risk of endometrial hyperplasia in women who have not undergone hysterectomy.

Attenuation of the symptoms of menopause occurs within the first few weeks of treatment. The termination of regular menstrual bleeding occurs in 93% of women with an average duration of 3-4 days.

Deficiency of estrogen during the menopause is associated with an increase in the rate of bone tissue renewal and 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 decrease in bone mass occurs in the same degree as in women who have not undergone treatment. Study WHI and meta-analyzes of various 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 caused by 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.

Studies based on the measurement of bone mineral density, show that Trisekvens® effective as a drug that prevents osteoporosis in postmenopausal women. After 2 years of treatment, the mineral density of the bone mass of the spinal column increases by 5.14%, and the hip joint by 3.12%.

Pharmacokinetics:

After oral administration 17β-estradiol in micronized form occurs its rapid absorption in the gastrointestinal tract. The drug is subjected to primary metabolism in the liver and intestines. A maximum plasma concentration of approximately 44 pg / ml (30-53 pg / ml) is achieved 6 hours after taking 2 mg. Half-life 17β-Extradiol is about 18 hours. It circulates in the blood as a complex with globulin, binding sex hormones SHGG (37%), and albumin (61%), and only 1-2% remains unbound. Metabolism 17β-estradiol occurs mainly in the liver and intestines, as well as target organs and includes the formation of less active and inactive metabolites, including estrone, catechol estrogens and various estrogen sulfates and glucuronides. Estrogens are released together with bile, where they are partially hydrolyzed and again enter the intestinal hepatic circulation (recirculation), and the bulk of estrogens is excreted from the body together with urine in a biologically inactive form.

After oral administration norethisterone rapidly absorbed and converted into norethisterone (NET). The maximum plasma concentration, approximately 9 ng / ml (6-11 ng / ml), is achieved 1 hour after taking 1 mg. The half-life of the NET is approximately 10 hours. NET binds to SHBG (36%) and albumin (61%). It is subjected to presystemic metabolism in the liver and intestine. The most important metabolites of NET are isomers of 5α-dihydro-NET and tetrahydro-NET, which are excreted mainly with urine in the form of sulfate or glucuronide conjugates.

In elderly people, pharmacokinetic studies have not been conducted.

Indications:

Hormone replacement therapy (HRT) in women with symptoms of estrogen deficiency.

Prevention of osteoporosis in postmenopausal women in the presence of a high risk of fracture in those patients who do not tolerate or which are contraindicated in other drugs intended for the prevention of osteoporosis.

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

Contraindications:

- Breast cancer (established, in anamnesis, and also suspicion of it)

- An established or suspected estrogen-dependent tumor (including endometrial cancer)

- Pathological bleeding from the genitals of an unclear etiology.

- Untreated endometrial hyperplasia

- Recently transferred or in the active phase of venous thromboembolic diseases (deep vein thrombosis, pulmonary embolism, pulmonary embolism)

- Recently transferred or in the active phase arterial thromboembolic diseases (including angina pectoris, myocardial infarction)

- Acute liver disease or liver disease in an anamnesis, in which the liver function was not normalized

- Congenital lactase deficiency, lactose intolerance, glucose-galactose malabsorption

- Hypersensitivity to the active substance or other components that make up the drug

- Porphyria

Carefully:

If the patient has any of the diseases listed below and / or if the disease occurred earlier and / or worsened during pregnancy or previous hormonal treatment, then such a patient should be under close medical supervision. It should be taken into account that these diseases can recur or worsen during the treatment with Trisekvens®, especially in the following diseases:

- Leiomyoma (uterine fibroadenoma) or endometriosis (see below)

- Risk factors for thromboembolism or history of thromboembolism (see below)

- Risk factors for the development of estrogen-dependent tumors (for example, the presence of relatives of the first degree of kinship, suffering from breast cancer)

- Arterial hypertension

- Diseases of the liver (including liver adenoma)

- Diabetes mellitus with or without vascular disease

- Chololithiasis

- Migraines or severe headaches

- Systemic lupus erythematosus

- Endometrial hyperplasia in the anamnesis (see below)

- Epilepsy

- Bronchial asthma

- Otosclerosis

Pregnancy and lactation:

Trisequence® is not indicated during pregnancy.

