VA Class:AM500

AHFS Class:

• Antituberculosis Agents 8:16.04

Generic Name(s):

• Isoniazid

Isoniazid is a synthetic, isonicotinic acid-derivative antituberculosis agent.

Tuberculosis

Active Tuberculosis

Isoniazid is used in conjunction with other antituberculosis agents in the treatment of clinical tuberculosis.176

The American Thoracic Society (ATS), US Centers for Disease Control and Prevention (CDC), and Infectious Diseases Society of America (IDSA) currently recommend several possible multiple-drug regimens for the treatment of culture-positive pulmonary tuberculosis.176 These regimens have a minimum duration of 6 months (26 weeks), and consist of an initial intensive phase (2 months) and a continuation phase (usually either 4 or 7 months).176 Isoniazid is considered a first-line antituberculosis agent for the treatment of all forms of tuberculosis caused by Mycobacterium tuberculosis known or presumed to be susceptible to the drug.176 For information on general principles used in the treatment of tuberculosis, see the Antituberculosis Agents General Statement 8:16.04.

Isoniazid is commercially available in the US alone or in fixed combination with rifampin (Rifamate^®)143 or in fixed combination with rifampin and pyrazinamide (Rifater^®).141 The fixed-combination preparation containing rifampin, isoniazid, and pyrazinamide (Rifater^®) is designated an orphan drug by the US Food and Drug Administration (FDA) for use in the treatment of tuberculosis.104 Although oral isoniazid is preferred for the treatment of tuberculosis, the drug may be given IM for initial or retreatment of the disease when the drug cannot be given orally.

Latent Tuberculosis Infection

Isoniazid usually is used alone for the treatment of latent tuberculosis infection to prevent the development of clinical tuberculosis.145,166 Previously, “preventive therapy” or “chemoprophylaxis” was used to describe a simple drug regimen (e.g., isoniazid monotherapy) used to prevent the development of active tuberculosis disease in individuals known or likely to be infected with M. tuberculosis .166 However, since use of such a regimen rarely results in true primary prevention (i.e., prevention of infection in individuals exposed to infectious tuberculosis), the ATS and CDC currently state that “treatment of latent tuberculosis infection” rather than “preventive therapy” more accurately describes the intended intervention and potentially will result in greater understanding and more widespread implementation of this tuberculosis control strategy.166

Individuals at risk for developing tuberculosis include those who have been recently infected with M. tuberculosis and those who have clinical conditions that increase the risk of latent tuberculosis infection progressing to active disease.166 The likelihood that a positive tuberculin test represents a true infection with M. tuberculosis is influenced by the prevalence of infection in the population being tested.121,166 The ATS and CDC state that since the general population of the US has an estimated M. tuberculosis infection rate of 5-10% and the annual incidence of new tuberculosis infection without known exposure is estimated to be 0.01-0.1%, the tuberculin skin test has a low positive predictive value in individuals without a known or likely exposure to M. tuberculosis .174 To prioritize the use of resources for identifying those at risk for developing tuberculosis and minimize the incidence of false-positive tuberculin test results, the ATS and CDC currently recommend that tuberculin testing be targeted toward groups at high risk and discouraged in those at low risk.166 The ATS and CDC currently define positive (i.e., significant) tuberculin reactions (i.e., reactions highly likely to indicate true infection with M. tuberculosis ) in terms of 3 cut-off points (i.e., levels of induration) based on the sensitivity, specificity, and prevalence of tuberculosis in different groups: 5 mm or more of induration for individuals at highest risk for developing clinical tuberculosis, 10 mm or more of induration for those with an increased probability of infection or with clinical conditions predisposing to enhanced progression of infection to active tuberculosis, and 15 mm or more of induration for individuals at low risk in whom tuberculin testing generally is not indicated.166 (See Tuberculosis under Interpretation: Mantoux Test, in Tuberculin 36:84.)

The following individuals or groups with clinical risk factors should be targeted for tuberculin testing and, if appropriate, treated for latent tuberculosis infection following exclusion of active tuberculosis disease:166

• Individuals with known or suspected human immunodeficiency virus (HIV) infection.124,133,136,145,163,166 In several randomized, controlled trials, isoniazid therapy for 6-12 months substantially reduced the incidence of clinical tuberculosis in patients with HIV infection who had induration reactions to tuberculin skin tests of 5 mm or greater.166,167,168,169,170,171,172,173 HIV infection contributes most to an increased risk of progression of latent tuberculosis infection to the active disease, and patients of any age with HIV infection who have an induration reaction of 5 mm or greater to the Mantoux tuberculin skin test should receive therapy for latent tuberculosis infection after excluding the presence of clinically active tuberculosis,124,133,147,163,166 unless such therapy is medically contraindicated.163 In addition, falsely insignificant tuberculin reactions may occur in patients with human immunodeficiency virus (HIV) infection because of immunosuppression associated with this infection,154,155,156,157,158,159,163 and the ATS, CDC, and some clinicians recommend that patients with HIV infection and known exposure to active tuberculosis be given preventive therapy even in the presence of a negative (< 5 mm induration) tuberculin skin test reaction.133,136,145,147,148,150,163,166 Patients with HIV infection, whether symptomatic or asymptomatic, may be anergic,154,155,156,157,159 and it had previously been recommended that all individuals who were HIV seropositive be evaluated for cell-mediated immunity (delayed-type hypersensitivity) using at least two other antigens (i.e., mumps skin test antigen, candida, tetanus toxoid) at the time tuberculin skin testing was performed.154 However, the ATS and CDC no longer recommend anergy testing for use in identifying tuberculosis infection, including in HIV-infected individuals because the usefulness of such testing in identifying tuberculin-negative, HIV-infected individuals who might benefit from treatment of latent tuberculosis infection has not been demonstrated.148,163,166,174 Instead, the ATS, CDC, and some experts state that there may be selected situations in which evaluation of anergy may assist in guiding individual decisions about therapy for latent tuberculosis infection (e.g., in individuals with insignificant reactions to tuberculin from populations at high risk for Mycobacterium tuberculosis infection).147,148 (See Tuberculosis: Anergic Individuals at Risk of Tuberculosis, in Uses in Tuberculin 36:84.) Although therapy for latent tuberculosis infection in tuberculin-negative HIV-infected patients has not proven effective, therapy with isoniazid may be beneficial for tuberculin-negative children who are born to HIV-infected women and who are close contacts of an individual who has infectious tuberculosis, as well as in HIV-infected adults who reside or work in institutions (e.g., prisons, jails, homeless shelters) and are continually and unavoidably exposed to patients who have infectious tuberculosis.148,163,166 Some experts recommend continuing isoniazid therapy for latent tuberculosis infection indefinitely in HIV-infected individuals who have an ongoing high risk for exposure to M. tuberculosis (e.g., inmates of prisons in which the prevalence of tuberculosis is high).148 Since HIV-infected individuals are at risk for peripheral neuropathy, those receiving isoniazid should also be given pyridoxine.147 (See Cautions: Nervous System Effects.) Because the risk of tuberculosis appears to be increased in patients with HIV infection, and the association between tuberculosis and AIDS is most evident in IV drug abusers, attempts should be made to identify IV drug abusers who have a significant reaction to the Mantoux tuberculin skin test and to initiate isoniazid treatment of latent tuberculosis infection in such individuals regardless of their age.114

