Isoniazid

(BAN, pINN)
Isoniazid Chemical formula
Synonyms: INAH; INH; Isoniatsidi; Isoniazida; Isoniazide; Isoniazidum; Isonicotinic Acid Hydrazide; Isonicotinylhydrazide; Isonicotinylhydrazine; Izoniazid; Izoniazidas; Izoniazyd; Tubazid. Isonicotinohydrazide.
Cyrillic synonym: Изониазид.

💊 Chemical information

Chemical formula: C6H7N3O = 137.1.
CAS — 54-85-3.
ATC — J0 4AC01.
ATC Vet — QJ0 4AC0 1.

Pharmacopoeias.

In Chin., Eur., Int., Jpn, US, and Viet.

Ph. Eur. 6.2

(Isoniazid). A white or almost white, crystalline powder or colourless crystals. Freely soluble in water; sparingly soluble in alcohol. A 5% solution in water has a pH of 6.0 to 8.0.

USP 31

(Isoniazid). Colourless, or white, odourless crystals, or white crystalline powder. Soluble 1 in 8 of water and 1 in 50 of alcohol; slightly soluble in chloroform; very slightly soluble in ether. pH of a 10% solution in water is between 6.0 and 7.5. Store in airtight containers at a temperature of 25°, excursions permitted between 15° and 30°. Protect from light.

Incompatibility.

It has been recommended that sugars such as glucose, fructose, and sucrose should not be used in isoniazid syrup preparations because the absorption of the drug was impaired by the formation of a condensation product. 1 Sorbitol may be a suitable substitute if necessary. 1. Rao KVN, et al. Inactivation of isoniazid by condensation in a syrup preparation. Bull WHO 1971; 45: 625–32.

Sterilisation.

Solutions of isoniazid should be sterilised by autoclaving.

💊 Adverse Effects

Isoniazid is generally well tolerated at currently recommended doses. However, patients who are slow acetylators of isoniazid and those with advanced HIV disease appear to have a higher incidence of some adverse effects. Also patients whose nutrition is poor are at risk of peripheral neuritis which is one of the commonest adverse effects of isoniazid. Other neurological adverse effects include psychotic reactions and convulsions. Pyridoxine may be given to prevent or treat these adverse effects. Optic neuritis has also been reported. Transient increases in liver enzymes occur in 10 to 20% of patients during the first few months of treatment and usually return to normal despite continued treatment. Symptomatic hepatitis occurs in about 0.1 to 0.15% of patients given isoniazid as monotherapy, but this can increase with age, regular alcohol consumption, and in those with chronic liver disease. The influence of acetylator status is uncertain. Elevated liver enzymes associated with clinical signs of hepatitis such as nausea and vomiting, or fatigue may indicate hepatic damage; in these circumstances, isoniazid should be stopped pending evaluation and should only be reintroduced cautiously once hepatic function has recovered. Fatalities have occurred due to liver necrosis. Haematological effects reported on use of isoniazid include various anaemias, agranulocytosis, thrombocytopenia, and eosinophilia. Hypersensitivity reactions occur infrequently and include skin eruptions (including erythema multiforme), fever, and vasculitis. Other adverse effects include nausea, vomiting, dry mouth, constipation, pellagra, purpura, hyperglycaemia, lupus-like syndrome, vertigo, hyperreflexia, urinary retention, and gynaecomastia. Symptoms of overdosage include slurred speech, metabolic acidosis, hallucinations, hyperglycaemia, respiratory distress or tachypnoea, convulsions, and coma; fatalities can occur.

Carcinogenicity.

Concern about the carcinogenicity of isoniazid arose in the 1970s when an increased risk of bladder cancer in patients treated with isoniazid was reported.1-3 However, no evidence to support a carcinogenic effect of isoniazid was found in more than 25 000 patients followed up for 9 to 14 years in studies organised by the USA Public Health Service4 and in 3842 patients followed up for 16 to 24 years in the UK.5
1. Miller CT. Isoniazid and cancer risks. JAMA 1974; 230: 1254
2. Kerr WK, Chipman ML. The incidence of cancer of bladder and other sites after INH therapy. Am J Epidemiol 1976; 104: 335–6
3. Miller CT, et al. Relative importance of risk factors in bladder carcinogenesis. J Chron Dis 1978; 31: 51–6
4. Glassroth JL, et al. An assessment of the possible association of isoniazid with human cancer deaths. Am Rev Respir Dis 1977; 116: 1065–74
5. Stott H, et al. An assessment of the carcinogenicity of isoniazid in patients with pulmonary tuberculosis. Tubercle 1976; 57: 1–15.

Effects on the blood.

In addition to the effects mentioned above, rare reports of adverse effects of isoniazid on the blood include bleeding associated with acquired inhibition of fibrin stabilisation1 or of factor XIII,2 and red cell aplasia.3-5 For a reference to neutropenia, see Effects on the Blood, under Ethambutol Hydrochloride.
1. Otis PT, et al. An acquired inhibitor of fibrin stabilization associated with isoniazid therapy: clinical and biochemical observations. Blood 1974; 44: 771–81
2. Krumdieck R, et al. Hemorrhagic disorder due to an isoniazidassociated acquired factor XIII inhibitor in a patient with Waldenström’s macroglobulinemia. Am J Med 1991; 90: 639–45
3. Claiborne RA, Dutt AK. Isoniazid-induced pure red cell aplasia. Am Rev Respir Dis 1985; 131: 947–9
4. Lewis CR, Manoharan A. Pure red cell hypoplasia secondary to isoniazid. Postgrad Med J 1987; 63: 309–10
5. Veale KS, et al. Pure red cell aplasia and hepatitis in a child receiving isoniazid therapy. J Pediatr 1992; 120: 146–8.

