Drug Monograph
Isoniazid
INH — isonicotinic acid hydrazide
Pharmacokinetic Profile
Half-Life
Rapid acetylators ~1 h; slow acetylators ~3 h
Metabolism
Hepatic acetylation (NAT2 polymorphism) & dehydrazination
Protein Binding
Very low (negligible)
Bioavailability
Well absorbed (fasting); reduced with food
Volume of Distribution
~0.6–0.8 L/kg
Clinical Information
Drug Class
Isonicotinic acid hydrazide (antimycobacterial)
Available Doses
100 mg, 300 mg tablets; 50 mg/5 mL oral solution
Route
Oral, IM
Renal Adjustment
Not required
Hepatic Adjustment
Use with caution; contraindicated in acute liver disease
Pregnancy
Category C — benefit outweighs risk for active TB
Lactation
Compatible; supplement infant with pyridoxine
Schedule
Rx only (not controlled)
Generic Available
Yes
Black Box Warning
Yes — severe/fatal hepatitis
Indications
| Indication | Approved Population | Therapy Type | Status |
|---|---|---|---|
| All forms of tuberculosis (drug-susceptible) | Adults and children | Combination therapy (multi-drug regimen) | FDA Approved |
| Latent tuberculosis infection (LTBI) — preventive therapy | Adults and children at risk | Monotherapy or combination | FDA Approved |
Isoniazid remains one of the most important first-line drugs for tuberculosis treatment and prevention worldwide. For active TB, it is always used in combination with other agents (rifampin, pyrazinamide, ethambutol) to prevent resistance. For LTBI, isoniazid can be given as monotherapy for 6–9 months or in shorter combination regimens with rifampin or rifapentine. It is bactericidal against actively growing intracellular and extracellular M. tuberculosis.
Off-Label Uses
Mycobacterium kansasii infection: Used as part of multi-drug regimens for susceptible strains. Evidence quality: Moderate (guideline-supported).
Post-exposure prophylaxis in neonates of TB-positive mothers: INH 10–15 mg/kg daily until TST can be evaluated at 3–4 months. Evidence quality: High (AAP and CDC recommendation).
Dosing
Adult Dosing
| Clinical Scenario | Starting Dose | Maintenance Dose | Maximum Dose | Notes |
|---|---|---|---|---|
| Active TB — daily regimen (intensive + continuation) | 5 mg/kg once daily | 5 mg/kg once daily | 300 mg/day | Part of 4-drug regimen (INH+RIF+PZA+EMB) for 2 months, then INH+RIF for ≥4 months Always co-prescribe pyridoxine 25–50 mg/day |
| Active TB — twice-weekly DOT | 15 mg/kg twice weekly | 15 mg/kg twice weekly | 900 mg/dose | Only under directly observed therapy Higher dose compensates for intermittent schedule |
| LTBI — 9-month isoniazid monotherapy (daily) | 5 mg/kg once daily | 5 mg/kg once daily | 300 mg/day | Preferred duration 9 months; minimum 6 months acceptable CDC now preferentially recommends shorter rifamycin-based regimens |
| LTBI — 9-month isoniazid monotherapy (twice weekly) | 15 mg/kg twice weekly | 15 mg/kg twice weekly | 900 mg/dose | Must be given by DOT 52 doses over 9 months minimum |
| LTBI — 3HP regimen (INH + rifapentine weekly × 12) | 15 mg/kg once weekly | 15 mg/kg once weekly | 900 mg/dose | 12 weekly doses with rifapentine; DOT or self-administered CDC-preferred regimen; higher completion rates than 9H |
| LTBI — 3-month INH + rifampin (daily) | 5 mg/kg once daily | 5 mg/kg once daily | 300 mg/day | Given with rifampin 10 mg/kg (max 600 mg) daily for 3 months |
Pediatric Dosing
| Clinical Scenario | Starting Dose | Maintenance Dose | Maximum Dose | Notes |
|---|---|---|---|---|
| Active TB — daily | 10–15 mg/kg once daily | 10–15 mg/kg once daily | 300 mg/day | Combined with RIF, PZA, EMB AAP recommends 10–15 mg/kg for daily regimen |
