Isoniazid

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT ISONIAZID (ISONIAZID)

Composition:

Active substance: isoniazid;

1 tablet contains isoniazid (calculated on dry basis) 100 mg or 200 mg;

Excipients: povidone, maize starch, crospovidone, calcium stearate.

Pharmaceutical form. Tablets.

Main physicochemical properties:

100 mg tablets: round-shaped tablets, white or almost white, with a double-convex surface;

200 mg tablets: round-shaped tablets, white or almost white, with a flat surface, bevelled edges (chamfered) and a score line.

Pharmacotherapeutic group. Antituberculosis agents. ATC Code J04A C01.

Pharmacological properties.

Pharmacodynamics.

Isoniazid has high bacteriostatic activity against actively multiplying Mycobacterium tuberculosis, and is less effective against bacteria in the resting phase. Its mechanism of action is associated with inhibition of the synthesis of long-chain mycolic acids, which are components of the mycobacterial cell wall. The drug inhibits the growth of mycobacteria in humans at a concentration of 0.03 mcg/mL. The drug has no significant chemotherapeutic effect on other common infectious disease pathogens.

Pharmacokinetics.

Well absorbed from the gastrointestinal tract, readily penetrates the blood-brain barrier, and is distributed into various tissues and body fluids. After oral administration, maximum plasma concentration is observed within 1–4 hours; the antituberculosis concentration in blood persists for 6–24 hours after a single dose.

The drug is primarily excreted by the kidneys. Based on the amount of active isoniazid excreted in urine relative to the administered dose, patients are classified into "slow" and "fast" inactivators. The first category includes patients who excrete up to 10% of isoniazid in urine per day, the second category—over 10% per day.

The half-life of isoniazid in plasma is 0.5–1.6 hours in fast acetylators, 2–4 hours in slow acetylators, 2–5 hours in renal insufficiency, and 5–7 hours in severe renal insufficiency.

Clinical characteristics.

Indications.

• In combination with 3–4 other antituberculosis drugs – for the treatment of active tuberculosis of all forms and localizations;
• as monotherapy – for the treatment of latent tuberculosis infection and for prevention of tuberculosis in individuals who were or are in close contact with tuberculosis patients.

Contraindications.

• Hypersensitivity to isoniazid or to other components of the drug;
• epilepsy, predisposition to seizures;
• severe psychoses (including in medical history);
• poliomyelitis (including previously experienced);
• history of toxic hepatitis due to use of hydrazine derivatives of isonicotinic acid (e.g., phthivazide);
• acute hepatic and/or renal failure;
• pronounced atherosclerosis;
• doses exceeding 10 mg/kg body weight in patients with III-degree cardiopulmonary insufficiency, II–III stage arterial hypertension, ischemic heart disease, nervous system disorders, chronic renal failure, active-phase hepatitis, liver cirrhosis, bronchial asthma, psoriasis, exacerbation-phase eczema, hypothyroidism, myxedema.

Interaction with other medicinal products and other types of interactions.

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

To enhance efficacy, isoniazid should be used in combination with other antituberculosis medicinal products (e.g., rifampicin, ethambutol, pyrazinamide), and in mixed infections – simultaneously with broad-spectrum antibiotics: fluoroquinolones (e.g., ofloxacin, ciprofloxacin), sulfonamides (e.g., co-trimoxazole), macrolides (e.g., clarithromycin, azithromycin, roxithromycin).

Isoniazid slows hepatic metabolism of certain drugs, potentially increasing their toxicity. These include: carbamazepine, primidone, phenytoin, diazepam, triazolam, chlorzoxazone, disulfiram.

Potentially hepatotoxic and neurotoxic agents (including ethanol, rifampicin, paracetamol) – increased risk of toxic hepatitis and neuropathy (with paracetamol, increased risk of hepatotoxic effects).

Prolonged use of isoniazid may reduce plasma clearance and prolong the action of alfentanil.

Concomitant use of isoniazid:

with levodopa – reduced therapeutic effect;

with rifampicin – increased risk of liver damage;

with glucocorticosteroids – increased metabolism and elimination of isoniazid;

with itraconazole – possible significant reduction in its serum concentration and absence of therapeutic effect. Concomitant use is not recommended;

with ketoconazole – possible reduction in ketoconazole serum levels: serum concentration should be monitored and dosage increased if necessary;

with acetaminophen – increased toxicity due to generation and accumulation of toxic metabolites in the liver, potentially leading to serious adverse reactions;

with theophylline – increased theophylline plasma concentration: theophylline levels should be monitored and doses adjusted accordingly;

with valproate – increased valproate plasma concentration: valproate doses should be adjusted;

with stavudine – increased risk of distal sensory neuropathy;

with cycloserine – increased risk of toxic effects on the central nervous system (CNS);

with ethosuximide – inhibition of ethosuximide metabolism (increased plasma concentration and risk of toxicity);

with isoflurane – increased risk of hepatotoxicity;