The CDC states that HIV-infected patients with a history of prior untreated or inadequately treated tuberculosis that healed who have no history of adequate treatment for tuberculosis should receive therapy for latent tuberculosis infection regardless of their age or the results of tuberculin skin tests.163

• Close contacts of individuals with recently diagnosed clinical tuberculosis. Contacts of individuals with infectious pulmonary tuberculosis who have a standard Mantoux tuberculin skin test induration reaction of 5 mm or more (significant reaction) and do not have a history of significant reactions in the past should be considered as recently infected and should, regardless of age, receive therapy for latent tuberculosis infection.145,166 The AAP states that regardless of the results of tuberculin skin testing, therapy for latent tuberculosis infection should be given to individuals exposed within the previous 3 months to a potentially contagious case of tuberculosis, especially contacts of immunologically impaired (e.g., HIV-infected) individuals and all household contacts younger than 4 years of age who are exposed to any adult with active tuberculosis, once clinical disease has been ruled out.145 The ATS and CDC state that children younger than 5 years of age should be treated for latent tuberculosis infection regardless of their tuberculin skin test results because of their susceptibility to severe disease.166 Recent contacts and household contacts of any age, particularly if they are from a population with a high prevalence of tuberculosis, also should receive treatment for latent tuberculosis infection even in the absence of a significant tuberculin test result.145 These contacts should be tested again 8-12 weeks after the last exposure to the infectious source and if they still have an insignificant reaction and exposure has ended, therapy may be discontinued.145,166

The ATS, CDC, and AAP state that management of a neonate whose mother or other household contact has tuberculosis should be individualized.145,166 In an infant whose mother or other household contact has a significant reaction to the Mantoux tuberculin skin test and no evidence of current tuberculosis, the ATS and CDC state that a Mantoux tuberculin test (5 TU/0.1 mL) should be administered at 4-6 weeks of age and again at 3-4 months of age. The AAP states that management of a neonate whose mother (or household contact) has latent or active tuberculosis is based on categorization of the infection.145 If the mother (or household contact) has a normal chest radiograph and is asymptomatic, the mother or contact usually is a candidate for treatment of latent tuberculosis infection; the infant needs no special evaluation or therapy and need not be separated from the mother.145 However, if the mother (or household contact) has an abnormal chest radiograph, the AAP advises that the mother or contact and infant be separated until the mother or contact has been evaluated for clinical tuberculosis and, if active tuberculosis is found, is receiving appropriate antituberculosis therapy.145 (See Tuberculosis During Pregnancy under General Principles in Antituberculosis Therapy: Initial Treatment of Tuberculosis, in Uses in the Antituberculosis Agents General Statement 8:16.04.) Evaluation of other members of the household or extended family to whom the infant may later be exposed also is indicated.145 When the family cannot be tested promptly, the ATS and CDC state that administration of isoniazid 10 mg/kg daily to the infant should be considered until skin testing of the family has excluded contact with a case of active tuberculosis; isoniazid treatment in the mother also should be considered.166,145

In a neonate whose mother has current tuberculosis, the AAP recommends that the infant be evaluated for congenital tuberculosis and tested for HIV infection.145,166 A chest roentgenogram and Mantoux tuberculin test should be performed at 4-6 weeks of a if the results of these tests are negative, the infant should be tested again at 3-4 months and at 6 months of age.138 The ATS, CDC, and AAP state that the infant should receive isoniazid even if the tuberculin skin test and chest roentgenogram do not suggest tuberculosis since cell-mediated immunity of a degree sufficient to mount a significant reaction to tuberculin skin testing may not develop until as late as 6 months of age in an infant infected at birth.138,145 Isoniazid can be discontinued if the results of a Mantoux skin test are negative at 6 months of age138,166 (or at 3-4 months of age according to the AAP)145 and active tuberculosis is not present in family members or if active disease is being treated and family members are no longer contagious.138,145 The infant should be examined at monthly intervals during treatment.138,145 If nonadherence to the antituberculosis regimen by the mother is documented, the mother has sputum cultures or smears positive for acid-fast bacilli, and supervision is impossible, the ATS, CDC, and AAP state that administration of BCG vaccine to the infant may be considered.138,145 (See Uses: Tuberculosis, in BCG Vaccine 80:12.) However, the ATS, CDC, and AAP state that response to the vaccine in infants may be delayed and inadequate to prevent tuberculosis disease.138,145

In a neonate whose mother has hematogenous spread of tuberculosis (e.g., meningitis, miliary disease, bone involvement), congenital tuberculosis in the infant is possible.145,176 If the infant is suspected of having congenital tuberculosis, the AAP recommends that a Mantoux tuberculin skin test, chest radiograph, lumber puncture, and appropriate cultures should be performed promptly, and regardless of the skin test results, treatment of the infant should be initiated promptly.176 (See Neonates under Treatment of Active Tuberculosis: Active Tuberculosis in Pediatric Patients in the Antituberculosis Agents General Statement 8:16.04.) If clinical and roentgenographic findings do not support the diagnosis of congenital tuberculosis, the infant should be separated from the mother until she is judged to be noninfectious.145,166 If the diagnosis of congenital tuberculosis is excluded, the AAP states that isoniazid should be given until the infant is 3-4 months old; the skin test should be repeated following isoniazid therapy.138,145 If the skin test is positive, isoniazid should be continued for a total of at least 9 months in HIV-negative children 145,163 or for 9-12 months in HIV-infected children.145

• Individuals receiving organ (e.g., renal, cardiac) transplants or prolonged corticosteroid or other immunosuppressive therapy.145,166 Although the exact risk is unknown, individuals receiving prednisone in daily dosages of 15 mg or more (or its equivalent) for at least 1 month are at increased risk for reactivation of tuberculosis; risk increases with increasing dosage and duration of corticosteroid therapy.166 Such individuals should receive treatment for latent tuberculosis infection if they have tuberculin skin test reactions of 5 mm or greater.166 The ATS and CDC further state that immunosuppressed individuals, including those with HIV infection, who are contacts of those with active tuberculosis should receive treatment for latent tuberculosis infection even in the absence of a significant tuberculin skin test upon repeated testing.166
• Individuals with pulmonary fibrotic changes on chest radiographs that are consistent with prior, healed tuberculosis.166 Such individuals reportedly have a risk for progression to active tuberculosis of 2-13.6 cases per 1000 patient-years of observation166 and should receive treatment for latent tuberculosis infection when they have tuberculin induration reactions of 5 mm or more.166
• Individuals with an induration reaction of 10 mm or more to the standard Mantoux tuberculin skin test who have other clinical conditions associated with an increased risk of tuberculosis, including those with silicosis, hematologic and reticuloendothelial diseases such as leukemias or lymphomas (e.g., Hodgkin's disease), individuals who have diabetes mellitus or chronic renal failure, and individuals known to be seronegative for HIV who inject illicit drugs.133,166 Individuals with clinical situations associated with substantial, rapid weight loss (10% or more of body weight) or chronic undernutrition, including intestinal (jejunoileal) bypass surgery for obesity, gastrectomy, or carcinomas of the head or neck and lung, should also receive isoniazid preventive therapy if they have an induration reaction of 10 mm or more to the standard Mantoux tuberculin skin test.133,166

