Zafrilla pills 2mg, 28pcs

Composition

1 tablet contains:

Active ingredient:

dienogest (micronized) 2 mg.

Excipients: lactose monohydrate, pregelatinized starch, microcrystalline cellulose, povidone-K 25, crospovidone (type A), talc, magnesium stearate.

Pharmacological action

Pharmacotherapeutic group: progestogen.

ATX code: G03DB08

Pharmacological properties

Pharmacodynamics

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

Dienogest affects endometriosis by suppressing the trophic effects of estradiol on the autopical 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 initial decidualization of endometrial tissue, followed by atrophy of endometrioid foci. Other pharmacological properties of dienogest, such as its immunomodulatory and anti-angiogenic properties, probably contribute to its suppressive effect on cell proliferation.

The benefit of dienogest over placebo for pelvic pain associated with endometriosis was demonstrated in 198 patients in a 3-month clinical trial. Pelvic pain associated with endometriosis was assessed using a visual analog scale (VAS,0-100 mm). After 3 months of treatment with dienogest, there was a statistically significant difference with placebo (∆ = 12.3 mm; 95% CI: 6.4-18.1; p

After 3 months of treatment, and 37.3% of patients noted a decrease in the intensity of pelvic pain associated with endometriosis,50% or more without a corresponding increase in the dose of additional analgesic, which they took (in the placebo group: from 19.8 per cent); in 18.6% of patients noted a decrease in the intensity of pelvic pain associated with endometriosis,75% or more without an increase in the dose of additional analgesic, which they took (placebo: 7.3 per cent).

In the extended open-label phase of this placebo-controlled study, a steady reduction in pelvic pain associated with endometriosis was observed with a treatment duration of up to 15 months.

The results of the placebo-controlled part of the study were confirmed by the results obtained in a study with an active control group (taking a gonadotropin-releasing hormone (GnRH) agonist) lasting 6 months in 252 patients with endometriosis.

Three studies involving a total of 252 patients receiving a daily dose of dienogest 2 mg showed a significant reduction in endometrioid foci after 6 months of treatment.

In a small study (n = 8 in each dose group), it was shown that dienogest at a daily dose of 1 mg after 1 month caused the development of anovulatory status. The contraceptive efficacy of dienogest has not been studied in larger studies.

During dienogest therapy, there is a moderate decrease in the concentration of endogenous estrogens. Currently, there are no data on long-term studies of bone mineral density (BMD) and the risk of fractures when taking dienogest.

BMD was assessed in 21 adult patients before starting treatment and after 6 months of using the drug; there was no decrease in the average BMD index. After the same period of treatment with leuprorelin acetate (LA),29 patients showed a decrease in BMD by 4.04% ± 4.84 (∆ between groups = 4.29%; 95% CI: 1.93 – 6.66; p

During the use of dienogest for up to 15 months, no significant effect of the drug on standard laboratory parameters, including hematology, blood chemistry, liver enzymes, lipids and glycated hemoglobin, was observed.

In a 12-month study involving 111 adolescent patients,103 patients had an average relative change in the BMD index of the lumbar spine (vertebrae L2 ‒ L4) compared to the initial indicator of 1.2%.6 months after the end of treatment, during the extended follow – up period, this parameter was measured again in a group of patients who had a decrease in BMD, and the analysis showed an increase in the BMD level towards the initial indicator to the level of-0.6%.

Preclinical data obtained from standard studies of pharmacological safety, multiple-dose toxicity, genotoxicity, carcinogenic potential, and reproductive toxicity do not indicate the existence of a specific risk to humans. However, it should be borne in mind that sex hormones can stimulate the growth of a number of hormone-dependent tissues and tumors.

Pharmacokinetics

Suction

Dienogest is rapidly and almost completely absorbed after oral use. The maximum plasma concentration of 47 ng / ml is reached approximately 1.5 hours after a single oral dose. Bioavailability is about 91%. The pharmacokinetics of dienogest in the dose range from 1 to 8 mg is characterized by dose dependence.

