isoniazid (INH)
Isotamine ◆, Laniazid, Nydrazid, PMS Isoniazid ◆

Available forms
Available by prescription only
Injection: 100 mg/ml
Oral solution: 50 mg/5 ml
Tablets: 100 mg, 300 mg

Indications and dosages
 Primary treatment against actively growing tubercle bacilli. Adults: 5 mg/kg P.O. or I.M. daily in a single dose, up to 300 mg daily, continued for 9 months to 2 years.
Infants and children: 10 mg/kg P.O. or I.M. daily in a single dose, up to 300 mg daily, continued for 18 months to 2 years. Concomitant administration of at least one other effective antituberculotic is recommended.
 Prophylaxis against tubercle bacilli of those closely exposed or with positive skin test. Adults: 300 mg P.O. daily in a single dose, continued for 6 months to 1 year.
Infants and children: 10 mg/kg P.O. daily in a single dose, up to 300 mg daily, continued for 6 months to 1 year.

Pharmacodynamics
Antituberculotic action: INH interferes with lipid and DNA synthesis, thus inhibiting bacterial cell wall synthesis. Its action is bacteriostatic or bactericidal, depending on organism susceptibility and drug concentration at infection site. INH is active against Mycobacterium tuberculosis, M. bovis, and some strains of M. kansasii.
 Resistance by M. tuberculosis develops rapidly when INH is used to treat tuberculosis, and it’s usually combined with another antitubercular agent to prevent or delay resistance. During prophylaxis, however, resistance isn’t a problem and isoniazid can be used alone.

Pharmacokinetics
Absorption: Rapidly and completely absorbed from the GI tract after oral administration. INH also is absorbed readily after I.M. injection.
Distribution: Distributed widely into body tissues and fluids, including ascitic, synovial, pleural, and cerebrospinal fluids; lungs and other organs; and sputum and saliva. Drug crosses the placental barrier and enters breast milk in levels similar to plasma.
Metabolism: Inactivated primarily in the liver by genetically controlled acetylation. Rate of metabolism varies individually; fast acetylators metabolize drug five times as rapidly as others. About 50% of blacks and whites are slow acetylators of INH, whereas more than 80% of Chinese, Japanese, and Eskimos are fast acetylators.
Excretion: About 75% of a dose is excreted in urine as unchanged drug and metabolites in 24 hours; some drug is excreted in saliva, sputum, feces, and breast milk. Plasma half-life in adults is 1 to 4 hours, depending on metabolic rate. Drug is removed by peritoneal dialysis or hemodialysis.

Contraindications and precautions
Contraindicated in patients with acute hepatic disease or drug-related hepatic damage. Use cautiously in the elderly and in patients with severe, non-INH-associated hepatic disease, seizure disorders (especially those taking phenytoin), severe renal impairment, or chronic alcoholism.

Interactions
Drug-drug. Antacids: Decreases oral absorption of INH. Give antacid at least 1 hour before INH.
Anticoagulants: May increase anticoagulant activity. Dosage adjustment may be needed.
Benzodiazepines (such as diazepam), carbamazepine, phenytoin: Causes INH-induced inhibition of metabolism and elevation of serum levels, causing toxicity. Monitor patient closely.
Corticosteroids: May decrease INH efficacy. Monitor patient for drug effects.
Cycloserine: Increases hazard of CNS toxicity, drowsiness, and dizziness. Monitor patient for safety.
Disulfiram: May cause coordination difficulties and psychotic episodes. Observe patient closely.
Rifampin: May accelerate INH metabolism to hepatotoxic metabolites. Use cautiously.
Drug-lifestyle. Alcohol use: Increases risk of INH-induced hepatitis and seizures. Discourage alcohol use.

Adverse reactions
CNS: peripheral neuropathy (dose-related and especially in patients who are malnourished, alcoholic, diabetic, or slow acetylators), usually preceded by paresthesia of hands and feet, seizures,toxic encephalopathy, memory impairment, toxic psychosis.
EENT: optic neuritis, atrophy.
GI: nausea, vomiting, epigastric distress.
Hematologic: agranulocytosis, hemolytic anemia, aplastic anemia, eosinophilia, thrombocytopenia, sideroblastic anemia.
Hepatic: hepatitis, jaundice, bilirubinemia.
Metabolic: hyperglycemia, metabolic acidosis, pyridoxine deficiency, hypocalcemia, hypophosphatemia.
Skin: irritation at I.M. injection site.
Other: gynecomastia, rheumatic and lupus-like syndromes, hypersensitivity reactions (fever, rash, lymphadenopathy, vasculitis).

