Revmelid^® (Tablets) Instructions for Use

Marketing Authorization Holder

Gedeon Richter, Plc. (Hungary)

ATC Code

G03FA01 (Norethisterone and estrogens)

Active Substances

Estradiol (Rec.INN registered by WHO)

Norethisterone (Rec.INN registered by WHO)

Dosage Form

Revmelid®

Film-coated tablets, 1 mg+0.5 mg: 28 pcs.

Dosage Form, Packaging, and Composition

Film-coated tablets white or almost white, round, biconvex, with “G33” engraved on one side; on the break: the core is white or almost white; the shell is white or almost white.

Excipients : colloidal silicon dioxide – 0.35 mg, potato starch – 0.75 mg, magnesium stearate – 0.75 mg, povidone – 1.5 mg, talc – 1.5 mg, corn starch – 22.58 mg, lactose monohydrate – 46.035 mg.

Shell composition colloidal silicon dioxide – 0.054 mg, titanium dioxide (E171) – 0.192 mg, macrogol – 0.332 mg, sepifilm 003 – 4.422 mg: macrogol-40 stearate (E431) – 8-12%, microcrystalline cellulose (E460) – 35-45%, hypromellose (E464) – 45-55%.

28 pcs. – blisters (1) – cardboard packs.

Clinical-Pharmacological Group

Anticlimacteric drug

Pharmacotherapeutic Group

Combined antimenopausal agent (estrogen + gestagen)

Pharmacological Action

A combined medicinal product containing an estrogen and a progestogen intended for continuous hormone replacement therapy.

Estradiol: the active ingredient, synthetic 17β-Estradiol, is identical in chemical structure and biological properties to endogenous human estradiol. It eliminates estrogen deficiency in postmenopausal women and reduces the severity of menopausal symptoms. Estrogens prevent the decrease in bone mineralization caused by menopause or oophorectomy.

Norethisterone: the additional administration of a progestogen significantly reduces the risk of endometrial hyperplasia caused by estrogens in women who have not undergone hysterectomy.

It is not a contraceptive.

Pharmacokinetics

The active substances are absorbed from the gastrointestinal tract.

After taking estradiol, the time to reach C_max is 5-8 hours, C_max is 35 pg/ml (21-52 pg/ml). Protein binding: with albumin – 61%, with globulins – 37%, 1-2% is in unbound form. T_1/2 is 12-14 hours.

Estradiol is metabolized in the liver to form estrone, catecholestrogens, estrogen sulfates and glucuronides.

It is excreted by the kidneys as metabolites and partially unchanged, a small amount is excreted through the intestines.

Estrogens pass into breast milk.

After oral administration, norethisterone acetate is rapidly absorbed and converted to Norethisterone. The time to reach C_max is 0.5-1.5 hours, C_max is 3.9 ng/ml (1.4-6.8 ng/ml). Protein binding: with albumin – 61%, with globulins – 36%. T_1/2 is 8-11 hours.

It is metabolized in the liver to form 5-alpha-dihydro-norethisterone and tetrahydronorethisterone, which are excreted mainly in the urine as sulfate and glucuronide conjugates.

Indications

Climacteric disorders in the postmenopausal period (not earlier than 1 year after menopause): “hot flashes”, increased sweating, sleep disorders, irritability, depression, forgetfulness, postmenopausal osteoporosis, degenerative changes in the skin and mucous membranes (brittle nails, thinning skin, wrinkle formation, dryness of the mucous membranes of the urogenital organs).

Prevention of postmenopausal osteoporosis (belonging to the European or Asian race, short stature, underweight, early menopause, family history of osteoporosis, insufficient dietary Ca²⁺ intake, physical inactivity, smoking, ethanol abuse).

ICD codes

Dosage Regimen

Take one tablet orally once daily, at approximately the same time each day.

Swallow the tablet whole with a small amount of water, with or without food.

Begin treatment no earlier than one year after the last spontaneous menstrual period (confirmed postmenopausal status).

Continue therapy for as long as the therapeutic benefit for menopausal symptom relief or osteoporosis prevention outweighs the potential risks.

Adhere strictly to the prescribed regimen; do not exceed the recommended daily dose.

If a dose is missed and less than 12 hours have passed, take the missed tablet immediately. If more than 12 hours have passed, skip the missed dose and continue the regular schedule. Do not take a double dose to compensate for a missed one.

In case of persistent vaginal bleeding or breakthrough bleeding occurring after the initial months of therapy, consult a physician for gynecological investigation.

Immediately discontinue use if pregnancy is confirmed, jaundice occurs, a significant increase in blood pressure is detected, or a migraine-type headache develops for the first time.

Prior to major elective surgery requiring prolonged immobilization, consider discontinuing therapy 4 to 6 weeks beforehand. Do not resume treatment until full mobility is restored.

Adverse Reactions

From the digestive system abdominal pain, flatulence, cholelithiasis, cholecystitis.

From the skin and subcutaneous tissue: alopecia, hirsutism, acne, skin itching, urticaria, skin rash, chloasma, exudative polymorphic erythema, erythema nodosum, vascular purpura.

From the cardiovascular system increased blood pressure, cerebrovascular accident, myocardial infarction.

From the nervous system headache, migraine or worsening of migraine, dizziness, depression, worsening of its course, irritability, dementia, insomnia, anxiety, change in libido

From the musculoskeletal system calf muscle cramps, back pain, arthralgia, myalgia.

From the blood coagulation system thromboses, thromboembolism.

From the reproductive system: breast pain or tenderness, vaginal bleeding, breast swelling or enlargement, uterine fibrosis, worsening of uterine fibrosis or relapse, endometrial hyperplasia, dysmenorrhea, breast cancer, vulvovaginal itching, vaginal candidiasis or vaginitis.

