Isoniazid-darnitsa

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT IZONIAZID-DARNITSA (Isoniazid-Darnitsa)

Composition:

Active substance: isoniazid;

1 ml of solution contains isoniazid 100 mg;

Excipient: water for injections.

Pharmaceutical form. Injection solution.

Main physicochemical properties: clear, colorless or slightly colored liquid.

Pharmacotherapeutic group. Antituberculosis agents. ATC code J04A C01.

Pharmacological properties.

Pharmacodynamics.

Isoniazid inhibits DNA-dependent RNA polymerase and suppresses the synthesis of mycolic acids in the cell wall of Mycobacterium tuberculosis. The drug exhibits high bacteriostatic activity against Mycobacterium tuberculosis, inhibiting their growth at a concentration of 0.03 mcg/mL. It is particularly active against rapidly multiplying microorganisms. It has weak effects on pathogens of other infectious diseases.

Pharmacokinetics.

After parenteral administration, the drug rapidly penetrates into body tissues and biological fluids. It crosses the blood-brain barrier, especially during inflammation of the meninges, and penetrates into bones. Isoniazid is metabolized in the liver, with the rate depending on individual genetic characteristics—either rapidly or slowly. It is excreted by the kidneys. The elimination half-life is 0.5–1.5 hours in fast metabolizers and 4–6 hours in slow metabolizers. The drug is excreted primarily via bile; about 30% of the dose is excreted in urine.

Clinical characteristics.

Indications.

Treatment of all forms and localizations of active tuberculosis in adults and children (as a first-line agent).

Contraindications.

Hypersensitivity to isoniazid or to excipients of the medicinal product.

Epilepsy and other disorders associated with a predisposition to seizures, severe psychosis, poliomyelitis (including in medical history), toxic hepatitis in medical history due to use of hydrazide derivatives of isonicotinic acid (phthivazide), pronounced atherosclerosis, acute hepatic and/or renal failure.

Administration of isoniazid at doses exceeding 10 mg/kg body weight per day is contraindicated during pregnancy, in case of cardiopulmonary insufficiency, arterial hypertension stage II–III, ischemic heart disease, disorders of the nervous system, bronchial asthma, chronic renal failure, hepatitis in the phase of exacerbation, liver cirrhosis, psoriasis, eczema in the phase of exacerbation, hypothyroidism, myxedema.

Interaction with other medicinal products and other types of interactions.

Indirect anticoagulants, benzodiazepines, phenytoin, carbamazepine, theophylline, MAO inhibitors – isoniazid potentiates the effects of these medicinal products (including toxic effects).

Isoniazid may reduce the therapeutic effect of levodopa.

Concomitant use of isoniazid:

With itraconazole – a significant decrease in its serum concentration and absence of therapeutic effect are possible. Concomitant use is not recommended.

With ketoconazole – may reduce ketoconazole serum levels: monitoring of drug concentration in blood is required and dose adjustment may be necessary.

With acetaminophen – increases its toxicity due to generation and accumulation of toxic metabolites in the liver, which may lead to serious adverse reactions.

With glucocorticoids – metabolism and elimination of isoniazid are increased.

With phenytoin, theophylline, carbamazepine, benzodiazepines, and other medicinal products metabolized by specific cytochrome P450 enzymes – isoniazid inhibits metabolism of the listed medicinal products, leading to increased plasma concentrations and possible enhancement of toxic effects.

Isoniazid may reduce hepatic metabolism of benzodiazepines (e.g., diazepam, flurazepam, triazolam, midazolam), resulting in increased plasma concentrations. Patients should be carefully monitored for signs of benzodiazepine toxicity, and benzodiazepine doses should be adjusted accordingly.

With diphenylhydantoin (phenytoin) – isoniazid enhances the antiarrhythmic effect of phenytoin.

With potentially hepatotoxic and neurotoxic agents (including alcohol, rifampicin) – increases the risk of developing toxic hepatitis and neuropathy (with paracetamol, the risk of hepatotoxic effects increases).

With valproate – concomitant use increases valproate plasma concentration.

With stavudine – increases the risk of developing distal sensory neuropathy.

With vitamin B6 and glutamic acid – combination reduces the likelihood of isoniazid adverse effects.

Since clearance of isoniazid is doubled with zalcitabine in HIV-infected patients, concentrations of isoniazid and zalcitabine should be monitored to ensure treatment efficacy.

When prescribing isoniazid to patients with slow inactivation of the drug who are simultaneously receiving para-aminosalicylic acid, tissue concentration of the drug may be increased, thereby increasing the risk of adverse effects.

Isoniazid may slow hepatic metabolism of primidone, triazolam, chlorzoxazone, disulfiram, which may lead to increased toxicity.