Effects on the CNS.

In addition to the peripheral neuropathy that is a well-established adverse effect of isoniazid, effects on the CNS have also been reported, including ataxia and cerebellar toxicity,1,2 psychotic reactions3-5 (generally characterised by delusions, hallucinations, and confusion), and seizures, particularly after overdosage.6 Encephalopathy has been reported in dialysis patients.7,8 Encephalopathy may also be a symptom of pellagra, which may be associated with isoniazid treatment.9
1. Blumberg EA, Gil RA. Cerebellar syndrome caused by isoniazid. DICP Ann Pharmacother 1990; 24: 829–31
2. Lewin PK, McGreal D. Isoniazid toxicity with cerebellar ataxia in a child. CMAJ 1993; 148: 49–50
3. Pallone KA, et al. Isoniazid-associated psychosis: case report and review of the literature. Ann Pharmacother 1993; 27: 167–70
4. Alao AO, Yolles JC. Isoniazid-induced psychosis. Ann Pharmacother 1998; 32: 889–91
5. Witkowski AE, et al. Isoniazid-associated psychosis. Gen Hosp Psychiatry 2007; 29: 85–6
6. Shah BR, et al. Acute isoniazid neurotoxicity in an urban hospital. Pediatrics 1995; 95: 700–4
7. Cheung WC, et al. Isoniazid induced encephalopathy in dialysis patients. Tubercle Lung Dis 1993; 74: 136–9
8. Wang HY, et al. Encephalopathy caused by isoniazid in a patient with end stage renal disease with extrapulmonary tuberculosis. Ren Fail 2003; 25: 135–8
9. Ishii N, Nishihara Y. Pellagra encephalopathy among tuberculous patients: its relation to isoniazid therapy. J Neurol Neurosurg Psychiatry 1985; 48: 628–34.

Effects on the liver.