| Active TB — twice-weekly DOT | 20–40 mg/kg twice weekly | 20–40 mg/kg twice weekly | 900 mg/dose | Only under directly observed therapy |
| LTBI — daily monotherapy (9 months) | 10–20 mg/kg once daily | 10–20 mg/kg once daily | 300 mg/day | FDA PI: 10 mg/kg daily (up to 300 mg) Give pyridoxine to breastfed infants of mothers on INH |
| Neonatal window prophylaxis (mother with active TB) | 10–15 mg/kg once daily | 10–15 mg/kg once daily | 300 mg/day | Continue for 3–4 months, then perform TST; continue to 9 months if TST positive AAP/CDC recommendation |
Clinical Pearl: Pyridoxine Co-Prescription
Pyridoxine (vitamin B6) 25–50 mg daily should be co-prescribed with isoniazid for all adults to prevent peripheral neuropathy. It is especially important in patients at higher risk: those who are malnourished, diabetic, HIV-positive, pregnant or breastfeeding, elderly, alcoholic, uremic, or who are slow acetylators. For children, pyridoxine supplementation is recommended for those who are malnourished, HIV-positive, or breastfed by a mother taking INH. Pyridoxine does not interfere with isoniazid’s antimycobacterial activity.
Pharmacology
Mechanism of Action
Isoniazid is a prodrug that requires activation by the mycobacterial catalase-peroxidase enzyme KatG. Once activated, it generates reactive intermediates (including isonicotinic acyl radicals) that form adducts with NAD+ and NADP+, inhibiting InhA (enoyl-ACP reductase), an enzyme essential for the synthesis of mycolic acids. Mycolic acids are critical structural components of the M. tuberculosis cell wall, and their depletion leads to loss of acid-fast integrity and bactericidal killing. Isoniazid is highly active against rapidly dividing organisms but has limited activity against dormant bacilli. Resistance arises primarily through mutations in the katG gene (reducing prodrug activation) or the inhA promoter region (overexpressing the drug target), and develops rapidly with monotherapy.
ADME Profile
| Parameter | Value | Clinical Implication |
|---|---|---|
| Absorption | Rapidly absorbed; Tmax 1–2 h; levels decline to ≤50% within 6 h | Food reduces absorption; administer on empty stomach (1 h before or 2 h after meals). Appreciable first-pass effect, especially in rapid acetylators. |
| Distribution | Vd ~0.6–0.8 L/kg; negligible protein binding; penetrates CSF, pleural fluid, ascites, saliva, sputum | Freely distributes into all body compartments including CSF, making it effective for TB meningitis. Crosses placenta; present in breast milk at plasma-comparable levels. |
| Metabolism | Hepatic N-acetylation via NAT2 (genetically polymorphic) to acetylisoniazid; also dehydrazination to isonicotinic acid | Slow acetylators (~50% of Black/Caucasian populations) have longer t½ (~3 h), higher drug levels, and potentially greater neuropathy and hepatotoxicity risk. Rapid acetylators (majority of East Asian populations) have t½ ~1 h. |
| Elimination | 50–70% excreted in urine within 24 h (as metabolites and unchanged drug) | No dose adjustment for renal impairment. Renal excretion is relatively unimportant for clearance even in slow acetylators. |
Side Effects
≥10%Very Common
| Adverse Effect | Incidence | Clinical Note |
|---|---|---|
| Transient LFT elevation (AST/ALT) | 10–20% | Usually appears in the first 1–3 months; self-limiting in most cases. Distinguish from progressive hepatitis by magnitude of rise and presence of symptoms. |
1–10%Common
| Adverse Effect | Incidence | Clinical Note |
|---|---|---|
| Peripheral neuropathy (without pyridoxine) | ~2% (standard dose); up to 17% at >6 mg/kg/day | Dose-related; higher in slow acetylators, malnourished, diabetics, and alcoholics. Preventable with pyridoxine 25–50 mg/day. |
