Zafrilla, tablets 2 mg 28 pcs

Pharmacotherapeutic group: gestagen.

ATX code: G03DB08

Pharmacological properties

Pharmacodynamics

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

Dienogest affects endometriosis by suppressing the trophic effects of estradiol against autopic and ectopic endometrium, due to decreased estrogen production in the ovaries and reduced plasma concentrations.

Long-term use causes initial decidualization of endometrial tissue with subsequent 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 versus placebo for endometriosis-associated pelvic pain 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 dienogestem, there was a statistically significant difference with placebo (∆ = 12.3 mm; 95% CI: 6.4-18.1; p < 0.0001) and a clinically significant reduction in pain compared with baseline (mean reduction = 27.4 mm ± 22.9).

After 3 months of treatment, 37.3% of patients showed a 50% or greater reduction in endometriosis-associated pelvic pain intensity without a corresponding increase in the dose of the additional analgesic they were taking (in the placebo group: 19.8%); 18.6% of patients showed a 75% or greater reduction in the intensity of endometriosis-associated pelvic pain without a corresponding increase in the dose of the additional analgesic they were taking (placebo: 7.3%).

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

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

The three studies, which included a total of 252 patients who received a daily dose of dienogest 2 mg, demonstrated 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 caused the development of anovulatory status after 1 month. The contraceptive efficacy of dienogest has not been studied in larger studies.

A moderate decrease in the concentration of endogenous estrogens has been observed during therapy with dienogest. There are currently no long-term studies of bone mineral density (BMD) and fracture risk while taking dienogest.

The BMD was evaluated in 21 adult patients before treatment and after 6 months of the drug, and no decrease in mean BMD was observed. After the same period of treatment with leuprorelin acetate (LA), 29 patients showed a 4.04% ± 4.84 decrease in IPC (∆ between groups = 4.29%; 95% CI: 1.93 to 6.66; p < 0.0003).

There were no significant effects of the drug on standard laboratory parameters, including hematology, blood chemistry, liver enzymes, lipids, and glycated hemoglobin, during use of dienogest for up to 15 months.

Preclinical data from standard pharmacological safety studies, multiple dose toxicity, genotoxicity, carcinogenic potential and reproductive toxicity indicate no specific risk to humans. However, it should be considered that sex hormones can stimulate the growth of a number of hormone-dependent tissues and tumors.

Pharmacokinetics

absorption

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 plasma albumin and does not bind to sex hormone-binding globulin (hSPH) or corticosteroid-binding globulin (CRB). 10% of the total plasma concentration of the substance is in the form of a free steroid, whereas about 90% is unspecifically bound to albumin. The apparent volume of distribution of dienogest is 40 liters.

Metabolism

Dienogest is almost completely metabolized primarily by hydroxylation to form several virtually inactive metabolites. Based on in vitro and in vivo studies, CYP3A4 is the main enzyme involved in the metabolism of dienogest. The metabolites are excreted very rapidly, so that the predominant fraction in plasma is unchanged dienogest.

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

Evolution

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

Equilibrium concentration

The pharmacokinetics of dienogest is independent of hGH levels. The plasma concentration of dienogest increased approximately 1.24-fold after daily administration, reaching equilibrium concentration after 4 days of administration. The pharmacokinetics of dienogest after multiple uses of the drug can be predicted based on the pharmacokinetics after a single use.

Pharmacokinetics in special patient groups

Patients with renal impairment<

There have been no studies of the pharmacokinetics of dienogest in patients with impaired renal function.

Patients with hepatic impairment

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

Indications

Active ingredient

Composition

1 tablet contains:

Active substance:

Dienogest (micronized) 2 mg.

Ancillary substances: lactose monohydrate, pregelatinized starch, microcrystalline cellulose, povidone-K25, crosspovidone (type A), talc, magnesium stearate.

How to take, the dosage

Orally, regardless of meals.

Before starting Zafrilla®, the use of any hormonal contraception should be stopped. If contraception is necessary, non-hormonal methods (e.g., barrier methods) should be used.

The start of Zafrilla® is possible on any day of the menstrual cycle.

The drug is taken 1 tablet a day continuously, preferably at the same time, with a small amount of fluid if necessary. The tablets should be taken regularly, regardless of vaginal bleeding. After completing the tablets in one package, start Zafrilla® from the next package, without interruption of the drug.

