Dienil (Climodien) tablets 21pcs - Instructions

Pharmacological properties of the drug Climodien

Climodien contains estradiol valerate, which is a prodrug of 17β-estradiol, and a synthetic progestogen, dienogest. The inclusion of estradiol in the drug provides hormone replacement therapy (HRT) after the onset of the menopausal period, as well as effective treatment of psycho-vegetative symptoms of menopause: hot flashes, episodes of increased sweating, sleep disturbances, nervousness, irritability, dizziness, headache, degenerative changes in the skin and mucous membranes genitourinary system, namely urinary incontinence, dryness and irritation of the vaginal mucosa, dyspareunia. The inclusion of dienogest in a continuous therapy regimen prevents the development of endometrial hyperplasia and leads to its atrophy, as well as a decrease in the severity and, in many cases, a further cessation of vaginal bleeding. After 3 months of therapy, menstrual bleeding stopped in approximately 67% of women, and after 12 months - in 85%. The results of clinical studies show that when using the drug Climodien, the total level of cholesterol and LDL decreases, and the level of HDL increases, as a result of which the HDL/LDL ratio increases significantly. It is believed that estrogens have a direct effect on the vascular system. During the use of the drug Climodien, the level of marker substances in the urine associated with the vasodilatory effect increases. Estradiol inhibits postmenopausal bone loss caused by estrogen deficiency. Long-term HRT has been shown to reduce the risk of distal bone fractures in postmenopausal women, mainly due to inhibition of osteoclast function, which promotes the formation of new bone tissue during the process of bone remodeling. This effect of Climodien was demonstrated by measuring specific bone markers such as ALP, pyridinoline and deoxypyridinoline compounds. The results of clinical studies involving women with sleep disorders caused by postmenopausal syndrome prove that the use of Climoden improves the quality of sleep. Based on observational data using a combination of conjugated equine estrogens with medroxyprogesterone acetate, it is assumed that the incidence of colon cancer in women receiving HRT is reduced. In a study with conjugated equine estrogens monotherapy, no reduction in this risk was observed; It is unknown whether these findings apply to other HRT medications. Dienogest, considered the only nortestosterone derivative with antiandrogenic properties, has a pronounced progestogenic effect. This in vivo may be explained by its high serum concentration after oral administration; 10% of the substance in the blood is present in the form of unbound free steroid. The mechanism of action of dienogest does not involve inhibition of cytochrome P450 in vitro , therefore dienogest is not expected to interact with other drugs at this level. The toxicity profile of estradiol and estradiol valerate has been well studied. There is no preclinical data to supplement the information provided in the instructions regarding the safety of estradiol valerate. Data from preclinical studies based on the results of standard studies of safety, toxicity with single and repeated use of genotoxicity, reproductive toxicity and carcinogenicity of the drug were not identified. Estradiol valerate Estradiol valerate is rapidly and completely absorbed. During absorption and first passage through the liver, the steroid ester is broken down into estradiol and valeric acid. Estradiol is further metabolized into estrone, estriol and estrone sulfate. After oral administration of estradiol valerate, only about 3% of estradiol is bioavailable. Eating food does not affect the bioavailability of estradiol. Within 60 minutes after taking the tablet, the concentration of estradiol in the serum increases rapidly and reaches an average value (approximately 18 pg/ml). After this, the concentration of the steroid in the blood serum slowly increases to a maximum, which is about 30 pg/ml, and is reached approximately 8 hours after taking the tablet. Estradiol binds to albumin and sex steroid binding globulin (SGBS). Only 1–1.5% of the total serum estradiol concentration exists in an unbound state, and 30–40% is bound to sex steroid binding globulin. After breaking the ester bond of exogenously administered estradiol valerate, the metabolism of the substance occurs in the same way as endogenous estradiol. Estradiol is primarily metabolized in the liver, but also outside it (eg in the intestines, kidneys, skeletal muscles and target organs). During metabolism, estrone, estriol, catecholestrogens and conjugates of these compounds with sulfuric and glucuronic acids are formed. Within 24 hours after a single oral dose of estradiol valerate, serum estradiol levels decrease to 10 pkg/ml. The half-life until the terminal phase cannot be accurately determined. Estradiol metabolites are excreted from the body in the form of sulfates and glucuronides in the urine. After repeated use, serum estradiol levels are more than 3 times higher (compared to a single dose). On average, the concentration of estradiol ranges from 40 pg/ml (minimum) to 90 pg/ml (maximum). After completion of therapy with Climodien, the levels of estradiol and estrone observed at the beginning of treatment are achieved over the next 2–3 days. Dienogest After oral administration, dienogest is rapidly and completely absorbed. The maximum serum concentration is reached within 1 hour after a single oral dose and is approximately 54 pg/ml. The absolute bioavailability of dienogest after oral administration exceeds 90%. Dienogest binds to albumin and does not bind to SHBG or corticoid-binding globulin (CBG). Only 10% of the total dienogest serum concentration is in the form of free steroid, and 90% is nonspecifically bound to albumin. Dienogest is completely metabolized primarily by hydroxylation, but also by hydrogenation, conjugation and the formation of aromatic compounds to form inactive metabolites. The clearance of metabolites from serum is approximately 0.85 ml/min/kg. Serum dienogest levels decrease biphasically. The final phase is characterized by a half-life of about 11 hours. Dienogest is not excreted unchanged. Metabolites are excreted mainly by the kidneys. The pharmacokinetics of dienogest does not depend on the level of SHB. When taken daily, the concentration of the substance in the serum increases by 1.3 times, reaching a steady state during the first half of the treatment cycle.

Climodien®

Climodien is not used for contraception.

If contraception is necessary, non-hormonal methods should be used (with the exception of calendar and temperature methods).

If any of the following conditions, diseases or risk factors are present or worsening, the risk-benefit ratio of treatment should be assessed individually for each woman before starting or continuing HRT.

