SUMMARY OF PRODUCT CHARACTERISTICS |. NAME OF THE MEDICINAL PRODUCT. Neurobion coated tablets 2. QUALITATIVE AND QUANTITATIVE COMPOSITION One coated tablet contains: ‘Thiamine disulphide (vitarain Bx) 200 mg, Pyridoxine hydrochloride (vitamin Bs) 200 mg. Cyanooobalamin (vitemin Biz) 200 ue Excipients: Contains 133.22 mg sucrose. For a complete list of excipients see section 6.1. 3. PHARMACEUTICAL FORM Coated tablet White, shiny, round, biconvex coated tablet, cur ICAL PARTICULARS, 4.1 Therapeutic indications Neurological diseases caused by vitamin B deficiencies. 42 Posology and method of administration Posology ‘One coated tablet once daily. In individual cases, the dose may be increased to one costed tablet 3 times daily. ‘The 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 shoufd be decided whether to reduce the dose. (See section 44 ‘Special warnings and precautions for use”) Paediairic population ‘Neurobion coated tablets must not be used in children and adolescents (< 18 years) 43° Contraindications ~ Hypersensitivity to the active substances or to any of the excipients listed in section 6.1. ~ Neurabioit coated tablets must not be used in children and adolescents due to their high active substance content. Neuroblon fabs SPC 17v042 CCDS (ATI61017) Page 1 of744 Special warnings and precautions for use ‘The clinical picture as well as the laboratory parameters of funicular myelosis or of pernicious anaemia can lose specificity by administration of vitamin Bie. if symptoms of peripheral sensory neuropathy (parnesthesia) 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 50 mg vitamin Bg as wel! as in short-term intake (over 2 months) of more than | g vitamin Be per day. Therefore, regular monitoring is recommended under long-term treatment ‘This drug contains sucrose; therefore its use is not recommended in patients with rare hereditary problems of fructose intolerance, gluease-gelactose malabsorption or sucrase-isomaltasc insufficiency. 4S Interaction with other medici J products and other forms of interaction ‘Thiamine is inactivated by S-fluorouraci as the later competitively inhibits the phosphorylation of imine 1 thiamine pyrophosphate. Antacids diminish the absorption of thiamine, Loop diuretics, eg, 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~dope, vitamin B. can lessen the dopa effect. ‘The simultancous 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 fea diminish the absorption of thiomine, Beverages containing sulphite (e.g, wine) enhance thiamine degradation. 46 Fertility , pregnaney and lactation Pregnancy During pregnancy and the nursing period the generally recommended 1.4 mg and of vitamin Bs 1.9 mg. ‘These dosages may be excecded in pregnant patients with manifest vitamin By and Bg 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 produet 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. dosage of vitamin Br is, Breast-feeding Vitamins By, Bs and Bz are secreted into human breast milk. High concentrations of vitamin B, Le. > 600 mg 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 thetapeutic benefit for the women in order to decide (o either discontinue breast-feeding or therapy with Neurobion. 47 Effects on abitity to drive and use machines Neurobion coated tablets do not affect the capabi to drive a vehicle or to operate machinery. Neurebion tabs SPC 17v042 GODS (ATIB1017) Page 2 of748 Undesirable effects In the following, the undesirable effects arc classified by organ system and frequency, The assessment ‘of undesirable effects is based on the following frequency groupi Very common(2 1/10) Common (21/100, to <1/10) Uncommon 11.000, to <1/00) Rare {©1/10.000, to <1/1.000) Very rare (<1/10.000), Not known (frequency cannot be estimated from the available data) Nervous systom disorders: ‘Not known: Long-term intake (> 6-12 months) of a daily dosage > $0 mg vitamin Bs may cause peripheral sensory neuropathy. Gostrointestinal disorders: ‘Unknown: Gastrointestinal complaints such as nausea, vomiting, diarrhoca and abdominal pain. Inmime sysiem disorders: ‘Very rare: Hypersensitivity reactions such as sweating, tachycardia and skin reactions like itching anal urticaria, Renal and wrinary disorders ‘Not knossn: Chromaturia (“reddish urine”, appeared during the first 8 hours after an administration and typically resolves within 48 hours). Reporting of suspected adverse reactions: Reporting suspected adverse reactions is an snonitor the benefit/risk balance of the medicinal product, Any suspected adverse reactions should be reported to Pharmaceutical Services, Ministry of Health, CY-1475, [Link]/phs Fax: + 357 22608649 49 Overdose Viternin By: ‘Thiamine has a broad therapeutic range, Very high doses (over 10 g) have a ganglion-blocking effect, similar to that of eurare, and suppress the conduction of nerve impulses. Vitamin Bes The toxic potential of vitamin Bg can be