DlyaJens^® progi (Tablets) Instructions for Use

Marketing Authorization Holder

Pharmasintez-Tyumen, LLC (Russia)

ATC Code

G03CA03 (Estradiol)

Active Substance

Estradiol valerate (Rec.INN registered by WHO)

Dosage Form

DlyaJens® progi

Film-coated tablets, 2 mg: 21 pcs.

Dosage Form, Packaging, and Composition

Film-coated tablets white or almost white; round, biconvex; the tablet core on the cross-section is white or almost white.

Excipients: lactose monohydrate, hypromellose E15, corn starch, colloidal silicon dioxide, magnesium stearate; film coating: hypromellose E5, macrogol 6000 (polyethylene glycol), titanium dioxide (E171), polysorbate 80 (tween 80).

21 pcs. – blister packs (1) – cardboard packs.

Clinical-Pharmacological Group

Anticlimacteric estrogenic drug

Pharmacotherapeutic Group

Sex hormones and modulators of the genital system, natural and semi-synthetic estrogens

Pharmacological Action

Estrogen, a drug for replacement therapy. Estradiol valerate has a specific estrogenic effect: it causes proliferation of the endometrium, stimulates the development of the uterus and secondary female sexual characteristics in case of their underdevelopment, softens and eliminates general disorders arising in a woman’s body due to insufficient function of the gonads during the climacteric period or after gynecological operations.

Estradiol valerate maintains the balance between osteoblasts and osteoclasts, reduces bone resorption and promotes its formation.

Pharmacokinetics

After oral administration, Estradiol valerate is rapidly and completely absorbed from the gastrointestinal tract. C_max of estradiol in blood plasma is reached in 0.5 – 3 hours. The absolute bioavailability of estradiol is 3-5% of the oral dose of estradiol valerate. Plasma protein binding is 50%. It is rapidly metabolized in the liver to form estriol and estrone. It undergoes the “first-pass” effect through the liver and, to some extent, enterohepatic recirculation. Estradiol and its metabolites are excreted by the kidneys (mainly in the form of sulfates, glucuronides) and through the intestines in a ratio of 9:1. Within 5 days, 78-96% of the taken dose is excreted. T_1/2 is about 27 hours.

Indications

Hot flashes, increased sweating, sleep disorders, depression, nervousness, irritability, headaches, dizziness upon cessation of menstruation during menopause, after surgical removal of the ovaries or their irradiation; bladder hyperesthesia, degenerative changes in the skin and mucous membranes, osteoporosis in the climacteric period.

It is used mainly as part of combined preparations.

ICD codes

Dosage Regimen

Administer orally with water. Swallow the tablet whole; do not crush or chew.

The recommended daily dose is 1 mg to 2 mg of estradiol valerate. The specific dose and regimen are determined by the indication and individual patient status.

For menopausal symptoms, initiate therapy with the lowest effective dose. Adjust the dose based on clinical response and tolerability.

For postmenopausal osteoporosis prevention, use the minimum effective dose for the shortest duration, consistent with treatment goals and risks.

Take tablets continuously or in cyclical regimens as prescribed. Adhere strictly to the prescribed schedule to maintain stable hormone levels.

In women with an intact uterus, add a progestogen for at least 12 days per cycle to reduce the risk of endometrial hyperplasia. Estrogen monotherapy is contraindicated in these patients.

Begin therapy or resume treatment only after a comprehensive medical evaluation, including a personal and family history and gynecological examination.

Periodically re-evaluate the need for continued therapy. Discontinue treatment immediately if jaundice, severe hypertension, migraine, or pregnancy occurs.

Adverse Reactions

Benign, malignant and unspecified neoplasms (including polyps and cysts): breast cancer, endometrial cancer.

From the organ of vision: visual impairment, contact lens intolerance.

From the immune system: hypersensitivity reactions, exacerbation of hereditary angioedema.

From metabolism: increase or decrease in body weight, impaired carbohydrate tolerance, increased appetite, porphyria.

From the nervous system: headache, dizziness, stroke, migraine, chorea.

From the psyche: low mood, symptoms of depression.

From the cardiovascular system: palpitations, increased blood pressure, thrombophlebitis, venous thromboembolism, myocardial infarction.

From the digestive system: nausea, abdominal pain, vomiting, bloating, flatulence.

From the liver and biliary tract: gallbladder diseases, incl. cholestasis.

From the skin and subcutaneous tissues: skin rash, itching, erythema nodosum, eczema, urticaria, hair loss, hirsutism, acne, erythema multiforme, hemorrhagic rash, chloasma.

From the musculoskeletal system: muscle cramps, pain in the lower extremities.

From the reproductive system and mammary gland: endometrial hyperplasia, menorrhagia, abnormal bleeding, dysmenorrhea, change in the nature of vaginal discharge, premenstrual syndrome (PMS) symptom complex, increase in the size of uterine fibroids, candidal vaginitis; feeling of tension, pain in the mammary glands, discharge from the mammary glands, enlargement of the mammary glands; decrease or increase in libido.

General reactions: peripheral edema, increased fatigue, nosebleed.

