Isoniazid (Systemic)


VA CLASSIFICATION
Primary: AM500
{09}
Commonly used brand name(s): Isotamine; Laniazid; Nydrazid; PMS Isoniazid.

Another commonly used name is
INH .
Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).



Category:


Antibacterial (antimycobacterial)—

Indications

Note: Bracketed information in the Indications section refers to uses that are not included in U.S. product labeling.


General considerations
Tuberculosis is a highly infectious life-threatening bacterial disease with 8 million new cases and 3 million deaths reported worldwide each year to the World Health Organization (WHO) {74}. The vast majority of these cases are in developing countries; however, tuberculosis also has emerged as an important public health problem in the U.S. in recent years after the decline in number of cases observed between 1950 and 1980 {74}.

The resurgence of tuberculosis in the U.S. has been complicated by an increase in the proportion of patients with strains resistant to antituberculosis medications. Outbreaks of multidrug-resistant tuberculosis have been documented in hospitals and prisons {75} {80} {86} {88}. Drug-resistant tuberculosis, particularly that caused by strains resistant to isoniazid and rifampin, is much harder to treat and often is fatal {80} {88}. Among acquired immunodeficiency syndrome (AIDS) patients infected with tuberculosis bacilli resistant to both rifampin and isoniazid, a case-fatality rate of 91% has been reported {90}. Recent investigations of outbreaks of multidrug-resistant tuberculosis have found an extraordinarily high case-fatality rate, with the median time to mortality being reached between 4 and 16 weeks {97}. In almost all instances, these outbreaks have involved patients with severe immunosuppression by infection with the human immunodeficiency virus (HIV) {97}.

Acquired drug resistance develops during treatment for drug-sensitive tuberculosis with regimens that are poorly conceived or poorly complied with, allowing the emergence of naturally occurring drug-resistant mutations {95}. Resistant organisms from affected patients may subsequently infect other people who have not been infected with M. tuberculosis previously, resulting in primary drug resistance {95}.

Resistance to antituberculosis agents can develop not only in the strain that caused the initial disease, but also as a result of reinfection with a new strain of M. tuberculosis that is drug-resistant {99}. Reinfection with a new multidrug-resistant M. tuberculosis strain can occur during therapy for the original infection or after completion of therapy {99}. Most recent data suggest that outcomes can be improved if patients promptly begin therapy with two or more drugs that have in vitro activity against the multidrug-resistant isolate {97}.

HIV infection is the strongest risk factor yet identified for the development of active tuberculosis disease in persons infected with tuberculosis {73} {75} {76} {78} {85} {89} {90} {95} {99} {101} {103}. In addition, persons with HIV infection are at an increased risk of tuberculosis resulting either from newly acquired disease or from reactivation of latent infections {74}. Tuberculosis is a major clinical manifestation of immunodeficiency induced by HIV {104}. In hospital-based retrospective studies, high rates of tuberculosis have been found among patients with AIDS {104}. In communities where tuberculosis and HIV infection are common, the prevalence of HIV seropositivity among patients with tuberculosis is greatly increasing {104}.

WHO has estimated that 5.6 million people worldwide and 80,000 people in the U.S. are infected with both HIV and tuberculosis {74}. Persons dually infected with M. tuberculosis and HIV have a high risk of developing clinically active tuberculosis {104}. One study of HIV-positive drug users with positive tuberculin skin test results found a rate of the development of active tuberculosis to be 8 cases per 100 person-years (8% yearly) as compared with the 10% lifetime risk (1 to 3% risk within the first year after skin test conversion) in the general population {95}.

Persons who are known to be HIV-infected and who are contacts of patients with infectious tuberculosis should be carefully evaluated for evidence of tuberculosis {78} {84}. If there are no findings suggestive of current tuberculosis, preventive therapy with isoniazid should be given {84}. Because HIV-infected contacts are not managed in the same way as those who are not HIV-infected, HIV testing is recommended if there are known or suspected risk factors for their acquiring of HIV infection {78} {84}.

According to investigators at the National Institute of Allergy and Infectious Diseases (NIAID), levels of HIV in the bloodstream increase 5- to 160-fold in HIV-infected persons who develop active tuberculosis {91}. Clinical and epidemiologic observations have demonstrated that HIV-infected individuals have an estimated 113-times higher risk and AIDS patients have a 170-times higher risk compared with uninfected persons {74}. Furthermore, the problem of drug resistance may worsen as the HIV epidemic spreads {80} {90}. Immunosuppressed patients with HIV infection who subsequently become infected with M. tuberculosis have an extraordinarily high risk of developing active tuberculosis within a short period of time {90}.