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

with vitamin B6 and glutamic acid – reduced likelihood of isoniazid side effects;

with diphenylhydantoin (phenytoin) – enhanced antiarrhythmic properties of diphenylhydantoin;

with antacids – reduced absorption of isoniazid (interval between administration should be at least 1 hour);

with indirect anticoagulants, monoamine oxidase inhibitors (MAO inhibitors) – isoniazid potentiates the effects (including toxic effects) of these drugs;

with phenobarbital – possible enhancement of hepatotoxicity;

with aminazine (chlorpromazine) – possible worsening of isoniazid metabolism. Patients should be monitored for isoniazid toxicity;

with haloperidol – possible increase in haloperidol plasma levels. Haloperidol dosage should be adjusted;

with anticoagulants (coumarin- or indandione derivatives, e.g., warfarin) – possible inhibition of enzymatic metabolism of anticoagulants, leading to increased plasma concentration and increased risk of bleeding. Prothrombin time should be carefully monitored;

with enflurane – isoniazid may increase the formation of potentially nephrotoxic inorganic fluorides – metabolites of enflurane;

with procainamide – increased isoniazid plasma concentration. Monitoring of patients for isoniazid toxicity is required;

with corticosteroids (e.g., prednisolone) – isoniazid dosage should be adjusted;

with aluminum hydroxide – reduced absorption of isoniazid. During isoniazid therapy, acid-suppressing agents or antacids not containing aluminum hydroxide should be used.

The metabolism of isoniazid and its metabolite acetylisoniazid is not altered by alcohol consumption, but may be increased in chronic alcoholics.

Possible interaction of isoniazid with food products containing histamine and tyramine (e.g., hard cheese, red wine, tuna, tropical fish): adverse reactions such as headache, sweating, palpitations, flushing, and arterial hypotension may occur.

Special precautions.

Monotherapy with isoniazid leads to the development of resistant strains of mycobacteria; therefore, it should be used in combination with other antituberculosis agents. The dose should be properly adjusted according to the patient's ability to inactivate isoniazid. Prior to prescribing isoniazid, it is advisable to determine its inactivation rate by measuring active substance levels in blood and urine. Patients with rapid inactivation should receive higher doses of isoniazid. To reduce adverse effects, pyridoxine hydrochloride (orally or intramuscularly) or glutamic acid, thiamine chloride or thiamine bromide (intramuscularly), or sodium ATP salt should be administered concomitantly with isoniazid.

In mixed infections, broad-spectrum antibiotics, fluoroquinolones, and sulfonamides should be prescribed simultaneously with isoniazid.

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

Liver function should be monitored in all patients during treatment.

Special precautions should be observed in patients with impaired liver function. Any deterioration in liver function in these patients is an indication for discontinuation of treatment. If serum AST levels increase by more than three times the upper limit of normal or if bilirubin levels rise, the drug should be discontinued.

Treatment should be immediately discontinued upon the first signs of hepatitis (malaise, fatigue, nausea, loss of appetite).

Caution is advised when prescribing isoniazid to patients with diabetes mellitus, chronic alcoholism, severe impairment of liver or kidney function, or those taking other potentially hepatotoxic drugs.

The risk of isoniazid-induced hepatotoxicity increases in patients aged 35 years and older, particularly women, slow inactivators, HIV-infected individuals, patients with malnutrition, and those with neuropathy.

Isoniazid should not be prescribed to individuals with serious adverse drug reactions, including drug-induced liver disease.

In patients with diabetes mellitus, a positive result in glucose urine tests is possible.

Pyridoxine should be prescribed to patients at risk of developing neuropathy or pyridoxine deficiency (diabetic patients, chronic alcoholics, patients with hypotrophy, end-stage renal failure, pregnant women, and HIV-infected individuals).

Isoniazid should not be taken with food. Studies have shown that the bioavailability of isoniazid is significantly reduced when administered with food.

Alcoholic beverages should be avoided during treatment.

Use during pregnancy or breastfeeding.

Isoniazid may be used during pregnancy, considering the benefit-risk ratio, at a dose of up to 10 mg/kg body weight per day. However, it should be noted that isoniazid crosses the placenta and may cause myelomeningocele and hypospadias, hemorrhages (due to vitamin K deficiency), and delayed psychomotor development in 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 stop using the drug.

Effect on the ability to drive or operate machinery.

The possibility of adverse effects on the nervous system, which may affect the ability to concentrate and reaction speed when driving or operating machinery, should be taken into account.

Dosage and Administration.

The daily and course doses should be determined individually, depending on the course and form of the disease, the degree of isoniazid inactivation, the effectiveness of therapy, and the patient's tolerance to the drug. Isoniazid should be administered orally before meals or 30–40 minutes after eating.

