Изониазид-Ферейн®

General characteristics. Structure:

Active ingredient: 100 mg of an isoniazid.

Excipients: water for injections.

Pharmacological properties:

Pharmacodynamics. Antituberculous remedy; works bacteriostatically. Is pro-medicine - the mikobakterialny catalase peroxidase metabolizes an isoniazid to an active metabolite which, communicating with enoil-(acyl - the transferring protein) - reductase of synthase of fatty acids II, breaks transformation of delta2-unsaturated fatty acids into mikolevy acid. The last represents fatty acid with a branched chain which, connecting to arabinogalactan (polysaccharide), participates in formation of components of a cell wall of Mycobacterium tuberculosis. The isoniazid is also inhibitor of a mikobakterialny catalase - peroxidases that reduces protection of a microorganism against active forms of oxygen and hydrogen peroxide.

The isoniazid is also active concerning a small amount of strains of Mycobacterium kansasii (at the infections caused by this activator, before an initiation of treatment it is necessary to define sensitivity to an isoniazid).

Pharmacokinetics. Communication with proteins insignificant - to 10%. Distribution volume - 0,57-0,76 l/kg. The isoniazid is well distributed on all organism, getting into all fabrics and liquids, including cerebrospinal, pleural, ascitic; high concentration are created in pulmonary fabric, kidneys, a liver, muscles, saliva and a phlegm. Gets through a placental barrier and into breast milk. Is exposed to metabolism in a liver by acetylation with formation of inactive products. In a liver it is acetylated by N-acetyltransferase with formation of N-atsetilizoniazida which then turns into isonicotinic acid and моноацетилгидразин, having a hepatotoxic action by education by system of P450 cytochrome at a N-hydroxylation of an active intermediate metabolite.

Speed of acetylation is genetically determined; people with "slow" acetylation have not enough N-acetyltransferase. Is SUR2E1 isoenzyme inductor. An elimination half-life (T1/2) for "bystry acetylizers" - 0,5-1,6 h; for "slow" - 2-5 h. At a renal failure of T1/2 about 6,7 p. T1/2 for children aged from 1,5 up to 15 years - 2,3-4,9 h can increase, and newborns have 7,8-19,8 h (that is explained by imperfection of processes of acetylation at newborns). At repeated purposes of T1/2 it is shortened to 2-3 h. It is removed generally by kidneys: during 24 h 75-95% of drug, generally in the form of inactive metabolites - N-atsetilizoniazida and isonicotinic acid are removed.

At the same time at "bystry acetylizers" the maintenance of N-atsetilizoniazida makes 93%, and at "slow" - no more than 63%. Small amounts are removed by intestines. At a hemodialysis a significant amount of an isoniazid is removed (during 5 h to 73%); efficiency of peritoneal dialysis is limited.

Indications to use:

Treatment of tuberculosis (any localization, at adults and children, as a part of a combination therapy).

Route of administration and doses:

The isoniazid is applied intramusculary, intravenously, in a cavity. Daily and course doses of an isoniazid are established for each patient individually depending on character and a form of a disease, speed of acetylation and portability of drug.

Intramusculary an isoniazid enter in the form of 10% of solution in a dose 5-12 mg/kg a day. The drug is administered in 1-2 introductions. Duration of a course of intramuscular introduction of an isoniazid makes 2-6 months depending on efficiency of therapy and portability of drug. For the purpose of prevention - intramusculary - to 300 mg of 1 times a day within 2 months. Intramuscular introduction of an isoniazid is combined using a pyridoxine (B6 vitamin). The pyridoxine is accepted in 60 - 100 mg along with an injection of an isoniazid or enter intramusculary in a dose 100-125 mg in 30 min. after an injection.

Intravenously an isoniazid enter in the form of 10% of solution in a dose 10-15 mg/kg a day during 30-60 pages. For adults: 200-300 mg, for children - 100-300 mg (10-20 mg/kg of body weight), for newborns - 3-5 mg/kg, but no more than 10 mg/kg of body weight a day. The course of treatment consists of 30-150 injections depending on efficiency of therapy and portability of drug. After introduction it is necessary to observe a bed rest during 1-1,5 h. Intravenous administration of an isoniazid is combined using B6 vitamin and glyutaminovy acid (for the purpose of the prevention of by-effects). B6 vitamin is accepted in 60 mg in 2 hours after intravenous administration of an isoniazid or enter intramusculary in a dose 100-125 mg in 30 min. after an injection. Glyutaminovy acid accept from 1 to 1,5 g in a daily dose.

It is intravenously possible to appoint an isoniazid with all antitubercular drugs, except Cycloserinum.

