Savis tablets 2 mg No. 28

Instructions for Savis tablets 2 mg No. 28

Composition

active ingredient: dienogest;

1 tablet contains dienogest 2 mg;

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

Dosage form

Pills.

Main physicochemical properties: white or almost white, round, flat tablets, with a bevel and engraving "16G93' coordsize = "1000,1000"> " on one side, "RG" - on the other. Diameter 7 mm.

Pharmacotherapeutic group

Hormones of the sex glands and drugs used in pathologies of the genital organs. Progestogens. ATX code G03D B08.

Pharmacological properties

Pharmacodynamics

Dienogest is a nortestosterone derivative without androgenic and with some antiandrogenic activity, which is approximately one third of the activity of cyproterone acetate. Dienogest binds to progesterone receptors in the uterus with only 10% relative affinity. Despite its low affinity for progesterone receptors, dienogest exhibits a strong progestogenic effect in vivo. Dienogest does not exhibit significant androgenic, mineralocorticoid, or glucocorticoid activity in vivo.

Dienogest affects endometriosis by reducing endogenous estradiol production and thus inhibiting the trophic effects of estradiol on eutopic and ectopic endometrium. With continuous use, dienogest leads to the creation of a hypoestrogenic, hypergestagenic endocrine environment, which causes initial decidualization of endometrial tissue with subsequent atrophy of endometrioid foci.

Performance data

In a three-month study in 198 patients with endometriosis, dienogest 2 mg was shown to be superior to placebo. Pelvic pain associated with endometriosis was measured using a visual analogue scale (0-100 mm). After 3 months of treatment, a statistically significant difference compared to placebo (D = 12.3 mm; 95% CI: 6.4 - 18.1; p<0.0001) and a clinically meaningful reduction in pain compared to baseline (mean reduction = 27.4 mm ± 22.9) were observed.

After 3 months of treatment, a reduction of pelvic pain associated with endometriosis by 50% or more was achieved in 37.3% of patients receiving dienogest, tablets 2 mg (placebo: 19.8%) without a corresponding increase in the dose of concomitant analgesic; a reduction of pelvic pain associated with endometriosis by 75% or more (also without a corresponding increase in the dose of concomitant analgesic) was achieved in 18.6% of patients receiving dienogest, tablets 2 mg (placebo: 7.3%).

An open-label extension of this placebo-controlled study showed continued reduction in endometriosis-related pelvic pain with treatment duration of up to 15 months.

The results of the placebo-controlled studies were confirmed by the results obtained in a six-month active-controlled study compared with a gonadotropin-releasing hormone agonist in 252 patients with endometriosis.

Three studies involving 252 patients receiving dienogest 2 mg daily demonstrated a significant reduction in endometrioid lesions after 6 months of treatment.

In a small study (n=8 per dose group), dienogest 1 mg/day was found to be anovulatory after 1 month of therapy. Dienogest has not been studied for contraceptive efficacy in larger studies.

Safety data

Endogenous estrogen levels are only moderately suppressed during treatment with dienogest, 2 mg tablets.

Long-term results of studies of bone mineral density (BMD) and fracture risk in patients using dienogest 2 mg tablets are not yet available. BMD was assessed in 21 adult patients before and after 6 months of treatment with dienogest 2 mg tablets. No decrease in mean BMD was observed. In 29 patients receiving leuprorelin acetate, a mean decrease of 4.04% ± 4.84 was observed over the same period (D between groups = 4.29%, 95% CI: 1.93-6.66, p < 0.0003).

No significant effects on standard laboratory parameters, including blood count, blood chemistry, liver enzymes, lipids, and HbA1C, were observed during treatment with dienogest 2 mg tablets for 15 months (N = 168).

Safety data for teenagers

The safety of dienogest, 2 mg tablets, on BMD was investigated in a 12-month uncontrolled study in 111 adolescent patients (aged 12 to <18 years) with clinically suspected or confirmed endometriosis. The mean relative change from baseline in lumbar spine BMD (L2-L4) in 103 patients at the end of treatment was -1.2%. Repeat measurement 6 months after the end of treatment in the subgroup with decreased BMD values showed an increase in BMD to -0.6%.

Preclinical safety data

Non-clinical data reveal no special hazard for humans based on conventional studies of repeated dose toxicity, genotoxicity, carcinogenic potential, and toxicity to reproduction. However, it should be noted that sex steroids may induce the growth of certain hormone-dependent tissues and tumors.

Pharmacokinetics

After oral administration, dienogest is rapidly and completely absorbed. The maximum serum concentration is reached within 1.5 hours after a single oral dose and is 47 ng/ml. Bioavailability is approximately 91%. The pharmacokinetics of dienogest are dose-dependent in the dose range of 1-8 mg.