| Nausea / vomiting / epigastric distress | 1–5% | Taking with a small amount of food may help; however food decreases absorption |
| Rash | ~2% | Morbilliform or maculopapular; discontinue if severe or exfoliative |
| Fever (drug fever) | ~1.2% | May occur as part of hypersensitivity syndrome; rule out other causes before attributing to INH |
| Hepatitis (clinical, with jaundice) | 0.1–2.3% (age-dependent) | Rates by age: <20 yr: 0.1%; 20–34: 0.3%; 35–49: 1.2%; 50–64: 2.3%; >65: 0.8% (FDA PI) |
SeriousSerious (Regardless of Frequency)
| Adverse Effect | Estimated Frequency | Typical Onset | Required Action |
|---|---|---|---|
| Severe hepatitis / fulminant liver failure | Fatal hepatitis: ~0.05–0.1% | Usually first 3 months; can occur at any time | Discontinue immediately if ALT >3× ULN with symptoms or >5× ULN without symptoms. Do not rechallenge without specialist review. |
| Severe cutaneous reactions (SJS, TEN, DRESS, AGEP) | Rare | Days to weeks | Immediate permanent discontinuation; emergency dermatology |
| Optic neuritis | Rare (primarily with high doses) | Weeks to months | Discontinue; ophthalmology referral; may be reversible |
| Seizures / toxic encephalopathy | Rare (mostly with overdose) | Hours (acute overdose); variable with chronic use | Administer pyridoxine IV (gram-for-gram antidote in overdose); benzodiazepines for seizure control |
| Agranulocytosis / aplastic anemia | Very rare | Variable | Discontinue; haematology consultation; supportive care |
| Drug-induced lupus (SLE-like syndrome) | Uncommon; more in slow acetylators | Months of therapy | Discontinue INH; symptoms usually resolve within weeks to months |
| Sideroblastic anemia | Rare | Weeks to months | Responds to pyridoxine supplementation; consider INH discontinuation if severe |
DiscontinuationDiscontinuation Rates
LTBI — 9-Month INH
~5–10% (adverse events)
Top reasons: Hepatotoxicity, GI intolerance, rash. Completion rates ~60% (substantially lower than 4-month rifampin ~80%).
Active TB (Multi-Drug Regimen)
<5%
Context: Discontinuation due to INH-specific adverse effects is uncommon; hepatotoxicity may be difficult to attribute to a single agent in multi-drug regimens.
| Reason for Discontinuation | Incidence | Context |
|---|---|---|
| Hepatotoxicity (ALT >5× ULN or symptomatic) | ~1–3% | Age-dependent; higher in patients >35 years, alcohol users, and those co-treated with rifampin |
| GI intolerance | ~1–2% | Nausea, vomiting leading to non-adherence |
| Peripheral neuropathy | <1% | Rare cause of discontinuation when pyridoxine is co-prescribed |
Managing INH Hepatotoxicity
INH hepatitis typically presents with prodromal symptoms: anorexia, nausea, fatigue, malaise, and right upper quadrant discomfort. Dark urine and jaundice follow if not recognised early. The U.S. Public Health Service Surveillance Study found 8 deaths among 174 hepatitis cases in 13,838 patients. Monthly symptom assessment is mandatory for all patients; laboratory monitoring (ALT) should be obtained at baseline and monthly for patients aged >35, daily alcohol users, those with chronic liver disease, HIV-positive patients, injection drug users, and postpartum women. Hold INH if ALT >3× ULN with symptoms or >5× ULN without symptoms.
Drug Interactions
Isoniazid is a moderate inhibitor of CYP3A4 and CYP2C19 and an inducer of CYP2E1. It also possesses weak monoamine oxidase (MAO) inhibiting activity. Its interaction profile is narrower than rifampin’s but clinically significant interactions can occur, particularly with narrow-therapeutic-index drugs metabolised by CYP pathways.
