Isoniazid-Ferein (Isoniazid-Ferein)

Composition Pharmacodynamics Indications Carefully Contraindications Dosing and Administration Side effects Form release / dosage
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Active substanceIsoniazidIsoniazid
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    • Dosage form: & nbspinjection
    Composition:

    1 ml of solution for injection contains:

    Active substance:

    Isoniazid (in terms of 100% substance) -100 mg

    Excipient:

    Water for injections - up to 1 ml

    Description:Transparent colorless or slightly colored solution.
    Pharmacotherapeutic group:Anti-tuberculosis drug
    ATX: & nbsp

    J.04.A.C.01   Isoniazid

    Pharmacodynamics:

    Anti-tuberculosis drug; acts bacteriostatically. Is a prodrug - mycobacterial catalase peroxidase metabolizes isoniazid to the active metabolite, which, when bound to the enoyl (acyl-transfer protein) reductase of fatty acid synthase II, disrupts the conversion of delta2-unsaturated fatty acids into mycolic acid. The latter is a branched chain fatty acid that, when combined with arabinogalactan (polysaccharide), participates in the formation of the components of the cell wall of Mycobacterium tuberculosis. Isoniazid is also an inhibitor of mycobacterial catalase-peroxidase, which reduces the protection of the microorganism against reactive oxygen species and hydrogen peroxide.

    Isoniazid is also active against a small number of strains of Mycobacterium kansasii (for infections caused by this pathogen, it is necessary to determine the sensitivity to isoniazid before starting treatment).

    Pharmacokinetics:

    The connection with proteins is insignificant - up to 10%. The volume of distribution is 0.57-0.76 l / kg. Isoniazid well distributed throughout the body, penetrating all tissues and fluids, including cerebrospinal, pleural, ascites; high concentrations are created in the lung tissue, kidneys, liver, muscles, saliva and sputum.

    Penetrates through the placental barrier and into breast milk.

    It is metabolized in the liver by acetylation with the formation of inactive products. The liver is acetylated with N-acetyltransferase to form N-acetylisoiniazide, which is then converted to isonicotinic acid and monoacetylhydrazine, which has a hepatotoxic effect by forming a cytochrome P450 system upon N-hydroxylation of the active intermediate metabolite.The rate of acetylation is genetically determined; in people with "slow" acetylation, there is little N-acetyltransferase. Is the inducer of the isoenzyme CUR2E1. The half-life (T1 / 2) for "fast acetylators" is 0.5-1.6 h; for "slow" - 2-5 hours. In case of renal insufficiency, T1 / 2 can increase to 6.7 hours. T1 / 2 for children aged 1.5 to 15 years - 2.3-4.9 hours, while newborns - 7,8-19,8 h (which is due to the imperfection of the processes of acetylation in newborns). With repeated appointments, T1 / 2 is shortened to 2-3 hours. It is excreted mainly by the kidneys: 75-95% of the drug is excreted within 24 hours, mainly in the form of inactive metabolites - N-acetylisoniases and isonicotinic acid. At the same time, "fast acetylators" contain N-acetylisiniazide content of 93%, while "slow" - not more than 63%. Small amounts are excreted by the intestine. When hemodialysis removes a significant amount of isoniazid (within 5 hours to 73%); the effectiveness of peritoneal dialysis is limited.

    Indications:
    Treatment of tuberculosis (any localization, in adults and children, as part of combination therapy).
    Contraindications:Hypersensitivity to isoniazid, drug hepatitis and liver failure (against the background of previous treatment with isoniazid), liver disease in the acute stage.
    Carefully:Alcoholism, hepatic insufficiency, renal failure, seizures, age over 35, long-term use of other drugs, cancellation of isoniazid therapy in history, peripheral neuropathy, HIV infection, decompensated diseases of the cardiovascular system (chronic heart failure, angina pectoris, arterial hypertension ), hypothyroidism, pregnancy (not prescribe in a dose above 10 mg / kg).
    Pregnancy and lactation:

    The use of the drug in a dose exceeding 10 mg / kg is contraindicated in pregnancy.

    Penetrates through the hematoplacental barrier, is determined in the fetal blood serum in concentrations comparable or exceeding the serum in the mother. Perhaps the emergence of myelomeningocele, hypospadias and hemorrhages (due to hypovitaminosis K) in the fetus, may further lead to a delay in the development of psychomotor development in the child.

    Penetrates into breast milk, reaching concentrations comparable to the concentration in the blood plasma. The child receives 0.75-2.3% of the dose taken by the mother; possibly the occurrence of hepatitis and peripheral neuritis.

    If it is necessary to use the drug during lactation, it is necessary to solve the problem of abolishing breastfeeding.

    Dosing and Administration:

    Isoniazid is used intramuscularly, intravenously, into the cavity. Daily and course doses of isoniazid are set for each patient individually, depending on the nature and form of the disease, the rate of acetylation and the tolerability of the drug.

