Neurological disease caused by vitamin B deficiencies

Posology

One film-coated tablet once daily. In individual cases, the dose may be increased to one film-coated tablet 3 times daily.

The film-coated tablets are to be swallowed whole with plenty of liquid after meals.

Duration of administration

The physician in charge should decide on the duration of administration.

After a maximum period of four weeks, it should be decided whether to reduce the dose.

(See section 4.4 ‘Special warnings and precautions for use’)

Paediatric population

3V film-coated tablets must not be used in children and adolescents (< 18 years).

The clinical picture as well as the laboratory parameters of funicular myelosis or of pernicious anaemia can lose specificity by administration of vitamin B₁₂.

If symptoms of peripheral sensory neuropathy (paraesthesia) occur, the dosage should be reviewed and treatment with the medicinal product discontinued, if necessary. Neuropathies have been observed under long-term intake (over 6-12 months) of daily dosages exceeding 50mg vitamin B₆ as well as in short-term intake (over 2 months) of more than 1 g vitamin B₆ per day. Therefore, regular monitoring is recommended under long-term treatment.

3V film-coated tablets contain Lactose monohydrate. therefore, its use is not recommended in patients with rare hereditary problems of galactose intolerance, total lactose deficiency or glucose-galactose malabsorption.

Thiamine is inactivated by 5-fluorouracil as the latter competitively inhibits the phosphorylation of thiamine to thiamine pyrophosphate.

Antacids diminish the absorption of thiamine.

Loop diuretics, e.g. furosemide that inhibit tubular reabsorption may cause increased excretion of thiamine in long-term therapy and, thus, lowering of the thiamine serum level.

If taken simultaneously with L-dopa, vitamin B₆ can lessen the dopa effect.

The simultaneous administration of pyridoxine antagonists (e.g. isoniazide (INH), hydralazine, D-penicillamine or cycloserine) may decrease the efficacy of vitamin B₆ (pyridoxine).

Long term use of acid lowering agents may lead to vitamin B₁₂ deficiency.

Alcohol and black tea diminish the absorption of thiamine.

Beverages containing sulphite (e.g. wine) enhance thiamine degradation.

Pregnancy

During pregnancy and the nursing period the generally recommended daily dosage of vitamin B₁ is 1.4 mg and of vitamin B₆ 1.9 mg.

These dosages may be exceeded in pregnant patients with manifest vitamin B₁ and B₆ deficiencies only as the safety of doses higher than the recommended daily dosage has not yet been demonstrated.

There are only insufficient animal studies on the effect of this medicinal product on pregnancy, embryo-foetal, prenatal and postnatal development. The possible risk for human beings is not known. The treating physician should decide about the use of this product during pregnancy after carefully weighing the risk-to-benefit ratio.

Breastfeeding

Vitamins B₁, B₆ and B₁₂ are secreted into human breast milk. High concentrations of vitamin B₆ i.e. > 600mg daily, can inhibit the production of breast milk. Data on the extent of secretion into breast milk from animal studies are not available. Therefore, the advantages of breast-feeding for the infant should be carefully weighed against the therapeutic benefit for the women in order to decide to either discontinue breast-feeding or therapy with the tablets.

The film-coated tablets do not affect or has negligible influence on the capability to drive a vehicle or to operate machinery.

In the following, the undesirable effects are classified by organ system and frequency. The assessment of undesirable effects is based on the following frequency grouping:

§ 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)

§ Very rare (< 1/10,000),

§ Not known (frequency cannot be estimated from the available data)

Nervous system disorders:

Not known: Long-term intake (> 6-12 months) of a daily dosage > 50 mg vitamin B₆ may cause peripheral sensory neuropathy.

Gastrointestinal disorders:

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

Immune system disorders:

Very rare: Hypersensitivity reactions such as sweating, tachycardia and skin reactions like itching and urticaria.

Renal and urinary disorders:

Not known: Chromaturia (“reddish urine”, appeared during the first 8 hours after an administration and typically resolves within 48 hours).

