Vigest-qd

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT VIGEST-KV (VIGEST-KV)

Composition:

Active substance: 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.

Pharmaceutical form. Tablets.

Main physicochemical properties: round-shaped tablets with "D2" imprint on one side and no imprint on the other side, white or slightly yellowish in color.

Pharmacotherapeutic group. Sex gland hormones and drugs used in pathologies of genital organs. Progestogens. ATC code G03DB08.

Pharmacological properties.

Pharmacodynamics.

Dienogest is a derivative of nortestosterone without androgenic activity and with certain antiandrogenic activity, approximately one-third 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 exerts 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, thereby suppressing the trophic effects of estradiol on eutopic and ectopic endometrium. With continuous administration, dienogest promotes the formation of a hypoestrogenic, hypergestagenic endocrine environment, leading to initial decidualization of endometrial tissue followed by atrophy of endometriotic lesions.

Efficacy data

Superiority of dienogest 2 mg over placebo was demonstrated in a 3-month study involving 198 patients with endometriosis. Pelvic pain associated with endometriosis was measured using a visual analog scale (0–100 mm). After 3 months of treatment with dienogest 2 mg, a statistically significant difference compared to placebo was demonstrated (Δ = 12.3 mm; 95% confidence interval (CI): 6.4–18.1; p < 0.0001), along with clinically significant pain reduction compared to baseline (mean reduction was 27.4 ± 22.9 mm).

After 3 months of treatment, a reduction in severity of pelvic pain associated with endometriosis by 50% or more—without a corresponding increase in dose of concomitant analgesic—was achieved in 37.3% of patients receiving dienogest 2 mg (placebo: 19.8%). A reduction in severity of pelvic pain associated with endometriosis by 75% or more (also without a corresponding increase in 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 continuous reduction in endometriosis-associated pelvic pain with treatment up to 15 months.

Results from placebo-controlled studies were confirmed by findings from a 6-month active-controlled study comparing dienogest 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 endometriotic lesions after 6 months of treatment.

In a small study (n = 8 per dosage group), administration of dienogest at a dose of 1 mg daily resulted in absence of ovulation after 1 month of therapy. Dienogest 2 mg has not been investigated 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 evaluated in 21 adult patients before and after 6 months of treatment with dienogest 2 mg. No mean reduction in BMD was observed. In 29 patients receiving leuprolide acetate, a mean reduction of 4.04 ± 4.84% was observed over the same period (Δ between groups was 4.29%, 95% CI: 1.93–6.66, p < 0.0003).

No significant impact on standard laboratory parameters—including blood count, blood biochemistry, liver enzyme levels, lipid levels, and HbA1c—was observed during 15 months of treatment with dienogest 2 mg (n = 168).

Safety data in adolescents

The safety of dienogest 2 mg regarding BMD was evaluated in a 12-month clinical study involving 111 adolescent patients (aged 12 to <18 years) with clinically suspected or confirmed endometriosis. The mean relative change in lumbar spine (L2–L4) BMD from baseline to end of treatment in 103 patients was –1.2%. Re-measurement 6 months after completion of treatment in a subgroup with reduced BMD values showed an increase in BMD to –0.6%.

Non-clinical safety data

Non-clinical studies do not indicate a specific risk for humans based on standard repeated-dose toxicity, genotoxicity, carcinogenicity, and reproductive toxicity studies. However, it should be noted that sex steroids may promote the growth of certain hormone-dependent tissues and tumors.

Pharmacokinetics.

Absorption. After oral administration, dienogest is rapidly and completely absorbed. Maximum serum concentration is reached within 1.5 hours after a single oral dose and amounts to 47 ng/mL. The bioavailability of dienogest is approximately 91%. The pharmacokinetics of dienogest are dose-dependent within the dose range of 1–8 mg.

Distribution. Dienogest binds to serum albumin and does not bind to sex hormone-binding globulin (SHBG) or corticosteroid-binding globulin (CBG). Only 10% of the total dienogest concentration in serum exists as free steroid, while 90% is nonspecifically bound to albumin. The apparent volume of distribution of dienogest is 40 L.

Metabolism. Dienogest is completely metabolized via known steroid metabolic pathways, forming predominantly endocrinologically inactive metabolites. Based on in vitro and in vivo studies, CYP3A4 is the primary enzyme involved in the metabolism of dienogest. These metabolites are rapidly eliminated such that unchanged dienogest remains the predominant compound in plasma.