considered as very low. Long-term intake (> 6-12 months) of ‘a daily dosage > 50 mg vitamin Bs may, however, cause peripheral sensory neuropathy and other sensorial neuropathy syndromes. These symptoms improve gradually upon vitamin discontinuation. Continuous intake of vitamin Bg ata daily dosage of more than | 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 seborthoeic dermatitis have been described after administration of more then 2 g daily, Vitamin B Allergic reactions, eezematous skin changes and a benign form of acne have been observed after high Parenteral doses (in rare cases also after oral doses). Neurabion tabs SPC 17v042 CCDS (ATIE1017) Page 3 ot75. PHARMACOLOGICAL PROPERTIES 3.1 Pharmacodynamic properties Pharmacotherapeutic group: Vitamin B; in combination with vitamin Be and/or vitarnin Bis ATC Code: ALIDB ‘Neurobion coated tablets contain a combination of neurotropic active substances of the vitamin B complex, The vitamins thiamine (B1), pyridoxine (Be) and cobalamin (B12) contained play a particular role as coenzymes in the intermediary metabolism of the central and peripheral nervous system. Like all other vitarnins, they are essential nutrients which the body cannot synthesise itself, ‘Therapeutic supply of vitamins By, Bs and Biz may supplement inadequate nutritive vitamin intake and thus ensure the availability of the requited quantities of coenzymes. ‘The therapeutic use of these vitamins in diseases 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 stitmulate natural repair mechanisms. ‘Thiamine (vitamin 81) ‘Thiamine pyrophosphate (TPP) isthe effective form of vitamin Bl and acts as a coenzyme for 8 number of enzymes (e.g. pyruvate dehydragenase and transketolase). Accordingly, vitamin BI is marily involved in the carbohydrate metabolism; however, it also intervenes in the synthesis of lipids and amino acids. Nerve cells cover their eneray requirement exclusively via enzymatic tion and decarboxylation of glucose, so that an adequate supply of vitamin BI is of crucfal importance, Thiamine is also involved in the conduction of nerve impulses. Models used in animal studies have indicated analgetic activity for vitamin BI. ‘Manifestations of vitamin 81 deficiency are very multifaceted and can involve central and peripheral nervous system, the cardiovascular system, skin end other body systems . Specific symptoms can include polyneuropathy with paracsthesia (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. Iti involved in the formation of phystologically nctive amines (e.g. serotonin, histamine, adrenalin) through decarboxylation processes, as well as in anabolic and catabolic processes through transamination. Pyridioxal phosphate plays an essential role in the nervous system, especially in the enzymatically conuolled neurotranstnitter metabolism, As a catalyst of the first biosynthesis steps of sphingosine, pysidonal 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 vitemin B6 has an analgesic effect. Visamin BG 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 cof nucleic acids) and in lipid metabolism, via the conversion of propionic acid into succinic acid, Vitamin B12 is involved in the methylation of the myclin 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 ‘Nevrobion tabs SPC 17¥042 GEDS (ATI61017) Page dofVitamin B12 deficiency can result in neurological symptoms like paresthesia, numbness, gait, impairment, irypaired vibration sense, potyncuritis (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, 86 and B12 alone, and in combination as the reset of biochemical synergy, have special significance for the metabolism of the nervous system, which justifies their combined awe. Farther, in most of the patient populations such as elderly, diabetic patlents and others, deficiency of all three neurotropic vitamins is present. Animal studies have shown that this combination of neurotropie B vitamins accelerates regenerative processes in damaged nerve fibres, which finally leads to enhanced restoration of function and muscle innervation. In the mode! 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 hes been proven to have a synergistic effect when ‘combined with NSAIDs in the treatment of pain, 52 Pharmacokinetic properties Combined administration of vitamins BI, B6 and B12 is not expected to have a negative effect on the pharmacokinetics of the individual vitamins. ‘Thiarnine( vitamin B1) + Has after oral administration a dose-dependent dual transport mechanism: Active absorption up to concentrations of 2 mmol and passive diffusion in concentrations over 2 pmol). ‘There is almost no absorption in the stomach and in distal segments of the small intestine. Thia formed by the large intestinal fora is not absorbed. Absorption of thiamine takes place after phosphorylation in the epithelial cells; a carrier meckanism is assumed to be involved in the passage through the intestinal wall. ‘Afier 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 hous. ‘The human body can stare approx. 