1 coated tablet contains 150 mg of benfotiamine (lipid-soluble vitamin B1 derivative).
Excipients/Inactive Ingredients: Microcrystalline cellulose, talc, povidone (K30), highly dispersed silicon dioxide, croscarmellose sodium, higher-chain partial glycerides, sucrose, calcium carbonate, titanium dioxide (E171), shellac, gum arabic, maize starch, glycerol, macrogol (6000), polysorbate 80, Montan glycol wax.
Pharmacotherapeutic group: Vitamins, neuropathy preparations. ATC Code: A11DA03 and N07XB56.
Pharmacology: Pharmacodynamics: Mechanism of action: Benfotiamine is a fat soluble form of vitamin B1 (Thiamine). Vitamin B1 is an essential cofactor in all living systems. It is not synthesized in humans and is therefore an essential nutrient. Body stores of thiamine are relatively low and a regular intake is required to avoid deficiency states. Benfotiamine is a source of vitamin B1.
Pharmacodynamic effects: The major coenzymatic form of thiamine or benfotiamine is thiamine diphosphate (TDP). TDP functions as a coenzyme in many reactions involved in carbohydrate and energy metabolism, including α-keto acid dehydrogenases, α-keto acid decarboxylases, phosphoketolases, and transketolase catalysed reactions of the pentose phosphate pathway, A non-coenzymatic function has been proposed in nervous tissue. TDP is concentrated in neuronal cells and other excitable tissues such as skeletal muscle and is hydrolysed more rapidly during nerve stimulation. Because energy production in nerve cells is principally realised by oxidative glucose breakdown an adequate supply of vitamin B1 is indispensable for neural function. B vitamin, given in larger doses, has analgesic and antineuralgic properties. These are due to their influence on mediators, which presumably exert an analgesic effect directly on the nerves.
Vitamin B1 deficiency in humans results in the disease known as beriberi, the major manifestations of which mainly affect the nervous system (dry beriberi) and the cardiovascular system (wet beriberi). The most striking clinical signs of thiamine deficiency are related to the nervous system. Polyneuritis and paralysis of the peripheral nerves predominate. In the human central nervous system, thiamine deficiency can lead to Wernicke encephalopathy and peripheral neuropathies.
In addition experimental and clinical studies hint at an effectiveness going beyond the substitution of B1 deficiency, primarily in the medical treatment of disturbances of the carbohydrate metabolism and its consequences. The most extensive findings exist for the treatment of diabetic polyneuropathy.
Vitamin B1 deficiency can occur in the following cases: deficient diet and malnutrition, long-term parenteral nutrition, null diet, haemodialysis, malabsorption, chronic alcoholism, increased requirement (e.g. pregnancy and lactation).
The consequences of a clinically relevant B1 deficiency are considerable health disturbances with that which absolutely require the medical treatment.
Measurements of TDP-dependent enzyme activities in erythrocytes such as transketolase (ETK) and the extent of their activation (activation coefficient α-ETK) are suitable for determining vitamin B1 status.
Clinical efficacy and safety: The treatment of diseases caused by deficiency of vitamin B1 requires the substitution of vitamin B1, regardless of cause and manifestation of deficiency. For decades already, this is well-known and internationally recognised standard and published in the relevant specialized literature. The human use of benfotiamine is based primarily on this internationally recognized importance of the substitution of this biofactor for the treatment of neurological and cardiovascular deficiency states.
Furthermore, the efficacy of benfotiamine in diabetic polyneuropathy has been documented in several double-blind, placebo-controlled studies.
Benfotiamine is characterized by a very low toxicity and good tolerance. It is reported generally about a good tolerance and missing side effects. In clinical studies with benfotiamine, in single cases gastrointestinal complaints like flatulence, diarrhoea, constipation, nausea, and abdominal pain were documented. A causal relationship to benfotiamine is not yet cleared sufficiently and may be dose dependent. In very rare cases allergic reactions are reported.
Pharmacokinetics: Absorption: Benfotiamine is a prodrug of vitamin B1 in which the thiazole ring, which is essential for the vitamin properties, is open to be closed during passage through the mucosal barrier. After oral absorption, benfotiamine passes the stomach unchanged, because it is stable in acidic environment. It is absorbed in the duodenum in a dose-dependent manner, in contrast to water-soluble thiamine derivatives, which show saturation kinetics in the small intestine.
Comparative investigations have demonstrated that benfotiamine is absorbed faster and better and to a greater extent than the water-soluble thiamine hydrochloride. After the oral administration of benfotiamine, higher and longer-lasting concentrations of thiamine and the biologically active coenzymes are found in the plasma and centrifuged blood cells than after the equivalent quantities of thiamine hydrochloride.
Distribution: After the oral administration of benfotiamine, dephosphorylation to S-benzoylthiamine (SBT) is induced in the intestine by phosphatases. SBT is lipoid-soluble and therefore displays a high degree of permeability. It is also resorbed without any significant conversion to thiamine. Enzymatic debenzoylation to thiamine and the biologically active coenzymes only occurs at a later stage.
It has been demonstrated for benfotiamine that from the two substances (benfotiamine and thiamine) in the organism the biologically active coenzyme thiamine diphosphate (TDP) and thiamine triphosphate are produced. Using whole-animal auto-radiographs it has been possible to show particularly high levels of radioactivity in the blood, liver, kidney, musculature and brain using marked benfotiamine.
Biotranformation: The dissociation of the benzoyl group through which thiamine arises from ring closure is carried out in the intestinal mucosa and other thioesterases containing cell barriers. Already during the passage through the mucosa, compounds containing sulfhydryl groups, such as cysteine and glutathione, may cause rapid intracellular reduction of allithiamines to thiamine.