It is necessary to immediately stop HRT if the following disorders occur:

- the first occurrence of migraine or any unusually frequent or unusually severe headaches, sudden impairment of vision or hearing, as well as other symptoms indicating the possibility of cerebrovascular occlusion;

- development of jaundice, including recurrence of cholestatic jaundice or cholestatic itching, which were first observed during pregnancy or previous treatment with sex steroid hormones;

- the appearance of symptoms of thrombotic disorders or if their occurrence is suspected. If the health status changes and/or risk factors appear (the emergence of new disorders, worsening of existing ones), it is necessary to re-evaluate the risk/benefit ratio of the therapy for the patient, without excluding the possibility of discontinuing treatment.

Venous thromboembolism

A number of controlled randomized as well as epidemiological studies have revealed an increased relative risk of developing venous thromboembolism (VTE) during HRT, i.e. deep vein thrombosis or pulmonary embolism. Therefore, when prescribing HRT to women with risk factors for VTE, the risk-benefit ratio of treatment should be carefully weighed and discussed with the patient.

Risk factors for developing VTE include individual and family history (the presence of VTE in first-degree relatives at a relatively young age may indicate a genetic predisposition) and severe obesity. The risk of VTE also increases with age. The possible role of varicose veins in the development of VTE remains controversial.

The risk of VTE may temporarily increase with prolonged immobilization, “major” elective and trauma surgeries, or major trauma.

Depending on the cause or duration of immobilization, the question of the advisability of temporarily stopping HRT should be decided.

Arterial thromboembolism

Large clinical trials using conjugated equine estrogens (CEE) and medroxyprogesterone acetate (MPA) found a small increase in the risk of coronary heart disease (CHD) in the first year of use, followed by a lack of benefit against CHD.

One large clinical trial using CLE alone found a potential reduction in the incidence of CAD in a subgroup of women aged 50–59 years, but no overall reduction in the incidence of CAD among all women in the study. As a secondary outcome, two large clinical trials using CLE as monotherapy or in combination with MPA found a 30-40% increase in the risk of stroke. It is unknown whether these data can be extrapolated to other drugs for HRT, including those not administered orally.

Gallbladder diseases

It is known that estrogens increase the lithogenicity of bile. Some women are predisposed to developing gallstones when treated with estrogen.

Dementia

There is limited evidence from clinical trials with conjugated equine estrogens containing products to suggest that hormonal therapy first started in women aged 65 years or older may increase the risk of eventual dementia. However, the risk of developing dementia may be reduced if treatment is started in early postmenopause, as has been observed in other studies. It is not known whether these data may apply to other HRT drugs.

Endometrial cancer

With long-term estrogen monotherapy, the risk of developing endometrial hyperplasia or carcinoma increases. Studies have confirmed that the addition of gestagens prevents an increase in the risk of endometrial hyperplasia and cancer.

Mammary cancer

Clinical trials and observational studies have found an increase in the relative risk of developing breast cancer (BC) in women who have used HRT for several years compared with women of the same age who have never received it. This may be due to earlier diagnosis, accelerated growth of an existing tumor during HRT, or a combination of both factors.

The increased risk of breast cancer has been suggested based on the results of more than 50 epidemiological studies (risk ranges from 1 to 2). Two large randomized trials of conjugated equine estrogens (CEE) alone or chronically combined with medroxyprogesterone acetate (MPA) reported estimated risk ratios of 0.77 (95% CI, 0.59 to 1.01) or 1.24 (95% CI, 0.59 to 1.01). 1.01 – 1.54) after 6 years of HRT use. It is unknown whether this increased risk also applies to other HRT drugs.

The relative risk increases with duration of treatment but may be absent or reduced with estrogen monotherapy.

A comparable increase in the risk of breast cancer is also observed in women with each year of delay in the onset of natural menopause, as well as with obesity and alcohol abuse.

The increased risk gradually decreases to normal levels over several years after stopping HRT.

According to research, breast cancer detected in women taking HRT is usually more differentiated than in women not taking it.

Evidence regarding the spread of cancer beyond the breast remains controversial.

HRT increases mammographic breast density, which in some cases may have a negative effect on X-ray detection of breast cancer.

Liver tumor

During the use of sex steroids, which include drugs for HRT, in rare cases benign, and even more rarely, malignant liver tumors were observed. In some cases, these tumors have resulted in life-threatening intra-abdominal bleeding. When carrying out differential diagnosis in the case of pain in the upper abdomen, liver enlargement or signs of intra-abdominal bleeding, a liver tumor should be excluded.

Other states

The relationship between HRT and the development of clinically significant arterial hypertension has not been established. A slight increase in blood pressure has been described in women taking HRT; clinically significant increases are rare. However, in some cases, if persistent clinically significant arterial hypertension develops while taking HRT, discontinuation of HRT may be considered.

For mild liver dysfunction, including various forms of hyperbilirubinemia, such as Dubin-Johnson syndrome or Rotor syndrome, medical supervision is necessary, as well as periodic liver function tests. If liver function tests worsen and/or jaundice develops, HRT should be discontinued.

Special monitoring is required for women with moderately elevated triglyceride levels. In such cases, the use of HRT may cause a further increase in blood triglyceride levels, which increases the risk of acute pancreatitis.

Although HRT may have an effect on peripheral insulin resistance and glucose tolerance, there is usually no need to change the treatment regimen in patients with diabetes when undergoing HRT. However, women with diabetes should be monitored when undergoing HRT.

Some patients may develop undesirable effects of estrogen during HRT, such as abnormal uterine bleeding. Frequent or persistent pathological uterine bleeding during treatment is an indication for assessing the condition of the endometrium.

Under the influence of estrogens, uterine fibroids can increase in size. In such cases, treatment should be discontinued.

It is recommended to discontinue treatment if endometriosis relapses during HRT.

If prolactinoma is suspected, this disease should be excluded before starting therapy.

