Efficacy and safety of long-term use of dienogest in women with deep infiltrative endometriosis

Relevance

Endometriosis is
a pathological process in which benign growth of tissue occurs outside the uterine cavity, similar in morphological and functional properties to the endometrium [1]. Despite the existence of many controversies regarding the mechanisms responsible for its pathogenesis and progression, it is widely known that endometriosis is an estrogen-dependent chronic inflammatory disease [2], and genetic and epigenetic mechanisms are also considered [3].

The problem of treating endometriosis (both internal and external) remains unresolved to this day. The main goals of treatment for this disease are: removal of the focus of endometriosis; reduction in pain intensity; infertility treatment; prevention of progression; prevention of relapses, which reduces the need for radical surgery and allows preserving a woman’s reproductive function [1].

The variety of clinical manifestations and variability of responses to hormonal therapy require an individual approach to each specific case. According to the practice committee of the American Society for Reproductive Medicine, “endometriosis should be considered a chronic disease that requires a lifelong treatment plan to maximize the use of medical options and prevent repeated surgical procedures” [4].

Deep infiltrative endometriosis is a form of endometriosis in which pathological tissue can penetrate up to 5 mm below the surface of the affected structure [5]. The frequency of deep infiltrative forms is 20% of all cases of the disease, with the uterosacral ligaments being the most common location [6]. Two pathogenetic mechanisms explain the pain associated with deep infiltrative endometriosis: chronic inflammation associated with the metabolic activity of the ectopic epithelium, and secondary fibrosis caused by the invasion of endometriotic glands into scar tissue [7]. Treatment of deep infiltrative endometriosis can be either surgical, aimed at restoring normal anatomy by removing endometriotic lesions, or conservative (hormonal). Deeply infiltrating endometriosis causes the most severe pain, with potentially serious clinical consequences and the greatest risk if surgery is performed. Patients with this pathology should be considered a high-risk group, and progestins should be prescribed as first-line therapy [8]. Numerous published studies indicate that the choice of tactics aimed at surgical treatment of deep infiltrative endometriosis is in many cases considered a difficult task, because the operation can be associated with significant technical difficulties and the risk of serious complications [9]. With deep infiltrative endometriosis, the most complete excision of the lesions is required to reduce symptoms associated with the lesion [10]. However, surgical treatment is not always adequate. Thus, according to some authors, the rate of postoperative recurrence of endometriosis was 30% and 43% 4 and 8 years after surgery, respectively [11]. Therefore, there remains a need for effective, safe and well-tolerated drug therapy that can be used long-term if necessary. To reduce the frequency of recurrence and intensity of pelvic pain, conservative therapy, primarily hormones, is required [7, 12, 13]. However, the problem of targeted selection of a drug for drug therapy continues to be a priority. The principle of “no more than one operation in a patient with endometriosis” or an attempt to avoid surgical treatment altogether force us to choose not only highly effective, but also safe medications. Most international recommendations include combined oral contraceptives (COCs) and progestins as first-line medications. However, COCs do not have officially registered indications for the treatment of endometriosis, as well as clinical evidence of effectiveness [14]. The potential adverse effect of long-term COC use on the progression of endometriosis should be considered. In contrast, there are randomized controlled trials that support the use of progestins, not only for the treatment of pelvic pain associated with endometriosis, but also for suppressing the growth of endometrial ectopia. Therefore, they should be considered as first-line drugs in the treatment of endometriosis [15].

Gonadotropin-releasing hormone (GnRH) agonists cannot be considered as drugs of choice for long-term therapy due to the adverse vasomotor effects and decreased bone mineral density associated with estrogen deficiency [16].

Compound

Active substance: micronized dienogest 2 mg
Excipients: lactose monohydrate - 62.8 mg; potato starch - 36 mg; MCC - 18 mg; povidone K25 - 8.1 mg; talc - 4.05 mg; crospovidone - 2.7 mg; magnesium stearate – 1.35 mg

Description of the dosage form

Round white or off-white tablets with a flat surface and beveled edges, engraved “B” on one side.

pharmachologic effect

Pharmacological action: progestogenic, antiandrogenic.

