Isoniazid

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

Composition:

Active substance: isoniazid;

1 tablet contains 100 mg or 300 mg of isoniazid;

Excipients: calcium hydrogen phosphate, corn starch, disodium edetate, talc, colloidal anhydrous silicon dioxide, magnesium stearate.

Pharmaceutical form. Tablets.

Main physicochemical properties:

100 mg tablets: biconvex round tablets, white to almost white in color, with a score line on one side and smooth on the other;

300 mg tablets: biconvex round tablets, white to almost white in color, smooth on both sides.

Pharmacotherapeutic group.

Antituberculosis agents. ATC code J04A C01.

Pharmacological Properties

Pharmacodynamics

Isoniazid is highly active against Mycobacterium tuberculosis. It exerts bactericidal effects in vitro and in vivo against mycobacteria. Its mechanism of action is associated with inhibition of the synthesis of long-chain mycolic acids, which are components of the mycobacterial cell wall. Resistance to isoniazid develops rapidly when it is used as a monotherapy in the treatment of clinical diseases caused by mycobacteria.

Pharmacokinetics

Isoniazid is well absorbed from the gastrointestinal tract and readily penetrates the blood-brain barrier. The time to reach maximum plasma concentration is 1–4 hours. Plasma protein binding is up to 10%. The volume of distribution is 0.56–0.76 L/kg. Tuberculostatic concentrations are maintained for 6–24 hours after a single dose. Isoniazid is widely distributed into tissues and body fluids, including cerebrospinal fluid, pleural effusion, ascitic fluid, skin, lungs, sputum, saliva, and caseous masses. It crosses the placenta and is excreted into breast milk.

Metabolism occurs in the liver via acetylation. The rate of acetylation is genetically determined and dependent on the activity level of N-acetyltransferase. Based on acetylation rate, patients are classified as "fast" or "slow" inactivators. In "fast" inactivators, the half-life of isoniazid is 0.5–1.6 hours, and less than 10% of the unchanged drug is excreted in the urine per day. In "slow" inactivators, the half-life is 2–5 hours, and more than 10% of the unchanged drug is excreted in the urine per day.

Clinical characteristics.

Indications.

Treatment of tuberculosis caused by Mycobacterium tuberculosis.

The drug is prescribed according to official guidelines for tuberculosis treatment, e.g., WHO recommendations.

Contraindications.

Isoniazid is contraindicated in patients with:

• hypersensitivity to isoniazid or to excipients of the drug;
• epilepsy or predisposition to seizures;
• severe psychosis (including in history);
• poliomyelitis (including previously suffered);
• history of toxic hepatitis due to use of hydrazide derivatives of isonicotinic acid (e.g., phthivazide);
• pronounced atherosclerosis;
• acute hepatic and/or renal failure.

The use of isoniazid in doses exceeding 10 mg/kg body weight per day is contraindicated during pregnancy, cardiac-pulmonary insufficiency, stage II–III arterial hypertension, ischemic heart disease, neurological disorders, bronchial asthma, chronic renal failure, active hepatitis, liver cirrhosis, psoriasis, acute eczema, myxedema, and hypothyroidism.

Interaction with other medicinal products and other forms of interactions.

Antacids: reduced absorption of isoniazid (the interval between administration should be at least 1 hour).

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

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

Phenobarbital: concomitant use with isoniazid may enhance hepatotoxicity.

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

Valproate: concomitant use increases valproate plasma concentration.

Stavudine: increased risk of developing distal sensory neuropathy.

Since the clearance of isoniazid is doubled when coadministered with zalcitabine in HIV-infected patients, monitoring of isoniazid and zalcitabine concentrations is required to ensure treatment efficacy in such patients.

Vitamin B6 and glutamic acid: combined use reduces the likelihood of isoniazid-related adverse effects.

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

Enhances antiarrhythmic properties of phenytoin.

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

Glucocorticoids: concomitant use increases metabolism and elimination of isoniazid.