To enhance efficacy, the medicinal product Isoniazid-Darnytsia should be used in combination with other antituberculosis medicinal products (e.g., rifampicin, ethambutol, pyrazinamide), and in case of mixed infection – simultaneously with broad-spectrum antibiotics: fluoroquinolones (e.g., ofloxacin, ciprofloxacin), sulfonamides, macrolides.

Concomitant use of isoniazid with phenobarbital may lead to enhanced hepatotoxicity.

Chlorpromazine – concomitant use may impair metabolism of isoniazid. Patients should be monitored for isoniazid toxicity.

Haloperidol – concomitant use may increase haloperidol plasma levels. Dose adjustment of haloperidol is required.

Anticoagulants (coumarin- or indandione-derivatives, e.g., warfarin) – concomitant use may inhibit enzymatic metabolism of anticoagulants, leading to increased plasma concentration and increased risk of bleeding. Prothrombin time should be carefully monitored.

Enflurane – when used concomitantly, isoniazid may increase formation of potentially nephrotoxic inorganic fluorides – metabolites of enflurane.

Theophylline – theophylline plasma concentration increases; therefore, theophylline blood levels should be monitored and the dose adjusted accordingly.

Procainamide – increases plasma concentration of isoniazid. Monitoring of patients for isoniazid toxicity is required.

Corticosteroids (e.g., prednisolone) – dose of isoniazid should be adjusted.

Aluminum hydroxide – absorption of isoniazid is impaired. During isoniazid therapy, acid-suppressing medicinal products or antacids not containing aluminum hydroxide should be used.

Also, possible interaction of isoniazid with food products containing histamine and tyramine (hard cheese, red wine, tuna, and other tropical fish) – adverse reactions such as headache, increased sweating, palpitations, flushing, arterial hypotension may develop.

Special precautions.

Medical supervision is required during treatment, along with regular performance of liver function tests and ophthalmological examinations. During the first month, examinations should be performed at least twice; thereafter, once a month.

To reduce adverse effects if they occur, pyridoxine (1–2 mL of 5% solution intramuscularly per day), thiamine chloride (1 mL of 5% solution intramuscularly per day), or thiamine bromide (1 mL of 6% solution intramuscularly per day), glutamic acid, and sodium ATP salt should be administered.

To prevent possible hepatotoxic effects of isoniazid, it should be prescribed in combination with hepatoprotectors (silymarin, ursodeoxycholic acid).

Alcoholic beverages should be avoided during treatment.

Since resistance to isoniazid develops rapidly during monotherapy (in 70% of cases), to delay this process, the drug should be prescribed only in combination with other antituberculosis agents. In mixed infections, broad-spectrum antibiotics, fluoroquinolones, and sulfonamides should be administered simultaneously with isoniazid.

In patients with diabetes mellitus, a positive glucosuria test may occur.

Use during pregnancy or breastfeeding.

The use of the drug is contraindicated during pregnancy at doses exceeding 10 mg/kg per day. When administered to pregnant women (at a daily dose up to 10 mg/kg body weight), it should be noted that isoniazid crosses the placenta and may cause myelomeningocele and hypospadias, hemorrhages (due to vitamin K deficiency), as well as delayed psychomotor development of the fetus.

Isoniazid passes into breast milk; therefore, considering the potential risk of hepatitis and peripheral neuritis in the infant, a decision should be made either to discontinue breastfeeding or to discontinue the drug.

Ability to affect reaction rate while driving or operating machinery.

Drivers and operators of complex machinery should be aware of the possibility of adverse effects on the nervous system that may impair the ability to concentrate and reaction speed.

Administration and Dosage

Isoniazid-Darnitsia should be administered intramuscularly, intravenously, by inhalation, or intracavitarily.

Intravenous administration of Isoniazid-Darnitsia is indicated for the treatment of disseminated pulmonary tuberculosis, massive bacterial excretion, concomitant gastrointestinal disorders, in patients who avoid taking the drug orally, and in cases of ineffectiveness of oral administration.

The daily intravenous dose is: 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 body weight per day. The drug is administered intravenously as a 2.5–10% solution (if necessary, the drug may be diluted with water for injections or 0.9% sodium chloride solution) once daily, over 30–60 seconds. The treatment course depends on therapeutic efficacy and drug sensitivity – 30–150 injections. To prevent adverse effects during intravenous administration of Isoniazid-Darnitsia, vitamin B6 (pyridoxine) and glutamic acid should be used. Pyridoxine is administered intramuscularly (100–125 mg) 30 minutes after Isoniazid-Darnitsia, or orally (60–100 mg) every 2 hours after each intravenous injection of Isoniazid-Darnitsia. Glutamic acid should be taken at a daily dose of 1–1.5 g. Bed rest for 1–1.5 hours is required after intravenous administration of the drug.