Transient abnormalities in liver function are common during the early stages of antituberculous therapy with isoniazid and other first-line antituberculous drugs, but sometimes hepatotoxicity may be more serious and require a change of treatment. Drug-induced hepatitis usually occurs within the first few weeks of treatment and it may not be possible to identify which drug or drugs are responsible. Isoniazid and pyrazinamide are thought to have a greater potential for hepatotoxicity than rifampicin.1 Risk factors for hepatotoxicity include alcoholism, old age, female gender, malnutrition, HIV infection, and chronic hepatitis B and C infections.1 Speculation that fast acetylators of isoniazid could be at increased risk of hepatotoxicity due to production of a hepatotoxic hydrazine metabolite has not been supported;2 in fact, slow acetylators have generally been found to have a higher risk than fast acetylators.3,4 This could reflect a reduced rate of subsequent metabolism to non-toxic compounds. In addition, concentrations of hydrazine in the blood have not been found to correlate with acetylator status.5,6 A multicentre study7 considered the incidence of hepatotoxicity from a short-term regimen of daily isoniazid, rifampicin, and pyrazinamide for 8 weeks in the initial phase followed by daily isoniazid and rifampicin for 16 weeks in the continuing phase. Analysis from 617 patients showed an incidence of hepatotoxic reactions of 1.6%; the incidence of elevated aspartate aminotransferase was 23.2%. In the same study, 445 patients on a 9month regimen of daily isoniazid and rifampicin had a 1.2% incidence of hepatotoxicity and 27.1% incidence of elevated liver enzymes. A similar incidence of hepatitis of 1.4% among 350 patients on a 9-month regimen of rifampicin and isoniazid has also been reported.8 A retrospective analysis9 of 430 children on isoniazid and rifampicin revealed hepatotoxic reactions in 3.3%, the highest incidence being in children with severe disease. The Joint Tuberculosis Committee of the British Thoracic Society has published recommendations10 for initial measurement of liver function in all patients and regular monitoring in patients with known chronic liver disease. Details are given concerning the response to deteriorating liver function depending on the clinical situation, and guidelines included for prompt re-introduction of appropriate antituberculosis therapy once normal liver function is restored. Similar guidelines have been produced in the USA.11,12 The incidence of hepatotoxicity is lower in patients receiving isoniazid for prophylaxis than in those receiving treatment for active disease. During a 7-year period13 an incidence of 0.15% was recorded in 11 141 patients who started prophylactic therapy, whereas it was 1.25% amongst 1427 patients receiving treatment. A similar study14 in a slightly older patient population reported an incidence of 0.56%. No cases of hepatotoxicity were reported in 556 HIV-infected patients taking a 3-month prophylactic regimen of isoniazid and rifampicin for latent tuberculosis.15 A meta-analysis16 concluded that daily isoniazid and rifampicin for 3 months appeared to be as safe as treatment with isoniazid alone for 6 to 12 months.
1. Yew WW, Leung CC. Antituberculosis drugs and hepatotoxicity. Respirology 2006; 11: 699–707
2. Gurumurthy P, et al. Lack of relationship between hepatic toxicity and acetylator phenotype in three thousand South Indian patients during treatment with isoniazid for tuberculosis. Am Rev Respir Dis 1984; 129: 58–61
3. Dickinson DS, et al. Risk factors for isoniazid (INH)-induced liver dysfunction. J Clin Gastroenterol 1981; 3: 271–9
4. Pande JN, et al. Risk factors for hepatotoxicity from antituberculosis drugs: a case-control study. Thorax 1996; 51: 132–6
5. Gent WL, et al. Factors in hydrazine formation from isoniazid by paediatric and adult tuberculosis patients. Eur J Clin Pharmacol 1992; 43: 131–6
6. Donald PR, et al. Hydrazine production in children receiving isoniazid for the treatment of tuberculous meningitis. Ann Pharmacother 1994; 28: 1340–3
7. Combs DL, et al. USPHS tuberculosis short-course chemotherapy trial 21: effectiveness, toxicity, and acceptability: the report of final results. Ann Intern Med 1990; 112: 397–406
8. Dutt AK, et al. Short-course chemotherapy for extrapulmonary tuberculosis: nine years’ experience. Ann Intern Med 1986; 104: 7–12
9. O’Brien RJ, et al. Hepatotoxicity from isoniazid and rifampin among children treated for tuberculosis. Pediatrics 1983; 72: 491–9
10. Joint Tuberculosis Committee of the British Thoracic Society. Chemotherapy and management of tuberculosis in the United Kingdom: recommendations 1998. Thorax 1998; 53: 536–48. [Although these guidelines were replaced by ones issued by NICE in 2006 the latter do not "explain tuberculosis or its treatment in detail" and therefore reference to the earlier guidelines has been retained] Also available at: http://www.brit-thoracic.org.uk/ Portals/0/Clinical%20Information/Tuberculosis/Guidelines/ Chemotherapy.pdf (accessed 29/07/08
11. American Thoracic Society, CDC, and the Infectious Diseases Society of America. Treatment of tuberculosis. MMWR 2003; 52 (RR-11): 1–77. Also available at: http://www.cdc.gov/ mmwr/PDF/rr/rr5211.pdf (accessed 03/10/07) Correction. ibid. 2005; 53: 1203. [dose
12. Saukkonen JJ, et al. American Thoracic Society. An official ATS statement: hepatotoxicity of antituberculosis therapy. Am J Respir Crit Care Med 2006; 174: 935–52. Also available at: http:// www.thoracic.org/sections/publications/statements/resources/ hepatotoxicity-of-antituberculosis-therapy.pdf (accessed 05/10/07
13. Nolan CM, et al. Hepatotoxicity associated with isoniazid preventive therapy: a 7-year survey from a public health tuberculosis clinic. JAMA 1999; 281: 1014–18
14. Fountain FF, et al. Isoniazid hepatotoxicity associated with treatment of latent tuberculosis infection: a 7-year evaluation from a public health tuberculosis clinic. Chest 2005; 128: 116–23
15. Whalen CC, et al. A trial of three regimens to prevent tuberculosis in Ugandan adults infected with the human immunodeficiency virus. N Engl J Med 1997; 337: 801–8
16. Ena J, Valls V. Short-course therapy with rifampin plus isoniazid, compared with standard therapy with isoniazid, for latent tuberculosis infection: a meta-analysis. Clin Infect Dis 2005; 40: 670–6.

Effects on the pancreas.

Cases of isoniazid-induced pancreatitis have been rarely reported;1-4 pancreatitis resolved in these patients once treatment with isoniazid was stopped, and recurred on rechallenge. It is recommended if isoniazid-induced pancreatitis is proven that the drug should be permanently avoided.4Chronic pancreatic insufficiency, after an acute episode, was reported in a patient given isoniazid, rifampicin, ethambutol, and pyrazinamide and was considered to be a drug hypersensitivity reaction.5
1. Chan KL, et al. Recurrent acute pancreatitis induced by isoniazid. Tubercle Lung Dis 1994; 75: 383–5
2. Rabassa AA, et al. Isoniazid-induced acute pancreatitis. Ann Intern Med 1994; 121: 433–4
3. Stephenson I, et al. Acute pancreatitis induced by isoniazid in the treatment of tuberculosis. Am J Gastroenterol 2001; 96: 2271–2
4. Chow KM, et al. Recurrent acute pancreatitis after isoniazid. Neth J Med 2004; 62: 172–4
5. Liu BA, et al. Pancreatic insufficiency due to antituberculous therapy. Ann Pharmacother 1997; 31: 724–6.

Effects on the skin and hair.

