Endomeklin^® (Tablets) Instructions for Use

Marketing Authorization Holder

Akvion, JSC (Russia)

Manufactured By

Beijing Zizhu Pharmaceutical Co. Ltd. (China)

ATC Code

G03DB08 (Dienogest)

Active Substance

Dienogest (Rec.INN registered by WHO)

Dosage Form

Endomeklin®

Tablets 2 mg

Dosage Form, Packaging, and Composition

Tablets

14 pcs. – blister packs (2 pcs.) – cardboard packs (28 pcs.) – By prescription
14 pcs. – blister packs (6 pcs.) – cardboard packs (84 pcs.) – By prescription

Clinical-Pharmacological Group

Gestagen

Pharmacotherapeutic Group

Sex hormones and modulators of the genital system; progestogens; pregnadiene derivatives

Pharmacological Action

Dienogest is a derivative of norethisterone and is characterized by antiandrogenic activity, which is approximately one-third of the activity 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 potent progestogenic effect in vivo. Dienogest does not possess significant mineralocorticoid or glucocorticoid activity in vivo.

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

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 suppressive effect on cell proliferation.

No decrease in bone mineral density (BMD) was observed, nor any significant effect of dienogest on standard laboratory parameters, including general and biochemical blood parameters, liver enzymes, lipids, and HbA1c. Dienogest moderately reduces estrogen production in the ovaries.

Pharmacokinetics

After oral administration, Dienogest is rapidly and almost completely absorbed. The C_max in serum, which is 47 ng/ml, is reached approximately 1.5 hours after a single oral dose. The bioavailability is about 91%. The pharmacokinetics of dienogest in the dose range from 1 to 8 mg is dose-dependent. Dienogest binds to serum albumin and does not bind to sex hormone-binding globulin (SHBG) or corticosteroid-binding globulin (CBG). 10% of the total serum concentration of the substance is in the form of free steroid, while about 90% is non-specifically bound to albumin. The apparent V_d of dienogest is 40 L. The pharmacokinetics of dienogest is independent of SHBG levels. The serum concentration of dienogest after daily administration increases by approximately 1.24 times, reaching steady-state concentration after 4 days of administration.

Dienogest is almost completely metabolized, primarily by hydroxylation, forming several practically 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 excreted very rapidly, so that the predominant fraction in plasma is unchanged Dienogest. The metabolic clearance rate from serum is 64 ml/min.

The serum concentration of dienogest decreases in a biphasic manner. The T_1/2 in the terminal phase is approximately 9-10 hours. After oral administration of a dose of 0.1 mg/kg, Dienogest is excreted as metabolites, which are eliminated via the kidneys and intestine in a ratio of approximately 3:1. The T_1/2 of metabolites upon their renal excretion is 14 hours. After oral administration, approximately 86% of the administered dose is excreted within 6 days, with the majority excreted within the first 24 hours, primarily by the kidneys.

Indications

Treatment of endometriosis.

ICD codes

Dosage Regimen

Take one 2 mg tablet orally once daily.

Begin treatment on the first day of your menstrual period.

Take tablets continuously, without a treatment-free interval.

Swallow the tablet whole with water, with or without food. For consistent serum levels, take at the same time each day.

If a dose is missed by less than 12 hours, take the missed tablet immediately and the next dose at the regular time.

If a dose is missed by more than 12 hours, skip the missed dose and continue the regular schedule. Use a non-hormonal barrier contraceptive (e.g., condom) for the next 7 days if contraception is required.

In case of severe diarrhea or vomiting, absorption may be impaired. Use a non-hormonal barrier contraceptive until 7 days after recovery.

The treatment duration is determined by the physician based on the clinical response.

Regular gynecological monitoring is required during therapy.

Discontinue use immediately if pregnancy is confirmed.

Adverse Reactions

Reproductive system common – breast discomfort (including breast enlargement and breast pain), ovarian cyst (including hemorrhagic cyst), hot flashes, uterine bleeding/vaginal bleeding (including spotting, metrorrhagia, menorrhagia, irregular bleeding), amenorrhea; uncommon – vaginal candidiasis, vulvovaginal dryness (including dryness of mucous membranes), genital discharge (including vaginal discharge), pelvic pain, atrophic vulvovaginitis, fibrocystic mastopathy, breast induration.