30 mg 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 ‘taximam between 2 and 5 hours, Vitamins are bound to albumin, Vitamin B6 passes into the spinal fluid, is secreted into beast milk, and permeates the placenta, The principal excrction product is 4-pyridoxic acid; the amount of the latter depending on the vitamin B6 dose taken up. ‘Vitamin BG is phosphorylated mainly in the liver, forming the biologically active pyridoxal phosphate. To cross cell membranes, phosphorylated vitamin 36 must be hydralysed by alkaline phesphatase to free vitamin BG, Transport into the celts 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 BG is 14 to 42 days. Approx. 40 t0 150 mg can be stored, 1.7 t0 3.6 mg is exereted in the urine per day. Neurobien tabs SPC 17v042 CCDS (ATIE1017) Page 507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 meximum of 1. coral vitamin 112 is absorbed via this mecaanisin + independently of the intrinsic factor through passive influx in the blood ‘At doses over 1.5 jg the latter mechanism increases in significance. Patients with pernicious anaemia absorb approx, 1% of oral doses of 100 11g and over. Vitamin B12 is stoted predominantly in the liver, the daily requirement is | pig ‘The turnover rate is 2.5 j4g Bia per day, ot 0.05% of the stored quantity. The biological half-life is about I year. Vitamin B 2 is mainly secreted into bile and largely reabsorbed during the enterohepatic circulation. 2ugof 5.3 Preciinical safety data ‘The toxicity of vitamins B, Bs and Bia 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 By, Bg and Byz have carcinogenic, mutagenic or teratogenic properties. ‘Chronic toxisity: In animals, very hight doses of vitamin B, cause bradycardia, Other symptoms are blockade of vegetative ganglia and motor end plates. The oral administration of 150-200 mg of vitamin Boke 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 eonvutsions and impaired coordination after high doses of vitamin By, ‘Mutagenic and tumorigenic potential: Mutagenic effects of vitamin B, and vitamin Bg 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 Be. Reproduction toxicity: Thiamine is transporced actively to the foetus. Concentrations in the foctus and. the newborn exceed maternal concentrations of vitamin By, Systematic investigations on human ‘embryonal and foetal development in connection with the use of vitamin By at doses exceeding, the stated daily requirements are not available. Vitamin Bis 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 Be induced damage to spermatogenesis. ina 6. PHARMACEUTICAL PARTICULARS: 6.1 List of excipients Tablet core: Magnesium stearate, Math! cellutose, sodium starch glycolate Gelatin, mannitol Tale, Glycerol 85%, colloidal anhydrous sitca, purified water Mentan-zlyco! wax, Gelat ‘Neurobion tabs SPC 17v0e2 CCDS (ATIET017) Page 6or7Methyl cellulose, Acacia, Glycerol 85 %, Povidone, Calcium carbonate, Colloidal anhydrous silica, Kolin, Titanium dioxide (E171), Tale, Sucrose 62 Incompauibtiities Not applicable. 63° Shelf life 2 years 64 Special precautions for storage Do not store above 25°C, 6.5 Nature and contents of container PYC fil coated with PYDC (40 gf m2) Aluminum Foil Water based print primer lacquer outside Packayo size 0 coated tablets 6.6 Special precautions for disposal No special requirements. 7. MARKETING AUTHORISATION HOLDER ave. (Building B") 15123 Marousi, Athens Greece 8. MARKETING AUTHORISATION NUMBER 794 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 05.04.1971 10, DATE OF REVISION OF THE TEXT: 31.03.2017 Neurobion tabs SPC 17042 OCOS {ATI61017) Page 7087SUMMARY OF PRODUCT CHARACTERISTICS NAME OF THE MEDICINAL PRODUCT ‘Neurobion ampoules 2, QUALITATIVE AND QUANTITATIVE COMPOSITION 3 ml of aqueous solution (J ampoule) contains: ‘Thiamine chloride hydrochloride (vitamin B,) 100 mg Pyridoxine hydrochloride (vitatnin Be) 100 mg Cyanecobatamin (vitamin Biz) Img Excipients: Contains 42 mg sodium per ampoule and traces of potassium. For a full list of excipients see section 6.1 3. PHARMACEUTICAL FORM Solution for injection Red, clear solution 4. CLINICAL PARTICULARS 4.1 Therapeutic indications Neurological diseases caused by severe vitamin B;, Be and Bra deficiencies that cannot be remedied by means of oral therapy. 