Vitaprompt®

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT VITAPROMPT®

Composition:

Active substance: cyanocobalamin;

1 ml of solution contains 1000 mcg of cyanocobalamin (vitamin B12);

Excipients: sodium chloride, hydrochloric acid, water for injections.

Pharmaceutical form. Solution for injection.

Main physicochemical properties: clear red solution.

Pharmacotherapeutic group. Antianaemic agents. Cyanocobalamin.

ATC code B03B A01.

Pharmacological Properties

Pharmacodynamics

Vitamin B12 is required as a cofactor of the prosthetic group of methylmalonyl-CoA mutase for the conversion of propionic acid into succinic acid. In addition, like folic acid, vitamin B12 is involved in the formation of labile methyl groups, which are transferred to other methyl acceptors via transmethylation processes. The vitamin also influences the synthesis of nucleic acids, particularly during hematopoiesis, as well as other cellular maturation processes.

Availability and Meeting Requirements

For therapeutic purposes, vitamin B12 is administered in the form of cyanocobalamin (as well as hydroxocobalamin and hydroxocobalamin acetate). These two forms are "prodrugs" that are converted in the body into active forms—methylcobalamin and 5-adenosylcobalamin.

The human body is unable to synthesize vitamin B12 independently and must obtain it from dietary sources. Foods containing vitamin B12 include liver, kidneys, heart, fish, oysters, milk, egg yolks, and meat.

Vitamin B12 is primarily absorbed in the small intestine, but only if the vitamin has previously bound to intrinsic factor, a glycoprotein produced in the stomach. The body stores only such an amount of vitamin B12 as is necessary to meet daily requirements, approximately 1 µg.

Deficiency

Impaired or absent absorption of vitamin B12 over many years leads to the appearance of deficiency symptoms when plasma concentrations of vitamin B12 fall below 200 pg/mL. Hematologically, changes in blood parameters manifest as megaloblastic anemia. Neurologically, deficiency presents with symptoms affecting the peripheral and central nervous systems. Signs of polyneuropathy may occur together with spinal cord involvement and psychiatric disorders. Early signs of deficiency include fatigue, pallor, paresthesia in the hands and feet, unsteady gait, and decreased physical strength.

Pharmacokinetics

Vitamin B12 is absorbed via two pathways:

• Active absorption in the small intestine requires the presence of intrinsic factor (Castle's factor). Transport of vitamin B12 to tissues requires binding to transcobalamins, which are beta-globulins of blood plasma.
• Independent of intrinsic factor, vitamin B12 can also enter the bloodstream via passive diffusion through the gastrointestinal tract or mucous membranes. Approximately 1–3% (depending on dose) of orally administered vitamin B12 reaches the bloodstream.

Studies involving healthy volunteers have shown that, on average, a maximum of 1.5 µg of vitamin B12 is absorbed from oral doses (greater than 5 µg) via intrinsic factor. In patients with pernicious anemia, maximum absorption rates of 1% have been observed after oral intake of 100 µg or more of vitamin B12.

Vitamin B12 stored in the body is retained in tissue reservoirs, the most important of which is located in the liver. The amount of vitamin B12 consumed as daily requirement is very low, approximately 1 µg, while the turnover rate of vitamin B12 is 2.5 µg. The biological half-life is approximately 1 year. About 2.55 µg of vitamin B12 is metabolized per day, or 0.051% of total body stores.

Vitamin B12 is primarily excreted in bile, and up to 1 µg is reabsorbed via enterohepatic circulation. If the body's storage capacity is exceeded due to high doses, particularly after parenteral administration, the unabsorbed fraction is excreted in urine.

Plasma vitamin B12 levels provide information about the body's vitamin B12 stores. In a healthy individual deprived of any vitamin B12 intake, critical levels indicating vitamin deficiency are reached after 3 to 5 years.

Between 50 and 90% of an intramuscular or intravenous dose of 0.1 to 1 mg of cyanocobalamin is excreted in urine within 48 hours, with urinary excretion occurring more rapidly after intravenous administration. In contrast, after administration of hydroxocobalamin, more prolonged serum levels are observed, with only 16 to 66% of the dose appearing in urine within 72 hours, and peak hydroxocobalamin levels occurring at 24 hours.

However, it is considered that this effect is lost no later than one month of continuous treatment; therefore, there are no significant differences in the absorption and accumulation characteristics between hydroxocobalamin and cyanocobalamin.

Clinical characteristics.

Indications.

Vitamin B12 deficiency that cannot be corrected by an adequate diet.

Vitamin B12 deficiency that may manifest as the following conditions:

• Hyperchromic macrocytic megaloblastic anemia (pernicious anemia, Addison-Biermer disease);
• Subacute combined degeneration of the spinal cord (funicular myelosis).

Laboratory-confirmed vitamin B12 deficiency that may arise due to the following causes:

• Exclusion of animal-derived products from the diet (e.g., due to a strict vegetarian diet);
• Impaired nutrient absorption in the small intestine, malabsorption syndrome due to:
  • insufficient production of intrinsic factor;
  • diseases of the terminal ileum, e.g., sprue;
  • fish tapeworm infestation;
  • blind loop syndrome;
  • congenital defects in vitamin B12 transport.

Contraindications.

Hypersensitivity to the active substance or to any of the excipients listed in the section "Composition".

Neoplastic diseases, except in cases associated with anemia and vitamin B12 deficiency. Acute thromboembolic disorders. High functional class exertional angina.

Special precautions.

Parenteral medicinal products must be visually inspected before use. Only clear solutions free from particulate matter should be used.