Distribution

Dienogest is bound to serum albumin and does not bind to sex steroid binding globulin (SSGB) or corticoid binding globulin (CBG). Only 10% of the total serum concentration of dienogest is found as free steroid, and 90% is non-specifically bound to albumin. The apparent volume of distribution (Vd/F) of dienogest is 40 l.

Metabolism

Dienogest is completely metabolized by the known pathways of steroid metabolism, with the formation of mainly endocrinologically inactive metabolites. Based on in vitro and in vivo studies, CYP3A4 is the main enzyme involved in the metabolism of dienogest. These metabolites are very rapidly eliminated from the blood plasma in such a way that the dominant fraction in the blood plasma is dienogest in unchanged form.

The clearance rate (Cl/F) from serum is 64 ml/min.

Breeding

The serum level of dienogest decreases in a biphasic manner with a half-life of 9-10 hours. Dienogest is excreted as metabolites in urine and feces in a ratio of approximately 3:1 after oral administration of 0.1 mg/kg. The half-life of metabolites in urine is approximately 14 hours.

After oral administration, 86% of the administered dose is excreted from the body within 6 days, most of this amount is excreted in the first 24 hours, mainly in the urine.

State of equilibrium

The pharmacokinetics of dienogest are independent of the level of GSH. With daily administration, the concentration of the substance in the blood serum increases by 1.24 times, reaching an equilibrium state after 4 days of use. The pharmacokinetics of dienogest after repeated administration of dienogest, 2 mg tablets, can be predicted based on data on the pharmacokinetics of a single dose.

Pharmacokinetics in special patient groups

The pharmacokinetics of Savis 2 mg tablets have not been studied in patients with renal impairment.

The pharmacokinetics of Savis 2 mg tablets have not been studied in patients with hepatic impairment.

Indication

Treatment of endometriosis.

Contraindication

Savis should not be used if any of the following conditions or diseases are present. This information is partly derived from the use of other progestogen-only products. If any of these conditions or diseases occur for the first time while using Savis, the drug should be stopped immediately:

Active venous thromboembolism; Current or history of arterial or cardiovascular disease (e.g. myocardial infarction, cerebrovascular accident, ischemic heart disease); Diabetes mellitus with vascular disease; Current or history of severe liver disease until liver function tests return to normal; Current or history of liver tumors (benign or malignant); Known or suspected malignant tumors dependent on sex hormones; Vaginal bleeding of unknown etiology; Hypersensitivity to the active substance or to any of the excipients of the drug (see section "Composition").

Interaction with other medicinal products and other types of interactions

Note: To identify possible interactions, consult the instructions for medical use of concomitantly used medications.

The effect of other drugs on Savis

Progestogens, including dienogest, are metabolized primarily by the cytochrome P450 3A4 (CYP3A4) system, which is located in the intestinal mucosa and in the liver. Therefore, inducers or inhibitors of CYP3A4 may affect progestogen metabolism.

Increased clearance of sex hormones due to enzyme induction may reduce the therapeutic effect of Savis and lead to undesirable effects, such as changes in the pattern of menstrual bleeding.

Reduced clearance of sex hormones due to enzyme inhibition may reduce the therapeutic effect of Savis and lead to the development of adverse reactions.

Substances that increase the clearance of sex hormones (reduced efficacy by enzyme induction), e.g. phenytoin, barbiturates, primidone, carbamazepine, rifampicin, and possibly oxcarbazepine, topiramate, felbamate, griseofulvin and products containing St. John's wort (Hypericum perforatum).

Enzyme induction may occur after a few days of therapy. Maximum enzyme induction is generally seen after a few weeks. Enzyme induction may persist for up to 4 weeks after cessation of therapy.

The effect of the CYP 3A4 inducer rifampicin was studied in healthy postmenopausal women. Co-administration of rifampicin with estradiol valerate/dienogest tablets resulted in a significant decrease in the steady-state concentration and systemic exposure of dienogest and estradiol. The steady-state systemic exposure of dienogest and estradiol, as measured by AUC (0-24 hours), was reduced by 83% and 44%, respectively.

Concomitant use of a large number of combinations of HIV protease inhibitors and non-nucleoside reverse transcriptase inhibitors, in combination with combinations of hepatitis C virus inhibitors, with sex hormones may increase or decrease progestin plasma levels. The cumulative effect of these changes may be clinically significant in some cases.

Substances that reduce the clearance of sex hormones (enzyme inhibitors).

Dienogest is a substrate of cytochrome P450 (CYP) 3A4.