Distribution

Dienogest binds to plasma 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 plasma is in the form of a free steroid, while about 90% is non-specifically associated with albumin. The apparent volume of distribution of dienogest is 40 liters.

Metabolism

Dienogest is almost completely metabolized mainly by hydroxylation with the formation of several practically inactive metabolites. Based on the results of in vitro and in vivo studies, the main enzyme involved in dienogest metabolism is CYP3A4. Metabolites are eliminated very quickly, so that the predominant fraction in the blood plasma is unchanged dienogest.

The rate of metabolic clearance from blood plasma is 64 ml/min.

Deduction

The concentration of dienogest in the blood plasma decreases biphasically. The terminal half-life is approximately 9-10 hours. After oral use at a dose of 0.1 mg / kg, dienogest is excreted as metabolites by the kidneys and through the intestine in a ratio of approximately 3: 1. The half-life of metabolites by the kidneys is 14 hours. After oral use, approximately 86% of the dose received is eliminated within 6 days, with the majority being eliminated in the first 24 hours, mainly by the kidneys.

The steady

-state pharmacokinetics of dienogest are independent of SHBG levels. The concentration of dienogest in the blood plasma after daily use increases approximately 1.24 times, reaching an equilibrium concentration after 4 days of use. The pharmacokinetics of dienogest after repeated use of the drug can be predicted based on the pharmacokinetics after a single application.

Pharmacokinetics in special groups of patients

Patients with renal insufficiency

The pharmacokinetics of dienogest in patients with impaired renal function have not been studied.

Patients with hepatic insufficiency

The pharmacokinetics of dienogest in patients with hepatic insufficiency have not been studied.

Indications

Endometriosis treatment

Use during pregnancy and lactation

Pregnancy

Data on the use of dienogest in pregnant women are very limited. In animal studies, reproductive toxicity, genotoxicity, and carcinogenicity were not detected when dienogest was administered. The use of the drug during pregnancy is contraindicated due to the lack of need for endometriosis therapy during pregnancy.

Breast-feeding period

TakingZafrilla® during breastfeeding is contraindicated. Animal studies have shown that dienogest penetrates the milk of lactating animals. It is not known whether dienogest passes into human breast milk. Discontinuation of breast-feeding or Zafrilla therapy should be considered.

The decision to stop breastfeeding or to stoptaking Zafrilla® is made based on an assessment of the ratio of the benefits of breastfeeding for the child and the benefits of dienogest therapy for the woman.

Contraindications

The use of Zafrilla® is contraindicated in the presence of any of the following conditions/diseases/risk factors, some of which are common to all drugs containing only the progestogen component.

– Acute venous thrombophlebitis, venous thromboembolism (VTE).

– Diseases of the heart and arteries, which are based on atherosclerotic vascular lesions (including coronary heart disease, myocardial infarction, cerebrovascular accident) at the present time or in the anamnesis.

– Diabetes mellitus with angiopathy.

– Severe liver diseases at present or in the anamnesis before normalization of liver function indicators.

– Liver tumors (benign or malignant) at present or in the anamnesis.

– Diagnosed or suspected hormone-dependent malignant diseases of the genitals or breast.

– Bleeding from the vagina of unknown origin.

– Hypersensitivity to dienogesEffect of dienogest on other medicinal products

Based on data from in vitro inhibition studies, a clinically significant interaction of dienogest with other drugs metabolized by cytochrome P450 isoenzymes is unlikely.

Note: To clarify possible interactions, please refer to the instructions for use of concomitant medications.

Interaction with food products

High-fat food intake did not affect the bioavailability of dienogest.

Other types of interaction

The use of progestogens may affect the results of some laboratory tests, including biochemical parameters of liver, thyroid, adrenal and kidney function, plasma protein concentrations – carriers, for example, lipid/lipoprotein fractions, parameters of carbohydrate metabolism, blood clotting and fibrinolysis.