Intramuscular administration for adults and children: administer the ready-to-use undiluted 10% solution of Isoniazid-Darnitsia at a dose of 5–12 mg/kg once daily for 2–5 months. To reduce adverse effects with this route of administration, pyridoxine should be administered orally simultaneously with Isoniazid-Darnitsia at a dose of 60–100 mg (pyridoxine may also be administered intramuscularly at a dose of 100–125 mg/kg 30 minutes after Isoniazid-Darnitsia).

Inhalation administration: Isoniazid-Darnitsia should be administered 1–2 times daily as a ready-to-use undiluted 10% solution. The daily dose is 0.005–0.01 g (5–10 mg) per 1 kg body weight. Inhalations should be performed daily for 1–6 months.

For patients with fibrocavitary and cavitary forms of tuberculosis with bacterial excretion and in the preoperative period, the ready-to-use undiluted 10% solution of Isoniazid-Darnitsia should be administered at a daily dose of 10–15 mg/kg once daily, primarily via intracavitary administration or intratracheal instillation.

The maximum daily and total course dose of the drug should be determined based on the nature and form of the disease, the degree of inactivation, and individual tolerance to isoniazid.

Children

The drug may be administered to children starting from the neonatal period.

Overdose

Overdose symptoms may appear 0.5–3 hours after drug administration and include gastrointestinal disturbances, nausea, vomiting, anorexia, neurotoxic manifestations, dizziness, fever, headache, blurred vision, slurred speech, and visual hallucinations. Severe intoxication may lead to respiratory and central nervous system depression, seizures, and coma. Typical laboratory findings in overdose include metabolic acidosis, ketonuria, and hyperglycemia.

Treatment: induce vomiting, gastric lavage, activated charcoal, intravenous administration of high-dose pyridoxine. Hemodialysis is effective.

Seizure management: administration of magnesium sulfate solution, diazepam.

Management of liver function disturbances: methionine, lipamide, ATP, vitamin B12.

Subsequent treatment should focus on careful monitoring and support of pulmonary ventilation and correction of metabolic acidosis. There is no specific antidote.

Adverse reactions.

Eye disorders: optic neuritis, optic nerve atrophy.

Ear and labyrinth disorders: hearing loss, tinnitus in patients with end-stage renal disease.

Respiratory, thoracic and mediastinal disorders: allergic pneumonitis.

Gastrointestinal disorders: dry mouth, anorexia, nausea, vomiting, constipation, flatulence, acute pancreatitis.

Hepatobiliary and biliary tract disorders: liver function abnormalities, hepatitis, increased serum transaminases (SGOT, SGPT), hyperbilirubinemia, bilirubinuria, fulminant hepatic failure which may lead to necrosis.

Renal and urinary disorders: dysuria, urinary retention, nephrotoxicity, including interstitial nephritis.

Endocrine disorders: pyridoxine deficiency, pellagra, hyperglycemia, metabolic acidosis.

Nervous system disorders: insomnia, dizziness, headache, irritability, euphoria, sleep disturbances, sensory disturbances, paresthesia, hyperreflexia, peripheral neuritis.

Psychiatric disorders: psychotic reactions (including toxic psychosis), ranging from minor personality changes to severe mental disorders, increased frequency of seizures in patients with epilepsy, convulsions, toxic encephalopathy, memory disorders, confusion, disorientation, hallucinations.

Cardiac disorders: palpitations, chest pain and cardiac area pain, arterial hypertension, myocardial ischemia in elderly patients.

Blood and lymphatic system disorders: agranulocytosis, hemolytic anemia, sideroblastic anemia, aplastic anemia, thrombocytopenia, eosinophilia, leukopenia, neutropenia.

Immune system disorders: hypersensitivity reactions, including Quincke's edema, breathing difficulties, skin itching, dermatitis, fever, lymphadenopathy, vasculitis, skin rashes (exfoliative, maculopapular, purpura, erythema multiforme, lupus-like syndrome, rheumatic syndrome), Stevens-Johnson syndrome, toxic epidermal necrolysis, interstitial pneumonitis, edema of bronchial mucosa.

Reproductive system and breast disorders: gynecomastia and menorrhagia.

General disorders and administration site conditions: possible changes at the injection site.

Adverse effects usually resolve with dose reduction or temporary discontinuation of the drug.

Reporting of suspected adverse reactions.

Reporting suspected adverse reactions after drug authorization is an important procedure. It allows continuous monitoring of the benefit-risk ratio for the respective medicinal product. Healthcare professionals should report any suspected adverse reactions via the national reporting system.

Shelf life. 2 years.

Storage conditions.

Store in original packaging at a temperature of 2 to 8 °C.

Keep out of reach of children.

Packaging.

5 ml in a vial; 5 vials in a blister pack, 2 blister packs in a carton.

Prescription category. Prescription only.

Manufacturer. JSC "Pharmaceutical Company "Darnytsia".

Manufacturer's address and place of business.

13 Boryspylska Street, Kyiv, 02093, Ukraine.