Zafrilla tabs 2mg #28

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Zafrilla instruction

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Composition

1 tablet contains:
Active ingredient: dienogest (micronized) 2 mg.
Excipients: lactose monohydrate, pregelatinized starch, microcrystalline cellulose, povidone-K25, crospovidone (type A), talc, magnesium stearate.

Pharmacodynamics

Dienogest is a derivative of nortestosterone, characterized by antiandrogenic activity, accounting for approximately one third of that of cyproterone 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 potent progestogenic effect in vivo. Dienogest has no significant androgenic, mineralocorticoid, or glucocorticoid activity in vivo.
Dienogest acts on endometriosis by suppressing the trophic effects of estradiol in relation to the autopic 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, followed by atrophy of endometrioid foci. Other pharmacological properties of dienogest, such as immunomodulatory and antiangiogenic, probably contribute to its suppressive effect on cell proliferation.
The advantage of dienogest over placebo for pelvic pain associated with endometriosis was demonstrated in 198 patients in a 3-month clinical study. Pelvic pain associated with endometriosis was assessed using a visual analogue scale (VAS, 0-100 mm). After 3 months of treatment with dienogest, a statistically significant difference from placebo was shown (Δ = 12.3 mm; 95% CI: 6.4-18.1; p <0.0001), as well as a clinically significant reduction in pain from baseline. (average decrease = 27.4 mm ± 22.9).
After 3 months of treatment, 37.3% of patients showed a decrease in the intensity of pelvic pain associated with endometriosis by 50% or more without a corresponding increase in the dose of additional anesthetic that they took (in the placebo group: 19.8%); 18.6% of patients experienced a 75% or more reduction in the intensity of pelvic pain associated with endometriosis without increasing the dose of additional pain reliever they were taking (placebo: 7.3%).
In the extended open phase of this placebo-controlled study, there was a sustained reduction in pelvic pain associated with endometriosis with treatment durations 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) for 6 months in 252 patients with endometriosis.
Three studies involving a total of 252 patients who received a daily dose of 2 mg dienogest demonstrated a significant reduction in endometriotic lesions 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 study of the contraceptive effectiveness of dienogest in larger studies has not been conducted.
During the period of therapy with dienogest, there is a moderate decrease in the concentration of endogenous estrogens. There are currently no data from a long-term study of bone mineral density (BMD) and the risk of fractures when taking dienogest.
The BMD was assessed in 21 adult patients before the start of treatment and after 6 months of using the drug; there was no decrease in the average BMD. After the same period of treatment with leuprorelin acetate (LA), 29 patients showed a decrease in BMD by 4.04% ± 4.84 (Δ between groups = 4.29%; 95% CI: 1.93-6.66; p <0 , 0003).
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, in 103 patients the mean relative change in BMD of the lumbar spine (L2-L4 vertebrae) compared with the baseline was 1.2%. 6 months after the end of treatment, within the framework of the follow-up period, in the group of patients who had a decrease in BMD, this parameter was measured again, and the analysis showed an increase in the BMD level towards the initial indicator to a level of 0.6%.
Preclinical data obtained from standard studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential and toxicity to the reproductive system 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 of Zafrilla

Suction

Dienogest is rapidly and almost completely absorbed after oral administration. 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 dose-dependent.

Distribution

Dienogest binds to albumin in the blood plasma and does not bind to sex hormone binding globulin (SHBG), as well as to corticosteroid binding globulin (CSG). 10% of the total concentration of a substance in blood plasma is in the form of a free steroid, while about 90% is nonspecifically bound to albumin. The apparent volume of distribution of dienogest is 40 liters.

Metabolism

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 plasma is 64 ml / min.

Withdrawal

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

Equilibrium concentration

The pharmacokinetics of dienogest does not depend on the level of SHBG. The concentration of dienogest in blood plasma after daily use increases by about 1.24 times, reaching an equilibrium concentration after 4 days of administration. The pharmacokinetics of dienogest after repeated use of the drug can be predicted on the basis of the pharmacokinetics after a single use.

Pharmacokinetics in special patient groups

Patients with renal impairment

Pharmacokinetics studies of dienogest in patients with impaired renal function have not been conducted.

Patients with hepatic impairment

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


Indications for Zafrilla

    Endometriosis treatment.