42. Posology and method of administration Posolozy In severe (acute) cases: One ampoule daily untit the acute symptoms subside, After improvement of symptoms: One ampoule 1-3 times per week. Paediatric population ‘Neurobion ampoules are contraindicated in children below 14 years (see section 4.3). Method of administratior For intramuscular administration. Neurobion ampoules are to be administered intramuscularly (by deep intragluteal injection). ‘Neurobion coated tablets are recommended for supporting or continuing ongoing injection therapy and for relapse prophylaxi ‘Neurobion inj SPC 17043 CCDS (ATIGIOINN) Page 101843° Contraindications ~ Hypersensitivity to the active substances or to any of the excipients listed in seetion 6.1. ~ children below the age of 14 years (due to the high doses of the active ingredients) 44 Special warnings and precautions for use ‘Neurobion ampoutes must not be administered by intravenous injection, Short-term parenteral vitamin B12 administration may temporavily impair the diagnosis of funicular myelosis or pernicious anemia. If symptoms of peripheral sensory neuropathy (paraesthesia) oceur, the dosage should be reviewed and treatment with the medicinal product discontinued, if necessary. Newropathies have been observed under long-term administration (over 6-12 months) of daily dosages exceeding 50 mg vitamin Be as well as in short-term administration (over 2 months) of more than I g vitamin Bs per day. Therefore, regular monitoring is recommended under long-term treatment. -Neurobion ampoules must not be used tn children below the age of 14 years (due to their high active substance content). Each ampoule contains 42 mg sodium. This is to be taken into account in persons under sodium-restricted diet (low in table salt/sodium). Each ampoule contains traces of potassium. 45 _Imteraction with other medicinal products and other forms of interaction ‘Thiamine is inactivated by S-fluorouracil as the latter competitively inhibits the phosphorylation of thiamine to thiamine pyrophosphate, Loop diuratics, 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, 1Ftaken simultaneously with L-dopa, vitamin Bs can lessen the dopa effect. ‘The simultaneous administration of pyridoxine antagonists (¢.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. 46 Fertility, pregnancy and lactation 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 ‘Neurobion inj SPC 170043 CCDS (ATIGION) Page 208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. Breast-feeding Vitamins B:, Bs and B}9 are secreted into human breast milk. High concentrations of vitamin Bg, ic, > 600 mg 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 shoutd be carefully weighed against the therapeutic benefit for the women in order to decide to either discontinue breast-feeding or therapy with Neurobion. 4.7 Effects on ability to drive and use machines Neurobion ampoules do not affect the capability to drive a vehicle or to operate machinery. 48 Undesirable effects In the fotlowing, the undesirable effects are classified by organ system and frequency. The assessment of undesirable effects is based on the following frequency grouping: Very common (21/10) Common (21/100 to <1/10) ‘Uncommon (21/1,000 to <1/100) Rare (21/10,000 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 me vitamin Be may cause peripheral sensory neuropathy, Gasirointestinal disorders: Noi known: Gastrointestinal complaints such as nausea, vomiting, diarrhoea and abdominal pain, Inmame 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 Biz. Renal and urinary disorders: Not known; Chromauuria (“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. ‘Neurobioa inj SPC 17.043 CCDS (ATISIOIN) Page 3078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 Pharmaceutical Services, Ministry of Health, CY-1475, website: [Link]/phs Fax: +357 22608649 49° Overdose Vitamin Br: 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 Be: The toxic potential of vitamin Bg can be considered as very low. Long-term treatment (> 6-12 months) of a daily dosage > 50 mg vitamin Bg may, however, cause peripheral sensory neuropathy. These symptoms improve gradually upon vitamin discontinuation. Continuous intake of vitamin Be 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 scborrhocic dermatitis have been doscribed after administration of more than 2 g daily. Vitamin Biz: Allergic reactions, eczematous skin alterations and a benign form of acne have been observed after high-dose parenteral administration, 5, PHARMACOLOGICAL PROPERTIES 5.1 Pharmacodynamic properties Pharmacotherapeutic group: Vitamin By in combination with vitamin Bs and/or vitamin Br2 ATC Code: ALIDB Neurobion ampoules contain a combination of neurotropic active substances of the vitarnin B complex, The vitamins thiamine (B1), pyridoxine (Bc) and cobatamin (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 B), Be and Biz balances deficiencies due to inadequate autritive vitamin intake and thus ensures the availability of the required quantities of coenzymes. ‘Thiamine (vitamin B1) ‘Neurobion inj SPC 174043 CCDS (ATIGIOIT) Page 4018Thiamine pyrophosphate (TPP) is the effective form of vitamin B1 and acts as a coenzyme for a number of enzymes (c.g, pyruvate dehydrogenase and transketolase). Accordingly, vitamin BI is primarily involved in the carbohydrate metabolism; however, it also intervenes in the synthesis of lipids and amino acids, Nerve cells cover their energy requiremem exclusively via enzymatic oxidation and decarboxylation of glucose, so that an adequate supply of vitamin BL 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 BI 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) Vitarnin B12 in its coenzyme forms (S-deoxyadenosy! cobalamin and methyl cobalamin) is ‘olved in enzymatically catalysed intramolecular hydrogen displacements and in intramolecular transfers of methy! 