If pregnancy occurs on the background of treatment with Trisekvens®, then treatment should be stopped immediately.

Data based on a limited number of pregnancies, during which patients took hormonal drugs, indicate the adverse effect of norethisterone on the fetus. At doses exceeding those commonly used in HRT, masculinization of female fetuses was observed. The results of most of the epidemiological studies conducted to date, relating to the unintentional effects on the fetus of combined estrogen and progestogen compositions, indicate the absence of teratogenic and fetotoxic effects.

Reception of the drug Trisekvens® is not indicated during the period of breastfeeding.

Dosing and Administration:

Trisequens® is a drug for permanent, consistent use for HRT. Tablets containing estrogen are taken continuously. Tablets containing progestagen are added sequentially over 10 days of each 28-day cycle. Take 1 tablet orally 1 time per day, without interruption, preferably at the same time each day.Begin taking pills containing estradiol (blue tablet) for 12 days, followed by treatment with estradiol / norethisterone (white tablet) for the next 10 days and then with estradiol (red tablet) for 6 days. During the action phase of the red tablets, the functional layer of the endometrium is regularly separated. After taking the last tablets of red, the treatment is continued, taking the first tablet of the blue color from the new package the next day.

Women with amenorrhea who do not take HRT drugs, or women with irregular bleeding, or women who are transferred with continuous therapy with combined HRT drugs, can start treatment with Triesquens® on any convenient day. Women switching from another regimen of coherent HRT or women still continuing the course of sequential HRT, treatment with Triesquens® should be started on the 5th day of the period. To begin and continue treatment for postmenopausal symptoms, the lowest effective dose should be given for the shortest period (see "Special instructions").The appointment of a higher dose of the combined drug may be indicated if the response to a drug after three months of treatment is not sufficient to satisfactorily alleviate the symptoms.

If the patient forgot to take one pill, then the forgotten pill should not be taken. Bypassing the drug may increase the chance of resuming vaginal bleeding and the appearance of smearing vaginal discharge.

In all cases, at least once a year, a careful assessment of the risk-benefit ratio should be carried out and HRT should be continued only as long as the benefits from the use of the drug exceed the risk of associated side effects.

Side effects:

Clinical experience

Side effects most frequently encountered in clinical trials of the Trisekwens® drug include vaginal bleeding and pain / tenderness in the mammary gland, reported by approximately 10% to 20% of patients. Vaginal bleeding usually occurred during the first months of treatment. The pain in the mammary glands usually disappeared after several months of treatment.All adverse events observed in randomized clinical trials of Tricequence® or similar HRT with a higher frequency than placebo, and which are generally believed to be associated with HRT are presented below.

Violations of the genitals and mammary gland

Very often (> 1/10): pain or pain in the mammary glands, menstrual irregularities or menorrhagia.

Often (> 1/100; <1/10): swelling or enlargement of the mammary glands, an increase or relapse of the uterine fibroadenoma or the development of a primary uterine fibroadenoma.

Infrequently (> 1/1 000; <1/100): endometrial hyperplasia, dysmenorrhea.

Infections and invasions

Often (> 1/100; <1/10): vaginal candidiasis or vaginitis.

Disorders from the metabolism and nutrition

Often (> 1/100; <1/10): fluid retention.

Disorders of the psyche

Often (> 1/100; <1/10): Depression or worsening of depression.

Infrequently (> 1/1 000; <1/100): nervousness.

Disturbances from the nervous system

Often (> 1/100; <1/10): headache, migraine, or exacerbation of migraine.

Disorders from the gastrointestinal tract

Often (> 1/100; <1/10): nausea, abdominal pain, flatulence, or abdominal discomfort.

Infrequently (> 1/1 000; <1/100): flatulence or bloating.

