Summary of Product Characteristics (SmPC) - Neurobion 100 mg/50 mg/1 mg film-coated tablets

1 NAME OF THE MEDICINAL PRODUCT

Neurobion 100 mg/50 mg/1 mg film-coated tablets

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each film-coated tablet contains: 100 mg thiamine nitrate, 50 mg pyridoxine hydrochloride and 1 mg cyanocobalamin.

Excipients with known effect

Each film-coated tablet contains 1.2 mg of sodium.

For the full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Film-coated tablet

White round, biconvex, film-coated tablet

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

Neurobion is indicated for the prevention and treatment of vitamin B1, B6 and B12 deficiencies in adults. These deficiencies may result in mixed sensory-motor polyneuropathy in certain circumstances: where intake is insufficient, absorption is impaired or there is increased loss or requirement of these vitamins.

4.2 Posology and method of administration

Posology

Adults:

1 tablet daily.

Patients should be advised to consult their doctor if symptoms persist after 30 days of treatment or if symptoms get worse.

Paediatric population:

Neurobion is contraindicated in children and adolescents below the age of 18 years (see section 4.3).

Method of administration

Oral use only. The tablet should be swallowed whole with liquid and taken with or after meals.

4.3 Contraindications

Hypersensitivity to the active substances or to any of the excipients listed in section 6.1.

Children and adolescents below the age of 18 years due to high dose of the active ingredients.

4.4 Special warnings and precautions for use

Patients should be advised to stop treatment and consult a physician if they experience any new symptoms.

Vitamin B12 (cyanocobalamin) may improve folate-deficient megaloblastic anaemia. Use of this product may improve this condition due to the presence of vitamin B12 (cyanocobalamin) and care should be taken that a correct diagnosis is not masked.

Excipients with known effect

Sodium: this medicine contains less than 1 mmol sodium (23 mg) per film-coated tablet, that is to say essentially ‘sodium-free’.

4.5 Interaction with other medicinal products and other forms of interaction

Vitamin B6 (pyridoxine) may decrease the therapeutic effect of L-DOPA.
DOPA decarboxylase inhibitors such as carbidopa or benserazide bind to pyridoxal phosphate and may lead to vitamin B6 depletion.
Pyridoxine antagonists such as isoniazide, cycloserine, penicillamine, or hydralazine may decrease the efficacy of vitamin B6 (pyridoxine).
Long-term use of loop diuretics such as furosemide may accelerate the elimination and thus decrease the serum levels of vitamin B1 (thiamine) and may also decrease the serum levels of vitamin B6 (pyridoxine).
Alcohol reduces the absorption and reabsorption of vitamin B1 (thiamine).

4.6 Fertility, pregnancy and lactation

Fertility

The effect of the combination of vitamin B1, B6, B12 on human fertility has not been proven in clinical trials.

Pregnancy

The potential risk for humans is unknown. Use during pregnancy should only be considered upon careful benefit/risk assessment by a physician.

Breast-feeding

Thiamine, pyridoxine and cyanocobalamin are secreted into human breast milk, but risks of overdose for the infant are not known.

Use during breastfeeding should only be considered upon careful benefit/risk assessment by a physician.

4.7 Effects on ability to drive and use machines

Neurobion has no influence on the ability to drive and use machines.

4.8 Undesirable effects

Adverse events are listed below by system organ class and frequency. Frequencies are defined as: 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) and very rare (<1/10,000) including isolated reports. Frequency not known (cannot be estimated from the available data).

As most undesirable effects are based on post-marketing spontaneous reporting, precise frequency estimation is not possible.

Immune system disorders:

Frequency not known: Hypersensitivity reactions, such as sweating, tachycardia, and skin reactions with itching and urticaria.

Gastrointestinal disorders:

Frequency not known: Gastrointestinal complaints, such as nausea, vomiting, diarrhoea and abdominal pain.

Renal and urinary disorders:

Frequency not known: Chromaturia (“reddish urine”, appeared during the first hours after an administration and typically resolves shortly after product discontinuation).

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme website at www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9 Overdose

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

Neuropathies are described in the literature following long term intake (6 months or longer) of more than 50 mg mean daily dose of vitamin B6, which improve gradually upon vitamin discontinuation.

Treatment of overdose consists of discontinuation of the product and other measures as clinically indicated.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: vitamin B1 in combination with B6 and/or B12

ATC-Code: A11DB

The product contains vitamins B1, B6 and B12 which act as coenzymes essential for the metabolism of different tissues including peripheral and central nerve cells. Thus, these vitamins play an important role in maintaining the structural and functional properties of the nervous system. Vitamins B1, B6 and B12, play essential roles in the metabolism, regeneration, and maintenance of nerves through various neurotrophic and neuroprotective effects. This may explain why neurological signs and symptoms (e.g., tingling, numbness or hypersensitivity, allodynia, neuropathic pain, paraesthesia, impairment of sensation, perception threshold, slowed nerve conduction velocity, temperature sensitivity) can manifest in cases of deficiency.

