Alvovizan tablets 2mg, No. 28

Monotherapy: treatment of endometriosis.

In combination with estrogens: contraception.

For oral administration.
Before you start taking Alvovizan, you must stop using any hormonal contraception. If necessary, contraception uses non-hormonal methods (for example, barrier).
It is possible to start taking Alvovizan on any day of the menstrual cycle. The drug is taken 1 tablet per day continuously, preferably at the same time, if necessary with a small amount of liquid. You can take the tablet on an empty stomach or with a meal. The tablets should be taken regularly, regardless of vaginal bleeding. After the completion of taking the tablets from one package, they start taking the drug Alvovizan from the next package, without taking a break in taking the drug.
In case of missed pills, vomiting and / or diarrhea (if this occurs within 3-4 hours after taking the pill), the effectiveness of Alvovizan may decrease. If one or more pills are missed, the woman should take only one pill at once, as soon as she remembers, then continue taking the pills the next day at the usual time. If absorption of the drug is impaired due to vomiting or diarrhea, one tablet should also be taken.
The duration of the drug intake is 6 months. The decision on further therapy with dienogest is made by the doctor depending on the clinical picture.

The use of the drug in special clinical groups of patients
Adolescent girls under the age of 18
The use of the drug in adolescent girls under the age of 18 is contraindicated due to the lack of data on the efficacy and safety of dienogest in this age category.
Patients older
substantiate indications for use Alvovizan drug in elderly patients are missing.
Patients with impaired liver function
The drug Alvovizan is contraindicated in patients with severe liver disease - current or history (see section 'Contraindications').
Patients with impaired renal function
There is no evidence of the need for dose adjustment in patients with impaired renal function.

White film-coated tablets, round, biconvex, engraved with '2' on one side; cross-section - white core and film shell.

1 tab. dienogest 2 mg

Excipients: lactose monohydrate - 57.2 mg, corn starch - 12 mg, povidone K30 - 3 mg, sodium carboxymethyl starch (type A) - 5 mg, magnesium stearate - 0.8 mg.

• Acute thrombophlebitis, venous thromboembolism at present;

• diseases of the heart and arteries, which are based on atherosclerotic vascular lesions (including coronary artery disease, myocardial infarction, stroke and transient ischemic attack) at present or in history;

• diabetes mellitus with vascular complications;

• severe liver disease at present or in history (in the absence of normalization of liver function tests);

• liver tumors (benign and malignant), currently or in history;

• identified or suspected hormone-dependent malignant tumors, incl. mammary cancer;

• vaginal bleeding of unknown origin; history of cholestatic jaundice of pregnant women;

• children and adolescents up to 18 years old; hypersensitivity to dienogest.

pharmachologic effect

Dienogest is a derivative of nortestosterone, characterized by antiandrogenic activity, which is approximately one third of that of cyproterone acetate. Dienogest binds to progesterone receptors in the human uterus, having only 10% of the relative affinity of progesterone. Despite its low affinity for progesterone receptors, dienogest is characterized by a potent progestogenic effect in vivo. Dienogest has no significant mineralocorticoid or glucocorticoid activity in vivo.

Dienogest acts on endometriosis by suppressing the trophic effects of estrogens in relation to the eutopic and ectopic endometrium, due to a decrease in the production of estrogens in the ovaries and a decrease in their concentration in plasma.

With prolonged use, it causes an initial decidualization of endometrial tissue with subsequent atrophy of endometrioid foci. Additional properties of dienogest, such as immunological and anti-angiogenic effects, appear to contribute to its suppressive effect on cell proliferation.

There was no decrease in bone mineral density (BMD), as well as a significant effect of dienogest on standard laboratory parameters, including general and biochemical parameters of blood, liver enzymes, lipids and HbA1C. Dienogest moderately reduces the production of estrogen in the ovaries.

Pharmacokinetics

After oral administration, dienogest is rapidly and almost completely absorbed. Cmax in serum of 47 ng / ml is reached approximately 1.5 hours after a single oral administration. Bioavailability is about 91%. The pharmacokinetics of dienogest in the dose range from 1 to 8 mg is dose-dependent. Dienogest binds to serum albumin and does not bind to sex hormone binding globulin (SHBG) or corticosteroid binding globulin (CSG). 10% of the total concentration of the substance in the blood serum is in the form of a free steroid, while about 90% is nonspecifically bound to albumin. The apparent Vd of dienogest is 40 liters. The pharmacokinetics of dienogest does not depend on the level of SHBG. The concentration of dienogest in the blood serum after daily intake increases by about 1.24 times,reaching an equilibrium concentration after 4 days of admission.

Dienogest is almost completely metabolized mainly by hydroxylation to form several practically inactive metabolites. Based on the results of in vitro and in vivo studies, the main enzyme involved in the metabolism of dienogest is CYP3A4. Metabolites are excreted very quickly, so that the predominant fraction in the blood plasma is unchanged dienogest. The metabolic clearance rate from blood serum is 64 ml / min.