In addition, individuals in the following high-incidence groups who have induration reactions of 10 mm or greater to the Mantoux tuberculin skin test should be considered candidates for treatment of latent tuberculosis infection even if they have none of the risk factors listed above:

• Recent immigrants (within the past 5 years) from countries with a high prevalence of tuberculosis (e.g., Latin America, Asia, Africa).133
• Residents of facilities for long-term care (e.g., correctional institutions, nursing homes, mental institutions), hospitals and other health-care facilities, residential facilities for patients with acquired immunodeficiency syndrome [AIDS], homeless shelters).133,166 Staff of facilities (e.g., correctional institutions, nursing homes, mental institutions, other health-care facilities, schools, child-care facilities) in which an individual with current tuberculosis would pose a risk to large numbers of susceptible individuals and mycobacteriology laboratory personnel, also may be considered for therapy of latent tuberculosis infection.133,166
• Children younger than 4 years of age or infants, children, and adolescents exposed to adults in high-risk categories.166 Some evidence suggests that untreated infants with latent tuberculosis infection have up to a 40% risk of developing tuberculosis; the risk for progression of infection to active disease gradually decreases throughout childhood.166 Isoniazid therapy for latent tuberculosis infection is more effective in reducing the risk of clinical tuberculosis in children than in adults, with reported risk reductions of 70-90% in clinical trials.166 Therefore, such therapy is recommended in children and adolescents who have tuberculin skin test reactions of 10 mm of induration or greater following exposure to adults at high risk for tuberculosis infection or disease.166

The ATS and CDC state that routine tuberculin skin testing is not recommended for populations at low-risk for latent tuberculosis infection.166 However, if tuberculin testing is conducted in such individuals (e.g., at a work site in which risk of exposure to tuberculosis is anticipated and an ongoing testing program is in place), treatment for latent tuberculosis infection may be considered in those who have a tuberculin reaction (induration of 15 mm or greater) based on an individual assessment of risks and benefits.166

Prior to initiation of isoniazid therapy for latent tuberculosis infection, patients should be screened to exclude from therapy those with clinical tuberculosis, those who have previously received adequate therapy or for latent or active tuberculosis, those with acute or unstable liver disease of any etiology, and those with a history of severe adverse reactions to isoniazid or other conditions that may necessitate special precautions or contraindicate use of the drug.133,166 (See Cautions and also see Drug Interactions.) Because of the risk of inducing isoniazid resistance if the drug is used alone in an individual with current tuberculosis, one of the recommended regimens for treatment of tuberculosis should be used until the diagnosis is clarified. (See General Principles of Antituberculosis Therapy in the Antituberculosis Agents General Statement 8:16.04.) If the evaluation confirms that the patient has latent (not active) tuberculosis, multiple-drug therapy may be discontinued after 4 months in adults or 6 months in children.138

Isoniazid Monotherapy

The ATS and CDC currently recommend a 9-month daily isoniazid regimen or, alternatively, a 9-month twice-weekly isoniazid regimen for both HIV-infected and HIV-negative adults.166 A 9-month daily or twice-weekly isoniazid regimen also is recommended for treatment of latent tuberculosis in most infants and children;166 some experts recommend that isoniazid be given for 9-12 months in HIV-infected children with latent tuberculosis infection.145

Although a 9-month regimen is preferred, the ATS and CDC state that a 6-month daily isoniazid regimen or, alternatively, a 6-month twice-weekly isoniazid regimen can be used in HIV-negative adults.166 The 6-month regimens provide substantial protection and may offer a more cost-effective outcome than the 9-month regimen based on individual decisions by health departments or other providers.166 However, 6-month regimens are not recommended for children, HIV-infected individuals, or individuals with radiographic evidence of prior tuberculosis.166

Isoniazid treatment for latent tuberculosis infection has been given for 6-12 months.124,145,166 Regimens shorter than 6 months may not be effective. A large (about 28,000 individuals), controlled, 5-year follow-up study conducted by the Committee on Prophylaxis of the International Union against Tuberculosis (IUAT) showed that administration of isoniazid for 3 months to individuals with a positive tuberculin skin test reaction and with previously untreated, fibrotic, pulmonary lesions was no more effective than placebo in preventing tuberculosis during the 5-year follow-up period, whereas a 6-month regimen was more effective than placebo.167 Studies comparing various lengths of isoniazid therapy (e.g., 3-12 months) for treatment of latent tuberculosis infection in patients not known to be infected with HIV indicate that the optimal duration appears to be 9 months and that therapy for longer than 12 months does not provide additional benefit.163,166 Although the benefit of a 12-month regimen was better than placebo, overall it was not substantially better than the 6-month regimen, principally because of patient noncompliance during the last 6 months of therapy.167 Among individuals with good compliance during the entire 12 months, the 12-month regimen was substantially more effective in preventing tuberculosis among patients with small pulmonary lesions than the 6-month regimen.166,167 Similar levels of protection against tuberculosis disease have been observed with isoniazid therapy for latent infection regardless of the patient's HIV serostatus or whether the drug was given intermittently twice weekly rather than daily (for 6 months).163,166 Therefore, although the recommended duration of therapy for latent tuberculosis infection is 9 months, the ATS and CDC suggest that every effort should be made to ensure compliance with isoniazid preventive therapy for at least 6 months.124

The ATS and CDC state that completion of therapy for latent tuberculosis infection is based on the total number of administered drug doses, not the duration of therapy alone.163,166 Interruptions in antituberculosis preventive therapy because of drug toxicity or other reasons should be considered when calculating the point at which such therapy is to be discontinued.163,166 Regimens in which isoniazid is given daily should consist of at least 270 doses administered within 12 months (allowing for interruptions in the usual 9-month regimen).163,166 The 6-month isoniazid regimen should consist of at least 180 doses given within 9 months.166 Isoniazid regimens in which the drug is given twice weekly should consist of at least 76 doses administered within 12 months (for the 9-month regimen) or at least 52 doses within 9 months (or the 6-month regimen).163 Reinstitution of therapy in patients whose treatment has been interrupted might require a continuation of the regimen originally prescribed (as long as needed to complete the recommended duration of the particular regimen) or a complete renewal of the regimen.163,166 In either situation, when therapy is resumed after an interruption of 2 months or longer, a medical examination is indicated to rule out tuberculosis disease.163,166

All patients receiving an intermittent (twice-weekly) isoniazid regimen for the treatment of latent tuberculosis infection should receive directly observed therapy (DOT); the ATS and CDC state that when feasible, DOT also should be used in some special settings (e.g., some institutional settings, community outreach programs, household contacts of patients with tuberculosis who are receiving home-based DOT).166 AAP states that when the patient cannot be relied on to adhere to daily isoniazid therapy, the drug may be given twice weekly by directly observed therapy (DOT), preferably after 1 month of daily therapy.145

Alternative Regimens

While isoniazid monotherapy generally is the regimen of choice for the treatment of latent tuberculosis infection,101,102,103,133,145,166 a 4-month regimen of daily rifampin monotherapy can be used as an alternative regimen in both HIV-positive and HIV-negative patients, especially when isoniazid cannot be used because of resistance or intolerance.166 (See Latent Tuberculosis Infection under Uses: Tuberculosis, in Rifampin 8:16.04.)