Thiamine (vitamin B1)

Thiamine pyrophosphate (TPP) is the effective form of vitamin B1 and acts as a coenzyme for a number of enzymes (e.g. pyruvate dehydrogenase and transketolase). Accordingly, vitamin B1 is primarily involved in the carbohydrate metabolism; however, it also intervenes in the synthesis of lipids and amino acids. Nerve cells cover their energy requirement exclusively via enzymatic oxidation and decarboxylation of glucose, so that an adequate supply of vitamin B1 is of crucial importance. Thiamine is also involved in the conduction of nerve impulses. Furthermore, results obtained in experiments indicate an antinociceptive effect.

Vitamin B1 deficiency can occur e.g. in diabetic patients, elderly, patients with gastrointestinal diseases, haemodialysis patients, malabsorption, chronic alcoholism or increased requirements of vitamin B1. The major clinical manifestations and disorders of vitamin B1 deficiency in humans involve the nervous and cardiovascular systems. Fatigue, irritability, weakness, aching, burning sensation in hands and feet, sensation disturbances, gait ataxia, indigestion, irritability, depression may appear within days to weeks of nutritional deficiency as early symptoms.

Pyridoxine (vitamin B6)

Pyridoxal phosphate, the biologically active form of pyridoxine, is the determinative coenzyme in amino acid metabolism. It is involved in the formation of physiologically active amines (e.g. serotonin, histamine, adrenalin) through decarboxylation processes, as well as in anabolic and catabolic processes through transamination.

Pyridoxal phosphate plays an essential role in the nervous system, especially in the enzymatically controlled neurotransmitter metabolism. As a catalyst of the first biosynthesis steps of sphingosine, pyridoxal phosphate also has a key role in the metabolism of sphingolipids. Sphingolipids are essential constituents of the myelin sheaths of nerve cells.

Vitamin B6 deficiency in adults may affect the nerves resulting in polyneuropathy and seizures as well as possibly impaired cognitive functions. Other affected body parts are the skin (seborrheic dermatitis), mucous membranes, circulatory system and the immune system. A lack of B6 also can cause nausea, vomiting, depression, disorders of oxalate metabolism, and anaemia. There are different risk groups, which require a higher amount of vitamin B6 e.g. diabetic patients, elderly, patients with gastrointestinal diseases etc. Low vitamin B6 intake and status have been associated with impaired immune function and susceptibility to infections, especially in the elderly. Vitamin B6 is unique in that either deficiency or excess can cause peripheral neuropathy symptoms.

Cobalamin (vitamin B12)

Vitamin B12 in its coenzyme forms (5-deoxyadenosyl cobalamin and methyl cobalamin) is involved in nucleic acid metabolism and DNA synthesis, especially haematopoiesis, myelin synthesis and maintenance of myelin sheaths, and synthesis of epithelial tissue. Vitamin B12 is also involved in the synthesis of neurotransmitters and is a principal component of fatty acid and carbohydrate metabolism.

Different populations are at risk of developing vitamin B12 deficiency e.g., diabetic patients, elderly, patients with gastrointestinal diseases and others. Vegetarians and vegans in particular, have an increased risk of developing a vitamin B12 deficiency since foods from animal sources are the only sources of vitamin B12. Also particularly at risk are infants from mothers with a vitamin B12 deficiency. Malabsorption of vitamin B12 leading to deficiency can occur at several points during digestion. The most important condition resulting in vitamin B12 malabsorption and deficiency is auto-immune gastritis called pernicious anaemia which is characterized by destruction of the gastric mucosa, and the presence of parietal cell and intrinsic factor antibody. Vitamin B12 deficiency can result in neurological symptoms like paresthesia, numbness, gait impairment, polyneuritis (particularly sensory, in the distal extremities) and others. Further symptoms can be anaemia, optic atrophy, altered mental status and others.

Combination of vitamins B1, B6, and B12

Neurotropic vitamins B1, B6 and B12 alone, and in combination as the result of biochemical synergy, have special significance for the metabolism of the nervous system, which justifies their combined use. Additionally, all three neurotropic B vitamins contribute to nerve health via a different mode of action and all three are essential.

Further, in most of the patient populations such as elderly, diabetic patients, patients with gastro-intestinal diseases such as inflammatory bowel disease, gastro-intestinal surgery (e.g. bariatric surgery), gastritis, celiac disease, repeated vomiting and prolonged diarrhoea and others, deficiency of all three neurotropic vitamins is present.

Further, the combination of vitamins B1, B6 and B12 has been proven to have a synergistic effect when combined with NSAIDs in the treatment of pain.

