Indivina (Tablets) Instructions for Use

Marketing Authorization Holder

Orion Corporation Orion Pharma (Finland)

ATC Code

G03FA12 (Medroxyprogesterone and estrogens)

Active Substances

Estradiol valerate (Rec.INN registered by WHO)

Medroxyprogesterone (Rec.INN registered by WHO)

Dosage Forms

	Indivina	Tablets 1 mg+2.5 mg: 28 or 84 pcs.
		Tablets 1 mg+5 mg: 28 or 84 pcs.
		Tablets 2 mg+5 mg: 28 or 84 pcs.

Dosage Form, Packaging, and Composition

Tablets are white, round, flat, with a beveled edge and the code “1+2.5” printed on one side.

Excipients: lactose monohydrate, corn starch, gelatin, magnesium stearate.

28 pcs. – blisters (1) – cardboard packs.
28 pcs. – blisters (3) – cardboard packs.

Tablets are white, round, flat, with a beveled edge and the code “1+5” printed on one side.

Excipients: lactose monohydrate, corn starch, gelatin, magnesium stearate.

28 pcs. – blisters (1) – cardboard packs.
28 pcs. – blisters (3) – cardboard packs.

Tablets are white, round, flat, with a beveled edge and the code “2+5” printed on one side.

Excipients: lactose monohydrate, corn starch, gelatin, magnesium stearate.

28 pcs. – blisters (1) – cardboard packs.
28 pcs. – blisters (3) – cardboard packs.

Clinical-Pharmacological Group

Anticlimacteric drug

Pharmacotherapeutic Group

Antimenopausal agent (estrogen + progestogen)

Pharmacological Action

Indivina is a combined anticlimacteric drug containing an estrogen and a progestogen.

Estradiol valerate is an ester of the natural estrogen, estradiol. The pharmacological effects of estradiol are realized through specific estrogen receptors in target tissues. The steroid-receptor complex binds to cellular DNA and stimulates the synthesis of specific proteins.

Medroxyprogesterone acetate is a derivative of natural progesterone – 17-alpha-hydroxy-6-methylprogesterone. Medroxyprogesterone acetate binds to progestin-specific receptors and acts on the endometrium, transforming it from the proliferative phase to the secretory phase.

Estradiol stimulates endometrial proliferation, simultaneously increasing the risk of endometrial hyperplasia and cancer. Medroxyprogesterone acetate counteracts this effect.

Estradiol prevents the development of postmenopausal osteoporosis by reducing bone resorption. This effect is dose-dependent. In postmenopausal women, the drug containing Estradiol valerate at a dose of 1 mg has a less pronounced effect on the mineral density of vertebral bones than at a dose of 2 mg.

In addition, it has been shown that Indivina affects the serum lipid spectrum: it reduces the level of total cholesterol (Ch) and LDL-Ch, increases the level of HDL-Ch, and improves the HDL/Ch ratio.

Indivina is a drug for long-term continuous combined hormone replacement therapy (HRT), which is prescribed to avoid regular withdrawal bleeding associated with cyclic or sequential HRT. In the first months of treatment, breakthrough uterine bleeding and menstrual-like bleeding may sometimes be observed, which decrease and stop over time. After 10-12 months from the start of treatment, amenorrhea was observed in 90% of women who received Estradiol valerate at a dose of 1 mg, and in almost 80% of women who received it at a dose of 2 mg.

Pharmacokinetics

Estradiol valerate

Absorption

After oral administration, it is absorbed from the gastrointestinal tract and rapidly hydrolyzed to estradiol by esterases. C_max is reached within 4-6 hours.

Distribution

Circulating estradiol binds to plasma proteins, mainly to sex hormone-binding globulin and serum albumin.

Metabolism and excretion

It undergoes intensive biotransformation. Its metabolites are excreted in the urine as glucuronide and sulfate conjugates. Estradiol is excreted unchanged in insignificant amounts. An insignificant part of the dose is excreted in the feces.

Medroxyprogesterone acetate

Absorption

Absorption after oral administration is low due to its poor solubility and is characterized by significant individual differences. It is practically not subject to the first-pass effect through the liver. After oral administration of 1 tablet of Indivina, C_max of medroxyprogesterone acetate in plasma is reached within 1-2 hours.

Distribution

It binds to plasma proteins by more than 90% (mainly to albumin).

Metabolism

It undergoes intensive metabolism in the liver by hydroxylation and conjugation. Its metabolism is insufficiently studied, and the pharmacological activity of the metabolites is unknown.