In some cases, chloasma may occur, especially in women with a history of chloasma during pregnancy. During HRT, women prone to chloasma should avoid prolonged exposure to the sun or ultraviolet radiation.

Taking exogenous estrogens may cause or worsen symptoms of angioedema in women with hereditary angioedema.

Medical examination and consultation

Before starting or resuming HRT, a woman is recommended to undergo a thorough general medical and gynecological examination, including examination of the mammary glands, abdominal and pelvic organs, cytological examination of scrapings from the cervix (Papanicolaou test), blood pressure measurement, and rule out pregnancy. In addition, disorders of the blood coagulation system should be excluded. The scope of additional studies and the frequency of follow-up examinations are determined individually.

Impact on the ability to drive a car and control complex mechanisms

Not observed.

Use of the drug Climodien

If a woman is not taking estrogens or switching to Climodien after using another combination drug for continuous use, then treatment can be started at any time. Patients starting to take Climodien after using a cyclic combination drug for HRT should begin taking it after the end of the current cycle of therapy. Doses Take one tablet daily. Method of use Each package is designed for 28 days of treatment. Treatment is carried out continuously, that is, the next package of tablets begins immediately after the end of the previous one. The tablets should be taken without chewing with a small amount of liquid. It is advisable to maintain a constant time of day for taking. Missed pills A missed pill should be taken as soon as possible. If you are more than 24 hours late in taking the pill, you should not take an additional pill. If you miss several tablets, bleeding may occur. Nature of bleeding: Climodien can be used in women no earlier than one year after the onset of menopause, that is, no earlier than one year after the last menstrual bleeding. When taking the drug during perimenopause, there is a high risk of irregular breakthrough bleeding due to possible cyclic hormonal activity of the ovaries. HRT ensures that there are no cyclic bleedings, but they may occur during the first few cycles of using the drug. Bleeding may be unexpected in nature, but it is unlikely that its intensity will be excessive. Patients should be warned about this and explained that bleeding decreases significantly and usually stops completely over time. If severe bleeding is prolonged or if bleeding or spotting becomes unbearable, discontinuation of therapy or switching to cyclic HRT should be considered.

Contraindications to the use of the drug Climodien

HRT should not be started for any of the following conditions. If any of these conditions occur during HRT, use of the drug should be discontinued immediately. During pregnancy and breastfeeding. Vaginal bleeding of unknown etiology. Diagnosed or suspected breast cancer. Diagnosed precancerous conditions or malignant tumors dependent on sex steroids, or suspicion of their presence. Current or history of liver tumors (benign or malignant). Severe liver diseases. Arterial thromboembolism in the acute stage (for example, myocardial infarction, stroke). Exacerbation of deep vein thrombosis, current thromboembolic disorders or a history of such diseases. Severe form of hypertriglyceridemia. Hypersensitivity to the active substances or to any of the auxiliary components of the drug.

Side effects of the drug Climodien

In the table below, data on side effects is distributed by organs and systems. The frequency of adverse reactions is based on data from clinical studies, and a probable connection with therapy with Climodien has been established.

When using the drug Climodien, the following side effects may be noted, recorded as isolated reactions during clinical trials of drugs for HRT: fungal infections, increased appetite, inhibition of the activity of liver enzymes, an increase in the size of uterine fibroids. Very rarely, erythema nodosum, exudative erythema multiforme, chloasma and hemorrhagic dermatitis (vascular purpura) were noted in women using HRT.

Dienil (Climodien) tablets 21pcs - Instructions

DOSAGE FORM

Film-coated tablets, 28 pieces in a package.

COMPOUND

Active ingredients: 1 tablet contains 30 mcg ethinyl estradiol and 2 mg dienogest.

Excipients: lactose, corn starch, corn starch, povidone K25, magnesium stearate, sucrose, glucose syrup, calcium carbonate, titanium dioxide (E 171), red iron oxide (E172), macrogol 35000, carnauba wax.

PHARMACOLOGICAL GROUP

Hormones of the sex glands and drugs used for pathology of the genital area. Combined preparations containing gestagens and estrogens.

PHARMACOLOGICAL PROPERTIES

Pharmacodynamics.

Ethinyl Estradiol.

The active substance, synthetic 17β-estradiol, is chemically and biologically identical to estradiol, which is found in the human body. It compensates for decreased estrogen production in menopausal women and reduces symptoms associated with this condition.

Dienogest.

Dienogest is a derivative of nortestosterone, which in vitro exhibits 10-30 times less affinity for progesterone receptors compared to other synthetic progestogens. Data from in vivo animal studies indicate its significant progestagenic effect. In vivo, dienogest does not exhibit pronounced androgenic, mineralocorticoid or glucocorticoid effects.

Because estrogens promote endometrial growth, estrogen monotherapy increases the risk of endometrial hyperplasia and carcinoma. Concomitant use of a progestogen significantly reduces the risk of endometrial hyperplasia caused by estrogen in women without hysterectomy.

Information on clinical trial materials:

• reducing symptoms of estrogen deficiency and bleeding intensity;
• a decrease in the intensity of menopausal symptoms is achieved within the first few weeks of treatment;
• after 10-12 months of treatment, amenorrhea occurs in approximately 83-86% of women. Breakthrough bleeding and/or spotting occurred in 28-33% of women during the first three months of treatment and in 14-17% of women during 10-12 months of treatment.

Pharmacokinetics.

Ethinyl Estradiol.

Ethinyl Estradiol is completely absorbed after oral administration. Disintegration occurs upon absorption in the intestinal mucosa or during first passage through the liver.

This leads to an increase in the level of natural estradiol and its metabolites estrone and estriol. Valeric acid is subject to very rapid metabolism. After oral administration, only 3-6% of the dose is directly bioavailable as estradiol.

After taking 30 mcg of ethinyl estradiol, high plasma levels are achieved within 30-60 minutes. Peak serum concentrations are achieved within 2–10 hours, with an estrone/estradiol ratio of 4:1.

