Combilipen^® (Solution) Instructions for Use

Marketing Authorization Holder

Pharmstandard-UfaVITA OJSC (Russia)

ATC Codes

A11DB (Vitamin B1 in combination with vitamins B6 and/or B12)

N07X (Other nervous system drugs)

Dosage Form

Combilipen®

Intramuscular injection solution 100 mg+100 mg+1 mg+20 mg/2 ml: amp. 5 or 10 pcs.

Dosage Form, Packaging, and Composition

Solution for intramuscular injection transparent, pinkish-red in color, with a specific odor.

Excipients: benzyl alcohol – 40 mg, sodium tripolyphosphate – 20 mg, potassium hexacyanoferrate – 0.2 mg, sodium hydroxide – to adjust pH to 4.5±0.2, water for injection – up to 2 ml.

2 ml – dark glass ampoules (5) – contour cell packaging (1) – cardboard packs.
2 ml – dark glass ampoules (5) – contour cell packaging (2) – cardboard packs.

Clinical-Pharmacological Group

B complex vitamins

Pharmacotherapeutic Group

B vitamins + other preparations

Pharmacological Action

Combined medicinal product. The action of this product is determined by the properties of the vitamins it contains. Neurotropic B vitamins have a beneficial effect on inflammatory and degenerative diseases of the nervous system and the musculoskeletal system.

Thiamine (vitamin B₁) plays a key role in carbohydrate metabolism processes, which are crucial in the metabolic processes of nervous tissue (participates in nerve impulse conduction), as well as in the Krebs cycle with subsequent participation in the synthesis of thiamine pyrophosphate (TPP) and adenosine triphosphate (ATP).

Pyridoxine (vitamin B₆) has a vital influence on the metabolism of proteins, carbohydrates, and fats, is necessary for normal hematopoiesis, and the functioning of the central and peripheral nervous system. It ensures synaptic transmission, inhibition processes in the central nervous system, participates in the transport of sphingosine, which is part of the nerve sheath, and participates in the synthesis of catecholamines.

The physiological function of both vitamins (B₁ and B₆) is to potentiate each other’s action, manifested in a positive effect on the nervous, neuromuscular, and cardiovascular systems.

Cyanocobalamin (vitamin B₁₂) participates in the synthesis of nucleotides, is an important factor for normal growth, hematopoiesis, and the development of epithelial cells, and is necessary for the metabolism of folic acid and the synthesis of myelin.

Lidocaine has an anesthetic effect at the injection site, dilates blood vessels, promoting the absorption of vitamins. The local anesthetic effect of lidocaine is due to the blockade of voltage-gated sodium channels, which prevents the generation of impulses in the endings of sensory nerves and the conduction of pain impulses along nerve fibers.

Pharmacokinetics

Thiamine

After intramuscular administration, thiamine is rapidly absorbed from the injection site and enters the bloodstream (484 ng/ml after 15 minutes on the first day of a 50 mg dose administration) and is unevenly distributed in the body, with its content in leukocytes being 15%, in erythrocytes 75%, and in blood plasma 10%. Due to the absence of significant vitamin reserves in the body, it must be supplied daily. Thiamine crosses the blood-brain and placental barriers and is found in breast milk.

Thiamine is excreted by the kidneys in the alpha phase after 0.15 hours, in the beta phase – after 1 hour, and in the final (terminal) phase – within 2 days. The main metabolites are: thiamine carboxylic acid, pyramine, and some unknown metabolites. Of all vitamins, thiamine is retained in the body in the smallest amounts. The adult human body contains about 30 mg of thiamine: 80% as thiamine pyrophosphate, 10% as thiamine triphosphate, and the remainder as thiamine monophosphate.

Pyridoxine

After intramuscular injection, pyridoxine is rapidly absorbed from the injection site and distributed throughout the body, acting as a coenzyme after phosphorylation of the CH₂OH group at the 5th position. About 80% of the vitamin binds to plasma proteins. Pyridoxine is distributed throughout the body, crosses the placental barrier, and is found in breast milk. It accumulates in the liver and is oxidized to 4-pyridoxic acid, which is excreted by the kidneys maximally 2-5 hours after absorption.

The human body contains 40-150 mg of vitamin B₆, and its daily elimination rate is about 1.7-3.6 mg with a replenishment rate of 2.2-2.4%.

Cyanocobalamin

Cyanocobalamin, after intramuscular administration, binds to transcobalamins I and II and is transported to various body tissues. C_max after intramuscular administration is reached after 1 hour. Binding to plasma proteins is 90%. It crosses the placental barrier and is found in breast milk.