Contraindications

The use of Zafrilla is contraindicated in the presence of any of the conditions / diseases / risk factors listed below, some of which are common to all drugs containing only a gestagenic component.
    Acute venous thrombophlebitis, venous thromboembolism (VTE).
    Diseases of the heart and arteries, which are based on atherosclerotic vascular lesions (including ischemic heart disease, myocardial infarction, cerebrovascular accident), currently or in history.
    Diabetes mellitus with angiopathy.
    Severe liver disease at present or in history prior to normalization of liver function indicators.
    Liver tumors (benign or malignant), current or history.
    Diagnosed hormone-dependent malignant diseases of the genital organs or mammary gland, or suspicion of them.
    Vaginal bleeding of unknown origin.
    Hypersensitivity to dienogest or any of the excipients.
    Pregnancy and the period of breastfeeding.
    Hereditary lactose intolerance, lactase deficiency, glucose-galactose malabsorption.
    Age up to 18 years (due to the lack of data on the efficacy and safety of dienogest in this age group).
If any of these conditions / diseases / risk factors develop while using the drug, the drug should be stopped immediately.

Carefully

History of depression, history of ectopic pregnancy, arterial hypertension, chronic heart failure, migraine with aura, diabetes mellitus without vascular complications, hyperlipidemia, history of deep vein thrombophlebitis, personal and family history of VTE (see section "Special instructions") ...

Application Zafrilla during pregnancy and breastfeeding

Pregnancy

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

Breastfeeding period

Taking Zafrilla during breastfeeding is contraindicated. Animal studies have shown that dienogest is absorbed into the milk of lactating animals. It is not known whether dienogest passes into human breast milk. It is necessary to resolve the issue of stopping breastfeeding or therapy with Zafrilla.
The decision to stop breastfeeding or to stop taking Zafrilla is made based on an assessment of the balance between the benefits of breastfeeding for the child and the benefits of dienogest therapy for the woman.

Method of administration and dosage

Inside, regardless of the meal.
Before you start taking Zafrilla, you must stop using any hormonal contraception. If necessary, contraception uses non-hormonal methods (for example, barrier).
It is possible to start taking Zafrilla 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. The tablets should be taken regularly, regardless of vaginal bleeding. After the completion of taking the tablets from one package, start taking Zafrilla 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 Zafrilla may decrease. If one or more pills are missed, a woman should take only one pill at once, as soon as she remembers about it, then the next day, continue taking the pills 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.

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 efficacy and safety of dienogest in this age category.

Elderly patients (over 65 years old)

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

Patients with hepatic impairment

Zafrilla is contraindicated in patients with severe liver disease - current or history (see section "Contraindications").

Patients with renal impairment

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

Side effect of Zafrilla

Adverse reactions (HP) more often occur in the first months after starting therapy with Zafrilla and decrease with continued treatment. Changes in the nature of the bleeding are possible, for example, "spotting" spotting, irregular bleeding, or amenorrhea. The most common HPs seen with dienogest are headache, breast discomfort, depressed mood and acne. In addition, in most patients receiving dienogest, the pattern of menstrual bleeding changes. During the first 90 days of dienogest therapy, the following types of menstrual irregularities were observed: amenorrhea, infrequent bleeding, frequent bleeding, irregular bleeding, prolonged bleeding.

Overdose

Serious overdose irregularities have not been reported.
Symptoms that may occur in case of an overdose: nausea, vomiting, "smearing" spotting or metrorrhagia.
Treatment: there is no specific antidote, symptomatic treatment should be carried out.


Interaction with other medicinal products

The effect of other drugs on dienogest

Gestagens, including dienogest, are metabolized mainly with the participation of isoenzymes of the cytochrome P450 ZA4 (CYP3A4) system in the intestinal and liver mucosa. Therefore, inducers or inhibitors of CYP3A4 can affect the metabolism of gestagens.
The increased clearance of sex hormones, due to the induction of enzymes, can lead to a decrease in the therapeutic effect of dienogest, and also cause HP, for example, a change in the nature of uterine bleeding.
Decreased sex hormone clearance due to enzyme inhibition can increase dienogest exposure and cause HP.

Substances that increase the clearance of sex hormones (decrease in effectiveness by induction of enzymes)

Phenytoin, barbiturates, primidone, carbamazepine, rifampicin, and possibly oxcarbazepine, topiramate, felbamate, griseofulvin, and herbal medicines containing St. John's wort (Hypericum perforatum). Enzyme induction, as a rule, is noted several days after the start of therapy, the maximum induction is noted for several weeks and then can persist for 4 weeks after the cessation of therapy.
The effect of the CYP3A4 inducer rifampicin has been studied in healthy postmenopausal women. With the simultaneous use of rifampicin with a combination of estradiol valerate + dienogest, 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 h), was reduced by 83%.

Medicines with a variable effect on the clearance of sex hormones

When used simultaneously with sex hormones, many combinations of protease inhibitors and non-nucleoside reverse transcriptase inhibitors for the treatment of HIV infection and viral hepatitis C can increase or decrease the concentration of progestogen in blood plasma. The cumulative effects of these changes in some cases may be clinically significant.

