ISONIAZID- isoniazid tablet
Northwind Pharmaceuticals, LLC

Boxed Warning


Severe and sometimes fatal hepatitis associated with isoniazid therapy has been re-

ported and may occur or may develop even after many months of treatment. The risk of developing hepatitis is age related. Approximate case rates by age are: less than 1 per 1,000 for persons under 20 years of age, 3 per 1,000 for persons in the 20-34 year age group, 12 per 1,000 for persons in the 35-49 year age group, 23 per 1,000 for persons in the 50-64 year age group, and 8 per 1,000 for persons over 65 years of age. The risk of hepatitis is increased with

daily consumption of alcohol. Precise data to provide a fatality rate for isoniazid-related hepatitis is not available; however, in a U.S. Public Health Service Surveillance Study in- volving 13,838 persons taking isoniazid, there were 8 deaths among 174 cases of hepatitis.

Therefore, patients given isoniazid should be carefully monitored and interviewed at monthly intervals. For persons 35 and older, in addition to monthly symptom reviews, hepatic enzymes

(specifically, AST and ALT (formerly SGOT and SGPT, respectively)) should be measured prior to starting isoniazid therapy and periodically throughout treatment. Isoniazid-associated hepatitis usually occurs during the first three months of treatment. Usually, enzyme levels return to normal despite continuance of drug, but in some cases progressive liver dysfunction occurs. Other factors associated with an increased risk of hepatitis include daily use of alcohol, chronic liver disease and injection drug use. A recent report suggests an increased risk of fatal

hepatitis associated with isoniazid among women, particularly black and Hispanic women. The risk may also be increased during the post partum period. More careful monitoring should be considered in these groups, possibly including more frequent laboratory monitoring. If abnor- malities of liver function exceed three to five times the upper limit of normal, discontin- uation of isoniazid should be strongly considered. Liver function tests are not a substitute for a clinical evaluation at monthly intervals or for the prompt assessment of signs or symptoms of adverse reactions occurring between regularly scheduled evaluations. Patients should be instructed to immediately report signs or symptoms consistent with liver damage or other adverse effects. These include any of the following: unexplained anorexia, nausea, vomiting, dark urine, icterus, rash, persistent paresthesias of the hands and feet, persistent fatigue, weakness or fever of greater than 3 days duration and/or abdominal tenderness, especially right

upper quadrant discomfort. If these symptoms appear or if signs suggestive of hepatic damage are detected, isoniazid should be discontinued promptly, since continued use of the drug in these cases has been reported to cause a more severe form of liver damage.

Patients with tuberculosis who have hepatitis attributed to isoniazid should be given appro- priate treatment with alternative drugs. If isoniazid must be reinstituted, it should be reinsti-

tuted only after symptoms and laboratory abnormalities have cleared. The drug should be restarted in very small and gradually increasing doses and should be withdrawn immedi-

ately if there is any indication of recurrent liver involvement.

Preventive treatment should be deferred in persons with acute hepatic diseases.


Isoniazid is an antibacterial available as 100 mg or 300 mg tablets for oral administration. Isoniazid is chemically known as isonicotinyl hydrazine or isonicotinic acid hydrazide. 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.

Inactive Ingredients: Colloidal silicon dioxide, crospovidone, hydrogenated vegetable oil, microcrystalline cellulose, pregelatinized starch and talc.

Clinical Pharmacology


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 within 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 inacti- vators”, 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.

Mechanism of Action

Isoniazid inhibits the synthesis of mycoloic acids, an essential component of the bacteri-

al cell wall. At therapeutic levels isoniazid is bacteriocidal against actively growing intra-

cellular 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 0.1 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.

tuberculos is using either the BACTEC or the proportion method has not been determined.

Indications and Usage

Isoniazid is recommended for all forms of tuberculos 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 tuberculos 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):

1. 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.

2. Close contacts of persons with newly diagnosed infectious tuberculosis (≥ 5 mm). In addition,

tuberculin-negative (< 5mm) children and adolescents who have been close contacts of in-

fectious 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.

3. 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.

4. 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.

5. Intravenous drug users known to be HIV-seronegative (> 10 mm).

6. Persons with the following medical conditions that have been reported to increase the risk of

tuberculosis (≥ 10 mm): silicosis; diabetes mellitus; prolonged therapy with adrenocorti-

costeroids; 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 under nutrition (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 under served 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 listed above (1-6) and on an individual basis insituations where there is likelihood of serious consequences to contacts who may become infected.

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