Pharmacodynamics

Dienogest is a derivative of nortestosterone, characterized by antiandrogenic activity that is approximately one third of that of cyproterone acetate. Dienogest binds to progesterone receptors in the human uterus, having only 10% of the relative affinity of progesterone. Despite its low affinity for progesterone receptors, dienogest is characterized by a powerful progestogenic effect in vivo. Dienogest does not have significant mineralocorticoid or glucocorticoid activity in vivo.

Dienogest acts on endometriosis by suppressing the trophic effects of estrogens in relation to the eutopic and ectopic endometrium, due to a decrease in the production of estrogens in the ovaries and a decrease in their concentration in plasma.

With prolonged use, it causes initial decidualization of endometrial tissue followed by atrophy of endometriotic lesions. Additional properties of dienogest, such as immunological and antiangiogenic effects, appear to contribute to its inhibitory effects on cell proliferation.

There was no decrease in bone mineral density, nor a significant effect of Visanne on standard laboratory parameters, including general and biochemical blood parameters, liver enzymes, lipids and HbA1C. Dienogest moderately reduces the production of estrogen in the ovaries.

Pharmacokinetics

Absorption. After oral administration, dienogest is rapidly and almost completely absorbed. Cmax in the blood serum of 47 ng/ml is achieved approximately 1.5 hours after a single oral dose. Bioavailability is about 91%. The pharmacokinetics of dienogest in the dose range from 1 to 8 mg is characterized by dose dependence.

Distribution. Dienogest binds to serum albumin and does not bind to sex hormone binding globulin (SHBG) or corticosteroid binding globulin. 10% of the total concentration of the substance in the blood serum is in the form of free steroid, while about 90% is nonspecifically bound to albumin. The apparent Vd of dienogest is 40 l.

Metabolism. Dienogest is almost completely metabolized, predominantly by hydroxylation to form several virtually 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 eliminated very quickly, so that the predominant fraction in the blood plasma is unchanged dienogest. The rate of metabolic clearance from serum is 64 ml/min.

Elimination. The concentration of dienogest in the blood serum decreases in two phases. T1/2 in the terminal phase is approximately 9–10 hours. After oral administration at a dose of 0.1 mg/kg, dienogest is excreted in the form of metabolites, which are excreted through the kidneys and intestines in a ratio of approximately 3:1 .T1/2 of metabolites when excreted by the kidneys is 14 hours. After oral administration, approximately 86% of the dose received is excreted within 6 days, with the main part excreted in the first 24 hours, mainly by the kidneys.

Equilibrium concentration. The pharmacokinetics of dienogest do not depend on SHBG levels. The serum concentration of dienogest after daily administration increases approximately 1.24 times, reaching Css after 4 days of administration. The pharmacokinetics of dienogest after repeated doses of Visanne can be predicted on the basis of the pharmacokinetics after a single dose.

Indications for Visanne

Treatment of endometriosis.

Contraindications

• Visanne should not be used in the presence of any of the conditions listed below, some of which are common to all drugs containing only a progestogen component. If any of these conditions develop while taking Visanne, use of the drug should be stopped immediately.
• acute thrombophlebitis, venous thromboembolism at present;
• diseases of the heart and arteries, which are based on atherosclerotic vascular lesions (including ischemic heart disease, myocardial infarction, stroke and transient ischemic attack) currently or in history;
• diabetes mellitus with vascular complications;
• severe liver disease currently or in history (in the absence of normalization of liver function tests);
• liver tumors (benign and malignant) currently or in history;
• identified or suspected hormone-dependent malignant tumors, incl. mammary cancer;
• bleeding from the vagina of unknown origin;
• history of cholestatic jaundice in pregnancy;
• hypersensitivity to the active substances or any of the excipients;
• galactose intolerance, lactase deficiency, glucose-galactose malabsorption;
• children and adolescents up to 18 years of age (the effectiveness and safety of use in adolescents has not been established).

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, history of venous thromboembolism (see section "Special Instructions") .