The plasma half-life of ethinyl estradiol is approximately 90 minutes. Its metabolites are predominantly excreted in the urine, with only about 10% excreted in the feces.

After repeated use of the drug Dienil 1 time per day, the average steady-state concentration of estradiol is about 61 pg/ml. C max is 105 pg/ml, minimum concentration is 51 pg/ml.

Dienogest.

Dienogest is rapidly and almost completely absorbed. Bioavailability is more than 90%. After oral administration, maximum plasma concentration is achieved after 1-2 hours.

After repeated use of the drug Climodien 1 time per day, the average steady-state concentration of dienogest is about 26 ng/ml. C max is 66 ng/ml, minimum concentration is 11 ng/ml.

About 90% of dienogest is protein bound. It does not bind to specific transport proteins such as sex hormone binding globulin (SHBG) and corticosteroid binding globulin (GGC).

The half-life of dienogest from blood plasma ranges from 6.5 to 12:00. Dienogest accumulates very gradually after three cycles of treatment (accumulation coefficient according to AUC (0-24 hours) = 1.3). The total clearance (Cl / F) of dienogest after oral administration of the drug Climodien in postmenopausal women is about 3.2 l / hour.

About 86% of the dose taken is eliminated within 6 days, about 60% is eliminated within the first 24 hours.

The pharmacokinetics of dienogest are dose proportional within the dose range of 1-8 mg. After repeated use of the drug Climodien with a dosage frequency of 1 time per day, the equilibrium state of dienogest is achieved by the 3rd dose with an average concentration of about 26 ng/ml. The pharmacokinetics of dienogest after repeated administration of Climodien can be predicted based on pharmacokinetic data after a single dose.

Dienogest is metabolized mainly by hydroxylation and conjugation to form predominantly endocrine-inactive metabolites. These metabolites are very quickly cleared from the blood plasma, so no significant metabolites are detected in human plasma, except for the unchanged dienogest.

There are no pharmacokinetic data for Climodien in patients with renal or hepatic insufficiency.

Preclinical safety data

Ethinyl Estradiol. The toxicity profile of estradiol has been well studied. There is no additional preclinical data other than the information provided in other sections of the instructions for the medical use of the drug.

Dienogest. The results of traditional pharmacological studies on safety, single dose toxicity, repeated dose toxicity, genotoxicity, reproductive toxicity and carcinogenic potential do not indicate the presence of a specific hazard to humans.

INDICATIONS FOR USE

Hormone replacement therapy (HRT) for symptoms of estrogen deficiency in women with a preserved uterus during the postmenopausal period, which is more than 1 year.

Experience with the drug in people over 65 years of age is limited.

METHOD OF APPLICATION AND DOSES

For oral administration.

How to start using Climodien

If a woman does not receive HRT or switches to Dienyl from another drug for continuous HRT, then she can begin treatment at any time.

Treatment for women who are switching to this type of treatment from continuous-sequential HRT should begin on the day after the completion of the treatment cycle of the previous treatment option.

Treatment for women who switch to this type of treatment after cyclic HRT should begin on the day after the break in taking these drugs.

Doses.

Take 1 tablet daily. Each package is designed for 28 days of treatment.

Mode of application

Take the tablets without chewing, with a small amount of liquid. Treatment should be carried out continuously, that is, the next package of tablets should be started immediately after finishing the previous one. It is advisable to take the tablets at the same time every day.

The missed tablet should be taken as soon as possible. If you are more than 24 hours late in taking your pill, you do not need to take an additional pill. If you miss several tablets, bleeding may begin.

To initiate and continue treatment of postmenopausal symptoms, the minimum effective dose should be used for a shorter period of time (see also section "Peculiarities of use").

CONTRAINDICATIONS

• Existing or past breast cancer or suspicion of it.
• An estrogen-dependent malignant tumor or suspicion of one has been detected (for example, endometrial cancer).
• Genital bleeding of unknown etiology.
• Untreated endometrial hyperplasia.
• Venous thromboembolism, existing or transferred (deep vein thrombosis, pulmonary embolism).
• Has or has had arterial thromboembolic disease (eg, angina, myocardial infarction).
• Conditions characterized by an increased tendency to form thrombosis (for example, deficiency of protein C, protein S or antithrombin, see section “Peculiarities of use”).
• Acute liver disease or history of liver disease (until function tests return to normal).
• Porphyria.
• Hypersensitivity to the active substances or to any of the auxiliary components of the drug.

INTERACTIONS WITH OTHER MEDICINES AND OTHER TYPES OF INTERACTIONS

The metabolism of estrogen and dienogest may be increased by concomitant use of drugs that induce enzymes that break down this drug, namely the cytochrome P450 enzyme. These drugs include anticonvulsants (eg, phenobarbital, phenytoin, carbamazepine) and antibiotics (eg, rifampicin, rifabutin, nevirapine, efavirenz).

When used concomitantly with nonsteroidal hormones, ritonavir and nelfinavir acquire enzyme-stimulating properties, although they are known to be strong enzyme inhibitors.

Herbal medicines containing St. John's wort (Hypericum perforatum) may enhance the metabolism of estrogens and dienogest.

In clinical settings, increased metabolism of estrogen and dienogest may lead to decreased effectiveness of these hormones and changes in uterine bleeding patterns.

APPLICATION FEATURES

HRT should be started to treat only those menopausal symptoms that worsen the patient's quality of life. An assessment of the benefit-risk ratio must be carried out at least once a year. HRT should only be used when the potential benefits outweigh the risks.

There is insufficient data to assess the risk of HRT in cases of premature menopause. But because the absolute risk of adverse reactions is generally lower in younger women, the benefit-to-risk ratio may be better in younger women than in older women.

Medical examination/consultation.

