Isoniazid

137.14

137.14

119374

200-214-6

V83O1VOZ8L

1258

757078|9659

DTXSID8020755

C600

COLORLESS OR WHITE CRYSTALS, OR A WHITE, CRYSTALLINE POWDER|Crystals from alcohol

QI01AN01|J04AC01|J - Antiinfectives for systemic use

2933399090

68

-0.7

White or colorless Crystals or Crystalline Powder

1.420 g/cm³

171.4 °C

>250°C

1.584

H2O: 14 g/100 mL (25 ºC)

Refrigerator

4.6X10-5 mm Hg at 25 deg C /Estimated/

LD50 in mice (mg/kg): 151 i.p., 149 i.v. (Jenney, Pfeiffer)

pH of a 1% aqueous solution 5.5 to 6.5

1.82(at 20 °C)

Henry's Law constant = 1.2X10-14 atm-cu m/mole at 25 °C /Estimated/

1.82 (at 20 °C)|pK1= 1.75; pK2= 3.57; pK3= 10.75

125.6 Ų [M+H]+ [CCS Type: TW, Method: calibrated with polyalanine and drug standards]

Can react as weak acid or weak base; can be hydrolyzed to release hydrazine; lysed at hydrazine moiety by redox reactions.|Aqueous solutions may be sterilized at 120 °C for 30 minutes.|An equimolecular salt produced by dissolving the components in hot dil alc, followed by cooling and evapn ... MW: 290.27. Yellow crystals from methanol or ethanol; mp 142-144 °C. Sparingly soluble in water, uv max 272, 303 nm (E(1%)(1 cm) 550, 445). /4-Aminosalicylate/|MW: 231.23. Crystals, dec 187-189 °C /Methanesulfonate/|For more Other Experimental Properties (Complete) data for ISONIAZID (7 total), please visit the HSDB record page.

Sensitive to air and light. Absorbs insignificant amounts of moisture at 77°F at relative humidities up to approximately 90%. Water soluble. Dust can be explosive when suspended in air at specific concentrations.

Amides and Imides

ISONIAZID is incompatible with chloral, aldehydes, iodine, hypochlorites and ferric salts. It is also incompatible with oxidizers. It may react with sugars and ketones. It can react as a weak acid or a weak base. It can be decomposed by oxidative and reductive reactions. (NTP, 1992)

III

2811

3

22-38-40-36/37/38

37-36/37/39-26

NS1751850

Xn

Cool. Well closed.

Stability Stable, but may be air or light sensitive. Combustible. Incompatible with strong oxidizing agents, chloral, aldehydes, iodine, ferric salts, hypochlorites.

P301 + P312 + P330

H302-H315

SRP: The most favorable course of action is to use an alternative chemical product with less inherent propensity for occupational exposure or environmental contamination. Recycle any unused portion of the material for its approved use or return it to the manufacturer or supplier. Ultimate disposal of the chemical must consider: the material's impact on air quality; potential migration in soil or water; effects on animal, aquatic, and plant life; and conformance with environmental and public health regulations.

The Approved Drug Products with Therapeutic Equivalence Evaluations List identifies currently marketed prescription drug products, incl isoniazid, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act.

Currie B et al; Acetylator Phenotype and Short-course Chemotherapy for Tuberculosis in Papua New Guinea. P N G Med J 32 (4): 259-62 (1989). Acetylator status and other factors influencing isoniazid-induced peripheral neuropathy are discussed, and statistics from Papua New Guinea are presented.|Holdiness MR; Teratology of the Antituberculosis Drugs. Early Hum Dev 15 (2): 61-74 (1987). The teratogenic effects of twelve antituberculosis drugs in animal models and man are reviewed. Isoniazid is considered one of the safest for maternal use.|Holdiness MR; Transplacental Pharmacokinetics of the Antituberculosis Drugs. Clin Pharmacokinet 13 (Aug): 125-9 (1987). A review of reports of antituberculosis drugs given during pregnancy shows information indicating placental transfer of isoniazid.

This chemical is combustible. (NTP, 1992)|Combustible. Gives off irritating or toxic fumes (or gases) in a fire.

|Warning|H302 (98.38%): Harmful if swallowed [Warning Acute toxicity, oral]|P264, P270, P280, P301+P312, P302+P352, P321, P330, P332+P313, P362, and P501|Aggregated GHS information provided by 370 companies from 12 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.|Danger|H302: Harmful if swallowed [Warning Acute toxicity, oral]|P201, P202, P260, P264, P270, P273, P281, P301+P312, P307+P311, P308+P313, P314, P321, P330, P405, and P501

Fires involving this material can be controlled with a dry chemical, carbon dioxide or Halon extinguisher. A water spray may also be used. (NTP, 1992)|Use water spray, powder, foam, carbon dioxide.

SMALL SPILLS AND LEAKAGE: If you spill this chemical, you should dampen the solid spill material with water, then transfer the dampened material to a suitable container. Use absorbent paper dampened with water to pick up any remaining material. Seal your contaminated clothing and the absorbent paper in a vapor-tight plastic bag for eventual disposal. Wash all contaminated surfaces with a soap and water solution. Do not reenter the contaminated area until the Safety Officer (or other responsible person) has verified that the area has been properly cleaned. STORAGE PRECAUTIONS: You should protect this chemical from exposure to light. Keep the container tightly closed under an inert atmosphere, and store under ambient temperatures. (NTP, 1992)

RECOMMENDED RESPIRATOR: Where the neat test chemical is weighed and diluted, wear a NIOSH-approved half face respirator equipped with a combination filter cartridge, i.e. organic vapor/acid gas/HEPA (specific for organic vapors, HCl, acid gas, SO2 and a high efficiency particulate filter). (NTP, 1992)

Sweep spilled substance into covered sealable containers. If appropriate, moisten first to prevent dusting. Carefully collect remainder. Then store and dispose of according to local regulations. Personal protection: P2 filter respirator for harmful particles.