Plasma clearance is 64 mL/min.

Elimination. Serum dienogest levels decline in a biphasic manner with an elimination half-life of 9–10 hours. Dienogest is excreted in the form of metabolites in urine and feces in a ratio of approximately 3:1 after an oral dose of 0.1 mg/kg. The elimination half-life of metabolites in urine is approximately 14 hours. After oral administration, 86% of the administered dose is excreted within 6 days, with most of this amount eliminated within the first 24 hours, primarily via urine.

Steady state. The pharmacokinetics of dienogest are independent of SHBG levels. With daily administration, serum concentration increases by a factor of 1.24, reaching steady state within 4 days of treatment. The pharmacokinetics of dienogest after repeated dosing can be predicted based on single-dose pharmacokinetic data.

Pharmacokinetics in special patient populations.

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.

Clinical characteristics.

Indications.

For the treatment of endometriosis.

Contraindications.

Vigest-KV should not be used in the presence of any of the following conditions or diseases. This information is partly based on the use of other drugs containing only progestogen. If any of these conditions or diseases occurs for the first time during treatment with Vigest-KV, the drug should be discontinued immediately.

• Active venous thromboembolism (VTE).
• Arterial or cardiovascular diseases currently present or in medical history (e.g. myocardial infarction, cerebrovascular event, ischemic heart disease).
• Diabetes mellitus with vascular complications.
• Severe liver disease currently present or in medical history, until liver function tests return to normal.
• Liver tumors currently present or in medical history (benign or malignant).
• Known or suspected hormonally-dependent malignant tumors.
• Vaginal bleeding of unknown etiology.
• Hypersensitivity to the active substance or to any of the excipients of the drug.

Interaction with other medicinal products and other forms of interaction.

Note: To identify possible interactions, refer to the instructions for medical use of concomitantly administered medicinal products.

Effect of other drugs on Vigest-KV

Progestogens, including dienogest, are primarily metabolized by the cytochrome P450 3A4 (CYP3A4) system located in the intestinal mucosa and 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 Vigest-KV and lead to adverse effects, such as changes in menstrual bleeding pattern.

Decreased 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 via 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 be observed after several days of therapy. Maximum enzyme induction is generally reached 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. Concomitant administration of rifampicin with an oral formulation of estradiol valerate/dienogest resulted in a significant reduction in the steady-state concentration and systemic exposure of dienogest and estradiol. The systemic exposure of dienogest and estradiol at steady state, measured as AUC (0–24 hours), decreased by 83% and 44%, respectively.

• Substances with variable effects on the clearance of sex hormones.

Concomitant use of sex hormones with a large number of combinations of HIV protease inhibitors and non-nucleoside reverse transcriptase inhibitors in combination with hepatitis C virus inhibitors may increase or decrease plasma levels of progestin. 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 administration with the strong CYP3A4 inhibitor ketoconazole resulted in a 2.9-fold increase in AUC (0–24 hours) of dienogest at steady state. Concomitant administration with the moderate inhibitor erythromycin resulted in a 1.6-fold increase in AUC (0–24 hours) of dienogest at steady state.

Effect of dienogest on other medicinal products

Based on in vitro inhibition studies, clinically significant interactions between dienogest and other drugs whose metabolism is mediated by cytochrome P450 enzymes are unlikely.

Interaction with food

Administration with a high-fat meal did not affect the bioavailability of Vigest-KV.

Laboratory tests

The use of progestogens may affect the results of certain laboratory tests, including liver biochemical parameters, thyroid and adrenal gland function, kidney function, plasma protein levels (carriers) (e.g. SHBG and lipid/lipoprotein fractions), carbohydrate metabolism parameters, and coagulation and fibrinolysis parameters. Changes are usually within the laboratory normal range.

Special precautions for use

Warnings

Since Vigest-KV is a medicinal product containing only a progestogen, specific warnings and safety precautions applicable to progestogen-containing medicinal products are considered relevant for Vigest-KV, although not all such warnings and precautions are based on specific study results with this particular medicinal product.