For adults and children aged 4 years and older, the daily dose is 5 mg/kg body weight once daily when administered daily, or 10 mg/kg body weight when administered intermittently (three times per week). The maximum daily dose is 600 mg for adults and 500 mg for children.

Treatment of active tuberculosis lasts 6–8 months; for prophylactic purposes, treatment lasts 2–3 months.

Children.

Isoniazid in this pharmaceutical form is indicated for children aged 4 years and older.

Overdose.

Symptoms: symptoms of overdose may appear from 30 minutes to 3 hours after ingestion and include gastrointestinal dysfunction (including liver function) – nausea, vomiting, anorexia; neurotoxic manifestations – dizziness, fever, headache, convulsions, visual and hearing disturbances, lethargy, disorientation, hyperreflexia, slurred speech, stupor, visual hallucinations. Over time, respiratory distress syndrome and coma may develop. Laboratory findings typically include acetone in urine, severe metabolic acidosis, hyperglycemia, and glucosuria.

Treatment: induce vomiting, gastric lavage via tube, and administer activated charcoal within 2–3 hours after ingestion. Subsequently, provide supportive therapy: intravenous pyridoxine (vitamin B6), repeated every 5–30 minutes as needed. Hemodialysis effectively removes isoniazid from the blood (up to 73% of isoniazid during a single five-hour session). In case of seizures, diazepam, magnesium sulfate solution, and vitamin B6 should be administered. In case of liver dysfunction, methionine, lipamid, ATP, and vitamin B12 are indicated.

Further treatment should focus on careful monitoring and support of pulmonary ventilation and correction of metabolic acidosis with sodium bicarbonate. Forced diuresis and peritoneal dialysis are also effective. There is no specific antidote.

Adverse Reactions.

In patients with slow inactivation of isoniazid, the risk of toxic effects of the drug is significantly increased.

Gastrointestinal system: nausea, vomiting, dry mouth, abdominal discomfort, anorexia, constipation, flatulence, acute pancreatitis.

Immune system: allergic reactions, including hypersensitivity reactions such as drug fever, skin rashes (morbilliform, maculopapular dermatitis, purpura, or exfoliative dermatitis), pruritus, interstitial pneumonitis, lymphadenopathy, and vasculitis; possible exacerbation of systemic lupus erythematosus symptoms or development of a lupus-like syndrome. Skin and subcutaneous tissue: multiforme erythema, Stevens-Johnson syndrome, toxic epidermal necrolysis.

Nervous system: headache, dizziness, irritability, nervousness, sleep disturbances, insomnia, paresthesia, peripheral neuropathy/neuritis, sensory disturbances.

Psychiatric disorders: psychotic reactions (toxic psychoses), ranging from minor personality changes to severe mental disorders, which usually resolved upon discontinuation of the drug; increased frequency of seizures in patients with epilepsy, muscle twitching and convulsions, hyperreflexia, toxic encephalopathy, memory disorders, confusion, disorientation, hallucinations.

Sensory organs: optic neuritis, optic nerve atrophy, tinnitus and hearing loss in patients with end-stage renal failure.

Respiratory system, thoracic organs and mediastinum: pneumonitis (allergic).

Cardiovascular system: arterial hypertension, palpitations, chest pain and cardiac area pain, worsening of myocardial ischemia in elderly individuals.

Renal and urinary system: difficulty in urination, urinary retention; nephrotoxicity, including interstitial nephritis.

Hepatobiliary system: liver damage, elevated serum transaminase levels (ALT, AST), jaundice, hepatitis, isoniazid-associated hepatitis (especially in patients with chronic liver disease or those who abuse alcohol), fulminant hepatic failure which may lead to liver necrosis (particularly in patients over 35 years of age), bilirubinemia, bilirubinuria.

Endocrine system and metabolic disorders: pyridoxine deficiency affecting the conversion of tryptophan to nicotinic acid, pellagra, Cushing's syndrome, hyperglycemia, metabolic acidosis.

Reproductive system and breast functions: gynecomastia in males, menorrhagia in females.

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

Musculoskeletal system: rheumatoid syndrome, muscle twitching.

Other: malaise, weakness; "withdrawal syndrome" including headache, insomnia, irritability, nervousness, bronchial mucosa edema.

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

Reporting of suspected adverse reactions.

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

Shelf life. 6 years.

Storage conditions. In the original packaging at a temperature not exceeding 25°C.

Keep out of reach of children.

Packaging. 10 tablets per blister, 5 blisters per carton.

Prescription status. Prescription only.

Manufacturer. Public Joint-Stock Company "Scientific-Production Center "Borshchagov Chemical and Pharmaceutical Plant".

Manufacturer's address and location of business activity.

17 Miru Street, Kyiv, 03134, Ukraine.