Neurobion® advance

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT NEUROBION® ADVANCE (NEUROBION® ADVANCE)

Composition:

Active substances:

One film-coated tablet contains thiamine nitrate (vitamin B1) 100 mg, pyridoxine hydrochloride (vitamin B6) 50 mg, cyanocobalamin (vitamin B12) 1 mg;

Excipients: gelatin, microcrystalline cellulose, sodium starch glycolate (type A), sodium croscarmellose, hypromellose, colloidal anhydrous silicon dioxide, magnesium stearate; tablet coating: Opadry AMB II 88A190022 Clear (polyvinyl alcohol, talc, glycerin monocaprylocaprate, sodium lauryl sulfate), Opadry II OY-GM-7305 White (hypromellose, polydextrose, titanium dioxide (E 171), macrogol), white beeswax, carnauba wax.

Pharmaceutical form. Film-coated tablets.

Main physicochemical characteristics: white or almost white, round, biconvex, film-coated tablets.

Pharmacological properties.

Pharmacodynamics.

The medicinal product contains vitamins B1, B6, and B12, which act as coenzymes and are therefore essential substances for metabolism. Their role in the metabolism of various tissues, including peripheral and central nervous cells as well as their supporting cells, should be considered in relation to the maintenance of structural and functional properties of the nervous system. All three—vitamins B1, B6, and B12—play an indispensable role in the metabolism, regeneration, and maintenance of nerve function due to their various neurotrophic and neuroprotective effects. This may explain why neurological signs and symptoms (e.g., tingling, sensory disturbances (numbness or hyperesthesia), allodynia, neuropathic pain, paresthesia, altered sensory threshold, perception, nerve conduction velocity, temperature sensation) may predominate in cases of deficiency of these vitamins.

Thiamine (vitamin B1)

Thiamine pyrophosphate is the active form of vitamin B1 and acts as a coenzyme for several enzymes (such as pyruvate dehydrogenase and transketolase). As a result, vitamin B1 is primarily involved in carbohydrate metabolism, although it also plays a role in the synthesis of lipids and amino acids. Nerve cells derive energy exclusively through the enzymatic oxidation and decarboxylation of glucose, making an adequate supply of vitamin B1 critically important. Thiamine also participates in the conduction of nerve impulses. In addition, experimental results indicate antinociceptive activity.

Vitamin B1 deficiency may occur, for example, in patients with diabetes mellitus, elderly individuals, patients with gastrointestinal disorders, patients on hemodialysis, those with malabsorption, chronic alcoholism, or increased demand for vitamin B1. Major clinical manifestations and disorders due to vitamin B1 deficiency in humans include those affecting the nervous and cardiovascular systems. Deficiency of vitamin B1 over days or weeks may lead to early symptoms such as increased fatigue, irritability, weakness, malaise, burning sensations in the hands and soles of the feet, sensory disturbances, ataxia during walking, digestive disturbances, irritability, and depression.

Pyridoxine (vitamin B6)

Pyridoxal phosphate, the biologically active form of pyridoxine, is a key coenzyme in amino acid metabolism. Through decarboxylation, it participates in the formation of physiologically active amines (such as serotonin, histamine, and adrenaline), as well as in anabolic and catabolic processes via transamination.

Pyridoxal phosphate plays an essential role in the function of the central nervous system, particularly in enzyme-controlled neurotransmitter metabolism. Pyridoxal phosphate is also crucial in sphingolipid metabolism, as it catalyzes the first step in sphingosine biosynthesis. Sphingolipids are essential components of the myelin sheath of nerve cells.

Vitamin B6 deficiency in adults may negatively affect nerves, leading to polyneuropathy and seizures, as well as possible cognitive impairment. Other body systems and organs may also be affected, such as the skin (seborrheic dermatitis), mucous membranes, the circulatory system, and the immune system. Vitamin B6 deficiency may also cause nausea, vomiting, depression, disturbances in oxalate metabolism, and anemia. There are various groups at increased risk who require higher amounts of vitamin B6, such as patients with diabetes mellitus, elderly individuals, and patients with gastrointestinal disorders, among others. Inadequate intake and low levels of vitamin B6 are associated with impaired immune function and increased susceptibility to infections, particularly in the elderly. Vitamin B6 is important in that both deficiency and excess can cause symptoms of peripheral neuropathy.