Cool. Well closed.

Evaporation at 20 °C is negligible; a harmful concentration of airborne particles can, however, be reached quickly when dispersed, especially if powdered.

The substance may cause effects on the nervous system, eyes and kidneys. Exposure at high levels could cause death. Exposure could cause convulsions. The substance is irritating to the eyes, skin and respiratory tract.

The substance may have effects on the central nervous system and liver. This may result in tissue lesions and impaired functions. Repeated or prolonged contact with skin may cause dermatitis.

NO open flames.

PREVENT DISPERSION OF DUST!

Use local exhaust or breathing protection.

Protective gloves.

Wear safety spectacles.

LD50 100 mg/kg (Human, oral). Adverse reactions include rash, abnormal liver function tests, hepatitis, peripheral neuropathy, mild central nervous system (CNS) effects. In vivo, Isoniazid reacts with pyridoxal to form a hydrazone, and thus inhibits generation of pyridoxal phosphate. Isoniazid also combines with pyridoxal phosphate; high doses interfere with the coenzyme function of the latter.|IDENTIFICATION: Isoniazid is used for the treatment of tuberculosis. Isoniazid is a colorless, odorless, white crystalline powder slowly affected by exposure to air and to light. It is soluble in water, alcohol, slightly soluble in chloroform and very slightly soluble in ether. Isoniazid is an antimycobacterial agent which is bactericidal for both extracellular and intracellular organisms. It is the primary drug for the treatment of tuberculosis when the disease is caused by isoniazid-sensitive strains of the Mycobacterium tuberculosis. In combination with rifampicin, ethambutol or pyrazinamide, isoniazid INH line agent in the treatment of pulmonary and extrapulmonary tuberculosis. It is a component of all combined antituberculosis chemotherapy regimens. Isoniazid may be used for tuberculosis prophylaxis. HUMAN EXPOSURE: Main risks and target organs: CNS is the target organ of isoniazid acute toxicity. Isoniazid induces generalized convulsions, coma and metabolic acidosis. Death may occur from acute respiratory failure or hypotension. Liver and peripheral nervous and hematologic systems are the main target organs of isoniazid chronic toxicity. Isoniazid INH may induce acute hepatitis, peripheral neuropathy, haemolytic anemia. Summary of clinical effects: Toxicity appears after a short delay of 0.5 to 4 hours following ingestion. Symptoms may include: slurred speech, hallucinations, coma; generalized convulsions, status epilepticus; respiratory failure, hypotension; severe metabolic acidosis, fever; rhabdomyolysis; gastrointestinal symptoms (nausea, vomiting) are frequent prior to the onset of convulsions. Hepatitis, peripheral neuropathy and hemolytic anemia are manifestations of chronic toxicity. Severe isoniazid poisoning is characterized by the clinical triad of: repetitive convulsions not responsive to usual treatment; metabolic acidosis and coma. Chronic isoniazid toxicity produces nausea, vomiting, restlessness, fever and many other signs and symptoms. Toxic hepatitis and hemolytic anemia may be observed, as well as other hematological effects and psychosis. Contraindications: Known severe adverse reactions or hypersensitivity due to the drug. Previous hepatitis associated with isoniazid. Isoniazid should not be used in patients with acute liver disease. Isoniazid may precipitate porphyria. Convulsions may be precipitated in patients with epilepsy. Liver function should be monitored regularly in patients with previous hepatic disease. Routes of entry: Oral: This is the most frequent route of intoxication because the drug is usually administered orally. Parenteral: No case has been reported, but isoniazid intoxication may occur after parenteral administration. Absorption by route of exposure: Oral: isoniazid is rapidly and almost completely (90-95%) absorbed from the gastrointestinal tract. Peak plasma concentrations are reached within 1 to 2 hours after ingestion. When INH is administered with food, the extent of absorption and the peak plasma concentration may be reduced. Distribution by route of exposure: Protein binding is less than 10 to 15 %. Isoniazid is distributed into all body tissues and fluids (pleural, ascitic fluids, saliva, CSF) with tissue or fluid levels similar to serum levels. Skin contains large amounts and acts as a storage depot. Isoniazid penetrates well into caseous lesions. Isoniazid readily crosses the placenta. The concentrations in milk are approximately equal to plasma maternal concentrations. Biological half-life by route of exposure: The plasma half-life in patients with normal renal and hepatic function is 1 to 4 hours, depending on the rate of metabolism: it is 0.5 to 1.6 hours in fast acetylators and 2 to 5 hours in slow acetylators. The plasma halflife may be prolonged to 4.3 hours in patients with impaired hepatic function or severe renal impairment. Plasma half life may also be prolonged in acute overdose. Metabolism: The major route of isoniazid metabolism is hepatic acetylation by N-acetyl transferase which produces acetylisoniazid. The rate of acetylation is genetically determined. Acetyisoniazid is further hydrolysed to isonicotinic acid and acetylhydrazine, both of which are excreted in the urine. Isonicotinic acid is conjugated with glycine. Acetylhydrazine is further metabolized to diacetylhydrazine and may be converted by the hepatic microsomal enzymes to the reactive metabolite (presumed to be hydrazine) which are thought responsible for isoniazid-induced hepatotoxicity. Elimination and excretion: Kidney: In adults with normal renal function, approximately 50 to 70% of a 5 mg/kg oral dose is excreted in urine within 24 hours as unchanged drug and as metabolites. The percentage of the different compounds excreted varies with the acetylator phenotype. Breast milk: 0.75 to 2.3% of the dose is excreted into breast milk in 24 hours. This