Isoniazid enter into a cavity by installation 10% of solution in a daily dose of 10-15 mg/kg. Punctures of a cavity carry out 2-3 times a week, and at drainage of a cavity installation should be carried out daily. Instillations are carried out in the conditions of a surgical hospital. During pregnancy, at a severe form of a pulmonary heart, the expressed atherosclerosis, coronary heart disease, arterial hypertension it is not necessary to appoint more than 10 mg/kg in doses.

Features of use:

Pregnancy and lactation. Use of drug in a dose over 10 mg/kg is contraindicated at pregnancy. Gets through a gematoplatsentarny barrier, is defined in fruit blood serum in the concentration comparable or exceeding serumal at mother. Emergence of a myelomeningocele, hypospadias and hemorrhages is possible (owing to a hypovitaminosis To) at a fruit, further can lead to a delay of psychomotor development in the child. Gets into breast milk, reaching the concentration comparable to concentration in a blood plasma. The child receives 0,75-2,3% of the dose accepted by mother; developing of hepatitis and peripheral neuritis is possible. In need of use of drug in the period of a lactation it is necessary to resolve an issue of breastfeeding cancellation.

Even in several months after the end of use there can be fatal medicinal hepatitis. The risk increases with age (the largest frequency in an age group of 35-64 years), especially at the daily use of ethanol. Therefore it is monthly necessary to control function of a liver, to persons 35 years function of a liver in addition are more senior investigate before an initiation of treatment.

Except the ethanol use accessory factors of risk are chronic diseases of a liver, parenteral use of medicines and the puerperal period; under these circumstances control of function of a liver (laboratory and clinical) should be carried out more often. Patients have to be informed on need to report about any manifestations of damage of a liver (inexplicable anorexia, nausea, vomiting, urine darkening, jaundice, rash, paresthesias of brushes and feet, weakness, fatigue or fever lasting more than 3 days, abdominal pains, especially in right hypochondrium). In these cases the isoniazid is immediately cancelled.

To the patients who earlier had izoniazidny hepatitis appoint alternative antitubercular medicines. In need of therapy resuming, it is begun after full permission of clinical and laboratory signs of hepatitis with the subsequent constant control of function of a liver. At any signs of a recurrence the isoniazid is immediately cancelled. At patients with acute diseases of a liver preventive reception of an isoniazid should be postponed.

For delay of development of microbic stability appoint together with other antitubercular medicines. Due to the different speed of metabolism before use of an isoniazid it is reasonable to determine the speed of its inactivation (by dynamics of maintenance in blood and urine). At "bystry acetylizers" the isoniazid is applied in higher doses.

At risk of development of peripheral neuritis (patients are more senior than 65 years, the accompanying diabetes mellitus, pregnancy, a chronic renal failure, alcoholism, B6 hypovitaminosis owing to defective food, the accompanying anticonvulsant therapy) purpose of 10-25 mg/days of a pyridoxine is recommended.

During treatment it is necessary to avoid the use of cheese (especially Swiss or Cheshire), fishes (especially a tuna, a sardinella, a skipdzhek) as at their simultaneous use with an isoniazid emergence of the reactions (a dermahemia, an itch, feeling of heat or cold, heartbeat, the increased sweating, a fever, a headache, dizziness) connected with suppression of activity of monoamine oxidase and diaminoxidase and leading to disturbance of metabolism of tyramine and the histamine which are contained in fish and cheese is possible.
It must be kept in mind that the isoniazid can cause a hyperglycemia with a secondary glucosuria; tests with recovery of ions of copper can be false positive; drug does not influence fermental glucose tests.

Influence on ability to manage vehicles and mechanisms. During use of drug it is recommended to refuse control of vehicles, mechanisms and the occupations demanding concentration of attention and speed of psychomotor reactions.

Side effects:

From a nervous system: headache, dizziness, paresthesias, numbness of extremities, peripheral neuropathy, excessive fatigue or weakness, irritability, euphoria, sleeplessness, optic neuritis, polyneuritis, toxic psychosis, emotional lability, depression, spasms, toxic neuropathy, memory disturbance.

From cardiovascular system: heartbeat, stenocardia, increase in arterial pressure.

From the alimentary system: nausea, vomiting, gastralgia; increase in activity of alaninaminotranspherase, aspartataminotrans-feraza, a hyperbilirubinemia, a bilirubinurea, jaundice, toxic hepatitis, including with a lethal outcome.

From bodies of a hemopoiesis: agranulocytosis, hemolitic, sideroblastny or aplastic anemia, thrombocytopenia, eosinophilia.

Allergic reactions: skin rash (korevidny, makulopapulezny, exfoliative, purpura), itch, fever, arthralgia, lymphadenopathy, vasculitis.

From a metabolism: B6 hypovitaminosis, pellagra, hyperglycemia, metabolic acidosis, gynecomastia.

Local reactions: irritation in the place of an injection.

Others: menorrhagia, tendency to bleedings and hemorrhages.

