Benfotiamine, Pyridoxine Hydrochloride

Pharmacological properties

neurotropic vitamins of the group B have a positive effect in inflammatory and degenerative diseases of the nerves and musculoskeletal system. they are prescribed to eliminate deficient conditions, and in high doses they have an analgesic effect, improve blood circulation, normalize the functioning of the nervous system and the process of blood formation.

Vitamin B₁ is an important active substance. In the body, it is phosphorylated with the formation of biologically active thiamine diphosphate (cocarboxylase) and thiamine triphosphate (TTP).

Thiamine diphosphate as a coenzyme takes part in important functions of carbohydrate metabolism, which are crucial in the metabolic processes of nerve tissue, and affects the conduction of nerve impulses in synapses. With Vitamin B Deficiency₁ In the tissues, metabolites accumulate, primarily lactic and pyruvic acids, which leads to various pathological conditions and impaired function of the nervous system.

Vitamin B₆ in phosphorylated form (pyridoxal-5’-phosphate - PALP) is a coenzyme of a number of enzymes that interact in the general non-oxidative metabolism of amino acids. Through decarboxylation, they participate in the formation of physiologically active amines (e.g. adrenaline, histamine, serotonin, dopamine, tyramine), through transamination - in anabolic and catabolic metabolic processes (e.g. glutamate-oxaloacetate transaminase, glutamate pyruvate transaminase, glutamate pyruvate transaminase, glutamate, splitting and synthesis of amino acids. Vitamin B₆ acts on 4 different stages of tryptophan metabolism. In the process of hemoglobin synthesis, vitamin B₆ catalyzes the formation of α-amino-β-ketoadininic acid.

Vitamin B₁₂ necessary for cell metabolism processes. It affects the function of hematopoiesis (external antianemic factor), takes part in the formation of choline, methionine, creatinine, nucleic acids, and has an analgesic effect.

Pharmacokinetics When taken orally, vitamin B₆ and its derivatives, in the majority, are rapidly absorbed in the upper part of the digestive tract by passive diffusion and are excreted within 2–5 hours. After parenteral administration, thiamine is distributed in the body. About 1 mg of thiamine is metabolized daily. Metabolites are excreted in the urine. Dephosphorylation occurs in the kidneys. The biological half-life of thiamine is 0.35 hours. Accumulation of thiamine in the body does not occur due to poor dissolution in fats.

Vitamin B₆ phosphorylates and oxidizes to pyridoxal-5’-phosphate. In plasma, pyridoxal-5’-phosphate and pyridoxal bind to albumin. It is transported in the form of pyridoxal. To pass through the cell membrane, pyridoxal-5’-phosphate bound to albumin is hydrolyzed by alkaline phosphatase to pyridoxal.

Vitamin B₁₂ after parenteral administration forms transport protein complexes that are rapidly absorbed by the liver, bone marrow and other organs. Vitamin B₁₂ enters the bile and takes part in the intestinal-hepatic circulation, penetrates the placental barrier.

Indications

Tablets. with neurological diseases caused by a proven deficiency of vitamins B1, B6.

Rr for injections. Neurological diseases of various origins: neuritis, neuralgia, polyneuropathy (diabetic, alcoholic), radicular syndrome, retrobulbar neuritis, facial nerve damage.

Application

Milgamma tablets. apply inside, washing down with a sufficient amount of liquid.

The recommended dose is 1 tablet per day. In individual cases, the dose is increased and 1 tablet is used 3 times a day.

Tablets should be taken whole, washed down with liquid, after a meal.

The duration of the course of treatment is determined by the doctor individually in each case.After the maximum treatment period (4 weeks), a decision is made to correct and reduce the dose of the drug.

Milgamma solution for injection. For i / m administration.

In severe (acute) cases, treatment begins with 2 ml of a solution of v / m 1 time per day until acute symptoms are eliminated. To continue treatment, 2 ml (1 injection) is prescribed 2-3 times a week. The course of treatment is at least 1 month.

In / m injection should be performed in the upper outer quadrant of the gluteal muscle.

To maintain or continue the course of therapy or to prevent relapse, the drug Milgamma, coated tablets are recommended.

Contraindications

Tablets. hypersensitivity to the components of the drug. intake of vitamin B1 is contraindicated in allergic reactions. intake of vitamin B6 is contraindicated in peptic ulcer of the stomach and duodenum in the acute stage (since an increase in the acidity of gastric juice is possible).

During pregnancy and breastfeeding

Rr for injections. Hypersensitivity to the components of the drug; acute violation of cardiac conduction, acute form of decompensated heart failure.

Vitamin B₁ contraindicated in allergic reactions.

Vitamin B₆ it is contraindicated for use in cases of gastric and duodenal ulcer in the acute stage (since an increase in the acidity of gastric juice is possible).