If any of the conditions or risk factors listed below worsen or occur for the first time, an individual benefit-risk assessment should be performed before initiating or continuing treatment with Vigest-KV.

Severe uterine bleeding

Uterine bleeding, for example in women with adenomyosis or uterine leiomyoma, may increase during treatment with Vigest-KV. If bleeding is heavy and persistent over a prolonged period, it may lead to anaemia (in some cases severe). In such cases, discontinuation of the medicinal product should be considered.

Changes in bleeding pattern

In most patients, treatment with 2 mg of dienogest leads to changes in the pattern of menstrual bleeding (see section "Adverse reactions").

Circulatory disorders

Epidemiological studies have provided some evidence of an association between the use of progestogen-only medicinal products and an increased risk of myocardial infarction or cerebral thromboembolism. The risk of cardiovascular and cerebrovascular events is more likely related to age, arterial hypertension, and smoking. In women with hypertension, the risk of stroke is slightly increased with the use of progestogen-only medicinal products.

Some studies suggest a certain statistically non-significant increase in the risk of venous thromboembolism (deep vein thrombosis, pulmonary embolism) associated with the use of progestogen-only medicinal products. Well-known risk factors increasing the risk of venous thromboembolism (VTE) include: personal or family history of VTE (e.g. VTE in siblings or parents at a relatively young age), advanced age, obesity, prolonged immobilization, major surgical procedures, or trauma. In case of prolonged immobilization, it is recommended to discontinue Vigest-KV (at least 4 weeks before a planned surgery) and not restart treatment until at least 2 weeks after full recovery.

An increased risk of thromboembolism in the postpartum period should also be kept in mind.

Treatment should be discontinued if symptoms of venous or arterial thrombotic disorders occur or are suspected.

Tumors

A meta-analysis of epidemiological studies indicates a slight increase in relative risk (RR = 1.24) of breast cancer in women using oral contraceptives (OCs), primarily combined estrogen-progestogen products. This increased risk gradually disappears within 10 years after discontinuation of combined oral contraceptives (COCs). Since breast cancer is rare in women under 40 years of age, the increase in diagnosed cases among women currently or recently using COCs is small relative to the overall risk of breast cancer. The risk of detecting breast cancer is similar in women using progestogen-only products or COCs. However, data on progestogen-only products are based on a much smaller number of users and are therefore less conclusive than data on COCs. These study results do not provide evidence of a causal relationship. The increased risk may be due to earlier diagnosis of breast cancer in OC users, a biological effect of these products, or a combination of both factors. A trend has been observed that breast cancer diagnosed in women who have ever used OCs is clinically less severe than in those who have never used oral contraceptives.

In rare cases, benign and even more rarely malignant liver tumors have been observed in women using hormonal substances similar to the one contained in Vigest-KV, which in some cases led to life-threatening intra-abdominal bleeding. In case 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 of women taking Vigest-KV.

Osteoporosis

Changes in bone mineral density (BMD).

Treatment with 2 mg of dienogest in adolescents (12–18 years) over a 12-month treatment period was associated with a mean decrease in BMD at the lumbar spine (L2–L4) of 1.2%. After discontinuation of treatment, BMD increased again in these patients.

The mean relative change in BMD from baseline to the end of treatment was 1.2%, with a range between –6% and 5% (95% CI: –1.70% to –0.78%, n = 103). Repeat measurements 6 months after treatment in a subgroup with reduced BMD values showed a trend towards recovery (mean relative change from baseline: –2.3% at end of treatment and –0.6% at 6 months after treatment, range between –9% and 6% [95% CI: –1.20% to 0.06%, n=60]).

Changes in bone mineral density are of particular importance during adolescence and early puberty, which is a critical period for bone growth. It is unknown whether the reduction in BMD in this population will reduce peak bone mass or increase the risk of fractures in later life (see sections "Paediatric population" and "Pharmacological properties").

Before initiating treatment, the physician should weigh the benefits of using Vigest-KV against potential risks for each individual adolescent, taking into account also the presence of significant risk factors for osteoporosis.

Adequate intake of calcium and vitamin D through diet or dietary supplements is important for maintaining healthy bone status in women of all age groups.

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

Other conditions

Patients with a history of depression should be closely monitored, and treatment should be discontinued if severe depressive symptoms develop.