Metabolism common – weight gain; uncommon – weight loss, increased appetite.

Nervous system common – headache, migraine, depressed mood, sleep disorder (including insomnia), nervousness, loss of libido, mood changes; uncommon – peripheral nervous system imbalance, attention disturbance, anxiety, depression, mood swings.

Digestive system common – nausea, abdominal pain (including lower abdominal pain and epigastric pain), flatulence, abdominal distension sensation, vomiting; uncommon – diarrhea, constipation, abdominal discomfort, inflammatory gastrointestinal diseases, gingivitis.

Skin and subcutaneous tissue common – acne, alopecia; uncommon – dry skin, hyperhidrosis, pruritus, hair growth abnormalities, including hirsutism and hypertrichosis, onychoclasis, dandruff, dermatitis, photosensitivity reactions, pigmentation disorder.

Musculoskeletal system common – back pain; uncommon – bone pain, muscle spasms, pain in extremity, feeling of heaviness in limbs.

Sensory organs uncommon – dry eye sensation, tinnitus.

Cardiovascular system uncommon – unspecified circulatory disorder, palpitations, arterial hypotension.

Respiratory system uncommon – dyspnea.

Hematopoietic system uncommon – anemia.

Urinary system uncommon – urinary tract infection (including cystitis).

General disorders common – asthenic condition (including fatigue, asthenia and malaise), irritability; uncommon – edema (including facial edema).

Contraindications

Acute thrombophlebitis, current venous thromboembolism; heart and arterial diseases based on atherosclerotic vascular lesions (including coronary artery disease, myocardial infarction, stroke and transient ischemic attack) current or in history; diabetes mellitus with vascular complications; severe liver diseases current or in history (in the absence of normalization of liver function tests); liver tumors (benign and malignant) current or in history; identified or suspected hormone-dependent malignant tumors, including breast cancer; vaginal bleeding of unknown origin; history of cholestatic jaundice of pregnancy; children and adolescents under 18 years of age; hypersensitivity to dienogest.

Use in Pregnancy and Lactation

Data on the use of dienogest in pregnant women are limited. Data obtained from animal studies and data on the use of dienogest in women during pregnancy have not revealed a specific risk for pregnancy, fetal development, childbirth, and child development after birth. Dienogest should not be prescribed to pregnant women due to the lack of need for endometriosis treatment during pregnancy.

It is not recommended to use Dienogest during breastfeeding, as animal studies indicate the excretion of dienogest in breast milk.

Special Precautions

Use with caution in patients with a 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.

Before starting dienogest, pregnancy must be excluded. During the use of dienogest for the treatment of endometriosis, if contraception is necessary, patients are advised to use non-hormonal contraceptive methods (e.g., barrier).

According to available data, the physiological menstrual cycle is restored within 2 months after discontinuation of dienogest for the treatment of endometriosis.

The decision to use dienogest in women with a history of ectopic pregnancy or with impaired fallopian tube function should be made only after a thorough assessment of the expected benefit versus the possible risk.

It should be borne in mind that special warnings and precautions for the use of other progestogens are also valid for dienogest.

If any of the conditions or risk factors listed below are present or worsen, an individual benefit-risk assessment should be performed before starting or continuing dienogest.

Epidemiological studies have provided insufficient evidence to confirm an association between the use of progestogen-only preparations and an increased risk of myocardial infarction or cerebral thromboembolism. The risk of cardiovascular episodes and cerebrovascular disorders is more likely related to increasing age, arterial hypertension, and smoking. The risk of stroke in women with arterial hypertension may be slightly increased while taking progestogen-only preparations.

Epidemiological studies indicate the possibility of a statistically insignificant increase in the risk of venous thromboembolism (deep vein thrombosis, pulmonary embolism) associated with the use of progestogen-only preparations. Recognized risk factors for the development of venous thromboembolism (VTE) include a relevant family history (VTE in a sibling or parent at a relatively young age), age, obesity, prolonged immobilization, major surgery, or massive trauma. In case of prolonged immobilization, it is recommended to discontinue dienogest (for planned surgery, at least 4 weeks before it) and resume use only two weeks after full restoration of mobility.

The increased risk of thromboembolism in the postpartum period should be considered.