Cyanocobalamin (vitamin B12)

Vitamin B12, in the form of coenzymes (5-deoxyadenosylcobalamin and methylcobalamin), participates in nucleic acid metabolism and DNA synthesis, particularly in hematopoiesis, myelin synthesis, and maintenance of myelin sheath function, as well as in epithelial tissue synthesis. Vitamin B12 also participates in neurotransmitter synthesis and is one of the key components in fatty acid and carbohydrate metabolism.

The risk of vitamin B12 deficiency may occur in various populations, such as patients with diabetes mellitus, elderly individuals, and patients with gastrointestinal disorders, among others. Increased risk of vitamin B12 deficiency is particularly observed in vegetarians and vegans, as animal-derived foods are the only source of vitamin B12. Infants born to mothers with vitamin B12 deficiency are also at special risk. Malabsorption of vitamin B12, leading to its deficiency, may occur at various stages of digestion. A dangerous and serious condition resulting from malabsorption and deficiency of vitamin B12 is autoimmune gastritis, known as pernicious anemia, characterized by destruction of the gastric mucosa, presence of antibodies to parietal cells, and lack of intrinsic factor. Vitamin B12 deficiency may lead to neurological symptoms such as paresthesia, numbness, gait disturbances, polyneuritis (especially sensory, in the distal parts of the limbs), and others. Other symptoms may include anemia, optic nerve atrophy, and changes in mental status.

Combination of vitamins B1, B6, and B12

Neurotropic vitamins B1, B6, and B12, individually and in combination, have particular significance for metabolic processes in the nervous system due to biochemical synergy, justifying their combined use. All three neurotropic B vitamins contribute to nerve health through different mechanisms of action, and all three are essential.

Moreover, deficiency of neurotropic B vitamins is observed in most patient groups, such as the elderly, patients with diabetes mellitus, patients with gastrointestinal disorders (e.g., inflammatory bowel disease), patients after gastrointestinal surgery (e.g., bariatric surgery), patients with gastritis, celiac disease, recurrent vomiting, and prolonged diarrhea, among others.

In addition, the combination of vitamins B1, B6, and B12 has demonstrated a synergistic effect when used concomitantly with nonsteroidal anti-inflammatory drugs for pain treatment.

Pharmacokinetics.

No adverse interaction in the pharmacokinetics of each of these vitamins is expected with combined administration of vitamins B1, B6, and B12.

Thiamine (vitamin B1)

Orally administered vitamin B1 is considered to enter the body via a dose-dependent dual transport mechanism: active absorption—up to a concentration of 2 µmol—and passive diffusion—at concentrations above 2 µmol. Absorption occurs primarily in the proximal segment of the small intestine. Thiamine absorption takes place after phosphorylation in epithelial cells; it is believed that passage through the intestinal wall is mediated by a specific carrier.

After absorption by the intestinal mucosa, thiamine is transported to the liver via the portal circulation. In the liver, thiamine is phosphorylated by thiamine kinase to thiamine pyrophosphate (TPP) and thiamine triphosphate (TTP).

Vitamin B1 is found in all body tissues; particularly high concentrations are observed in the brain, skeletal muscles, liver, heart, and kidneys.

Vitamin B1 is excreted predominantly in urine, either unchanged or as several metabolites (approximately 20).

The biological half-life of thiamine in humans is approximately 9.5 to 18.5 days, and the elimination half-life is approximately 4 hours. Body stores of vitamin B1 may last for 4–10 days.

Pyridoxine (vitamin B6)

Vitamin B6 (pyridoxine, pyridoxal, and pyridoxamine) is rapidly absorbed, primarily in the upper gastrointestinal tract, and transported to organs and tissues in an albumin-bound form (especially as pyridoxal phosphate).