MajorAcetaminophen (Paracetamol)
MechanismINH induces CYP2E1, increasing formation of the hepatotoxic metabolite NAPQI
EffectIncreased risk of acetaminophen hepatotoxicity, even at therapeutic doses
ManagementLimit acetaminophen to ≤2 g/day during INH therapy; monitor LFTs; consider alternative analgesics
FDA PIMajorPhenytoin
MechanismINH inhibits CYP2C19 metabolism of phenytoin
EffectElevated phenytoin levels; risk of phenytoin toxicity (ataxia, nystagmus, sedation)
ManagementMonitor phenytoin levels; reduce dose as needed. Slow acetylators at higher risk.
FDA PIMajorCarbamazepine
MechanismINH slows carbamazepine metabolism via CYP3A4 inhibition
EffectIncreased carbamazepine levels; risk of toxicity (dizziness, diplopia, ataxia)
ManagementObtain baseline carbamazepine level; monitor closely; adjust dose as needed
FDA PIModerateRifampin (additive hepatotoxicity)
MechanismAdditive hepatotoxic potential; rifampin may increase formation of toxic INH metabolites via enzyme induction
EffectHigher rate of symptomatic hepatitis (~2.5–3%) than either drug alone
ManagementStandard TB combination; monitor LFTs and hepatitis symptoms closely
ATS StatementModerateTyramine- and Histamine-Containing Foods
MechanismINH has weak MAO and diamine oxidase inhibiting activity
EffectHeadache, flushing, palpitations, sweating, hypotension after eating aged cheese, red wine, or certain fish (tuna, skipjack)
ManagementAdvise patients to avoid tyramine-rich and histamine-rich foods during therapy
FDA PIModerateTheophylline
MechanismINH may increase theophylline levels through hepatic enzyme inhibition
EffectTheophylline toxicity (tremor, tachycardia, seizures)
ManagementMonitor theophylline levels closely; adjust dose as needed
FDA PIModerateValproate
MechanismINH may increase plasma valproate concentrations
EffectPotential valproate toxicity (tremor, sedation, hepatotoxicity)
ManagementMonitor valproate levels; adjust dose accordingly
FDA PIMinorAluminum-Containing Antacids
MechanismReduced GI absorption of isoniazid
EffectDecreased INH efficacy
ManagementSeparate administration by at least 1 hour
FDA PIMonitoring
- Hepatic Enzymes (ALT, AST)Baseline; monthly for high-risk patients
RoutineBaseline for all patients ≥35 years, daily alcohol users, chronic liver disease, HIV-positive, injection drug users, postpartum women, and those on concomitant hepatotoxic drugs. Monthly monitoring during therapy for these groups. Hold INH if ALT >3× ULN with symptoms or >5× ULN without symptoms. - Clinical Symptom ReviewMonthly
RoutineInterview at every visit about anorexia, nausea, vomiting, dark urine, icterus, rash, fatigue, weakness, fever >3 days, abdominal tenderness, and numbness/tingling in hands and feet. This is a mandatory requirement per the FDA boxed warning. - Peripheral Neuropathy AssessmentAt each visit
RoutineAsk about paresthesias of hands and feet. Ensure pyridoxine co-prescription. Higher risk in slow acetylators, diabetics, alcoholics, malnourished, and HIV-positive patients. - CBCBaseline; as clinically indicated
Trigger-basedMonitor for agranulocytosis, thrombocytopenia, or sideroblastic anemia. Repeat if unexplained bruising, bleeding, or fatigue develops. - Sputum CulturesBaseline and monthly until conversion
RoutineFor active TB: confirm susceptibility before starting. Monthly cultures until sputum conversion. Persistent positivity at 3 months warrants review for resistance or non-adherence. - Visual AcuityIf symptoms develop
Trigger-basedOptic neuritis is rare with conventional doses but should be assessed if patient reports visual changes. Distinguish from ethambutol-induced optic neuropathy in combination regimens.