Vitamin B₁₂ It is contraindicated for use in erythremia, erythrocytosis, thromboembolism.

Lidocaine. Hypersensitivity to lidocaine or other amide local anesthetics, a history of epileptiform seizures when taking lidocaine, severe bradycardia, severe arterial hypotension, cardiogenic shock, severe forms of chronic heart failure (II — III degree), sinus node weakness syndrome, WPW cm , Adams-Stokes syndrome, AV blockade of the II and III degrees, hypovolemia, severe hepatic / renal impairment, porphyria, myasthenia gravis.

During pregnancy and breastfeeding.

Side effects

Tablets

From the digestive tract: nausea, vomiting, diarrhea, abdominal pain, increased acidity of gastric juice.

From the cardiovascular system: tachycardia.

From the immune system: hypersensitivity reactions, including anaphylactic shock; anaphylaxis; hives.

On the part of the skin: skin rashes, itching.

In extremely rare cases - a shock condition.

From the nervous system: prolonged use (more than 6-12 months) in doses of more than 50 mg of vitamin B₆ daily can lead to peripheral sensory neuropathy, nervous agitation, dizziness, headache.

From the endocrine system: the release of prolactin is inhibited.

Rr for injections. Long-term use (more than 6-12 months) of vitamin B₆ at a dose of 50 mg daily can lead to peripheral sensory neuropathy, nervous agitation, malaise, dizziness, headache.

From the digestive tract: gastrointestinal disorders, including nausea, vomiting, diarrhea, abdominal pain, increased acidity of gastric juice.

On the part of the immune system: hypersensitivity reactions (skin rash, respiratory failure, anaphylactic shock, Quinckes edema), increased sweating.

On the part of the skin: itching, urticaria, acne; extremely rarely - generalized exfoliative dermatitis, angioedema.

From the side of the cardiovascular system: tachycardia, arrhythmia, bradycardia, cardiac conduction deceleration, transverse heart block, cardiac arrest, peripheral vasodilation, collapse; very rarely - tachycardia, increase / decrease in blood pressure, heart pain.

From the nervous system: CNS excitation (when used in high doses), anxiety, headache, dizziness, sleep disturbance, confusion, drowsiness, loss of consciousness, coma; in patients with hypersensitivity - euphoria, tremor, trismus, motor anxiety, paresthesia, convulsions.

From the side of the organ of vision: nystagmus, reversible blindness, diplopia, flickering flies before the eyes, photophobia, conjunctivitis.

On the part of the organ of hearing: auditory disorders, tinnitus, hyperacusis.

From the respiratory system: shortness of breath, rhinitis, oppression or respiratory arrest.

Others: sensation of heat, cold or numbness of the extremities, swelling, weakness, malignant hyperthermia, sensitivity disorders, motor block.

General disorders: reactions at the injection site.

In the case of very rapid parenteral administration, the development of systemic reactions in the form of seizures is possible.

special instructions

Tablets. the question of the use of the drug milgam for the treatment of patients with severe and acute form of decompensated heart failure is decided by the doctor individually, taking into account the patients condition.

When using vitamin B₁₂ the clinical picture, as well as laboratory tests for funicular myelosis or pernicious anemia, may lose their specificity.

Since the drug contains vitamin B₆, it is necessary to appoint it with caution in patients with a stomach ulcer and duodenal ulcer, a serious history of liver and kidney failure.

Milgam should not be used in patients with neoplasms, with the exception of cases associated with megaloblastic anemia and vitamin B deficiency₁₂. The drug is used in severe or acute form of decompensated cardiac activity and angina pectoris.

If signs of peripheral sensory neuropathy (paresthesia) appear, the dose should be reviewed and the use of Milgam should be stopped, if necessary. With prolonged use (more than 6-12 months) of daily doses exceeding 50 mg of vitamin B₆, as well as with a short-term intake (more than 2 months) of more than 1 g of vitamin B₆ per day, neuropathies were observed, in connection with this, constant monitoring with long-term use is recommended.

The product contains sucrose. Patients with rare hereditary fructose intolerance, glucose-galactose malabsorption, or sucrose-isomaltase deficiency should not use this drug.

Rr for injections. The drug should not be administered iv. V / m injection of vitamin B₁₂ may cause anaphylactoid reactions in patients with hypersensitivity.

Parenteral Administration of Vitamin B₁₂ may temporarily affect the diagnosis of funicular myelosis or pernicious anemia.

Long-term use of vitamin B₆ (more than 6-12 months) in doses above 50 mg daily or above 1000 mg / day (more than 2 months) can lead to reversible peripheral sensory neuropathy. If symptoms of peripheral sensory neuropathy (paresthesia) occur, dose adjustment or discontinuation of the drug is necessary.

