Hepadiff®

INSTRUCTION for medical use of the medicinal product HEPADIF® (HEPADIF)

Composition:

Active substances: one vial contains carnitine orotate 300.0 mg (equivalent to orotic acid 147.6 mg, carnitine 152.4 mg), carnitine hydrochloride 184.0 mg (equivalent to carnitine 150.0 mg), detoxifying fraction of liver extract 25.0 mg (cyanocobalamin content not less than 0.00025 mg), adenosine 5.0 mg, pyridoxine hydrochloride 25.0 mg, cyanocobalamin 0.25 mg;

Excipients: mannitol (E 421), methylparahydroxybenzoate (E 219), propylparahydroxybenzoate (E 217).

Pharmaceutical form. Powder for solution for injection.

Main physicochemical properties: heterogeneous porous mass from light pink to brownish-pink in color.

Pharmacotherapeutic group. Agents affecting the digestive system and metabolic processes. Combinations with amino acids. ATC code A16AA.

Pharmacological properties.

Pharmacodynamics.

Gepadif® is a combination drug whose effects are due to the combined action of its components. It stimulates fat metabolism – specifically the β-oxidation of free fatty acids in hepatocyte mitochondria – and biosynthetic processes, prevents hepatocyte necrosis, normalizes hepatocyte proliferation, regulates the hepatic enzyme system, and restores normal liver function. The presence of adenosine, a component of coenzymes and nucleic acids, ensures regulation of hematopoietic processes. B-group vitamins (cyanocobalamin, pyridoxine) regulate redox processes and participate in protein, lipid, and carbohydrate metabolism, as well as in the metabolism of tryptophan, methionine, cysteine, glutamic acid, and other amino acids. Pyridoxine promotes normalization of lipid metabolism and supports the function of the peripheral and central nervous systems. Cyanocobalamin participates in transmethylation processes, hydrogen transport, and the formation of methionine, nucleic acids, choline, and creatine. It helps normalize impaired functions of the liver, nervous system, and hematopoietic system, and enhances tissue regenerative capacity. Cyanocobalamin and pyridoxine reduce fatty infiltration of the liver and lower hyperhomocysteinemia.

Carnitine regulates fat metabolism, promotes the breakdown of long-chain fatty acids, shifts fatty acid metabolic shunting toward carbohydrates, reduces indicators of hepatic fatty dystrophy, and improves food assimilation.

The detoxifying fraction of liver extract contains essential and non-essential amino acids that participate in protein synthesis, act as donors of sulfhydryl and methyl groups, and exert detoxifying and antioxidant effects.

The drug stimulates bile secretion, supports digestion processes, facilitates carbohydrate absorption in the small intestine, and is necessary for maintaining normal intestinal microflora. It enhances glycogen-fixing, synthetic, and detoxifying functions of the liver, increases cellular sensitivity to insulin, and promotes insulin release.

Pharmacokinetics.

After intravenous infusion, the distribution of the drug's active components – water-soluble B-group vitamins (cyanocobalamin, pyridoxine), carnitine, the detoxifying fraction of bovine liver extract, and adenosine – occurs predominantly in the liver and kidneys. Pyridoxine is metabolized in the liver to form pharmacologically active metabolites (pyridoxal phosphate, pyridoxamine phosphate) and is distributed into muscles, liver, and the central nervous system. Elimination occurs primarily via the kidneys.

Clinical characteristics.

Indications.

As part of complex therapy:

• Acute and chronic hepatitis, liver cirrhosis;
• Fatty liver disease (hepatic steatosis);
• Alcohol-induced liver damage;
• Intoxication due to prolonged use of antineoplastic and antituberculosis agents.

Contraindications.

Hypersensitivity to the components of the drug. Nephrolithiasis, erythremia, erythrocytosis, thromboembolism, peptic ulcer of the stomach and duodenum in the stage of exacerbation.

Interaction with other medicinal products and other types of interactions.

Vitamin B6 reduces the effect of levodopa and prevents or diminishes toxic manifestations observed during the use of isoniazid and other antituberculosis drugs.

PAS, cimetidine, calcium preparations, and ethanol reduce vitamin B12 absorption.

Interactions due to the presence of cyanocobalamin

• Aminoglycosides, salicylates, antiepileptic drugs, colchicine, potassium preparations* reduce the absorption of the drug and affect its kinetics.

When used concomitantly with kanamycin, neomycin, polymyxins, tetracyclines, absorption of cyanocobalamin is reduced.

Pharmaceutically incompatible with ascorbic acid, heavy metal salts (inactivation of cyanocobalamin); thiamine bromide, pyridoxine, riboflavin (the cobalt ion present in the cyanocobalamin molecule destroys other vitamins).

Thiamine – increased risk of thiamine-induced allergic reactions.

Chloramphenicol – reduces the hematopoietic response to the drug.

Citamen – the effect of Citamen is reduced when used concomitantly.

Oral contraceptives – reduce cyanocobalamin blood concentration.

Interactions due to the presence of pyridoxine hydrochloride

Diuretics – combined use with pyridoxine enhances the diuretic effect.

Hormonal contraceptives, cycloserine, penicillamine, isoniazid, hydralazine sulfate, ethionamide, immunosuppressants – combined use with pyridoxine reduces the effect of pyridoxine.

Sedatives and hypnotics – combined use with pyridoxine reduces the hypnotic effect.

Antiparkinsonian agents – combined use with pyridoxine reduces the effectiveness of Parkinson's disease treatments.

Phenytoin – combined use with pyridoxine reduces the effect of phenytoin.

Corticosteroids – combined use with pyridoxine reduces the amount of vitamin B6 in the body.