Limited data suggest that a short-course (e.g., 2-month) regimen consisting of rifampin and pyrazinamide given daily is effective in treating latent tuberculosis infection in HIV-infected patients,163,166 and the ATS and CDC state that the efficacy of this regimen is not expected to differ in HIV-negative patients.166 However, hepatotoxicity (including some fatalities) has been reported in patients receiving rifampin and pyrazinamide regimens for the treatment of latent tuberculosis and, although multiple-drug regimens containing rifampin and pyrazinamide are still recommended for the treatment of active tuberculosis, the ATS, CDC, and IDSA now state that regimens containing both rifampin and pyrazinamide generally should not be offered for the treatment of latent tuberculosis in either HIV-infected or HIV-negative individuals.177 (See Cautions: Hepatic Effects, in Rifampin 8:16.04.)

HIV-infected Individuals

Factors to consider in selecting the appropriate regimen for treatment of latent tuberculosis infection in HIV-infected individuals include the likelihood that the infecting organism is susceptible to isoniazid (isoniazid is the preferred agent for isoniazid-susceptible M. tuberculosis ), the potential for drug interactions with rifampin in patients receiving HIV protease inhibitors or NNRTIs, and the possibility of severe liver injury with pyrazinamide-containing regimens.147,163,166 Choice of therapy requires consultation with public health authorities if the infecting organism is resistant to isoniazid and rifampin.147

Recommendations for treatment of latent tuberculosis infection in HIV-infected adults generally are similar to those for HIV-negative adults; however, the 6-month isoniazid monotherapy regimen usually is not recommended and use of rifabutin monotherapy may be necessary instead of rifampin monotherapy if there are concerns about drug interactions with antiretroviral agents the patient may be receiving.166 The ATS and CDC recommend that HIV-infected adults and adolescents with latent M. tuberculosis infection receive a 9-month regimen of isoniazid given daily or twice weekly; a 4-month regimen of rifampin or rifabutin given daily; or a 2 to 3-month regimen of rifampin and pyrazinamide given daily (this regimen no longer recommended in most patients).147,163,166

For HIV-infected infants and children, recommended regimens for the treatment of latent tuberculosis infection are a 9- to 12-month regimen of isoniazid given daily or twice weekly or a 4- to 6-month regimen of rifampin given daily.145,147

Pregnant Women

For pregnant women who are at risk for progression of latent tuberculosis infection to active disease, particularly those who have HIV infection or have been infected recently, the ATS and CDC state that the initiation or discontinuance of therapy for latent tuberculosis infection should not be delayed on the basis of pregnancy alone, even during the first trimester.163,166 For women whose risk of active disease is lower, some experts recommend delaying treatment until after delivery.166 Patients with HIV infection or radiographic evidence of prior tuberculosis should receive 9 rather than 6 months of isoniazid therapy.166 The ATS and CDC state that some experts would use rifampin and pyrazinamide as an alternative regimen for treatment of latent tuberculosis infection in HIV-infected pregnant women, although pyrazinamide should be avoided during the first trimester.166 The ATS and CDC state that a regimen of isoniazid administered daily or twice weekly for 9 or 6 months is recommended in these pregnant women who do not have HIV infection.163,166

Drug-Resistant Latent Tuberculosis Infection

In individuals likely to be infected with M. tuberculosis organisms that are resistant to both isoniazid and rifampin and are at high risk for developing tuberculosis, the ATS and CDC recommend regimens consisting of pyrazinamide and ethambutol or pyrazinamide and a quinolone anti-infective (e.g., levofloxacin or ofloxacin) for 6-12 months if the organisms from the index case are known to be susceptible to these drugs.166 Immunocompetent contacts may be managed by observation alone or be treated with such regimens for 6 months; immunosuppressed individuals, including those with HIV infection, should be treated for 12 months.166 Clinicians should review the drug-susceptibility pattern of the M. tuberculosis strain isolated from the infecting source-patient before selecting a regimen for treating potentially multidrug-resistant tuberculosis infections.163 In individuals likely to have been infected with M. tuberculosis organisms that are resistant to both isoniazid and rifampin, the choice of drugs used for treatment of latent infection requires expert consultation.147,166 Prior to initiation of therapy for latent tuberculosis infection in patients with suspected multidrug-resistant tuberculosis, careful assessment to rule out active disease is necessary.166

The AAP states that, until susceptibility test results are available, both rifampin and isoniazid should be given to contacts who are likely to have been infected by an index case with isoniazid-resistant tuberculosis.145 If the index case is proven to be excreting organisms that are completely resistant to isoniazid, isoniazid should be discontinued and rifampin given for a total of at least 6 months.145 The AAP recommends consultation with an expert in making decisions about therapy for latent tuberculosis infection in children with isoniazid and/or rifampin-resistant M. tuberculosis .145

Administration

Isoniazid usually is administered orally. The drug may be given by IM injection when oral therapy is not possible.

The fixed-combination preparation containing isoniazid and rifampin (Rifamate^®) and the fixed-combination preparation containing isoniazid, rifampin, and pyrazinamide (Rifater^®) should be given either 1 hour before or 2 hours after a meal; the manufacturer states that Rifater^® should be given with a full glass of water.141,143

Dosage

Oral and IM dosages of isoniazid are identical.

Active Tuberculosis

In the treatment of clinical tuberculosis, isoniazid should not be given alone.176 The drug is considered a first-line agent for the treatment of all forms of tuberculosis.176 Therapy for tuberculosis should be continued long enough to prevent relapse. The minimum duration of treatment currently recommended for patients with culture-positive pulmonary tuberculosis is 6 months (26 weeks), and recommended regimens consist of an initial intensive phase (2 months) and a continuation phase (usually either 4 or 7 months).176 However, the American Thoracic Society (ATS), US Centers for Disease Control and Prevention (CDC), and the Infectious Diseases Society of America (IDSA) state that completion of treatment is determined more accurately by the total number of doses and should not be based solely on the duration of therapy.176 For information on general principles of antituberculosis therapy and recommendations regarding specific multiple-drug regimens and duration of therapy, see the Antituberculosis Agents General Statement 8:16.04.