In addition to the convincing evidence that HIV infection increases the risk and worsens the course of tuberculosis, there is increasing clinical evidence that coinfection with M. tuberculosis accelerates progression of disease caused by HIV infection {107}. Understanding the interaction of these two pathogens is clinically important, given the high prevalence of patients coinfected with HIV and M. tuberculosis in both the U.S. and Africa; it is estimated that by the year 2000 about 500,000 deaths per year will occur in coinfected patients worldwide {107}.

Persons with a positive tuberculin skin test and HIV infection, and persons with a positive tuberculin skin test and at risk of acquiring HIV infection with unknown HIV status should be considered for tuberculosis preventive therapy regardless of age {84}. One study showed that isoniazid prophylaxis in HIV-infected, tuberculin-positive individuals not only decreased the incidence of tuberculosis disease, but also delayed the progression to AIDS and death {74}.

Twelve months of preventive therapy is recommended for adults and children with HIV infection and other conditions associated with immunosuppression {84}. Persons with HIV infection should receive at least 6 months of preventive therapy. The American Academy of Pediatrics recommends that children receive 9 months of therapy {84}.

Tuberculosis control programs should ensure that drug susceptibility tests are performed on all initial isolates of M. tuberculosis and the results are reported promptly to the primary care provider and the local health department {76}. Tuberculosis control programs should monitor local drug resistance rates to assess the effectiveness of local tuberculosis control efforts and to determine the appropriateness of the currently recommended initial tuberculosis treatment regimen for the area {76}.

Relapse of rifampin-resistant tuberculosis has been reported in HIV-infected patients {92} {93}. Reinfection with new strains of M. tuberculosis has also been reported in these patients {92}. Rifampin-resistant tuberculosis is a serious threat because responses to therapy are more difficult to achieve and require long courses of treatment {92} {93}. Therefore, careful follow-up of HIV-infected patients with treated tuberculosis is essential {92} {93}.

Multidrug-resistant tuberculosis also has been transmitted to persons without HIV infection in health care facilities {99}. Together with the lack of effective agents for second-line treatment and methods of prophylaxis, the transmission of multidrug-resistant strains of M. tuberculosis may create a substantial reservoir of latently infected people and the potential for clinical multidrug-resistant tuberculosis for many years to come {99}.

Several studies have documented a high prevalence of extrapulmonary disease in HIV-infected patients with clinical tuberculosis disease, particularly in conjunction with pulmonary manifestations {105}. Cutaneous miliary tuberculosis, also known as tuberculosis cutis miliaris disseminata , was in the past, a rare entity in adults, with only 24 cases reported in nearly a century {105}. However, since the first reported case of cutaneous miliary tuberculosis in 1990 in a patient with AIDS, five additional cases have been reported in HIV-infected patients {105}. Its appearance can be quite nondescript; therefore, a high level of suspicion must be maintained, particularly for patients with a CD4+ cell count of < 200 per cubic millimeter, in order to diagnose the condition and initiate therapy appropriately {105}.

Accepted

Tuberculosis, latent infection (treatment)—Isoniazid is indicated alone in the treatment of latent tuberculosis infection{109}{110} in the following persons:    • Household members and other close contacts of patients with recently diagnosed tuberculosis who have a positive tuberculin skin test (PPD) of ³ 5 mm; [tuberculin-negative children and adolescents who have been close contacts of infectious persons within the past 3 months are also candidates for preventative therapy until a repeat PPD is done 12 weeks after contact with the infectious source]1 {48} {63};
   • [Human immunodeficiency virus (HIV)–infected persons of any age with a positive PPD of ³ 5 mm or a past history of a positive PPD; also, persons with risk factors for HIV infection whose HIV status is unknown but who are suspected of having HIV infection]1 {44} {48} {63};
   • Positive PPD reactors of ³ 5 mm with chest radiograph findings consistent with nonprogressive tuberculosis in whom there are neither positive bacteriologic findings nor a history of adequate chemotherapy for tuberculosis {52} {53} {63};
   • [Children with a positive PPD of ³ 5 mm who have an immunosuppressive condition, including HIV infection or immunosuppression due to corticosteroids]1 {63};
   • Adults with positive PPD reactions of ³ 10 mm who are receiving immunosuppressives or prolonged therapy with corticosteroids, who have certain hematologic and reticuloendothelial diseases such as leukemia or Hodgkin's disease, who have diabetes mellitus or silicosis, or who have undergone gastrectomy {48} {53};
   • Children up to 4 years of age with a positive PPD of ³ 10 mm who are at increased risk of dissemination because of their young age1 {63};
   • [Children with a positive PPD of ³ 10 mm who are at increased risk of dissemination because of medical risk factors other than immunosuppression due to corticosteroid therapy or HIV infection, such as Hodgkin's disease, lymphoma, diabetes mellitus, chronic renal failure, and malnutrition]1 {63};
   • [Positive PPD reactors with a PPD ³ 10 mm among intravenous drug abusers (IVDA) known to be HIV-negative, alcoholics, or homeless persons of any age, and children frequently exposed to these persons ]1 {46} {48} {63};
   • [Positive PPD reactions of ³ 10 mm in foreign-born persons up to 35 years of age, or children whose parents are from high-prevalence areas, such as Asia, Africa, or Latin America]1 {48} {63};
   • [Positive PPD reactions of ³ 10 mm in residents of long-term care facilities, prisons, nursing homes, and mental institutions, and children frequently exposed to these persons]1 {48} {63};
   • [Positive PPD reactions of ³ 10 mm in medically underserved low-income populations, up to 35 years of age, including high-risk racial or ethnic minority populations, especially blacks, Hispanics, and Native Americans]1 {48}; or
   • Recent converters, as indicated by a PPD increase of ³ 10 mm within 2 years for those up to 35 years of age, and a PPD increase of ³ 15 mm for those 35 years of age and older {48}; [ also, children 4 years of age and older with a PPD of ³ 15 mm without any risk factors]1 {63}.