Medicines that reduce the clearance of sex hormones (enzyme inhibitors)

Dienogest is a substrate of the CYP3A4 isoenzyme of the cytochrome P450 system.
Concomitant use of highly active CYP3A4 inhibitors can increase the concentration of dienogest in blood plasma.
Concomitant use with a strong inhibitor of CYP3A4 enzymes, ketoconazole, led to an increase in the AUC value (0-24 h) of dienogest at an equilibrium concentration by 2.9 times. The simultaneous use of a moderate inhibitor of erythromycin increased the AUC (0-24 h) of dienogest at an equilibrium concentration by 1.6 times.

Effect of dienogest on other drugs

Based on data from in vitro inhibition studies, a clinically significant interaction of dienogest with other drugs metabolized by isoenzymes of the cytochrome P450 system is unlikely.
Note: To clarify possible interactions, please see the instructions for use of concomitant medications.

Interaction with food

Eating a diet high in fat did not affect the bioavailability of dienogest.

Other interactions

The use of gestagens can affect the results of some laboratory tests, including biochemical parameters of liver, thyroid, adrenal and kidney function, plasma concentrations of carrier proteins, for example, lipid / lipoprotein fractions, carbohydrate metabolism parameters, blood coagulation and fibrinolysis.
Typically, these interactions are within the normal laboratory range.


Special instructions

Before starting to use the drug, pregnancy must be excluded. During the use of the drug, if contraception is necessary, patients are advised to use non-hormonal contraceptive methods (for example, barrier).

Fertility

Based on the available data, during the use of the drug in most patients, ovulation is suppressed. However, dienogest 2 mg is not a contraceptive.
According to available data, the physiological menstrual cycle returns to normal within 2 months after discontinuation of dienogest treatment.
The likelihood of an ectopic pregnancy is higher in patients taking drugs containing only a gestagenic component for contraception, compared with patients taking combined oral contraceptives. Thus, for women with a history of ectopic pregnancy or with obstruction of the fallopian tubes, the benefit / risk ratio should be assessed before using dienogest.

Changes in the nature of bleeding

In most women, the use of dienogest affects the pattern 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

In the course of epidemiological studies, an insufficiently convincing relationship has been shown between the use of progestogen monopreparations and an increased risk of myocardial infarction or cerebral 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 slightly increase with progestogen monotherapy. 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. The generally recognized risk factors for VTE are a history of VTE in patients or a family history (VTE in a brother / sister or parent less than 50 years of age), age, obesity, prolonged immobilization, major surgery, or major trauma. In such cases, you should stop taking dienogest (at least four weeks before the planned operation) and resume taking no earlier than 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, the use of 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 + gestagen). This increased risk gradually decreases over the 10 years after you stop taking combined oral contraceptives (COCs).
Since breast cancer is rare in women younger than 40 years of age, the slight 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 diagnosing breast cancer in women using progestogen monopreparations is approximately the same as when taking COCs. However, data on progestogen monotherapy have been obtained in significantly smaller patient populations and are less conclusive than data on COCs. 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 taking 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 have 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, a decrease in BMD was noted, therefore it is necessary to assess the expected benefit of its use in relation to the possible risk for each patient, taking into account the possibility of risk factors for the development of osteoporosis, especially in patients with an increased risk of osteoporosis, since during treatment with dienogest occurs a moderate decrease in the concentration of endogenous estrogens. It is important for women of all ages to take calcium and vitamin D supplements, regardless of diet or vitamin supplementation.

Other conditions

Patients with a history of depression should be closely monitored. If depression recurs in a severe 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 BP. However, if chronic, clinically significant arterial hypertension occurs against the background of the use of dienogest, it is recommended to discontinue the drug and begin 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 must be canceled.
Dienogest may have little effect on peripheral insulin resistance and glucose tolerance. Patients with diabetes mellitus, especially with a history of gestational diabetes mellitus, need careful monitoring during the period of dienogest therapy.
In some cases, chloasma may develop, especially in women with a history of pregnant chloasma. Women with a tendency to chloasma should avoid exposure to sunlight or ultraviolet radiation while using the drug.
During the period of drug therapy, persistent follicles in the ovaries (often called functional ovarian cysts) may occur. Most of these follicles are asymptomatic, although some may present with pelvic pain.

Lactose

One tablet of Zafrilla contains 62.8 mg of lactose monohydrate. Patients on a lactose-free diet with rare hereditary disorders, such as galactose intolerance, lactase deficiency or glucose-galactose malabsorption, are not allowed to use the drug.

Influence on the ability to drive vehicles and mechanisms

There was no negative effect of Zafrilla on the ability to drive vehicles and mechanisms, however, patients who have impaired concentration during the adaptation period (the first 3 months of using the drug) should be careful.

Storage conditions

In original packaging (blister in a pack) at a temperature not exceeding 30 ° С.
Keep out of the reach of children.
Shelf life - 3 years.
Do not use after the expiration date printed on the package.

Terms of sell

You can buy Zafrilla without a prescription.