corresponds to 6-20% of a usual therapeutic pediatric dose. Other routes: Small amounts of the drug are excreted in saliva, sputum and feces. Mode of action: Toxicodynamics: Tonic-clonic seizures and severe metabolic acidosis are the most common features in isoniazid overdose. Seizures: The precipitating mechanism of the seizures is not exactly known but it may be related to the isoniazid induced deficiency of pyridoxine. INH produces pharmacologic changes in pyridoxine metabolism. Increased renal excretion of pyridoxine by formation of isoniazid pyridoxine hydrazones. The hydrazones competitively inhibit pyridoxine kinase, the activating enzyme that converts pyridoxine to the physiologically active pyridoxal phosphate. Inactivation of the pyridoxal containing enzymes. The subsequent reduction in pyridoxine and pyridoxal phosphate inhibits the formation of the inhibitory neurotransmitter, gamma aminobutyric acid or GABA. This reduction in GABA levels may explain the seizures in patients with isoniazid poisoning. Metabolic acidosis: The metabolic acidosis may be related to: a lactic acidosis due to the seizures, a blockage in the conversion of lactate to pyruvate, an increased metabolism of fatty acids resulting from an impaired glucose metabolism with hyperglycemia and ketonuria. Neuropathy: Peripheral neuropathy secondary to chronic exposure is due to the deficiency of pyridoxine and pyridoxal phosphate. Hepatitis: Hepatitis is due to a toxic metabolite of monoacetyl hydrazine, which binds covalently to liver proteins. In some patients an allergic mechanism has also been proposed: acylation of hepatic macromolecules by acetyl hydrazine may lead to the release of antigenic macromolecules which induce the formation of antibodies directed against the liver. Pharmacodynamics: The exact mechanism of action of isoniazid is not known. Isoniazid may act by inhibition of mycolic acid synthesis and disruption of the cell wall in susceptible organisms. Since mycolic acids are unique to mycobacteria, this action explains the high degree of selectivity of the antimicrobial activity. Mutation conferring resistance may occur in susceptible microorganisms. There is a cross resistance between isoniazid, rifampicin and ethambutol. However the simultaneous use of two of these drugs markedly delays the emergence of resistant mutants either agent. Carcinogenicity: There is no evidence to support carcinogenic effects in humans. A recent study did not detect an increase in cancer deaths in a series of 338 women treated with INH for pulmonary tuberculosis. Several other studies fail to show a carcinogenic effect, including a study in which 25,000 patients followed up for 9 to 14 years and a study of 3,842 patients in the UK. Interactions: Several drugs may interact with INH: Drugs which interfere with INH pharmacokinetics: Aminosalicylic acid, procainamide, propranolol increase INH serum levels by reduction of the acetylation. Aluminium-containing antacids decrease the gastrointestinal absorption of the drug. Pyrazinamide decreases the serum levels of INH. Drugs which decrease serum levels when used with INH: Cyclosporine, enflurane, folic acid, ketoconazole, verapamil. Drugs which increase serum levels when used with INH: Carbamazepine, diazepam, dicoumarol, ethosuximide, phenytoin, primidone, theophylline. Other interactions: The concomitant administration of INH and the following drugs may produce: psychiatric responses: tricyclic antidepressants; hyperglycaemia: chlorpropamide; agitation or parkinsonian tremor: levodopa; hypotension: pethidine (meperidine); increased incidence of hepatotoxicity: rifampicin; hypertension, tachycardia, hyperthermia: monoamine oxidase inhibitors. Main adverse effects: Peripheral neuropathy and hepatotoxicity are the most frequently observed adverse effects of INH. Hepatotoxicity: Asymptomatic elevation of serum aspartate transferase (SGOT) is noted in 10-20 % of the patients. This increase is usually transient and the level returns to normal with continuing therapy. INH should be discontinued in patients with a transaminase level three times greater than normal. Hepatitis with jaundice may occur (0.5 %). In most cases, hepatitis occurs within the 3 months following the onset of the treatment. Some factors predisposing to INH hepatotoxicity include: age, alcohol, rapid acetylator status, concomitant administration of isoniazid and rifampicin. Peripheral neuropathies: Peripheral neuropathy is the most common side effect of INH. It is secondary to a pyridoxine deficiency. The predisposing factors are: alcohol, slow acetylator status, diabetes, malnutrition, pregnancy. Peripheral neuropathy is dose-related: it is uncommon at low doses and very frequent with high doses. Treatment and prophylaxis are based on administration of pyridoxine. Other adverse reactions: Hematologic: disseminated intravascular coagulation; granulocytosis, eosinophilia, anemia (hemolytic, aplastic, sideroblastic, megaloblastic), thrombocytopenia. Neurologic: peripheral neuropathy, hypersensitivity meningitis, dystonias, encephalopathy, seizures, cerebellar syndromes. Psychiatric: confusional states, transient memory impairment, delirium. Endocrine/metabolic: hyperglycemia, hypocalcemia, porphyria, gynecomastia. Gastrointestinal: abdominal pain, acute pancreatitis. Kidney: nephrotoxicity is a very rare complication, (1 case of acute renal insufficiency has been described). Ocular: optic neuropathy (especially when combined therapy with INH and ethambutol); optic atrophy Dermatologic: pellagra (due to a nicotinic acid deficiency), exfoliative dermatitis, Steven-Johnson syndrome; cutaneous reactions (2%), urticaria, angioneurotic oedema, morbilliform eruptions, purpura, acneiform eruptions, photosensitivity. Musculoskeletal: arthritis, arthralgias, systemic lupus erythematosis; antinuclear antibodies in the serum may appear, especially in slow acetylators, approximately five months after the onset of therapy.

