Neurological diseases caused by severe vitamin B₁, B₆ and B₁₂ deficiencies that cannot be remedied by means of oral therapy.

Posology

In severe (acute) cases: One ampoule daily until the acute symptoms subside.

After improvement of symptoms: One ampoule 1-3 times per week.

Paediatric population:

3V ampoules are contraindicated in children below 14 years (see section 4.3).

Method of administration

For intramuscular administration

3V ampoules are to be administered intramuscularly (by deep intragluteal injection).

3V film-coated tablets are recommended for supporting or continuing on going injection therapy and for relapse prophylaxis.

The ampoules must not be administered by intravenous injection.

Short-term parenteral vitamin B₁₂ administration may temporarily impair the diagnosis of funicular myelosis or pernicious anaemia.

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 administration (over 6-12 months) of daily dosages exceeding 50 mg vitamin B₆ as well as in short-term administration (over 2 months) of more than 1 g vitamin B₆ per day. Therefore, regular monitoring is recommended under long-term treatment.

The ampoules must not be used in children below the age of 14 years (due to their high active substance content).

Each ampoule contains sodium. This is to be taken into account in persons under sodium-restricted diet (low in table salt/sodium).

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

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.

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

Pregnancy

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.

Lactation

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 ampoules.

The ampoules do not affect 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, <1/10)

§ Uncommon (≥1/1,000, <1/100)

§ Rare (≥1/10,000, < 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, as well as anaphylaxis.

Skin and subcutaneous tissue disorders:

Not known: Allergic reactions, eczematous skin alterations and a benign form of acne have been observed after high-dose vitamin B₁₂.

Renal and urinary disorders:

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

General disorders and administration site conditions:

Not known: Injection-site reactions.

To report any side effect(s):

§ 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 treatment (> 6-12 months) of a daily dosage > 50 mg vitamin B₆ may, however, cause peripheral sensory neuropathy. 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 alterations and a benign form of acne have been observed after high-dose parenteral administration.

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

ATC Code: A11DB

3V ampoules 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 balances deficiencies due to inadequate nutritive vitamin intake and thus ensures the availability of the required quantities of coenzymes.

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 analgesic effect.

Manifestations of vitamin B₁ deficiency are very multifaceted and can involve the central and peripheral nervous system the cardiovascular system, the 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 B, 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.

Animal and clinical studies have indicated antinociceptive activity of vitamin B₁, B₆ and B₁₂.

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):

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

The reserve capacity is 4 - 10 days. The high turnover rate and limited storage of thiamine (20- 30 mg, mainly in the heart, brain, liver, and kidneys) require an adequate daily thiamine intake to meet requirements. Deficiency can present within 2-3 weeks of intake ceasing. Typical symptoms are tiredness, nausea, vomiting, obstipation, headache, tachycardia, and weak muscle reflexes.

Pyridoxine (vitamin B₆):

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. 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. Approx. 40 to 150 mg can be stored; 1.7 to 3.6 mg is excreted in the urine per day.

Cobalamin (vitamin B₁₂):

Oral vitamin B₁₂ is known to have a low absorption rate which may be further decreased, following bariatric surgery, in elderly patients, dialysis patients and patients with other conditions of malabsorption. Apart from saturable active absorption of oral vitamin B₁₂, leading to daily absorption of approximately I.5μg, vitamin B₁₂ is also absorbed by passive diffusion. The proportion absorbed by passive diffusion is only approximately 1% of the ingested quantity. This is further reduced in patients who have had bariatric surgery or have an impaired gastrointestinal absorption due to other diseases. In these patients, parenteral application may be indicated.

About 90% of plasma cobalamin is bound to proteins (transcobalamins). Most of the Vitamin B₁₂ not circulating in the plasma 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.

Vitamin B₁₂ is mainly excreted via the bile and largely reabsorbed during the enterohepatic circulation. If the body's storage capacity is exceeded as a result of high-dose and, in particular, parenteral administration, the portion not retained is excreted in the urine.

Results of pharmacokinetic studies using parenteral vitamin B preparations suggest that intramuscular and intravenous B-vitamins lead to higher cyanocobalamin plasma levels than high oral doses. In addition, parenteral and oral preparations of vitamins B₁, B₆ and B₁₂ are equally well tolerated. Consequently, parenteral application of vitamins B₁, B₆ and B₁₂ may be adequate for rapid restoration of vitamin stores in acute deficiencies and in patients with vitamin B absorption problems and in patients with an increased need due to certain pathological conditions.

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.

Inactive Ingredients:

1. Sodium hydroxide pellets
2. Benzyl alcohol
3. Water for injection
4. Nitrogen

None

Store at a temperature of 2-8ºC, protected from light and heat.

§ 3mL injection in an amber coloured glass ampoule with a printed label, 3 ampoules in an ampoule tray, packed in a printed carton along with a leaflet.

§ 3mL injection in an amber coloured glass ampoule with a printed label, 50 ampoules in an ampoule tray, packed in a printed carton along with a leaflet.

None