Dienogest generally does not affect blood pressure in normotensive women. However, if prolonged clinically evident hypertension develops during treatment, discontinuation of Vigest-KV is recommended, and hypertension should be treated.

Treatment with Vigest-KV should be discontinued in case of recurrence of cholestatic jaundice and/or pruritus that occurred during pregnancy or previous use of sex hormones.

Dienogest may have a minor influence on peripheral insulin resistance and glucose tolerance. Women with diabetes mellitus, particularly those with a history of gestational diabetes, should be closely monitored during treatment with Vigest-KV.

Chloasma may occasionally develop, especially in women with a history of chloasma of pregnancy. Women prone to chloasma should avoid direct sunlight or ultraviolet radiation during treatment with Vigest-KV.

The likelihood of ectopic pregnancy in women using progestogen-only contraceptives is higher than in women using COCs. Therefore, for women with a history of ectopic pregnancy or tubal dysfunction, the decision to use Vigest-KV should be made only after careful benefit-risk assessment.

During treatment with Vigest-KV, persistence of follicles (often referred to as functional ovarian cysts) may occur. Most of these follicles are asymptomatic, although some may be associated with pelvic pain.

Lactose

The medicinal product contains lactose and therefore should not be used in patients with rare hereditary conditions such as galactose intolerance, lactase deficiency, or glucose-galactose malabsorption.

Use during pregnancy or breastfeeding

Pregnancy. Data on the use of dienogest in pregnant women are limited. Animal studies do not indicate direct or indirect risks of reproductive toxicity (see section "Pharmacological properties").

Vigest-KV is not recommended during pregnancy as there is no need to treat endometriosis during pregnancy.

Breastfeeding. Treatment with Vigest-KV is not recommended during breastfeeding. It is unknown whether dienogest passes into human breast milk. Animal studies indicate that dienogest is excreted in milk. A decision should be made whether to discontinue breastfeeding or to discontinue therapy with Vigest-KV, taking into account the benefit of breastfeeding for the child and the necessity of treatment for the woman.

Fertility. Based on available data, ovulation is suppressed in most patients during treatment with Vigest-KV. However, Vigest-KV is not a contraceptive.

If contraception is needed, a non-hormonal method of contraception should be used additionally (see section "Dosage and administration").

Based on available data, the menstrual cycle returns to normal within 2 months after discontinuation of treatment with Vigest-KV.

Ability to affect reaction speed when driving or operating machinery

No effects on the ability to drive or operate machinery have been observed in patients taking dienogest-containing products.

Method of Administration and Dosage

Method of Administration

For oral use.

Dosage

Take 1 tablet daily without interruption, approximately at the same time each day, with a small amount of liquid. Tablets may be taken regardless of food intake.

Tablets should be taken regularly, regardless of menstrual bleeding. As soon as the tablets from one pack are finished, begin taking tablets from the next pack without any break in medication use.

There is no clinical experience with treatment of patients with endometriosis using Vigest-KV for longer than 15 months.

Treatment may be initiated on any day of the menstrual cycle.

Any hormonal contraceptives should be discontinued prior to starting therapy with Vigest-KV. If contraception is required, an additional non-hormonal method of contraception (e.g., a barrier method) should be used.

Missed Dose

If a tablet is missed, or if vomiting and/or diarrhea occur within 3–4 hours after taking the tablet, the effectiveness of Vigest-KV may be reduced. If one or more tablets are missed, take 1 tablet as soon as remembered, and take the next tablet at the usual time. A tablet that was not absorbed due to vomiting or diarrhea should be replaced in the same manner with another tablet.

Use in Special Patient Populations

Elderly Patients

There are no appropriate indications for the use of Vigest-KV in this patient group.

Hepatic Impairment

The drug is contraindicated in patients with severe liver disease, either currently or in the past (see section "Contraindications").

Renal Impairment

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

Children

Vigest-KV is not indicated for use in children before menarche.

The safety and efficacy of 2 mg dienogest were evaluated in an uncontrolled 12-month study involving 111 adolescent patients (12–<18 years) with clinically suspected or confirmed endometriosis (see sections "Special Instructions" and "Pharmacological Properties").