Isoniazid causes cutaneous drug reactions in less than 1% of patients.1,2 These reactions include urticaria, purpura, acneform syndrome,3 a lupus erythematosuslike syndrome4 (see below), and exfoliative dermatitis.5 Pellagra is also associated with isoniazid.6 Isoniazid was considered the most likely cause of alopecia in 5 patients receiving antituberculosis regimens which also included rifampicin, ethambutol, and pyrazinamide.7
1. Arndt KA, Jick H. Rates of cutaneous reactions to drugs: a report from the Boston Collaborative Drug Surveillance Program. JAMA 1976; 235: 918–23
2. Bigby M, et al. Drug-induced cutaneous reactions: a report from the Boston Collaborative Drug Surveillance Program on 15 438 consecutive inpatients, 1975 to 1982. JAMA 1986; 256: 3358–63
3. Thorne N. Skin reactions to systemic drug therapy. Practitioner 1973; 211: 606–13
4. Smith AG. Drug-induced photosensitivity. Adverse Drug React Bull 1989; 136: 508–11
5. Rosin MA, King LE. Isoniazid-induced exfoliative dermatitis. South Med J 1982; 75: 81
6. Ishii N, Nishihara Y. Pellagra encephalopathy among tuberculous patients: its relation to isoniazid therapy. J Neurol Neurosurg Psychiatry 1985; 48: 628–34
7. FitzGerald JM, et al. Alopecia side-effect of antituberculosis drugs. Lancet 1996; 347: 472–3.

Lupus.

Antinuclear antibodies have been reported to occur in up to 22% of patients receiving isoniazid; however, patients are usually asymptomatic and overt lupoid syndrome is rare.1,2 The incidence of antibody induction has been reported to be higher in slow acetylators than in fast acetylators,3 but the difference was not statistically significant and acetylator phenotype is not considered an important determinant of the risk of isoniazid-induced lupus.1,4,5 The syndrome appeared to be due to isoniazid itself rather than its metabolite acetylisoniazid.6
1. Hughes GRV. Recent developments in drug-associated systemic lupus erythematosus. Adverse Drug React Bull 1987; 123: 460–3
2. Siddiqui MA, Khan IA. Isoniazid-induced lupus erythematosus presenting with cardiac tamponade. Am J Ther 2002; 9: 163–5
3. Alarcon-Segovia D, et al. Isoniazid acetylation rate and development of antinuclear antibodies upon isoniazid treatment. Arthritis Rheum 1971; 14: 748–52
4. Clark DWJ. Genetically determined variability in acetylation and oxidation: therapeutic implications. Drugs 1985; 29: 342–75
5. Rychlik-Sych M, et al. Acetylation genotype and phenotype in patients with systemic lupus erythematosus. Pharmacol Rep 2006; 58: 22–9
6. Sim E, et al. Drugs that induce systemic lupus erythematosus inhibit complement component C4. Lancet 1984; ii: 422–4.

💊 Treatment of Adverse Effects

Pyridoxine hydrochloride 10 mg daily is usually recommended for prophylaxis of peripheral neuritis associated with isoniazid although up to 50 mg daily may be used. A dose of 50 mg three times daily may be given for treatment of peripheral neuritis if it develops. Nicotinamide has been given, usually with pyridoxine, to patients who develop pellagra. Isoniazid doses of 1.5 g or more are potentially toxic and doses of 10 to 15 g may be fatal without appropriate treatment. Treatment of overdosage is symptomatic and supportive and consists of activated charcoal, correction of metabolic acidosis, and control of convulsions. Large doses of pyridoxine may be needed intravenously for control of convulsions (see below) and should be given with diazepam. Isoniazid is removed by haemodialysis or peritoneal dialysis.

Overdosage.

In adults an initial intravenous dose of pyridoxine hydrochloride equivalent to the estimated amount of isoniazid ingested (or, if the amount ingested is unknown, pyridoxine hydrochloride 5 g) has been recommended by the UK National Poisons Information Service for the management of convulsions; diazepam should also be given. For children the recommended dose of pyridoxine hydrochloride is 70 mg/kg (to a maximum of 5 g). If convulsions continue or recur, this dose may be repeated. Oral activated charcoal (50 g for adults and 10 to 15 g in children) may be considered if this is given within 1 hour of ingestion of isoniazid.

Pyridoxine deficiency.

Pyridoxine deficiency associated with isoniazid in doses of 5 mg/kg daily is uncommon. Patients at risk of developing pyridoxine deficiency include those with diabetes, uraemia, alcoholism, HIV infection, and malnutrition.1,2 Supplementation with pyridoxine should be considered for these at-risk groups as well as for pregnant women and patients with seizure disorders.1 For the prophylaxis of peripheral neuritis it is common practice to give pyridoxine 10 mg daily, although 6 mg daily might be sufficient.3 However, in one patient a dose of pyridoxine 10 mg daily failed to prevent psychosis, the symptoms of which only resolved after stopping isoniazid and increasing the pyridoxine dosage to 100 mg daily.4
1. American Thoracic Society, CDC, and the Infectious Diseases Society of America. Treatment of tuberculosis. MMWR 2003; 52 (RR-11): 1–77. Also available at: http://www.cdc.gov/mmwr/ PDF/rr/rr5211.pdf (accessed 03/10/07) Correction. ibid. 2005; 53: 1203. [dose
2. Joint Tuberculosis Committee of the British Thoracic Society. Chemotherapy and management of tuberculosis in the United Kingdom: recommendations 1998. Thorax 1998; 53: 536–48. [Although these guidelines were replaced by ones issued by NICE in 2006 the latter do not "explain tuberculosis or its treatment in detail" and therefore reference to the earlier guidelines has been retained] Also available at: http://www.brit-thoracic.org.uk/Portals/0/ Clinical%20Information/Tuberculosis/Guidelines/Chemotherapy.pdf (accessed 29/07/08
3. Snider DE. Pyridoxine supplementation during isoniazid therapy. Tubercle 1980; 61: 191–6
4. Chan TYK. Pyridoxine ineffective in isoniazid-induced psychosis. Ann Pharmacother 1999; 33: 1123–4.