Tuberculosis (treatment)—Isoniazid is indicated, in combination with other antituberculars, in the treatment of all forms of tuberculosis, including tuberculous meningitis {15}.

—Resistance to isoniazid is a rapidly increasing problem. The primary cause of drug-resistance to antitubercular medications is inadequate therapy due to patient noncompliance. To try to avoid this continuing trend, administration of four-drug directly observed therapy (DOT) is currently recommended. (See General Dosing Information .) {64}

—Not all species or strains of a particular organism may be susceptible to isoniazid.

Unaccepted
Isoniazid is not recommended for use in the treatment of atypical mycobacterial infections, such as Mycobacterium avium complex (MAC), because isoniazid has weak activity against MAC compared to other antimycobacterial agents {67}.
1 

1 Not included in Canadian product labeling.



Pharmacology/Pharmacokinetics

Note: Preliminary data suggest that patients coinfected with human immunodeficiency virus (HIV) and mycobacteria (Mycobacterium tuberculosis or M. avium ) have altered pharmacokinetic profiles for antimycobacterial agents {83}. In particular, malabsorption of these agents appears to occur frequently, and could seriously affect the efficacy of treatment {83} {96}.


Physicochemical characteristics:
Molecular weight—
    137.14 {16}

Mechanism of action/Effect:

Isoniazid (INH) is a synthetic, bactericidal antitubercular agent that is active against many mycobacteria, primarily those that are actively dividing. Its exact mechanism of action is not known, but it may relate to inhibition of mycolic acid synthesis and disruption of the cell wall in susceptible organisms {19}.

Absorption:

Readily absorbed following oral administration {15}; however, may undergo significant first pass metabolism {32} {33}. Absorption and bioavailability are reduced when isoniazid is administered with food {33}.

Distribution:

Widely distributed to all fluids and tissues, including cerebrospinal fluid (CSF), pleural and ascitic fluids, skin, sputum, saliva, lungs, muscle, and caseous tissue. INH crosses the placenta and is distributed into breast milk {15} {19} {33}.

Vol D—0.57 to 0.76 L per kg {34} {35}.

Protein binding:

Very low (0 to 10%) {32} {33} {36}.

Biotransformation:

Hepatic; isoniazid is acetylated by N-acetyl transferase to N-acetylisoniazid; it is then biotransformed to isonicotinic acid and monoacetylhydrazine. Monoacetylhydrazine is associated with hepatotoxicity via formation of a reactive intermediate metabolite when N-hydroxylated by the cytochrome P450 mixed oxidase system {33}. The rate of acetylation is genetically determined {15}; slow acetylators are characterized by a relative lack of hepatic N-acetyltransferase.

Half-life:


Adults (including elderly patients):

Fast acetylators: 0.5 to 1.6 hours.

Slow acetylators: 2 to 5 hours.

Acute and chronic liver disease: May be prolonged (6.7 hours vs 3.2 hours in controls) {32}.



Children (age 1.5 to 15 years):

2.3 to 4.9 hours {33}.



Neonates:

7.8 and 19.8 hours in two newborns who received isoniazid transplacentally. The long half-life may be due to the limited acetylation capacity of neonates {39}.


Time to peak concentration:

1 to 2 hours {53}.

Peak serum concentration

3 to 7 mcg per mL after a single 300-mg oral dose {33} {37}.

Elimination:
    Renal; approximately 75–95% excreted by the kidneys within 24 hours, primarily as the inactive metabolites, N-acetylisoniazid and isonicotinic acid; of this amount, 93% of the isoniazid excreted in the urine may occur as the acetylated form in fast acetylators and 63% in slow acetylators, with the remainder, in both cases, occurring as the free or conjugated form.
    Small amounts are excreted in feces {15}.