Before starting or resuming HRT, the patient's individual and family history should be examined in detail. Taking into account the medical history, contraindications and features of use, it is necessary to conduct a clinical examination (including the pelvic organs and mammary glands). During treatment, it is recommended to conduct regular medical examinations, the frequency and nature of which are determined individually for each patient. Women should also be told what changes in the condition of their breasts they should inform their doctor about (see “Breast cancer” below). Tests, including imaging modalities such as mammography, should be performed according to current screening standards, taking into account the clinical needs of each woman.

Situations in which patients need supervision.

Patients who currently have or have a history of any of the following diseases and/or have experienced complications during pregnancy or previous hormonal therapy should be closely monitored. This also applies if any of the following conditions or illnesses occur or worsen during treatment with Climodien:

• leiomyoma (uterine fibroids) or endometriosis;
• risk factors for thromboembolism (see below);
• risk factors for estrogen-dependent tumors, such as breast cancer in first-degree relatives;
• arterial hypertension;
• liver diseases (for example, liver adenoma);
• diabetes mellitus with or without vascular damage;
• cholelithiasis;
• migraine or (severe) headache
• systemic lupus erythematosus (SLE)
• history of endometrial hyperplasia (see below);
• epilepsy
• asthma,
• otosclerosis.

Reasons for immediate discontinuation of therapy.

Treatment with the drug should be stopped immediately if any of the contraindications are identified, as well as in the presence of the following conditions:

• jaundice or liver dysfunction;
• significant increase in blood pressure;
• the appearance of migraine-like headaches;
• pregnancy.

Hyperplasia and endometrial cancer.

In women with a healthy uterus, the risk of endometrial hyperplasia or carcinoma increases during estrogen monotherapy. An increased risk of endometrial carcinoma in women receiving estrogen monotherapy has been reported to be 2 to 12 times higher than in women not receiving HRT, depending on the duration of use and dose of estrogen (see Adverse Reactions section). After treatment ends, the risk remains elevated for at least 10 years.

In women with a preserved uterus, additional cyclic administration of progestogen for at least 12 days in a 28-day cycle or long-term combined treatment with estrogen and progestogen can compensate for the additional risk that arises from estrogen monotherapy.

Breakthrough bleeding or spotting may occur during the first month of treatment. If such bleeding occurs later during therapy or after its completion, the cause should be determined and, if necessary, an endometrial biopsy should be performed to exclude the possibility of endometrial malignancy.

Mammary cancer.

Currently available data indicate an increased risk of developing breast cancer in women using combined estrogen-progestagen HRT, depending on the duration of this therapy. This may also apply to HRT using drugs containing only estrogen.

Combination therapy with estrogens and gestagens.

According to the randomized, placebo-controlled Women's Health Initiative Study (WHI), as well as epidemiological studies, it was found that the risk of breast cancer in women who used a combination of estrogen and progestogen during HRT rises. An increased risk was observed after approximately three years of use (see section "Adverse Reactions").

Estrogen monotherapy.

The WHI study found that the risk of breast cancer in women with hysterectomies who take estrogen monotherapy is not increased. Observational studies predominantly reported a small increase in the risk of developing breast cancer, which was significantly less than that observed in women receiving combination therapy with estrogens and progestogens (see Adverse Reactions section).

The risk remains elevated for several years of use, but after a few (maximum 5) years it returns to a level consistent with the woman's normal age.

HRT, especially combined treatment with estrogens and progestogens, leads to an increase in breast tissue density, which can complicate the process of radiological diagnosis of breast cancer using mammography.

Ovarian cancer.

Ovarian cancer is much less common than breast cancer. Long-term use (at least 5-10 years) of estrogen monotherapy for hormone replacement therapy is associated with a slight increase in the risk of ovarian cancer (see Section "Adverse Reactions"). Some studies, including the WHI study, indicate that the risk with long-term combined HRT is the same or lower (see Adverse Reactions section).

Venous thromboembolism.

HRT is associated with an increased (1.3-3 times) risk of developing venous thromboembolism (VTE) (previously deep vein thrombosis or pulmonary embolism). During the first year of HRT, the likelihood of VTE is higher than with further use (see Section “Adverse Reactions”).

Patients with known thrombophilic conditions have an increased risk of VTE. HRT may increase this risk and is therefore contraindicated in such patients (see section "Contraindications").

Commonly known risk factors for VTE include: estrogen use, older age, major surgery, prolonged immobilization, excess weight (body mass index > 30 kg/m2), pregnancy/postpartum, systemic lupus erythematosus (SLE), and cancer. The possible role of varicose veins in the development of VTE remains controversial.

Preventative measures should be taken to avoid VTE after surgery, as in all patients in the postoperative period. If long-term immobilization is expected after planned surgery, then HRT should be completed 4-6 weeks before surgery. Treatment should be continued only when the patient completely restores motor activity.

For women without a history of VTE, but with first-degree relatives with a history of VTE at a young age, it may be advisable to conduct a screening study to determine the tendency to form venous thrombosis. Before this, the patient should be informed about the limited information content of such a study (only part of the defects that lead to the formation of blood clots is determined).

The use of HRT is contraindicated if thrombophilic disorders are detected, the patient has a family history of thrombosis, or if such disorders are severe (for example, deficiency of antithrombin, protein S or protein C).

In patients undergoing long-term treatment with anticoagulants, the benefit/risk ratio should be carefully assessed before starting HRT.

If VTE develops after starting HRT, the drug should be discontinued. Patients should be informed of the need to immediately consult a doctor if they experience symptoms of possible thromboembolism (eg, painful swelling of the lower extremity, sudden chest pain, shortness of breath).

Cardiac ischemia.

At the moment, there is no data from randomized controlled trials that would indicate that combined HRT (with estrogen and progestin) or estrogen monotherapy prevents myocardial infarction in women, regardless of the presence of coronary heart disease.

Combination therapy with estrogens and gestagens.

The relative risk of coronary heart disease increases slightly when using combined HRT with estrogen and gestagens. Because the initial risk of coronary heart disease depends significantly on the woman's age, the incidence of additional cases that arise from estrogen-progestin HRT among healthy premenopausal women is low. This amount increases with age.