💊 Precautions

Isoniazid should be used with caution in patients with convulsive disorders, a history of psychosis, or hepatic or renal impairment. Patients who are at risk of neuropathy or pyridoxine deficiency, including those who are diabetic, alcoholic, malnourished, uraemic, pregnant, or infected with HIV, should be given pyridoxine, usually in a dose of 10 mg daily, although up to 50 mg daily may be used. If symptoms of hepatitis develop, such as malaise, fatigue, anorexia, and nausea, isoniazid should be stopped pending evaluation. Liver function should be checked before treatment with isoniazid and special care should be taken in alcoholic patients or those with pre-existing liver disease. Regular monitoring of liver function is recommended in patients with pre-existing liver disease, and the British Thoracic Society has recommended that isoniazid treatment be suspended if serum aminotransferase concentrations are elevated to more than 5 times the normal upper limit or the bilirubin concentration rises. They allow cautious sequential re-introduction of antimycobacterial drugs once liver function has returned to normal: first isoniazid, then rifampicin, and then pyrazinamide. Careful monitoring should be considered for black and Hispanic women, in whom there may be an increased risk of fatal hepatitis. When visual symptoms occur during isoniazid treatment periodic eye examinations have been suggested.

Breast feeding.

Peak concentrations of isoniazid in breast milk were 6 micrograms/mL after a dose of 5 mg/kg and were 16.6 micrograms/mL after a 300-mg dose.1 However, drug concentrations in the breast milk are too low to prevent or treat tuberculosis in infants. Adverse effects on breast-fed infants have not been reported and the American Academy of Pediatrics thus considers isoniazid to be usually compatible with breast feeding,2 although such infants should be monitored for toxic reactions.
1. Snider D, Powell KE. Should women taking antituberculosis drugs breast-feed? Arch Intern Med 1984; 144: 589–90
2. American Academy of Pediatrics. The transfer of drugs and other chemicals into human milk. Pediatrics 2001; 108: 776–89. Correction. ibid.; 1029. Also available at: http://aappolicy.aappublications.org/cgi/content/full/ pediatrics%3b108/3/776 (accessed 03/10/07)

Porphyria.

Isoniazid is considered to be unsafe in patients with porphyria although there is conflicting experimental evidence of porphyrinogenicity.

Pregnancy and the neonate.

In a review1 of antituberculous treatment in pregnant patients it was reported that over 95% of 1480 pregnancies in which isoniazid had been given resulted in a normal term infant. Slightly more than 1% of the infants/fetuses were abnormal and many of these abnormalities were CNS related. Isoniazid is therefore recognised as being suitable for use in regimens for the treatment of tuberculosis in pregnant patients.2,3 Pyridoxine supplementation is recommended2 (see Treatment of Adverse Effects, above). Preventive therapy with isoniazid is generally delayed until after delivery unless other risk factors are present.
1. Snider DE, et al. Treatment of tuberculosis during pregnancy. Am Rev Respir Dis 1980; 122: 65–79
2. American Thoracic Society, CDC, and the Infectious Diseases Society of America. Treatment of tuberculosis. MMWR 2003; 52 (RR-11): 1–77. Also available at: http://www.cdc.gov/mmwr/ PDF/rr/rr5211.pdf (accessed 03/10/07) Correction. ibid. 2005; 53: 1203. [dose
3. Joint Tuberculosis Committee of the British Thoracic Society. Chemotherapy and management of tuberculosis in the United Kingdom: recommendations 1998. Thorax 1998; 53: 536–48. [Although these guidelines were replaced by ones issued by NICE in 2006 the latter do not "explain tuberculosis or its treatment in detail" and therefore reference to the earlier guidelines has been retained] Also available at: http://www.brit-thoracic.org.uk/Portals/0/ Clinical%20Information/Tuberculosis/Guidelines/Chemotherapy.pdf (accessed 29/07/08)

💊 Interactions

The risk of hepatotoxicity may be increased in patients receiving isoniazid with a rifamycin or other potentially hepatotoxic drugs, including alcohol. Isoniazid can inhibit the hepatic metabolism of a number of drugs, in some cases leading to increased toxicity. These include the antiepileptics carbamazepine, ethosuximide, primidone, and phenytoin, the benzodiazepines diazepam and triazolam, chlorzoxazone, theophylline, and disulfiram. The metabolism of enflurane may be increased in patients receiving isoniazid, resulting in potentially nephrotoxic levels of fluoride. Isoniazid has been associated with increased concentrations and en hanced effects or toxicity of clofazimine, cycloserine, and warfarin. For interactions affecting isoniazid, see below.

Alcohol.

The metabolism of isoniazid may be increased in chronic alcoholics: this may lead to reduced isoniazid effectiveness.1 These patients may also be at increased risk of developing isoniazid-induced peripheral neuropathies and hepatic damage (see Precautions, above).
1. Anonymous. Interaction of drugs with alcohol. Med Lett Drugs Ther 1981; 23: 33–4.

Antacids.