Adult Dosage

The ATS, CDC, and IDSA recommend that when isoniazid is used in conjunction with other antituberculosis agents in a daily regimen, adults and children 15 years of age or older should receive an isoniazid dosage of 5 mg/kg (up to 300 mg) once daily.176

When an intermittent multiple-drug regimen is used for the treatment of tuberculosis, the ATS, CDC, and IDSA recommend that adults and children 15 years of age or older receive isoniazid in a dosage 15 mg/kg (up to 900 mg) once, twice, or 3 times weekly.176

Pediatric Dosage

Infants and children tolerate larger doses of isoniazid than do adults and may be given isoniazid in a dosage up to 10-20 mg/kg once daily, depending on the severity of the disease. The maximum dosage of isoniazid recommended by the manufacturers for children is 300-500 mg daily.

The ATS, CDC, IDSA, and American Academy of Pediatrics (AAP) recommend that when isoniazid is used in daily multiple-drug regimens in pediatric patients, an isoniazid dosage of 10-15 mg/kg (up to 300 mg) daily should be used.176 The AAP cautions that use of an isoniazid dosage exceeding 10 mg/kg daily in conjunction with rifampin may increase the incidence of hepatotoxicity.145

When an intermittent multiple-drug regimen is used for the treatment of tuberculosis in pediatric patients, the ATS, CDC, IDSA, and AAP recommend an isoniazid dosage of 20-30 mg/kg (up to 900 mg) twice weekly.145,176

Fixed-Combination Preparations

When isoniazid is administered as the fixed combination containing isoniazid and rifampin (Rifamate^®) as part of a multiple-drug regimen for the treatment of pulmonary tuberculosis, the usual adult dosage of Rifamate^® is 2 capsules (600 mg of rifampin and 300 mg of isoniazid) once daily.143,176 Although the fixed-combination preparation was formulated for daily regimens, the ATS, CDC, and IDSA state that Rifamate^® can be used in twice-weekly regimens† provided additional isoniazid is administered concomitantly.176 When used in an intermittent multiple-drug regimen, these experts state that 2 capsules of Rifamate^® (600 mg of rifampin and 300 mg of isoniazid) and an additional 600 mg of isoniazid (i.e., 900 mg of isoniazid total) may be given twice weekly using directly observed therapy (DOT).176 The manufacturer states that Rifamate^® should not be used for the initial treatment of tuberculosis and should only be used after efficacy of the rifampin and isoniazid dosages contained in the fixed-combination preparation has been established by titrating the individual components in the patient.143

When isoniazid is administered as the fixed combination containing isoniazid, rifampin, and pyrazinamide (Rifater^®) in the initial phase (e.g., initial 2 months) of multiple-drug therapy for pulmonary tuberculosis, the manufacturer states that the adult dosage of Rifater^® given as a single daily dose is 4 tablets (480 mg of rifampin, 200 mg of isoniazid, 1.2 g of pyrazinamide) in patients weighing 44 kg or less, 5 tablets (600 mg of rifampin, 250 mg of isoniazid, and 1.5 g of pyrazinamide) in those weighing 45-54 kg, and 6 tablets (720 mg of rifampin, 300 mg of isoniazid, 1.8 g of pyrazinamide) in patients weighing 55 kg or more.141 In individuals weighing more than 90 kg, additional pyrazinamide may need to be given in conjunction with the fixed-combination preparation to obtain an adequate dosage of this drug.176 The ratio of rifampin, isoniazid, and pyrazinamide in Rifater^® may not be appropriate in children or adolescents under the age of 15 because of the higher mg/kg doses of isoniazid usually given in children compared with those given in adults.141

Latent Tuberculosis Infection

For treatment of latent tuberculosis infection, isoniazid usually is given as the sole antituberculosis drug for a minimum of 6 months.145,147,163,164,165,166 Every effort should be made to assure compliance for at least 6 months, since preventive therapy of shorter duration appears to provide little benefit.124,133,163 If drug administration cannot be directly observed, the use of spot testing of urine for isoniazid metabolites has been recommended for assessing compliance.117 The ATS and CDC currently recommend a 9-month daily isoniazid regimen or, alternatively, a 9-month twice-weekly isoniazid regimen for adults regardless of HIV infection status.166 Continuing isoniazid therapy for latent tuberculosis infection for longer than 12 months provides no additional benefit.163,166 It also is recommended that isoniazid therapy for latent tuberculosis infection be continued for 9-12 months in HIV-infected infants and children.145,163 The ATS and CDC state that completion of therapy for latent tuberculosis infection is determined more accurately by the total number of doses and should not be based solely on the duration of therapy.163,166 The 9-month daily isoniazid regimen should consist of at least 270 doses administered within 12 months (allowing for interruptions in the usual 9-month regimen)163,166 and the 6-month daily isoniazid regimen should consist of at least 180 doses given within 9 months.166 Isoniazid regimens in which the drug is given twice weekly should consist of at least 76 doses administered within 12 months (for the 9-month regimen)163,166 or at least 52 doses within 9 months (for the 6-month regimen).166 (See Latent Tuberculosis Infection under Uses: Tuberculosis.)

Adult Dosage

The usual adult dosage of isoniazid for treatment of latent tuberculosis infection is 5 mg/kg (up to 300 mg) once daily.166 If daily supervision is not possible in high-risk individuals who are likely to be noncompliant (e.g., the homeless, inmates of correctional facilities), the ATS and CDC recommend that a twice-weekly isoniazid regimen with direct supervision be used as an alternative to the preferred daily regimen;124,125,133,166 if this twice-weekly regimen is used, isoniazid is given in a dosage of 15 mg/kg (up to 900 mg) twice weekly.124,133,147,166

Pediatric Dosage

For treatment of latent tuberculosis infection in infants and children, the ATS and CDC recommend an isoniazid dosage of 10-20 mg/kg (up to 300 mg) daily.166 The AAP and others recommend a pediatric isoniazid dosage of 10-15 mg/kg (up to 300 mg) daily.145,147 When compliance with the daily regimen cannot be assured, the ATS and CDC suggest that children may receive 20-40 mg/kg (up to 900 mg) twice weekly.166 The AAP and others suggest that, when an intermittent regimen is used, children should receive 20-30 mg/kg (up to 900 mg) of isoniazid twice weekly (under supervised administration) for 9 months, preferably after completion of 1 month of daily isoniazid therapy.145,147

Nervous System Effects

Peripheral neuritis, usually preceded by paresthesia of the feet and hands, is the most common adverse effect of isoniazid and occurs most frequently in malnourished patients and those predisposed to neuritis (e.g., alcoholics, diabetics). Rarely, other adverse nervous system effects have also occurred including seizures, toxic encephalopathy, muscle twitching, ataxia, stupor, tinnitus, euphoria, memory impairment, separation of ideas and reality, loss of self-control, dizziness, and toxic psychosis. Neurotoxic effects may be prevented or relieved by the administration of 10-50 mg of pyridoxine hydrochloride daily during isoniazid therapy, and pyridoxine should be administered in malnourished patients, pregnant women, and those predisposed to neuritis (e.g., HIV-infected individuals). In addition, optic neuritis and atrophy have been reported with isoniazid.