Use during pregnancy and breastfeeding

Pregnancy. Data on the use of Visanne in pregnant women are limited. Data obtained from animal studies and data on the use of dienogest in women during pregnancy did not reveal a specific risk for pregnancy, fetal development, labor and child development after birth. The drug Visanne should not be prescribed to pregnant women due to the lack of need for treatment of endometriosis during pregnancy.

Breastfeeding period. Taking Visanne during breastfeeding is not recommended, because Animal studies indicate that dienogest is excreted in breast milk. The decision to stop breastfeeding or to refuse to take Visanne is made based on an assessment of the balance between the benefits of breastfeeding for the child and the benefits of treatment for the woman.

Side effects

Side effects occur more often in the first months of taking Visanne, and their number decreases over time. The most common side effects include: vaginal bleeding (including spotting, metrorrhagia, menorrhagia, irregular bleeding), headache, breast discomfort, decreased mood and acne.

Table 1 lists adverse drug reactions (ADRs) categorized by organ system class. Side effects in each frequency group are presented in descending order of frequency. Frequency is defined as “common” (≥1/100 to <1/10) and “uncommon” (≥1/1000 to <1/100).

Table 1

Categorized indicators of the relative incidence of ADRs in women

Interaction

The influence of other drugs on the drug Visanne

Selected enzyme inducers or inhibitors (CYP3A isoenzyme)

Gestagens, incl. dienogest are metabolized primarily with the participation of the cytochrome P450 3A4 (CYP3A4) system, located both in the intestinal mucosa and in the liver. Therefore, inducers or inhibitors of CYP3A4 may affect the metabolism of progestin drugs.

Increased clearance of sex hormones due to enzyme induction can lead to a decrease in the therapeutic effect of Visanne and also cause side effects, such as changes in the nature of uterine bleeding.

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

— Substances capable of inducing enzymes

There may be an interaction with drugs that induce microsomal enzymes (for example, the cytochrome P450 system), as a result of which the clearance of sex hormones can increase (such drugs include phenytoin, barbiturates, primidone, carbamazepine, rifampicin and possibly also oxcarbazepine, topiramate, felbamate, nevirapine, griseofulvin, as well as preparations containing St. John's wort).

Maximum enzyme induction, as a rule, is observed no earlier than 2–3 weeks, but can then persist for at least 4 weeks after cessation of therapy.

The effect of the CYP3A4 inducer rifampicin was studied in healthy postmenopausal women. When rifampicin was taken concomitantly with estradiol valerate/dienogest tablets, a significant decrease in Css and systemic exposure of dienogest was observed. Systemic exposure of dienogest at Css, determined by AUC 0–24 h, was reduced by 83%.

— Substances capable of inhibiting enzymes

Known CYP3A4 inhibitors such as azole antifungals (eg, ketoconazole, itraconazole, fluconazole), cimetidine, verapamil, macrolides (eg, erythromycin, clarithromycin, and roxithromycin), diltiazem, protease inhibitors (eg, ritonavir, saquinavir, indinavir, nelfinavir), antidepressants (eg, nefazodone) , fluvoxamine, fluoxetine) and grapefruit juice can increase the concentration of gestagens in the blood plasma and cause side effects.

In one study examining the effect of CYP3A4 inhibitors (ketoconazole, erythromycin), plasma concentrations of estradiol valerate and dienogest were increased in Css. In the case of simultaneous administration with the powerful inhibitor ketoconazole, the AUC0–24 h value at equilibrium concentration of dienogest increased by 186%. When administered concomitantly with the moderate CYP3A4 inhibitor erythromycin, dienogest's AUC0–24 h at Css increased by 62%. The clinical significance of these interactions is unclear.

The effect of dienogest on other drugs

Based on in vitro inhibition studies, a clinically significant interaction of Visanne with cytochrome P450 enzyme-mediated metabolism of other drugs is unlikely.

Note: To identify possible interactions, you should read the instructions for accompanying drugs.

Food interaction

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

Other types of interaction

Reception of gestagens may affect the results of some laboratory tests, including biochemical parameters of liver, thyroid, adrenal and kidney function, plasma concentrations of protein(s), such as lipid/lipoprotein fractions, parameters of carbohydrate metabolism and coagulation parameters.