Disturbances from musculoskeletal and connective tissue

Often (> 1/100; <1/10): pain in the back, cramps in the calf muscles.

General disorders and disorders at the site of administration

Often (> 1/100; <1/10): peripheral edema, weight gain.

Immune system disorders

Infrequently (> 1/1 000; <1/100): hypersensitivity reactions.

Vascular disorders

Infrequently (> 1/1 000; <1/100): thrombophlebitis of superficial veins.

Rarely (> 1/1 0000; <1/1000): pulmonary embolism, deep vein thrombophlebitis.

Disturbances from the skin and subcutaneous tissues

Infrequently (> 1/1 000; <1/100): alopecia, hirsutism or acne, an itchy rash or hives.

Other

Infrequently (> 1/1 000; <1/100): no effect of the drug.

Experience in the post-marketing use of the drug

In addition to the aforementioned adverse reactions that occur with the use of Trisekvens®, listed below are those adverse reactions that may be related to treatment with Triesequens®.

The incidence of such adverse reactions can be classified, as very rarely (<1 / 100,000 patient-years):

- Benign and malignant neoplasms (including cysts and polyps): endometrial cancer

- Disorders of the psyche: insomnia, anxiety, changes in libido

- Disturbances from the nervous system: dizziness, impaired cerebral circulation

- Disturbances on the part of the organ of vision: visual impairment

- Vascular disorders: exacerbation of hypertension

- Heart Disease: myocardial infarction

- Disorders from the gastrointestinal tract: dyspepsia, vomiting

- Disturbances from the liver and biliary tract: cholecystitis,

cholelithiasis, exacerbation of cholelithiasis

- Disorders from the skin and subcutaneous tissues: seborrhea, rash,

angioedema

- Violations of the genitals and mammary gland: vulvovaginal pruritus

- Other: weight loss, increased blood pressure.

Mammary cancer

According to a large number of epidemiological studies and one randomized placebo-controlled study conducted by the Women's Right to Health organization (WHI, Women’s Health Initiative study), the overall risk of developing breast cancer increases with the duration of HRT.

The relative risk assessment, obtained by re-analysis of the original data 51 epidemiological studies (in which more than 80% of women undergoing HRT with estrogen only) and the result of the analysis of the epidemiological study data "Million women" (MWS, Million Women Study) are practically the same: 1.35 (confidence interval 95%, 1.21 - 1.49) and 1.30 (confidence interval 95%, 1.21-1.40), respectively.

The results of individual epidemiological studies indicate, in general, a higher risk of developing breast cancer in women undergoing combined hormone replacement therapy (estrogen plus progestogen), compared with those who took estrogens alone.

Research data MWS show that compared to women who have never undergone HRT, the use of different types of combined (estrogen plus progestogen) HRT is associated with a higher risk of developing breast cancerRR = 2.00, at 95% confidence interval: 1.88-2.12), compared with those who took only estrogens (RR = 1.30, with 95% confidence interval 1.21-1.40) or took tibolone (RR= 1.45, 95% confidence interval: 1.25-1.68).

According to the research WHI For all women enrolled in combined (estrogen plus progestogen) HRT for 5.6 years, the risk was 1.24 (95% confidence interval: 1.01 to 1.54) compared with placebo.

Absolute risk indicators calculated from research data MWS and WHI, are presented below:

Using the known proportion of the disease of women with breast cancer in developed countries, in the study MWS found that:

- Breast cancer is diagnosed in about 32 out of 1000 women who do not use HRT, between the ages of 50 and 64 years.

- For 1000 women undergoing or recently undergoing HRT, the number of additional cases of breast cancer development during the relevant period will be:

With substitution therapy only estrogen:

between 0 and 3 (the most accurate estimate = 1.5) with a 5-year course
between 3 and 7 (the most accurate estimate = 5) with a 10-year course

When combined, estrogen plus progestogen, HRT:

between 5 and 7 (the most accurate estimate = 6) with a 5-year course
between 18 and 20 (the most accurate estimate = 19) with a 10-year course.