Interaction with other medicines:

At a combination with paracetamol also nephrotoxicity increases gepato-; the isoniazid induces system of P450 cytochrome therefore metabolism of paracetamol increases up to toxic products.

Ethanol raises a hepatotoxic of an isoniazid and accelerates his metabolism. Reduces theophylline metabolism that can lead to increase in its concentration in blood.

Reduces metabolic transformations and increases concentration in alfentanil blood.

Cycloserinum and Disulfiramum strengthen adverse central effects of an isoniazid.

Raises a rifampicin hepatotoxic.

The combination to a pyridoxine reduces danger of development of peripheral neuritis.

With care it is necessary to combine with potentially neuro, gepato-and nefrotoksichny medicines because of danger of strengthening of side effect.

Strengthens action of derivatives of coumarin and an indandion, benzodiazepines, carbamazepine, theophylline as reduces their metabolism due to activation of isoenzymes of P450 cytochrome.

Glucocorticosteroids accelerate metabolism in a liver and reduce active concentration in blood.

Suppresses metabolism of Phenytoinum that leads to increase in its concentration in blood and to strengthening of toxic effect (correction of the mode of dosing of Phenytoinum, especially at patients with "slow" acetylation of an isoniazid can be required); it is necessary to consider at appointment as an anticonvulsant at overdose as an isoniazid.

At simultaneous use with enflurany the isoniazid can increase formation of the inorganic fluoric metabolite possessing nefrotoksichny action.

At combined use with rifampicin reduces concentration of a ketokonazol in blood.

Increases concentration of valproic acid in blood (control of concentration of valproic acid is necessary; correction of the mode of dosing can be required).

Contraindications:

Hypersensitivity to an isoniazid, medicinal hepatitis and a liver failure (against the background of the previous treatment by an isoniazid), liver diseases in an aggravation stage.

With care: alcoholism, a liver failure, a renal failure, convulsive attacks, age is more senior than 35 years, long reception of other medicines, therapy cancellation by an isoniazid in the anamnesis, peripheral neuropathy, HIV infection, dekompensirovanny diseases of cardiovascular system (chronic heart failure, stenocardia, arterial hypertension), a hypothyroidism, pregnancy (not to appoint higher than 10 mg/kg in a dose).

Overdose:

Symptoms are shown during 0,5-3 h after introduction: nausea, vomiting, dizziness, the greased speech, a vision disorder, visual hallucinations. At the expressed overdose: a respiratory distress - a syndrome, the oppression of the central nervous system which is quickly passing from a stupor into a coma, the heavy not stopped spasms, a heavy metabolic acidosis, acetonuria, a hyperglycemia.

Treatment: at the expressed overdose (80-150 mg/kg) insufficient therapy leads to a neurotoxicity with a lethal outcome. At adequate therapy the forecast favorable. At asymptomatic overdose: at use in a dose more than 80 mg/kg in the same dose in/in enter a pyridoxine if the dose of the applied isoniazid is unknown, then the adult in/in enter 5 g of a pyridoxine, to children - 80 mg/kg within 30-60 min. At clinical manifestations: adequate ventilation, maintenance of activity of serdechnoksosudisty system, prevention of aspiration of gastric contents. If the dose of the applied isoniazid is known, in/in bolyusno enter the same quantity of a pyridoxine within 3-5 min.

If the dose of the applied isoniazid is unknown, then the adult in/in enter 5 g of a pyridoxine, to children - 80 mg/kg. If spasms do not stop, the dose can be repeated. Seldom it is necessary to appoint a dose more than 10 g. The maximum safe dose of a pyridoxine at overdose by an isoniazid is unknown. At inefficiency of a pyridoxine appoint diazepam. It is necessary to control the content of electrolytes, urea, glucose and the partial pressure of gases in blood. At development of a metabolic acidosis Natrii hydrocarbonas can strengthen a hypercapnia (continuous monitoring is necessary). Dialysis is appointed if spasms and acidosis were not stopped by a pyridoxine, diazepam and Natrii hydrocarbonas.

Storage conditions:

In the dry, protected from light place at a temperature from 0 to 25 °C. To store in the place, unavailable to children. A period of validity - 4 years. Not to use after the term specified on packaging.

Issue conditions:

According to the recipe

Packaging:

Solution for injections of 100 mg/ml. On 5 ml in ampoules of neutral glass. On 5 ampoules in a blister strip packaging from a PVC film. On 5 ampoules in a blister strip packaging from a film of PVC and flexible packaging on the basis of aluminum foil, or the packing material combined on a paper basis. 1 or 2 blister strip packagings with ampoules together with the application instruction place in a pack from a cardboard for a retail container. Packaging for hospitals. 10, 20, 25, 50, 100, 200 blister strip packagings with ampoules together with the equal number of application instructions place in a box of corrugated fibreboard or a cardboard for a retail container.