isoniazid 300 mg Tablet, 100-count — NDC 81665-108-10 (Billing 81665-0108-10)

WARNINGS See the boxed warning. Severe Cutaneous Adverse Reactions Severe cutaneous adverse reactions (SCARs) including toxic epidermal necrolysis (TEN), Stevens-Johnson syndrome (SJS), drug reaction with eosinophilia and systemic symptoms (DRESS), and acute generalized exanthematous pustulosis (AGEP) have been reported with the use of isoniazid (see ADVERSE REACTIONS). Symptoms can be serious and potentially life threatening.

If symptoms or signs of SCARs develop, discontinue isoniazid tablets immediately and institute appropriate therapy. Cerebellar Syndrome Cerebellar syndrome which may include abnormal motor coordination presenting as gait, trunk, and limb ataxia, dysmetria and dysdiadochokinesia, intention tremor, dysarthria, or nystagmus, has been reported in postmarketing case reports with the use of isoniazid (see ADVERSE REACTIONS). Most cases of cerebellar syndrome involved patients with chronic kidney disease (CKD), however, cerebellar syndrome was also reported in patients without CKD.

Discontinue isoniazid tablets if symptoms or signs of cerebellar syndrome occur.

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% 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 .

PRECAUTIONS General 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: 1. Daily users of alcohol. Daily ingestion of alcohol may be associated with a higher incidence of + isoniazid hepatitis.

2. Patients with active chronic liver disease or severe renal dysfunction. 3.

Age > 35. 4. Concurrent use of any chronically administered medication.

5. History of previous discontinuation of isoniazid. 6.

Existence of peripheral neuropathy or conditions predisposing to neuropathy. 7. Pregnancy.

8. Injection drug use. 9.

Women belonging to minority groups, particularly in the post-partum period. 10. HIV seropositive patients.

Information for Patients Patients should be counseled to notify their healthcare provider immediately if they experience any of the following: rash with fever or blisters, with or without peeling skin, slurred speech, unsteady gait, loss of coordination, intentional tremor, or involuntary eye movements. Laboratory Tests 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. 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% after 5 months of concurrent isoniazid and rifampin therapy 4 .

Phenytoin Isoniazid may increase serum levels of phenytoin… [Excerpted — this section continues on DailyMed.]