Usually, these interactions do not go beyond the normal laboratory parameters.

How to take, course of use and dosage

Inside, regardless of food intake.

Any hormonal contraception should be discontinued prior to taking Zafrilla. If contraception is necessary, use non-hormonal methods (for example, barrier).

You can start taking Zafrilla® on any day of your menstrual cycle.

The drug is taken 1 tablet a day continuously, preferably at the same time, if necessary, with a small amount of liquid. You should take the pills regularly, regardless of vaginal bleeding. After completing taking tablets from one package, start takingZafrilla® from the next package, without taking a break in taking the drug.

If you miss a pill, vomit and / or have diarrhea (if this occurs within 3-4 hours after taking the pill), the effectiveness of Zafril® may decrease. If you miss taking one or more pills, the woman should take only one tablet as soon as she remembers, then continue taking the pills at the usual time the next day. If the absorption of the drug is impaired due to vomiting or diarrhea, you should also take one tablet.

The duration of taking the drug is 6 months. The decision on further therapy with dienogest is made by the doctor depending on the clinical picture.

Special patient groups

Teenage 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 effectiveness and safety of dienogest in this age category.

Elderly patients (over 65 years of age)

There are no reasonable indications for the use ofZafrilla in elderly patients.

Patients with hepatic insufficiency

Zafrilla® is contraindicated in patients with severe liver disease ‒ current or in the anamnesis (see the section “Contraindications”).

Patients with renal insufficiency

There are no data indicating the need for dose adjustment in patients with impaired renal function.

Overdose

No serious overdose violations were reported.

Symptomsthat can occur with an overdose: nausea, vomiting, “smearing” spotting or metrorrhagia.

Treatment: There is no specific antidote, and symptomatic treatment should be performed.

Description

Round flat tablets of white or almost white color with a chamfer and engraving ” G93 “on one side and” RG ” on the other side.

Special instructions

Before using the drug, it is necessary to exclude pregnancy. During the use of the drug, if contraception is necessary, patients are recommended to use non-hormonal contraceptive methods (for example, barrier).

Fertility

Based on the available data, ovulation suppression occurs during the use of the drug in most patients. However, dienogest at a dosage of 2 mg is not a contraceptive drug.

According to available data, the physiological menstrual cycle returns to normal within 2 months after discontinuation of dienogest treatment.

The probability of ectopic pregnancy is higher in patients taking contraceptive drugs containing only the progestogen component, compared with patients taking combined oral contraceptives. Therefore, for women with a history of ectopic pregnancy or with an obstruction of the fallopian tubes, the benefit-risk ratio should be evaluated before using dienogest.

Changing the nature of bleeding

In most women, the use of dienogest affects the nature of menstrual bleeding.

When using dienogest, it is possible to increase uterine bleeding, for example, in women with uterine adenomyosis and uterine leiomyomas. With severe and prolonged bleeding, anemia (sometimes severe) may develop. In case of anemia, discontinuation of the drug should be considered.

Circulatory disorders

Epidemiological studies have shown an insufficiently convincing relationship between the use of progestogen monopreparations and an increased risk of myocardial infarction or cerebral vascular thromboembolism. To a greater extent, the risk of cardiovascular and cerebral diseases is associated with age, the presence of arterial hypertension and smoking. In women with hypertension, the risk of stroke may increase slightly when taking progestogen monopreparations. Some studies have shown a small and statistically insignificant increase in the risk of venous thromboembolism (deep vein thrombosis, pulmonary embolism) when using progestogen monopreparations. Generally recognized risk factors for VTE include a history of VTE in patients or a family history (VTE in a sibling or parent less than 50 years of age), age, obesity, prolonged immobilization, major surgery, or extensive trauma. In such cases, you should stop taking dienogest (at least four weeks before elective surgery) and resume taking it no earlier than two weeks after full recovery of motor activity.