Oral absorption of isoniazid is reduced by aluminium-containing antacids; isoniazid should be given at least 1 hour before the antacid.1
1. Hurwitz A, Schluzman DL. Effects of antacids on gastrointestinal absorption of isoniazid in rat and man. Am Rev Respir Dis 1974; 109: 41–7.

Antifungals.

Serum concentrations of isoniazid were below the limits of detection in a patient also receiving rifampicin and ketoconazole.1 For the effect of isoniazid on ketoconazole.
1. Abadie-Kemmerly S, et al. Failure of ketoconazole treatment of Blastomyces dermatitidis due to interaction of isoniazid and rifampin. Ann Intern Med 1988; 109: 844–5. Correction. ibid. 1989; 111: 96.

Antivirals.

The clearance of isoniazid was approximately doubled when zalcitabine was given to 12 HIV-positive patients.1 In addition, care is needed since stavudine and zalcitabine may also cause peripheral neuropathy; use of isoniazid with stavudine has been reported to increase its incidence.2
1. Lee BL, et al. The effect of zalcitabine on the pharmacokinetics of isoniazid in HIV-infected patients. Intersci Conf Antimicrob Agents Chemother 1994; 34: 3(A4)
2. Breen RAM, et al. Increased incidence of peripheral neuropathy with co-administration of stavudine and isoniazid in HIV-infected individuals. AIDS 2000; 14: 615.

Corticosteroids.

Giving prednisolone 20 mg to 13 slow acetylators and 13 fast acetylators receiving isoniazid 10 mg/kg reduced plasma concentrations of isoniazid by 25 and 40% respectively.1 Renal clearance of isoniazid was also enhanced in both acetylator phenotypes and the rate of acetylation increased in slow acetylators only.1 The clinical significance of this effect is not established.
1. Sarma GR, et al. Effect of prednisolone and rifampin on isoniazid metabolism in slow and rapid inactivators of isoniazid. Antimicrob Agents Chemother 1980; 18: 661–6.

Food.

Palpitations, headache, conjunctival irritation, severe flushing, tachycardia, tachypnoea, and sweating have been reported in patients taking isoniazid after ingestion of cheese,1,2 red wine,1 and some fish.3,4 Accumulation of tyramine1 or histamine3has been proposed as the cause of these food-related reactions, and they could be mistaken for anaphylaxis.4
1. Toutoungi M, et al. Cheese, wine, and isoniazid. Lancet 1985; ii: 671
2. Carvalho ACC, et al. Reaction to cheese during TB treatment. Thorax 2004; 59: 635
3. Kottegoda SR. Cheese, wine and isoniazid. Lancet 1985; ii: 1074
4. O’Sullivan TL. Drug-food interaction with isoniazid resembling anaphylaxis. Ann Pharmacother 1997; 31: 928.

Opioid analgesics.

For a report of an interaction between isoniazid and pethidine, attributed to isoniazid’s inhibitory actions on monoamine oxidase.

💊 Antimicrobial Action

Isoniazid is highly active against Mycobacterium tuberculosis and may have activity against some strains of other mycobacteria including M. kansasii.
Although it is rapidly bactericidal against actively dividing M. tuberculosis, it is considered to be only bacteriostatic against semi-dormant organisms and has less sterilising activity than rifampicin or pyrazinamide. Resistance of M. tuberculosis to isoniazid develops rapidly if it is used alone in the treatment of clinical infection, and may be due in some strains to loss of the gene for catalase production. Resistance is delayed or prevented by the combination of isoniazid with other antimycobacterials which appears to be highly effective in preventing emergence of resistance to other antituberculous drugs. Resistance does not appear to be a problem when isoniazid is used alone in prophylaxis, probably because the bacillary load is low.

Mycobacterium avium complex.

Synergistic activity of isoniazid plus streptomycin and, to a lesser degree, isoniazid plus clofazimine, against Mycobacterium avium complex (MAC) has been demonstrated in vitro and in vivo.1
1. Reddy MV, et al. In vitro and in vivo synergistic effect of isoniazid with streptomycin and clofazimine against Mycobacterium avium complex (MAC). Tubercle Lung Dis 1994; 75: 208–12.

💊 Pharmacokinetics

Isoniazid is readily absorbed from the gastrointestinal tract and after intramuscular injection. Peak concentrations of about 3 to 7 micrograms/mL appear in blood 1 to 2 hours after an oral fasting dose of 300 mg. The rate and extent of absorption of isoniazid is reduced by food. Isoniazid is not considered to be bound appreciably to plasma proteins and distributes into all body tissues and fluids, including the CSF. It appears in fetal blood if given during pregnancy (see below), and is distributed into breast milk (see under Precautions, above). The plasma half-life for isoniazid ranges from about 1 to 6 hours, with shorter half-lives in fast acetylators. The primary metabolic route is the acetylation of isoniazid to acetylisoniazid by N-acetyltransferase found in the liver and small intestine. Acetylisoniazid is then hydrolysed to isonicotinic acid and monoacetylhydrazine; isonicotinic acid is conjugated with glycine to isonicotinyl glycine (isonicotinuric acid) and monoacetylhydrazine is further acetylated to diacetylhydrazine. Some unmetabolised isoniazid is conjugated to hydrazones. The metabolites of isoniazid have no tuberculostatic activity and, apart from possibly monoacetylhydrazine, they are also less toxic. The rate of acetylation of isoniazid and monoacetylhydrazine is genetically determined and there is a bimodal distribution of persons who acetylate them either slowly or rapidly. Ethnic groups differ in their proportions of these genetic phenotypes. When isoniazid is given daily or 2 or 3 times weekly, clinical effectiveness is not influenced by acetylator status. In patients with normal renal function, over 75% of a dose appears in the urine in 24 hours, mainly as metabolites. Small amounts of drug are also excreted in the faeces. Isoniazid is removed by haemodialysis.