The clinical significance of potential interactions with enzyme inhibitors remains unknown.

Concomitant use of strong CYP3A4 inhibitors may increase plasma concentrations of dienogest.

Concomitant use with the strong CYP3A4 inhibitor ketoconazole resulted in a 2.9-fold increase in the AUC (0-24 hours) of dienogest at steady state. Concomitant use with the moderate inhibitor erythromycin resulted in a 1.6-fold increase in the AUC (0-24 hours) of dienogest at steady state.

The effect of Savis on other medicines

Based on the results of in vitro inhibition studies, clinically significant interactions of dienogest with other drugs metabolized by cytochrome P450 enzymes are unlikely.

Interaction with food products

Consuming a high-fat meal did not affect the bioavailability of Savis.

Laboratory tests

The use of progestogens may affect the results of some laboratory tests, including biochemical parameters of the liver, thyroid gland, renal and adrenal function, levels of plasma proteins (carriers) (e.g., GSK and lipid/lipoprotein fractions), parameters of carbohydrate metabolism, and indicators of coagulation and fibrinolysis. Changes usually remain within the laboratory norm.

Application features

Reservation.

Since Savis is a progestogen-only preparation, it is considered that the special warnings and precautions for the use of progestogen-containing preparations also apply to Savis, although not all warnings and precautions are based on the relevant results of clinical studies with tablets containing 2 mg dienogest.

If any of the following conditions/risk factors worsen or first appear, an individual risk/benefit analysis should be performed before initiating or continuing the use of Savis.

Heavy uterine bleeding

Uterine bleeding, for example in women with uterine adenomyosis or uterine leiomyoma, may increase with the use of Savis. If the bleeding is severe and does not stop for a long time, it may lead to anemia (in some cases severe). In this case, it is necessary to consider stopping the drug.

Change in bleeding pattern

Treatment with dienogest, 2 mg tablets, affects the pattern of menstrual bleeding in most women (see section "Adverse reactions").

Circulatory disorders

Based on the results of epidemiological studies, there is limited evidence of an association between the use of progestogen-only contraceptives and an increased risk of myocardial infarction or cerebral thromboembolism. The risk of cardiovascular and cerebral events is more likely to be related to age, hypertension and smoking. In women with hypertension, the risk of stroke may be slightly increased with the use of progestogen-only contraceptives.

Some studies suggest a slight, but not statistically significant, increase in the risk of venous thromboembolism (deep vein thrombosis, pulmonary embolism) associated with the use of progestogen-only products. Generally accepted factors that increase the risk of venous thromboembolism (VTE) include: personal or family history (e.g., VTE in siblings or parents at a relatively young age), age, obesity, prolonged immobilization, major surgery or trauma. In the event of prolonged immobilization, it is recommended to discontinue the use of Savis (at least 4 weeks before elective surgery) and not to restart it until 2 weeks after complete remobilization.

The increased risk of thromboembolism in the postpartum period should be taken into account.

If symptoms of venous and arterial thrombotic diseases occur or are suspected, treatment should be discontinued.

A meta-analysis of 54 epidemiological studies suggests a slightly increased relative risk (RR = 1.24) of breast cancer in women using oral contraceptives (OCs), mainly those containing estrogen-progestogen. This increased risk gradually disappears within 10 years after stopping combined oral contraceptives (COCs). Since breast cancer is rare in women under 40 years of age, the increase in breast cancer diagnoses in women who use or have recently used COCs is small in relation to the overall risk of breast cancer. There is a similar risk of breast cancer in women who have used progestogen-only or COCs. However, the information on progestogen-only products is based on a much smaller number of women using them and is therefore less conclusive than the data on COCs. The results of these studies do not provide evidence of a causal relationship. The increased risk may be due to earlier diagnosis of breast cancer in women who use COCs, the biological action of these drugs, or a combination of both. There is a trend that breast cancer detected in women who have ever used COCs is clinically less severe than in those who have never used COCs.

In isolated cases, benign and, even more rarely, malignant liver tumors have been observed in women taking hormonal agents similar to those contained in Savis, which in some cases led to life-threatening intra-abdominal bleeding. In the event of complaints of severe epigastric pain, liver enlargement or signs of intra-abdominal bleeding, the possibility of a liver tumor should be considered in the differential diagnosis in women taking dienogest, 2 mg tablets.

Osteoporosis

Changes in bone mineral density (BMD).