Directions for use and doses

Inside. The drug Visanne is prescribed for 6 months. The decision on further therapy is made by the doctor depending on the clinical picture.

Reception scheme

You can start taking pills on any day of the menstrual cycle. Take one tablet per day without interruption, preferably at the same time every day, if necessary, with water or other liquid. The tablets must be taken continuously, regardless of vaginal bleeding. After completing the intake of tablets from one package, begin taking tablets from the next without taking a break from taking the drug.

If you skip tablets and in case of vomiting and/or diarrhea (if this occurs within 3-4 hours after taking the tablet), the effectiveness of Visanne may be reduced. If one or more tablets are missed, the woman should take one tablet as soon as she remembers and then continue taking the tablets at the usual time the next day. One tablet should also be taken instead of a tablet that is not absorbed due to vomiting or diarrhea.

Overdose

No serious adverse events have been reported following overdose.

Symptoms that may occur in case of overdose: nausea, vomiting, spotting or metrorrhagia.

There is no specific antidote; symptomatic treatment should be carried out.

special instructions

Before starting to take Visanne, pregnancy must be ruled out. While taking Visanne, if contraception is necessary, patients are advised to use non-hormonal contraceptive methods (for example, barrier).

Fertility

According to available data, while taking Visanne, most patients experience suppression of ovulation. However, Visanne is not a contraceptive.

According to available data, the physiological menstrual cycle is restored within 2 months after stopping Visanne.

The use of Visanne in women with a history of ectopic pregnancy or dysfunction of the fallopian tubes should be decided only after a careful assessment of the ratio of expected benefits and possible risks.

Since Visanne is a progestogen-only drug, it can be assumed that special warnings and precautions for the use of other drugs of this type apply to Visanne, although not all of them were confirmed in clinical studies of Visanne.

If any of the following conditions or risk factors are present or worsened, an individual benefit-risk assessment should be performed before starting or continuing to take Visanne.

Circulatory disorders

In the process of epidemiological studies, insufficient evidence was obtained to confirm the existence of a connection between the use of drugs with only a progestin component and an increased risk of myocardial infarction or cerebral thromboembolism. The risk of cardiovascular events and cerebrovascular accidents is more likely to be associated with increasing age, arterial hypertension and smoking. The risk of stroke in women with arterial hypertension may increase slightly when taking drugs with only a progestin component.

Epidemiological studies indicate the possibility of a statistically insignificant increase in the risk of venous thromboembolism (deep vein thrombosis, pulmonary embolism) due to the use of drugs with only a progestin component. Well-established risk factors for the development of venous thromboembolism (VTE) include a relevant family history (VTE in a sibling or parent at a relatively early age), age, obesity, prolonged immobilization, major surgery, or major trauma. In case of prolonged immobilization, it is recommended to stop taking Visanne (for planned surgery, at least four weeks before it) and resume use of the drug only two weeks after complete restoration of motor ability.

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

If arterial or venous thrombosis develops or is suspected, the drug should be stopped immediately.

Tumors

A meta-analysis of 54 epidemiological studies revealed a small increase in the relative risk (RR = 1.24) of developing breast cancer in women who were using oral contraceptives (OCs), predominantly estrogen-progestin drugs, at the time of the study. This increased risk gradually disappears within 10 years of stopping PC use. Because breast cancer is rare in women under 40 years of age, the slight increase in breast cancer diagnoses in women who are currently taking combination OCs or who have previously used combination OCs is small relative to the overall risk of breast cancer. The risk of breast cancer detection in women using progestin-only hormonal contraceptives is probably similar in magnitude to the corresponding risk associated with OC use. However, the evidence for progestin-only drugs is based on much smaller populations of women using them and is therefore less convincing than the data for PCs. It is not possible to establish a cause-and-effect relationship based on these studies. The observed pattern of increased risk may be due to earlier diagnosis of breast cancer in women taking OCs, the biological effects of OCs, or a combination of both factors. Malignant breast tumors that are diagnosed in women who have ever used OCs are usually clinically less severe than in women who have never used hormonal contraception.