The drug contains sodium compounds. This should be considered for patients who are on a salt-free diet. Each ampoule may contain potassium residues.

Because Milgamma contains Vitamin B₆, it should be used with caution in patients with a history of peptic ulcer and duodenal ulcer, with severe renal and hepatic impairment.

In patients with neoplasms, except in cases accompanied by megaloblastic anemia and vitamin B deficiency₁₂, the drug should not be used.

The drug is not used for severe decompensation of cardiac activity and angina pectoris.

Since Milgamma contains lidocaine, it should be noted that when treating the injection site with disinfectant solutions containing heavy metals, the risk of developing a local reaction in the form of pain and swelling increases.

Since lidocaine has a pronounced antiarrhythmic effect and can itself act as an arrhythmogenic factor that can lead to the development of arrhythmia, the drug should be used with caution in patients with a history of arrhythmia.

It is used with caution in patients with moderate heart failure, moderate arterial hypotension, incomplete AV blockade, impaired intraventricular conduction, moderate hepatic and renal impairment (creatinine clearance 10 ml / min), respiratory failure, epilepsy, after operations on heart, with a genetic predisposition to hyperthermia, in debilitated patients and elderly patients.

When using lidocaine, ECG monitoring is mandatory. In case of disturbances in the sinus node, lengthening of the P – Q interval, expansion of the QRS, or with the development of new arrhythmia, the dose should be reduced or the drug should be canceled.

Before using lidocaine for heart diseases (hypokalemia reduces the effectiveness of lidocaine), it is necessary to normalize the level of potassium in the blood.

With v / m administration, an increase in creatinine concentration is possible, which can lead to an error in the diagnosis of acute myocardial infarction.

Use during pregnancy or lactation. During pregnancy and lactation, the recommended daily intake of vitamin B₁ is 1.4–1.6 mg for vitamin B₆ 2.4–2.6 mg. During pregnancy, these doses may be exceeded if the patient has a deficiency of vitamins B₁ and B₆.

Vitamins B₁ and B₆ penetrate into breast milk. High doses of Vitamin B₆ may reduce the amount of milk.

The solution in the form of a solution contains 100 mg of vitamin B₆ in ampoules, so it should not be used during pregnancy and lactation.

Children. The effectiveness and safety of the drug in children have not been established, so it is not used in patients of this age category.

The ability to influence the reaction rate when driving vehicles or other mechanisms. The drug does not affect the ability to drive vehicles and work with complex mechanisms.

If dizziness is noted during treatment, one should refrain from driving vehicles or working with other mechanisms.

Interactions

The action of thiamine is inactivated by fluorouracil, since the latter competitively inhibits thiamine phosphorylation to thiamine pyrophosphate. loop diuretics, such as furosemide, inhibiting tubular reabsorption, with prolonged therapy can increase the excretion of thiamine, thereby reducing its level.

Concomitant use with levodopa is contraindicated, since vitamin B₆ may reduce the severity of the antiparkinsonian effect of levodopa. Concomitant use with pyridoxine antagonists (e.g. isoniazid, hydralazine, penicillamine or cycloserine), oral contraceptives may increase the need for vitamin B₆.

Drinking sulfite-containing beverages (such as wine) increases the degradation of thiamine.

Lidocaine enhances the inhibitory effect on the respiratory center of drugs for anesthesia (hexobarbital, thiopental sodium iv), sleeping pills and sedatives; weakens the cardiotonic effect of digitoxin. With simultaneous use with hypnotics and sedatives, it is possible to increase the inhibitory effect on the central nervous system.

Ethanol enhances the inhibitory effect of lidocaine on respiration.

Adrenoreceptor blockers (including propranolol, nadolol) slow down the metabolism of lidocaine in the liver, enhance the effects of lidocaine (including toxic ones) and increase the risk of developing bradycardia and hypotension.

Curare-like drugs - it is possible to deepen muscle relaxation (to paralysis of the respiratory muscles).

Norepinephrine, mexiletine - the toxicity of lidocaine is increased (the clearance of lidocaine is reduced).

Isadrine and glucagon - increased lidocaine clearance.

Cimetidine, midazolam - increases the concentration of lidocaine in blood plasma. Cimetidine displaces from binding to proteins and slows the inactivation of lidocaine in the liver, which leads to an increased risk of increased side effects of lidocaine. Midazolam moderately increases the concentration of lidocaine in the blood.

Anticonvulsants, barbiturates (including phenobarbital) - it is possible to accelerate the metabolism of lidocaine in the liver, a decrease in blood concentration.

Antiarrhythmic drugs (amiodarone, verapamil, quinidine, aymalin, disopyramide), anticonvulsants (hydantoin derivatives) - cardiodepressive effect is enhanced; simultaneous use with amiodarone can lead to the development of seizures.