Contraindications & Cautions
Absolute Contraindications
- Previous isoniazid-associated hepatic injury
- Severe hypersensitivity reaction to isoniazid (drug fever, chills, severe arthritis)
- Acute liver disease of any aetiology
Relative Contraindications (Specialist Input Recommended)
- Chronic liver disease or active hepatitis B/C: Use only when benefit outweighs risk with close LFT monitoring every 2–4 weeks
- Daily alcohol use: Substantially higher hepatitis risk; consider closer monitoring or alternative LTBI regimen
- Concurrent hepatotoxic drugs (rifampin, pyrazinamide, methotrexate): Additive hepatotoxic potential; dedicated monitoring plan required
- Prior peripheral neuropathy or conditions predisposing to neuropathy: Diabetes, uremia, HIV, malnutrition — mandatory pyridoxine and close neurological follow-up
Use with Caution
- Age >35 years: Higher hepatitis risk; monthly LFT monitoring recommended
- Pregnancy: Active TB treatment should not be delayed; LTBI treatment generally deferred until postpartum unless high-risk; co-prescribe pyridoxine
- Postpartum women (especially minority women): Increased fatal hepatitis risk reported; more intensive monitoring
- Injection drug users: Higher hepatitis risk; adherence may be challenging
- Slow acetylator phenotype (known): Higher risk of neuropathy and possibly hepatotoxicity; pyridoxine essential
FDA Boxed Warning
Severe and Fatal Hepatitis
Severe and sometimes fatal hepatitis has been reported with isoniazid therapy. It may occur or develop even after many months of treatment. The risk is age-related: <1/1,000 under age 20; 3/1,000 ages 20–34; 12/1,000 ages 35–49; 23/1,000 ages 50–64; 8/1,000 over age 65. Risk is increased with daily alcohol consumption. In a USPHS study of 13,838 patients, there were 8 deaths among 174 hepatitis cases. Patients must be monitored at monthly intervals with symptom assessment. For patients ≥35, baseline and periodic hepatic enzyme measurements are required.
Patient Counselling
Purpose of Therapy
Isoniazid kills the tuberculosis bacteria that are causing your infection or that are dormant in your body and could become active later. Whether you are being treated for active TB or taking it to prevent TB from developing, completing the full course is essential. Stopping early can allow bacteria to survive and become resistant to treatment.
How to Take
Take isoniazid on an empty stomach, ideally 1 hour before or 2 hours after a meal. Swallow the tablets with a full glass of water. If you are taking the liquid form, measure carefully with the provided syringe or cup. Take your pyridoxine (vitamin B6) tablet at the same time every day. Do not take antacids within 1 hour of isoniazid.
Liver Problems (Hepatotoxicity)
Tell patientLiver damage is the most serious risk of isoniazid. Avoid alcohol completely during treatment. Keep all monthly appointments so your doctor can check for early signs. Do not take extra paracetamol (acetaminophen) — use ibuprofen if needed, or ask your doctor.
Call prescriberImmediately if you develop loss of appetite lasting more than a few days, unexplained nausea or vomiting, dark-coloured urine, yellowing of your skin or eyes, persistent fatigue, abdominal pain (especially on the right side), or fever lasting >3 days.
Numbness or Tingling (Peripheral Neuropathy)
Tell patientIsoniazid can affect the nerves in your hands and feet, causing numbness, tingling, or burning sensations. Taking your vitamin B6 (pyridoxine) every day as prescribed significantly reduces this risk. Do not skip the B6.
Call prescriberIf you notice any numbness, tingling, burning, or weakness in your hands or feet that is new or worsening.
Food Interactions
Tell patientAvoid foods high in tyramine (aged cheeses, cured meats, red wine, soy sauce) and histamine (certain fish like tuna and mackerel). These can interact with isoniazid and cause headaches, flushing, fast heartbeat, or sweating.
Call prescriberIf you experience severe headache, rapid heartbeat, or episodes of flushing and sweating after eating.
Adherence & Duration
Tell patientYou may need to take isoniazid for 6–9 months (for latent TB) or as part of a multi-drug regimen for several months (for active TB). Missing doses or stopping early can lead to drug resistance, which makes TB much harder to treat. Take every dose as scheduled.
Call prescriberIf you miss several doses or need to stop for any reason. Do not restart on your own.
Skin Reactions
Tell patientA mild rash can sometimes occur. Report any new rash to your doctor.
Call prescriberImmediately if rash is accompanied by blisters, peeling skin, mouth sores, fever, or swollen lymph glands — these may be signs of a serious allergic reaction.