Excretion

With oral administration, T_1/2 is about 24 hours, it is excreted in the urine and with bile.

Indications

• Hormone replacement therapy (HRT) for symptoms of estrogen deficiency.

ICD codes

Dosage Regimen

The drug is prescribed orally, 1 tablet/day daily without interruption. The tablets should be taken at approximately the same time each day.

Treatment with Indivina is recommended to start with tablets containing Estradiol valerate and medroxyprogesterone acetate in a ratio of 1 mg/2.5 mg. Depending on the clinical effect, the dose can be adjusted.

To prevent breakthrough bleeding, the use of Indivina tablets containing 2.5 mg of medroxyprogesterone acetate is usually sufficient. If such bleeding has started and continues, and endometrial pathology is excluded, the dose of medroxyprogesterone acetate can be increased by using 1 mg/5 mg tablets.

If 1 mg of estradiol valerate is insufficient to relieve symptoms of estrogen deficiency, the dose can be increased to 2 mg by using 2 mg/5 mg tablets.

The lowest effective doses should be used for maintenance therapy. Treatment with Indivina can be started on any day if a woman with amenorrhea has not previously received HRT or if a woman has received another combined drug for HRT in a continuous regimen. If a woman has previously received HRT in a cyclic regimen, treatment with Indivina should be started 1 week after the end of the next HRT cycle.

If a scheduled dose of the drug is missed, the tablet should be taken as soon as possible; if the intake is delayed by more than 12 hours, the missed tablet should not be taken. Missing a scheduled dose may cause breakthrough bleeding.

Adverse Reactions

In clinical studies (as the most frequently reported adverse effect), breast tension was described during treatment with Indivina, observed less frequently with the 1 mg dose of estradiol valerate. Uterine bleeding may occur at the beginning of treatment, but it usually decreases or stops with continued treatment. Uterine bleeding is observed more often in cases where treatment was started within the first 2 years after menopause.

From the central nervous system: headache, dizziness, migraine, sleep disorders, mood changes, including anxious and depressive mood, visual disturbances.

From the digestive system: nausea, abdominal pain, dyspepsia, vomiting, flatulence, cholecystitis, cholelithiasis, diarrhea or constipation, increased activity of liver transaminases (ALT and AST), alkaline phosphatase.

From the cardiovascular system: increased blood pressure; rarely – thrombosis, palpitations.

From the endocrine system: alopecia, hirsutism, breast engorgement, increase in myomatous nodes, change in libido.

From the reproductive system: uterine bleeding, vaginal candidiasis.

Allergic reactions: rash, itching, erythema multiforme, erythema nodosum.

Other: fluctuations in body weight, peripheral edema, muscle cramps in the lower extremities, increased GGT activity, lupus syndrome; very rarely – chloasma.

Contraindications

• Current or history of thromboembolic disorders;
• Deep vein thrombophlebitis of the lower extremities;
• Current or history of jaundice;
• Severe liver diseases, including liver tumors, current or history;
• Breast cancer (including suspected or history);
• Acute hepatitis;
• Congenital hyperbilirubinemias (Gilbert’s syndrome, Dubin-Johnson syndrome, Rotor syndrome);
• Hormone-dependent tumors of the endometrium, breast, or other organs;
• Endometriosis;
• Uterine bleeding of unknown etiology;
• Sickle cell anemia;
• Pituitary tumors;
• Severe renal failure;
• Pregnancy (established or suspected);
• Lactation period (breastfeeding);
• Hypersensitivity to the components of the drug.

With caution, the drug should be prescribed for multiple sclerosis, lupus syndrome, epilepsy, convulsive syndrome, diabetes mellitus with vascular complications, for benign breast neoplasms, arterial hypertension (resistant to therapy), chronic renal failure, chronic heart failure, bronchial asthma, porphyria, for otosclerosis with complications during previous pregnancy, for a history of estrogen-dependent tumors, cholelithiasis, severe obesity (including history), migraine.

Use in Pregnancy and Lactation

Indivina is contraindicated for use during suspected or established pregnancy and during lactation.

Use in Hepatic Impairment

Contraindicated in severe liver diseases (including liver tumors) current or history.

Use in Renal Impairment

Contraindicated in severe renal failure.

Special Precautions

Before starting or re-prescribing HRT, it is necessary to collect a complete personal and family history, as well as conduct a thorough general and gynecological examination to identify possible contraindications and observe the necessary precautions when taking the drug. Additional examinations are also recommended during the treatment process. The frequency of examinations and the methods used are determined individually for each specific patient. Breast examination and/or mammography are performed in accordance with accepted standards.