If arterial or venous thrombosis develops or is suspected, dienogest should be discontinued immediately.

The risk of detecting breast cancer in women using progestogen-only hormonal contraceptives is possibly similar in magnitude to the corresponding risk associated with the use of combined oral contraceptives. However, the evidence relating to progestogen-only preparations is based on much smaller populations of users and is therefore less convincing than the data for combined oral contraceptives. It is not possible to establish a causal relationship based on these studies. The observed pattern of increased risk may be due to earlier diagnosis of breast cancer in women taking oral contraceptives, the biological effects of oral contraceptives, or a combination of both factors. Malignant breast tumors diagnosed in women who have ever used oral contraceptives are generally clinically less pronounced than in women who have never used hormonal contraception.

In rare cases, benign, and even more rarely, malignant liver tumors have been observed during the use of progestogens. In some cases, these tumors have led to life-threatening intra-abdominal bleeding. If severe pain in the upper abdomen, enlarged liver, or signs of intra-abdominal bleeding occur during dienogest use, the possibility of a liver tumor should be considered in the differential diagnosis.

In most women, Dienogest affects the pattern of menstrual bleeding.

During the use of dienogest, 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 dienogest should be considered.

Patients with a history of depression require careful observation. If depression recurs in a serious form, Dienogest should be discontinued.

If persistent clinically significant arterial hypertension occurs during dienogest use, it is recommended to discontinue Dienogest and initiate antihypertensive treatment.

If cholestatic jaundice and/or cholestatic pruritus recur, which first occurred during pregnancy or previous use of sex steroids, Dienogest must be discontinued.

Dienogest may have a slight effect on peripheral insulin resistance and glucose tolerance. Women suffering from diabetes mellitus, especially those with a history of gestational diabetes, require careful observation during dienogest use.

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

During the use of dienogest, persistent ovarian follicles (often called functional ovarian cysts) may occur. Most of these follicles are asymptomatic, although some may be accompanied by pelvic pain.

The use of progestogens may affect the results of some laboratory tests, including biochemical parameters of liver, thyroid, adrenal and kidney function, plasma concentrations of (carrier) proteins, e.g., lipid/lipoprotein fractions, parameters of carbohydrate metabolism, and coagulation parameters.

Effect on ability to drive vehicles and operate machinery

As a rule, Dienogest does not affect the ability to drive a car and operate machinery, however, patients who experience impaired concentration should exercise caution.

Drug Interactions

Progestogens, including Dienogest, are metabolized primarily by CYP3A4, located both in the intestinal mucosa and in the liver. Therefore, inducers or inhibitors of CYP3A4 may affect the metabolism of progestogenic drugs.

Increased clearance of sex hormones due to enzyme induction may lead to a reduction in the therapeutic effect of dienogest, as well as cause side effects, for example, changes in the pattern of uterine bleeding.

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

Interaction with drugs that induce microsomal enzymes (e.g., cytochrome P450 system) is possible, as a result of which the clearance of sex hormones may 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 is generally not observed until after 2-3 weeks, but may then persist for at least 4 weeks after discontinuation 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 the steady-state concentration and systemic exposure of dienogest was observed. The systemic exposure of dienogest at steady-state, determined by the AUC (0-24 h) value, was reduced by 83%.

Known inhibitors of CYP3A4, such as azole antifungal drugs (e.g., ketoconazole, itraconazole, fluconazole), cimetidine, verapamil, macrolides (e.g., erythromycin, clarithromycin and roxithromycin), diltiazem, protease inhibitors (e.g., ritonavir, saquinavir, indinavir, nelfinavir), antidepressants (e.g., nefazodone, fluvoxamine, fluoxetine) and grapefruit juice, may increase the plasma concentration of progestogens and cause side effects.

In a study investigating the effect of CYP3A4 inhibitors (ketoconazole, erythromycin), the plasma concentrations of estradiol valerate and dienogest at steady-state were increased. With concomitant administration of the potent inhibitor ketoconazole, the steady-state AUC (0-24 h) value for dienogest increased by 186%. With concomitant use of the moderate CYP3A4 inhibitor erythromycin, the steady-state AUC (0-24 h) value for dienogest increased by 62%. The clinical significance of this interaction is not known.

Storage Conditions

Store at 2°C (36°F) to 25°C (77°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.