Effects on lab test results
• May increase transaminase, glucose, and bilirubin levels. May decrease calcium and phosphate levels.
• May increase eosinophil count. May decrease hemoglobin, hematocrit, and granulocyte and platelet counts.

Overdose and treatment
Early signs and symptoms of overdose include nausea, vomiting, slurred speech, dizziness, blurred vision, and visual hallucinations, occurring 30 minutes to 3 hours after ingestion; gross overdose causes CNS depression progressing from stupor to coma, with respiratory distress, intractable seizures, and death.
 To treat, establish ventilation; control seizures with diazepam. Pyridoxine is administered to equal dose of INH. Initial dose is 1 to 4 g pyridoxine I.V., followed by 1 g every 30 minutes thereafter, until the entire dose is given. Clear drug with gastric lavage after seizure control, and correct acidosis with parenteral sodium bicarbonate; force diuresis with I.V. fluids and osmotic diuretics, and, if necessary, enhance clearance of the drug with hemodialysis or peritoneal dialysis.

Special considerations
• At least 12 months of preventive therapy is recommended for patients with previous tuberculosis and patients infected with HIV.
• If compliance is a problem, twice-weekly supervised drug administration may be effective. Recommended twice-weekly dose for adults is 15 mg/kg P.O., not to exceed 900 mg.
• Oral doses should be taken on empty stomach for maximum absorption, or with food if gastric irritation occurs.
• Aluminum-containing antacids or laxatives should be taken 1 hour after oral dose of INH.
• Drug may hinder stabilization of serum glucose level in patients with diabetes mellitus.
• Pyridoxine 50 mg P.O. daily is sometimes recommended to prevent peripheral neuropathy from large doses of INH. It also may be useful in patients at risk of developing peripheral neuropathy (malnourished patients, diabetics, and alcohol abusers). Pyridoxine (50 to 200 mg daily) has been used to treat drug-induced neuropathy.
• Because drug is dialyzable, patients undergoing hemodialysis or peritoneal dialysis may need dosage adjustments.
• INH alters results of urine glucose tests that use cupric sulfate method (Benedict’s reagent, Diastix, or Chemstrip uG).
• Monitor patient for adverse effects, especially hepatic dysfunction, CNS toxicity, and optic neuritis.
• Monitor blood, renal, and hepatic function studies before and periodically during therapy to minimize toxicity; assess visual function periodically.
• Elevated liver function test values occur in about 15% of cases; most abnormalities are mild and transient, but some persist throughout treatment.
• Hepatotoxicity appears to be age-related and may limit use for prophylaxis. Alcohol consumption and history of alcohol-related liver disease also increase risk of hepatotoxicity.
• Improvement is usually evident after 2 to 3 weeks of therapy.
Pregnant patients
• Safe use of drug during pregnancy hasn’t been established. Potential benefits to the woman should be weighed against the risks to the fetus.
Breast-feeding patients
• Drug appears in breast milk; use cautiously in breast-feeding women, and monitor infants for possible INH-induced toxicity.
Pediatric patients
• Infants and children tolerate larger doses of drug.
Geriatric patients
• Use cautiously in elderly patients because risk of hepatic effects increases after age 35. Occasionally severe and sometimes fatal hepatitis has occurred, especially in elderly patients.
• Drug prophylaxis in patients with a positive purified protein derivative test may not be indicated in older patients because of risk of hepatotoxicity.

Patient education
• Instruct patient on the proper administration of drug and the potential for adverse reactions.
• Warn patient to avoid alcohol.
• Urge patient to comply with and complete prescribed regimen.
• Advise patient not to discontinue drug without medical approval.
• Explain importance of follow-up appointments.

Reactions may be common, uncommon, life-threatening, or COMMON AND LIFE THREATENING.
◆ Canada only
◇ Unlabeled clinical use