ISONIAZID TABLETS, USP

R_x only

Isoniazid is an antibacterial available as 100 mg and 300 mg tablets for oral administration. Each tablet also contains as inactive ingredients: colloidal silicon dioxide, lactose monohydrate, pregelatinized starch, povidone, and stearic acid.

Isoniazid is chemically known as isonicotinyl hydrazine or isonicotinic acid hydrazide. It has an empirical formula of C₆H₇N₃O and a molecular weight of 137.14. It has the following structure:

Isoniazid is odorless, and occurs as a colorless or white crystalline powder or as white crystals. It is freely soluble in water, sparingly soluble in alcohol, and slightly soluble in chloroform and in ether. Isoniazid is slowly affected by exposure to air and light.

Within 1 to 2 hours after oral administration, isoniazid produces peak blood levels which decline to 50 percent or less within 6 hours. It diffuses readily into all body fluids (cerebrospinal, pleural, and ascitic fluids), tissues, organs, and excreta (saliva, sputum, and feces). The drug also passes through the placental barrier and into milk in concentrations comparable to those in the plasma. From 50 to 70 percent of a dose of isoniazid is excreted in the urine in 24 hours.

Isoniazid is metabolized primarily by acetylation and dehydrazination. The rate of acetylation is genetically determined. Approximately 50 percent of Blacks and Caucasians are "slow inactivators" and the rest are "rapid inactivators"; the majority of Eskimos and Orientals are "rapid inactivators."

The rate of acetylation does not significantly alter the effectiveness of isoniazid. However, slow acetylation may lead to higher blood levels of the drug and, thus, to an increase in toxic reactions.

Pyridoxine (vitamin B₆) deficiency is sometimes observed in adults with high doses of isoniazid and is considered probably due to its competition with pyridoxal phosphate for the enzyme apotryptophanase.

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.

Isoniazid resistant Mycobacterium tuberculosis bacilli develop rapidly when isoniazid monotherapy is administered.

Two standardized in vitro susceptibility methods are available for testing isoniazid against Mycobacterium tuberculosis organisms. The agar proportion method (CDC or NCCLS M24-P) utilizes middlebrook 7H10 medium impregnated with isoniazid at two final concentrations, 0.2 and 1.0 mcg/mL. MIC₉₉, values are calculated by comparing the quantity of organisms growing in the medium containing drug to the control cultures. Mycobacterial growth in the presence of drug ≥ 1% of the control indicates resistance.

The radiometric broth method employs the BACTEC 460 machine to compare the growth index from untreated control cultures to cultures grown in the presence of 0.2 and 1.0 mcg/mL of isoniazid. Strict adherence to the manufacturer's instructions for sample processing and data interpretation is required for this assay.

Mycobacterium tuberculosis isolates with an MIC₉₉≤ 0.2 mcg/mL are considered to be susceptible to isoniazid. Susceptibility test results obtained by the two different methods discussed above cannot be compared unless equivalent drug concentrations are evaluated.

The clinical relevance of in vitro susceptibility for mycobacterium species other than M. tuberculosis using either the BACTEC or the proportion method has not been determined.

Isoniazid is recommended for all forms of tuberculosis in which organisms are susceptible. However, active tuberculosis must be treated with multiple concomitant anti-tuberculosis medications to prevent the emergence of drug resistance. Single-drug treatment of active tuberculosis with isoniazid, or any other medication, is inadequate therapy.

Isoniazid is recommended as preventive therapy for the following groups, regardless of age. (Note: the criterion for a positive reaction to a skin test (in millimeters of induration) for each group is given in parenthesis):

• Persons with human immunodeficiency virus (HIV) infection (≥5 mm) and persons with risk factors for HIV infection whose HIV infection status is unknown but who are suspected of having HIV infection. Preventive therapy may be considered for HIV infected persons who are tuberculin-negative but belong to groups in which the prevalence of tuberculosis infection is high. Candidates for preventive therapy who have HIV infection should have a minimum of 12 months of therapy.
• Close contacts of persons with newly diagnosed infectious tuberculosis (≥5 mm). In addition, tuberculin-negative (<5 mm) children and adolescents who have been close contacts of infectious persons within the past 3 months are candidates for preventive therapy until a repeat tuberculin skin test is done 12 weeks after contact with the infectious source. If the repeat skin test is positive (> 5 mm), therapy should be continued.
• Recent converters, as indicated by a tuberculin skin test (≥10 mm increase within a 2-year period for those <35 years old; ≥15 mm increase for those ≥35 years of age). All infants and children younger than 4 years of age with a > 10 mm skin test are included in this category.
• Persons with abnormal chest radiographs that show fibrotic lesions likely to represent old healed tuberculosis (≥5 mm). Candidates for preventive therapy who have fibrotic pulmonary lesions consistent with healed tuberculosis or who have pulmonary silicosis should have 12 months of isoniazid or 4 months of isoniazid and rifampin, concomitantly.
• Intravenous drug users known to be HIV-seronegative (>10 mm).
• Persons with the following medical conditions that have been reported to increase the risk of tuberculosis (≥10 mm): silicosis; diabetes mellitus; prolonged therapy with adrenocorticosteroids; immunosuppressive therapy; some hematologic and reticuloendothelial diseases, such as leukemia or Hodgkin's disease; end-stage renal disease; clinical situations associated with substantial rapid weight loss or chronic undernutrition (including: intestinal bypass surgery for obesity, the postgastrectomy state (with or without weight loss), chronic peptic ulcer disease, chronic malabsorption syndromes, and carcinomas of the oropharynx and upper gastrointestinal tract that prevent adequate nutritional intake). Candidates for preventive therapy who have fibrotic pulmonary lesions consistent with healed tuberculosis or who have pulmonary silicosis should have 12 months of isoniazid or 4 months of isoniazid and rifampin, concomitantly.