In dialysis—
        Significant amounts of isoniazid are removed from the blood by hemodialysis. A single 5-hour hemodialysis period has removed up to 73% of the isoniazid in the blood {33}.
        Peritoneal dialysis is of limited benefit {38}.



Precautions to Consider

Cross-sensitivity and/or related problems

Patients hypersensitive to ethionamide, pyrazinamide, niacin (nicotinic acid), or other chemically related medications may be hypersensitive to this medication also.

Carcinogenicity/Tumorigenicity

Isoniazid has been shown to cause pulmonary tumors in a number of strains of mice. However, isoniazid has not been shown to be carcinogenic or tumorigenic in humans {02} {08} {15}.

Pregnancy/Reproduction

Note: Tuberculosis in pregnancy should be managed in concert with an expert in the management of tuberculosis {106}. Women who have only pulmonary tuberculosis are not likely to infect the fetus until after delivery, and congenital tuberculosis is extremely rare {106}. In utero infections with tubercle bacilli, however, can occur after maternal bacillemia occurs at different stages in the course of tuberculosis {106}. Miliary tuberculosis can seed the placenta and thereby gain access to the fetal circulation {106}. In women with tuberculous endometritis, transmission of infection to the fetus can result from fetal aspiration of bacilli at the time of delivery {106}. A third mode of transmission is through ingestion of infected amniotic fluid in utero {106}.
If active disease is diagnosed during pregnancy, a 9-month regimen of isoniazid and rifampin, supplemented by an initial course of ethambutol if drug resistance is suspected, is recommended. Pyrazinamide usually is not given because of inadequate data regarding teratogenesis {106}. Hence, a 9-month course of therapy is necessary for drug-susceptible disease {106}. When isoniazid resistance is a possibility, isoniazid, ethambutol, and rifampin are recommended initially {106}. One of these medications can be discontinued after 1 or 2 months, depending on results of susceptibility tests {106}. If rifampin or isoniazid is discontinued, treatment is continued for a total of 18 months; if ethambutol is discontinued, treatment is continued for a total of 9 months {106}. Prompt initiation of chemotherapy is mandatory to protect both the mother and fetus {106}. If isoniazid or rifampin resistance is documented, an expert in the management of tuberculosis should be consulted {106}.
Asymptomatic pregnant women with positive tuberculin skin tests and normal chest radiographs should receive preventive therapy with isoniazid for 9 months if they are HIV seropositive or have recently been in contact with an infectious person {106}. For these individuals, preventive therapy should begin after the first trimester {106}. In other circumstances in which none of these risk factors is present, although no harmful effects of isoniazid to the fetus have been observed, preventive therapy can be delayed until after delivery {106}.
For all pregnant women receiving isoniazid, pyridoxine should be prescribed {106}. Isoniazid, ethambutol, and rifampin appear to be relatively safe for the fetus {106}. The benefit of ethambutol and rifampin for therapy of active disease in the mother outweighs the risk to the infant {106}. Streptomycin and pyrazinamide should not be used unless they are essential to the control of the disease {106}.


Pregnancy—
Isoniazid crosses the placenta, resulting in fetal serum concentrations that may exceed maternal serum concentrations. However, problems in humans have not been documented {64}.

Studies in rats and rabbits have shown that isoniazid may be embryocidal. However, isoniazid has not been shown to be teratogenic in mice, rats, or rabbits {15}.

FDA Pregnancy Category C {53}.

Breast-feeding

Isoniazid is distributed into breast milk. An estimated 0.75 to 2.3% of the daily adult dose could be ingested by the nursing infant {33}. Problems in nursing newborns have not been documented and breast-feeding should not be discouraged. However, because isoniazid concentrations are so low in breast milk, breast-feeding cannot be relied upon for adequate tuberculosis prophylaxis or therapy for nursing infants {64}.