The injection solution is intended for single use only. Administration must be performed immediately after opening the ampoule. Any unused portions must be discarded.

The injection solution may be mixed with isotonic saline to prepare an infusion solution. The volume of infusion suitable for intravenous administration is selected by the physician, taking into account the required dosage (see section "Administration and dosage").

For stability reasons, the injection solution must not be diluted below a concentration of 2.00 mcg cyanocobalamin/ml.

Physicochemical stability of the injection solution has been demonstrated up to a maximum dilution of 2.00 mcg cyanocobalamin/ml in isotonic saline (corresponding to 1 ml of injection solution in up to 500 ml of isotonic saline) at room temperature (up to 25°C) and protected from light for 24 hours.

When preparing mixtures with infusion solutions, contamination with microorganisms must be avoided.

When combining with infusion solutions, the information provided by the respective manufacturer regarding their infusion solutions must be observed, including compatibility, contraindications, adverse reactions, and interactions.

The injection solution must not be mixed with other medicinal products, solvents, or infusion solutions except those listed.

Unused medicinal products or waste materials must be disposed of in accordance with national requirements.

Interaction with other medicinal products and other types of interactions.

Aminoglycosides, salicylates, antiepileptic drugs, colchicine, potassium preparations reduce the absorption of the medicinal product and affect its pharmacokinetics.

Concomitant use with kanamycin, neomycin, polymyxins, tetracyclines decreases cyanocobalamin absorption.

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 medicinal product.

Oral contraceptives – reduce cyanocobalamin blood concentration.

Special precautions for use.

During therapy, it is necessary to monitor peripheral blood parameters: on days 5–8 after the start of treatment, determine reticulocyte count and iron concentration. Red blood cell count, hemoglobin concentration, and color index should be monitored once or twice weekly during the first month, and thereafter 2–4 times per month. Hematological remission is achieved when red blood cell count reaches 4.0–4.5*10^12/l, red blood cells return to normal size, anisocytosis and poikilocytosis disappear, and reticulocyte levels normalize following the reticulocyte crisis. After achieving hematological remission, peripheral blood monitoring should be performed no less frequently than once every 4–6 months.

In case of tendency to develop leukocytosis or erythrocytosis, the dose of the drug should be reduced or treatment temporarily discontinued.

Cyanocobalamin must not be used concomitantly with drugs that enhance blood coagulation.

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

Vitaprompt®, solution for injection, contains less than 1 mmol of sodium (23 mg) per ampoule, i.e. it is practically sodium-free.

Use during pregnancy or breastfeeding.

The use of Vitaprompt®, solution for injection, is not recommended during pregnancy and breastfeeding.

Ability to influence reaction speed when driving or operating machinery.

Vitaprompt®, solution for injection, has no effect or has negligible effect on the ability to drive vehicles or operate machinery.

Dosage and Administration

Dosage

At the beginning of treatment, administer 1 ampoule of Vitaprompt®, solution for injection (equivalent to 1000 mcg of cyanocobalamin) twice weekly for the first few weeks after diagnosis.

In cases of confirmed impaired intestinal absorption of vitamin B12, 1000 mcg of cyanocobalamin should be administered once a month.

With good tolerability, duration of treatment is not limited. If impaired intestinal absorption of vitamin B12 is confirmed, vitamin B12 is usually administered for life.

Administration

Parenteral medicinal products should be inspected visually before use. Only clear solutions free from particles should be used.

Vitaprompt®, solution for injection, is usually administered intramuscularly. However, it may also be given slowly intravenously or subcutaneously.

For compatibility instructions of Vitaprompt®, solution for injection, with other medicinal products, see section "Special precautions".

Children

Insufficient clinical data available.

Overdose

Vitamin B12 has a wide therapeutic safety margin. Symptoms of poisoning or overdose are unknown.

Adverse Reactions.

Gastrointestinal disorders: diarrhea.

Metabolism and nutritional disorders: acne, bullous eruptions, nausea, sweating, purine metabolism disturbances, hypokalemia.

Cardiovascular disorders: tachycardia, chest pain, congestive heart failure, peripheral vascular thrombosis, low blood pressure, cardiac arrest.

Blood disorders: hypercoagulability.

General disorders and administration site conditions: malaise, fever; at injection site: hyperemia, itching, pain, swelling, induration, and necrosis.

Immune system disorders: allergic reactions, including skin manifestations such as hyperemia, urticaria, rash, itching, dermatitis, edema, including Quincke's edema; respiratory disturbances, including dyspnea attacks; very rarely (< 1/10,000), anaphylactic or anaphylactoid reactions occur.

Skin and subcutaneous tissue disorders: very rarely (< 1/10,000), acne, eczema, and urticaria have been observed.

Reporting suspected adverse reactions

Reporting of suspected adverse reactions after authorization of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Medical and pharmaceutical professionals, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of efficacy via the Automated Information System for Pharmacovigilance at https://aisf.dec.gov.ua.

Shelf life. 5 years.

Storage conditions.

Store ampoules in the outer packaging to protect from light. Keep out of reach of children.

Incompatibilities.

Due to the instability of vitamin B12 and the potential loss of its efficacy, the injectable solution should not be mixed with other medicinal products, except for the diluent specified in the section "Special precautions for handling".

Packaging.

1 ml of solution in an ampoule; 5 ampoules per pack.

Prescription status. Prescription only.

Manufacturer. mibe GmbH Arzneimittel.

Manufacturer's address and place of business.

Muenchenstrasse 15, Brehna, Saxony-Anhalt, 06796, Germany.