Estrogen monotherapy.

Randomized controlled trials have found no evidence of an increased risk of coronary heart disease in women with hysterectomies who receive estrogen monotherapy.

Ischemic stroke.

Combined treatment with estrogen and gestagen, as well as estrogen monotherapy, are associated with a 1.5-fold increase in the risk of ischemic stroke. This relative risk is independent of age and time since menopause. So the risk of stroke depends largely on age, and the overall risk of stroke in women using HRT increases with age (see section “Adverse reactions”).

Other diseases.

Estrogens can cause fluid retention in the body, so the health of patients with cardiac or kidney problems should be carefully monitored. Due to the possibility of increasing the level of circulating active substances of the drug Climodien, careful monitoring of the condition of patients with end-stage renal failure should be ensured.

Women with pre-existing hypertriglyceridemia should be closely monitored during estrogen replacement therapy or other HRT agents, as significant increases in plasma triglyceride levels with subsequent development of pancreatitis have been reported in rare cases with estrogen therapy.

Estrogens increase the concentration of thyroxine thyroid globulin (TSG), which leads to an increase in the total amount of circulating thyroid hormone, as measured by protein thyroid iodine (PVI) levels, T4 levels (measured by column analysis or radioimmunoassay), or T3 levels (measured by using radioimmunoassay). The level of bound T3 decreases, which is associated with an increase in the level of TSH. The concentrations of free T 4 and T 3 do not change. Serum levels of other binding proteins, GOC and SHBG, may increase, resulting in a corresponding increase in circulating concentrations of corticosteroids and sex hormones.

The concentrations of free or biologically active hormones remain unchanged. Levels of other plasma proteins (angiotensinogen/renin substrate, α-1-antitrypsin, ceruloplasmin) may also increase.

Cognitive properties do not improve during HRT. There is anecdotal evidence of an increased risk of dementia if HRT or estrogen monotherapy is started in women over 65 years of age.

In women with hereditary angioedema, exogenous estrogens may induce or aggravate its symptoms.

Excipients.

The drug Climodien contains sucrose, lactose and glucose.

Patients with rare hereditary diseases of fructose intolerance or sucrase-isomaltase deficiency should not use this drug. Patients with rare hereditary galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption should not use this drug.

USE DURING PREGNANCY OR BREAST-FEEDING

Pregnancy.

The drug is contraindicated during pregnancy. If pregnancy occurs during treatment with Dienil, its use should be discontinued immediately.

There are no clinical data on the effects of dienogest during pregnancy. Animal studies did not reveal reproductive toxicity, which could be associated with the progestogen action of dienogest (see section "Pharmacological properties"). The potential risk to humans is unknown. In most of the currently available epidemiological studies, the subject of which was the effect of the combination of estrogens with other progestogens on the fetus, it was not established that this combination has a teratogenic or fetotoxic effect.

Breastfeeding.

The drug Dienil is not used during breastfeeding.

ABILITY TO INFLUENCE REACTION SPEED WHEN DRIVING VEHICLES OR OTHER MECHANISMS

There have been no studies on the ability of the drug Dienil to influence the reaction rate when driving vehicles or other mechanisms.

CHILDREN

Do not use in children.

OVERDOSE

The results of acute toxicity studies of the drug do not indicate the existence of a risk of acute side effects, even with accidental use of a dose several times higher than the therapeutic dose. Overdose may cause nausea and vomiting, as well as withdrawal bleeding in some women. There are no specific antidotes.

ADVERSE REACTIONS

The most common adverse reactions reported in clinical studies involving 1,834 women using Dienyl (Climodien) for at least six cycles were breakthrough bleeding (24%) and breast pain/tenderness (13%).

Risk of developing breast cancer.

The risk of breast cancer almost doubled in women who received combination therapy with estrogen-progestogen-containing drugs for more than 5 years.

The risk in patients treated with estrogen monotherapy is significantly lower than in those women who took combination drugs with estrogen and progestogen.

The risk depends on the duration of use of the drug (see Section “Peculiarities of use”). The risk of developing breast cancer was estimated from the largest randomized placebo-controlled trial (WHI study) and the largest epidemiological study (MWS).

One Million Women Study (MWS) - calculated increased risk of developing breast cancer after 5 years of therapy

WHI study in the USA - increased risk of developing breast cancer after 5 years of therapy

Risk of developing endometrial cancer.

Post-menopausal women with unremoved uterus

About 5 in 1,000 women with a uterus that has not been removed and not treated with HRT will develop endometrial cancer. For women with a non-removed uterus, HRT with estrogen alone is not recommended, as it increases the risk of endometrial cancer (see Section “Peculiarities of Use”).

In epidemiological studies, the risk of endometrial cancer increased by 5 to 55 additional cases per 1000 women aged 50 to 65 years, depending on the duration of estrogen monotherapy and the dose used.

Adding a progestogen to estrogen monotherapy for at least 12 days per cycle reduces the risk. In the MWS study, the risk of endometrial cancer was NOT increased after 5 years of HRT (sequential or continuous) (HR 1 (95% CI 0.8-1.2)).

Ovarian cancer.

Long-term use of single drugs with estrogen and combined drugs with estrogen and progestogen during HRT is associated with a slight increase in the risk of ovarian cancer. The MWS study found one additional case per 2500 women after 5 years of HRT.

Risk of developing venous thromboembolism.

The relative risk of venous thromboembolism (VTE), such as deep vein thrombosis of the legs or pulmonary embolism, increases by 1.3-3 times when using HRT. The occurrence of such a condition is most likely during the first year of hormonal therapy (see Section “Peculiarities of Application”). Below is data obtained from the WHI studies.

WHI study - increased risk of VTE over 5 years of therapy

* Study in women with a removed uterus.

Risk of developing coronary heart disease.