Despite its limited use, isoniazid remains one of the most common causes of serious, idiosyncratic liver injury in the United States. Therapy with isoniazid is associated with transient serum aminotransferase elevations in 10% to 20% of patients, and levels rising above 5 times the upper limit of the normal range (ULN) in 3% to 5%. These enzyme elevations are usually asymptomatic and often resolve even with continuation of therapy without dose adjustment (Case 1 and 2).

Concurrent use of prednisolone, and probably other related adrenocorticoids, with isoniazid may increase hepatic metabolism and/or excretion of isoniazid, leading to decreased plasma concentration and effectiveness of isoniazid, especially in patients who are rapid acetylators; isoniazid dosage adjustments may be required.|Concurrent daily use of alcohol may result in increased incidence of isoniazid-induced hepatotoxicity and increased metabolism of isoniazid; dosage adjustments of isoniazid may be necessary; patients should be monitored closely for signs of hepatotoxicity and should be advised to restrict intake of alcoholic beverages.|Chronic preoperative or perioperative use of isoniazid, a hepatic enzyme inhibitor, may decrease the plasma clearance and prolong the duration of action of alfentanil.|Antacids may delay and decrease absorption and serum concentrations of orally administered isoniazid; concurrent use should be avoided, or patients should be advised to take oral isoniazid at least 1 hour before aluminum-containing antacids.|For more Interactions (Complete) data for ISONIAZID (23 total), please visit the HSDB record page.

LD50 Mouse ip 100 mg/kg|LD50 Rat oral 650 mg/kg

... ... Isonicotinic acid hydrazide (INH) was ... selected for immunotoxicity studies /using female B6C3F1 mice/. Female B6C3F1 mice ... were administered isonicotinic acid hydrazide daily for 14 days at doses of 25, 50 and 100 mg/kg by oral gavage. In some of the studies, an additional 150 mg/kg dose group was added to better characterize the dose-response relationship for the assay. ... Daily oral administration of isonicotinic acid hydrazide to female B6C3F1 mice for 14 days at 25, 50 and 100 mg/kg (and 150 mg/kg for a standard toxicity evaluation) did not affect body weight gain/loss nor was any organ gross pathology observed. There was a modest increase in liver and kidney weight in animals exposed to 150 mg/kg and a small, but significant, increase in spleen weight in the 100 mg/kg group only. Hematology was unremarkable. ... B cell and T cell numbers including T cell subsets were not altered by isonicotinic acid hydrazide. Serum titers of IgM anti-sRBC were decreased 33% in animals given 100 mg/kg isonicotinic acid hydrazide and the results of trend analysis were positive. isonicotinic acid hydrazide exposure for 14 days did not alter spleen IgM antibody-forming cell activity. The mixed leukocyte response was essentially normal. Cytotoxic T cell activity appeared to be stimulated at 25 and 50 mg/kg, but no effect was detected at 100 mg/kg. Natural killer cell activity remained normal at all isonicotinic acid hydrazide dose levels nor was the functional activity of the reticuloendothelial system affected. ... Isonicotinic acid hydrazide had essentially no effect in the B16F10 melanoma and Listeria monocytogenes host resistance assays. However, isonicotinic acid hydrazide at 100 mg/kg did tend to afford some protection in the Streptococcus pneumonia host resistance assay. Overall, at relatively high exposure levels, isonicotinic acid hydrazide may adversely affect the antibody cell response while stimulating cytotoxic T cell activity.|... Isonicotinic acid hydrazide (INH) was ... selected for immunotoxicity studies /using female B6C3F1 mice/. There were no significant changes in body weights for any isonicotinic acid hydrazide-treated group compared to controls. However, trend analysis of body weight changes over weekly intervals as a function of exposure revealed a tendency toward a reduced rate of weight gain for days 8 through 22 of exposure. Slight hepatomegaly was observed at the highest dose level. The WBC count was reduced by about 25% in the low dose group only. Mean corpuscular hemaglobin (MCH) and mean corpuscular hemaglobin concentration (MCHC) increased slightly, but significantly, in the high dose group (150 mg/kg). SGPT levels were significantly decreased in two of the four dose groups. SGPT values for the low (25 mg/kg) dose group were decreased 20% compared to the vehicle controls. At the 150 mg/kg dose level, the decrease was 24%. Exposure to isonicotinic acid hydrazide decreased the albumin to globulin ratio 24% in the high dose group. ... The absolute number of TH cells was decreased by 35% at the low dose only, and the total number of T cells was increased by 17% at the 50 mg/kg exposure only when expressed as a percent value. All other cell assessments were unaffected. No significant effect of isonicotinic acid hydrazide exposure was evident when each exposure group was compared to controls. However, trend analysis indicated an impaired AFC response over the isonicotinic acid hydrazide dose range tested. Isonicotinic acid hydrazide significantly reduced serum anti-sRBC titer over the dose range tested even though the spleen AFC response was only marginally affected. Isonicotinic acid hydrazide was without effect on the MLR. A 44% increase in cytotoxic T cell activity was seen at the 50 mg/kg dose level, but only at an E:T ratio of 1.5:1. This effect appears to be spurious given an absence of effect under all other conditions. There was no effect of isonicotinic acid hydrazide on the vascular clearance rate as reflected in the lack of effect on the half-life of the radiolabled sheep erythrocytes, even though hepatic uptake was marginally decreased in the 100 mg/kg group when expressed as cpm/mg. Isonicotinic acid hydrazide exposure had no effect on NK cell activity. ... Isonicotinic acid hydrazide exposure had no effect on the outcome of the Streptococcus pneumoniae host resistance assay. In summary, the data derived from this study indicate a low order of toxicity for isonicotinic acid hydrazide. Isonicotinic acid hydrazide significantly impaired an antibody response to the antigen sRBC, as reflected in serum anti-sRBC titers. The AFC response to sRBC was also decreased as shown by trend analysis. All other immunological parameters assessed were essentially normal.