5.2 Pharmacokinetic properties

Combined administration of vitamins B1, B6 and B12 is not expected to have a negative effect on the pharmacokinetics of the individual vitamins.

Thiamine (vitamin B1)

Vitamin B1 administered orally is assumed to have a dose-dependent dual transport mechanism, namely active absorption at concentrations of up to 2 µmol and passive diffusion at concentrations exceeding 2 µmol. Absorption takes place primarily in the proximal part of the small intestine. Absorption of thiamine takes place after phosphorylation in the epithelial cells; a carrier mechanism is assumed to be involved in the passage through the intestinal wall.

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

Vitamin B1 is found throughout the body, and has particularly high concentrations in the brain, skeletal muscle, liver, heart, and kidney.

Vitamin B1 is eliminated mainly in the urine either unchanged or as several (about

20) metabolites.

The biological half-life of thiamine in humans is about 9.5 to 18.5 days, with an elimination half-life of approximately 4 hours. The reserve capacity is 4 to 10 days.

Pyridoxine (vitamin B6)

Vitamin B6 (pyridoxine, pyridoxal and pyridoxamine) is rapidly absorbed, predominantly in the upper gastrointestinal tract, and transported bound to albumin (especially pyridoxalphosphate) to organs and tissues.

Vitamin B6 is phosphorylated mainly in the liver, forming the biologically active pyridoxal phosphate. To cross cell membranes, phosphorylated vitamin B6 must be hydrolysed by alkaline phosphatase to free vitamin B6. Transport into the cells is by simple diffusion followed by rephosphorylation, and a specialized intestinal carrier-mediated system for pyridoxine uptake has been discussed recently. Peak concentrations are reached after 3.5 to 4 hours. The biological half-life of pyridoxal phosphate is about 15 - 25 days with an elimination half-life of approximately 3 hours. The storage capacity for vitamin B6 is 14 to 42 days.

Vitamin B6 is excreted in urine. The principal excretion product is 4-pyridoxic acid; the amount of the latter depending on the vitamin B6 dose taken up. Vitamin B6 is secreted into breast milk and permeates the placenta.

Cobalamin (vitamin B12)

Absorption of vitamin B12 from the gastrointestinal tract takes place by two mechanisms:

An active mechanism is mediated by the “intrinsic factor” (IF), which is secreted by the parietal cells in the gastric mucosa. After release from haptocorrin, vitamin B12 immediately binds to the intrinsic factor. The cobalamin-intrinsic-factor-complex is formed and attached to a specific ileal receptor protein on the luminal surface of the ileal mucosa. The complex enters mucosal cells by receptor mediated endocytosis. A maximum of 1.5-2µg of oral vitamin B12 is absorbed via this mechanism.

Independently of the intrinsic factor, vitamin B12 may enter the bloodstream by passive, non-saturable diffusion. Passive diffusion accounts for 1-2% of total absorption and is unaffected in patients with gastro-duodenal surgical resection or other gastro-intestinal diseases affecting the IF mediated B12 absorption and can take place along the entire small intestine.

In the body, vitamin B12 is stored in depots, the liver being the most important of these (about 1.5mg), followed by the kidneys, heart, spleen and brain. The total body content of vitamin B12 varies; however, most estimates are ~2–3mg. The turnover rate is 2.5µg B12 per day, or 0.05% of the total amount stored in the body. The biological half-life is about 1 year.

Vitamin B12 is mainly secreted in the bile and is largely reabsorbed via the enterohepatic circulation. If the storage capacity of the body is exceeded by high doses of B12, particularly due to parenteral administration, the proportion which cannot be retained is excreted in the urine.

5.3 Preclinical safety data

Available literature does not contain any findings indicating that thiamine, pyridoxine and cyanocobalamin have carcinogenic, mutagenic or teratogenic properties.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Tablet core

microcrystalline cellulose

gelatin

croscarmellose sodium

hypromellose

magnesium stearate

silica colloidal anhydrous

sodium starch glycolate

Clear coating

poly (vinyl alcohol)

talc

glycerol monocaprylocaprate

sodium laurilsulfate

White coating

hypromellose

polydextrose

titanium dioxide

macrogol

Polish

beeswax white

carnauba wax

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

2 years

6.4 Special precautions for storage

This medicinal product does not require any special storage conditions.

6.5 Nature and contents of container

Each pack contains 30 tablets which are packed in a PVC blister foil coated with PVDC. The blister is covered by an aluminium foil.

6.6 Special precautions for disposal

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

7 MARKETING AUTHORISATION HOLDER

Procter & Gamble (Health and Beauty Care) Limited

The Heights

Brooklands

Weybridge

Surrey

KT13 0XP

8 MARKETING AUTHORISATION NUMBER(S)

PL 00129/0364

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE

AUTHORISATION

03/04/2024

10 DATE OF REVISION OF THE TEXT