Contraindications

Hypersensitivity to estradiol valerate; pregnancy, breastfeeding period; diagnosed breast cancer (BC) – in history or suspected, diagnosed or suspected estrogen-dependent tumors (e.g., endometrial cancer), untreated endometrial hyperplasia; presence of venous thrombosis or thromboembolism (VTE) currently or in history (deep vein thrombosis, pulmonary embolism), presence of high-risk factors for the development of venous and arterial thrombosis and thromboembolism, diagnosed congenital or acquired predisposition to arterial or venous thrombosis (e.g., deficiency of protein C, protein S, antithrombin III), arterial thrombosis or thromboembolism (ATE), incl. myocardial infarction, stroke, cerebrovascular disorders or prodromal conditions (incl. transient ischemic attack, angina pectoris); acute liver diseases or severe liver diseases in history (if liver function indicators have not normalized), severe hypertriglyceridemia, porphyria; children and adolescents under 18 years of age.

With caution

Leiomyoma (uterine fibroids) or endometriosis; risk factors for the development of thrombosis and thromboembolism; risk factors for estrogen-dependent tumors, incl. presence in the family history of BC in first-line relatives (mother, sisters); arterial hypertension; benign liver tumors (e.g., liver adenoma); diabetes mellitus with or without diabetic angiopathy; history of hypertriglyceridemia; cholelithiasis; cholestatic jaundice or cholestatic itching in history during previous pregnancy; congenital hyperbilirubinemias (Gilbert, Dubin-Johnson and Rotor syndromes); hereditary angioedema; chronic heart or renal failure; migraine or severe headache; systemic lupus erythematosus; history of endometrial hyperplasia; epilepsy; bronchial asthma; otosclerosis.

In the presence (incl. in history) of the above diseases/conditions or risk factors, Estradiol valerate should be used under careful medical supervision.

Use in Pregnancy and Lactation

Contraindicated for use during pregnancy and lactation (breastfeeding).

Use in Hepatic Impairment

Contraindicated in acute liver diseases or severe liver diseases in history (if liver function indicators have not normalized). Should be used with caution in benign liver tumors (e.g., liver adenoma).

Use in Renal Impairment

Should be used with caution in patients with chronic renal failure.

Pediatric Use

Contraindicated for use in children and adolescents under 18 years of age.

Special Precautions

Estradiol valerate is used mainly as part of combined preparations.

HRT for the treatment of symptoms of estrogen deficiency in postmenopause should be carried out only in the presence of symptoms that adversely affect the quality of life of a woman. A thorough assessment of the benefit-risk ratio of HRT should be carried out at least once a year.

There is limited data regarding the risks associated with HRT in the treatment of premature menopause. Due to the low level of absolute risk in young women, the benefit-risk ratio in them may be more favorable than in older women.

Before starting or resuming HRT after its interruption, it is necessary to collect a detailed individual and family history, conduct a general and gynecological examination (including examination of the mammary glands and pelvic organs). During the therapy, periodic medical examinations are recommended, the frequency and nature of which are determined individually.

Therapy with estradiol valerate should be immediately discontinued if the following conditions occur: jaundice or deterioration of liver function, significant increase in blood pressure, occurrence of migraine-type headache, upon pregnancy.

In women with an intact uterus, the risk of endometrial hyperplasia and cancer increases with HRT in the form of estrogen monotherapy for a long time.

During the first months of using estradiol valerate, spotting or “breakthrough” bleeding is possible. If spotting/vaginal bleeding appears several months after starting estradiol valerate or persists after discontinuation of HRT, an appropriate examination should be performed to exclude malignant neoplasms of the endometrium (including endometrial biopsy). The patient should be informed about the need to inform the attending physician in case of the appearance or continuation of genital bleeding.

Estrogen stimulation can lead to precancerous or malignant transformation in residual foci of endometriosis. In this regard, in the presence of diagnosed residual foci of endometriosis in women with hysterectomy for endometriosis, the addition of a progestogen is required for HRT in the form of estrogen monotherapy.

When conducting HRT, the risk of BC increases in women receiving combined therapy with estrogen and progestogen, and also, possibly, receiving HRT with estrogen only. The risk of developing BC depends on the duration of HRT.

The use of sex hormones may affect the results of certain laboratory tests, including indicators of liver, thyroid, adrenal and kidney function, the concentration of proteins (carriers) in blood plasma, for example, SHBG fraction, and lipid/lipoprotein fractions, coagulation and fibrinolysis parameters, glucose metabolism indicators.

Drug Interactions

The metabolism of estrogens (and progestogens) may increase with the simultaneous use of drugs that induce liver microsomal enzymes (in particular, cytochrome P450 system isoenzymes), such as antiepileptic drugs (phenobarbital, phenytoin, carbamazepine), antibacterial and antiviral drugs (e.g., rifampicin, rifabutin, nevirapine, efavirenz) and, possibly, also felbamate, griseofulvin, oxcarbazepine, topiramate and herbal preparations containing St. John’s wort (Hypericum perforatum).

Increased metabolism of estrogens (and progestogens) may lead to a decrease in their clinical effect and a change in the profile of uterine bleeding.

Induction of liver microsomal enzymes can be observed within a few days of co-administration, maximum enzyme induction is usually observed within a few weeks. After discontinuation of co-administration of the inducer drug and estrogen (and progestogen), induction of liver microsomal enzymes may persist for another 4 weeks.

When used concomitantly with sex hormones, many HIV or hepatitis C virus protease inhibitors and non-nucleoside reverse transcriptase inhibitors can either increase or decrease the plasma concentration of estrogen or progestogen.

Strong and moderate CYP3A4 inhibitors, such as azole antifungal drugs (e.g., fluconazole, itraconazole, ketoconazole, voriconazole), verapamil, macrolides (e.g., clarithromycin, erythromycin), diltiazem, as well as grapefruit juice may increase the plasma concentrations of progestogen or estrogen, or both hormones.

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.