isoniazid

INDICATIONS AND USAGE Isoniazid tablets are 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 tablets are 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): 1. Persons with human immunodeficiency virus (HIV) infection (greater than or equal to 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. 2. Close contacts of persons with newly diagnosed infectious tuberculosis (greater than or equal to 5 mm). In addition, tuberculin-negative (less than 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 (greater than 5 mm), therapy should be continued. 3. Recent converters, as indicated by a tuberculin skin test (greater than or equal to 10 mm increase within a 2-year period for those less than 35 years old; greater than or equal to 15 mm increase for those greater than or equal to 35 years of age). All infants and children younger than 4 years of age with a greater than 10 mm skin test are included in this category. 4. Persons with abnormal chest radiographs that show fibrotic lesions likely to represent old healed tuberculosis (greater than or equal to 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. 5. Intravenous drug users known to be HIV-seronegative (greater than 10 mm). 6. Persons with the following medical conditions that have been reported to increase the risk of tuberculosis (greater than or equal to 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: 1. Foreign-born persons from high-prevalence countries who never received BCG vaccine. 2. Medically underserved low-income populations, including high-risk racial or ethnic minority populations, especially blacks, Hispanics and Native Americans. 3. Residents of facilities for long-term care (e.g., correctional institutions, nursing homes and mental institutions …

DOSAGE AND ADMINISTRATION (See also INDICATIONS AND USAGE ) 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. For Treatment of Tuberculosis 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): Adults 5 mg/kg up to 300 mg daily in a single dose; or 15 mg/kg up to 900 mg/day, two or three times/week Children 10 mg/kg to 15 mg/kg up to 300 mg daily in a single dose; or 20 mg/kg to 40 mg/kg up to 900 mg/day, two or three times/week Patients with Pulmonary Tuberculosis Without HIV Infection There are 3 regimen options for the initial treatment of tuberculosis in children and adults: Option 1: Daily isoniazid, rifampin, and pyrazinamide for 8 weeks followed by 16 weeks of isoniazid and rifampin daily or 2 to 3 times weekly. Ethambutol or streptomycin should be added to the initial regimen until sensitivity to isoniazid and rifampin is demonstrated. The addition of a fourth drug is optional if the relative prevalence of isoniazid-resistant Mycobacterium tuberculosis isolates in the community is less than or equal to four percent. Option 2: Daily isoniazid, rifampin, pyrazinamide, and streptomycin or ethambutol for 2 weeks followed by twice weekly administration of the same drugs for 6 weeks, subsequently twice weekly isoniazid and rifampin for 16 weeks. Option 3: Three times weekly with isoniazid, rifampin, pyrazinamide and ethambutol or streptomycin for 6 months. * All regimens given twice weekly or 3 times weekly should be administered by directly observed therapy (see also Directly Observed Therapy (DOT)). The above treatment guidelines apply only when the disease is caused by organisms that are susceptible to the standard antituberculous agents. Because of the impact of resistance to isoniazid and rifampin on the response to therapy, it is essential that physicians initiating therapy for tuberculosis be familiar with the prevalence of drug resistance in their communities. It is suggested that ethambutol not be used in children whose visual acuity cannot be monitored. Patients with Pulmonary Tuberculosis and HIV Infection The response of the immunologically impaired host to treatment may not be as satisfactory as that of a person with normal host responsiveness. For this reason, therapeutic decisions for the impaired host must be individualized. Since patients co-infected with HIV may have problems with malabsorption, screening of antimycobacterial drug levels, especially in patients with advanced HIV disease, may be necessary to prevent the emergence of MDRTB. Patients with Extra Pulmonary Tuberculosis The basic principles that underlie the treatment of pulmonary tuberculosis also apply to Extra pulmonary forms of the disease. Although there have not been the same kinds of carefully conducted controlled trials of treatment of Extra pulmonary tuberculosis as for pulmonary disease, increasing clinical experience indicates that a 6 to 9 month short-course regimen is effective. Because of the insufficient data, miliary tuberculosis, bone/joint tuberculosis and tuberculous meningitis in infants and children should receive 12 month therapy. Bacteriologic evaluation of Extra pulmonary tuberculosis may be limited by the relative inaccessibility of the sites of disease. Thus, response to treatment often must be judged on …

CONTRAINDICATIONS 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.