Very low (0-10%)

Hepatotoxic metabolite acetylisoniazid found in breast milk but no documented problems. Concentration in milk is equal that in plasma.

NIOSH (NOES Survey 1981-1983) has statistically estimated that 2,924 workers (1,480 of these are female) are potentially exposed to isoniazid in the US(1).

For the treatment of all forms of tuberculosis in which organisms are susceptible.|For active immunisation of chicks from 1 day of age to reduce clinical signs (diarrhoea), intestinal lesions and oocysts output associated with coccidiosis caused by Eimeria acervulina, Eimeria brunetti, Eimeria maxima, Eimeria necatrix and Eimeria tenella.,

Isoniazid is the most reliable and most commonly used medication for tuberculosis. Isoniazid therapy is often associated with minor, transient and asymptomatic elevations in serum aminotransferase levels but, more importantly, isoniazid is a well known cause of acute clinically apparent liver injury which can be severe and is sometimes fatal.

Antituberculosis Agents

Antitubercular Agents|MEDICATION (VET): Antibacterial (tuberculostatic); anti-actinomycotic agent.|Isoniazid is indicated alone in the treatment of latent tuberculosis infection in the following persons: Household members and other close contacts of patients with recently diagnosed tuberculosis who have a positive tuberculin skin test (PPD) of greater than or equal to 5 mm; (tuberculin-negative children and adolescents who have been close contacts of infectious persons within the past 3 months are also candidates for preventative therapy until a repeat PPD is done 12 weeks after contact with the infectious source /NOT included in US product labeling/). /Included in US product labeling/|Isoniazid is indicated alone in the treatment of latent tuberculosis infection in the following persons: HIV-infected persons of any age with a positive tuberculin skin test of greater than or equal to 5 mm or a past history of a positive tuberculin skin test; also persons with risk factors for HIV infection whose HIV status is unknown but who are suspected of having HIV infection. /NOT included in US product labeling/|For more Therapeutic Uses (Complete) data for ISONIAZID (16 total), please visit the HSDB record page.

The incidence of and risk factors associated with hepatotoxicity in patients with chronic hepatitis have not been systematically studied. Therefore, we conducted a prospective study that included former drug users who were treated with isoniazid for latent tuberculosis infection. Of 415 patients, 20 (4.8%; 95% confidence interval [CI], 3-7.4) had hepatotoxicity diagnosed, and 6 (1.4%; 95% CI, 0.5-3.2) developed clinical hepatitis, none of whom had serious symptoms. The only 2 factors independently associated with isoniazid hepatotoxicity were excessive alcohol consumption (odds ratio [OR]; 4.2, 95% CI, 1.6-10.8; P=.002) and a high baseline alanine transaminase level (OR, 4.3; 95% CI, 1.6-11.4; P=.002). The presence of hepatitis C virus antibodies was associated with hepatotoxicity only on univariate analysis. Treatment with isoniazid in drug users appears to be safe and well tolerated, although frequent asymptomatic elevations in transaminase levels were observed.|Mild hepatic dysfunction, as evidenced by mild and transient increases in serum AST (SGOT), ALT (SGPT), and bilirubin concentrations, has occurred in approximately 10-20% of patients receiving isoniazid, usually during the first 4-6 months of therapy. In most cases, enzyme concentrations return to pretreatment values despite continuation of isoniazid, but progressive liver dysfunction, bilirubinuria, jaundice, and severe and sometimes fatal hepatitis have occurred rarely. The incidence of isoniazid-associated hepatitis is lowest in patients younger than 20 years of age and greatest in daily users of alcohol and patients 35 years of age or older. The American Academy of Pediatrics (AAP) states that the incidence of hepatitis during isoniazid therapy is so low in otherwise healthy infants, children, and adolescents that routine determination of serum aminotransferase concentrations are not recommended. The manufacturers state that progressive liver damage may occur in up to 2.3% of patients older than 50 years of age who receive isoniazid. However, data from one study suggest that hepatitis occurs in approximately 4.5% of patients older than 65 years of age who receive the drug. If symptoms of hepatitis or signs suggestive of hepatic damage occur during isoniazid therapy, the drug should be discontinued promptly.|Isoniazid has been reported to cause severe, and sometimes fatal, age related hepatitis. If signs and symptoms of hepatotoxicity occur, isoniazid should be discontinued promptly. The incidence of clinical hepatitis in young, healthy adults is 0.3%, but can increase to 2.6% for those who drink alcohol daily, have chronic liver disease, or are elderly.|Isoniazid may be taken with meals if gastrointestinal irritation occurs. Antacids may also be taken. However, isoniazid should be taken at least 1 hour before aluminum-containing antacids.|For more Drug Warnings (Complete) data for ISONIAZID (30 total), please visit the HSDB record page.

Isoniazid is a bactericidal agent active against organisms of the genus Mycobacterium, specifically M. tuberculosis, M. bovis and M. kansasii. It is a highly specific agent, ineffective against other microorganisms. Isoniazid is bactericidal when mycobacteria grow rapidly and bacteriostatic when they grow slowly.

