Instructions for Vigest-KV tablets 2 mg No. 28
Composition
active ingredient: 1 tablet contains micronized dienogest 2 mg;
Excipients: lactose monohydrate; povidone K30; pregelatinized corn starch; magnesium stearate; microcrystalline cellulose; crospovidone (type A); colloidal anhydrous silicon dioxide.
Dosage form
Pills.
Main physicochemical properties: round tablets with embossing "D2" on one side and no embossing on the other side, white or slightly yellowish in color.
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 activity and with some antiandrogenic activity, which is approximately one third of that of cyproterone acetate. Dienogest binds to progesterone receptors in the human 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 promotes the formation of a hypoestrogenic, hypergestagenic endocrine environment, which causes initial decidualization of endometrial tissue with subsequent atrophy of endometrioid foci.
Performance data
The superiority of dienogest 2 mg over placebo was demonstrated in a 3-month study in 198 patients with endometriosis. Pelvic pain associated with endometriosis was measured using a visual analogue scale (0-100 mm). After 3 months of treatment with dienogest 2 mg, a statistically significant difference was demonstrated compared to placebo (D = 12.3 mm; 95% confidence interval (CI): 6.4-18.1; p < 0.0001) and a clinically meaningful reduction in pain compared to baseline (mean reduction 27.4 ± 22.9 mm).
After 3 months of treatment, 37.3% of patients receiving dienogest 2 mg (placebo: 19.8%) achieved a 50% or greater reduction in endometriosis-related pelvic pain without a corresponding increase in the dose of concomitant analgesic; a 75% or greater reduction in endometriosis-related pelvic pain (also without a corresponding increase in the dose of concomitant analgesic) was achieved in 18.6% of patients receiving dienogest 2 mg (placebo: 7.3%).
An open-label extension of this 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 was found to be anovulatory after 1 month of therapy. Dienogest 2 mg 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.
To date, there are no long-term data on bone mineral density (BMD) and fracture risk in patients using dienogest 2 mg. BMD was assessed in 21 adult patients before and after 6 months of treatment with dienogest 2 mg. 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).
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 for 15 months (n = 168).
Safety data for teenagers
The safety of dienogest 2 mg on BMD was investigated in a 12-month clinical 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 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
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 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 of dienogest is 40 L.
Metabolism: Dienogest is completely metabolized by the known pathways of steroid metabolism 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.
Plasma clearance 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 administration can be predicted based on data on the pharmacokinetics of a single dose.
Pharmacokinetics in special patient groups.
The pharmacokinetics of dienogest have not been studied in patients with renal impairment.
The pharmacokinetics of dienogest have not been studied in patients with hepatic impairment.
Indication
For the treatment of endometriosis.
Contraindication
Vigest-KV should not be used in the presence of any of the following conditions or diseases. This information is partly derived from the use of other progestogen-only products. If any of these conditions or diseases appear for the first time while using Vigest-KV, the drug should be discontinued immediately.
Venous thromboembolism (VTE) in active form.
Current or history of arterial or cardiovascular disease (e.g. myocardial infarction, cerebrovascular event, 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 medicinal product.
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 Vigest-KV
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 progestogen metabolism. Increased clearance of sex hormones due to enzyme induction may reduce the therapeutic effect of Vigest-KV 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 Vigest-KV 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 several weeks.
Enzyme induction may persist for up to 4 weeks after discontinuation of therapy.
The effect of the CYP3A4 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 HIV protease inhibitor and non-nucleoside reverse transcriptase inhibitor combinations with sex hormones, in combination with hepatitis C virus inhibitor combinations, 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 Vigest-KV.
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 Vigest-KV is a progestogen-only medicinal product, it is considered that the special warnings and precautions for the use of progestin-containing medicinal products also apply to the medicinal product Vigest-KV, although not all warnings and precautions are based on the relevant results of studies with this medicinal product.
If any of the following conditions/risk factors worsen or first occur, an individual risk/benefit analysis should be performed before initiating or continuing the use of Vigest-KV.