Distribution.

Therapeutic concentrations of isoniazid have been detected in CSF1,2 and synovial fluid3 several hours after an oral dose. Diffusion into saliva is good and it has been suggested that salivary concentrations could be used in place of serum concentrations in pharmacokinetic studies.4
1. Forgan-Smith R, et al. Pyrazinamide and other drugs in tuberculous meningitis. Lancet 1973; ii: 374
2. Miceli JN, et al. Isoniazid (INH) kinetics in children. Fedn Proc 1983; 42: 1140
3. Mouries D, et al. Passage articulaire de l’isoniazide et de l’éthambutol: deux observations de synovite tuberculeuse du genou. Nouv Presse Med 1975; 4: 2734
4. Gurumurthy P, et al. Salivary levels of isoniazid and rifampicin in tuberculous patients. Tubercle 1990; 71: 29–33.

HIV-infected patients.

Malabsorption of isoniazid and other antituberculous drugs may occur in patients with HIV infection and tuberculosis, and may contribute to acquired drug resistance and reduced efficacy of tuberculosis treatment. For further information on the absorption of antituberculous drugs in HIV-infected patients see Pharmacokinetics, under Rifampicin.

Pregnancy.

Isoniazid crosses the placenta and average fetal concentrations of 61.5 and 72.8% of maternal serum or plasma concentration have been reported.1 The half-life of isoniazid may be prolonged in neonates.1
1. Holdiness MR. Transplacental pharmacokinetics of the antituberculosis drugs. Clin Pharmacokinet 1987; 13: 125–9.

💊 Uses and Administration

Isoniazid is a hydrazide derivative that is the mainstay of the primary treatment of pulmonary and extrapulmonary tuberculosis. It is used with other antituberculous drugs usually in regimens including rifampicin, ethambutol, and pyrazinamide. Isoniazid is also used in high-risk subjects for the prophylaxis of tuberculosis. Isoniazid is given in the initial and continuation phases of short-course tuberculosis regimens. The usual adult dose is 5 mg/kg, to a maximum of 300 mg, daily by mouth on an empty stomach. For intermittent therapy, WHO recommends 10 mg/kg three times a week or 15 mg/kg twice a week, while the recommended dose in the UK is 15 mg/kg three times a week and in the USA 15 mg/kg once weekly or two or three times a week is recommended. Caution is required in patients with hepatic impairment and doses may need to be reduced in those with severe renal impairment. Similar doses to those used orally may be given by intramuscular injection when isoniazid cannot be taken by mouth; it may also be given by intravenous injection. Isoniazid has also been given intrathecally and intrapleurally. In the treatment of latent tuberculosis, daily doses of 300 mg for 6 months are recommended by WHO and in the UK, while in the USA the preferred treatment regimen is oral isoniazid 5 mg/kg daily or 15 mg/kg twice weekly for 9 months. As an alternative to such regimens, isoniazid may be given with rifampicin for 3 months. For details of doses in infants, children, and adolescents, see below. Isoniazid aminosalicylate (pasiniazid) and isoniazid sodium glucuronate have also been used in the treatment of tuberculosis. Fixed-dose combination products containing 2, 3, or 4 drugs have been developed in order to improve patient compliance and avoid monotherapy, thereby decreasing the risk of acquired drug resistance. Products containing isoniazid in various combinations with rifampicin, ethambutol, and pyrazinamide are available in some countries.

Administration in children.

For the treatment of tuberculosis in infants, children, and adolescents the American Academy of Pediatrics (AAP) suggests an oral dose of isoniazid 10 to 15 mg/kg daily or 20 to 30 mg/kg twice weekly by mouth, for both the initial and continuation phases. For children 1 month and older the BNFC suggests oral doses of 5 to 10 mg/kg once daily or 15 mg/kg three times a week; WHO recommends 5 mg/kg once daily, or 10 mg/kg three times a week, or 15 mg/kg twice a week. For the treatment of latent tuberculosis the AAP and the American Thoracic society suggest oral doses of 10 to 20 mg/kg daily or 20 to 40 mg/kg twice weekly for 9 months. For children 1 month and older the BNFC suggests a dose of 5 mg/kg once daily for 6 months when used alone or for 3 months when given with rifampicin; WHO recommends 5 mg/kg once daily for 6 months. For daily dosing regimens the maximum oral dose of isoniazid is 300 mg and for intermittent regimens the maximum dose is 900 mg per dose.

💊 Preparations

BP 2008: Isoniazid Injection; Isoniazid Tablets; USP 31: Isoniazid Injection; Isoniazid Syrup; Isoniazid Tablets; Rifampin and Isoniazid Capsules; Rifampin, Isoniazid, and Pyrazinamide Tablets; Rifampin, Isoniazid, Pyrazinamide, and Ethambutol Hydrochloride Tablets.