The use of dienogest, 2 mg tablets, in adolescents (12-18 years) during a treatment period of 12 months was associated with a decrease in mean BMD at the lumbar spine (L2-L4) of 1.2%. After discontinuation of treatment, BMD increased again in these patients. The mean relative change in BMD from baseline to end of treatment was -1.2% with a range between -6% and 5% (95% CI: -1.70% and -0.78%, n=103). Repeated measurement 6 months after the end of treatment in the subgroup with reduced BMD values showed a trend towards recovery (mean relative change from baseline: -2.3% at the end of treatment and -0.6% 6 months after the end of treatment with a range between -9% and 6% (95% CI: -1.20% and 0.06% (n=60)).

BMD loss is of particular importance during adolescence and early puberty, a critical period of bone growth. It is unknown whether BMD reduction in this population will reduce peak bone mass and increase the risk of bone fracture in old age (see sections 5.1 and 5.2).

Before starting treatment, the doctor should weigh the benefits of using Savis and the possible risks of using it for each individual teenager, also taking into account the presence of significant risk factors for osteoporosis.

Adequate intake of calcium and vitamin D through diet or supplementation is important for bone health in women of all ages.

No decrease in BMD was observed in adults (see Pharmacodynamics section).

In patients at increased risk of osteoporosis, a careful risk/benefit assessment should be performed before initiating treatment with Savis, as endogenous estrogen levels are moderately reduced during Savis treatment (see section 5.1).

Other states

Patients with a history of depression should be carefully monitored and the drug should be discontinued if severe depression develops.

Dienogest usually does not affect blood pressure in normotensive women. However, if prolonged clinically significant hypertension occurs during use of the drug, it is recommended to discontinue Savis and treat the hypertension.

If cholestatic jaundice and/or pruritus that occurred during pregnancy or previous use of sex hormones recur, Savis should be discontinued.

Dienogest may have a minor effect on peripheral insulin resistance and glucose tolerance. Women with diabetes mellitus, especially with a history of gestational diabetes mellitus, should be carefully monitored during the use of Savis.

Chloasma may occasionally develop, especially in women with a history of chloasma during pregnancy. Women prone to chloasma should avoid exposure to direct sunlight or ultraviolet radiation while taking Savis.

Persistent follicles (often referred to as functional ovarian cysts) may occur during the use of Savis. Most of these follicles are asymptomatic, although some may be accompanied by pelvic pain.

Not used in geriatric practice.

One tablet of Savis contains 62.8 mg of lactose monohydrate. Patients with rare hereditary diseases associated with galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicine.

Ability to influence reaction speed when driving vehicles or other mechanisms

No effects on the ability to drive and use machines were observed in patients taking drugs containing dienogest.

Use during pregnancy or breastfeeding

Pregnancy

There are limited data from the use of dienogest in pregnant women. Animal studies do not indicate direct or indirect risks of reproductive toxicity (see section 5.1).

Savis is not recommended for use in pregnant women because there is no need to treat endometriosis during pregnancy.

Breastfeeding period

Treatment with Savis during breastfeeding is not recommended.

It is not known whether dienogest is excreted in human milk. Animal data indicate that dienogest is excreted in the breast milk of rats.

A decision should be made whether to discontinue breast-feeding or to discontinue Savis therapy taking into account the benefit of breast-feeding for the child and the need for therapy for the woman.

Fertility

Based on the available data, it can be stated that ovulation is inhibited in most patients during treatment with Savis. However, Savis is not a contraceptive.

If contraception is required, a non-hormonal method of contraception should be used in addition (see section “Method of administration and dosage”).

Based on the available data, it can be stated that the menstrual cycle returns to normal within 2 months after discontinuation of treatment with dienogest, 2 mg tablets.

Method of administration and doses

Method of application

For oral use.

Dosage

Take 1 tablet daily without a break in taking the drug at about the same time, if necessary with a small amount of liquid. The tablets can be taken regardless of food intake.

The tablets should be taken regularly, regardless of menstrual bleeding. As soon as the tablets from one package are finished, you should start taking the tablets from the next package without taking a break in taking the medicine.

There is no experience of treating patients with endometriosis with Savis for longer than 15 months.

You can start taking the drug on any day of the menstrual cycle.

The use of any hormonal contraceptives should be discontinued before starting therapy with Savis. If contraception is necessary, a non-hormonal method of contraception (e.g., a barrier method) should be used in addition.

Skipping pills

In case of missed tablets, vomiting and/or diarrhea (which occurred during
3-4 hours after taking the tablet), the effectiveness of Savis may be reduced. If one or more tablets are missed, one tablet should be taken as soon as the woman remembers, and the next one should be taken at the usual time. Similarly, a tablet that has not been absorbed due to vomiting or diarrhea should be replaced with another tablet.

Use in special patient groups

Elderly patients

There are no relevant indications for the use of Savis in patients in this group.