It is metabolized primarily in the liver to form adenosylcobalamin, which is the active form of cyanocobalamin. It is stored in the liver, enters the intestine with bile, and is reabsorbed into the blood (enterohepatic recirculation phenomenon). T_1/2 is long, excreted mainly by the kidneys (7-10%) and through the intestine (50%). With reduced renal function, it is excreted by the kidneys – 0-7% and through the intestine – 70-100%.

Lidocaine

After intramuscular administration, C_max of lidocaine in plasma is noted 5-15 minutes after injection. Depending on the dose, approximately 60-80% of lidocaine binds to plasma proteins. It is rapidly distributed (within 6-9 minutes) to organs and tissues with good perfusion, including the heart, lungs, liver, kidneys, and then to muscle and adipose tissue. It crosses the blood-brain and placental barriers and is found in breast milk (up to 40% of the concentration in maternal plasma).

It is metabolized in the liver with the participation of microsomal enzymes to form active metabolites – monoethylglycinexylidide and glycinexylidide, with T_1/2 of 2 hours and 10 hours, respectively. The intensity of metabolism decreases in liver diseases. It is excreted mainly as metabolites by the kidneys and up to 10% unchanged.

Indications

As part of complex therapy

• Mono- and polyneuropathies of various origins;
• Dorsalgia;
• Plexopathies;
• Lumboischialgia;
• Radicular syndrome caused by degenerative changes of the spine.

ICD codes

Dosage Regimen

Injections are performed deep intramuscularly.

In cases of severe pain syndrome, it is advisable to start treatment with intramuscular injection (deep) of 2 ml daily for 5-10 days, subsequently switching either to oral administration of the drug or to less frequent injections (2-3 times/week for 2-3 weeks) with possible continuation of therapy with the oral dosage form.

Weekly therapy monitoring by a physician is necessary. The duration of treatment is determined individually by the physician depending on the severity of the disease symptoms.

Transition to therapy with the oral dosage form is recommended to be carried out as soon as possible.

Adverse Reactions

Immune system disorders rarely – allergic reactions (skin rash, difficulty breathing, anaphylactic shock, angioedema).

Nervous system disorders frequency unknown – dizziness, confusion.

Cardiac disorders very rarely – tachycardia; frequency unknown – bradycardia, arrhythmia.

Gastrointestinal disorders frequency unknown – vomiting.

Skin and subcutaneous tissue disorders very rarely – increased sweating, acne, itching, urticaria.

Musculoskeletal and connective tissue disorders frequency unknown – convulsions.

General disorders and administration site conditions frequency unknown – irritation may occur at the injection site; systemic reactions are possible with rapid administration or overdose.

With rapid administration (e.g., due to unintentional intravascular injection or injection into highly vascularized tissues) or when the dose is exceeded, systemic reactions may develop, including confusion, vomiting, bradycardia, arrhythmia, dizziness, and convulsions.

Contraindications

• Hypersensitivity to the components of the combination;
• Acute heart failure;
• Chronic heart failure in the stage of decompensation;
• Pregnancy;
• Breastfeeding period;
• Age under 18 years (efficacy and safety have not been established).

Use in Pregnancy and Lactation

Use during pregnancy and breastfeeding is contraindicated.

Pediatric Use

Contraindicated for use in children and adolescents under 18 years of age.

Special Precautions

Administer intramuscularly only. In case of accidental intravenous administration, the patient should be under medical supervision or hospitalized depending on the severity of symptoms.

This product may cause neuropathies when used for more than 6 months.

Effect on ability to drive and operate machinery

However, caution is recommended, considering the possibility of adverse reactions from this product.

Drug Interactions

B vitamins

Vitamin B₁ (thiamine) completely decomposes in solutions containing sulfites. Consequently, thiamine decomposition products inactivate the actions of other vitamins.

Thiamine is incompatible with oxidizing and reducing compounds, including mercuric chloride, iodide, carbonate, acetate, tannic acid, iron-ammonium citrate, as well as phenobarbital, riboflavin, benzylpenicillin, dextrose, and metabisulfite.

Copper accelerates the destruction of thiamine; furthermore, thiamine loses its effectiveness with increasing pH values (above 3).

Therapeutic doses of vitamin B₆ (pyridoxine) weaken the effect of levodopa (the antiparkinsonian effect of levodopa is reduced) when used concurrently. Interaction with cycloserine, penicillamine, and isoniazid is also observed.

Vitamin B₁₂ (Cyanocobalamin) is incompatible with ascorbic acid and heavy metal salts.

Lidocaine

With parenteral use of lidocaine, in case of additional use of norepinephrine and epinephrine, an increase in adverse cardiac reactions is possible. Interaction with sulfonamides is also observed. In case of overdose of local anesthetics, epinephrine and norepinephrine should not be additionally administered.

Storage Conditions

Store at 2°C (36°F) to 8°C (46°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.