    Intramuscularly isoniazid administered as a 10% solution in a dose of 5-12 mg / kg per day. The drug is given in 1-2 injections. The duration of the course of intramuscular isoniazid is 2-6 months, depending on the effectiveness of therapy and the tolerability of the drug. For the purpose of prevention - intramuscularly - up to 300 mg once a day for 2 months. Intramuscular introduction of isoniazid is combined with the use of pyridoxine (vitamin B6). Pyridoxine take inside 60-100 mg concomitantly with the injection of isoniazid or injected intramuscularly at a dose of 100-125 mg 30 minutes after the injection.

    Intravenously isoniazid administered as a 10% solution at a dose of 10-15 mg / kg per day for 30-60 seconds. For adults: 200-300 mg, for children - 100-300 mg (10-20 mg / kg of body weight), for newborns 3-5 mg / kg, but not more than 10 mg / kg of body weight per day. The course of treatment consists of 30-150 infusions depending on the effectiveness of therapy and the tolerability of the drug. After the introduction, you must observe bed rest for 1-1.5 hours.Intravenous isoniazid is combined with vitamin B6 and glutamic acid (to prevent side effects). Vitamin B6 take inside 60 mg in 2 hours after intravenous introduction of isoniazid or injected intramuscularly at a dose of 100-125 mg 30 minutes after injection. Glutamic acid is taken in a daily dose of 1 to 1.5 g.

    Isoniazid intravenously can be administered with all antituberculosis drugs, except cycloserine.

    In the cavern isoniazid are introduced by installing a 10% solution in a daily dose of 10-15 mg / kg. Cavity punctures are performed 2-3 times a week, and when draining the cavity, the installation should be performed daily. Instillations are carried out in the conditions of a surgical hospital. During pregnancy, with severe form of pulmonary heart failure, severe atherosclerosis, ischemic heart disease, arterial hypertension should not be prescribed in doses greater than 10 mg / kg.

    Side effects:

    From the nervous system: headache, dizziness, paresthesia, numbness of the extremities, peripheral neuropathy, excessive fatigue or weakness, irritability, euphoria, insomnia,optic neuritis, polyneuritis, toxic psychosis, emotional lability, depression, convulsions, toxic neuropathy, memory impairment.

    From the cardiovascular system: palpitation, angina, increased blood pressure.

    From the digestive system: nausea, vomiting, gastralgia; increased activity of alanine aminotransferase, aspartate aminotransferase, hyperbilirubinemia, bilirubinuria, jaundice, toxic hepatitis, incl. with a lethal outcome.

    From the hematopoiesis: agranulocytosis, hemolytic, sideroblastic or aplastic anemia, thrombocytopenia, eosinophilia.

    Allergic reactions: skin rash (cortex, maculopapular, exfoliative, purpura), itching, fever, arthralgia, lymphadenopathy, vasculitis.

    From the side of metabolism: hypovitaminosis B6, pellagra, hyperglycemia, metabolic acidosis, gynecomastia.

    Local Reactions: irritation at the injection site.

    Other: menorrhagia, a tendency to bleeding and hemorrhage.

    Overdose:

    Symptoms occur within 0.5-3 h after administration: nausea, vomiting, dizziness, blurred speech, visual impairment, visual hallucinations.With severe overdose: respiratory distress syndrome, central nervous system depression rapidly shifting from stupor to coma, severe non-curable convulsions, severe metabolic acidosis, acetonuria, hyperglycemia.

    Treatment: in severe overdose (80-150 mg / kg), insufficient therapy leads to neurotoxicity with a fatal outcome. With adequate therapy, the prognosis is favorable. With asymptomatic overdose: when administered at a dose of more than 80 mg / kg at the same dose, IV is given pyridoxine, if the dose of isoniazid is unknown, then 5 g of pyridoxine is administered to adults IV, 80 mg / kg for children for 30-60 minutes. With clinical manifestations: adequate ventilation, maintenance of the cardiovascular system, prevention of aspiration of gastric contents. If the dose of isoniazid is known, the same amount of pyridoxine is injected into the bolus bolus within 3-5 minutes. If the dose of isoniazid is unknown, 5 g of pyridoxine are administered to adults IV, and 80 mg / kg for children. If the convulsions do not stop, the dose can be repeated. It is rare to prescribe a dose of more than 10 g. The maximum safe dose of pyridoxine in case of an overdose with isoniazid is unknown. If pyridoxine is ineffective, diazepam. It is necessary to control the content of electrolytes, urea, glucose and partial pressure of gases in the blood. With the development of metabolic acidosis sodium hydrogen carbonate can enhance hypercapnia (continuous monitoring is necessary). Dialysis is prescribed if seizures and acidosis are not stopped by pyridoxine, diazepam and sodium bicarbonate.

    Interaction:

    When combined with paracetamol, hepato- and nephrotoxicity increases; isoniazid induces a system of cytochrome P450, which increases the metabolism of paracetamol to toxic products.

    Ethanol increases the hepatotoxicity of isoniazid and speeds up its metabolism. Reduces the metabolism of theophylline, which can lead to an increase in its concentration in the blood.