Healthcare professionals are asked to report any suspected adverse reactions via:

§ Saudi Arabia:

The National Pharmacovigilance Centre (NPC):

-        Fax: +966-11-205-7662

-        SFDA Call Centre: 19999

-        E-mail: npc.drug@sfda.gov.sa

-        Website: https://ade.sfda.gov.sa/

§ Other GCC States:

-        Please contact the relevant competent authority.

Vitamin B₁:

Thiamine has a broad therapeutic range. Very high doses (over 10 g) have a ganglion-blocking effect, similar to that of curare, and suppress the conduction of nerve impulses.

Vitamin B₆:

The toxic potential of vitamin B₆ can be considered as very low. Long-term intake (> 6-12 months) of a daily dosage > 50 mg vitamin B₆ may, however, cause peripheral sensory neuropathy and other sensorial neuropathy syndromes. These symptoms improve gradually upon vitamin discontinuation.

Continuous intake of vitamin B₆ at a daily dosage of more than 1 g over more than two months may produce neurotoxic effects.

Neuropathies with ataxia and sensitivity disorders, cerebral convulsions with EEG changes as well as, in individual cases, hypochromic anaemia and seborrhoeic dermatitis have been described after administration of more than 2 g daily.

Vitamin B₁₂:

Allergic reactions, eczematous skin changes and a benign form of acne have been observed after high parenteral doses (in rare cases also after oral doses).

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

ATC Code: A11DB

3V film-coated tablets contain a combination of neurotropic active substances of the vitamin B complex. The vitamins thiamine (B₁), pyridoxine (B₆) and cobalamin (B₁₂) contained, play a particular role as coenzymes in the intermediary metabolism of the central and peripheral nervous system.

Like all other vitamins, they are essential nutrients which the body cannot synthesise itself.

Therapeutic supply of vitamins B₁, B₆ and B₁₂ may supplement inadequate nutritive vitamin intake and thus ensure the availability of the required quantities of coenzymes.

The therapeutic use of these vitamins in disease of the nervous system serves, on the one hand, to compensate for concomitant deficiencies (possibly due to an increased requirement induced by the disease) and on the other, to stimulate natural repair mechanisms.

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.

Models used in animal studies have indicated analgetic activity for vitamin B_1.

Manifestations of vitamin B₁ deficiency are very multifaceted and can involve central and peripheral nervous system the cardiovascular system, skin and other body systems. Specific symptoms can include polyneuropathy with paraesthesia (tingling, burning, numbness), hyperesthesia (increased sensitivity), muscle weakness, altered temperature sensitivity, oedema, and others.

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. Animal experimental models have demonstrated that vitamin B₆ has an analgesic effect. Vitamin B₆ deficiency can be associated with peripheral neuritis and neuropathy, paresthesia, burning, painful dysesthesia, disorders of oxalate metabolism, depression of immune responses, anemia, lesions of the mucous membranes and other symptoms.

Cobalamin (vitamin B₁₂)

Vitamin B₁₂ in its coenzyme forms (5-deoxyadenosyl cobalamin and methyl cobalamin) is involved in enzymatically catalysed intramolecular hydrogen displacements and in intramolecular transfers of methyl groups. Vitamin B₁₂ is also involved in methionine synthesis (closely coupled to the synthesis of nucleic acids) and in lipid metabolism, via the conversion of propionic acid into succinic acid. Vitamin B₁₂ is involved in the methylation of the myelin basic protein, a constituent of the myelin sheaths of the nervous system. Methylation increases the lipophilic properties of the myelin basic protein, which favours increased integration in the 

myelin sheaths.

Vitamin B₁₂ deficiency can result in neurological symptoms like paresthesia, numbness, gait impairment, impaired vibration sense, polyneuritis (particularly sensory, in the distal extremities), ataxia 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 atone, and in combination as the result of biochemical synergy, have special significance for the metabolism of the nervous system, which justifies their combined use.

Further, in most of the patient populations such as elderly, diabetic patients and others, deficiency of all three neurotropic vitamins is present.

