Visanne tablets 2 mg No. 28

Instructions for Visanne tablets 2 mg No. 28

Composition

active ingredient: dienogest;

1 tablet contains dienogest 2 mg;

excipients: lactose monohydrate, potato starch, microcrystalline cellulose, povidone K 25, talc, crospovidone, magnesium stearate.

Dosage form

Pills.

Main physicochemical properties: round tablets with a diameter of 7 mm with beveled edges, white or almost white in color, with the letter “B” embossed on one side.

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 has 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 effect 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

The superiority of Visanne over placebo was demonstrated in a three-month study in 198 patients with endometriosis. Pelvic pain associated with endometriosis was measured using a visual analogue scale (0-100 mm). Through
After 3 months of treatment with Visanne, 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 Visanne (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 Visanne (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 daily showed no ovulation after 1 month of therapy. Visanne has not been studied for contraceptive efficacy in larger studies.

Safety data

Endogenous estrogen levels are only moderately suppressed during treatment with Visanne.

Long-term results of studies on bone mineral density (BMD) and fracture risk in patients using Visanne are not available at this time. BMD was assessed in 21 adult patients before and after 6 months of treatment with Visanne. 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 was 4.29%, 95% CI: 1.93-6.66, p <0.0003).

There were no significant effects on standard laboratory parameters, including blood count, blood chemistry, liver enzymes, lipids, and HbA1C, during treatment with Visanne for 15 months (N = 168).

Safety data for teenagers

The safety of Visanne on BMD was investigated in a 12-month uncontrolled study in 111 adolescent patients (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 measurements 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 promote the growth of certain hormone-dependent tissues and tumors.

An observational, post-marketing study with active surveillance was conducted to determine the incidence of new onset or exacerbation of clinically significant depression and anemia. A total of 27,840 women who were first prescribed hormonal therapy for the treatment of endometriosis participated in the study and were followed for up to 7 years. 3,023 women were prescribed dienogest 2 mg, 3,371 patients were prescribed other drugs approved for the treatment of endometriosis. The overall adjusted hazard ratio for new onset anemia in patients taking dienogest compared with patients taking other drugs approved for the treatment of endometriosis was 1.1 (95% CI: 0.4-2.6). The adjusted hazard ratio for depression in patients taking dienogest compared with patients taking other drugs approved for the treatment of endometriosis was 1.8 (95% CI: 0.3-9.4). A small increased risk of depression in patients taking dienogest compared with patients taking other drugs approved for the treatment of endometriosis cannot be excluded.

Pharmacokinetics.

Absorption. 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. The bioavailability of dienogest is approximately 91%. The pharmacokinetics of dienogest are dose-dependent within the dose range
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 of dienogest is 40 l.

Metabolism: Dienogest is completely metabolized by the known steroid metabolism pathways to form 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 plasma such that the dominant metabolite in plasma is dienogest in unchanged form.

The clearance rate from blood serum is 64 ml/min.

Elimination: 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 being excreted in the first 24 hours, mainly in urine.

Steady state. 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 use of the drug Visanne can be predicted based on data on the pharmacokinetics of a single dose.

Pharmacokinetics in special patient groups. The pharmacokinetics of Visanne have not been studied in patients with renal impairment. The pharmacokinetics of Visanne have not been studied in patients with hepatic impairment.

Indication

Treatment of endometriosis.

Contraindication

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

Venous thromboembolism in active form.

Current or history of arterial or cardiovascular disease (e.g. myocardial infarction, cerebrovascular accident, ischemic heart disease).

Diabetes mellitus with vascular damage.

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 sex hormone-dependent malignant tumors.

Vaginal bleeding of unknown etiology.

Hypersensitivity to the active substance or to any of the components of the drug.

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 Visanne

Progestogens, including dienogest, are metabolized mainly 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 the metabolism of progestogens. Increased clearance of sex hormones due to enzyme induction may reduce the therapeutic effect of Visanne and lead to undesirable effects, such as changes in the pattern of menstrual bleeding.

- Substances that increase the clearance of sex hormones (reduced efficacy by enzyme induction), for example: 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 several weeks.

Enzyme induction may persist for up to 4 weeks after discontinuation 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 systemic exposure of dienogest and estradiol at steady state, as measured by AUC (0–24 hours), was reduced by 83% and

44% respectively.

- Substances with different effects on the clearance of sex hormones.

Concomitant use of a large number of combinations of HIV protease inhibitors and non-nucleoside reverse transcriptase inhibitors with sex hormones, in combination with combinations of hepatitis C virus inhibitors, 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.

Effect of dienogest on other medicinal products

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

Intake of a high-fat meal did not affect the bioavailability of Visanne.

Laboratory tests

The use of progestogens may affect the results of some laboratory tests, in particular biochemical parameters of the liver, thyroid gland, renal and adrenal function, levels of proteins (carriers) in the blood plasma (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 Visanne is a progestogen-only preparation, it is considered that the special warnings and precautions for the use of progestogen-containing preparations also apply to Visanne, although not all warnings and precautions are based on the relevant results of clinical studies with this particular preparation.

If any of the following conditions/risk factors worsen or appear for the first time, a risk/benefit analysis should be performed on an individual basis before initiating or continuing the use of Visanne.

Heavy uterine bleeding

Uterine bleeding, for example in women with uterine adenomyosis or uterine leiomyoma, may increase with the use of Visanne. 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, consideration should be given to discontinuing the drug.