A study conducted by the WHI found that after a course of treatment of 5.6 years in women between the ages of 50 and 79 years, the development of 8 additional cases of invasive breast cancer per 10,000 women may be due to a combined, estrogen plus progestogen, HRT CEE + MRA). Based on the calculations carried out in the study, it is established that:

- For 1,000 women taking placebo, approximately 16 cases of invasive breast cancer can be diagnosed within 5 years.

- For 1000 women who took a combined, estrogen plus progestogen, HRT (CEE + MRA), the number of additional cases could range from 0-9 (the most accurate estimate = 4) in 5 years of use.

The number of additional cases of breast cancer in women who take HRT is similar for women who started HRT, regardless of age at the start of therapy (between 45 and 65 years of age).

Endometrial cancer

The risk of endometrial hyperplasia and endometrial cancer in women with an intact uterus increases with the duration of intake of exclusively estrogen. According to epidemiological studies on the most accurate risk assessment, it is expected that approximately 5 out of 1000 women who do not undergo HRT can be diagnosed with endometrial cancer between the ages of 50 and 65 years. Depending on the duration of treatment and the dose of estrogen, the increased risk of developing endometrial cancer among patients taking exclusively estrogen, according to available data, varies from 2 to 12 times, compared to patients not taking estrogens.The addition of progestogen to monotherapy with estrogen alone significantly reduces this risk.

Other adverse reactions reported in connection with treatment with the estrogen / progestogen combination are:

- Disturbances from the skin and subcutaneous tissues: chloasma, exudative polymorphic erythema, erythema nodosum, vascular purpura.

- Possible dementia (see "Special instructions").

Overdose:Overdose may cause nausea and vomiting.

Treatment is symptomatic.

Interaction:

Metabolism of estrogens and progestogens can increase with the concomitant use of substances known as inducers of drug metabolism isozymes, in particular cytochrome P450 isoenzymes such as antiepileptic agents (for example, phenobarbital, phenytoin, carbamazepine) and antibiotics (for example, rifampicin, rifabutin, nevirapine, efavirenz).

Although ritonavir and nelfinavir are known as potent inhibitors, with concomitant use with steroid hormones, they exhibit stimulating properties on the metabolism of estrogens and progestogens.

Herbal preparations containing St. John's Wort (perforated)Hypericum perforatum), can also stimulate the metabolism of estrogens and progestogens.

Clinically, increased metabolism of estrogens and progestogens can lead to decreased efficacy and changes in the nature of uterine bleeding.

Drugs that inhibit the activity of hepatic microsomal enzymes of drug metabolism, for example, ketoconazole, can increase the concentration of active substances of the preparation Trisekvens®.

Special instructions:

When deciding whether to use HRT for the treatment of postmenopausal symptoms, it should only be started if there are symptoms that reduce the patient's quality of life. The frequency of medical examinations is individual, but at least 1 time in 6 months - to assess the need for further HRT. In all cases, HRT should at least continue until the benefits of using the drug exceed the risk of associated side effects.

Medical examination / control

Before starting or resuming HRT, the patient's medical history and family history should be studied.In this case, you should conduct a physical examination (including pelvic organs and mammary glands) and take into account contraindications and special precautions during use. During the treatment it is recommended to conduct periodic examinations of the patient, the frequency and volume of which must be selected for each patient individually. Women should be advised to report their observed changes in the mammary glands to the doctor or nurse (see "Mammary cancer"). In accordance with the currently accepted screening practice, examinations, including mammography, adjusted according to individual clinical indications should be carried out.

Reasons for immediate withdrawal of treatment

Treatment should be interrupted if a contraindication is found in the following situations:

- Jaundice or liver dysfunction

- Significant increase in blood pressure

- A new attack of a migraine headache

- Pregnancy

Endometrial hyperplasia

The risk of developing hyperplasia and endometrial cancer increases when certain estrogens are introduced for a long period of time (see "Side effects").The addition of progestogen to women who have not undergone hysterectomy for at least 10 days per cycle significantly reduces this risk. The development of bleeding and the appearance of spotting can occur during the first months of treatment. If the development of bleeding or the appearance of smearing secretions occurs some time after the start of treatment or continues after discontinuation of treatment, then the cause of this phenomenon should be investigated, for which an endometrial biopsy is done to exclude the possibility of malignant formation in the endometrium.

