Milgamma®

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT MИЛЬГАМА® (MILGAMMA®)

Composition:

Active substances: 1 ml of solution contains thiamine hydrochloride 50 mg, pyridoxine hydrochloride 50 mg, cyanocobalamin 500 μg;

Excipients: lidocaine hydrochloride, benzyl alcohol, sodium polyphosphate, potassium hexacyanoferrate(III), sodium hydroxide, water for injections.

Pharmaceutical form. Injection solution.

Main physicochemical characteristics: clear red-colored solution.

Pharmacotherapeutic group.
Vitamin B1 preparations in combination with vitamin B6 and/or vitamin B12. ATC code A11D B.

Pharmacological Properties

Pharmacodynamics

Neurotropic B-group vitamins exert beneficial effects on inflammatory and degenerative disorders of nerves and the musculoskeletal system. They are used to correct deficiency states, and in high doses possess analgesic properties, promote improved 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 the biologically active compounds thiamine diphosphate (cocarboxylase) and thiamine triphosphate (TTP).

Thiamine diphosphate acts as a coenzyme in essential carbohydrate metabolism processes, which are crucial for metabolic functions in nervous tissue and influence nerve impulse transmission at 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 a number of enzymes involved in general non-oxidative amino acid metabolism. Through decarboxylation, these enzymes participate in the formation of physiologically active amines (epinephrine, histamine, serotonin, dopamine, tyramine); through transamination, they contribute to anabolic and catabolic metabolic processes (e.g., glutamate-oxaloacetate transaminase, glutamate-pyruvate transaminase, γ-aminobutyric acid, α-ketoglutarate transaminase), as well as various processes of amino acid breakdown and synthesis. Vitamin B6 acts at four different stages in the metabolism of tryptophan. 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 the 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 metabolized daily. Metabolites are excreted in urine. Dephosphorylation occurs in the kidneys. The biological half-life of thiamine is 0.35 hours. 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, pyridoxal-5-phosphate, when bound to albumin, is hydrolyzed by alkaline phosphatase to 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 drug; acute impairment of cardiac conduction; acute form of decompensated heart failure.

Vitamin B1 – contraindicated in allergic reactions.

Vitamin B6 – contraindicated in peptic ulcer of the stomach and duodenum in the stage of exacerbation (since an increase in gastric juice acidity is possible).

Vitamin B12 – contraindicated in erythremia, erythrocytosis, thromboembolism.

Lidocaine. Hypersensitivity to lidocaine or to other amide-type local anesthetics, history of epileptiform seizures induced by lidocaine, severe bradycardia, severe arterial hypotension, cardiogenic shock, severe forms of chronic heart failure (II–III degree), 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 forms of interaction.

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 INH, D-penicillamine, and cycloserine.

When lidocaine is administered parenterally, cardiac adverse effects may be enhanced by epinephrine (adrenaline) or norepinephrine (noradrenaline). Other interactions exist with sulfonamides.

In case of overdose of local anesthetics, epinephrine (adrenaline) and norepinephrine (noradrenaline) must not be used.

Special precautions for use

Milgamma® contains lidocaine hydrochloride and therefore must be administered only by intramuscular injection. Intravenous (i.v.) administration into the bloodstream is not permitted. In case of accidental intravenous injection, medical monitoring or hospital observation may be required depending on the severity of symptoms developed. Prolonged use of the drug for more than 6 months may lead to reversible peripheral sensory neuropathy.

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

Milgamma® 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, particularly in patients with impaired liver or kidney function, as well as during pregnancy and breastfeeding.

Ability to influence reaction rate when driving or operating machinery.

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

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. The use of this medicinal product during pregnancy is recommended only if a vitamin B1 and B6 deficiency has been confirmed, as the safety of doses exceeding the recommended daily intake 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 are excreted into breast milk. High doses of vitamin B6 may reduce milk production.

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

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

Children.

Not recommended for use in pediatric patients.

Method of Administration and Dosage.

Dosage.

In cases of severe and acute pain, to achieve a rapid increase in drug levels in the blood, initially administer one injection (2 ml) once daily. After the acute phase has subsided and in mild conditions, administer one injection 2–3 times per week.

Weekly medical monitoring is recommended throughout the course of therapy.

Every effort should be made to switch to oral therapy as early as possible.

Method of Administration.

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

Warning to Prevent Accidental Intravenous Injection.

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

Between injections, for continued treatment and in mild cases, one tablet of Mylgama® should be administered three times daily.

Overdose.

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

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, as well as, in individual cases, hypochromic anemia and seborrheic dermatitis, have been reported after administration of more than 2 g per day.

Vitamin B12. Following parenteral administration (rarely, 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 agitation, 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 drug administration, oxygen therapy, anticonvulsants, vasoconstrictors (norepinephrine, mesaton), anticholinergics (0.5–1 mg atropine) in case of bradycardia. Endotracheal intubation, artificial ventilation of the lungs, and resuscitation measures may be necessary. Dialysis is ineffective.

Adverse Reactions

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

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

Cardiovascular system disorders:
Very rare: tachycardia.

Skin and subcutaneous tissue disorders:
Very rare: sweating, acne, skin reactions with pruritus and urticaria.

General disorders and administration site conditions:
Not known: systemic reactions may occur due to rapid accumulation (e.g., accidental intravenous injection, injection into highly vascularized tissue) or overdose. Possible symptoms include dizziness, vomiting, bradycardia, cardiac arrhythmia, and seizures.
Burning sensation at the injection site.

Shelf life
3 years.

Storage conditions
Store at a temperature not exceeding 2–8°C, in the original packaging to protect from light, and in a place inaccessible to children.

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 degradation products (low concentrations of iron ions may provide protection against this). Riboflavin, particularly under exposure to light, also exerts a destructive effect; nicotinamide accelerates photolysis, whereas antioxidants exert an inhibitory effect.

Packaging
2 ml in amber glass ampoules. Packs of 5, 10, or 25 ampoules in a cardboard box.

Prescription category
Prescription only.

Manufacturer
Solupharm Pharmazeutische Erzeugnisse GmbH, Germany.

Manufacturer's address and place of business
Industriestrasse 3, 34212 Melsungen, Germany.