The increased risk of developing thromboembolism in the postpartum period should be taken into account. If arterial or venous thrombosis develops or is suspected, the drug should be discontinued immediately.

Tumors

A meta-analysis of 54 epidemiological studies revealed a slight increase in the relative risk (RR = 1.24) of developing breast cancer (BC) in women taking oral contraceptives at the time of the study, mainly combined (estrogen + progestogen). This increased risk gradually decreases over 10 years after discontinuation of combined oral contraceptives (COCs).

Because breast cancer is rare in women younger than 40 years of age, some increase in the number of such diagnoses in women taking or recently taking COCs is small compared to the overall risk of breast cancer. The risk of breast cancer diagnosis in women using progestogen monopreparations is approximately the same as when taking COCs. However, data on progestogen monopreparations are obtained in significantly smaller patient populations and are less convincing than data on COC. 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, their biological effect, or a combination of these factors. Women who take oral contraceptives have earlier clinical stages of breast cancer compared to women who have never taken them.

In rare cases, benign and even less often malignant liver tumors have been reported in patients taking dienogest. In some cases, these tumors led to life-threatening intra-abdominal bleeding. If a woman taking the drug has severe pain in the upper abdomen, an enlarged liver, or signs of intra-abdominal bleeding, then the differential diagnosis should take into account the likelihood of a liver tumor.

Changes in bone mineral density (BMD)

While taking dienogest, there was a decrease in BMD, so it is necessary to evaluate the expected benefit of its use in relation to the possible risk for each patient, taking into account the possibility of risk factors for osteoporosis, especially in patients with an increased risk of osteoporosis, since during treatment with dienogest, there is a moderate decrease in the concentration of endogenous estrogens. It is important for women of all ages to take a calcium supplement and vitamin D supplement, regardless of whether they follow a specific diet or use vitamin supplements.

Other states

Patients with a history of depression should be carefully monitored. If the depression recurs in a serious form, the drug should be discontinued.

In general, it has been shown that the drug does not affect blood pressure (BP) in women with normal blood pressure. However, if chronic, clinically significant arterial hypertension occurs during the use of dienogest, it is recommended to cancel the drug and start antihypertensive treatment.

In case of recurrence of cholestatic jaundice and/or cholestatic pruritus, which first appeared during pregnancy or previous use of sex hormones, the drug should be discontinued.

Dienogest may have little effect on peripheral insulin resistance and glucose tolerance. Patients with diabetes mellitus, especially if there is a history of gestational diabetes mellitus, should be closely monitored during dienogest therapy.

In some cases, chloasma may develop, especially in women with a history of chloasma in pregnant women. Women with a tendency to chloasma should avoid exposure to sunlight or ultraviolet radiation during the use of the drug.

Persistent ovarian follicles (often referred to as functional ovarian cysts) may occur during treatment with the drug. Most of these follicles have no clinical manifestations, although some may be accompanied by pelvic pain.

Lactose

One tabletof Zafrilla® contains 62.8 mg of lactose monohydrate. Patients on a lactose-free diet with rare hereditary problems such as galactose intolerance, lactase deficiency or glucose-galactose malabsorption are contraindicated.

Influence on the ability to drive vehicles and mechanisms

There was no negative effectof Zafrilla® on the ability to drive vehicles and mechanisms, but patients who have impaired concentration of attention during the adaptation period (the first 3 months of using the drug) should exercise caution.

Form of production

Tablets,2 mg

14 tablets each in a blister of PVC-aluminum foil.

2 blisters in a cardboard box together with the instructions for use.

Storage conditions

In the original packaging (blister pack) at a temperature not exceeding 30 °C. Keep out of reach of children.

Shelf

life is 3 years. Do not use after the expiration date indicated on the package.

Active ingredient

Dienogest

Conditions of release from pharmacies

By prescription

Dosage form

Tablets