Mammary cancer

A randomized, placebo-controlled trial with WHI (Women’s Health Initiative study), as well as epidemiological studies, including MWS (Million Women Study), showed that there is an increased risk of developing breast cancer in women taking estrogens, estrogen-progestogen combinations or tibolone in the process of HRT for several years (see "Side effects"). In all cases of HRT over several years the risk is higher than normal and it increases with the duration of admission, but returns to its initial state for several years (maximum five) after discontinuation of treatment.

In the study MWS the relative risk of breast cancer associated with the administration of conjugated equine estrogens or estradiol (E2) was higher when the progestogen was added either sequentially or permanently, regardless of the type of progestogen. Data on the existence of a difference in risk for different routes of drug intake are not available.

In the study WHI Continuous use of the combined preparation on the basis of conjugated equine estrogen and medroxyprogesterone acetate (MPA) was associated with the development of breast cancer, which was slightly larger in size, and metastases to regional lymph nodes were more frequent than in placebo. In HRT, especially with the combined treatment of estrogen-progestogen, there is an increase in the density of mammographic images, which can make it difficult to radiological detection of breast cancer.

Venous thromboembolism

HRT is associated with a higher relative risk of venous thromboembolism (VTE), namely vein thrombosis or pulmonary embolism. In one randomized controlled trial and in epidemiological studies,a two to threefold increase in the risk for patients using HRT, compared with those who did not undergo this course of treatment. It was found that for women who did not undergo this course of treatment, the number of cases of VTE occurring over a 5-year period is approximately 3 per 1000 women aged 50-59 years and 8 per 1000 women aged 60-69 years. According to a rough estimate in healthy women who used HRT for 5 years, the number of additional cases of VTE for 5 years is 2-6 (the most accurate estimate = 4) per 1,000 women aged 50-59 years and 5-15 (the most accurate estimate = 9) per 1,000 women aged 60-69 years. The onset of this event is more likely in the first year of HRT than in the following period. To the recognized risk factors for the development of VTE are the severe personal obesity in the personal or family history (body mass index> 30 kg /m²) and systemic lupus erythematosus. There is no consensus on the possible role of varicose veins in the development of VTE. Patients with a history of VTE or known thrombophilic status have an increased risk of developing VTE. HRT may increase the risk. It is necessary to investigate seriouscases of thromboembolism or recurring cases of spontaneous abortion in a personal or family history in order to exclude a predisposition to thrombophilia. Until a thorough evaluation of thrombophilic factors or anticoagulant treatment is initiated, the appointment of HRT to such patients should be considered contraindicated. For the appointment of HRT to those women who are already taking anticoagulants, you must carefully weigh the benefit / risk ratio of HRT use. The risk of VTE may temporarily increase with prolonged immobilization, extensive trauma or radical surgery. In the postoperative period careful attention should be given to preventive measures to prevent cases of VTE. If the planned operation entails a state of prolonged immobilization, in particular, it may occur with abdominal intervention or orthopedic surgery of the lower extremities, it is necessary to consider temporarily suspending HRT 4-6 weeks before surgery. Treatment should not be resumed until the woman has acquired full mobility.

If VTE develops after the start of treatment, medication should be discontinued. Immediately, as soon as the patient noticed a possible thromboembolic symptom (painful puffiness of the lower limb, sudden chest pain, shortness of breath), he should inform his doctor about it.

Cardiac ischemia

Based on randomized controlled trials, conclusions can not be drawn about the benefits of continuous use of equine estrogens and MPA. Two large clinical studies (WHI and HERS i.e. Heart and oestrogen/progestin Replacement Study) showed the possibility of an increased risk of cardiovascular morbidity in the first year of the combination and generally showed no benefit. For other HRT preparations, only limited data are available from the results of randomized, controlled trials evaluating their effect on the incidence of the cardiovascular system or mortality.