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

Disulfiram: concomitant use with isoniazid may increase the frequency of central nervous system effects. Dose reduction or discontinuation of disulfiram may be necessary.

Isoniazid may slow hepatic metabolism of primidone, triazolam, chlorzoxazone, potentially leading to increased toxicity.

Isoniazid may reduce the therapeutic effect of levodopa.

Concomitant use with itraconazole is not recommended due to possible significant reduction in serum concentration of the latter and lack of therapeutic effect.

Isoniazid, when used concomitantly with ketoconazole, may reduce its serum levels; therefore, monitoring of blood levels is necessary and dose adjustment may be required.

Isoniazid, when used with acetaminophen, increases its toxicity due to generation and accumulation of metabolites in the liver, potentially leading to serious adverse reactions.

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 necessary.

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.

Alfentanil: chronic pre-/perioperative use of isoniazid may reduce plasma clearance and prolong the duration of action of alfentanil. Dose of alfentanil may need to be adjusted accordingly.

Enflurane: concomitant use may increase formation of potentially nephrotoxic inorganic fluorides – metabolites of enflurane.

Theophylline: increased plasma concentration of theophylline; therefore, theophylline blood levels should be monitored and dosage adjusted accordingly.

Procainamide: increased plasma concentration of isoniazid. Monitoring for isoniazid toxicity is required.

Corticosteroids (e.g., prednisolone): dose adjustment of isoniazid may be necessary.

Aluminum hydroxide: reduces absorption of isoniazid. During isoniazid therapy, acid-suppressing agents or antacids not containing aluminum hydroxide should be used.

Metabolism of isoniazid and its metabolite acetylisoniazid is not altered by excessive alcohol consumption, although increased levels may occur in patients with alcohol dependence; however, this effect is not well defined.

Possible interaction of isoniazid with food products containing histamine and tyramine (e.g., aged cheese, red wine, tuna, tropical fish) may lead to adverse reactions such as flushing or itching of the skin, burning sensation, headache or dizziness, chills, increased sweating, palpitations, hot flashes, and arterial hypotension.

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

Interaction with laboratory tests

Isoniazid may cause false-positive results in glucose urine tests; enzymatic glucose tests are not affected.

Special precautions for use.

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 selected based on the individual capacity for isoniazid inactivation. Prior to initiating isoniazid therapy, it is advisable to determine the rate of its inactivation by measuring active substance concentrations in blood and urine. Patients exhibiting rapid inactivation should receive higher doses of isoniazid. To reduce adverse effects, pyridoxine hydrochloride (administered orally or intramuscularly), glutamic acid, thiamine chloride or thiamine bromide (intramuscularly), or sodium ATP salt should be co-administered with isoniazid.

In cases of mixed infection, broad-spectrum antibiotics, fluoroquinolones, and sulfonamides should be administered concurrently with isoniazid.

Medical supervision is required throughout treatment, including regular liver function tests and ophthalmological examinations. During the first month of therapy, examinations should be performed at least twice monthly; thereafter, once monthly.

All patients must have liver function monitored during treatment. Severe, sometimes fatal, hepatitis associated with isoniazid therapy has been reported. Most cases occur within the first three months of treatment, although hepatotoxicity may develop after prolonged therapy. In addition to monthly clinical monitoring, liver enzymes (particularly AST and ALT) should be measured before initiating isoniazid therapy and periodically throughout treatment. Special precautions should be taken in patients with pre-existing liver dysfunction. Any signs of liver impairment in these patients are an indication to discontinue treatment. If serum aspartate aminotransferase (AST) levels rise more than three times the upper limit of normal or if bilirubin levels increase, the drug must be discontinued immediately.

Treatment should be stopped immediately upon the first signs of hepatitis (vomiting, dark urine, jaundice, rash, persistent paresthesias of hands and feet, weakness lasting more than 3 days, and/or abdominal pain—especially in the right upper quadrant—malaise, fatigue, nausea, loss of appetite), as continuing the drug in such cases may lead to more severe liver damage. Caution is advised when prescribing isoniazid to patients who chronically use other potentially hepatotoxic drugs, and to those with diabetes mellitus, chronic alcoholism, intravenous drug use, or pre-existing liver or kidney dysfunction.

