Isoniazid-Darnitsa - instructions for use, dose, side effects, contraindications

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 transferring protein) reductase of the fatty acid synthase I, 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 It is also active against a small amount of Mycobacterium kansasii strains (infections caused by the data agent, before treatment is necessary to determine susceptibility to isoniazid).

Pharmacokinetics:

TSmax - 1-2 hours, Cmax after oral intake of a single dose of 300 mg - 3-7 μg / ml. The connection with proteins is insignificant - up to 10%. The volume of distribution is 0.57-0.76 l / kg. 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. In the liver N-acetyltransferase is acetylated to form N- atsetilizoniazida which is then converted to isonicotinic acid and monoatsetilgidrazin, providing hepatotoxic action by formation of P450 cytochrome system when N-hydroxylation 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 CYP2E1. The half-life for "fast acetylators" is 0.5-1.6 hours; for "slow" - 2-5 hours. With renal failure, the elimination half-life can increase to 6.7 hours. The elimination half-life for children aged 1.5 to 15 years is 2.3-4.9 hours, and in newborns 7.8-19.8 hours (which is explained by the imperfection of acetylation processes in newborns). Despite the fact that the half-life index varies significantly depending on the individual intensity of the acetylation processes, the average value of the half-life is 3 hours (ingestion 600 mg) and 5.1 hours (900 mg). At repeated appointments the half-life period 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-acetylisiniazide 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.The drug is removed from the blood during hemodialysis; five-hour hemodialysis allows you to remove from the blood to 73% of the drug.

Indications:Tuberculosis (any localization, in adults and children, treatment and prevention, as part of combination therapy)

Contraindications:Hypersensitivity, drug-induced hepatitis and liver failure (against the background of the 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:Contraindicated use of the drug in pregnancy at a dose of more than 10 mg / kg per day. When using Isoniazid-Darnitsa in pregnant women (in a daily dose of up to 10 mg / kg body weight)that inosiazide penetrates the placenta and can cause the development of myelomeningocele and hypospadias, hemorrhages (due to hypovitaminosis K), as well as delayed psychomotor development of the fetus. Inosiazide enters breast milk, therefore, given the likelihood of developing hepatitis and peripheral neuritis in a child, it is necessary to decide whether to stop breastfeeding or stop using the drug.

Dosing and Administration:

Isoniazid-Darnitsa is used intravenously, intramuscularly, inhalation, endotracheally (into the cavern).

Intravenously Isoniazid-Darnitsa is administered for the treatment of advanced pulmonary tuberculosis, with massive bacterial excretion, concomitant diseases of the gastrointestinal tract, patients who shy away from taking the drug inside, in case of inefficiency in the oral route of administration.

Intravenous daily dose is 10-15 mg / kg / day in the form of 100 mg / ml solution: for adults 200-300 mg, for children - 100-300 mg (10-20 mg / kg body weight), for newborns 3- 5 mg / kg, but not more than 10 mg / kg of body weight per day. Intravenously injected in the form of 2.5-100 mg / ml solution (if necessary, the drug is diluted with water for injection or 0.9% solution of sodium chloride) for 30-60 sec once a day.The course of treatment depends on the effectiveness of therapy and the tolerability of the drug - 30-150 injections. To prevent side effects with intravenous Isoniazid-Darnitsa vitamin B (pyridoxine) and glutamic acid. Pyridoxine injected intramuscularly (100-125 mg) 30 minutes after isoniazid-darnitsa or appointed inside (60-100 mg) every 2 hours after intravenous Isoniazid-Darnitsa. Glutamic acid is taken in a daily dose of 1 to 1.5 g. With intravenous use of the drug must be observed bed rest for 1-1.5 hours.

Intramuscularly adults and children are injected with Isoniazid-Darnitsa solution at 5-12 mg / kg per day, 1-2 times a day, for 2-6 months. To alleviate the side effect with this route of administration in conjunction with the introduction of Isoniazid-Darnitsa appoint pyridoxine in a dose of 60-100 mg (can also be administered intramuscularly 30 minutes after isoniazid-darnitsa in a dose of 100-125 mg / kg).

Inhalation isoniazid-Darnitsa is prescribed in 1-2 divided doses. The daily dose is 0.005-0.01 g (5-10 mg) per 1 kg of body weight. Inhalation spend daily for 1-6 months.