Overdose

Acute toxicity studies conducted with dienogest did not indicate a risk of acute adverse reactions following unintentional ingestion of several daily therapeutic doses. No specific antidotes are available. The drug was well tolerated when 20–30 mg of dienogest per day (10–15 times higher than the dose in Vigest-KV tablets) was administered for more than 24 weeks.

Adverse Reactions

Adverse reactions are described according to MedDRA.

Adverse reactions most commonly occur during the first months after initiation of treatment with Vigest-KV and usually resolve during continued therapy. Changes in the pattern of menstrual bleeding such as spotting, irregular bleeding, or amenorrhea may occur.

The most frequently reported adverse reactions during treatment with dienogest 2 mg are headache (9.0%), breast pain (5.4%), depressed mood (5.1%), and acne (5.1%).

Additionally, in the majority of patients receiving dienogest 2 mg, changes in menstrual bleeding patterns were observed. Menstrual bleeding patterns were systematically assessed using patient diaries and analyzed according to WHO criteria 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., not falling into any 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 rarely reported as adverse reactions by patients.

The adverse reactions listed below are those reported during dienogest treatment, categorized according to MedDRA System Organ Classes (SOCs), along with their frequencies.

Within each group, adverse effects are listed in decreasing order of frequency: common (≥ 1/100 to <1/10) and uncommon (≥ 1/1000 to <1/100). Frequencies are based on pooled data from four clinical studies.

Blood and lymphatic system disorders: uncommon — anaemia.

Metabolism and nutrition disorders: common — weight increased; uncommon — weight decreased, increased appetite.

Psychiatric disorders: common — depressed mood, sleep disorders, nervousness, decreased libido, mood alterations; uncommon — anxiety, depression, mood lability.

Nervous system disorders: common — headache, migraine; uncommon — autonomic nervous system disorders, attention disturbances.

Eye disorders: uncommon — dry eyes.

Ear and labyrinth disorders: uncommon — tinnitus.

Cardiac disorders: uncommon — non-specific circulatory disorders, palpitations.

Vascular disorders: uncommon — arterial hypotension.

Respiratory, thoracic and mediastinal disorders: uncommon — dyspnea.

Gastrointestinal disorders: common — nausea, abdominal pain, flatulence, abdominal distension, vomiting; uncommon — diarrhea, constipation, abdominal discomfort, gastrointestinal inflammation, gingivitis.

Skin and subcutaneous tissue disorders: common — acne, alopecia; uncommon — dry skin, hyperhidrosis, pruritus, hirsutism, onychoclasis, dandruff, dermatitis, hair growth disorders, photosensitivity reactions, pigmentation changes.

Musculoskeletal and connective tissue disorders: common — back pain; uncommon — bone pain, muscle cramps, limb pain, sensation of heaviness in limbs.

Renal and urinary disorders: uncommon — urinary tract infection.

Reproductive system and breast disorders: common — breast discomfort, ovarian cyst, hot flushes, uterine/vaginal bleeding including spotting; uncommon — vaginal candidiasis, vulvar and vaginal dryness, genital discharge, pelvic pain, atrophic vulvovaginitis, breast enlargement, fibrocystic breast disease, breast tenderness.

General disorders and administration site conditions: common — asthenic conditions, irritability; uncommon — swelling.

Decrease in bone mineral density

In a study involving 111 adolescent patients (aged 12 to <18 years) receiving dienogest 2 mg, bone mineral density (BMD) was measured in 103 patients. A decrease in lumbar spine (L2–L4) BMD was observed in approximately 72% of study participants after 12 months of treatment (see section "Special instructions").

Reporting suspected adverse reactions

It is important to report suspected adverse reactions during drug use. This enables ongoing monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals should report all suspected adverse reactions through the national pharmacovigilance system.

Shelf life. 3 years.

Storage conditions.

Store in the original packaging at a temperature not exceeding 30°C.

Keep out of the reach and sight of children.

Packaging.

28 tablets in a blister; 1 blister per carton.

Prescription status.

Prescription only.

Manufacturer.

1. JSC "KYIV VITAMIN PLANT".
2. Sydnea Pharma, S.L.

Manufacturer's address and place of business.

1. 38 Kopilivska Street, Kyiv, 04073, Ukraine.
   Website: www.vitamin.com.ua

2. Poligono Industrial Emilian Revilla Sans, Avenida de Agreda, 31, Olvega, 42110 Soria, Spain