In rare cases, benign and, even more rarely, malignant liver tumors have been reported during the use of hormonal substances similar to that contained in Visanne. In some cases, these tumors have resulted in life-threatening intra-abdominal bleeding. If a woman taking Visanne 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 possibility of a liver tumor.

Change in bleeding pattern

For most women, taking Visanne affects the nature of menstrual bleeding.

During the use of the drug Visanne, uterine bleeding may increase, for example in women with adenomyosis or uterine leiomyoma. Heavy and prolonged bleeding can lead to anemia (in some cases severe). In such cases, discontinuation of Visanne should be considered.

Other states

Patients with a history of depression require careful monitoring. If depression recurs in a serious form, the drug should be discontinued.

Overall, Visanne does not appear to affect BP in women with normal BP. However, if persistent clinically significant arterial hypertension occurs while taking Visanne, it is recommended to discontinue the drug and prescribe antihypertensive treatment.

In case of relapse of cholestatic jaundice and/or cholestatic itching, which first appeared during pregnancy or previous use of sex steroids, Visanne should be discontinued.

Visanne may have minor effects on peripheral insulin resistance and glucose tolerance. Women with diabetes mellitus, especially those with a history of diabetes mellitus during pregnancy, require careful monitoring while taking Visanne.

In some cases, chloasma may occur, especially in women with a history of chloasma during pregnancy. Women prone to developing chloasma should avoid exposure to the sun or UV radiation while taking Visanne.

Persistent ovarian follicles (often called functional ovarian cysts) may occur while taking Visanne. Most of these follicles are asymptomatic, although some may be accompanied by pelvic pain.

Lactose

One tablet of Visanne contains 63 mg of lactose monohydrate. Patients on a lactose-free diet with rare hereditary disorders such as galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption should take into account the amount of lactose contained in Visanne.

Additional information for certain groups of patients

Children. Visanne is contraindicated in children and adolescents under 18 years of age (the effectiveness and safety of use in adolescents has not been established).

Postmenopausal women. Not applicable.

Patients with renal failure: There are no data indicating the need for dose adjustment in patients with renal disease.

Medical examination

Before starting or resuming taking Visanne, you should review the patient's medical history in detail and conduct a physical and gynecological examination. The frequency and nature of such examinations should be based on existing standards of medical practice with the necessary consideration of the individual characteristics of each patient (but at least once every 3–6 months) and should include blood pressure measurements, assessment of the condition of the mammary glands, abdominal cavity and pelvic organs, including cytological examination of the cervical epithelium.

Impact on the ability to drive a car or perform work that requires increased speed of physical and mental reactions.

As a rule, Visanne does not affect the ability to drive a car or operate machinery, however, patients who have difficulty concentrating should be careful.

Release form

Pills. 14 tablets each. in a blister of PVC/PVDC and aluminum foil. 2, 6 or 12 blisters are placed in a cardboard box.

Manufacturer

Bayer Weimar GmbH & Co. KG, Germany.

RU owner: Bayer Pharma AG, Germany.

For additional information and complaints, please contact: 107113, Moscow, 3rd Rybinskaya st., 18, building 2.

Tel.; Fax.

www.bayerpharma.ru

Conditions for dispensing from pharmacies

• On prescription.

Storage conditions for the drug Visanne

• At a temperature not exceeding 30 °C.

• Keep out of the reach of children.

Shelf life of Visanne

• 5 years.

• Do not use after the expiration date stated on the package.

Dienogest in the treatment of endometriosis

Progestins are considered as an alternative option for inhibiting estrogen-induced lesion proliferation and reducing pain associated with endometriosis [17]. By inducing amenorrhea and stopping menstrual bleeding (and reflux), or even simply reducing its severity, they lead to a decrease in the entry of red blood cells into the abdominal cavity. This leads to a reduction in oxidative stress, which is the main source of inflammation caused by excess free iron and heme in the pelvis [18]. Dienogest is the only progestogen that has been developed specifically for the treatment of endometriosis. Among oral progestins, dienogest is unique in that it is being systematically investigated for the treatment of endometriosis in comprehensive preclinical and clinical research programs [19–22]. Dienogest was registered in the Russian Federation in 2011.

