Diagama

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT DIAGMA (DIAGAMMA)

Composition:

Active substances: thiamine hydrochloride, pyridoxine hydrochloride, cyanocobalamin;

1 ml of solution contains thiamine hydrochloride (calculated as 100 % substance) 50 mg, pyridoxine hydrochloride (calculated as 100 % substance) 50 mg, cyanocobalamin (calculated as 100 % substance) 0.5 mg;

Excipients: lidocaine hydrochloride, benzyl alcohol, sodium polyphosphate, potassium ferrocyanide, sodium hydroxide, water for injections.

Pharmaceutical form. Injection solution.

Main physicochemical properties: clear red-colored liquid.

Pharmacotherapeutic group. Vitamin B1 preparations in combination with vitamin B6 and/or vitamin B12. ATC code A11DB.

Pharmacological Properties

Pharmacodynamics

Neurotropic vitamins of the B group exert beneficial effects on inflammatory and degenerative diseases of nerves and the musculoskeletal system. They are used to correct deficiency states. In high doses, they possess analgesic properties, improve circulation, and help normalize nervous system function and hematopoiesis.

Vitamin B1 is a highly important active substance. In the body, vitamin B1 is phosphorylated to form biologically active thiamine diphosphate (cocarboxylase) and thiamine triphosphate (TTP).

Thiamine diphosphate acts as a coenzyme involved in key carbohydrate metabolism processes, which are crucial for metabolic activities in nervous tissue and influence nerve impulse transmission in synapses. In vitamin B1 deficiency, metabolites accumulate in tissues—primarily lactic and pyruvic acids—leading to various pathological conditions and disturbances in nervous system function.

Vitamin B6 in its phosphorylated form (pyridoxal-5’-phosphate, PLP) serves as a coenzyme for several enzymes involved in general non-oxidative amino acid metabolism. Through decarboxylation, these enzymes contribute to the formation of physiologically active amines (adrenaline, histamine, serotonin, dopamine, tyramine). Through transamination, they participate in anabolic and catabolic metabolic processes (e.g., glutamate-oxaloacetate transaminase, glutamate-pyruvate transaminase, γ-aminobutyric acid, α-ketoglutarate transaminase), as well as in various processes of amino acid breakdown and synthesis. Vitamin B6 acts at four different stages of tryptophan metabolism. In hemoglobin synthesis, vitamin B6 catalyzes the formation of α-amino-β-keto-adipic acid.

Vitamin B12 is essential for cellular metabolic processes. It influences hematopoietic function (as an extrinsic anti-anemic factor), participates in the formation of choline, methionine, creatinine, and nucleic acids, and exerts analgesic effects.

Pharmacokinetics

After parenteral administration, thiamine is distributed throughout the body. Approximately 1 mg of thiamine is degraded daily. Metabolites are excreted in urine. Defosphorylation occurs in the kidneys. The biological half-life of thiamine is 21 minutes. Thiamine does not accumulate in the body due to its limited lipid solubility.

Vitamin B6 is phosphorylated and oxidized to pyridoxal-5-phosphate. In blood plasma, pyridoxal-5-phosphate and pyridoxal bind to albumin. Pyridoxal is the transport form. To cross the cell membrane, albumin-bound pyridoxal-5-phosphate is hydrolyzed by alkaline phosphatase into pyridoxal.

After parenteral administration, vitamin B12 forms transport protein complexes that are rapidly absorbed by the liver, bone marrow, and other proliferative tissues. Vitamin B12 is excreted into bile and participates in enterohepatic circulation. Vitamin B12 crosses the placenta.

Clinical characteristics.

Indications.

Systemic neurological disorders caused by a confirmed deficiency of vitamins B1, B6, and B12, when they cannot be corrected by dietary intake.

Contraindications.

Hypersensitivity to the components of the medicinal product; acute impairment of cardiac conduction; acute form of decompensated heart failure.

Vitamin B1 is contraindicated in allergic reactions.

Vitamin B6 is contraindicated in peptic ulcer of the stomach and duodenum in the acute phase (due to possible increase in gastric juice acidity).

Vitamin B12 is contraindicated in erythremia, erythrocytosis, and thromboembolism.

