Dienogest + Estradiol valerate - instructions for use, dose, side effects, contraindications

Clinical and pharmacological group: & nbsp

"Estrogens, gestagens, their homologues and antagonists"

Included in the formulation

АТХ:

G.03.F.B Progestogens in combination with estrogens (combinations for sequential administration)

Pharmacodynamics:

The drug is a combination of dienogest and estradiol. The contraceptive effect of combined oral contraceptives (CPC) is based on the interaction of various factors, the most important of which are suppression of ovulation and a change in the properties of cervical mucus. In women taking CPC, soreness and intensity of menstrual bleeding decreases, which reduces the risk of iron deficiency anemia. In addition, there are clinical data on the reduction in the risk of developing endometrial cancer and ovarian cancer.

Estradiol valerate - estrogen, the precursor of natural human estradiol (1 mg of estradiol valerate corresponds to 0.76 mg of 17β-estradiol).

Reception of a combination of dienogest and estradiol leads to a less pronounced effect on the liver compared to the three-phase PDA containing ethinyl estradiol and levonorgestrel. In combination with dienogestom estradiol valerate demonstrates an increase in HDL, while the concentration of LDL cholesterol is somewhat reduced.

Dienogest is a progestogen that works by oral administration, which is characterized by additional partial anti-androgenic effects. Its estrogenic, anti-estrogenic and androgenic properties are insignificant.

Pharmacokinetics:Suction

After oral administration dienogast quickly and almost completely absorbed. Maximum concentration in serum, which is 90.5 ng / ml, is achieved approximately 1 hour after oral administration of a tablet containing 2 mg of estradiol valerate + 3 mg of dienogest. Bioavailability is about 91%. The pharmacokinetics of dienogest in the dose range from 1 to 8 mg is characterized by dose dependence.

Simultaneous food intake does not have a clinically significant effect on the speed and degree of absorption of dienogest.

Distribution

A relatively large (10%) part of the circulating dienogest is unbound, when as much as 90% is nonspecifically associated with albumin. Dienogest does not bind to sex hormone binding globulin (SHBG), and corticosteroid binding globulin (CSG). For this reason, there is no possibility of displacing testosterone from its association with SHBG or cortisol from its association with CRS.Any influence on the physiological processes of transport of endogenous steroids, therefore, is unlikely. V_d dienogest at an equilibrium concentration of 46 liters after iv introduction of 85 μg of tritiated dienogest.When using the drug should take into account the possibility of a visual impairment or dizziness.

The pharmacokinetics of dienogest does not depend on the concentration of SHBG. The equilibrium concentration is achieved after 3 days of the same dose, which is 3 mg of dienogest in combination with 2 mg of estradiol valerate. Minimum, maximumand the average concentration of dienogest in the serum under the equilibrium state are 11.8, 82.9 and 33.7 ng / ml, respectively. The average coefficient of cumulation by AUC_{0-24 h} - 1.24.

Metabolism

Dienogest is almost completely metabolized, in accordance with the known ways of steroid hormone metabolism (hydroxylation, conjugation), with the formation of mainly hormoneally inactive metabolites. Metabolites are excreted very quickly, so the predominant fraction in the blood plasma is unchanged dienogast.

The total clearance after iv injection of a tritiated dienogest is 5.1 l / h.

Excretion

Half-lifedienogest of plasma is about 11 hours.After oral administration at a dose of 0.1 mg / kg dienogast is excreted in the form of metabolites, which are excreted by the kidneys and through the intestine in a ratio of approximately 3: 1. After oral administration, 42% of the dose is excreted within the first 24 hours, and 63% within 6 days by renal excretion. In 6 days, 86% of the dose is excreted by the kidneys and through the intestine.

Estradiol valerate

Suction

After oral administration estradiol valerate quickly and completely absorbed. Splitting into estradiol and valerian acid occurs during absorption in the mucosa of the gastrointestinal tract or during the first passage through the liver, resulting in the formation of estradiol and its metabolites are estrone and estriol. Maximum concentrationEstradiol in serum, equal to 70.6 pg / ml, is achieved between 1.5 and 12 hours after a single oral intake of a tablet containing 3 mg of estradiol valerate on the 1 st day of the course. Simultaneous food intake does not have a clinically significant effect on the rate and extent of absorption of estradiol valerate.

Metabolism

Valeric acid is very rapidly metabolized. After oral administration, approximately 3% of the dose becomes directly bioavailable in the form of estradiol. Estradiol is subjected to an intensive effect of the primary passage through the liver, and a significant part of the administered dose is already metabolized in the gastrointestinal mucosa. Together with the presystemic metabolism in the liver, about 95% of the ingested dose is metabolized before entering the systemic circulation. The main metabolites are estrone, estrone sulfate and estrone glucuronide.