The risk of isoniazid-induced hepatotoxicity increases in patients aged 35 years and older, particularly women; during pregnancy; in patients with slow drug inactivation; in HIV-infected individuals; in patients with malnutrition; and in those with peripheral neuropathy or predisposition to neuropathy.

The risk of isoniazid toxicity is also increased in severe renal insufficiency (creatinine clearance less than 10 mL/min).

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

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

Patients at risk of developing neuropathy or pyridoxine deficiency (e.g., those with diabetes, chronic alcoholism, hypotrophy, end-stage renal disease, pregnant women, or HIV-infected individuals) should be given pyridoxine.

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.

Isoniazid should not be prescribed in cases of epilepsy or seizure disorders.

Possible interaction may occur with foods containing histamine and tyramine (such as aged cheese, red wine, tuna, tropical fish), potentially causing adverse reactions such as headache, excessive sweating, palpitations, flushing, and hypotension.

Elevations in liver function markers (AST and ALT) are common during therapy with isoniazid tablets. These changes are usually mild or moderate and typically resolve spontaneously within three months, even if therapy continues.

If liver function test results exceed 3–5 times the upper limit of normal, discontinuation of isoniazid tablets should be considered.

Peripheral neuropathy is the most common toxic effect of isoniazid. Its incidence depends on dosage and predisposing conditions such as malnutrition, renal dysfunction, alcoholism, or diabetes. Concurrent administration of pyridoxine greatly reduces the risk of neuropathy. Therefore, pyridoxine should be co-administered at a dose of 10 mg daily.

Cross-sensitivity. Patients sensitive to ethionamide, pyrazinamide, niacin (nicotinic acid), or other chemically related drugs may also be sensitive to this drug.

Isoniazid should be used with caution in patients with a history of seizures, psychosis, or liver dysfunction.

Diabetes mellitus. Patients with diabetes should be closely monitored, as isoniazid may affect blood glucose control.

Renal dysfunction. In patients with impaired renal function, especially slow acetylators, the risk of isoniazid side effects such as peripheral neuropathy may be increased, and such patients should be monitored accordingly. As with other patients, pyridoxine supplementation should be considered to prevent neurotoxicity.

Use during pregnancy or breastfeeding.

Isoniazid may be used during pregnancy if the benefit outweighs the risk, 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 is excreted in breast milk. Therefore, considering the potential risk of hepatitis and peripheral neuritis in the infant, a decision must be made whether to discontinue breastfeeding or to discontinue the drug.

Ability to affect reaction speed when driving or operating machinery.

The possibility of adverse effects on the nervous system that may impair the ability to drive or operate machinery should be taken into account.

Method of Administration and Dosage

Administer orally.

Isoniazid tablets should be swallowed whole, without chewing, with water.

Tablets should be taken on an empty stomach (at least 1 hour before or 2 hours after meals).

Active tuberculosis

For the treatment of active tuberculosis, isoniazid should always be used in combination with other anti-tuberculosis agents.

Daily therapy: children – 10–15 mg/kg body weight per day; adults – 5 mg/kg body weight per day; maximum daily dose – no more than 300 mg.

Isoniazid Tablets 100 mg

Dosage for children

Dosage for adults

Isoniazid, tablets 100 mg, are not prescribed to children with body weight less than 3.5 kg.

Isoniazid, tablets 300 mg, are not prescribed to patients with body weight less than 45 kg.

The duration of therapy depends on the indication and the combination of drugs used together with isoniazid.

Latent tuberculosis (monotherapy)

Adults: 300 mg once daily for at least 6 months.

Children: 10 mg/kg body weight once daily (maximum daily dose – 300 mg) for at least 6 months.

Isoniazid, 300 mg tablets, are not used in children for the treatment of latent tuberculosis. In these cases, isoniazid in a lower dosage should be used.

