CYANOCOBALAMIN (VITAMIN B12)

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT CYANOCOBALAMIN (VITAMIN B12) [CYANOCOBALAMIN (VITAMIN B12)]

Composition:

Active ingredient: cyanocobalamin;

1 ml of solution contains 0.5 mg of cyanocobalamin;

Excipients: sodium chloride, water for injections.

Dosage form. Injection solution.

Main physicochemical properties: clear, bright red liquid.

Pharmacotherapeutic group. Vitamin B12 (cyanocobalamin and its analogues).

ATC code B03B A01.

Pharmacological properties.

Pharmacodynamics.

Vitamin B12 (cyanocobalamin) exerts metabolic and hematopoietic effects. In the body (mainly in the liver), it is converted into its coenzyme form – adenosylcobalamin, or cobamamide, which is the active form of vitamin B12. Cobamamide is a component of numerous enzymes, in particular reductase, which reduces folic acid to tetrahydrofolic acid. It has high biological activity. Cobamamide participates in the transfer of methyl and other one-carbon fragments; therefore, it is necessary for the formation of deoxyribose and DNA, creatine, and methionine – a donor of methyl groups, for the synthesis of the lipotropic factor – choline, for the conversion of methylmalonic acid into succinic acid, which is a component of myelin, and for the utilization of propionic acid. Cobamamide is essential for normal hematopoiesis, as it promotes erythrocyte maturation. It participates in the synthesis and accumulation in erythrocytes of compounds containing sulfhydryl groups, thereby increasing their resistance to hemolysis. It activates the blood coagulation system and, in high doses, increases thromboplastin activity and prothrombin activity. It reduces blood cholesterol levels. It has a positive effect on liver and nervous system function. It enhances tissue regenerative capacity.

Pharmacokinetics.

After parenteral administration, vitamin B12 rapidly enters the systemic circulation. In the blood, it binds to transcobalamins I and II, which transport it into tissues. It is predominantly stored in the liver. Protein binding in plasma is 90%. Time to reach maximum concentration (T_Cmax) after subcutaneous or intramuscular administration is about 1 hour. It is excreted from the liver into bile and reabsorbed into the blood. The half-life (T_1/2) from the liver is 500 days. It is excreted via the kidneys at a rate of 7–10% when kidney function is normal, and approximately 50% is excreted in feces; with impaired kidney function, 0–7% is excreted via kidneys and 70–100% in feces. It crosses the placental barrier.

Clinical characteristics.

Indications.

Treatment of malignant, post-hemorrhagic, and iron-deficiency anemias; aplastic anemias in children; nutritional anemias caused by toxic substances and drugs; anemias associated with vitamin B12 deficiency, regardless of the cause of deficiency (gastrectomy, helminthic infestations, impaired intestinal absorption, pregnancy). Polyneuropathies, trigeminal neuralgia, radiculitis, causalgia, migraine, diabetic neuropathies, amyotrophic lateral sclerosis, cerebral palsy in children, Down syndrome, alcoholic delirium. Used in children with dystrophy, following infectious diseases, in sprue (together with folic acid), liver diseases (hepatitis, cirrhosis, Botkin's disease), radiation sickness, psoriasis, dermatitis herpetiformis, neurodermatitis, and photodermatoses.

Contraindications.

Hypersensitivity to the components of the drug. Erythremias, erythrocytosis. Neoplasms, except in cases associated with megaloblastic anemia and vitamin B12 deficiency. Acute thromboembolic diseases. Angina pectoris, high functional class of exertion.

Interaction with other medicinal products and other types of interactions.

Aminoglycosides, salicylates, antiepileptic drugs, colchicine, and potassium preparations reduce the absorption of the drug and affect its kinetics. When used concomitantly with kanamycin, neomycin, polymyxins, and tetracyclines, absorption of cyanocobalamin is reduced. Pharmaceutically incompatible with ascorbic acid, heavy metal salts (inactivation of cyanocobalamin), thiamine bromide, pyridoxine, and riboflavin (the cobalt ion present in the cyanocobalamin molecule destroys other vitamins).

When used concomitantly with thiamine, the risk of thiamine-induced allergic reactions is increased.

Chloramphenicol reduces the hematopoietic response to the drug.

When used concomitantly with cytamum, the effect of cytamum is reduced.

Oral contraceptives reduce the concentration of cyanocobalamin in the blood.

Special precautions for use.

Cyanocobalamin should not be used with drugs that enhance blood coagulation. During cyanocobalamin therapy, peripheral blood parameters must be monitored: on days 5–8 of treatment, reticulocyte count and iron concentration should be determined. The number of erythrocytes, hemoglobin, and color index should be monitored once or twice weekly during the first month, and thereafter 2–4 times per month. Remission is achieved when erythrocyte count reaches 4.0–4.5*10¹²/L, erythrocyte size returns to normal, anisocytosis and poikilocytosis disappear, and reticulocyte levels normalize following the reticulocyte crisis. After achieving hematological remission, peripheral blood monitoring should be performed at least once every 4–6 months.