Lidocaine. Hypersensitivity to lidocaine or to other amide-type local anesthetics, history of lidocaine-induced epileptiform seizures, severe bradycardia, severe arterial hypotension, cardiogenic shock, severe forms of chronic heart failure (grades II–III), sinus node dysfunction syndrome, Wolff-Parkinson-White syndrome, Adams-Stokes syndrome, second- and third-degree atrioventricular (AV) block, hypovolemia, severe hepatic/renal dysfunction, porphyria, myasthenia gravis.

Pregnancy and breastfeeding period.

Interaction with other medicinal products and other types of interactions.

Thiamine is completely degraded by sulfite-containing solutions. Other vitamins may be inactivated in the presence of vitamin B1 degradation products. Therapeutic doses of vitamin B6 may reduce the effect of L-dopa. Other interactions occur with isoniazid, D-penicillamine, and cycloserine.

When lidocaine is administered parenterally, cardiac adverse effects may be potentiated by epinephrine or norepinephrine. Other interactions exist with sulfonamides.

In case of overdose of local anesthetics, epinephrine and norepinephrine must not be used.

Special precautions for use

Dygama contains lidocaine hydrochloride; therefore, the medicinal product should be administered only by intramuscular injection. Intravenous (i.v.) administration into the bloodstream is not permitted. In the event of accidental intravenous injection, medical monitoring or hospital observation is required depending on the severity of symptoms that arise.

Prolonged use of vitamin B6 (more than 6 months) may lead to reversible peripheral sensory neuropathy.

The medicinal product contains sodium compounds (23 mg of sodium per 2 ml) per unit dose (ampoule); therefore, this preparation is practically "sodium-free".

Dygama contains benzyl alcohol.

Benzyl alcohol has been associated with a risk of serious adverse effects ("gasping syndrome") in newborns and young children.

Due to the risk of accumulation and toxicity (metabolic acidosis), large amounts of benzyl alcohol should be used only with caution and only when absolutely necessary, especially in individuals with impaired liver or kidney function, as well as during pregnancy and breastfeeding.

Use during pregnancy or breastfeeding

During pregnancy, the recommended daily intake of vitamin B1 is 1.2 mg in the 2nd trimester and 1.3 mg in the 3rd trimester, while the recommended daily intake of vitamin B6 is 1.9 mg from the 4th month of pregnancy. During pregnancy, the use of this medicinal product should be limited to cases where vitamin B1 and B6 deficiency has been confirmed, as the safety of doses exceeding the recommended daily amounts has not been established.

Breastfeeding period. During breastfeeding, the recommended daily intake of vitamin B1 is 1.3 mg and of vitamin B6 is 1.9 mg.

Vitamins B1, B6, and B12 pass into breast milk. High doses of vitamin B6 may reduce milk production.

The medicinal product contains 100 mg of vitamin B6 per ampoule; therefore, it should not be used during pregnancy and/or breastfeeding.

The decision on using this medicinal product during pregnancy and breastfeeding should be made by a physician only after careful assessment of the risk-benefit ratio.

Ability to influence reaction speed when driving vehicles or operating machinery

The medicinal product does not affect the ability to drive vehicles or operate complex machinery.

However, if dizziness occurs during treatment with this product, driving vehicles or operating machinery should be avoided.

Method of Administration and Dosage

Dosage.

In severe (acute) cases, treatment should be initiated with 2 ml of the solution administered intramuscularly once daily until acute symptoms subside. For continuation of therapy and in mild cases, administer 2 ml (1 injection) 2–3 times per week.

Weekly medical supervision is recommended throughout the course of therapy.

To maintain or continue the therapeutic course of injections or to prevent relapse, oral medications of a similar pharmacotherapeutic group are recommended.

Method of Administration.

Injections are administered deep intramuscularly (i.m.).

Intramuscular injection should be performed into the upper outer quadrant of the gluteal muscle.

Warning on Prevention of Accidental Intravenous Injection.

Diagami is intended for intramuscular (i.m.) use only. Intravenous (i.v.) administration into the circulatory system is not permitted. In case of accidental intravenous injection, medical monitoring or hospital observation is required depending on the severity of symptoms.

Children.

This medicinal product must not be used in children.

Overdose.

