Isoxin

Isoniazid:

• Indications and usage
• Contraindications
• Warnings
• Precautions
• Adverse reactions
• Overdosage
• Dosage and administration
• How supplied
• References
• Isoxin (Isoniazid) reviews

INDICATIONS AND USAGE

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

Isoxin (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 Isoxin (Isoniazid) or 4 months of Isoxin (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 Isoxin (Isoniazid) or 4 months of Isoxin (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 Isoxin (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 Isoxin (Isoniazid) is recommended for those with the additional risk factors listed above (1-6) and on an individual basis in situations where there is likelihood of serious consequences to contacts who may become infected.

CONTRAINDICATIONS

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

WARNINGS

See the boxed WARNING .

PRECAUTIONS

General

All drugs should be stopped and an evaluation made at the first sign of a hypersensitivity reaction. If Isoxin 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 Isoxin (Isoniazid) should be carefully monitored in the following:

• Daily users of alcohol. Daily ingestion of alcohol may be associated with a higher incidence of + Isoxin (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 Isoxin (Isoniazid).
• Existence of peripheral neuropathy or conditions predisposing to neuropathy.
• Pregnancy.
• Injection drug use.
• Women belonging to minority groups, particularly in the post-partum period.
• HIV seropositive patients.

Laboratory Tests

Because there is a higher frequency of Isoxin (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, Isoxin (Isoniazid) should be temporarily discontinued and consideration given to restarting therapy.

Drug Interactions

Food

Isoxin should not be administered with food. Studies have shown that the bioavailability of Isoxin (Isoniazid) is reduced significantly when administered with food. Tyramine- and histamine-containing foods should be avoided in patients receiving Isoxin (Isoniazid). Because Isoxin (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 Isoxin (Isoniazid). It is believed that the toxicity may have resulted from a previously unrecognized interaction between Isoxin (Isoniazid) and acetaminophen and a molecular basis for this interaction has been proposed. However, current evidence suggests that Isoxin (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 Isoxin (Isoniazid) resulted in induction of P-450IIE1 in the patients 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 Isoxin (Isoniazid) potentiates acetaminophen hepatotoxicity in rats^1,2.

Carbamazepine

Isoxin is known to slow the metabolism of carbamazepine and increase its serum levels. Carbamazepine levels should be determined prior to concurrent administration with Isoxin (Isoniazid), signs and symptoms of carbamazepine toxicity should be monitored closely, and appropriate dosage adjustment of the anticonvulsant should be made³.

Ketoconazole

Potential interaction of ketoconazole and Isoxin (Isoniazid) may exist. When ketoconazole is given in combination with Isoxin (Isoniazid) and rifampin the AUC of ketoconazole is decreased by as much as 88% after 5 months of concurrent Isoxin (Isoniazid) and rifampin therapy⁴.

Phenytoin

Isoxin 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 Isoxin (Isoniazid) and theophylline may cause elevated plasma levels of theophylline, and in some instances a slight decrease in the elimination of Isoxin (Isoniazid). Since the therapeutic range of theophylline is narrow, theophylline serum levels should be monitored closely, and appropriate dosage adjustments of theophylline should be made⁷.

Valproate

A recent case study has shown a possible increase in the plasma level of valproate when co-administered with Isoxin. Plasma valproate concentration should be monitored when Isoxin (Isoniazid) and valproate are co-administered, and appropriate dosage adjustments of valproate should be made⁸.

Carcinogenesis and Mutagenesis:

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

Pregnancy

Teratogenic effects: Pregnancy Category C

Isoxin has been shown to have an embryocidal effect in rats and rabbits when given orally during pregnancy. Isoxin (Isoniazid) was not teratogenic in reproduction studies in mice, rats and rabbits. There are no adequate and well-controlled studies in pregnant women. Isoxin (Isoniazid) should be used as a treatment for active tuberculosis during pregnancy because the benefit justifies the potential risk to the fetus. The benefit of preventive therapy also should be weighed against a possible risk to the fetus. Preventive therapy generally should be started after delivery to prevent putting the fetus at risk of exposure; the low levels of Isoxin (Isoniazid) in breast milk do not threaten the neonate. Since Isoxin (Isoniazid) is known to cross the placental barrier, neonates of Isoxin (Isoniazid) treated mothers should be carefully observed for any evidence of adverse affects.

Nonteratogenic effects

Since Isoxin (Isoniazid) is known to cross the placental barrier, neonates of isoniazid-treated mothers should be carefully observed for any evidence of adverse effects.

Nursing Mothers

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

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".

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% of patients taking Isoxin (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 Isoxin (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.

To report SUSPECTED ADVERSE REACTIONS, contact West-ward Pharmaceutical Corp. at 1-877-233-2001, and the FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

OVERDOSAGE

Signs and Symptoms

Isoxin 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 Isoxin (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.

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 > 80 mg/kg should be treated with intravenous pyridoxine on a gram per gram basis equal to the Isoxin dose. If an unknown amount of Isoxin (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 Isoxin (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 Isoxin (Isoniazid) dose. If the quantity of Isoxin (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 Isoxin (Isoniazid) intoxication is not known. If the patient does not respond to pyridoxine, diazepam may be administered. Phenytoin should be used cautiously, because Isoxin (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 Isoxin (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.