The concentration of dienogest in the blood serum decreases in two phases. T1 / 2 in the terminal phase is approximately 9-10 hours. After oral administration at a dose of 0.1 mg / kg, dienogest is excreted in the form of metabolites, which are excreted through the kidneys and intestines in a ratio of approximately 3: 1. T1 / 2 of metabolites when they are excreted by the kidneys is 14 hours. After oral administration, approximately 86% of the dose received is excreted within 6 days, and the main part is excreted in the first 24 hours, mainly by the kidneys.

Side effect

From the reproductive system: often - discomfort in the mammary glands (including enlargement of the mammary glands and pain in the mammary glands), ovarian cyst (including hemorrhagic cyst), hot flashes, uterine bleeding / vaginal bleeding (including spotting, metrorrhagia, menorrhagia, irregular bleeding), amenorrhea; infrequently - vaginal candidiasis, dryness in the vulvovaginal area (including dryness of the mucous membranes), discharge from the genitals (including discharge from the vagina), pain in the pelvic region, atrophic vulvovaginitis, fibrocystic mastopathy, breast thickening.

From the side of metabolism: often - an increase in body weight; infrequently - weight loss, increased appetite.

From the nervous system: often - headache, migraine, low mood, sleep disturbance (including insomnia), nervousness, loss of libido, mood changes; infrequently - imbalance of the peripheral nervous system, impaired attention, anxiety, depression, mood swings.

From the digestive system: often - nausea, pain in the abdomen (including pain in the lower abdomen and pain in the epigastrium), flatulence, a feeling of bloating in the abdomen, vomiting; infrequently - diarrhea, constipation, abdominal discomfort, inflammatory diseases of the gastrointestinal tract, gingivitis.

From the side of the skin: often - acne, alopecia; infrequently - dry skin, hyperhidrosis, itching, hair growth abnormalities, incl. hirsutism and hypertrichosis, onychoclasia, dandruff, dermatitis, photosensitivity reactions, pigmentation disorders.

From the musculoskeletal system: often - back pain; infrequently - bone pain, muscle spasms, pain in the limbs, a feeling of heaviness in the limbs.

From the senses: infrequently - a feeling of dry eyes, ringing in the ears.

From the side of the cardiovascular system: infrequently - unspecified circulatory disorders, palpitations, arterial hypotension.

From the respiratory system: infrequently - shortness of breath.

From the hematopoietic system: infrequently - anemia.

From the urinary system: infrequently - urinary tract infection (including cystitis).

Others: often - asthenic state (including fatigue, asthenia and malaise), irritability; infrequently - edema (including facial edema).

Application during pregnancy and lactation

Data on the use of dienogest in pregnant women are limited. Data obtained in animal studies and data on the use of dienogest in women during pregnancy did not reveal a specific risk for pregnancy, fetal development, childbirth and child development after birth. Dienogest should not be prescribed to pregnant women due to the lack of the need for treatment of endometriosis during pregnancy.

It is not recommended to use dienogest during breastfeeding, because animal studies indicate the excretion of dienogest in breast milk.

special instructions

It should be used with caution in case of a history of depression, a history of ectopic pregnancy, arterial hypertension, chronic heart failure, migraine with aura, diabetes mellitus without vascular complications, hyperlipidemia, a history of deep vein thrombophlebitis, a history of venous thromboembolism.

Before you start taking dienogest, you must exclude pregnancy. While taking dienogest for the treatment of endometriosis, if contraception is required, patients are advised to use non-hormonal contraceptive methods (for example, barrier).

According to available data, the physiological menstrual cycle is restored within 2 months after discontinuation of dienogest for the treatment of endometriosis.

The question of the use of the drug dienogest in women with a history of ectopic pregnancy or with impaired function of the fallopian tubes should be resolved only after a careful assessment of the ratio of the expected benefit and possible risk.

It should be borne in mind that special warnings and precautions when using other progestogens also apply to dienogest.

If any of the following conditions or risk factors are present or worsened, an individual assessment of the benefit / risk ratio should be performed before starting or continuing to take dienogest.

In the course of epidemiological studies, insufficient evidence was obtained to confirm the existence of an association between the use of drugs with only a gestagenic component and an increased risk of myocardial infarction or cerebral thromboembolism. The risk of cardiovascular episodes and cerebrovascular accidents is associated, rather, with increasing age, hypertension and smoking. The risk of developing a stroke in women with arterial hypertension may slightly increase while taking drugs only with a progestogenic component.

Epidemiological studies indicate the possibility of a statistically insignificant increase in the risk of venous thromboembolism (deep vein thrombosis, pulmonary embolism) due to the use of drugs with only a gestagenic component. Commonly recognized risk factors for venous thromboembolism (VTE) include a related family history (sibling, or a parent's VTE at a relatively early age), age, obesity, prolonged immobilization, major surgery, or major trauma. In the case of prolonged immobilization, it is recommended to stop taking dienogest (with a planned operation, at least 4 weeks before it) and resume use only two weeks after the full recovery of motor activity.

Consideration should be given to the increased risk of thromboembolism in the postpartum period.

With the development or suspicion of the development of arterial or venous thrombosis, dienogest should be discontinued immediately.