    Reduces metabolic transformations and increases the concentration in the blood of alfentanil.

    Cycloserine and disulfiram enhance the adverse central effects of isoniazid.

    Increases hepatotoxicity of rifampicin.

    Combination with pyridoxine reduces the risk of peripheral neuritis.

    Caution should be combined with potentially neuro-, hepato- and nephrotoxic drugs because of the risk of side effects.

    Enhances the action of coumarin and indanedione derivatives, benzodiazepines, carbamazepine, theophylline, as it reduces their metabolism due to the activation of cytochrome P450 isoenzymes.

    Glucocorticosteroids accelerate metabolism in the liver and reduce active concentrations in the blood.

    Suppresses the metabolism of phenytoin, which leads to an increase in its concentration in the blood and increased toxic effect (correction of the dosing regimen of phenytoin may be necessary, especially in patients with "slow" acetylation of isoniazid); should be considered when administered as an anticonvulsant with an overdose of isoniazid.

    When used simultaneously with enflurane isoniazid can increase the formation of inorganic fluoride metabolite, which has a nephrotoxic effect.

    When combined with rifampicin reduces the concentration of ketoconazole in the blood.

    Increases the concentration of valproic acid in the blood (monitoring of valproic acid concentration is required, correction of the dosing regimen may be required).

    Special instructions:

    Even a few months after the end of the application, fatal medicinal hepatitis can occur.The risk rises with age (the highest frequency in the age group is 35-64 years), especially with daily consumption of ethanol. Therefore, every month it is necessary to monitor the function of the liver, people over 35 years of age, the function of the liver is further examined before treatment. In addition to ethanol use, additional risk factors are chronic liver disease, parenteral drug use and the postpartum period; under these circumstances, monitoring of liver function (laboratory and clinical) should be conducted more often. Patients should be informed of the need to report any manifestations of liver damage (unexplained anorexia, nausea, vomiting, darkening of the urine, jaundice, rash, paresthesia of the hands and feet, weakness, fatigue or fever lasting more than 3 days, abdominal pain, especially in the right upper quadrant ). In these cases isoniazid immediately cancel.

    Patients who have previously undergone isoniazid hepatitis are prescribed alternative antituberculous drugs. If it is necessary to resume therapy, it is started after a complete resolution of clinical and laboratory signs of hepatitis followed bypermanent control of liver function. With any signs of relapse isoniazid immediately cancel. In patients with acute liver disease, preventive isoniazid should be postponed.

    To slow the development of microbial resistance is prescribed together with other antituberculous drugs. In connection with the different metabolic rate before the use of isoniazid, it is expedient to determine the rate of its inactivation (by the dynamics of the content in the blood and urine). The "fast acetylators" isoniazid used in higher doses.

    At the risk of peripheral neuritis (patients over 65, concomitant diabetes, pregnancy, chronic renal failure, alcoholism, hypovitaminosis B6 due to malnutrition, concomitant anticonvulsant therapy), the appointment of 10-25 mg / day of pyridoxine is recommended.

    During the treatment, cheese (especially Swiss or Cheshire), fish (especially tuna, sardinella, skipjack) should be avoided, since with the simultaneous use of them with isoniazid, reactions (skin flushing, itching, heat or cold sensation, palpitation, increased sweating,chills, headache, dizziness) associated with the suppression of monoamine oxidase and diaminoxidase activity and leading to a disruption of the metabolism of tyramine and histamine contained in fish and cheese.

    It should be borne in mind that isoniazid can cause hyperglycemia with secondary glucosuria; tests with the reduction of copper ions can be false positive; the drug does not affect the enzymatic glucose tests.

    Effect on the ability to drive transp. cf. and fur:During the period of application of the drug it is recommended to abandon the management of vehicles, mechanisms and occupations requiring concentration of attention and speed of psychomotor reactions.
    Form release / dosage:
    Solution for injection 100 mg / ml.
    Packaging:

    5 ml into neutral glass ampoules.

    5 ampoules per contour pack of PVC film.

    5 ampoules per contour mesh package made of PVC film and flexible packaging on the basis of aluminum foil, or packaging material combined on a paper basis.

    1 or 2 contoured cells with ampoules together with the instruction for use are placed in a pack of cardboard for consumer containers.

    Packing for hospitals.

    10, 20, 25, 50, 100, 200 contour cell packs with ampoules, together with an equal number of instructions for use, are placed in a box of corrugated cardboard or cardboard for consumer containers.

    Storage conditions:In a dry, dark place at a temperature of 0 to 25 ° C. Keep out of the reach of children.
    Shelf life:4 years. Do not use after the expiration date indicated on the package.
    Terms of leave from pharmacies:On prescription
    Registration number:LP-001903
    Date of registration:14.11.2012 / 23.03.2017
    Expiration Date:14.11.2017
    The owner of the registration certificate:BRYNTSALOV-A, CJSC BRYNTSALOV-A, CJSC Russia
    Manufacturer: & nbsp
    Information update date: & nbsp23.10.2017
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