Vitamin B6 is primarily phosphorylated in the liver, forming the biologically active pyridoxal phosphate. To cross the cell membrane, phosphorylated vitamin B6 must be hydrolyzed by alkaline phosphatase to release free vitamin B6. Transport into the cell occurs via simple diffusion followed by rephosphorylation. Recently, a hypothesis has been proposed regarding a specialized pyridoxine uptake system in the intestine mediated by a specific carrier. Maximum concentrations are reached within 3.5–4 hours. The biological half-life of pyridoxal phosphate is 15–25 days, and the elimination half-life is approximately 3 hours. Body stores of vitamin B6 may last for 14–42 days.

Vitamin B6 is excreted in urine. The main excretory product is 4-pyridoxic acid, the amount of which depends on the dose of vitamin B6 administered. Vitamin B6 is secreted in breast milk and crosses the placenta.

Cobalamin (vitamin B12)

Absorption of vitamin B12 from the gastrointestinal tract occurs via two distinct mechanisms. The active mechanism is mediated by intrinsic factor, secreted by parietal cells of the gastric mucosa. After release of haptocorrin by gastric juice, vitamin B12 binds to intrinsic factor. The vitamin B12–intrinsic factor complex binds to a specific receptor protein on the luminal surface of the ileal mucosa. The complex enters mucosal cells via receptor-mediated endocytosis. This mechanism allows absorption of no more than 1.5–2 µg of orally administered vitamin B12.

Independently of intrinsic factor, vitamin B12 can enter the bloodstream via nonsaturable passive diffusion. Passive diffusion accounts for approximately 1–2% of total absorbed vitamin B12 and remains unchanged in patients who have undergone gastroduodenal resection, as well as in patients with other gastrointestinal disorders affecting intrinsic factor-mediated absorption of vitamin B12, and may occur throughout the small intestine. In the human body, vitamin B12 is stored in depots, the most important of which is the liver (about 1.5 mg), as well as in the kidneys, heart, spleen, and brain. Total body content of vitamin B12 varies, but is estimated at ~2–3 mg. The rate of turnover is 2.5 µg of vitamin B12 per day, or 0.05% of the total body content. The biological half-life is approximately 1 year.

Vitamin B12 is primarily secreted into bile and extensively reabsorbed via enterohepatic circulation. If the body's storage capacity is exceeded due to high-dose administration, particularly parenterally, the excess that cannot be stored is excreted in urine.

Clinical characteristics.

Indications.

Neurobion® Advance is indicated in adults for the prevention and treatment of vitamin B1, B6, and B12 deficiency, which under certain conditions may lead to mixed sensorimotor polyneuropathy, in cases of insufficient intake, impaired absorption, or increased loss of these vitamins, or elevated demand.

Contraindications.

Hypersensitivity to the active substances or to any of the excipients.

Due to the high content of active substances, the product must not be used in children (under 18 years of age).

Interaction with other medicinal products and other forms of interaction.

Vitamin B6 (pyridoxine) may reduce the therapeutic effect of levodopa.

Inhibitors of dopa-decarboxylase, such as carbidopa or benserazide, bind to pyridoxal phosphate and may lead to decreased levels of vitamin B6 in the body.

Antagonists of pyridoxine, such as isoniazid, cycloserine, penicillamine, or hydralazine, may reduce the effectiveness of vitamin B6 (pyridoxine).

Prolonged use of loop diuretics, such as furosemide, may accelerate excretion and thus reduce serum levels of vitamin B1 (thiamine), as well as decrease serum levels of vitamin B6 (pyridoxine).

Alcohol impairs absorption and reabsorption of vitamin B1 (thiamine).

Special precautions for use.

Patients should discontinue treatment and consult a physician if any new symptoms occur.

Vitamin B12 (cyanocobalamin) may improve the condition in folate-deficiency megaloblastic anemia. Treatment with this medicinal product may also improve the condition due to the presence of vitamin B12 (cyanocobalamin) in its composition. However, it is essential to ensure that the use of this product does not mask the correct diagnosis.