Animal studies have shown that this combination of neurotropic B vitamins accelerates regenerative processes in damaged nerve fibres, which finally leads to enhanced restoration of function and muscle innervation. In the model of experimental diabetes in rats, administration of B complex vitamins prevented or attenuated the characteristic nerve damage, so that deterioration of the functional properties was counteracted (antineuropathic effect).

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

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):

Has after oral administration a dose-dependent dual transport mechanism: Active absorption up to concentrations of 2 μmol and passive diffusion in concentrations over 2 μmol).

There is almost no absorption in the stomach and in distal segments of the small intestine. Thiamine formed by the large intestinal flora is not absorbed. 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.

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

The human body can store approx. 30mg thiamine. On account of the rapid metabolisation, the reserve capacity, at 4-10 days is very limited.

Pyridoxine (vitamin B₆):

Pyridoxine is absorbed very rapidly, mainly in the upper gastrointestinal tract, and is excreted with a maximum between 2 and 5 hours.

Vitamins are bound to albumin. Vitamin B₆ passes into the spinal fluid, is secreted into breast milk, and permeates the placenta. The principal excretion product is 4-pyridoxic acid; the amount of the latter depending on the vitamin B₆ dose taken up.

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. The storage capacity for vitamin B₆ is 14 to 42 days. Approx. 40 to 150 mg can be stored; 1.7 to 3.6 mg is excreted in the urine per day.

Cobalamin (vitamin B₁₂):

Cobalamin is absorbed from the gastrointestinal tract by means of 2 mechanisms:

§ Release through gastric acid and immediate binding to the intrinsic factor. A maximum of 1.5-2 μg of oral vitamin B₁₂ is absorbed via this mechanism

§ Independently of the intrinsic factor through passive influx in the blood

At doses over 1.5 μg the latter mechanism increases in significance.

Patients with pernicious anaemia absorb approx. 1% of oral doses of 100 μg and over.

Vitamin B₁₂ is stored predominantly in the liver; the daily requirement is 1 μg.

The turnover rate is 2.5 μg B₁₂ per day, or 0.05% of the stored quantity. The biological half-life is about 1 year.

Vitamin B₁₂ is mainly secreted into bile and largely reabsorbed during the enterohepatic circulation.

The toxicity of vitamins B₁, B₆ and B₁₂ is very low. The data available to date do not suggest any potential risk for humans.

The literature available on the subject does not contain any findings indicating that vitamins B₁, B₆ and B₁₂ have carcinogenic, mutagenic or teratogenic properties.

Chronic toxicity: In animals, very high doses of vitamin B₁ cause bradycardia. Other symptoms are blockade of vegetative ganglia and motor end plates. The oral administration of 150–200 mg of vitamin B₆/kg body weight/day over a period of 100-107 days caused ataxia, muscular asthenia, disorders of balance, as well as degenerative changes of axons and myelin sheaths in dogs. Animal studies also showed incidences of convulsions and impaired coordination after high doses of vitamin B₆.

Mutagenic and tumorigenic potential: Mutagenic effects of vitamin B₁ and vitamin B₆ are not to be expected under the conditions of clinical use.

There are no long-term animal studies available on the tumorigenic potential of thiamine and vitamin B₆.

Reproduction toxicity: Thiamine is transported actively to the foetus. Concentrations in the foetus and the newborn exceed maternal concentrations of vitamin B₁. Systematic investigations on human embryonal and foetal development in connection with the use of vitamin B₁ at doses exceeding the stated daily requirements are not available.

Vitamin B₆ is insufficiently investigated in animal studies. An embryotoxicity study in rats gave no indications of a teratogenic potential. In male rats the administration of very high doses of vitamin B₆ induced damage to spermatogenesis.

Not applicable.

Store below 30ºC, in dry place, protected from light.

§ Pack of 20 Tablets: 2 × 10's tablets in PVC Film, laminated with Aclar, packed in a printed carton along with leaflet.

§ Pack of 1000 Tablets: 100 × 10's tablets in PVC Film, laminated with Aclar, packed in a printed carton along with leaflet.

* Not all pack sizes may be marketed.

No special requirements.