ADVERSE REACTIONS 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". Cerebellar syndrome, which may include abnormal motor coordination manifesting as gait, trunk, and limb ataxia, dysmetria and dysdiadochokinesia, intention tremor, dysarthria, or nystagmus, have been reported in post marketing case reports (see WARNINGS). 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, vasculitis, acute generalized exanthematous pustulosis (AGEP), Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis, and drug reaction with eosinophilia syndrome (DRESS) (See WARNINGS). Metabolic and Endocrine Reactions: Pyridoxine deficiency, pellagra, hyperglycemia, metabolic acidosis and gynecomastia. Miscellaneous Reactions: Rheumatic syndrome and systemic lupus erythematosus-like syndrome. To report SUSPECTED ADVERSE REACTIONS, contact Omnivium Pharmaceuticals LLC at 1-888-807-1048 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

Drug Interactions Food Isoniazid should not be administered with food. Studies have shown that the bioavailability of isoniazid is reduced significantly when administered with food. Tyramine- and histamine-containing foods should be avoided in patients receiving isoniazid. Because isoniazid has some monoamine oxidase inhibiting activity, an interaction with tyramine-containing foods (cheese, red wine) may occur. Diamine oxidase may also be inhibited, causing exaggerated response (e.g., headache, sweating, palpitations, flushing, hypotension) to foods containing histamine (e.g., skipjack, tuna, other tropical fish). Acetaminophen A report of severe acetaminophen toxicity was reported in a patient receiving isoniazid. It is believed that the toxicity may have resulted from a previously unrecognized interaction between isoniazid and acetaminophen and a molecular basis for this interaction has been proposed. However, current evidence suggests that isoniazid does induce P-450IIE1, a mixed-function oxidase enzyme that appears to generate the toxic metabolites, in the liver. Furthermore it has been proposed that isoniazid resulted in induction of P-450IIE1 in the patient’s liver which, in turn, resulted in a greater proportion of the ingested acetaminophen being converted to the toxic metabolites. Studies have demonstrated that pretreatment with isoniazid potentiates acetaminophen hepatotoxicity in rats 1,2 . Carbamazepine Isoniazid is known to slow the metabolism of carbamazepine and increase its serum levels. Carbamazepine levels should be determined prior to concurrent administration with isoniazid, signs and symptoms of carbamazepine toxicity should be monitored closely and appropriate dosage adjustment of the anticonvulsant should be made 3 . Ketoconazole Potential interaction of ketoconazole and isoniazid may exist. When ketoconazole is given in combination with isoniazid and rifampin the AUC of ketoconazole is decreased by as much as 88 percent after 5 months of concurrent isoniazid and rifampin therapy 4 . Phenytoin Isoniazid may increase serum levels of phenytoin. To avoid phenytoin intoxication, appropriate adjustment of the anticonvulsant should be made 5,6 . Theophylline A recent study has shown that concomitant administration of isoniazid and theophylline may cause elevated plasma levels of theophylline and in some instances a slight decrease in the elimination of isoniazid. Since the therapeutic range of theophylline is narrow, theophylline serum levels should be monitored closely and appropriate dosage adjustments of theophylline should be made 7 . Valproate A recent case study has shown a possible increase in the plasma level of valproate when co-administered with isoniazid. Plasma valproate concentration should be monitored when isoniazid and valproate are co-administered and appropriate dosage adjustments of valproate should be made 5 .

Mechanism of Action Isoniazid inhibits the synthesis of mycoloic acids, an essential component of the bacterial cell wall. At therapeutic levels isoniazid is bactericidal against actively growing intracellular and extracellular Mycobacterium tuberculosis organisms. Resistance Resistance to isoniazid occurs because of mutations in the katG, inhA, kasA and ahpC genes. Resistance in M. tuberculosis develops rapidly when isoniazid monotherapy is administered.

DESCRIPTION Isoniazid, USP is an antibacterial available as 300 mg tablets for oral administration. Each tablet also contains as inactive ingredients: calcium sulfate dihydrate, pregelatinized starch, croscarmellose sodium, povidone, purified water, and calcium stearate. Isoniazid, USP is chemically known as isonicotinyl hydrazine or isonicotinic acid hydrazide. It has a molecular formula of C 6 H 7 N 3 O and a molecular weight of 137.14. It has the following structural formula: Isoniazid, USP 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, USP is slowly affected by exposure to air and light. Isoniazid Structure