Distribution

In the blood serum, 38% of estradiol is associated with SHBG, 60% with albumin, and 2-3% circulate unbound. Estradiol may slightly increase the concentration of SHBG in serum; this effect is dose dependent. On the 21st day of the intake cycle, the concentration of SHBG was approximately 148% of the initial, and by the 28th day (completion of the phase of inactive tablet intake) decreased to approximately 141% of the baseline. Apparent V_d after intravenous administration - 1.2 l / kg.

The pharmacokinetics of estradiol are affected by the concentration of SHBG. In women, the measured concentration of estradiol in the blood plasma is a combination of endogenous estradiol and estradiol, which was received with the drug. During the phase of taking tablets containing 2 mg of estradiol valerate + 3 mg dienogest, the maximumand the average concentration of estradiol in the serum under the equilibrium state is 66.0 and 51.6 pg / ml, respectively. During the entire 28-day cycle, stable minimum concentrations were maintainedEstradiol in the range from 28.7 to 64.7 pg / ml.

Excretion

Due to the large circulating pool of sulfates and estrogen glucuronides, as well as intestinal-hepatic recirculation, the half-lifeEstradiol in the terminal phase after oral administration is a complex parameter that depends on all these processes and is in the range of about 13-20 hours.

Estradiol and its metabolites are excreted mainly by the kidneys, with about 10% being excreted through the intestine.

Indications:

Oral contraception.

ICD-10

XXI.Z30-Z39.Z30.0 General advice and advice on contraception

XIV.N80-N98.N92 Abundant, frequent and irregular menstruation

XIV.N80-N98.N94 Pain and other conditions associated with female genital organs and menstrual cycle

Contraindications:

Trhomboids (venous and arterial) and thromboembolism now or in the past (including deep vein thrombosis (DVT), pulmonary embolism (PE), myocardial infarction (MI), stroke now or in the anamnesis); states preceding thrombosis (incl.transient ischemic attacks, angina pectoris) at present or in the anamnesis; presence of expressed or multiple risk factors for venous or arterial thrombosis (including extensive surgical intervention with prolonged immobilization, complicated heart valve disease, uncontrolled hypertension); Migraine with focal neurological symptoms, incl. in the anamnesis; diabetes mellitus with vascular complications; Pancreatitis with severe hypertriglyceridemia at present or in the anamnesis; hepatic failure and severe liver disease (before the normalization of liver function); liver tumors (benign and malignant) at present or in the anamnesis; identified hormone-dependent malignant tumors (including genitals or mammary glands) or suspected of them; bleeding from the vagina of unknown origin; pregnancy or suspected of it; hypersensitivity to active substances or any of the excipients.

Carefully:

Risk factors for thrombosis and thromboembolism (smoking, obesity, dyslipoproteinemia, arterial hypertension, migraine,heart valve disease, cardiac rhythm disturbance, prolonged immobilization, extensive surgical interventions, extensive trauma); other diseases in which peripheral circulation disorders may be noted (diabetes mellitus, systemic lupus erythematosus, hemolytic-uremic syndrome, Crohn's disease and ulcerative colitis, sickle-cell anemia); hereditary angioedema; hypertriglyceridemia; diseases that first appeared or worsened during pregnancy or against the background of previous reception of sex hormones (for example, cholestatic jaundice, cholestatic itching, cholelithiasis, otosclerosis with hearing impairment, porphyria, pregnant herpes, Sydenham's chorea); the postpartum period.

Pregnancy and lactation:

The drug is contraindicated during pregnancy. If the pregnancy occurred against the background of the drug, further reception should be discontinued. However, large-scale epidemiological studies did not reveal an increase in the risk of birth defects in children born in women who used CPC prior to pregnancy, as well as teratogenic effects of CPC in case of their accidental admission at the beginning of pregnancy.

PDA can influence lactation, as they can reduce the volume of produced breast milk, as well as change its composition. PDA is usually not recommended until the end of the lactation period. A small number of contraceptive hormones and / or their metabolites can be excreted in breast milk.

Dosing and Administration:

Inside, regardless of food intake.

Tablets should be taken in the order given on the packaging every day at approximately the same time, if necessary, washed down with water or another liquid. The tablets are taken continuously. It should be taken 1 tablet / day consecutively for 28 days. Each new packaging is started after receiving the last tablet from the previous calendar package. Menstruation-like bleeding usually begins during the reception of the last tablets of the calendar pack and may not be completed before the next calendar packing begins. In some women, menstrual bleeding begins after taking the first tablets from a new calendar package.