Glutamic acid, asparkam – combined use with pyridoxine increases resistance to hypoxia.

Cardiac glycosides – combined use with pyridoxine enhances the synthesis of contractile proteins in the myocardium.

Tricyclic antidepressants – combined use with pyridoxine alleviates side effects of tricyclic antidepressants related to their anticholinergic activity (dry mouth, urinary retention).

Resorptive-acting levomycetin preparations – combined use with pyridoxine prevents ophthalmological complications arising from prolonged use of resorptive-acting levomycetin preparations (sintomycin, chloramphenicol).

Special precautions for use.

Use with caution in patients with a history of peptic ulcer disease of the stomach and duodenum (due to possible increase in gastric juice acidity), severe heart and kidney diseases, and neoplasms.

The use of the drug may lead to false-positive urobilinogen tests when using Ehrlich's reagent.

Parenteral administration of vitamin B12 may temporarily affect the diagnosis of subacute combined degeneration of the spinal cord or pernicious anemia.

Cyanocobalamin should not be used with drugs that increase blood coagulation.

Caution is required and blood coagulation should be monitored in patients with a tendency to thrombosis and in patients with angina pectoris during treatment.

Alcoholic beverages should not be consumed during treatment.

Use during pregnancy or breastfeeding.

No adverse effects of the drug during pregnancy or breastfeeding have been reported. However, when prescribing Hepadif® to pregnant women or women who are breastfeeding, the benefit of using the drug should be carefully weighed against the potential risk to the fetus/child.

Ability to affect reaction speed when driving or operating machinery.

No adverse effects on the ability to drive or operate machinery have been reported.

Dosage and Administration

Hepadif® should be administered intravenously by infusion once daily. The average daily dose for adults is 8.625 mg of powder/kg body weight – the contents of 1 vial of the drug dissolved in 400–500 mL of 5% glucose solution. The maximum daily dose is 17.25 mg of powder/kg body weight – the contents of 2 vials of the drug dissolved in 400–500 mL of 5% glucose solution.

Dose adjustment is not required for elderly patients.

Children aged 7–14 years: the daily dose of the drug does not differ from the average daily dose for adults. The dose should be individually prescribed by a physician.

The duration of treatment depends on the course of the underlying disease and is determined individually by the physician.

Children

The drug is indicated for children aged 7 years and older.

Overdose

Symptoms: nausea, vomiting, diarrhea, and increased incidence of adverse reactions. With prolonged use at high doses, peripheral neuropathy may occur.

Pyridoxine hydrochloride. Prolonged use of vitamin B6 (more than 6–12 months) at doses exceeding 50 mg daily or doses greater than 1000 mg per day (over 2 months) may lead to reversible peripheral sensory neuropathy. If symptoms of peripheral sensory neuropathy (paresthesia) occur, the drug dosage should be adjusted and, if necessary, treatment discontinued.

Sensory neuropathies with ataxia and sensory disturbances, cerebral convulsions with EEG changes, and in isolated cases hypochromic anemia and seborrheic dermatitis have been reported after administration of doses exceeding 2 g per day.

Cyanocobalamin. After parenteral administration (rarely after oral administration) of doses higher than recommended, allergic reactions, eczematous skin disorders, and benign forms of acne have been observed.

With prolonged use at high doses, possible disturbances in liver enzyme activity, chest pain, and hypercoagulation may occur.

Treatment: gastric lavage, administration of activated charcoal, and hyperosmotic laxatives.

Adverse reactions.

The drug is usually well tolerated.

Blood-related: hypercoagulation.

Cardiovascular system: tachycardia, chest pain.

Nervous system: headache, dizziness, nervous excitement, drowsiness, coordination disturbances, paresthesia, numbness in extremities, sensation of constriction in extremities – "gloves and socks" symptom, loss of consciousness and development of seizures with rapid intravenous administration.

Respiratory system: dyspnea.

Metabolic disturbances: acne, bullous eruptions, nausea, sweating, purine metabolism disturbances, decreased folic acid levels.

Immune system: allergic reactions (hypersensitivity reactions), including skin manifestations such as erythema, urticaria, rash, pruritus, dermatitis, photosensitization, edema, including Quincke's edema; respiratory disturbances, including asthma attacks, anaphylactic shock, angioneurotic edema, anaphylactoid reactions.

Gastrointestinal tract: dyspepsia, abdominal pain and discomfort, epigastric pain, heartburn, increased gastric secretion, nausea, vomiting, diarrhea, constipation, loose stools.

Reproductive system and mammary glands: suppression of lactation during lactation period.

General disorders: malaise, weakness, fever.

Local reactions: injection site reactions including hyperemia, burning, pruritus, pain, swelling, induration, and necrosis at the injection site.

The presence of methylparahydroxybenzoate (E 219) and propylparahydroxybenzoate (E 217) in the formulation may cause allergic reactions (possibly delayed), and in individual cases – bronchospasm.

Incompatibility.

Use only the diluents specified in the instructions.

Do not mix with other medicinal products in the same container.

Shelf life.

3 years.

The drug must not be used after the expiry date stated on the packaging.

Storage conditions.

Store in original packaging at a temperature not exceeding 25 °C.

Keep out of reach of children.

Packaging.

942.05 mg of powder in a glass vial. 1, 5, or 10 vials per cardboard pack.

Prescription status.

Prescription only.

Manufacturer.

LLC "VALARTIN PHARMA".

Manufacturer's name and address of business location.

60, Hrushevskoho St., village Chayky, Kyiv-Sviatoshyn district, Kyiv region, 08135, Ukraine.