Dienogest (for example, the drug Visanne

) is a 4th generation progestogen and combines the pharmacological properties of the progesterone group and progesterone-like compounds, as well as 19-nortestosterone derivatives [21]. Dienogest is the first gestagen that provides a clinically significant antiandrogenic effect without exhibiting estrogenic and androgenic activity [23]. Studies have shown that dienogest has an anovulatory and antiproliferative effect by suppressing the secretion of cytokines in the stroma of endometrial cells. Progestins inhibit the growth of endometriotic tissue, causing decidualization followed by atrophy of endometriotic implants [4]. Additional mechanisms of action include inhibition of matrix metalloproteinase-mediated growth and implantation of ectopic endometrium [24] and inhibition of angiogenesis [25]. On the other hand, dienogest can improve sensitivity to progesterone in endometriotic tissue by increasing the ratio of progesterone receptor isoforms B/A [26]. The precise mechanisms behind the decreased progesterone response in patients with endometriosis remain unclear. It is possible that the impaired action of progesterone in the endometrium of patients with endometriosis may be associated with the innate resistance of the endometrium itself to progesterone, and not with a violation of progesterone secretion. The pharmacological mechanisms of action of dienogest may include antiovulatory activity leading to a decrease in serum estradiol levels, and direct antiproliferative and anti-inflammatory effects on endometrial cells. Dienogest significantly reduces estrogen levels in endometriotic tissue by inhibiting aromatase and 17β-hydroxysteroid dehydrogenase type 1 in stromal cells of ovarian endometriomas, increases apoptosis of endometriotic cells and reduces the production of proinflammatory cytokines by endometriotic stromal cells [27]. In addition, it reduces the production and release of estradiol-induced angiogenic factors such as vascular endothelial growth factor, which confirms the observed suppression of angiogenesis previously shown in a mouse model [28]. In addition, dienogest is able to stimulate apoptosis in endometrioid cells [29].

Analysis of long-term use of dienogest

The above requires analyzing the long-term use of dienogest for the treatment of endometriosis. A double-blind, placebo-controlled study showed that treatment with dienogest for 12 weeks. was more effective than placebo treatment in reducing pain associated with endometriosis. Approximately similar results were obtained when analyzing the use of dienogest at a dose of 2 mg/day for 24 weeks. [thirty]. Follow-up of patients up to 53 weeks. also showed a sustained reduction in pelvic pain with minimal side effects [31]. According to the instructions for medical use of the drug Visanne, the most common side effects include: vaginal bleeding, headache, discomfort in the mammary glands, decreased mood and acne [32]. Pooled analysis of four randomized European studies with treatment periods of dienogest 2 mg/day up to 65 weeks. showed that side effects associated with taking dienogest 2 mg were relatively rare and well tolerated by patients [33]. It is believed that the frequency of bleeding depends on the initial level of estrogen, which, in turn, depends on body weight. Thus, a study by T. Strowitzki et al. showed that the mean serum estradiol level in European women taking dienogest was approximately 66.7 pg/ml with an average body weight of 62.4 kg [34], while in Japan it was 38 pg/ml with an average body weight of 52 .1 kg [35].

The current pooled analysis shows that the mean change in body weight with continued treatment with dienogest up to 62 weeks. is small and does not differ significantly from that observed in the placebo group [33].

An important advantage of dienogest is that it does not reduce bone mineral density and does not cause side effects associated with hypoestrogenism, and therefore can be prescribed for a longer period [30]. The level of estradiol during treatment with dienogest at a dose of 2 mg/day progressively decreased and amounted to 36±13 pg/ml after 36 months. and 28±12 pg/ml after 60 months. treatment [34]. Thus, estradiol levels are maintained within the “therapeutic window” proposed by the Barbieri threshold theory of 30–50 pg/ml [36], at which estrogen suppression is sufficient to inhibit the growth of endometriotic lesions, but moderate enough to prevent hypoestrogenic side effects [37]. This is especially important for treating adolescent girls and young women because they have not yet reached maximum bone density.

For example, when GnRH agonists are used to treat endometriosis, the only option currently available to restore estradiol levels sufficient to avoid menopausal symptoms and loss of bone mineral density is the combined use of a GnRH agonist and estrogens/progestins (add-back therapy). However, additional administration of estrogens can lead to disease progression and increase the cost of treatment.