If hormonal contraception was not used before (the previous month)

Tablets begin to take on the 1st day of the natural menstrual cycle of a woman (ie, on the 1st day of menstrual bleeding).

Transition from another combined hormonal contraceptive (another PDA, vaginal ring or transdermal patch)

The woman should start taking the drug the day after the last active tablet (the tablet containing the active substances) was drained from the package of the previous PDA. When using a vaginal ring or transdermal patch, a woman should start taking the drug on the day they are removed.

If only a progestogenic method of contraception (mini-pil, injection, implant) or intrauterine system with the release of progestogen (IUD) was used previously,

A woman can switch to taking a drug from a mini-drip on any day (from an implant or an IUD on the day of removal, from an injection method on the day the next injection is prescribed), but in all cases during the first 9 days of taking the tablets, it is recommended In addition, use the barrier method of contraception.

After abortion in the first trimester of pregnancy

A woman can start taking pills immediately.In this case, there is no need for additional contraceptive measures.

After childbirth or abortion in the second trimester of pregnancy

It should be recommended to a woman to start taking pills on the 21-28th day after childbirth or abortion in the second trimester of pregnancy. If a woman starts taking pills later, she is recommended to use the barrier method of contraception during the first 9 days of taking the pills. However, if sexual intercourse has already taken place, before the actual start of the drug intake, pregnancy should be excluded, or the woman should wait for the onset of the first menstruation.

Acceptance of missed tablets

Missed (white) inactive tablets can be neglected. However, they should be discarded to avoid inadvertently prolonging the interval between taking active tablets.

Skipping active tablets

If the delay in taking any of the tablets is less than 12 hours, contraceptive protection is not reduced. A woman should drink a missed pill right away, as soon as she remembers it, and take the rest of the pills at the usual time.

If the delay in taking any of the tablets is more than 12 hours, contraceptive protection may decrease. A woman should take the last missed pill right away, as soon as she remembers it, even if it means that she will have to drink 2 tablets. Simultaneously. Then you need to continue taking the pill at the usual time.

Side effects:

Infections and invasions: fungal infection, vaginal candidiasis, vaginal infection, unspecified, candidiasis, herpes, presumed eye histoplasmosis syndrome, multi-colored lichen, urinary tract infection, bacterial vaginosis, vulvovaginal fungal infection.

Metabolism and alimentary disorders: increased appetite, fluid retention, hypertriglyceridemia.

From the side of the nervous system: headache (including tension headache), migraine, depression / mood reduction, decreased libido, mental disorder, mood changes, dizziness, affective lability, aggressiveness, anxiety, dysphoria, increased libido, nervousness, anxiety, sleep disturbance, stress, attention impairment, paresthesia, vertigo.

From the side of the organ of vision: intolerance of contact lenses.

From the cardiovascular system: increased blood pressure, bleeding from varicose veins, hot flushes to the face, lowering blood pressure, pain along the veins.

From the digestive system: abdominal pain (including bloating); diarrhea, nausea, vomiting, gastroesophageal reflux.

From the hepatobiliary system: increased ALT activity, focal nodular hyperplasia of the liver.

From the skin and subcutaneous tissue: acne, alopecia, itching (including generalized itching and itching rash), rash (including spotted rash); allergic skin reaction, including allergic dermatitis and urticaria, chloasma, dermatitis, hirsutism, hypertrichosis, neurodermatitis, pigmentation disorder, seborrhea, skin lesion, unspecified, including a feeling of skin tightness.

From the musculoskeletal system: back pain, muscle spasms, a sense of heaviness.

On the part of the reproductive system: amenorrhea, discomfort in the mammary glands, pain in the mammary glands, disorders in the nipple, pain in the nipples, dysmenorrhea, irregular menstrual bleeding (metrorrhagia); enlargement of the mammary glands, diffuse compaction of the mammary glands, dysplasia of the epithelium of the cervix,dysfunctional uterine bleeding, dyspareunia, fibrocystic mastopathy, menorrhagia, ovarian cysts, pelvic pain, premenstrual syndrome, uterine leiomyoma, spasms of the uterus, vaginal discharge, dryness in the vulvovaginal area; benign breast, breast cyst, hemorrhage during sexual intercourse, galactorrhea, bleeding from the vagina, hypomenorrhea, menstrual bleeding delay, rupture of the ovarian cyst, burning sensation in the vagina, uterine / vaginal bleeding (including spotting, odor from the vagina, vulvovaginal discomfort).

Common symptoms: weight gain, irritability, swelling, weight loss, lymphadenopathy, chest pain, fatigue, malaise.

Overdose:

No serious violations were reported with an overdose of the drug.

Symptoms: nausea, vomiting, spotting spotting or metrorrhagia.