Liver failure

The drug is contraindicated in patients with current or history of severe liver disease (see section "Contraindications").

Kidney failure

There are no data indicating the need for dose adjustment for patients with renal insufficiency.

Children

The drug Savis is not indicated for use in children before the onset of menarche.

The safety and efficacy of dienogest, 2 mg tablets, were investigated in an uncontrolled study over a period of 12 months in 111 adolescent patients (12 - <18 years) with clinically suspected or confirmed endometriosis (see sections “Pharmacological properties” and “Special instructions for use”).

The efficacy of dienogest, 2 mg tablets, has been demonstrated in the treatment of endometriosis associated with pelvic pain in adolescents (12–18 years) with an overall favorable safety and tolerability profile of the drug.

BMD loss is particularly important during adolescence and early puberty, a critical period of bone growth. It is not known whether decreased BMD in this population will reduce peak bone mass and increase the risk of bone fracture in old age. Therefore, the physician should weigh the benefits of Savis against the potential risks for each individual adolescent (see sections 4.4 and 5.1).

Overdose

Acute toxicity studies conducted with dienogest did not indicate a risk of acute adverse reactions in case of unintentional administration of several daily therapeutic doses. No specific antidotes exist. The use of 20-30 mg of dienogest per day (which is 10-15 times higher than the dose in a tablet of the drug Savis) for more than 24 weeks was very well tolerated.

Adverse reactions

Adverse reactions are described according to MedDRA.

Adverse reactions most often develop during the first months of use of the drug and disappear during treatment. Changes in bleeding patterns, such as spotting, irregular bleeding or amenorrhea, may occur.

The following adverse reactions have been reported during treatment with dienogest, 2 mg tablets. The most commonly reported adverse reactions during treatment with the drug included headache (9.0%), breast discomfort (5.4%), depressed mood (5.1%) and acne (5.1%).

In addition, the use of the drug affects the menstrual bleeding pattern in most women. The menstrual bleeding pattern was systematically assessed using patient diaries and analyzed using the WHO method during a 90-day reporting period. During the first 90 days of treatment with dienogest, 2 mg tablets, the following bleeding patterns were observed (n=290; 100%): amenorrhea (1.7%), infrequent bleeding (27.2%), frequent bleeding (13.4%), irregular bleeding (35.2%), prolonged bleeding (38.3%), normal menstrual bleeding, i.e. none of the previous categories (19.7%). During the fourth reporting period, the following bleeding patterns were observed (n=149; 100%): amenorrhea (28.2%), infrequent bleeding (24.2%), frequent bleeding (2.7%), irregular bleeding (21.5%), prolonged bleeding (4.0%), normal menstrual bleeding, i.e. not falling into any of the previous categories (22.8%). Changes in menstrual bleeding patterns were only occasionally reported as adverse reactions in patients (see table of adverse reactions).

Table 1 lists the adverse reactions according to the MedDRA classification (MedDRA SOCs) reported during use of the drug and their frequency. Within each group, adverse reactions are listed in order of decreasing frequency: common (≥ 1/100 < 1/10) and uncommon (≥ 1/1000 < 1/100).

The frequency is based on pooled data from four clinical studies involving 332 patients (100%).

Table 1

Adverse reactions, phase III clinical trials, N= 332

Other serious adverse reactions have been observed during the use of steroid sex hormones and progestogens (see section "Special warnings and precautions for use"): venous and arterial thromboembolic disorders, arterial hypertension, myocardial infarction, stroke, breast neoplasms, liver tumors, back discomfort, chloasma, cholestatic jaundice, osteoporosis (see below), changes in glucose tolerance or effects on peripheral insulin resistance.

Decreased bone mineral density

In an uncontrolled clinical study involving 111 adolescent patients (aged 12 to <18 years) treated with dienogest 2 mg tablets, 103 had BMD measured. Approximately 72% of the study participants had a decrease in lumbar spine BMD (L2-L4) after 12 months of treatment (see section 4.4).

Reporting of suspected adverse reactions

Reporting of suspected adverse reactions during post-marketing surveillance is very important. This allows monitoring of the benefit/risk balance of medicinal products. Healthcare professionals should report suspected adverse reactions.

Expiration date

3 years.

Storage conditions

The medicinal product does not require any special temperature storage conditions. Store in the original packaging in order to protect from light.

Keep out of reach of children.

Packaging

14 tablets in a blister; 2 blisters in a cardboard box.

Vacation category

According to the recipe.

Producer

Gedeon Richter OJSC, Hungary.

Location of the manufacturer and its business address

H-1103, Budapest, Demrei Street 19-21, Hungary.