Hepatic Effects

Mild hepatic dysfunction, as evidenced by mild and transient increases in serum AST (SGOT), ALT (SGPT), and bilirubin concentrations, has occurred in approximately 10-20% of patients receiving isoniazid, usually during the first 4-6 months of therapy. In most cases, enzyme concentrations return to pretreatment values despite continuation of isoniazid, but progressive liver dysfunction, bilirubinuria, jaundice, and severe and sometimes fatal hepatitis have occurred rarely. The incidence of isoniazid-associated hepatitis is lowest in patients younger than 20 years of age and greatest in daily users of alcohol and patients 35 years of age or older. The American Academy of Pediatrics (AAP) states that the incidence of hepatitis during isoniazid therapy in otherwise healthy infants, children, and adolescents is rare and that routine determination of serum aminotransferase concentrations are not recommended.145 (See Cautions: Precautions and Contraindications.) The manufacturers state that progressive liver damage may occur in up to 2.3% of patients older than 50 years of age who receive isoniazid. However, data from one study suggest that hepatitis occurs in approximately 4.5% of patients older than 65 years of age who receive the drug.115 If symptoms of hepatitis or signs suggestive of hepatic damage occur during isoniazid therapy, the drug should be discontinued promptly. (See Cautions: Precautions and Contraindications.)

Sensitivity Reactions

Hypersensitivity reactions, including fever, skin eruptions (morbilliform, maculopapular, purpuric, or exfoliative), lymphadenopathy, vasculitis, and, rarely, hypotension, have occurred rarely with isoniazid, usually 3-7 weeks following initiation of therapy. At the first sign of a hypersensitivity reaction, all drugs should be discontinued. If isoniazid is reinstituted, the drug should be restarted in small and gradually increasing doses only after symptoms have cleared. If there is any indication of recurrence of hypersensitivity, isoniazid should be discontinued immediately.

Hematologic Effects

Adverse hematologic effects, including agranulocytosis, eosinophilia, thrombocytopenia, methemoglobinemia, and hemolytic, sideroblastic, or aplastic anemia, have occurred in patients receiving isoniazid.

Other Adverse Effects

Other reported adverse effects of isoniazid include nausea, vomiting, epigastric distress, dryness of the mouth, pyridoxine deficiency, pellagra, hyperglycemia, metabolic acidosis, and urinary retention and gynecomastia in males. A systemic lupus erythematosus-like syndrome and a rheumatic syndrome with arthralgia have also occurred. IM administration of isoniazid has caused irritation at the site of injection.

Precautions and Contraindications

Liver function tests should be performed periodically in patients receiving isoniazid. In addition, patients should be questioned monthly for signs and symptoms of liver disease and should be instructed to report to their physician any of the prodromal symptoms of hepatitis (e.g., persistent fatigue, weakness or fever exceeding 3 days, malaise, nausea, vomiting, unexplained anorexia). If these symptoms appear or if signs suggestive of hepatic damage occur, isoniazid should be discontinued promptly, since continued use of the drug in these patients has been reported to cause a more severe form of liver damage. Some clinicians recommend discontinuing isoniazid therapy if serum aminotransferase concentrations are more than 3-5 times higher than the upper limit of the normal range or if patients develop manifestations of hepatitis.107 Patients who have had signs or symptoms of hepatic damage during isoniazid therapy generally should receive alternative antituberculosis agents, but if isoniazid must be reinstituted, the drug should be restarted only after hepatic symptoms and laboratory abnormalities have cleared. Isoniazid should be restarted in very small and gradually increasing dosages and should be discontinued immediately if there is any indication of recurrent liver involvement.

The AAP states that the incidence of hepatitis during isoniazid therapy in children is rare and that routine determination of serum aminotransferase concentrations is not recommended.145 However, liver function tests should be monitored approximately monthly during the first several months of treatment in children with severe tuberculosis, especially meningitis and disseminated disease.145 The AAP states that monitoring of liver function tests should also be performed in patients with concurrent or recent liver disease, those receiving a high daily dose of isoniazid (more than 10 mg/kg daily) in combination with rifampin and/or pyrazinamide, those who are pregnant or within 6 weeks postpartum, those with clinical evidence of hepatotoxicity, and those with hepatobiliary tract disease from other causes, and those receiving other hepatotoxic drugs concomitantly (especially anticonvulsants).145 In most other patients, monthly clinical evaluations for 3 months, followed by evaluation every 1-3 months to observe for manifestations of hepatitis or other adverse effects of drug therapy, is appropriate.145

Isoniazid should be used with caution in daily users of alcohol, individuals who inject illicit drugs, patients with chronic liver disease or severe renal impairment, and those with a history of prior therapy in whom isoniazid was discontinued because of adverse effects (e.g., headache, dizziness, nausea) possibly, but not definitely, related to the drug. Minor dosage adjustments may be necessary in patients with severe renal impairment. Limited data based on a retrospective analysis of isoniazid-associated hepatitis deaths suggest that the risk of fatal hepatitis associated with the drug may be increased in women, particularly black and Hispanic women, and during the postpartum period.139

Periodic ophthalmologic examinations should be performed in patients who develop visual symptoms while receiving the drug. The manufacturers recommend that ophthalmologic examinations (including ophthalmoscopy) be performed prior to initiation of isoniazid therapy and periodically during therapy with the drug, even without the occurrence of visual symptoms; however, some clinicians question the necessity of this precaution.106

Isoniazid should be used with caution in patients who are malnourished or predisposed to neuropathy (e.g., diabetics, alcoholics), and pyridoxine generally should be administered concomitantly. (See Cautions: Nervous System Effects.) The American Academy of Pediatrics (AAP) recommends concomitant pyridoxine therapy in children and adolescents who have an abnormally low milk and meat intake, in those with nutritional deficiencies (including all symptomatic HIV-infected children), in breast-feeding infants and their mothers, and pregnant women.145

Isoniazid is contraindicated in patients with acute liver disease or a history of previous isoniazid-associated hepatic injury. Isoniazid preventive therapy should be deferred in patients with acute liver disease; however, the ATS and CDC state that seropositivity for hepatitis B surface antigen is not in itself a contraindication for such therapy. Isoniazid is also contraindicated in patients with a history of severe adverse reactions to the drug, including severe hypersensitivity reactions or drug fever, chills, and arthritis.

Carcinogenicity

Isoniazid has been reported to induce pulmonary tumors in animals; however, there is no evidence to date to support carcinogenic effects in humans.