For women receiving HRT, the risk-benefit ratio of the treatment should be periodically carefully assessed.

The benefits and risks of treatment should be weighed especially carefully if there are, have ever occurred, occurred during pregnancy, or during previous courses of hormonal therapy, conditions for which the use of the drug is recommended with caution.

Estrogens can cause fluid retention, so patients with heart failure and impaired renal function require special medical supervision. In end-stage renal disease, particularly careful monitoring is necessary since an increase in the concentration of active substances of Indivina in the blood should be expected.

Some patients receiving estrogen/progestogen therapy may experience changes in glucose tolerance. In diabetes mellitus, blood glucose levels should be monitored during the first months of HRT.

Data from epidemiological studies suggest that HRT is associated with a relatively high risk of developing deep vein thrombosis of the lower extremities or pulmonary embolism. Recognized risk factors for thromboembolic diseases are their presence in personal and family history, severe obesity (body mass index >30 kg/m²), and systemic lupus erythematosus. There is no consensus on the possible role of varicose veins.

Prescribing HRT to patients with a history of recurrent or established deep vein thrombosis of the lower extremities while on anticoagulant therapy requires a careful assessment of the risk-benefit ratio of HRT.

To exclude a predisposition to thrombosis, a history of recurrent thrombosis or recurrent spontaneous abortions should be carefully studied. Until the above diagnosis is made or before starting anticoagulant therapy, the prescription of HRT should be considered contraindicated.

The risk of developing deep vein thrombosis of the lower extremities may temporarily increase with prolonged immobilization, extensive trauma, or major surgery. All patients in the postoperative period should pay special attention to preventive measures aimed at preventing thromboembolic complications. In cases where prolonged immobilization is necessary after surgical operations, in particular after operations on the abdominal organs and orthopedic operations on the lower extremities, the possibility of temporarily stopping HRT 4-6 weeks before surgery should be considered. The decision to resume HRT is made individually for each specific case.

If thrombosis develops after starting HRT, Indivina should be discontinued.

Patients should be instructed to immediately consult a doctor if pain and swelling of the lower extremities, sudden chest pain, or dyspepsia occur.

Data from epidemiological studies have shown some increase in the likelihood of developing breast cancer in women who have previously received or are currently receiving HRT. The detection of breast cancer may be associated with early diagnosis, the biological effects of HRT, or a combination of both factors. The likelihood of developing breast cancer increases with the duration of treatment and returns to the baseline level 5 years after stopping HRT.

In postmenopausal women receiving estrogens, the risk of developing cholelithiasis increases; during HRT, the risk of developing systemic lupus erythematosus increases.

With estrogen therapy, an increase in plasma triglyceride levels is possible, which in some cases contributes to the development of pancreatitis and other complications in patients with congenital defects of lipoprotein metabolism.

Breakthrough uterine bleeding and mild menstrual-like bleeding may be observed in the first months of treatment. If, despite dose adjustment, such bleeding does not stop, the drug should be discontinued until the cause of the bleeding is established. If bleeding recurs after a period of amenorrhea or continues after discontinuation of treatment, its etiology should be established. In this case, an endometrial biopsy may be required.

Against the background of estrogen use, changes in the results of glucose tolerance tests, thyroid function tests, and liver function tests are possible.

Clinical experience with the drug in women over 65 years of age is limited.

Effect on the ability to drive vehicles and mechanisms

Indivina does not affect the ability to drive vehicles and operate machinery.

Overdose

Symptoms: in case of estrogen overdose, nausea, headache, and uterine bleeding are possible. According to numerous reports of accidental ingestion of high doses of estrogen-containing oral contraceptives by young children, this does not cause serious consequences.

The use of medroxyprogesterone acetate in high doses in oncology practice does not lead to the development of serious side effects.

Treatment: symptomatic therapy is carried out.

Drug Interactions

The estrogenic effect of Indivina may decrease with simultaneous use with antihypertensive drugs, indirect anticoagulants, oral hypoglycemic drugs, hydantoin, ampicillin, tetracycline, as well as with inducers of microsomal liver enzymes (barbiturates, phenytoin, carbamazepine, griseofulvin, rifampicin).

The estrogenic effect of Indivina may increase with simultaneous use with drugs that inhibit microsomal oxidation (ketoconazole, cyclosporine).

Storage Conditions

The drug should be stored in the original packaging in a place inaccessible to children at a temperature not exceeding 30°C (86°F).

Shelf Life

The shelf life is 3 years.

Dispensing Status

The drug is dispensed by prescription.

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.