Heavy uterine bleeding
Uterine bleeding, for example in women with uterine adenomyosis or uterine leiomyoma, may increase with the use of Vigest-KV. 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
In most patients, when taking dienogest 2 mg, the pattern of menstrual bleeding changes (see section "Adverse reactions").
Circulatory disorders
Epidemiological studies have shown some 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 is slightly increased with the use of progestogen-only contraceptives.
Some studies suggest a statistically insignificant increase in the risk of venous thromboembolism (deep vein thrombosis, pulmonary embolism) associated with the use of progestogen-only products. The generally recognized factors that increase the risk of venous thromboembolism (VTE) are: personal or family history of VTE (for example, VTE in siblings or parents at a relatively young age), older age, obesity, prolonged immobilization, major surgery or trauma. In the event of prolonged immobilization, it is recommended to discontinue the use of Vigest-KV (at least 4 weeks before elective surgery) and not to restart it until 2 weeks after complete recovery.
It is important to remember the increased risk of thromboembolism in the postpartum period.
If symptoms of venous and arterial thrombotic diseases occur or are suspected, treatment should be discontinued.
A meta-analysis of 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 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 COCs, the biological action of these drugs, or a combination of both. There is a tendency for breast cancer detected in women who have ever used COCs 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 substances similar to those contained in Vigest-KV, which in some cases led to life-threatening intra-abdominal bleeding. In the event of complaints of severe pain in the epigastric region, liver enlargement, or signs of intra-abdominal bleeding, the possibility of a liver tumor should be considered in the differential diagnosis in women taking Vigest-KV.
Osteoporosis
Changes in bone mineral density (BMD).
The use of dienogest 2 mg in adolescents (12–18 years) over a treatment period of 12 months 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 from baseline to end of treatment in BMD 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 of particular importance 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 Vigest-KV and the possible risks of use 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.
In patients at increased risk of osteoporosis, a careful risk/benefit assessment should be performed before initiating treatment with Vigest-KV, as endogenous estrogen levels are moderately reduced during 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 Vigest-KV and treat the hypertension.
In case of recurrence of cholestatic jaundice and/or itching that occurred during pregnancy or previous use of sex hormones, the use of the drug Vigest-KV 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 Vigest-KV.
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 Vigest-KV.
Persistence of follicles (often referred to as functional ovarian cysts) may occur during the use of Vigest-KV. Most of these follicles are asymptomatic, although some may be accompanied by pelvic pain.
Lactose
The medicine contains lactose, therefore patients with rare hereditary diseases such as galactose intolerance, lactase deficiency or glucose-galactose malabsorption should not use it.
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).
Vigest-KV is not recommended for use in pregnant women, as there is no need to treat endometriosis during pregnancy.
Breastfeeding. Treatment with Vigest-KV during breastfeeding is not recommended. It is not known whether dienogest passes into breast milk. Data obtained in animal studies indicate that dienogest passes into breast milk. A decision should be made whether to discontinue breast-feeding or to discontinue Vigest-KV 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 during treatment with Vigest-KV, ovulation is suppressed in most patients. However, Vigest-KV 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 the drug Vigest-KV.
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.
There is no experience of treating patients with endometriosis with Vigest-KV for longer than 15 months.
You can start taking the drug on any day of the menstrual cycle.
Any hormonal contraceptives should be discontinued before starting therapy with Vigest-KV. If contraception is necessary, a non-hormonal method of contraception (e.g., barrier method) should be used in addition.
Skipping a medication
In case of missed tablets, vomiting and/or diarrhea (occurring within 3-4 hours after taking the tablet), the effectiveness of Vigest-KV may be reduced. In case of missed tablets, 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 was not absorbed due to vomiting or diarrhea should be replaced with another tablet in the same way.
Use in special patient groups
Elderly patients
There are no relevant indications for the use of the drug Vigest-KV in patients of 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 Vigest-KV is not indicated for use in children before the onset of menarche.