Pregnancy and Lactation

Pregnancy

No isoniazid-related congenital abnormalities have been observed in mammalian reproductive studies; however, it has been reported that isoniazid may exert an embryocidal effect when the drug is administered orally in pregnant rats and rabbits. Although safe use of the drugs during pregnancy has not been definitely established, isoniazid (combined with rifampin and/or ethambutol) has been used to treat clinical tuberculosis in pregnant women. The American Thoracic Society (ATS), US Centers for Disease Control and Prevention (CDC), and Infectious Diseases Society of America (IDSA) state that isoniazid is considered safe for use in pregnant women, but the risk of hepatitis may be increased in the peripartum period.176 The manufacturers state that the potential benefits of isoniazid therapy for latent tuberculosis infection during pregnancy should be weighed against the possible risks to the fetus. Use of antituberculosis agents for the treatment of latent tuberculosis infection in pregnant women is controversial.166 Some experts prefer to delay treatment until after delivery because pregnancy itself does not increase the risk for progression to disease and 2 studies suggest that there may be an increased risk of hepatotoxicity during pregnancy and the early postpartum period.166 However, the American Academy of Pediatrics (AAP) and other experts state that pregnant women who have positive tuberculin skin tests without evidence of clinical tuberculosis should receive therapy with isoniazid for latent tuberculosis infection if they are likely to have been infected recently or have high-risk medical conditions, especially human immunodeficiency virus (HIV) infection.145,166 The AAP recommends that such therapy begin after the first trimester.145

If isoniazid is administered during pregnancy, concomitant administration of pyridoxine (25 mg daily) is recommended.176

Lactation

Because isoniazid crosses the placenta and is distributed into milk, neonates and breast-fed infants of isoniazid-treated mothers should be carefully observed for evidence of adverse effects.

Antituberculosis Agents

There is some evidence that adverse nervous system effects of isoniazid, cycloserine, and ethionamide may be additive; therefore, isoniazid should be used with caution in patients receiving cycloserine or ethionamide.

Aminosalicylic acid appears to reduce the rate of acetylation of isoniazid; the effect is usually not clinically important.

Isoniazid inhibits multiplication of BCG; therefore BCG vaccine may not be effective if administered during therapy with the drug.

Carbamazepine

Initiation of isoniazid therapy (200 or 300 mg daily) in patients receiving carbamazepine has resulted in increased serum concentrations of the anticonvulsant and symptoms of carbamazepine toxicity, including ataxia, headache, vomiting, blurred vision, drowsiness, and confusion.120,121,122 These symptoms of carbamazepine toxicity subsided either when carbamazepine dosage was decreased or when the antituberculosis agent was discontinued.120,122 This interaction presumably occurs because isoniazid inhibits hepatic metabolism of carbamazepine.121,122 In at least one patient, concomitant use of carbamazepine and isoniazid also appeared to increase the risk of isoniazid-induced hepatotoxicity, apparently because the anticonvulsant promoted the metabolism of isoniazid to its hepatotoxic metabolites.121 If carbamazepine and isoniazid are administered concomitantly, serum concentrations of the anticonvulsant should be closely monitored and the patient observed for evidence of carbamazepine toxicity;120,122 carbamazepine dosage should be decreased if necessary.122

Phenytoin

Isoniazid inhibits hepatic metabolism of phenytoin, resulting in increased plasma phenytoin concentrations and toxicity in some patients. Phenytoin toxicity occurs mainly in slow isoniazid inactivators and in patients receiving both isoniazid and aminosalicylic acid. Patients receiving isoniazid and phenytoin concurrently should be observed for evidence of phenytoin intoxication, and the dosage of the anticonvulsant should be reduced accordingly.

Serotonergic Agents

Isoniazid appears to have some MAO-inhibiting activity.161 In addition, iproniazid, another antituberculosis agent structurally related to isoniazid that also possesses MAO-inhibiting activity, reportedly has resulted in serotonin syndrome in at least 2 patients when given in combination with meperidine.162 Pending further experience, clinicians should be aware of the potential for serotonin syndrome when isoniazid is given in combination with selective serotonin-reuptake inhibitor therapy or other serotonergic agents.161

Other Drugs

Aluminum hydroxide gel decreases GI absorption of isoniazid; isoniazid should be administered at least 1 hour before the antacid.

Coordination difficulties and psychotic episodes have occurred in patients receiving isoniazid and disulfiram concurrently, probably as a result of alterations in dopamine metabolism; concurrent administration of the drugs should be avoided.

Laboratory Test Interferences

Tests for Urinary Glucose

Isoniazid reportedly causes false-positive results with cupric sulfate solution (Benedict's reagent and Clinitest^®) for urine glucose determinations.

Acute Toxicity

Manifestations

Overdosage of isoniazid has produced nausea, vomiting, dizziness, slurred speech, blurred vision, and visual hallucinations (including bright colors and strange designs). Symptoms of overdosage usually occur within 30 minutes to 3 hours following ingestion of the drug. After marked overdosage, respiratory distress and CNS depression, progressing rapidly from stupor to coma, severe intractable seizures, metabolic acidosis, acetonuria, and hyperglycemia have occurred. If untreated or treated inadequately, isoniazid overdosage may be fatal. Isoniazid-induced seizures are thought to be associated with decreased γ-aminobutyric acid (GABA) concentrations in the CNS, possibly resulting from inhibition by isoniazid of brain pyridoxal-5-phosphate activity.

Treatment

In the management of isoniazid overdosage, an airway should be secured and adequate respiratory exchange established immediately. Seizures may be controlled with IV administration of diazepam or short-acting barbiturates and a dosage of pyridoxine hydrochloride equal to the amount of isoniazid ingested. Generally, 1-4 g of pyridoxine hydrochloride is given IV followed by 1 g IM every 30 minutes until the entire dose has been given. If seizures are controlled and overdosage is recent (within 2-3 hours), the stomach should be emptied by gastric lavage. Blood gases, serum electrolytes, glucose, and BUN determinations should be performed. Blood should be typed and cross-matched in case hemodialysis is required. IV sodium bicarbonate should be administered to control metabolic acidosis and repeated as needed; dosage should be adjusted on the basis of laboratory test results. Pyridoxine has also had a beneficial effect in correcting acidosis in some patients, possibly by controlling seizures and resulting lactic acidosis. Pyridoxine has been effective in treating isoniazid-induced seizures as well as other mental status changes associated with isoniazid overdosage.123 In several patients who remained comatose following initial treatment of seizures with diazepam and pyridoxine, administration of an additional 3- to 5-g dose of pyridoxine hydrochloride after 36-42 hours of coma resulted in complete awakening within 30 minutes.123 The fact that administration of high doses of pyridoxine can result in adverse neurologic effects should be considered whenever the drug is used in the treatment of isoniazid-induced seizures and/or coma.123

Forced osmotic diuresis should be initiated as soon as possible following isoniazid overdosage to increase renal clearance of the drug and should be continued several hours after clinical improvement to ensure complete clearance of the drug and prevent relapse. Fluid intake and output should be monitored. In severe cases, hemodialysis or, if hemodialysis is not available, peritoneal dialysis should be used in conjunction with forced diuresis. In addition, measures should be taken to protect against hypoxia, hypotension, and aspiration pneumonitis.