Pediatrics

Note: If an infant is suspected of having congenital tuberculosis, a Mantoux tuberculin skin test, chest radiograph, lumbar puncture, and appropriate cultures should be performed promptly {106}. Regardless of the skin test results, treatment of the infant should be initiated promptly with isoniazid, rifampin, pyrazinamide, and streptomycin or kanamycin {106}. In addition, the mother should be evaluated for the presence of pulmonary or extrapulmonary (including uterine) tuberculosis {106}. If the physical examination or chest radiograph support the diagnosis of tuberculosis, the patient should be treated with the same regimen as that used for tuberculous meningitis {106}. The drug susceptibilities of the organism recovered from the mother and/or infant should be determined {106}.
Possible isoniazid resistance should always be considered, particularly in children from population groups in which drug resistance is high, especially in foreign-born children from countries with a high prevalence of drug-resistant tuberculosis {106}. For contacts who are likely to have been infected by an index case with isoniazid-resistant but rifampin-susceptible organisms, and in whom the consequences of the infection are likely to be severe (e.g., children up to 4 years of age), rifampin (10 mg per kg of body weight, maximum 600 mg, given daily in a single dose) should be given in addition to isoniazid (10 mg per kg, maximum 300 mg, given daily in a single dose) until susceptibility test results for the isolate from the index case are available {106}. If the index case is known or proven to be excreting organisms resistant to isoniazid, then isoniazid should be discontinued and rifampin given for a total of 9 months {106}. Isoniazid alone should be given if no proof of exposure to isoniazid-resistant organisms is found {106}. Optimal therapy for children with tuberculosis infection caused by organisms resistant to isoniazid and rifampin is unknown {106}. In deciding on therapy in this situation, consultation with an expert is advised {106}.
Adjuvant treatment with corticosteroids in treating tuberculosis is controversial {106}. Corticosteroids have been used for therapy in children with tuberculous meningitis to reduce vasculitis, inflammation, and, as a result, intracranial pressure {106}. Data indicate that dexamethasone may lower mortality rates and lessen long-term neurologic impairment {106}. The administration of corticosteroids should be considered in all children with tuberculous meningitis, and also may be considered in children with pleural and pericardial effusions (to hasten reabsorption of fluid), severe miliary disease (to mitigate alveolocapillary block), and endobronchial disease (to relieve obstruction and atelectasis). Corticosteroids should be given only when accompanied by appropriate antituberculosis therapy {106}. Consultation with an expert in the treatment of tuberculosis should be obtained when corticosteroid therapy is considered {106}.


Studies performed in children have not demonstrated pediatrics-specific problems that would limit the usefulness of isoniazid in children. However, newborn infants may have a limited acetylation capacity, prolonging the elimination half-life of isoniazid {69}.

Children do not require routine hepatic function determinations unless they have pre-existing hepatic disease {68} {70}.

Pyridoxine supplementation is not usually required in children if dietary intake is adequate {68}.


Geriatrics


Appropriate studies on the relationship of age to the effects of isoniazid have not been performed in the geriatric population. However, patients over 50 years of age are more likely to develop hepatitis while receiving isoniazid than are patients in younger age groups {08} {11}.


Pharmacogenetics

Patients can be divided into two groups: slow and rapid acetylators of isoniazid. Approximately 50% of blacks and Caucasians are slow acetylators; the majority of Eskimos and Asians are rapid acetylators. The rate of acetylation does not significantly alter the effectiveness of isoniazid {11}. However, slow acetylation may lead to higher blood levels of isoniazid and thus, an increase in toxic reactions. Slow acetylators are characterized by a relative lack of hepatic N-acetyltransferase. Patients who are slow acetylators may be more prone to develop adverse effects, especially peripheral neuritis, and may require lower-than-usual doses. Rapid acetylators generally do not require higher doses, nor is isoniazid less effective in these patients {11}.

Drug interactions and/or related problems
The following drug interactions and/or related problems have been selected on the basis of their potential clinical significance (possible mechanism in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):


Note: Combinations containing any of the following medications, depending on the amount present, may also interact with this medication.

Acetaminophen    (concurrent use of acetaminophen with isoniazid may increase the potential for hepatotoxicity and, possibly, nephrotoxicity; isoniazid is thought to induce {54} cytochrome P450, resulting in a greater proportion of acetaminophen being converted to toxic metabolite {06} {54} {55})


» Alcohol    (concurrent daily use of alcohol may result in increased incidence of isoniazid-induced hepatotoxicity and increased metabolism of isoniazid; dosage adjustments of isoniazid may be necessary; patients should be monitored closely for signs of hepatotoxicity and should be advised to restrict intake of alcoholic beverages {15})


» Alfentanil    (chronic preoperative or perioperative use of isoniazid, a hepatic enzyme inhibitor, may decrease the plasma clearance and prolong the duration of action of alfentanil {05})


Antacids, especially aluminum-containing    (antacids may delay and decrease absorption and serum concentrations of orally administered isoniazid; concurrent use should be avoided, or patients should be advised to take oral isoniazid at least 1 hour before aluminum-containing antacids {18} {20})


Anticoagulants, coumarin- or indandione-derivative    (concurrent use with isoniazid may result in increased anticoagulant effect because of the inhibition of enzymatic metabolism of anticoagulants {18})


Benzodiazepines    (isoniazid may decrease the hepatic metabolism of benzodiazepines, such as diazepam, chlordiazepoxide, flurazepam, and prazepam, that are metabolized by phase I reactions [ N-demethylation and hydroxylation]; it may also impair the oxidation of triazolam, increasing plasma benzodiazepine concentrations; isoniazid may decrease first-pass metabolism and elimination of midazolam in the liver, probably by competitive inhibition at the cytochrome P450 binding sites, increasing steady-state plasma concentrations of midazolam {20} {42})