Other : visual impairment, fluid retention, peripheral edema, weight gain, estrogen-dependent benign and malignant tumors.

Contraindications

Hypersensitivity; pregnancy; lactation period; acute or chronic liver diseases; hepatic insufficiency; liver cancer; congenital hyperbilirubinemias (Gilbert, Dubin-Johnson and Rotor syndromes); hemangioma; cerebrovascular accidents (ischemic stroke, hemorrhagic stroke); breast cancer and suspicion of it; endometrial cancer; hyperlipoproteinemia; idiopathic jaundice (including during previous pregnancy); herpes (in history); vaginal bleeding; metrorrhagia of unclear genesis; coronary artery disease; atherosclerosis; heart disease; myocarditis, deep vein thrombophlebitis, thrombosis or thromboembolic diseases in the active phase or recently suffered (deep vein thrombosis, pulmonary embolism)/

With caution

Migraine, epilepsy, depression, severe headache, diabetes mellitus, diabetic angiopathy, bronchial asthma, chronic heart failure, otosclerosis, multiple sclerosis, arterial hypertension, hyperlipoproteinemia, idiopathic jaundice (including during previous pregnancy), thromboembolic disease, liver diseases with normal functional tests (including porphyria) and gallbladder diseases, leiomyoma, endometriosis, endometrial hyperplasia, breast fibroadenoma, estrogen-dependent tumors, uterine fibroids, mastopathy, ulcerative colitis, renal failure.

Use in Pregnancy and Lactation

Contraindicated during pregnancy and lactation (breastfeeding)

Use in Hepatic Impairment

Contraindicated in acute or chronic liver diseases, hepatic insufficiency, liver cancer.

With caution liver diseases with normal functional tests (including porphyria).

Use in Renal Impairment

With caution renal failure.

Pediatric Use

The drug is contraindicated for use in children and adolescents under 18 years of age

Special Precautions

Hormone replacement therapy is intended only for the treatment of those climacteric symptoms that interfere with the patient’s daily life. The benefit/risk assessment of treatment is carried out throughout the entire course of treatment, it is necessary to conduct periodic medical examinations, the frequency of which is established individually, but not less than once every 6 months, and which include blood pressure measurement, examination of the mammary glands, abdominal and pelvic organs, gynecological examination (including analysis of a cytological smear of the cervix and ultrasound examination to exclude endometrial hyperplasia).

Treatment with the drug is carried out only in women whose last menstruation was at least 1 year ago.

Conditions requiring immediate discontinuation of treatment: jaundice or impaired liver function; significant increase in blood pressure; the appearance of migraine-type headache; pregnancy.

In the first months of treatment, vaginal bleeding or spotting may occur. If such bleeding occurs at later stages of treatment, or continues after its cessation, a re-examination should be performed, possibly with endometrial biopsy to exclude a malignant neoplasm.

An increased risk of VTE is observed in the presence of a history of VTE or thrombophilia conditions. HRT may increase the degree of such risk. In the presence of a personal or family history of thromboembolism or repeated cases of spontaneous abortions, the patient should be examined to exclude a predisposition to thrombophilia. Prescription of HRT to such women is contraindicated until a thorough assessment of thrombophilic factors has been carried out or anticoagulant treatment has been started. The benefit/risk ratio of HRT use in women taking anticoagulants should be carefully weighed. The risk of VTE may temporarily increase with prolonged immobilization, extensive trauma, or radical surgery. In the postoperative period, careful attention should be paid to preventive measures to prevent cases of VTE. When planning surgery involving prolonged patient immobilization, in particular abdominal surgery or lower limb orthopedic surgery, HRT should be temporarily suspended, if possible, 4-6 weeks before surgery. Treatment should not be resumed until the woman has regained full mobility.- If VTE develops after starting treatment, the drug should be discontinued. Patients should be warned about the need to immediately seek medical help if signs of VTE appear (painful swelling of the lower limb, sudden chest pain, shortness of breath).

Patients with heart and kidney diseases require careful monitoring, because estrogens can cause fluid retention in the body.

When treating with this combination in the terminal stage of renal failure, strict medical supervision should be ensured due to a possible increase in plasma concentrations of active substances. Treatment of women with estrogens with pre-existing hypertriglyceridemia requires increased caution due to the danger of a significant increase in blood triglyceride concentrations with the subsequent development, in rare cases, of pancreatitis.

Estrogens increase the concentration of thyroxine-binding globulin, which leads to an increase in the total concentration of circulating thyroid hormones, determined by the content of protein-bound iodine, the concentration of thyroxine or triiodothyronine. The concentrations of free thyroxine and triiodothyronine remain unchanged. The concentrations of other serum binding proteins may increase, including corticosteroid-binding globulin, sex hormone-binding globulins, which leads to an increase in the concentrations of circulating corticosteroids and sex hormones, respectively. The concentrations of free or biologically active hormones remain unchanged.

Drug Interactions

Barbiturates, antiepileptic drugs (carbamazepine, phenytoin) enhance the metabolism of steroid hormones.

Antibiotics (ampicillin, rifampicin), by changing the intestinal microflora, reduce the effective concentration.

General anesthetics, narcotic analgesics, anxiolytics, antiepileptic drugs, some antihypertensive drugs, ethanol reduce effectiveness.

When co-administered, adjustment of the dosage regimen of hypoglycemic drugs may be required.

Preparations containing St. John’s wort (Hypericum perforatum) may stimulate the metabolism of estrogens and progestogens.

Storage Conditions

Store at 15°C (59°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.