In case of skipping tablets, vomiting and/or diarrhea (if this occurs within 3-4 hours after taking the tablet), the effectiveness of Zafrilla® may decrease. If one or more tablets are missed, the woman should take only one tablet as soon as she remembers it, then continue taking the tablets at the usual time the next day. If absorption is impaired by vomiting or diarrhea, one tablet should also be taken.

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

Particular groups of patients

Adolescent girls under 18 years of age

. The use of the drug in adolescent girls under 18 years of age is contraindicated due to the lack of data on the efficacy and safety of dienogest in this age group.

Elderly patients (>65 years)

The use of Zafrilla ® in elderly patients is not supported.

Patients with hepatic impairment

The drug Zafrilla® is contraindicated in patients with severe liver disease, either current or with a history of liver disease (see See Contraindications).

Patients with renal impairment

There is no evidence that doses need to be adjusted in patients with impaired renal function.

Interaction

Influence of other drugs on dienogest

Gestagens, including dienogest, are metabolized primarily by cytochrome P450 3A4 (CYP3A4) isoenzymes in the intestinal mucosa and liver. Consequently, inducers or inhibitors of CYP3A4 can affect the metabolism of gestagens.

Elevated clearance of sex hormones due to induction of enzymes may reduce the therapeutic effect of dienogest, and may also cause HP, such as altered uterine bleeding patterns.

Decreased clearance of sex hormones due to enzyme inhibition may increase exposure to dienogest and cause HP.

Substances that increase the clearance of sex hormones (decreased efficacy by enzyme induction)

Phenytoin, barbiturates, primidone, carbamazepine, rifampicin, and possibly oxcarbazepine, topiramate, felbamate, griseofulvin and herbal medicines containing St. John’s wort (Hypericum perforatum).

The induction of enzymes is usually noted within a few days after the start of therapy, the maximum induction is noted within a few weeks and then may persist for up to 4 weeks after discontinuation of therapy.

The effect of the CYP3A4 inducer rifampicin has been studied in healthy postmenopausal women. A significant decrease in equilibrium concentration and systemic exposure of dienogest was observed when rifampicin was used concomitantly with the combination of estradiol valerate + dienogest. Systemic exposure of dienogest at equilibrium concentration, determined by AUC(0-24 h) value, was reduced by 83%.

Drugs with variable effects on sex hormone clearance

. When used concomitantly 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 plasma progestagen concentrations. The cumulative effects of these changes may be clinically significant in some cases.

Medications that reduce clearance of sex hormones (enzyme inhibitors)

Dienogest is a substrate of cytochrome P450 system CYP3A4 isoenzyme.

The concomitant use of highly active CYP3A4 inhibitors may increase plasma concentrations of dienogest.

Concomitant use with strong CYP3A4 enzyme inhibitor ketoconazole resulted in 2.9-fold increase of AUC(0-24 h) of dienogest at equilibrium concentration. Concomitant use of a moderate erythromycin inhibitor increased AUC(0-24 h) of dienogest at equilibrium concentration by 1.6-fold.

Influence of dienogest on other drugs

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: For clarification of possible interactions, please refer to the instructions for use of concomitant medications.

Interaction with food

The bioavailability of dienogest was not affected by eating foods high in fat.

Other interactions

. The use of gestagens can affect the results of some laboratory tests, including biochemical parameters of liver, thyroid, adrenal and renal function, plasma concentrations of carrier proteins such as lipid/lipoprotein fractions, carbohydrate metabolism parameters, blood clotting and fibrinolysis parameters.

In general, these interactions are not beyond normal laboratory parameters.

Special Instructions

Pregnancy should be excluded before starting to use the drug. During the use of the drug, patients are advised to use non-hormonal contraceptive methods (e.g., barrier contraception) if contraception is necessary.

Fertility

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

The physiological menstrual cycle is reported to return to normal within 2 months after discontinuation of treatment with dienogest.

The likelihood of ectopic pregnancy is higher in patients taking contraceptives containing only the gestagen component compared to patients taking combined oral contraceptives. Therefore, for women with a history of ectopic pregnancy or fallopian tube obstruction, the benefit-risk ratio should be assessed before using dienogest.

Change in bleeding patterns

In most women, use of dienogest affects menstrual bleeding patterns.

The use of dienogestas may increase uterine bleeding, such as in women with uterine adenomyosis and uterine leiomyomas. Severe and prolonged bleeding may result in anemia (sometimes severe). In case of anemia, discontinuation of the drug should be considered.