In patients with a predisposition to thrombosis and in patients with angina pectoris, caution is required during treatment, and blood coagulation parameters should be monitored.

If there is a tendency toward leukocytosis or erythrocytosis, the dose of the drug should be reduced or treatment temporarily discontinued.

Use during pregnancy or breastfeeding.

Use during pregnancy is possible only under medical supervision and with caution, taking into account the risk/benefit ratio (there are individual reports of teratogenic effects of vitamin B₁₂ at high doses). Use during breastfeeding is possible only after evaluation of the risk/benefit ratio.

Ability to affect reaction rate when driving or operating machinery.

During treatment, patients should refrain from driving and from engaging in potentially hazardous activities that require heightened attention and rapid psychomotor reactions.

Administration and Dosage.

Cyanocobalamin is administered intramuscularly, subcutaneously, or intravenously. In cases of subacute combined (funicular) myelosis and amyotrophic lateral sclerosis, it is also administered intrathecally.

Adults.

For vitamin B₁₂-deficiency anemias, the drug is administered at doses of 100–200 mcg (0.1–0.2 mg) every other day until remission is achieved.

In the presence of symptoms of funicular myelosis or in macrocytic anemias with nervous system involvement, cyanocobalamin is administered at a single dose of 400–500 mcg (0.4–0.5 mg) or higher. During the first week, it is given daily, then every 5–7 days (folic acid is prescribed concurrently). In severe cases, the drug is administered intraspinally, starting with a single dose of 15–30 mcg, increasing the dose with each subsequent injection (50, 100, 150, 200 mcg). Intrathecal injections are performed every 3 days; a total of 8–10 injections are required per course. During remission, in the absence of funicular myelosis symptoms, maintenance therapy consists of 100 mcg twice a month; in the presence of neurological symptoms, 200–400 mcg 2–4 times per month.

In amyotrophic lateral sclerosis, encephalomyelitis, and neurological disorders with pain syndrome, the drug is administered in increasing doses from 200 to 500 mcg per injection (once improvement occurs, 100 mcg daily). The treatment course lasts 14 days. In peripheral nerve injuries, 200–400 mcg is administered once every 2 days for 40–45 days.

In hepatitis and liver cirrhosis, adults receive 15–30 mcg daily or 100 mcg every other day for 25–40 days.

In diabetic neuropathy, sprue, and radiation sickness, 60–100 mcg is administered daily for 20–30 days.

In vitamin B₁₂ deficiency, treatment consists of 1 mg intramuscularly or intravenously daily for 1–2 weeks; the maintenance dose is 1–2 mg intramuscularly or intravenously, from once a week to once a month. The duration of cyanocobalamin therapy and the need for repeated courses depend on the course of the disease and treatment efficacy.

Children.

Administered only subcutaneously.

In post-hemorrhagic and iron-deficiency anemias, 30–100 mcg is administered 2–3 times a week. In aplastic anemias in children, 100 mcg is administered until clinical and hematological improvement occurs. In alimentary anemias in children, 30 mcg is administered for 15 days.

In dystrophies in early childhood, Down syndrome, and cerebral palsy in children, 15–30 mcg is administered every other day.

In hepatitis and liver cirrhosis in children, 15–30 mcg daily or 100 mcg every other day is administered for 25–40 days.

Children.

This medicinal product in this formulation and dosage strength is not used in children under 3 years of age. Administration is only subcutaneous.

Overdose.

Overdose may result in pulmonary edema, congestive heart failure, and peripheral vascular thrombosis. Treatment is symptomatic.

Side effects.

Blood-related: hypercoagulation.

Cardiovascular system: tachycardia, chest pain.

Nervous system: headache, dizziness, nervous excitement.

Immune system: allergic reactions, including skin manifestations (hyperemia, urticaria, rash, itching, dermatitis), swelling, including Quincke's edema; respiratory disturbances, including asthma attacks, anaphylactic shock, anaphylactoid reactions.

Metabolic disorders: acne, bullous rashes, nausea, sweating, purine metabolism disturbances.

Gastrointestinal tract: loose stools.

General disorders: malaise, fever.

Local reactions: hyperemia, itching, pain, swelling, induration, and necrosis at the injection site.

Incompatibility.

When cyanocobalamin is used in the same solution with ascorbic acid or pyridoxine, mutual destruction of vitamins occurs; with nicotinic acid – destruction of cyanocobalamin; with riboflavin – accumulation of cobalt ions.

Shelf life. 2 years.

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

Keep out of reach of children.

Packaging. 1 ml in ampoules. 10 ampoules per box with partitions; or 5 ampoules in a single-sided blister, 2 blisters per box.

Prescription category. Prescription only.

Manufacturer. Private Joint-Stock Company "Lekhim-Kharkiv".

Manufacturer's address and place of business.

36 Severina Pototskogo Street, Kharkiv, Kharkiv Region, 61115, Ukraine.