Long-term therapy with dienogest at a dose of 2 mg/day also showed a significant reduction in pain after 24–52 weeks. with acceptable side effects [21]. Compared to progestins with androgenic activity, such as medroxyprogesterone acetate and norethindrone acetate, dienogest has a more favorable safety profile with low drops in androgenic effects. Dienogest at a dose of 2 mg/day has been shown to be more effective than dydrogesterone at a dose of 10 mg twice a day for the relief of endometriosis-associated pain, with a corresponding safety profile. This finding is significant because pelvic pain is one of the most important symptoms of endometriosis [38]. Early studies showed that there is no convincing evidence to support the therapeutic use of dydrogesterone in endometriosis [39]. In addition, national clinical guidelines for the treatment of endometriosis state that the use of progestogens in a cyclic regimen (dydrogesterone 40–60 mg for 6–18 months) is ineffective compared with placebo [40].

Byzanne

Use during pregnancy and breastfeeding

Data on the use of Visanne in pregnant women are limited.
Data obtained from animal studies and data on the use of dienogest in women during pregnancy have not identified a specific risk for pregnancy, fetal development, labor and development of the child after birth. The drug Visanne should not be prescribed to pregnant women due to the lack of need for treatment of endometriosis during pregnancy. Taking Visanne during breastfeeding is not recommended, because Animal studies indicate that dienogest is excreted in breast milk.

The decision to stop breastfeeding or to refuse to take Visanne is made based on an assessment of the ratio of the benefits of breastfeeding for the child and the benefits of treatment for the woman.

Use for liver dysfunction

Contraindicated: severe liver disease currently or in history (in the absence of normalization of liver function tests); liver tumors (benign and malignant) currently or in history. In rare cases, benign and, even less frequently, malignant liver tumors have been reported during the use of hormonal substances similar to those contained in Visanne. In some cases, these tumors have resulted in life-threatening intra-abdominal bleeding. If a woman taking Visanne 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 possibility of a liver tumor.

Use for renal impairment

There are no data indicating the need for dose adjustment in patients with kidney disease.

Use in children

Contraindicated in children and adolescents under 18 years of age (the effectiveness and safety of use in adolescents has not been established).

Use in elderly patients

Not used in postmenopausal women.

special instructions

Before starting to take Visanne, pregnancy must be ruled out. While taking Visanne, if contraception is necessary, patients are advised to use non-hormonal contraceptive methods (for example, barrier).

Fertility

According to available data, while taking Visanne, most patients experience suppression of ovulation. However, Visanne is not a contraceptive.

According to available data, the physiological menstrual cycle is restored within 2 months after stopping Visanne.

The use of Visanne in women with a history of ectopic pregnancy or dysfunction of the fallopian tubes should be decided only after a careful assessment of the ratio of expected benefits and possible risks.

Since Visanne is a progestogen-only drug, it can be assumed that special warnings and precautions for the use of other drugs of this type apply to Visanne, although not all of them were confirmed in clinical studies of Visanne.

If any of the following conditions or risk factors are present or worsened, an individual benefit-risk assessment should be performed before starting or continuing to take Visanne.

Circulatory disorders

In the process of epidemiological studies, insufficient evidence was obtained to confirm the existence of a connection between the use of drugs with only a progestin component and an increased risk of myocardial infarction or cerebral thromboembolism. The risk of cardiovascular events and cerebrovascular accidents is more likely associated with increasing age, arterial hypertension and smoking. The risk of stroke in women with arterial hypertension may increase slightly when taking drugs with only a progestin component.

Epidemiological studies indicate the possibility of a statistically insignificant increase in the risk of venous thromboembolism (deep vein thrombosis, pulmonary embolism) due to the use of drugs with only a progestin component. Well-established risk factors for the development of venous thromboembolism (VTE) include a relevant family history (VTE in a sibling or parent at a relatively early age), age, obesity, prolonged immobilization, major surgery, or major trauma. In case of prolonged immobilization, it is recommended to stop taking Visanne (for planned surgery, at least four weeks before it) and resume use of the drug only two weeks after complete restoration of motor ability.