Change in bleeding pattern

Treatment with Visanne 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 recognized 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 stop using Visanne (at least 4 weeks before elective surgery) and not to restart it until 2 weeks after full recovery.

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

Tumors

A meta-analysis of 54 epidemiological studies suggests a small 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 data from 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 OCs, or to the biological action of these drugs, or a combination of both factors. There is a tendency for breast cancer detected in women who have ever used OCs to be clinically less severe than in those who have never used oral contraceptives.

In isolated cases, benign and, even more rarely, malignant liver tumors have been observed in women taking hormonal agents similar to those contained in Visanne, which in some cases have 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 Visanne.

Osteoporosis

Changes in bone mineral density (BMD).

The use of Visanne in adolescents (12-18 years) over a 12-month treatment period was associated with a 1.2% decrease in mean lumbar spine BMD (L2-L4). BMD increased again in these patients after discontinuation of treatment.

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). Repeat measurement 6 months after end of treatment in the subgroup with reduced BMD values showed a trend towards recovery (mean relative change from baseline: -2.3% at end of treatment and -0.6% 6 months after end of treatment with a range between -9% and 6% (95% CI: -1.20% and 0.06% (n=60)).

Bone mineral density loss is particularly important during adolescence and early puberty, a critical period for bone growth. It is unknown whether a decrease in BMD in this population will reduce peak bone mass and increase the risk of bone fracture in old age (see sections 4.2 and 5.1).

Before starting treatment, the doctor should weigh the benefits of using Visanne and the possible risks of use for each individual adolescent, 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 section 5.1).

In patients at increased risk of osteoporosis, a careful risk/benefit assessment should be made before initiating treatment with Visanne, as endogenous estrogen levels are moderately reduced during treatment with Visanne (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 Visanne and treat the hypertension.

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

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

The risk of ectopic pregnancy in women using progestogen-only contraceptives is higher than in women using COCs. Therefore, in women with a history of ectopic pregnancy or tubal dysfunction, the use of Visanne should be considered only after a careful assessment of the benefit/risk ratio.

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

Not used in geriatric practice.

Lactose

Each tablet of Visanne contains 62.8 mg of lactose monohydrate. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption who are on a lactose-free diet should take into account the amount of this substance in the tablet of Visanne.

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).

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

Breastfeeding. Treatment with Visanne is not recommended during breast-feeding. It is not known whether dienogest is excreted in human milk. Animal data indicate that dienogest is excreted in human milk. A decision should be made whether to discontinue breast-feeding or to discontinue Visanne therapy, taking into account the benefit of breast-feeding for the child and the need for therapy for the woman.

Fertility: Based on available data, it can be stated that ovulation is inhibited in most patients during treatment with Visanne. However, Visanne 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 Visanne.

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.

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, with a small amount of liquid. The tablets can be taken regardless of meals.

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

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 Visanne. If contraception is necessary, a non-hormonal method of contraception (e.g. a barrier method) should be used in addition.

Skipping a medication

In case of missed tablets, vomiting and/or diarrhoea (which occurred within
3-4 hours after taking the tablet) the effectiveness of Visanne may be reduced. If one or more tablets are missed, 1 tablet should be taken as soon as the woman remembers, and the next one should be taken at the usual time. A tablet that has not been absorbed due to vomiting or diarrhea should be replaced with another tablet in the same way.

Additional information regarding use in special patient groups

Elderly patients

There are no relevant indications for the use of Visanne 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.

Visanne is not indicated for use in children before menarche.

The safety and efficacy of Visanne were studied in a 12-month uncontrolled study in 111 adolescent patients.
(12–<18 years) with clinically suspected or confirmed endometriosis (see sections “Special instructions for use” and “Pharmacological properties”).

The efficacy of Visanne 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.

Impaired bone mineral density is particularly important during adolescence and early puberty, a critical period for bone growth. It is unknown whether decreased BMD in this population will reduce peak bone mass and increase fracture risk in old age.

Therefore, the doctor should weigh the benefits of using Visanne and the possible risks of use for each individual adolescent (see sections “Special instructions for use”, “Pharmacodynamic properties”).

Overdose

Acute toxicity studies conducted with dienogest did not indicate a risk of acute adverse reactions in the event of inadvertent administration of multiple 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 Visanne tablet) for more than 24 weeks was very well tolerated.

Adverse reactions

Adverse reactions are described according to MedDRA.

Side effects most often develop during the first months of using Visanne 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 Visanne. The most commonly reported adverse reactions during treatment with Visanne include headache (9.0%), breast discomfort (5.4%), depressed mood (5.1%) and acne (5.1%).

In addition, treatment with Visanne 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 Visanne therapy, 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. bleeding not falling into any 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. bleeding 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).

The table lists the adverse reactions according to the MedDRA classification (MedDRA SOCs) reported during treatment with Visanne and their frequency.

Within each grouping, side effects are listed in order of decreasing frequency: common (from

≥ 1/100 to <1/10) and uncommon (≥ 1/1000 to <1/100). The frequency is determined based on pooled data from four clinical studies involving 332 patients (100%).

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 (12 to <18 years) treated with Visanne, BMD was measured in 103 patients. 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

5 years.

Storage conditions

No special storage conditions are required. Store in the original packaging, out of the reach of children.

Do not use the drug after the expiration date indicated on the package.

Packaging

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

Vacation category

According to the recipe.

Producer

Bayer Weimar GmbH & Co. KG.

Location of the manufacturer and its business address

Dobereinerstrasse 20, 99427 Weimar, Germany.