Treatment: symptomatic.

Interaction:

The effect of other drugs on the active components of the drug

The interaction of CPC with other drugs can lead to breakthrough uterine bleeding and / or lack of contraceptive effect.

The following types of interactions have been described in the literature on the PDA as a whole or have been studied in clinical trials of the drug.

Inductors or inhibitors of individual enzymes (isoenzyme CYP3A4)

Inductors of isoenzymes. There may be interaction with drugs inducing microsomal enzymes (eg, cytochrome P450 systems), resulting in increased sex hormone clearance (phenytoin, barbiturates, primidon, carbamazepine, rifampicin and, possibly, also oxcarbazepine, topiramate, felbamate, ritonavir, griseofulvin, as well as preparations containing St. John's wort pitted). It was reported that the influence on hepatic metabolism can also be caused by HIV protease inhibitors (for example, ritonavir), non-nucleoside reverse transcriptase inhibitors (eg, nevirapine) and their combinations.

Influence on enterohepatic circulation. Against the background of taking certain groups of antibiotics (for example, penicillin and tetracycline groups) enterohepatic circulation of estrogens may decrease, which can lead to a decrease in the concentration of estradiol.

Women who are treated with drugs that induce microsomal enzymes, or antibiotics, in addition to the drug is recommended to temporarily use the barrier method of contraception or choose another method of contraception. The barrier method of protection should be used during the entire period of taking concomitant medications and for another 28 days after their withdrawal.

Inhibitors of isoenzymes. Simultaneous reception of rifampicin together with tablets containing estradiol valerate and dienogast, led to a significant decrease in C_ss and systemic exposure of dienogest and estradiol. Systemic exposure of dienogest and estradiol at equilibrium concentration, measured on the basis of AUC_{0-24 h}, respectively, decreased by 83% and 44%.

Known inhibitors of CYP3A4, such as azole antifungal agents, cimetidine, verapamil, macrolides, diltiazem, antidepressants and grapefruit juice, can increase the concentration of dienogest in the blood plasma. When administered concomitantly with a potent ketoconazole inhibitor, the AUC_{0-24 h} in the equilibrium state, the dienogest increased by 186%, and in estradiol - by 57%.When used simultaneously with a moderate erythromycin inhibitor, the AUC_{0-24 h} in dienogest and estradiol in the equilibrium state, respectively, increased by 62% and 33%.

Effects of the drug in relation to other drugs: PDAs can affect the metabolism of a number of other drugs (eg, lamotrigine), which can lead to either an increase or a decrease in the concentration of these substances in blood plasma and tissues. However, based on in vitro studies, inhibition of CYP enzymes when a drug is administered at a therapeutic dose is unlikely.

Special instructions:

Before starting the preparation it is necessary to carefully evaluate the contraindications to prescribing the drug based on anamnesis of life, a family history of a woman, as well as general medical and gynecological examination. The frequency and nature of these surveys should be based on existing norms of medical practice, with the necessary consideration of the individual characteristics of each patient. As a rule, BP is measured, the condition of mammary glands, abdominal cavity and pelvic organs is checked, including cervical cytology.

It is necessary to explain to women that the drug does not protect against HIV infection (AIDS) and other sexually transmitted diseases.

Decreased efficiency

Effectiveness of the drug can be reduced by skipping tablets with active ingredients, gastrointestinal disorders during the intake of tablets with active ingredients, or against the background of concomitant drug treatment.

Insufficient control of the menstrual cycle

Against the background of the use of the drug, especially in the first months of admission, irregular menstrual bleeding (spotting or breakthrough uterine bleeding) may occur. Therefore, any irregular menstrual bleeding should be evaluated only after a period of adaptation, which is approximately 3 menstrual cycle-like.

If irregular menstrual bleeding is repeated or first occurs after previous regular cycles, the likelihood of non-hormonal causes should be considered and a thorough examination should be conducted to exclude malignancies or pregnancy.Such activities may include diagnostic scraping.

In some women, while receiving inactive white tablets, menstrual bleeding may not develop. If the drug is taken was carried out in accordance with the rules indicated in the section "Dosage regimen", pregnancy is unlikely. However, if before the first menstrual-like bleeding, tablets were taken irregularly or there are no contractions of menstrual bleeding, do not continue using the drug until pregnancy is excluded.

Impact on the ability to drive vehicles and manage mechanisms

There was no negative effect of the drug on the ability to drive and work with mechanisms, but patients who during the period of adaptation (the first 3 months of taking the drug) have episodes of dizziness and impaired concentration, should be careful.

Instructions

Dienogest + Estradiol valerate (Dienogestum + Oestradioli valeras)