Sources
Regulatory (PI / SmPC)
- Isoniazid Tablets, USP prescribing information. FDA label, revised 2016. FDA LabelPrimary source for the boxed warning, dosing, contraindications, adverse reactions, and age-specific hepatitis rates cited throughout this monograph.
- DailyMed. Isoniazid tablet — drug label information. National Library of Medicine. DailyMedSupplementary FDA label source confirming dosing, adverse effects, and drug interaction data.
Key Clinical Trials & Systematic Reviews
- Menzies D, Adjobimey M, Ruslami R, et al. Four months of rifampin or nine months of isoniazid for latent tuberculosis in adults. N Engl J Med. 2018;379(5):440–453. DOILandmark RCT comparing 4R to 9H for LTBI, demonstrating comparable efficacy with fewer grade 3–4 hepatic events in the rifampin arm.
- Comstock GW. How much isoniazid is needed for prevention of tuberculosis among immunocompetent adults? Int J Tuberc Lung Dis. 1999;3(10):847–850. PubMedAnalysis of optimal INH duration for LTBI, supporting the 9-month recommendation for maximum protective efficacy.
- Sterling TR, Villarino ME, Borisov AS, et al. Three months of rifapentine and isoniazid for latent tuberculosis infection. N Engl J Med. 2011;365(23):2155–2166. DOIThe PREVENT TB study establishing the 3HP (12-dose weekly INH + rifapentine) regimen as non-inferior to 9H with higher completion rates.
Guidelines
- Sterling TR, Njie G, Zenner D, et al. Guidelines for the treatment of latent tuberculosis infection: recommendations from the National Tuberculosis Controllers Association and CDC, 2020. MMWR Recomm Rep. 2020;69(1):1–11. DOICurrent CDC LTBI guidelines now preferentially recommending short-course rifamycin-based regimens over 6–9 month isoniazid.
- Nahid P, Dorman SE, Alipanah N, et al. Official ATS/CDC/IDSA clinical practice guidelines: treatment of drug-susceptible tuberculosis. Clin Infect Dis. 2016;63(7):e147–e195. DOIComprehensive active TB treatment guidelines providing INH dosing, duration, and combination regimen structure referenced in the dosing section.
- Saukkonen JJ, Cohn DL, Jasmer RM, et al. An official ATS statement: hepatotoxicity of antituberculosis therapy. Am J Respir Crit Care Med. 2006;174(8):935–952. DOIATS consensus on monitoring, risk factors, and management of anti-TB hepatotoxicity, informing the monitoring and side effects sections.
Mechanistic / Basic Science
- Timmins GS, Deretic V. Mechanisms of action of isoniazid. Mol Microbiol. 2006;62(5):1220–1227. DOIElucidates the KatG-dependent activation of INH and formation of INH-NAD adducts that inhibit InhA, forming the basis of the MOA section.
- LiverTox: Clinical and Research Information on Drug-Induced Liver Injury. Isoniazid. NIDDK, 2025. NCBIComprehensive NIH resource on INH hepatotoxicity patterns, risk factors, and clinical course informing the hepatotoxicity management callout.
Pharmacokinetics / Special Populations
- Weber WW, Hein DW. Clinical pharmacokinetics of isoniazid. Clin Pharmacokinet. 1979;4(6):401–422. DOIFoundational PK review describing NAT2 polymorphism effects on INH disposition, half-life differences between acetylator phenotypes, and renal handling.
- Ramachandran G, Swaminathan S. Role of pharmacogenomics in the treatment of tuberculosis: a review. Pharmgenomics Pers Med. 2012;5:89–98. DOIReview of NAT2 genotype influence on INH pharmacokinetics, hepatotoxicity, and treatment outcomes in diverse populations.
- Schaaf HS, Parkin DP, Seifart HI, et al. Isoniazid pharmacokinetics in children treated for respiratory tuberculosis. Arch Dis Child. 2005;90(6):614–618. DOIPediatric PK study supporting weight-based dosing and demonstrating lower INH exposures in rapid-acetylator children.