Circulatory disorders

Epidemiologic studies have shown a weak association between progestagen monotherapies and an increased risk of myocardial infarction or cerebral vascular thromboembolism. A greater risk of cardiovascular and cerebral events is associated with age, the presence of arterial hypertension, and smoking. In women with hypertension, the risk of stroke when taking progestagen monotherapies may increase slightly. Individual studies have shown a small and statistically insignificant increase in the risk of venous thromboembolism (deep vein thrombosis, pulmonary embolism) when using progestagen monotherapies. Commonly recognized risk factors for VTE are a history of VTE in patients or a family history (VTE in a sibling or parent less than 50 years old), age, obesity, prolonged immobilization, major surgery or extensive trauma. In such cases, dienogest should be discontinued (at least four weeks before elective surgery) and resumed at least two weeks after full restoration of motor activity.

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

Tumors

A meta-analysis of 54 epidemiologic studies found a slightly increased relative risk (OR = 1.24) of breast cancer (BC) in women taking oral contraceptives, mostly combined (estrogen + gestagen) at the time of the study. This increased risk gradually declines over a 10-year period after discontinuation of combined oral contraceptives (OCs).

Since breast cancer rarely occurs in women younger than 40 years of age, some increase in such diagnoses in women who are taking or have recently taken OCs is small compared to the overall risk of breast cancer. The risk of being diagnosed with breast cancer in women using progestogen monotherapies is similar to that of taking OCs. However, the data on progestogen monotherapies were obtained in much smaller patient populations and are less conclusive than the data on OCs. It is not possible to establish a cause-effect relationship based on these studies.

The pattern of increased risk may be due to earlier diagnosis of BC in women taking oral contraceptives, to their biological effects, or to a combination of these factors. Women taking oral contraceptives show earlier clinical stages of BC compared to women who have never taken them.

In rare cases, benign, and even rarer, malignant liver tumors have been reported in patients taking dienogest. In some cases, these tumors have resulted in life-threatening intra-abdominal bleeding. If a woman taking this medication has severe upper abdominal pain, an enlarged liver, or signs of intra-abdominal bleeding, the possibility of a liver tumor should be considered in the differential diagnosis.

Changes in bone mineral density (BMD)

. A decrease in BMD has been noted with dienogest, so the expected benefit of dienogest versus the possible risk for each patient should be evaluated, taking into account the possible risk factors for osteoporosis, especially in patients at increased risk for osteoporosis, because a moderate decrease in endogenous estrogen concentrations occurs during treatment with dienogest. For women of any age it is important to take calcium supplementation and vitamin D, regardless of the adherence to a certain diet or use of vitamin supplements.

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, the drug has not been shown to affect blood pressure (BP) in women with normal BP. However, if chronic, clinically significant arterial hypertension occurs with dienogest, it is recommended that the drug be discontinued and hypotensive treatment started.

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

Dienogest may have a minor effect on peripheral insulin resistance and glucose tolerance. Patients with diabetes mellitus, especially if there is a history of gestational diabetes mellitus, require close monitoring during therapy with dienogest.

In some cases it is possible to develop chloasma, especially in women with a history of pregnancy chloasma. Women with a history of chloasma should avoid exposure to sunlight or ultraviolet radiation while using the drug.

Persistent follicles in the ovaries (often called functional ovarian cysts) may occur during therapy with the drug. Most of these follicles have no clinical manifestations, although some may be accompanied by pelvic pain.

Lactose

One tablet of Zafrilla ® contains 62.8 mg of lactose monohydrate. It is contraindicated in patients on a lactose-free diet with rare hereditary disorders such as galactose intolerance, lactase deficiency or glucose-galactose malabsorption.

Influence on driving and operating ability

There have been no adverse effects of Zafrilla® on the ability to drive vehicles and machines, but patients who show disturbances in concentration during adaptation period (first 3 months of using the drug) should be treated with caution.

Synopsis

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 gestagen component.

– Acute venous thrombophlebitis, venous thromboembolism (VTE).

– Heart and arterial disease with atherosclerotic vascular lesions (including coronary heart disease, myocardial infarction, cerebral circulatory disorders) in the present or in the history.

– Diabetes mellitus with angiopathy.

– Severe liver disease, current or history until normalization of liver function.

– Liver tumors (benign or malignant), current or history.

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

– Vaginal bleeding of unclear genesis.

– Hypersensitivity to dienogest or any of the excipients.

– Pregnancy and breastfeeding.