» Carbamazepine    (concurrent use with isoniazid increases serum carbamazepine levels and toxicity, probably through inhibition of carbamazepine metabolism {23} {24}; also, carbamazepine may induce microsomal metabolism of isoniazid, increasing formation of an INH-reactive intermediate metabolite, which may lead to hepatotoxicity {08} {42})


Cheese, such as Swiss or Cheshire, or
Fish, such as tuna, skipjack, or Sardinella    (concurrent ingestion with isoniazid may result in redness or itching of the skin, hot feeling, rapid or pounding heartbeat, sweating, chills or clammy feeling, headache, or lightheadedness; this is thought to be due to the inhibition of plasma monoamine oxidase and diamine oxidase by isoniazid, interfering with the metabolism of histamine and tyramine found in fish and cheese {18} {40} {41})


Corticosteroids, glucocorticoid    (concurrent use of prednisolone, and probably other related corticosteroids, with isoniazid may increase hepatic metabolism and/or excretion of isoniazid, leading to decreased plasma concentrations and effectiveness of isoniazid, especially in patients who are rapid acetylators; isoniazid dosage adjustments may be required {20} {65})


Cycloserine    (concurrent use may result in increased incidence of central nervous system [CNS] effects such as dizziness or drowsiness; dosage adjustments may be necessary and patients should be monitored closely for signs of CNS toxicity {20})


» Disulfiram    (concurrent use in alcoholics may result in increased incidence of CNS effects such as dizziness, incoordination, irritability, or insomnia; reduced dosage or discontinuation of disulfiram may be necessary {20})


Enflurane    (isoniazid may increase formation of the potentially nephrotoxic inorganic fluoride metabolite when used concurrently with enflurane {20})


» Hepatotoxic medications, other (see Appendix II )    (concurrent use of other hepatotoxic medications with isoniazid may increase the potential for hepatotoxicity and should be avoided {04})


» Ketoconazole    (concurrent use of ketoconazole with isoniazid has been reported to decrease serum concentrations of ketoconazole; isoniazid should be used with caution when given concurrently with ketoconazole {22})


Neurotoxic medications, other (see Appendix II )    (concurrent use of other neurotoxic medications with isoniazid may produce additive neurotoxicity {21})


» Phenytoin    (concurrent use with isoniazid inhibits the metabolism of phenytoin, resulting in increased phenytoin serum concentrations and toxicity; phenytoin dosage adjustments may be necessary during and after isoniazid therapy, especially in slow acetylators of isoniazid {15} {66})


Pyridoxine    (isoniazid may cause peripheral neuritis by acting as a pyridoxine antagonist or increasing renal excretion of pyridoxine; requirements for pyridoxine may be increased in patients receiving isoniazid concurrently {15})


» Rifampin    (concurrent use of rifampin with isoniazid may increase the risk of hepatotoxicity, especially in patients with pre-existing hepatic impairment and/or in fast acetylators of isoniazid; patients receiving rifampin and isoniazid concurrently should be monitored closely for signs of hepatotoxicity during the first 3 months of therapy {20})


Theophylline    (concurrent use may reduce the metabolism of theophylline, increasing theophylline plasma concentrations {47})



Laboratory value alterations
The following have been selected on the basis of their potential clinical significance (possible effect in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):

With diagnostic test results
Glucose, urine{01}    (isoniazid may cause hyperglycemia with a secondary glycosuria, giving a positive response to copper sulfate tests; glucose enzymatic tests are not affected)

With physiology/laboratory test values
Alanine aminotransferase (ALT [SGPT]) and
Aspartate aminotransferase (AST [SGOT]) and    (values may be transiently and asymptomatically increased in approximately 10 to 20% of patients tested {11} {25})


Bilirubin, serum    (concentrations may be transiently and asymptomatically increased in approximately 10 to 20% of patients tested {11} {25})


Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).


Risk-benefit should be considered when the following medical problems exist
» Alcoholism, active or in remission, or
» Hepatic function impairment    (increased risk of hepatitis with daily consumption of alcohol or hepatic function impairment {07} {11} {15})


» Hypersensitivity to isoniazid, ethionamide, pyrazinamide, niacin (nicotinic acid), or other chemically related medications
Renal failure, severe    (there may be an increased risk of toxicity in patients who have severe renal failure [creatinine clearance < 10 mL/min] {53} {56})


Seizure disorders    (isoniazid may be neurotoxic and cause seizures {11})



Patient monitoring
The following may be especially important in patient monitoring (other tests may be warranted in some patients, depending on condition; » = major clinical significance):