Proprietary Preparations

Arg.: Isoniac; Belg.: Nicotibine; Canad.: Isotamine; Cz.: Nidrazid; Fin.: Tu bilysin; Fr.: Rimifon; Ger.: Isozid; Isozid comp N; tebesium; tebesium-s; Gr.: Cemidon; Dianicotyl; Isozid†; Nicozid; Hung.: Isonicid; India: Isokin; Isonex; Rifacom E-Z; Indon.: INH-Ciba; INHA; Inoxin; Medinh-OD; Niacifort6; Nufadoxin; Pulmolin; Pyravit; Pyrifort; Suprazid; TB Vit 6; Israel: Inazid; Ital.: Nicizina; Nicozid; Jpn: Hydra; Hydrazide; Mex.: Erbazid†; Hidrasix; Valifol; Philipp.: Comprilex; Curazid (Reformulated); Eurocoxin; Isodexid; Isoxin; Nicetal; Odinah; Techxafort; Terozid; Trisofort; Vamsoxid; Port.: Hidrazida; Spain: Cemidon; Cemidon B6; Swed.: Tibinide; Switz.: Rimifon; Thai.: Antimic; Myrin-P; Myrin†; Turk.: INH; Isovit; USA: Laniazid; Nydrazid. Multi-ingredient: Arg.: Bacifim; Rifinah; Risoniac†; Austria: Isoprodian; Myambutol-INH; Rifater; Rifoldin INH; Braz.: Isoniaton; Canad.: Rifater; Denm.: Rimactazid; Rimstar; Fin.: Rimactazid; Rimstar; Fr.: Rifater; Rifinah; Ger.: EMB-INH†; Iso-Eremfat; Isoprodian†; Myambutol-INH; Rifater; Rifinah; tebesium Duo; tebesium Trio; Gr.: Oboliz; Rifater; Rifinah; Rimactazid; Hong Kong: Rifater; Rifinah; Hung.: Rifazid; India: Akt-3; Akt-4; Arzide; Bicox-E†; Combunex; Coxina-3; Coxina-4; Coxinex; Cx-3; Cx-4; Cx-5; Gocox Compound; Gocox-3; Gocox-4†; Inabutol Forte; Inapas; Ipcacin Kid; Ipcazide; Isokin-300; Isokin-T Forte; Isorifam; Myconex; R-Cinex; R-Cinex Z; RHZ; RHZ-Plus; Rifa; Rifa E; Rifacomb Plus†; Rifacomb†; Rimactazid + Z; Rimpazid; Siticox-INH; Tibirim INH; Tricox; Wokex-2; Wokex-3; Wokex-4; Xeed-2; Xeed-3E; Xeed-4; Indon.: bacbutINH; Erabutol Plus; Meditam-6; Mycothambin-INH; Niazitol; Pulna; Ramicin-ISO; Rimactazid; Rimcure; Rimstar; Santibi Plus; Irl.: Rifater; Rifinah; Rimactazid; Ital.: Etanicozid B6; Miazide B6†; Rifater; Rifinah; Malaysia: Rimactazid; Rimcure; Mex.: Arpisen; Finater; Finateramida; Isonid†; Myambutol-INH†; Rifater; Rifinah; Neth.: Rifinah; NZ: Rifinah; Philipp.: 4D; Bifix; CombiKids; CombiPack; Continukit; Continukit Plus; Continupack; Econokit; Econokit-MDR; Econopack; Ethamizid; Ethi 400; Fixcom 3; Fixcom 4; Kidz Kit 2; Kidz Kit 3; Myrin; MyrinP; Quadtab; Refam Duo; Refam Pedia Kit; Rifater; Rifinah; Rifzin; Rimactazid; Rimcure; Rimstar; Sthamizide; SVM-Polypac-A; Tres; Triofix; Tritab; Viper; Pol.: Rifamazid; Port.: Rifater; Rifinah; Rus.: Isocomb (Изокомб); Lomecomb (Ломекомб); Phthizoetham (Фтизоэтам); Phthizopiram (Фтизопирам); Repin B (Репин В ); Rifacomb (Рифакомб); Rifacomb Plus (Рифакомб Плюс); Rimactazid (Римактазид); Rimecure 3-FDC (Римкур 3ФДС); Rimstar 4-FDC (Римстар 4-ФДС); S.Afr.: Myrin Plus†; Myrin†; Rifafour; Rifater; Rifinah; Rimactazid; Rimcure; Rimstar; Singapore: Rimactazid; Spain: Amiopia; Duplicalcio 150†; Duplicalcio B12; Duplicalcio Hidraz†; Rifater; Rifazida†; Rifinah; Rimactazid; Rimcure; Rimstar; Tisobrif; Swed.: Rimactazid; Rimcure; Rimstar; Switz.: Myambutol-INH†; Rifater; Rifinah; Thai.: Rifafour; Rifampyzid; Rifater; Rifinah; Rimactazid; Rimcure 3FDC; Rimstar; UK: Rifater; Rifinah; Rimactazid†; USA: IsonaRif; Rifamate; Rifater; Venez.: Rimactazid; Rimcure.
Published March 30, 2019.