Additionally, in the absence of any of the above risk factors, persons under the age of 35 with a tuberculin skin test reaction of 10 mm or more are also appropriate candidates for preventive therapy if they are a member of any of the following high-incidence groups:

• Foreign-born persons from high-prevalence countries who never received BCG vaccine.
• Medically underserved low-income populations, including high-risk racial or ethnic minority populations, especially blacks, Hispanics, and Native Americans.
• Residents of facilities for long-term care (e.g., correctional institutions, nursing homes, and mental institutions).

Children who are less than 4 years old are candidates for isoniazid preventive therapy if they have > 10 mm induration from a PPD Mantoux tuberculin skin test.

Finally, persons under the age of 35 who a) have none of the above risk factors (1-6); b) belong to none of the high-incidence groups; and c) have a tuberculin skin test reaction of 15 mm or more, are appropriate candidates for preventive therapy.

The risk of hepatitis must be weighed against the risk of tuberculosis in positive tuberculin reactors over the age of 35. However, the use of isoniazid is recommended for those with the additional risk factors uled above (1-6) and on an individual basis in situations where there is likelihood of serious consequences to contacts who may become infected.

Isoniazid is contraindicated in patients who develop severe hypersensitivity reactions, including drug-induced hepatitis; previous isoniazid-associated hepatic injury; severe adverse reactions to isoniazid such as drug fever, chills, arthritis; and acute liver disease of any etiology.

See the boxed warning.

All drugs should be stopped and an evaluation made at the first sign of a hypersensitivity reaction. If isoniazid therapy must be reinstituted, the drug should be given only after symptoms have cleared. The drug should be restarted in very small and gradually increasing doses and should be withdrawn immediately if there is any indication of recurrent hypersensitivity reaction.

Use of isoniazid should be carefully monitored in the following:

• Daily users of alcohol. Daily ingestion of alcohol may be associated with a higher incidence of + isoniazid hepatitis.
• Patients with active chronic liver disease or severe renal dysfunction.
• Age >35.
• Concurrent use of any chronically administered medication.
• History of previous discontinuation of isoniazid.
• Existence of peripheral neuropathy or conditions predisposing to neuropathy.
• Pregnancy.
• Injection drug use.
• Women belonging to minority groups, particularly in the postpartum period.
• HIV seropositive patients.

Because there is a higher frequency of isoniazid associated hepatitis among certain patient groups, including Age >35, daily users of alcohol, chronic liver disease, injection drug use and women belonging to minority groups, particularly in the post-partum period, transaminase measurements should be obtained prior to starting and monthly during preventative therapy, or more frequently as needed. If any of the values exceed three to five times the upper limit of normal, isoniazid should be temporarily discontinued and consideration given to restarting therapy.

Isoniazid has been shown to induce pulmonary tumors in a number of strains of mice. Isoniazid has not been shown to be carcinogenic in humans. (Note: a diagnosis of mesothelioma in a child with prenatal exposure to isoniazid and no other apparent risk factors has been reported). Isoniazid has been found to be weakly mutagenic in strains TA 100 and TA 1535 of Salmonella typhimurium (Ames assay) without metabolic activation.

The small concentrations of isoniazid in breast milk do not produce toxicity in the nursing newborn; therefore, breast feeding should not be discouraged. However, because levels of isoniazid are so low in breast milk, they can not be relied upon for prophylaxis or therapy of nursing infants.

The most frequent reactions are those affecting the nervous system and the liver.

Nervous System Reactions: Peripheral neuropathy is the most common toxic effect. It is dose-related, occurs most often in the malnourished and in those predisposed to neuritis (e.g., alcoholics and diabetics), and is usually preceded by paresthesias of the feet and hands. The incidence is higher in "slow inactivators".

Other neurotoxic effects, which are uncommon with conventional doses, are convulsions, toxic encephalopathy, optic neuritis and atrophy, memory impairment, and toxic psychosis.