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

If arterial or venous thrombosis develops or is suspected, the drug should be stopped immediately.

Tumors

A meta-analysis of 54 epidemiological studies revealed a small increase in the relative risk (RR = 1.24) of developing breast cancer in women who used oral contraceptives (OCs), predominantly estrogen-progestin drugs, at the time of the study. This increased risk gradually disappears over 10 years after stopping use of combined oral contraceptives. Because breast cancer is rare in women under 40 years of age, the slight increase in breast cancer diagnoses in women who are currently taking combined oral contraceptives or have previously used combined oral contraceptives is small relative to the overall risk of breast cancer. The risk of breast cancer detection in women using progestin-only hormonal contraceptives is probably similar in magnitude to the corresponding risk associated with the use of combined oral contraceptives. However, the evidence for progestin-only products is based on much smaller populations of women using them and is therefore less convincing than the evidence for combined oral contraceptives. It is not possible to establish a cause-and-effect relationship based on these studies. The observed pattern of increased risk may be due to earlier diagnosis of breast cancer in women taking OCs, the biological effects of OCs, or a combination of both factors. Malignant breast tumors that are diagnosed in women who have ever used OCs are usually clinically less severe than in women who have never used hormonal contraception.

In rare cases, benign and, even less frequently, malignant liver tumors have been reported during the use of hormonal substances similar to the one contained in Visanne. In some cases, these tumors have resulted in life-threatening intra-abdominal bleeding. If a woman taking Visanne 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 possibility of a liver tumor.

Change in bleeding pattern

For most women, taking Visanne affects the nature of menstrual bleeding.

During the use of the drug Visanne, uterine bleeding may increase, for example, in women with adenomyosis or uterine leiomyoma. Heavy and prolonged bleeding can lead to anemia (in some cases severe). In such cases, discontinuation of Visanne should be considered.

Other states

Patients with a history of depression require careful monitoring. If depression recurs in a serious form, the drug should be discontinued.

Overall, Visanne does not appear to affect blood pressure in women with normal blood pressure. However, if persistent clinically significant arterial hypertension occurs while taking Visanne, it is recommended to discontinue the drug and prescribe antihypertensive treatment.

In case of relapse of cholestatic jaundice and/or cholestatic itching, which first appeared during pregnancy or previous use of sex steroids, Visanne should be discontinued.

Visanne may have minor effects on peripheral insulin resistance and glucose tolerance. Women with diabetes mellitus, especially those with a history of diabetes mellitus during pregnancy, require careful monitoring while taking Visanne.

In some cases, chloasma may occur, especially in women with a history of chloasma during pregnancy. Women prone to developing chloasma should avoid exposure to the sun or ultraviolet radiation while taking Visanne.

Persistent ovarian follicles (often called functional ovarian cysts) may occur while taking Visanne. Most of these follicles are asymptomatic, although some may be accompanied by pelvic pain.

Lactose

1 tablet of Visanne contains 63 mg of lactose monohydrate. Patients on a lactose-free diet with rare hereditary disorders such as galactose intolerance, lapp lactase deficiency or glucose-galactose malabsorption should take into account the amount of lactose contained in Visanne.

Postmenopausal women

Not used in this category of patients.

Patients with renal failure

There are no data indicating the need for dose adjustment in patients with kidney disease.

Medical examination

Before starting or resuming taking Visanne, you should review the patient's medical history in detail and conduct a physical and gynecological examination. The frequency and nature of such examinations should be based on existing standards of medical practice with the necessary consideration of the individual characteristics of each patient (but at least once every 3-6 months) and should include blood pressure measurement, assessment of the condition of the mammary glands, abdominal cavity and pelvic organs, including cytological examination of the cervical epithelium.

Use in pediatrics

Visanne is contraindicated in children and adolescents under 18 years of age (the effectiveness and safety of use in adolescents has not been established).

Impact on the ability to drive vehicles and operate machinery

As a rule, Visanne does not affect the ability to drive a car or operate machinery, however, patients who have difficulty concentrating should be careful.