– Hereditary lactose intolerance, lactase deficiency, glucose-galactose malabsorption.

– Age less than 18 years (due to 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.

With caution

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, presence of VTE in a personal and family history (see “Special Precautions”). sect. “Special Precautions”).

Side effects

Adverse reactions (ARs) are more common in the first months after initiation of Zafrilla® therapy and decrease with continued treatment. Changes in bleeding patterns, such as “smeary” bleeding, irregular bleeding or amenorrhea, are possible. The most common BPs reported during treatment with dienogestem are headache, breast discomfort, depressed mood, and acne.

In addition, most patients receiving dienogest change their menstrual bleeding patterns. During the first 90 days of therapy with dienogest, the following types of menstrual disorders were observed: amenorrhea, infrequent bleeding, frequent bleeding, irregular bleeding, and prolonged bleeding.

The following are the HPs noted when using dienogest.

The NRs that are possible with dienogest, are categorized into system-organ classes according to MedDRA, with the frequency of occurrence according to WHO recommendations. Frequency is defined as “frequent” (≥1/100 to < 1/10) and “infrequent” (≥1/1000 to < 1/100).

The frequency of HP was calculated from pooled data from four clinical trials that included 332 patients (100%).

Class of organ systems (MedDRA)

often

.Infrequent

Blood and lymphatic system disorders

Infrequent

Anemia

Metabolic and nutritional disorders

Body weight gain

Decreased body weight

Increased appetite

Mental disorders

Depressed mood

Sleep disturbance (including

insomnia)

Nervousness

Loss of libido

Mood changes

Anxiety

Depression

Mood swings

Nervous system disorders

Headache

Migraine

An imbalance of the autonomic nervous system

Disordered concentration

Visual disturbances

Feeling of dry eyes

Hearing organ and labyrinth disorders

Tinnitus

Tinnitus.

Cardiac abnormalities

“Heart palpitations.”

Vascular disorders

Unspecified circulatory disorders

Decreased blood pressure

Disorders of the respiratory system, thoracic and mediastinal organs

Dyspnea

strong>Gastrointestinal tract disorders

Nausea

Pain in the stomach

p> Meteorism

Feeling of abdominal distention

Vomiting

Diarrhea

Contipation

Abdominal discomfort

Inflammatory diseases of the gastrointestinal tract

Gingivitis

Dermal and subcutaneous tissue disorders

Dermal and subcutaneous tissue disorders/p>

Acne

Alopecia

Dry skin

Hyperhidrosis

Itching

Hirsutism

Onychoclasia

Dandruff

Dermatitis

Abnormal hair growth

Photosensitivity reactions

Pigmentation disorders

Musculoskeletal and connective tissue disorders

Back pain

Bone pain

Muscle spasm

Pain in the extremities

Pain in the extremities

Sense of heaviness in the extremities

Urinary tract infection (including cystitis)

Genital and breast disorders

/strong>

Discomfort in the mammary glands

Ovarian cyst

/p>

“Hot flashes”

Bleeding from the genital tract, including “smeary” bloody discharge

Candidates

Vaginal candidiasis

Dryness of the vulva and vagina

Pelvic discharge

Pelvic pain

Pelvic pain/p>

Atrophic vulvovaginitis

Cystic Fibrotic Mastopathy

The thickening of breast tissue

Mammary tissue

General disorders and disorders at the injection site

Asthenic condition

Irritability

Oedema

Overdose

Serious abnormalities have not been reported in overdose.

Symptoms that may be seen in overdose: nausea, vomiting, “smeary” bloody discharge or metrorrhagia.

Treatment:no specific antidote, symptomatic treatment should be given.

Pregnancy use

Pregnancy

The data on the use of dienogest in pregnant women are very limited. No reproductive toxicity, genotoxicity and carcinogenicity have been identified in animal studies of dienogest administration. The use of the drug during pregnancy is contraindicated due to the lack of necessity of endometriosis therapy during pregnancy.

Breastfeeding

The use of Zafrilla® during breastfeeding is contraindicated. Animal studies have shown that dienogestrone penetrates the milk of lactating animals. It is not known whether dienogestetes penetrates into human breast milk. Discontinuation of breastfeeding or therapy with Zafrilla® should be considered.

The decision to stop breastfeeding or to discontinue Zafrilla® is based on an assessment of the balance between the benefits of breastfeeding for the baby and the benefits of dienogest therapy for the woman.

Similarities