Therefore, it remains unclear whether this influence also extends to other HRT preparations.

Violation of cerebral circulation

A large randomized clinical trial (WHI) revealed, as a secondary result,increased risk of development of ischemic stroke in healthy women who underwent continuous treatment with a combination of equine estrogens and MPA. According to the evaluation, in women who have not undergone HRT, the number of cases of cerebral circulation that may occur during 5 years is approximately 3 per 1,000 women aged 50-59 years and 11 cases per 1000 women aged 60-69 years . In those women who took a combination of conjugated estrogens and MPA for 5 years, the number of additional cases of cerebral circulation disorder ranges from 0 to 3 (the most accurate estimate is 1) per 1000 women aged 50-59 years, and 1-9 cases per 1000 women aged 60-69 years (the most accurate estimate = 4). Data on whether this increased risk for other HRT drugs are unknown.

Ovarian Cancer

Prolonged use (at least for 5-10 years) of only estrogen preparations for HRT in women with a distant uterus is associated in some epidemiological studies with an increased risk of ovarian cancer. It remains unclear whether prolonged use of combined HRT drugs increases the risk of ovarian cancer, compared with the risk associated with the use of only estrogen-containing drugs.

Other states

Estrogens can lead to fluid retention in the body, and therefore patients with dysfunction of the cardiovascular system or kidneys should be closely monitored. Patients with terminal renal insufficiency should be closely monitored, as the level of circulating active components is expected to increase with the use of Trisequens®.

Women with hypertriglyceridemia who are history should be closely monitored in HRT, as there are reports that, in this condition, rare cases of a significant increase in triglyceride levels in plasma that lead to pancreatitis are noted in estrogen treatment.

Estrogens increase the concentration of thyroxine-binding globulin, which leads to an increase in the total concentration of circulating thyroid hormones determined by the content of protein-bound iodine, thyroxine concentration (determined by column chromatography or radioimmunoassay) or triiodothyronine (determined by radioimmunological examination).The level of absorption of triiodothyronine (T3) decreases, indicating an increase in the concentration of thyroxin-binding globulin (TSH). The concentrations of free thyroxine (T4) and triiodothyronine (T3) remain unchanged. Concentrations of other binding proteins of blood serum can be increased, incl. corticoid-binding globulin, globulins, binding sex hormones, which leads to an increase in the concentration of circulating corticosteroids and sex hormones, respectively. Concentrations of free or biologically active hormones do not change. The concentration of other plasma proteins (angiotensinogen / renin substrate, alpha1-antitrypsin, ceruloplasmin) can also increase.

There is no conclusive evidence of improvement cognitive function. There is obtained in WHI research some evidence of the existence of the risk of possible dementia in women who after age 65 began to constantly take a combination drug containing equine estrogens and MPA. It is not known whether this applies to women at a younger age in the postmenopausal state or to other HRT preparations.

Trisequens® does not have a contraceptive effect.

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

Unknown.

Form release / dosage:Film-coated tablets.

Packaging:

For 28 tablets (12 blue, 10 white, 6 red), packed in a plastic calendar disk.

1 calendar disk with instructions for use in a cardboard box.

Storage conditions:

Store at a temperature not exceeding 25 ° C.

Do not freeze.

Keep the disc with tablets in a cardboard box.

Keep out of the reach of children.

Shelf life:

4 years.

Do not use after expiry date.

Terms of leave from pharmacies:On prescription

Registration number:П N013450 / 01

Date of registration:28.09.2011

Date of cancellation:2017-01-31

The owner of the registration certificate:Novo Nordisk A / SNovo Nordisk A / S Denmark

Manufacturer: & nbsp

NOVO NORDISK, A / S Denmark

Representation: & nbspNOVO NORDISK TOVNOVO NORDISK TOVDenmark

Information update date: & nbsp31.01.2017

Illustrated instructions

Instructions

Triesequence® (Trisequens®)