DOSAGE AND ADMINISTRATION

: 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 - Isoxin (Isoniazid) is used in conjunction with other effective anti-tuberculosis agents. Drug susceptibility testing should be performed on the organisms initially isolated from all patients with newly diagnosed tuberculosis. If the bacilli become 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: 10-15 mg/kg up to 300 mg daily in a single dose; or
  

  20-40 mg/kg up to 900 mg/day, two or three time/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 Isoxin (Isoniazid), rifampin, and pyrazinamide for 8 weeks followed by 16 weeks of Isoxin (Isoniazid) and rifampin daily or 2-3 times weekly. Ethambutol or streptomycin should be added to the initial regimen until sensitivity to Isoxin (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 Isoxin (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 Isoxin (Isoniazid) and rifampin for 16 weeks.

Option 3: Three times weekly with Isoxin (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.

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 Isoxin (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 months 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 the basis of clinical and radiographic findings.

The use of adjunctive therapies such as surgery and corticosteroids is more commonly required in Extra pulmonary tuberculosis than in pulmonary disease. Surgery may be necessary to obtain specimens for diagnosis and to treat such processes as constrictive pericarditis and spinal cord compression from Pott's Disease. Corticosteriods have been shown to be of benefit in preventing cardiac constriction from tuberculous pericarditis and in decreasing the neurologic sequelae of all stages of tuberculosis meningitis, especially when administered early in the course of the disease.

Pregnant Women with Tuberculosis

The options listed above must be adjusted for the pregnant patient. Streptomycin interferes with in utero development of the ear and may cause congenital deafness. Routine use of pyrazinamide is also not recommended in pregnancy because of inadequate teratogenicity data. The initial treatment regimen should consist of Isoxin and rifampin. Ethambutol should be included unless primary Isoxin (Isoniazid) resistance is unlikely (isoniazid resistance rate documented to be less than 4%).

Treatment of Patients with Multi-Drug Resistant Tuberculosis (MDRTB)

Multiple-drug resistant tuberculosis (i.e., resistance to at least Isoxin (Isoniazid) and rifampin) presents difficult treatment problems. Treatment must be individualized and based on susceptibility studies. In such cases, consultation with an expert in tuberculosis is recommended.

Directly Observed Therapy

A major cause of drug-resistant tuberculosis is patient non-compliance with treatment. The use of DOT can help assure patient compliance with drug therapy. DOT is the observation of the patient by a health care provider or other responsible person as the patient ingests anti-tuberculosis medications. DOT can be achieved with daily, twice weekly or thrice weekly regimens, and is recommended for all patients.

For Preventative Therapy of Tuberculosis

Before Isoxin (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.

Adults over 30 Kg: 300 mg per day in a single dose.

Infants and Children: 10 mg/kg (up to 300 mg daily) in a single dose. In situations where adherence with daily preventative therapy cannot be assured, 20-30 mg/kg (not to exceed 900 mg) twice weekly under the direct observation of a health care worker at the time of administration⁸.

Continuous administration of Isoxin (Isoniazid) for a sufficient period is an essential part of the regimen because relapse rates are higher if chemotherapy is stopped prematurely. In the treatment of tuberculosis, resistant organisms may multiply and the emergence of resistant organisms during the treatment may necessitate a change in the regimen.

For following patient compliance: the Potts-Cozart test⁹, a simple colorimetric⁶ method of checking for Isoxin (Isoniazid) in the urine, is a useful tool for assuring patient compliance, which is essential for effective tuberculosis control. Additionally, Isoxin (Isoniazid) test strips are also available to check patient compliance.

Concomitant administration of pyridoxine (B₆) is recommended in the malnourished and in those predisposed to neuropathy (e.g., alcoholics and diabetics).

HOW SUPPLIED

Isoxin (Isoniazid) Tablets, USP 100 mg: White, Round Tablets; Debossed "West-ward" on one side and "260" on the Scored side.

• Bottles of 100 tablets
• Bottles of 1000 tablets
• Unit Dose Boxes of 100 tablets

Isoxin (Isoniazid) Tablets, USP 300 mg: White, Round Tablets; Debossed "West-ward 261" on one side and Scored on the other side.

• Bottles of 30 tablets
• Bottles of 100 tablets
• Bottles of 1000 tablets
• Unit Dose Boxes of 100 tablets

Store at 20-25°C (68-77°F). Protect from light and moisture.

Dispense in a tight, light-resistant container as defined in the USP using a child-resistant closure.

References

• 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;J uly; 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.
• Jonville, 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: p 1359-1374.

• 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^rd edition; p487.

• Schraufnagel, DE; Testing for Isoxin (Isoniazid); Chest (United States) 1990, August: 98(2) p314-316.

Manufactured by:

West-ward Pharmaceutical Corp.

Eatontown, NJ 07724

Revised February 2011

Isoxin (Isoniazid) 300mg Tablet

Structural Formula