Hepatic function determinations    (AST [SGOT], ALT [SGPT], and serum bilirubin determinations may be required prior to and monthly or more frequently during treatment; however, elevated serum enzyme values may not be predictive of clinical hepatitis and values may return to normal despite continued treatment; therefore, routine measurement of hepatic function is generally not recommended unless there is pre-existing hepatic disease {19} {71}; patients should be instructed to report promptly any prodromal symptoms of hepatitis; if signs and symptoms of hepatotoxicity occur, isoniazid should be promptly discontinued; if isoniazid therapy must be reinstituted, very small and gradually increasing doses should be used, and then only after signs and symptoms of hepatotoxicity have cleared; isoniazid should be withdrawn immediately if any further evidence of hepatotoxicity occurs {07})


» Ophthalmologic examinations    (if symptoms of optic neuritis occur in either adults or children during treatment, ophthalmologic examinations may be required immediately and periodically thereafter; ophthalmologic examinations are not recommended in asymptomatic patients {08})




Side/Adverse Effects

Note: Isoniazid has been reported to cause severe, and sometimes fatal, age-related hepatitis. If signs and symptoms of hepatotoxicity occur, isoniazid should be discontinued promptly {07}. The incidence of clinical hepatitis in young, healthy adults is 0.3%, but can increase to 2.6% for those who drink alcohol daily, have chronic liver disease, or are elderly {25}.
Patients with advanced HIV disease have been reported to have an increased incidence of adverse reactions to antitubercular medications. This was not found in HIV-seropositive patients being treated for tuberculosis {42} {43}.
Pyridoxine deficiency is sometimes observed in adults receiving high doses of isoniazid and probably results from isoniazid's competition with pyridoxal phosphate for the enzyme apotryptophanase.
Peripheral neuritis usually is preventable by administering 10 to 25 mg of pyridoxine per day. It is recommended for patients at risk of neuritis, including those over 65 years of age, pregnant women, patients with diabetes mellitus, chronic renal failure, alcoholism, malnutrition, and those taking anticonvulsant medications {25}.

The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:

Those indicating need for medical attention
Incidence more frequent
    
Hepatitis (dark urine, yellow eyes or skin)
    
hepatitis prodromal symptoms (loss of appetite, nausea or vomiting, unusual tiredness or weakness)
    
peripheral neuritis {11}(clumsiness or unsteadiness ; numbness, tingling, burning, or pain in hands and feet )

Incidence rare
    
Blood dyscrasias {19}{32}(fever and sore throat, unusual bleeding and bruising, unusual tiredness or weakness)
    
hypersensitivity {19}{32}(fever, joint pain, skin rash)
    
neurotoxicity ( seizures, mental depression, mood or other mental changes)
    
optic neuritis {11}(blurred vision or loss of vision, with or without eye pain)



Those indicating need for medical attention only if they continue or are bothersome
Incidence more frequent
    
Gastrointestinal disturbances {11}{19}(diarrhea, nausea and vomiting, stomach pain)

Incidence not reported
    
Local irritation at the site of intramuscular injections {11}





Overdose
For specific information on the agents used in the management of isoniazid overdose, see

   • Pyridoxine (Systemic) monograph;
   • Diazepam in Benzodiazepines (Systemic) monograph; and/or
   • Thiopental in Barbiturates (Systemic) monograph.
For more information on the management of overdose or unintentional ingestion, contact a Poison Control Center (see Poison Control Center Listing ).

The information below applies to the clinical effects and treatment of isoniazid overdose.

Clinical effects of isoniazid overdose {60} {61} {62}
The following effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:
Acute and chronic effects
    
Gastrointestinal disturbances (severe nausea and vomiting )
    
neurotoxicity ( dizziness; slurred speech; lethargy; disorientation; hyperreflexia; seizures; coma)

Note: Patients may be asymptomatic for 30 minutes to 2 hours after an acute overdose. Early symptoms include nausea and vomiting, dizziness, slurred speech, lethargy, disorientation, and hyperreflexia. Seizures usually occur within 1 to 3 hours after ingestion, and are often repetitive and refractory to treatment with usual anticonvulsants. Lactic acid accumulation produces an anion-gap metabolic acidosis within a few hours, which is often severe and refractory to treatment with sodium bicarbonate. Hyperglycemia, glycosuria, and ketonuria have also been reported.




Treatment of isoniazid overdose {60} {61} {62}


To decrease absorption:
Because seizures may occur soon after ingestion, induction of emesis with ipecac is not recommended. Gastric lavage may be performed within 2 to 3 hours of ingestion, and activated charcoal and a cathartic may be administered if the patient's seizures are controlled and the airway protected.