Mechanism of Action

Isoniazid may be bacteriostatic or bactericidal in action, depending on the concentration of the drug attained at the site of infection and the susceptibility of the infecting organism. The exact mechanism of action of isoniazid has not been fully elucidated, but several mechanisms including interference with metabolism of bacterial proteins, nucleic acids, carbohydrates, and lipids have been proposed. One of the principal actions of the drug appears to be inhibition of mycolic acid synthesis in susceptible bacteria which results in loss of acid-fastness and disruption of the bacterial cell wall. Isoniazid is active against susceptible bacteria only when they are undergoing cell division. Susceptible bacteria may undergo 1 or 2 divisions before multiplication is arrested.

Spectrum

Isoniazid is a highly specific agent and is active only against organisms of the genus Mycobacterium. Isoniazid is active in vitro and in vivo against M. tuberculosis , M. bovis , and some strains of M. kansasii. In vitro, the minimum inhibitory concentration (MIC) for most susceptible mycobacteria is 0.02-0.2 mcg/mL in Lowenstein-Jensen media.

Resistance

Natural and acquired resistance to isoniazid have been demonstrated in vitro and in vivo in strains of M. tuberculosis. In vitro, resistance to isoniazid develops in a stepwise manner. The mechanism of resistance may be related to failure of the drug to penetrate or be taken up by the resistant bacteria. Resistant strains of initially susceptible bacteria develop rapidly if isoniazid is used alone in the treatment of clinical tuberculosis; however, development of resistance does not appear to be a major problem when the drug is used alone in preventive therapy. When isoniazid is combined with other antituberculosis agents in the treatment of clinical tuberculosis, emergence of resistant strains may be delayed or prevented.

Pharmacokinetics

Absorption

Isoniazid is readily absorbed from the GI tract and from IM injection sites. When administered orally with food, the extent of absorption and peak plasma concentrations of the drug may be reduced. Following oral administration, peak plasma concentrations of the drug are attained within 1-2 hours. In general, plasma concentrations of the drug in rapid isoniazid inactivators are 20-50% of those in slow isoniazid inactivators. In one study in healthy fasting adults, plasma concentrations of isoniazid 6 hours after a single oral dose of 9 mg/kg averaged 4.5 mcg/mL in slow inactivators and 1 mcg/mL in rapid inactivators.

In a single-dose study in healthy fasting males, the extent of absorption (as measured by area under the plasma concentration-time curve) of isoniazid, rifampin, or pyrazinamide in dosages of 250 mg, 600 mg, or 1500 mg, respectively, was similar whether the drugs were administered individually as capsules (rifampin) and tablets (isoniazid and pyrazinamide) or as a fixed combination containing isoniazid 50 mg, rifampin 120 mg, and pyrazinamide 300 mg per tablet.

Distribution

Isoniazid is distributed into all body tissues and fluids. CSF concentrations of the drug are reported to be 90-100% of concurrent plasma concentrations. Isoniazid is not substantially bound to plasma proteins. Isoniazid readily crosses the placenta. Isoniazid is distributed into milk in concentrations approximately equal to maternal plasma concentrations.

Elimination

The plasma half-life of isoniazid in patients with normal renal and hepatic function ranges from 1-4 hours, depending on the rate of metabolism. The plasma half-life may be prolonged in patients with impaired hepatic function or severe renal impairment.

Isoniazid is inactivated in the liver, mainly by acetylation and dehydrazination. Metabolites of the drug include acetylisoniazid, isonicotinic acid, monoacetylhydrazine, diacetylhydrazine, and isonicotinyl glycine. The rate of acetylation is genetically determined and is subject to individual variation; however, it is usually constant for each person. Slow inactivation is an autosomal recessive trait and results from a relative deficiency of the hepatic enzyme N -acetyltransferase. Approximately 50% of whites and blacks are slow inactivators of isoniazid; the majority of native Alaskans, Japanese, and Chinese are rapid inactivators. Although more than 80% of native Alaskans, Japanese, and Chinese are rapid inactivators, some 30-50% overall would be homozygous rapid inactivators and the remaining would be heterozygous intermediate rapid inactivators.

The rate of isoniazid acetylation does not appear to alter efficacy when the drug is administered daily or 2 or 3 times weekly; however, a relationship between rapid inactivation and poor therapeutic response has been noted in once-weekly intermittent regimens.

Acetylation of acetylisoniazid results in the formation of monoacetylhydrazine which has been shown to be a potent hepatotoxin in animals. Microsomal metabolism of monoacetylhydrazine in animals results in production of a reactive acylating species capable of covalently binding with tissue macromolecules (i.e., liver protein) and subsequently causing hepatic necrosis. Although attempts have been made to correlate acetylator phenotype with risk of isoniazid-induced hepatotoxicity, published reports are equivocal, with some showing an association with slow inactivators and others showing an association with rapid inactivators. It has been suggested that acetylator phenotype is probably not a major determinant of isoniazid-induced hepatotoxicity, since the rate of acetylation of toxic monoacetylhydrazine to nontoxic diacetylhydrazine is also determined by acetylator phenotype. Thus, although rapid inactivators form more monoacetylhydrazine, they also inactivate it more rapidly.

In adults with normal renal function, approximately 75-96% of a 5-mg/kg oral dose of isoniazid is excreted in urine within 24 hours as unchanged drug and metabolites. Small amounts of the drug are also excreted in saliva, sputum, and feces. Isoniazid is removed by hemodialysis or peritoneal dialysis.

Chemistry and Stability

Chemistry

Isoniazid is a synthetic, isonicotinic acid-derivative antituberculosis agent. The drug occurs as colorless or white crystals or as a white, crystalline powder and has solubilities of approximately 125 mg/mL in water and 20 mg/mL in alcohol at 25°C. Isoniazid injection is a clear, colorless to faintly greenish-yellow liquid; sodium hydroxide and/or hydrochloric acid may have been added during manufacture to adjust the pH to 6-7.

Oral isoniazid is commercially available alone, in fixed combination with rifampin,143 and in fixed combination with rifampin and pyrazinamide.141

Stability

Isoniazid preparations should be protected from light, air, and excessive heat. Isoniazid tablets should be stored in well-closed, light-resistant containers at a temperature less than 40°C, preferably between 15-30°C. Tablets containing the fixed combination of rifampin, isoniazid, and pyrazinamide (Rifater^®) should be protected from excessive humidity and stored at 15-30°C.141

Isoniazid injection should be protected from light and stored at a temperature less than 40°C, preferably between 15-30°C; freezing should be avoided. At low temperatures, isoniazid in solution tends to crystallize, and the injection should be warmed to room temperature to redissolve the crystals prior to use.

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