Hepatic Reactions: See boxed warning. Elevated serum transaminase (SGOT; SGPT), bilirubinemia, bilirubinuria, jaundice, and occasionally severe and sometimes fatal hepatitis. The common prodromal symptoms of hepatitis are anorexia, nausea, vomiting, fatigue, malaise, and weakness. Mild hepatic dysfunction, evidenced by mild and transient elevation of serum transaminase levels occurs in 10 to 20 percent of patients taking isoniazid. This abnormality usually appears in the first 1 to 3 months of treatment but can occur at any time during therapy. In most instances, enzyme levels return to normal, and generally, there is no necessity to discontinue medication during the period of mild serum transaminase elevation. In occasional instances, progressive liver damage occurs, with accompanying symptoms. If the SGOT value exceeds three to five times the upper limit of normal, discontinuation of the isoniazid should be strongly considered. The frequency of progressive liver damage increases with age. It is rare in persons under 20, but occurs in up to 2.3 percent of those over 50 years of age.

Gastrointestinal Reactions: Nausea, vomiting, and epigastric distress.

Hematologic Reactions: Agranulocytosis; hemolytic, sideroblastic, or aplastic anemia, thrombocytopenia; and eosinophilia.

Hypersensitivity Reactions: Fever, skin eruptions (morbilliform, maculopapular, purpuric, or exfoliative), lymphadenopathy, and vasculitis.

Metabolic And Endocrine Reactions: Pyridoxine deficiency, pellagra, hyperglycemia, metabolic acidosis, and gynecomastia.

Miscellaneous Reactions: Rheumatic syndrome and systemic lupus erythematosus-like syndrome.

Isoniazid overdosage produces signs and symptoms within 30 minutes to 3 hours after ingestion. Nausea, vomiting, dizziness, slurring of speech, blurring of vision, and visual hallucinations (including bright colors and strange designs) are among the early manifestations. With marked overdosage, respiratory distress and CNS depression, progressing rapidly from stupor to profound coma, are to be expected, along with severe, intractable seizures. Severe metabolic acidosis, acetonuria, and hyperglycemia are typical laboratory findings.

Untreated or inadequately treated cases of gross isoniazid overdosage, 80 mg/kg - 150 mg/kg, can cause neurotoxicity⁶ and terminate fatally, but good response has been reported in most patients brought under adequate treatment within the first few hours after drug ingestion.

(See also INDICATIONS ):

NOTE--For preventive therapy of tuberculous infection and treatment of tuberculosis, it is recommended that physicians be familiar with the following publications: (1) the recommendations of the Advisory Council for the Elimination of Tuberculosis, published in the MMWR: vol 42; RR-4, 1993 and (2)Treatment of Tuberculosis and Tuberculosis Infection in Adults and Children, American Journal of Respiratory and Critical Care Medicine: vol 149; 1359-1374, 1994.

Isoniazid is used in conjunction with other effective anti-tuberculous agents. Drug susceptibility testing should be performed on the organisms initially isolated from all patients with newly diagnosed tuberculosis. If the bacilli becomes resistant, therapy must be changed to agents to which the bacilli are susceptible.

Usual Oral Dosage (depending on the regimen used):

Before isoniazid preventive therapy is initiated, bacteriologically positive or radiographically progressive tuberculosis must be excluded. Appropriate evaluations should be performed if Extra pulmonary tuberculosis is suspected.

Isoniazid Tablets, USP 100 mg: white, round, biconvex, scored on one side, and debossed with over and "4354" below the score. Available in opaque white bottles of 30, 100 and 1000.

Isoniazid Tablets, USP 300 mg: white, round, biconvex, scored on one side, and debossed with over and "4350" below the score. Available in opaque white bottles of 30, 100 and 1000.

Store at 20°-25°C (68°-77°F)[See USP Controlled Room Temperature]. Protect from moisture and light.

• Murphy, R., et al: Annuals of Internal Medicine; 1990: November 15; volume 113: 799-800.
• Burke, R.F., et al: Res Commun Chem Pathol Pharmacol; 1990: July; vol. 69: 115-118.
• Fleenor, M. F., et al: Chest (United States) Letter; 1991; June; 99 (6): 1554.
• Baciewicz, A.M. and Baciewicz, Jr. F.A.: Arch Int Med 1993: September; volume 153: 1970-1971.
• Jonviller, A.P., et al:European Journal of Clinical Pharmacol (Germany), 1991: 40 (2) p198.
• American Thoracic Society/Centers for Disease Control: Treatment of Tuberculosis and Tuberculosis Infection in Adults and Children. Amer. J. Respir Crit Care Med.1994;149: p1359-1374.
• Hoglund P., et al: European Journal of Respir Dis (Denmark) 1987: February; 70 (2) p110-116.
• Committee on infectious Diseases American Academy of Pediatrics:1994, Red Book: Report of the Committee on Infectious Diseases; 23 edition; p487.
• Schraufnagel, DE; Testing for Isoniazid; Chest (United States) 1990: August; 98 (2) p314-316.