Overdose results in an intensification of the drug's adverse effects.

Vitamin B1 has a wide therapeutic range. Very high doses (more than 10 g) may produce curare-like effects, suppressing nerve impulse conduction.

Vitamin B6 has very low toxicity.

Excessive use of vitamin B6 in doses exceeding 1 g per day over several months may lead to neurotoxic effects.

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 more than 2 g per day.

Vitamin B12: following parenteral administration (rarely also after oral use) of doses higher than recommended, allergic reactions, eczematous skin disorders, and benign forms of acne have been observed.

Prolonged use in high doses may lead to impaired liver enzyme activity, chest pain, and hypercoagulability.

Treatment: symptomatic therapy.

Lidocaine. Symptoms: psychomotor excitation, dizziness, general weakness, decreased arterial pressure, tremor, visual disturbances, tonic-clonic seizures, coma, collapse, possible atrioventricular block, central nervous system depression, respiratory arrest. Initial symptoms of overdose in healthy individuals occur at blood lidocaine concentrations exceeding 0.006 mg/kg; seizures occur at 0.01 mg/kg.

Treatment: discontinue administration of the drug, oxygen therapy, anticonvulsants, vasoconstrictors (norepinephrine, mesaton), in case of bradycardia – anticholinergics (0.5–1 mg atropine). Endotracheal intubation, artificial ventilation of the lungs, and resuscitation measures may be necessary. Dialysis is ineffective.

Side effects

The frequency of adverse reactions is defined as follows:

Very common: (≥1/10);
Common: (≥1/100 to <1/10);
Uncommon: (≥1/1000 to <1/100);
Rare: (≥1/10,000 to <1/1,000);
Very rare: (<1/10,000);
Not known: (frequency cannot be estimated from the available data).

Immune system disorders:
Not known: benzyl alcohol may cause allergic reactions;
Very rare: hypersensitivity reactions (e.g., exanthema, dyspnea, shock, angioneurotic edema).

Skin and subcutaneous tissue disorders:
Very rare: skin reactions with itching and urticaria, acneiform eruptions, sweating.

Cardiovascular system disorders:
Very rare: tachycardia.

General disorders and administration site conditions:
Not known: systemic reactions may occur due to rapid accumulation (e.g., accidental intravenous injection, injection into tissue with high blood supply) or overdose. Dizziness, vomiting, bradycardia, cardiac arrhythmias, and seizures are possible.
Burning sensation at the injection site.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after marketing authorization is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals and patients, as well as their legal representatives, are encouraged to report all suspected adverse reactions and lack of efficacy via the automated pharmacovigilance information system at: https://aisf.dec.gov.ua.

Shelf life.
2 years.

Storage conditions.
Keep out of reach of children. Store in the original packaging at a temperature of 2 °C to 8 °C.

Incompatibilities.
Thiamine is incompatible with oxidizing and reducing agents: mercury chloride, iodides, carbonates, acetates, tannic acid, iron-ammonium citrate, as well as with sodium phenobarbital, riboflavin, benzylpenicillin, glucose, and metabisulfite, as it becomes inactivated in their presence. Copper accelerates thiamine degradation; in addition, thiamine loses its activity at increased pH values (above 3).

Vitamin B12 is incompatible with oxidizing and reducing agents and with heavy metal salts.

In solutions containing thiamine, vitamin B12 and other components of the B-complex group are rapidly degraded by thiamine breakdown products (low concentrations of iron ions may offer protection). Riboflavin, particularly under exposure to light, also exerts a degrading effect; nicotinamide accelerates photolysis, whereas antioxidants exert an inhibitory effect.

Packaging.
2 ml in a vial; 5 vials in a blister pack, 1 blister pack in a carton.

Prescription status.
Prescription only.

Marketing Authorization Holder.
Limited Liability Company "SYSTEM PHARM".

Address of the Marketing Authorization Holder.
100/5 Shevchenka Street, Boryspil, Kyiv Oblast, 08300, Ukraine.

Manufacturer.
Private Joint Stock Company "LEKHEM-KHARKIV".

Manufacturer's address and site of manufacturing activity.
36 Severin Pototskoho Street, Kharkiv, Kharkiv Oblast, 61115, Ukraine.