This medicinal product contains less than 1 mmol of sodium (23 mg) per film-coated tablet, i.e. it is practically sodium-free.

Use during pregnancy or breastfeeding.

Pregnancy

The potential risk to humans is unknown. The physician should determine the appropriateness of using this medicinal product during pregnancy after carefully evaluating the benefit-risk ratio.

Breastfeeding

Thiamine, pyridoxine, and cyanocobalamin are excreted in human breast milk; however, the risk of overdose for the infant is unknown.

The physician should determine the appropriateness of using this medicinal product during breastfeeding after carefully evaluating the benefit-risk ratio.

Fertility

Clinical trials to confirm the effect of the combination of vitamins B1, B6, and B12 on human fertility have not been conducted.

Ability to affect reaction speed when driving or operating machinery.

Neurobion® Advance has no influence on the ability to drive or operate machinery.

Dosage and method of administration.

One film-coated tablet once daily.

For oral use only. The tablet should be swallowed whole with liquid, during or after a meal.

Patients should consult a physician if symptoms persist after 30 days of treatment or if symptoms worsen.

Children.

Neurobion® Advance is contraindicated in children (under 18 years of age) (see section "Contraindications").

Overdose.

No cases of overdose have been reported with thiamine or cyanocobalamin.

Publications describe neuropathies occurring after prolonged use (6 months or more) of vitamin B6 at average daily doses exceeding 50 mg, which gradually resolved after discontinuation of the vitamin.

Treatment of overdose consists of discontinuing the drug and implementing other measures as indicated by clinical circumstances.

Adverse Reactions

The undesirable effects listed below are classified by system organ class and frequency. Frequency is defined as follows: very common (≥ 1/10); common (≥ 1/100, < 1/10); uncommon (≥ 1/1000, < 1/100); rare (≥ 1/10,000, < 1/1000); very rare (< 1/10,000), including isolated reports; frequency not known (frequency cannot be estimated from the available data).

Since most adverse effects were identified from spontaneous reports during the post-marketing period, it is not possible to precisely estimate their frequency.

Immune system disorders:
Rash, skin hyperemia, anaphylaxis.
Frequency not known: hypersensitivity reactions such as sweating, anaphylactic shock, tachycardia, and skin reactions including acne, eczema, pruritus, and urticaria.

Gastrointestinal disorders:
Increased gastric juice acidity.
Frequency not known: gastrointestinal complaints such as nausea, vomiting, diarrhea, and abdominal pain.

Skin and subcutaneous tissue disorders:
Frequency not known: eczematous skin lesions, acne, and acneiform rashes have been observed following high-dose vitamin B12 administration.

Renal and urinary disorders:
Frequency not known: chromaturia (red discoloration of urine, observed within the first hours after administration and usually disappearing shortly after discontinuation of the drug).

Nervous system disorders:
Nervous excitement, malaise, dizziness, headache.
Frequency not known: long-term use (more than 6–12 months) of vitamin B6 at doses exceeding 50 mg per day may lead to peripheral sensory neuropathy. Symptoms gradually diminish after discontinuation of the vitamin.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after a medicinal product is authorized is of great importance. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals, as well as patients or their legal representatives, are encouraged to report all suspected adverse reactions and lack of efficacy via the Automated Information System for Pharmacovigilance at the following link: https://aisf.dec.gov.ua

Shelf life.

2 years.

Storage conditions.

Store at a temperature not exceeding 25 °C. Keep out of reach of children.

Packaging.

10 tablets per blister, 3 blisters per cardboard box, or 15 tablets per blister, 2 blisters per cardboard box.

Availability.

Over-the-counter.

Manufacturer.

P&G Health Austria GmbH & Co. OG, Austria.

Manufacturer’s address and place of business.

Hosslgasse 20, 9800 Spittal an der Drau, Austria.

To report an adverse reaction or lack of efficacy with the medicinal product, please contact Dr. Reddy’s Laboratories Ltd., Ukraine, at the following numbers (available 24/7):
+380 44 207 51 97 or +380 50 414 39 39; or by email: [email protected]