Novocaine, Novocainamide - when combined with lidocaine, CNS excitation and the occurrence of hallucinations are possible.

MAO inhibitors, chlorpromazine, buvicain, amitriptyline, nortriptyline, imipramine - when combined with lidocaine, the risk of developing arterial hypotension increases and the local anesthetic effect of lidocaine is prolonged.

Narcotic analgesics (morphine, etc.) - when combined with lidocaine, the analgesic effect of narcotic analgesics increases, and respiratory depression increases.

Prenylamine - increases the risk of developing ventricular arrhythmias like pirouette.

Propafenone - an increase in the duration and severity of side effects from the central nervous system is possible.

Rifampicin - a decrease in the concentration of lidocaine in the blood is possible.

Polymyxin B - Respiratory function should be monitored.

Procainamide - hallucinations are possible.

Cardiac glycosides - when combined with lidocaine, the cardiotonic effect of cardiac glycosides is weakened.

Digitalis glycosides - against the background of intoxication, lidocaine may increase the severity of AV block.

Vasoconstrictors (epinephrine, methoxamine, phenylephrine) - when combined with lidocaine, they slow down the absorption of lidocaine and prolong the effect of the latter.

Guanadrel, guanethidine, mecamylamine, trimethafan - when combined for spinal and epidural anesthesia, the risk of severe hypotension and bradycardia increases.

Β-adrenoreceptor blockers - when combined, they slow down the metabolism of lidocaine in the liver, the effects of lidocaine (including toxic ones) are enhanced, and the risk of developing bradycardia and arterial hypotension is increased. With the simultaneous use of β-adrenergic receptor blockers and lidocaine, it is necessary to reduce the dose of the latter.

Acetazolamide, thiazide and loop diuretics - when combined with lidocaine as a result of the development of hypokalemia, the effect of the latter decreases.

Anticoagulants (including ardeparin, dalteparin, danaparoid, enoxaparin, heparin, warfarin, etc.) - when combined with lidocaine, the risk of bleeding increases.

Anticonvulsants, barbiturates (phenytoin) - when combined with lidocaine, acceleration of the metabolism of lidocaine in the liver, a decrease in blood concentration, and an increase in the cardiac depressant effect are possible.

Drugs that cause blockade of neuromuscular transmission - when combined with lidocaine, the effect of drugs that cause blockade of neuromuscular transmission is enhanced, since the latter reduce the conductivity of nerve impulses.

Incompatibility. Pyridoxine is incompatible with drugs containing levodopa, since with simultaneous use, the peripheral decarboxylation of the latter is enhanced and, thus, the severity of its antiparkinsonian effect is reduced.

Thiamine is incompatible with oxidizing and reducing compounds: mercury chloride, iodide, carbonate, acetate, tannic acid, ammonium iron citrate, as well as sodium phenobarbital, riboflavin, benzylpenicillin, glucose and metabisulfite, since it is inactivated in their presence. Copper accelerates the breakdown of thiamine; in addition, thiamine loses its activity with increasing pH 3. Vitamin B₁₂ incompatible with salts of heavy metals.

Overdose

Vitamin B1 has a wide therapeutic range. very high doses (more than 10 g) exhibit a curariform effect, suppressing the conduction of nerve impulses.

Vitamin B₆ It has a very low toxicity.

Excessive Vitamin B Use₆ in doses of more than 1 g / day for several months can lead to a neurotoxic effect.

Neuropathies with ataxia and sensitivity disorders, cerebral seizures with changes in the EEG, as well as in some cases hypochromic anemia and seborrheic dermatitis have been described after administration at a dose above 2 g / day.

Vitamin B₁₂: after parenteral administration (in rare cases, after oral administration) in doses higher than recommended, allergic reactions, eczematous skin disorders and a benign form of acne were noted.

With prolonged use in high doses, a violation of the activity of liver enzymes, pain in the heart, and hypercoagulation are possible.

Treatment: symptomatic therapy.

Lidocaine. Symptoms: psychomotor agitation, dizziness, general weakness, decreased blood pressure, tremor, visual impairment, tonic-clonic convulsions, coma, collapse, AV blockade, central nervous system depression, respiratory arrest are possible. The first symptoms of an overdose in healthy people occur with a concentration of lidocaine in the blood of 0.006 mg / kg body weight, convulsions at 0.01 mg / kg.

Treatment: cessation of drug administration, oxygen therapy, anticonvulsants, vasoconstrictors (norepinephrine, mesatone), with bradycardia - anticholinergic drugs (0.5–1 mg of atropine). Perhaps intubation, mechanical ventilation, resuscitation. Dialysis is ineffective.

Storage conditions

Tablets: at a temperature not exceeding 25 ° C.

Injection solution: at a temperature not exceeding 2-8 ° C in the original packaging to protect from light.