The risk of coronary heart disease is slightly increased for women over 60 years of age who undergo combined estrogen and progestogen HRT (see section “Peculiarities of use”).

Risk of developing ischemic stroke.

Monotherapy with estrogens or combined therapy with estrogens and progestogen is associated with a 1.5-fold increase in the risk of ischemic stroke. The risk of hemorrhagic stroke does not increase during HRT.

This relative risk is independent of age and duration of use. However, because the initial risk is largely dependent on age, the overall risk increases with increasing age of the woman using HRT (see section "Peculiarities of use").

WHI combined studies - increased risk of ischemic stroke* over 5 years of therapy

* Differentiation between ischemic and hemorrhagic stroke has not been made.

Other adverse reactions have been reported during treatment of women with estrogens and progestogens:

• gallbladder diseases;
• disorders of the skin and subcutaneous tissue (chloasma, erythema multiforme, erythema nodosum, vascular purpura);
• dementia in women over 65 years of age (see section “Peculiarities of application”).

In women with hereditary angioedema, exogenous estrogens can induce or enhance the symptoms of angioedema (see section "Peculiarities of use").

BEST BEFORE DATE

3 years.

STORAGE CONDITIONS

Store out of the reach of children at a temperature not exceeding 25 ° C.

VACATION CATEGORY

On prescription.

Special instructions for the use of the drug Climodien

Climodien is not a contraceptive or fertility aid. If necessary, non-hormonal methods of contraception should be used, excluding calendar and temperature methods. Before starting HRT, the specified conditions/risk factors should be taken into account when assessing the risk/benefit of treatment, taking into account the individual characteristics of the patient. The use of HRT should be stopped immediately if any of the contraindications are identified, as well as in the presence of the following conditions and diseases:

• migraine-like or frequent and unusually severe headache that appears for the first time, or other symptoms that are likely prodromal signs of cerebral vascular occlusion;
• recurrence of cholestatic jaundice or cholestatic pruritus first noted during pregnancy or previous use of sex steroids;
• symptoms of thrombotic disorders or suspicion of their occurrence.

In the event of a relapse or exacerbation of any of the following diseases or risk factors, it is recommended to repeat an individual analysis of the balance of benefits and risks of therapy, taking into account the possible need to discontinue treatment. Venous thromboembolism (VTE) Epidemiological and randomized controlled studies suggest an increased risk of developing VTE, i.e. deep vein thrombosis or pulmonary embolism. Therefore, when prescribing HRT to women with a risk factor for developing VTE, the risk-benefit ratio of treatment should be carefully weighed. Generally recognized risk factors for the development of VTE include personal and family history (a case of VTE in a close relative at a relatively early age may indicate a genetic predisposition) and severe obesity. The risk of VTE also increases with age. The possible role of varicose veins in the development of VTE remains controversial. The risk of VTE may temporarily increase with prolonged immobilization, after major elective or major surgery, or after severe trauma. The issue of temporary cessation of HRT should be decided depending on the nature of the surgical intervention and the duration of immobilization. Arterial thromboembolism The results of two large clinical studies using a combination of conjugated equine estrogens and medroxyprogesterone acetate (MPA) in a continuous regimen indicate a possible increase in the risk of developing coronary artery disease during the first year of use; with continued treatment, the risk remained stable. Another negative consequence identified during therapy is an increase in the risk of stroke by 30–40% with estrogen monotherapy or their use in combination with MPA. Gallstone disease Estrogens are known to increase the lithogenicity of bile. Some women are prone to gallbladder disease during estrogen treatment. Dementia Based on clinical studies with products containing conjugated equine estrogens, there is no evidence that hormonal use may increase the risk of developing dementia when treatment is initiated in women aged 65 years or older. The risk may be reduced if treatment is started early in menopause. Tumors Breast cancer Based on clinical studies and observations, an increased risk of developing breast cancer in women using HRT for several years has been shown. These facts may be associated with earlier diagnosis, the stimulating effect of HRT on pre-existing tumors and the combined influence of these factors. The overall relative risk of diagnosing breast cancer in more than 50 epidemiological studies conducted was generally between 1 and 2. The relative risk increases with duration of treatment and may be lower, or more likely unchanged, with estrogen monotherapy. A similar increase in the incidence of breast cancer is noted, for example, in women with a delay in the onset of natural menopause or with alcohol consumption or obesity. A few years after starting HRT therapy, the increase in risk is leveled out. It is noted that tumors identified in women using or recently using HRT are characterized by a higher degree of differentiation than tumors identified in women not using HRT. When using HRT, the density of images during mammographic examinations increases, which in some cases can complicate the diagnosis of breast diseases. Endometrial cancer Long-term estrogen monotherapy increases the risk of developing endometrial hyperplasia or carcinoma. Based on research results, it is believed that the appropriate inclusion of progestogens in the treatment regimen will eliminate this increased risk. Liver tumors After using hormonal drugs, including HRT, benign, and even less often, malignant liver tumors were noted in isolated cases. In isolated cases, these tumors caused life-threatening intra-abdominal bleeding. If there is pain in the upper abdomen, an enlarged liver, or signs of intra-abdominal bleeding, the differential diagnosis must take into account the likelihood of a liver tumor. Other conditions No general association has been established between the use of HRT and the development of clinical hypertension. A slight increase in blood pressure has been reported in women receiving HRT; a clinically significant increase in blood pressure has rarely been observed. However, if in some cases persistent clinically significant hypertension develops during HRT, the advisability of discontinuing HRT should be considered. For mild liver dysfunction, including various forms of hyperbilirubinemia, such as Dubin-Johnson syndrome or Rotor syndrome, patients should be under close medical supervision with periodic determination of liver function. If liver function tests worsen, HRT should be discontinued. Women with moderately elevated TG levels require special monitoring. In such cases, the use of HRT may cause a further increase in TG levels, which threatens the risk of developing acute pancreatitis. Although HRT may affect peripheral insulin resistance and glucose tolerance, there is generally no need to change the therapeutic regimen for diabetic patients using HRT. However, women with diabetes should be under close medical supervision during HRT. Some patients may develop undesirable manifestations of estrogen stimulation during HRT, such as abnormal uterine bleeding. Frequent or constant bleeding during treatment is an indication for examination of the condition of the endometrium. Under the influence of estrogens, the size of uterine fibroids can increase. In this case, treatment should be stopped. It is recommended to discontinue treatment if recurrence of endometriosis is observed during therapy. If you suspect the presence of prolactinoma, before starting HRT, you should exclude the possibility of this disease. In some cases, chloasma may occur, especially in women with a history of chloasma during pregnancy. When taking a course of HRT, women predisposed to chloasma should avoid exposure to the sun or ultraviolet radiation. It has been found that the following conditions and diseases may occur or worsen when using HRT. Although it cannot be confidently stated that these changes are associated with HRT, patients taking HRT who have the following diseases should be closely monitored: epilepsy; benign diseases of the mammary glands; BA; migraine; porphyria; otosclerosis; systemic lupus erythematosus; chorea. Medical examination/consultation Before starting or resuming HRT, the patient's medical history and physical examination should be carefully reviewed, taking into account contraindications (see CONTRAINDICATIONS) and precautions (see SPECIAL INSTRUCTIONS), and such examinations should be repeated periodically. The frequency and nature of examinations should be based on existing standards of medical practice, taking into account the individual characteristics of the patient. As a rule, the pelvic organs are subject to examination, including standard cytological analysis of the cervix, examination of the abdominal cavity, mammary glands, and blood pressure measurement. During pregnancy and breastfeeding. HRT is not prescribed during pregnancy and breastfeeding. If pregnancy occurs during treatment with Climodien, its use should be discontinued immediately. Based on the results of studies, steroid therapy for the purpose of contraception and HRT or accidental use during early pregnancy has not revealed an increased risk of congenital malformations in newborns. Small amounts of sex hormones can be excreted in breast milk. Effect on the ability to drive vehicles and operate machinery: not noted.