Compounds that interfere with FATTY ACID SYNTHASE resulting in a reduction of FATTY ACIDS. This is a target mechanism in humans of some ANTINEOPLASTIC AGENTS and ANTI-OBESITY AGENTS and of some ANTI-INFECTIVE AGENTS which interfere with CELL WALL and CELL MEMBRANE formation. (See all compounds classified as Fatty Acid Synthesis Inhibitors.)|Drugs used in the treatment of tuberculosis. They are divided into two main classes: "first-line" agents, those with the greatest efficacy and acceptable degrees of toxicity used successfully in the great majority of cases; and "second-line" drugs used in drug-resistant cases or those in which some other patient-related condition has compromised the effectiveness of primary therapy. (See all compounds classified as Antitubercular Agents.)

Readily absorbed following oral administration; however, may undergo significant first pass metabolism. Absorption and bioavailability are reduced when isoniazid is administered with food.|From 50 to 70 percent of a dose of isoniazid is excreted in the urine within 24 hours.|ISONIAZID DIFFUSES READILY INTO ALL BODY FLUIDS AND CELLS. THE DRUG IS DETECTABLE IN SIGNIFICANT QUANTITIES IN PLEURAL AND ASCITIC FLUIDS; CONCENTRATIONS IN CEREBROSPINAL FLUID ARE SIMILAR TO THOSE IN THE PLASMA. ISONIAZID PENETRATES WELL INTO CASEOUS MATERIAL. THE CONCENTRATION OF THE AGENT IS INITIALLY HIGHER IN THE PLASMA AND MUSCLE THAN IN THE INFECTED TISSUE, BUT THE LATTER RETAINS THE DRUG FOR A LONG TIME IN QUANTITIES WELL ABOVE THOSE REQUIRED FOR BACTERIOSTASIS.|FROM 75 TO 95% OF A DOSE OF ISONIAZID IS EXCRETED IN THE URINE WITHIN 24 HR, MOSTLY AS METABOLITES.|Readily absorbed following oral administration; however, may undergo significant first pass metabolism. Absorption and bioavailability were reduced when isoniazid was administered with food.|Widely distributed to all fluids and tissues, including cerebrospinal fluid, pleural and ascitic fluids, skin, sputum, saliva, lungs, muscle, and caseous tissue. Crosses the placenta and is excreted in breast milk.|For more Absorption, Distribution and Excretion (Complete) data for ISONIAZID (10 total), please visit the HSDB record page.

Primarily hepatic. Isoniazid is acetylated by N -acetyl transferase to N -acetylisoniazid; it is then biotransformed to isonicotinic acid and monoacetylhydrazine. Monoacetylhydrazine is associated with hepatotoxicity via formation of a reactive intermediate metabolite when N-hydroxylated by the cytochrome P450 mixed oxidase system. The rate of acetylation is genetically determined. Slow acetylators are characterized by a relative lack of hepatic N -acetyltransferase.|Isoniazid is inactivated in the liver, mainly by acetylation and dehydrazination. Metabolites of the drug include acetylisoniazid, isonicotinic acid, monoacetylhydrazine, diacetylhydrazine, and isonicotinyl glycine.|/IN MAN/ ... MOST IMPORTANT METABOLITES OF INH IN URINE /WERE FOUND/ TO BE 1-ACETYL-2-ISONICOTINOYLHYDRAZINE (ACETYL INH), N-ACETYL-N'-ISONICOTINIC ACID, ISONICOTINYLGLYCINE, PYRUVIC ACID ISONICOTINYLHYDRAZONE AND ALPHA-OXOGLUTARIC ACID ISONICOTINYLHYDRAZONE ... .|IN VIVO METABOLISM OF INH IN RABBIT ... YIELDS ISONICOTINIC ACID AND AMMONIA, LATTER BEING DERIVED FROM RAPID BREAKDOWN OF HYDRAZINE GROUP ... .|Acetylation of acetylisoniazid results in the formation of monoacetylhydrazine which has been shown to be a potent hepatotoxin in animals. Microsomal metabolism of monoacetylhydrazine in animals results in production of a reactive acylating species capable of covalently binding with tissue macromolecules (i.e., liver protein) and subsequently causing hepatic necrosis.|For more Metabolism/Metabolites (Complete) data for ISONIAZID (6 total), please visit the HSDB record page.|Isoniazid has known human metabolites that include 3,4,5-Trihydroxy-6-[2-(pyridine-4-carbonyl)hydrazinyl]oxane-2-carboxylic acid and isoniazid N-acetyl.

Fast acetylators: 0.5 to 1.6 hours. Slow acetylators: 2 to 5 hours.|Adults (including elderly patients)- Fast acetylators: 0.5 to 1.6 hr. Slow acetylators: 2 to 5 hr. Acute and chronic liver disease: May be prolonged (6.7 hr vs 3.2 hr in controls),|Children (age 1.5 to 15 years)-2.3 to 4.9 hours.|Neonates-7.8 and 19.8 hours in newborns who received isoniazid transplacentally. The long half-life may be due to the limited acetylation capacity of neonates.