Patients with fibrous-cavernous and cavernous forms of tuberculosis during bacterial isolation and inpreoperative period prescribed solution of Isoniazid-Darnitsa in a daily dose of 10-15 mg / kg, 1 time per day. Enter mainly intra-cavernous, by means of endotracheal infusions.

The maximum daily and course dose of the drug is determined depending on the nature and form of the disease, the degree of inactivation and the individual tolerance of isoniazid.

For the purpose of prophylaxis - intramuscularly - up to 300 mg once a day for 2 months. In severe forms of pulmonary heart failure, severe atherosclerosis, coronary heart disease and hypertension should not be prescribed in doses greater than 10 mg / kg.

Children

The drug is given to children from birth.

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 side of the cardiovascular system: palpitation, angina, increased blood pressure.

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

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

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

From the side of metabolism: hypovitaminosis Vb, 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 hours after administration: nausea, vomiting, dizziness, blurred speech, visual impairment, visual hallucinations.

In 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 used at a dose of more than 80 mg / kg in the same dose intravenously administered pyridoxine, if the dose of isoniazid is unknown, then 5 g of pyridoxine are administered intravenously to adults, 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 administered intravenously bolus within 3-5 minutes. If the dose of isoniazid is unknown, then 5 g of pyridoxine are injected intravenously, 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 an isoniazid overdose 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 cytochrome system R₄₅₀, resulting in increased 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 rifampin.

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 effect of derivatives of coumarin and indandione, benzodiazepines, carbamazepine, theophylline, since it reduces their metabolism by activating the cytochrome system R₄₅₀.

Stavudine - increases the risk of developing distal sensory neuropathy. 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 rifampin 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:

In some cases, fatal drug hepatitis develops during treatment, which can occur even a few months after the end of the application.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.

Given that with monotherapy with isoniazid, the resistance of pathogens develops rapidly (in 70% of cases), to delay this process, the drug is prescribed only together with other antituberculous drugs. With a mixed infection, simultaneously with inosiazide, antibiotics of a wide spectrum of action, fluoroquinolones, sulfonamides and the like are prescribed.

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 a risk of peripheral neuritis (patients over 65 years of age, concomitant diabetes, pregnancy, chronic renal failure, alcoholism, hypovitaminosis B₆due 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 recovery FROMu²⁺can be false positive; the drug does not affect the enzymatic glucose tests.

To enhance the effectiveness of isoniazid-darnitsa used in combination with other anti-tuberculosis drugs (for example, rifampicin, ethambutol, pyrazinamide), and with mixed infection - simultaneously with broad-spectrum antibiotics: fluoroquinolones, sulfonamides, macrolides (and the like).

Effect on the ability to drive transp. cf. and fur:Drivers and operators of complex mechanisms need to consider the likelihood of developing side effects from the nervous system, which can affect the ability to concentrate attention and reaction speed.

Form release / dosage:

Solution for intravenous and intramuscular, inhalation and endotracheal administration 100 mg / ml.

Packaging:

For 5 ml in a vial of neutral colorless glass.

It is allowed to paste a label with self-adhesive paper on the ampoule.

5 ampoules with an opening knife or a scapegrator ampoule in a contour acrylic package from a polystyrene tape or a polyvinylchloride film.

2 contour squares with instructions for use in a cardboard bundle.

For 10 ampoules with instructions and an autopsy knife or a scarifier in a box with a corrugated liner. Boxes are pasted with a label-parcel of paper label or offset paper.

When you pack the ampoules with a ring or break point, the opener or the ampoule scaper are not put in.

Storage conditions:Keep out of reach of children, at a temperature of 2 ° C to 8 ° C.

Shelf life:

2 years.

Do not use after the expiration date printed on the package.

Terms of leave from pharmacies:On prescription

Registration number:П N010671

Date of registration:06.03.2012 / 25.04.2013

Expiration Date:Unlimited

The owner of the registration certificate:DARNITSA PHARMACEUTICAL FIRM, CJSCDARNITSA PHARMACEUTICAL FIRM, CJSC Ukraine

Manufacturer: & nbsp

DARNITSA PHARMACEUTICAL FIRM, PAO Ukraine

Information update date: & nbsp23.10.2017

Illustrated instructions

Instructions

Isoniazid-Darnitsa (Isoniazid-Darnitsa)