Oral administration of benfotiamine rapidly increases thiamine activity in whole blood, red blood cells, cerebrospinal fluid, and urine in normal and thiamine deficient subjects. Within the organism thiamine and its lipid-soluble derivatives are converted into thiamine diphosphate (TDP) which is the biological active metabolite, and to a less extent to other phosphorylated forms (TMP and TTP).
By enzymatic transformation of benfotiamine into thiamine benzoic acid and hippuric acid are formed. Then, thiamine is metabolised to the known metabolites (thiamine acid, methylthiazole acetic acid and pyramine).
Elimination: At low intake of thiamine and/or benfotiamine, little or no unchanged thiamine is excreted in the urine. However, absorbed and/or in the body arising thiamine that is in excess of tissue stores and coenzyme needs is rapidly cleared by the kidneys and excreted in the urine unchanged, free or phorphorylated, or as metabolites, including pyrimidine and thiazole moieties.
Because of the restricted storage capacity thiamine must be taken up daily in a sufficient quantity. The mean elimination half-time (t½) in plasma for benfotiamine is 3.6 h. For thiamine arising from benfotiamine an elimination half-life α-phase of 5 hours and a β-phase of 16 hours was found.
Toxicology: Preclinical safety data: Acute, subchronic and chronic toxicity: Very high doses of vitamin B1 cause bradycardias in the animal model. In addition, symptoms of blockade of the vegetative ganglia and muscle end plates occur.
In animal studies on chronic toxicity, no organopathological changes were found at doses of 100 mg/kg of benfotiamine.
Mutagenic and tumourogenic potential: Under conditions of clinical use no mutagenic effects of vitamin B1 are anticipated.
No long-term studies in animals on tumourogenic potential of vitamin B1 are available.
Reproductive toxicity: Vitamin B1 is actively transported into the foetus. Concentrations in the foetus and neonate are greater than the maternal vitamin B1 concentrations.
High doses of vitamin B1 have not been adequately studied in animal experiments.
Treatment of neuropathies and prophylaxis of clinical vitamin B1 deficiency conditions, if these cannot be resolved by dietary such as treatment of neuropathies.
Unless otherwise prescribed, the usual dosage is 150 - 450 mg benfotiamine depending on the severity of the deficiency. Dosage recommendations are provided as follows. (See Table 1.)
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Milgamma mono 150 is initially taken over a period of at least 3 weeks. Thereafter maintenance treatment is governed by therapeutic response. In case of missing or insufficient therapeutic response after 4 weeks, therapy should be reconsidered.
Method of administration: Method and duration of administration:
Benfotiamine 150 mg coated tablets should be swallowed whole with some fluid. The duration of administration is determined by the therapeutic response. Benfotiamine 150 mg coated tablets are initially taken over a period of at least 3 weeks in cases of vitamin B1 deficiency. Thereafter maintenance treatment is governed by therapeutic response with 150 or 300 mg benfotiamine (1-2 Benfotiamine 150 mg coated tablets). In case of missing or insufficient therapeutic response after 3 weeks in cases of vitamin B1 deficiency, therapy should be reconsidered.
The safety and efficacy in children and adolescents up to 18 years have not been established. For this reason Milgamma mono 150 should not be used in children and adolescents below the age of 18 years.
No dose adjustment is required for elderly patients.
Patients with renal impairment:
No dose adjustment is required for patients with renal impairment.
Patients with hepatic impairment:
No dose adjustment is required for patients with hepatic impairment.
With the current oral administration and because of the wide therapeutic range overdose is unknown at this time.
Hypersensitivity to the active substance or thiamine or any excipients listed in Description.
Patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiency should not take this medicine.
Effects on the ability to drive and use machines: Milgamma mono 150 has no or negligible influence on the ability to drive and use machines.
Pregnancy: During pregnancy and the lactation period the recommended daily intake of vitamin B1 is 1.2-1.4 mg. This dose may be exceeded only if the patient has a demonstrated vitamin B1 deficiency, because to date the safety of administration higher than the recommended daily dose has not been documented. There are no adequate data from the use of benfotiamine in pregnant woman. A decision on the use of Milgamma mono 150 during pregnancy in cases of severe vitamin B1 deficiency should only be taken by the attending physician after careful consideration of the risks and benefits.
Breast-feeding: Vitamin B1 passes into the human breast milk. There is insufficient information on the effect of benfotiamine in newborns/infants. Milgamma mono 150 should not be used during breast-feeding.
Any assessment of side effects is usually based on the following specifications of frequency: See Table 2.
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Immune system disorders:
Very rare: Hypersensitivity reactions (urticaria, exanthema).
Very rare: In clinical studies with benfotiamine, gastrointestinal disorders like nausea and other gastrointestinal complaints were documented in single cases. However, the frequency did not differ significantly from placebo treated groups. A causal relationship to benfotiamine is not clearly established and may be dose dependent.
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 national reporting system.
Thiamine is deactivated by 5-fluoruracil since 5-fluoruracil competitively inhibits the phosphorylation of thiamine to thiamine pyrophosphate.
Thiamine may intensify the effect of muscle relaxants. Therefore thiamine intake should generally be discontinued several days in advance of planned surgery.
Incompatibilities: Not applicable.
Special precautions for storage: Store below 30°C and in the original packaging.
Shelf life: 3 years.
A11DA03 - benfotiamine ; Belongs to the class of vitamin B1. Used as dietary supplements.
Sugar-coated tab 150 mg (white biconvex with smooth surface) x 3 x 10's.