If a dose is missed, it should be taken as soon as possible, provided that the next scheduled dose is not due within 6 hours.

Children.

Applicable to children (see section "Dosage and Administration").

Overdose.

Symptoms: anorexia, nausea, vomiting, gastrointestinal disturbances, fever, headache, dizziness, slurred speech; hallucinations and/or visual hallucinations occurring within 30 minutes to 3 hours after drug intake. Isoniazid overdose (≥80 mg/kg body weight) leads to rapidly progressing respiratory insufficiency and central nervous system depression, progressing from stupor to deep coma, accompanied by severe seizures. Typical laboratory findings include severe metabolic acidosis, ketonuria, and hyperglycemia.

Treatment: induced vomiting, gastric lavage, and activated charcoal may be beneficial only within a few hours after overdose. Subsequently, pyridoxine (intravenous, one gram per gram of isoniazid base equivalent; if the ingested dose is unknown, the initial dose should be 5 g in adults or 80 mg/kg body weight in children), intravenous diazepam (if seizures persist despite pyridoxine), and possible hemodialysis. Further management should focus on careful monitoring and support of pulmonary ventilation and correction of metabolic acidosis. 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 disorders: nausea, vomiting, constipation, dry mouth, discomfort or abdominal pain, anorexia, acute pancreatitis, flatulence.

Immune system disorders: allergic reactions, including hypersensitivity reactions such as drug fever, exanthema, erythema, skin rashes (measles-like maculopapular dermatitis, purpura or exfoliative dermatitis), pruritus, fever, leukopenia, anaphylaxis, neutropenia, eosinophilia, interstitial pneumonitis, lymphadenopathy, and vasculitis; possible exacerbation of systemic lupus erythematosus symptoms or development of lupus-like syndrome, Stevens-Johnson syndrome, toxic epidermal necrolysis, and erythema multiforme.

Nervous system disorders: tremor, vertigo, headache, peripheral neuropathy/neuritis, dizziness, seizures, hyperreflexia, confusion, disorientation, hallucinations, increased frequency of seizures in patients with epilepsy, toxic encephalopathy, memory disturbances, sleep disorders, psychotic reactions (toxic psychoses), ranging from minor personality changes to severe mental disorders, which usually resolved upon discontinuation of the drug.

Eye disorders: optic neuritis, optic nerve atrophy.

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

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

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

Hepatobiliary disorders: liver damage, elevated liver enzymes, jaundice, hepatitis, isoniazid-associated hepatitis (especially in patients with chronic liver disease or those who abuse alcohol); fulminant hepatic failure, which may lead to hepatic necrosis (especially in patients aged 35 years and older); bilirubinemia; transient increase in serum transaminases.

Endocrine disorders: gynecomastia in males, menorrhagia in females, Cushing's syndrome, hyperglycemia, metabolic acidosis, pyridoxine deficiency affecting the conversion of tryptophan to nicotinic acid, pellagra.

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

Musculoskeletal and connective tissue disorders: rheumatoid syndrome, muscle twitching, arthritis.

Respiratory disorders: pneumonitis (allergic).

Psychiatric disorders: memory impairment, toxic psychosis, confusion, disorientation, hallucinations.

Metabolic and nutritional disorders: hyperglycemia, metabolic acidosis, pellagra.

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

Shelf life. 4 years.

Storage conditions.

Store at a temperature not exceeding 30 °C in the original packaging.

Keep out of reach of children.

Packaging.

10 tablets per blister, 3, 9 or 10 blisters per cardboard pack.

28 tablets per blister, 3 or 24 blisters per cardboard pack.

1000 tablets in a polyethylene bag; 1 bag in a plastic container.

Prescription category. Prescription only.

Manufacturer.

Macleods Pharmaceuticals Limited.

Manufacturer's address and place of business.

Phase II, Plot No. 12, 15, 21, 23, 24, 25, 26, 27, 28 and 30, Survey No. 366, Premier Industrial Estate, Kachigam, Daman, 396210, India.