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 ‘Neurotropie 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, 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 Neurobioa inj SPC 17v043 CCDS (ATIBION) Page 5 of8of B complex vitamins prevented or attenuated the characteristic nerve damage, so that deterioration of the functional properties was counteracted (antineuropathic effect) Purther, the combination of B}, 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 antin« ity of vitamin By, Bs and Bia. 5.2 Pharmacokinetic properties Combined administration of vitamins BI, B6 and B12 is not expected to have a negative effect on the pharmacokinetics of the individual vitamins, ‘Thiamine (vitamin BL): ‘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 tumover 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 rephosphorytation. 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 fow absorption rate which may be further decreused, 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 1.5yg, 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 seduced 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 Vitarnin B12 not circulating in the plasma is stored predominantly in the liver, the daily requirement is | pg. The turnover rate is 2.5 ug Bio per day, or 0.05% of the stored quantity. Vitamin Biz 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 BI, B6 and B12 are ‘Neurobion inj SPC 17043 CCDS (ATIGIONT) Page 6018equally well tolerated. Consequently, parenteral application of vitamins BI, B6 and B12 may be aclequate 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. 5.3. Preclinical safety data ‘The toxicity of vitamins B), Bs and Bjais very low. The data available to date do not suggest any potential risk for humans, ‘The titerature available on the subject does not contain any findings indicating that vitamins By, Bo and Biz have carcinogenic, mutagenic or teratogenic properties, Chronic toxicity: In animals, very high doses of vitamin B: cause bradycardia. Other symptoms are blockade of vegetative ganglia and motor end plates, The oral administration of 150-200 mg of vitamin Bokg body weight/day over a period of 100-107 days caused ataxis, 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 Bs, Mutagenic and tumorigenic potential: Mutagenic effects of vitamin By and vitamin Bg 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 Be Reproduction toxicity: Thiamine is transported actively to the foetus. Concentrations in the foetus and the newbom exceed maternal concentrations of vitamin By. Systematic investigations on human embryonal and foetal development in connection with the use of vitamin By at doses exceeding the stated daily requirements are not available. Vitamin Be is insufficiently investigated in animal studies. An embryotoxicity study in rats gave no indications of a teratogenic-potential. In mate rats the administration of very high doses of vitamin Bs induced damage to spermatogenesis. 6, PHARMACEUTICAL PARTICULARS 6.1 List of excipients Sodium hydroxide (for pH adjustment) Potassium cyanide Water for injection 6.2 Incompatibilities It is not recommended to use Neurobion ampoules together with other drugs in a ‘mixed injection’ or infusion. Vitamin By is completely degraded by sulphite-containing infusion solutions. Other vitamins, especially cyanocobelamin, may be inactivated in the presence of vitamin By degradation products. ‘Neurobion inj SPC 17043 CCDS (ATIOION?) Page 7or863° Shelf tife 3 years, 6.4 Special precautions for storage Store in the reftigerator (at 2°C to 8°C). Store the ampoules in the original carton to protect them from light, 65 Nature and contents of container Amber glass ampoules (Type I) with 3 ml injection solution Package sizes: 3 Ampules Not all pack sizes may be marketed. 6.6 Special precautions for disposal and other notes on handling Do not re-use syringes and necdles. Syringes and needles must be disposed immediately after use. Used syringes and needles must not be disposed in waste bins or toilets, but they must be disposed in a special sharps container. 7, MARKETING AUTHORIZATION HOLDER Merck A.B. 41-45 Kifisias ave, (Building B) 15123 Marousi, Athens Greece 8 MARKETING AUTHORIZATION NUMBER 795 9. DATE OF FIRST AUTHORIZATION/RENEWAL OF AUTHORIZATION 05/04/1971 10. DATE OF (PARTIAL) REVISION OF THE TEXT 2 May 2017 ‘Neurabion inj SPC 17,043 CCDS (AFISI0I7) Page Boi 8