Isoniazid is a prodrug and must be activated by bacterial catalase. Specficially, activation is associated with reduction of the mycobacterial ferric KatG catalase-peroxidase by hydrazine and reaction with oxygen to form an oxyferrous enzyme complex. Once activated, isoniazid inhibits the synthesis of mycoloic acids, an essential component of the bacterial cell wall. At therapeutic levels isoniazid is bacteriocidal against actively growing intracellular and extracellular Mycobacterium tuberculosis organisms. Specifically isoniazid inhibits InhA, the enoyl reductase from Mycobacterium tuberculosis, by forming a covalent adduct with the NAD cofactor. It is the INH-NAD adduct that acts as a slow, tight-binding competitive inhibitor of InhA.|Although the mechanism of action of isoniazid is unknown, several hypotheses have been proposed. These include effects on lipids, nucleic acid biosynthesis, and glycolysis. ... /It has been suggested that/ a primary action of isoniazid /is/ to inhibit the biosynthesis of mycolic acids, important constituents of the mycobacterial cell wall. Because mycolic acids are unique to mycobacteria, this action would explain the high degree of selectivity of the antimicrobial activity of isoniazid. Exposure to isoniazid leads to a loss of acid fastness and a decrease in the quantity of methanol-extractable lipid of the microorganisms.|Isoniazid is bacteriostatic for "resting" bacilli but is bactericidal for rapidly dividing microorganisms. The minimal tuberculostatic concentration is 0.025 to 0.05 ug/ml.

SYMPTOMS: Symptoms of exposure to this compound include irritation of the skin, peripheral nerve sensory changes, somnolence, anorexia, sweating, respiratory depression, urine changes and toxic psychosis. Other symptoms include dizziness, paresthesias, fatal hepatitis, metabolic acidosis, convulsions and coma. It can cause headache, muscle twitching, deafness, polyneuritis, paralysis and pyridoxine deficiency. It can also cause nausea, vomiting, atropinic signs such as mydriasis, brightly colored lights and other visual hallucinations, tachycardia, peripheral neuropathy, other central nervous system reactions, stupor, exhaustion, urinary retention, liver damage, bone marrow damage and death. Exposure may cause fatigue, weakness, malaise, toxic encephalopathy, optic neuritis, optic atrophy, memory impairment, epigastric distress, elevated serum transaminases (SGOT, SGPT), bilirubinemia, bilirubinuria, jaundice, agranulocytosis hemolytic anemia, sideroblastic anemia, aplastic anemia, thrombocytopenia, eosinophilia, fever, skin eruptions (morbilliform, maculopapular, purpuric or exfoliative), lymphadenopathy, vasculitis, pellagra, hyperglycemia, gynecomastia, rheumatic syndrome, systemic lupus erythematosus-like syndrome, blurred vision, respiratory distress, central nervous system depression, severe and intractable seizures and acetonuria. Exposure may also cause gastrointestinal effects, liver necrosis, slight euphoria, irritability, nervousness, insomnia, excessive dreaming and giddiness. Other symptoms include peripheral neuritis, burning of the feet, reduction of central vision and papilledema. Hyperreflexia, vertigo, ataxia, tinnitus, hepatic reactions, hypersensitivity reactions and lethargy may occur. Constipation, difficulty in starting urination, dryness of the mouth, mood-elevating effect and mental disturbances, ranging from minor personality changes to major mental derangements. This compound may also cause skin rash, urticaria, arthritic symptoms such as back pain, bilateral proximal interphalangeal joint involvement, arthralgia of the knees, elbows and wrists and "shoulder-hand" syndrome; separation of ideas and reality, florid psychosis, loss of self-control, excessive sedation, incoordination and methemoglobinemia. ACUTE/CHRONIC HAZARDS: This compound is an irritant of the skin, eyes, mucous membranes and upper respiratory tract. It is harmful by ingestion, inhalation and skin absorption. When heated to decomposition it emits toxic fumes of carbon monoxide, carbon dioxide, nitrogen oxides, ammonia and partially oxidized hydrocarbons. (NTP, 1992)

EYES: First check the victim for contact lenses and remove if present. Flush victim's eyes with water or normal saline solution for 20 to 30 minutes while simultaneously calling a hospital or poison control center. Do not put any ointments, oils, or medication in the victim's eyes without specific instructions from a physician. IMMEDIATELY transport the victim after flushing eyes to a hospital even if no symptoms (such as redness or irritation) develop. SKIN: IMMEDIATELY flood affected skin with water while removing and isolating all contaminated clothing. Gently wash all affected skin areas thoroughly with soap and water. If symptoms such as redness or irritation develop, IMMEDIATELY call a physician and be prepared to transport the victim to a hospital for treatment. INHALATION: IMMEDIATELY leave the contaminated area; take deep breaths of fresh air. IMMEDIATELY call a physician and be prepared to transport the victim to a hospital even if no symptoms (such as wheezing, coughing, shortness of breath, or burning in the mouth, throat, or chest) develop. Provide proper respiratory protection to rescuers entering an unknown atmosphere. Whenever possible, Self-Contained Breathing Apparatus (SCBA) should be used; if not available, use a level of protection greater than or equal to that advised under Protective Clothing. INGESTION: DO NOT INDUCE VOMITING. If the victim is conscious and not convulsing, give 1 or 2 glasses of water to dilute the chemical and IMMEDIATELY call a hospital or poison control center. Be prepared to transport the victim to a hospital if advised by a physician. If the victim is convulsing or unconscious, do not give anything by mouth, ensure that the victim's airway is open and lay the victim on his/her side with the head lower than the body. DO NOT INDUCE VOMITING. IMMEDIATELY transport the victim to a hospital. OTHER: Since this chemical is a known or suspected carcinogen you should contact a physician for advice regarding the possible long term health effects and potential recommendation for medical monitoring. Recommendations from the physician will depend upon the specific compound, its chemical, physical and toxicity properties, the exposure level, length of exposure, and the route of exposure. (NTP, 1992)

Fresh air, rest. Refer immediately for medical attention.

Remove contaminated clothes. Rinse and then wash skin with water and soap.

First rinse with plenty of water for several minutes (remove contact lenses if easily possible), then refer for medical attention.