Climodien

Before starting and during treatment, gynecological monitoring should be carried out every 6 months, including analysis of a cytological smear of the cervix and examination of the mammary glands. It is necessary to regularly monitor liver function, blood pressure, urine composition, and lipid metabolism.

If an anterior pituitary adenoma is suspected, the diagnosis should be excluded or confirmed before starting treatment.

The drug is not a contraceptive! Does not affect the ability to conceive. If the patient was taking oral or other hormonal contraceptives, they must be replaced with non-hormonal contraceptives before starting the drug.

The risk of deep vein thrombosis may be temporarily increased as a result of surgery, serious injury or immobilization, so if you are undergoing hospitalization or surgery, you should tell your doctor about taking the drug.

The risk of developing endometrial cancer increases with long-term use of estrogens alone. The gestagen contained in the drug reduces this risk.

Studies have found that breast cancer is slightly more common in women who have received hormone replacement therapy for more than 5 years, compared with women of the same age who have never received it. When hormone replacement therapy is stopped, the risk gradually decreases and after 5 years becomes the same as in patients who have never received it. Breast cancer diagnosed in women taking hormone replacement therapy is less likely to metastasize than in women who did not receive it (a cause-and-effect relationship has not been established). The risk of developing breast cancer increases with the duration of treatment, but this increase is comparable to the increase in risk of breast cancer observed in women with each year of delay in natural menopause.

In rare cases, the development of liver tumors has been observed with the use of sex hormones. In some cases, bleeding from such tumors into the abdominal cavity can be life-threatening. The connection with ongoing hormone replacement therapy has not been proven.

In the event of a migraine attack (throbbing headache and vomiting preceded by visual impairment), exacerbation of an existing migraine, any unusually frequent or unusually severe headaches, sudden visual or hearing impairment, phlebitis, thrombosis, you must immediately stop taking the drug. Signs of possible thrombosis include: coughing up blood, unusual pain or swelling in the extremities, sudden shortness of breath, or fainting.

The drug should also be stopped immediately if pregnancy or jaundice develops.

Dosage adjustment of hypoglycemic drugs may be required.

During the treatment period, you should refrain from excessive consumption of ethanol.

May affect laboratory results.

Drug interactions Climodien

The use of hormonal contraceptives should be discontinued at the start of HRT, and if necessary, non-hormonal methods of contraception should be recommended. Treatment with drugs that affect the activity of liver enzymes (for example, some anticonvulsants and antimicrobials) for a long time can increase the clearance of sex hormones and reduce their clinical effectiveness. Such liver enzyme inducing properties have been identified in hydantoins, barbiturates, primidone, carbamazepine and rifampicin, and the presence of these properties can also be expected in oxcarbazepine, topiramate, felbamate and griseofulvin. Maximum induction of enzymes, as a rule, is observed no earlier than 2–3 weeks from the start of use and persists for 4 weeks after discontinuation of the drug. In isolated cases, during concomitant use of certain types of antibiotics (for example, penicillin and tetracycline groups), a decrease in estradiol levels was noted. Substances that form conjugates (eg paracetamol) can increase the bioavailability of estradiol by competitively inhibiting conjugation systems during adsorption. In some cases, the need for oral antidiabetic agents or insulin may change due to the effect of Climodien on glucose tolerance. in vitro studies showed that dienogest at standard concentrations does not inhibit isoenzymes of the cytochrome P450 system. Given this, drug interactions at this level are unlikely. Interaction with alcohol Excessive alcohol consumption during HRT may lead to increased plasma estradiol levels. Influence on laboratory test results. Taking sex steroids may affect the results of certain laboratory tests, including biochemical parameters of liver, thyroid, adrenal and kidney function, levels of transport proteins such as corticosteroid binding globulin and lipid/lipoprotein fractions, parameters of carbohydrate metabolism, and parameters coagulation and fibrinolysis.