The risk of detecting breast cancer in women using hormonal contraceptives only with a gestagenic component may be similar in magnitude to the corresponding risk in connection with the use of combined oral contraceptives. However, the evidence for progestogen-only drugs is based on much smaller populations of women using them and is therefore less convincing than the data for combined oral contraceptives. It is not possible to establish a causal relationship based on these studies. The revealed pattern of increased risk may be due to an earlier diagnosis of breast cancer in women taking oral contraceptives, the biological effect of oral contraceptives, or a combination of both factors. Malignant tumors of the breast,diagnosed in women who have ever used PC are usually less clinically pronounced than in women who have never used hormonal contraception.

In rare cases, against the background of the use of progestogens, benign, and even less often, malignant liver tumors were noted. In some cases, these tumors have resulted in life-threatening intra-abdominal bleeding. If, while taking dienogest, severe pain in the upper abdomen occurs, the liver is enlarged, or there are signs of intra-abdominal bleeding, then the differential diagnosis should take into account the likelihood of a hepatic tumor.

In most women, dienogest affects the pattern of menstrual bleeding.

Against the background of the use of dienogest, an increase in uterine bleeding is possible, for example, in women with adenomyosis or uterine leiomyoma. Heavy and prolonged bleeding can lead to anemia (in some cases, severe). In such cases, consideration should be given to discontinuing dienogest.

Patients with a history of depression need close monitoring. If depression recurs severely, dienogest should be discontinued.

If persistent clinically significant arterial hypertension occurs while taking dienogest, it is recommended to discontinue dienogest and prescribe antihypertensive treatment.

In case of recurrence of cholestatic jaundice and / or cholestatic pruritus, which first appeared during pregnancy or previous use of sex steroids, dienogest should be canceled.

Dienogest may have little effect on peripheral insulin resistance and glucose tolerance. Women suffering from diabetes mellitus, especially with a history of pregnancy diabetes mellitus, need careful monitoring while taking dienogest.

In some cases, chloasma may occur, especially in women with a history of chloasma during pregnancy. Women prone to chloasma should avoid exposure to the sun or ultraviolet radiation while taking dienogest.

Persistent ovarian follicles (often called functional ovarian cysts) may develop during dienogest use. Most of these follicles are asymptomatic, although some may present with pelvic pain.

Taking progestogens can affect the results of some laboratory studies, including biochemical parameters of liver, thyroid, adrenal and kidney function, plasma concentrations of proteins (carriers), for example, lipid / lipoprotein fractions, carbohydrate metabolism parameters and clotting parameters.

Influence on the ability to drive vehicles and use mechanisms

As a rule, dienogest does not affect the ability to drive and work with mechanisms, however, patients who have impaired concentration should be careful.

Drug interactions

Gestagens, incl. dienogest, metabolized mainly with the participation of CYP3A4, located both in the intestinal mucosa and in the liver. Therefore, inducers or inhibitors of CYP3A4 can affect the metabolism of progestogen drugs.

The increased clearance of sex hormones due to the induction of enzymes can lead to a decrease in the therapeutic effect of dienogest, as well as cause side effects, for example, a change in the nature of uterine bleeding.

Decreased sex hormone clearance due to enzyme inhibition can increase dienogest exposure and cause side effects.

Possible interaction with drugs that induce microsomal enzymes (for example, cytochrome P450 systems), as a result of this, the clearance of sex hormones may increase (such drugs include phenytoin, barbiturates, primidone, carbamazepine, rifampicin and, possibly, also oxcarbazepine, topiramate, felbamate, nevirapine, griseofulvin, and preparations containing St. John's wort).

The maximum induction of enzymes, as a rule, is noted no earlier than 2-3 weeks, but then it can persist for at least 4 weeks after stopping therapy.

The effect of the CYP3A4 inducer rifampicin has been studied in healthy postmenopausal women. With the simultaneous administration of rifampicin with estradiol valerate / dienogest tablets, a significant decrease in the equilibrium concentration and systemic exposure of dienogest was noted. The systemic exposure of dienogest at equilibrium concentration, determined by the value of AUC (0-24 hours), was reduced by 83%.

Known CYP3A4 inhibitors such as azole antifungals (eg, ketoconazole, itraconazole, fluconazole), cimetidine, verapamil, macrolides (eg erythromycin, clarithromycin, and roxithromycin), diltiazem, protease inhibitors (eg, indacvinafironavir), antidepressants (eg, nefazodone, fluvoxamine, fluoxetine) and grapefruit juice can increase the concentration of gestagens in the blood plasma and cause side effects.

In a study in which the effect of CYP3A4 inhibitors (ketoconazole, erythromycin) was studied, the concentrations of estradiol valerate and dienogest in blood plasma at an equilibrium concentration were increased. In the case of simultaneous administration with a powerful inhibitor ketoconazole, the AUC value (0-24 hours) at equilibrium concentration in dienogest increased by 186%. With simultaneous use with a moderate CYP3A4 inhibitor erythromycin, the AUC value (0-24 hours) for dienogest at an equilibrium concentration increased by 62%. The clinical significance of this interaction has not been clarified.