The safety and efficacy of 2 mg dienogest were studied in a 12-month uncontrolled study in 111 adolescent patients (12–<18 years) with clinically suspected or confirmed endometriosis (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. When using 20-30 mg of dienogest per day (which is 10-15 times higher than the dose in a Vigest-KV tablet) for more than 24 weeks, the drug was very well tolerated.
Side effects
Adverse reactions are described according to MedDRA.
Side effects most often develop during the first months after starting Vigest-KV and disappear during treatment. Changes in the pattern of menstrual bleeding, such as spotting, irregular bleeding or amenorrhea, may occur.
In addition, most patients treated with dienogest 2 mg experienced a change in menstrual bleeding pattern. Menstrual bleeding patterns were systematically assessed using patient diaries and analyzed using the WHO method over a 90-day reporting period. During the first 90 days of treatment with dienogest 2 mg, 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 reference 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 described as adverse reactions in patients.
The following are the adverse reactions according to the MedDRA classification (MedDRA SOCs) reported during treatment with dienogest and their frequency.
Within each grouping, adverse reactions are listed in order of decreasing frequency: common (≥ 1/100 to < 1/10) and uncommon (≥ 1/1000 to < 1/100). The frequencies are based on pooled data from four clinical trials.
From the blood and lymphatic system: infrequently - anemia.
Metabolism and metabolic disorders: often - weight gain; infrequently - weight loss, increased appetite.
On the part of the psyche: often - depressed mood, sleep disturbances, nervousness, decreased libido, mood changes; infrequently - anxiety, depression, mood lability.
From the nervous system: often - headache, migraine; infrequently - impaired autonomic regulation, impaired attention.
On the part of the organs of vision: infrequently - dry eyes.
From the side of the organs of hearing and vestibular apparatus: infrequently - tinnitus.
Cardiac disorders: infrequently - nonspecific circulatory disorders, palpitations.
Vascular disorders: infrequently - arterial hypotension.
Respiratory, thoracic and mediastinal disorders: infrequently - dyspnea.
Gastrointestinal: often - nausea, abdominal pain, flatulence, bloating, vomiting; infrequently - diarrhea, constipation, abdominal discomfort, gastrointestinal inflammation, gingivitis.
Skin and subcutaneous tissue disorders: common: acne, alopecia; uncommon: dry skin, hyperhidrosis, itching, hirsutism, onychoclasia, dandruff, dermatitis, hair growth disorders, photosensitivity reactions, pigmentation changes.
Musculoskeletal and connective tissue disorders: common: back pain; uncommon: bone pain, muscle cramps, pain in extremities, feeling of heaviness in extremities.
Renal and urinary disorders: uncommon - urinary tract infection.
Reproductive system and breast disorders: common: breast discomfort, ovarian cyst, hot flashes, uterine/vaginal bleeding, including spotting; uncommon: vaginal candidiasis, vulvar and vaginal dryness, genital discharge, pelvic pain, atrophic vulvovaginitis, breast enlargement, cystic fibrosis of the breast, breast engorgement.
General disorders and local reactions: often - asthenic conditions, irritability; infrequently - edema.
Decreased bone mineral density
In a study involving 111 adolescent patients (12 to <18 years) treated with dienogest 2 mg, 103 patients 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
It is important to report any suspected adverse reactions when using a medicinal product. This allows the benefit/risk balance of the medicinal product to be monitored. Healthcare professionals should report all suspected adverse reactions via the national pharmacovigilance system.
Expiration date
3 years.
Storage conditions
Store in the original packaging at a temperature not exceeding 30 °C.
Keep out of reach of children.
Packaging
28 tablets in a blister; 1 blister in a pack.
Vacation category
According to the recipe.
Producer
JSC "KYIV VITAMIN FACTORY".
Sindea Pharma, S.L.
Location of the manufacturer and address of its place of business.
04073, Ukraine, Kyiv, Kopylivska St., 38.
Website: www.vitamin.com.ua
Poligono Industrial Emiliano Revilla Sans. Avenida de Agreda, 31, Olvega, 42110 Soria, Spain