Emergency and supportive measures; 1. Maintain an open airway and assist ventilation if necessary. 2. Treat coma, seizures, and metabolic acidosis if they occur. Administer diazepam, 0.1-0.2 mg/kg IV, for treatment of seizures.|Specific drugs and antidotes. Pyridoxine (vitamin B6) is specific antidote and usually terminates diazepam-resistant seizures and results in improved mental status. Administer at least 5 g IV if the amount of INH ingested is not know; if the amount is known, give an equivalent amount in grams of pyridoxine to grams of ingested INH. Concomitant treatment with diazepam may improve outcome. If no pyridoxine is available, high-dose diazepam (0.3-0.4 mg/kg) may be effective for status epilepticus. Pyridoxine treatment may also hasten the resolution of metabolic acidosis.|Decontamination; 1. Prehospital. Administer activated charcoal if available. Do not induce vomiting because of the risk of rapid onset of coma and seizures. 2. Hospital. Administer activated charcoal. Consider gastric lavage for massive ingestions.|Enhanced elimination; Forced diuresis and hemodialysis have been reported to be successful, but are unnecessary for most cases, because the half-life of INH is relatively short (1-5 hours, depending on acetylator status), and toxicity can usually be easily managed with pyridoxine and diazepam. Symptoms generally resolve over a course of 8-24 hours.

/SIGNS AND SYMPTOMS/ Patients may be asymptomatic for 30 minutes to 2 hours after an acute overdose. Early symptoms include nausea and vomiting, dizziness, slurred speech, lethargy, disorientation, and hyperreflexia. Seizures usually occur within 1 to 3 hours after ingestion, and are often repetitive and refractory to usual anticonvulsants. Lactic acid accumulation produces an anion gap metabolic acidosis within a few hours, which is often severe and refractory to sodium bicarbonate. Hyperglycemia, glycosuria, and ketonuria have also been reported.|/SIGNS AND SYMPTOMS/ Overdosage of isoniazid has produced nausea, vomiting, dizziness. slurred speech, blurred vision, and visual hallucinations (including bright colors and strange designs). Symptoms of overdosage usually occur within 30 minutes to 3 hours following ingestion of the drug. After marked overdosage, respiratory distress and CNS depression, progressing rapidly from stupor to coma, severe intractable seizures, metabolic acidosis, acetonuria, and hyperglycemia have occurred. If untreated or treated inadequately, isoniazid overdosage may be fatal. Isoniazid-induced seizures are thought to be associated with decreased gamma-aminobutyric acid (GABA) concentrations in the CNS, possibly resulting from inhibition by isoniazid of brain pyridoxal-5-phosphate activity.|/CASE REPORTS/ Accidental or intentional isoniazid overdose is not uncommon. Two patients suffering from pulmonary tuberculosis ingested isoniazid (9 g and 12 g respectively) intentionally following acute personal stress. One patient presented with oliguria and coma whereas seizures were the dominant feature in the second case. Serum levels of isoniazid were high in both cases. Satisfactory clinical recovery followed after the administration of iv pyridoxine.|/CASE REPORTS/ Two cases of acute isoniazid poisoning in patients who ingested 7.5 g and 5.0 g of isoniazid respectively, with the intention of committing suicide are presented. Both were admitted unconscious, with ventilatory insufficiency and convulsions. Hepatic dysfunction and peripheral neuropathy were notable complications.

Acid Vanillylidenehydrazide, Isonicotinic

The substance can be absorbed into the body by ingestion.

Sore throat. Cough. Nausea. Vomiting. Hallucinations. Tremor.

Redness. Pain.

TOTAL US CONSUMPTION IN 1971 WAS ESTIMATED TO BE 1X10+6 GRAMS

... INH IS AVAILABLE IN A USP GRADE CONTAINING A MIN OF 98% OF ACTIVE INGREDIENT. SMALL AMT OF ISOMERIC COMPD AND HYDRAZINE MAY BE PRESENT.|Rifampicin is also supplied in combination with isoniazid...this combination is known as Rifamate (Merrell Dow), Rifinah (Merrell Dow), and Rimactazid (CIBA).|Powder: Oral: Solution: 50 mg/5 mL, Isoniazid Syrup (with sorbitol 70%), (Allscripts, Carolina Medical, Versa); Tablets: 100 mg, 300 mg. Parenteral: Injection: 100 mg/mL, Nydrazid (with chlorobutanol 0.25%), (Sandoz).

4-Pyridinecarboxylic acid, hydrazide: ACTIVE|Prepn: Meyer, Mally, Monatsh. 33, 400 (1912); Lock, Pharm. Ind. 14, 366 (1952); Urbanski et al., Rocz. Chem. 27, 161 (1953); Gasson, U.S. Pat. 2,830,994 (1958 to Distillers).

Many methods for the quantitative estimation of INH are known including iodometric, bromometric and argentometric methods, a vanadametric method, a potentiometric determination, a chromatographic determination, a gas chromatographic determination, color reactions and using chloramine-T.|FILTRATION, EVAPORATION; DETERMINATION OF ABSORBANCE FROM BENZYLIDINE ISONICOTINYLHYDRAZINE.|Method: AOAC 958.15, p-Aminosalicylic Acid and Isoniazid in Drugs; Procedure: spectrophotometric method; Analyte: isoniazid; Matrix: drugs; Detection Level: not provided.[

ISONIAZID IS EXTRACTED FROM ALKALINIZED SERUM SAMPLE & THEN REEXTRACTED INTO DILUTE ACID. AFTER REACTION WITH TRANS-CINNAMALDEHYDE IT CAN BE IDENTIFIED & QUANTITATED BY SPECTROPHOTOMETRY.|DETERMINATION OF ISONIAZID IN BLOOD PLASMA BY SPECTROPHOTOMETRY.

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