OVERDOSAGE Signs and Symptoms 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. Treatment Untreated or inadequately treated cases of gross isoniazid overdosage, 80 mg/kg to 150 mg/kg, can cause neurotoxicity 6 and terminate fatally, but good response has been reported in most patients brought under adequate treatment within the first few hours after drug ingestion. For the Asymptomatic Patient Absorption of drugs from the GI tract may be decreased by giving activated charcoal. Gastric emptying should also be employed in the asymptomatic patient. Safeguard the patient's airway when employing these procedures. Patients who acutely ingest greater than 80 mg/kg should be treated with intravenous pyridoxine on a gram per gram basis equal to the isoniazid dose. If an unknown amount of isoniazid is ingested, consider an initial dose of 5 grams of pyridoxine given over 30 to 60 minutes in adults or 80 mg/kg of pyridoxine in children. For the Symptomatic Patient Ensure adequate ventilation, support cardiac output and protect the airway while treating seizures and attempting to limit absorption. If the dose of isoniazid is known, the patient should be treated initially with a slow intravenous bolus of pyridoxine, over 3 to 5 minutes, on a gram per gram basis, equal to the isoniazid dose. If the quantity of isoniazid ingestion is unknown, then consider an initial intravenous bolus of pyridoxine of 5 grams in the adult or 80 mg/kg in the child. If seizures continue, the dosage of pyridoxine may be repeated. It would be rare that more than 10 grams of pyridoxine would need to be given. The maximum safe dose for pyridoxine in isoniazid intoxication is not known. If the patient does not respond to pyridoxine, diazepam may be administered. Phenytoin should be used cautiously, because isoniazid interferes with the metabolism of phenytoin. General Obtain blood samples for immediate determination of gases, electrolytes, BUN, glucose, etc.; type and cross-match blood in preparation for possible hemodialysis. Rapid Control of Metabolic Acidosis Patients with this degree of INH intoxication are likely to have hypoventilation. The administration of sodium bicarbonate under these circumstances can cause exacerbation of hypercarbia. Ventilation must be monitored carefully, by measuring blood carbon dioxide levels and supported mechanically, if there is respiratory insufficiency. Dialysis Both peritoneal and hemodialysis have been used in the management of isoniazid overdosage. These procedures are probably not required if control of seizures and acidosis is achieved with pyridoxine, diazepam and bicarbonate. Along with measures based on initial and repeated determination of blood gases and other laboratory tests as needed, utilize meticulous respiratory and other intensive care to protect against hypoxia, hypotension, aspiration, pneumonitis, etc.

Isoniazid Tablets USP are available as follows: HOW SUPPLIED Isoniazid Tablets USP are available as follows: 300 mg: White to off-white, oval-shaped, scored, flat-faced, beveled-edge tablet, debossed with stylized b on one side and 071 over 300 on the other side. Available in bottles of 30 tablets (NDC 63187-978-30), 60 tablets (NDC 63187-978-60) and 90 tablets (NDC 63187-978-90). Protect from moisture and light. Dispense in a tight, light-resistant container as defined in the USP, with a child-resistant closure (as required). Store at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature]. KEEP THIS AND ALL MEDICATIONS OUT OF THE REACH OF CHILDREN. References 1. Murphy, R., et al: Annuals of Internal Medicine ; 1990: November 15; volume 113: 799-800. 2. Burke, R.F., et al: Res Commun Chem Pathol Pharmacol; 1990: July; vol. 69: 115-118. 3. Fleenor, M.F., et al: Chest (United States) Letter ; 1991; June; 99 (6): 1554. 4. Baciewicz, A.M. and Baciewicz, Jr. F.A.: Arch Int Med 1993: September; volume 153: 1970-1971. 5. Jonviller, A.P., et al: European Journal of Clinical Pharmacol (Germany) , 1991: 40 (2) p198. 6. 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. 7. Hoglund P., et al: European Journal of Respir Dis (Denmark) 1987: February; 70 (2) p110-116. 8. Committee on infectious Diseases American Academy of Pediatrics: 1994, Red Book: Report of the Committee on Infectious Diseases; 23 edition; p487. 9. Schraufnagel, DE; Testing for Isoniazid; Chest (United States) 1990: August; 98 (2) p314-316. 10. Clinical and Laboratory Standards Institute (CLSI). Susceptibility Testing of Mycobacteria, Nocardiae, and Other Aerobic Actinomycetes; Approved Standard-Second Edition. CLSI Document M24-A2. Wayne, PA: Clinical and Laboratory Standards Institute, 2011. To report SUSPECTED ADVERSE REACTIONS, contact Teva Pharmaceuticals USA, Inc. at 1-866-832-8537 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . Teva Pharmaceuticals USA, Inc. North Wales, PA 19454 Repackaged by Proficient Rx LP Thousand Oaks CA. 91320 Rev. B 7/2016