Specific treatment:
Administering intravenous pyridoxine in a gram-for-gram dose, equivalent to the amount of isoniazid ingested; dose should be administered as a 5 or 10% solution in water for injection over 30 to 60 minutes. If the amount of isoniazid ingested is unknown, administering 5-gram doses of pyridoxine every 5 to 30 minutes until seizures stop or consciousness is regained.

Controlling seizures with diazepam, which acts synergistically with pyridoxine. Phenytoin should be used with caution, if at all, since isoniazid inhibits phenytoin metabolism. Thiopental has been effective in treating refractory seizures.

Carefully administering sodium bicarbonate if pyridoxine and diazepam do not control seizure activity. Use caution against overcorrection and watch for hypokalemia or hyperkalemia.



Supportive care:
Supportive measures such as establishing intravenous lines, hydration, correction of electrolyte imbalance, oxygenation, and support of ventilatory function are essential for maintaining the vital functions of the patient. Patients in whom intentional overdose is confirmed or suspected should be referred for psychiatric consultation.



Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Isoniazid (Systemic).
In providing consultation, consider emphasizing the following selected information (» = major clinical significance):

Before using this medication
»   Conditions affecting use, especially:
Hypersensitivity to isoniazid, ethionamide, pyrazinamide, niacin (nicotinic acid), or other chemically related medications

Pregnancy—Isoniazid crosses the placenta; fetal serum concentrations may exceed maternal serum concentrations





Breast-feeding—Isoniazid is distributed into breast milk





Use in children—Children may be less susceptible to pyridoxine deficiency and hepatotoxicity than adults, unless they have pre-existing hepatic disease; newborn infants may have prolonged elimination






Use in the elderly—Patients over the age of 50 have the highest incidence of hepatitis
Other medicines, especially daily alcohol use, alfentanil, carbamazepine, disulfiram, other hepatotoxic medications, ketoconazole, phenytoin, or rifampin
Other medical problems, especially alcoholism, active or in remission, or hepatic function impairment

Proper use of this medication
Taking this medication with food or antacids, but not within 1 hour of aluminum-containing antacids, if gastrointestinal irritation occurs (oral only)

Proper administration technique for oral liquids

» Compliance with full course of therapy, which may take 6 months to 2 years {04} {27} {28}

» Taking pyridoxine concurrently to prevent or minimize symptoms of peripheral neuritis; not usually required in children if dietary intake is adequate {04} {26}

» Proper dosing
Missed dose: Taking as soon as possible; not taking if almost time for next dose; not doubling doses

» Proper storage

Precautions while using this medication
» Regular visits to physician to check progress, as well as ophthalmologic examinations if signs of optic neuritis occur in either adults or children

Checking with physician if no improvement within 2 to 3 weeks

Checking with physician if vascular reactions occur following concurrent ingestion of cheese or fish with isoniazid {04}

» Avoiding alcoholic beverages while taking this medication

» Need to report to physician promptly prodromal signs of hepatitis or peripheral neuritis

» Diabetics: False-positive reactions with copper sulfate urine glucose tests may occur


Side/adverse effects
Hepatitis may be more likely to occur in patients over 50 years of age {29} {30} {31}

Signs of potential side effects, especially hepatitis, peripheral neuritis, blood dyscrasias, hypersensitivity, neurotoxicity, and optic neuritis


General Dosing Information
All patients may be divided into two groups: slow and fast acetylators of isoniazid. Patients who are slow acetylators may be more prone to development of adverse effects, especially peripheral neuritis, and may require lower-than-usual doses {11}. Fast acetylators do not generally require higher doses, nor is isoniazid less effective in these patients. Eskimo, Oriental, and American Indian populations have the lowest prevalence of slow acetylators, while Egyptian, Israeli, Scandinavian, other Caucasian, and black populations have the highest prevalence of slow acetylators {11}.

The duration of treatment with an antituberculosis regimen is at least 6 months, and may be continued for 2 years {84}. Uncomplicated pulmonary tuberculosis is often successfully treated within 6 to 12 months. Several different treatment regimens are currently recommended {84}.

The duration of antituberculosis therapy is based on the patient's clinical and radiographic responses, smear and culture results, and susceptibility studies of Mycobacterium tuberculosis isolates from the patient or the suspect source case {106}. With directly observed therapy (DOT), clinical evaluation is an integral component of each visit for administration of medication {106}. Careful monitoring of the clinical and bacteriologic responses to therapy on a monthly basis in sputum-positive patients is important {106}.

If therapy is interrupted, the treatment schedule should be extended to a later completion date {106}. Although guidelines cannot be provided for every situation, the following factors need to be considered in establishing a new date for completion {106}:    • The length of interruption {106};
   • The time during therapy (early or late) in which interruption occurred {106}; and
   • The patient's clinical, radiographic, and bacteriologic status before, during, and after interruption {106}. Consultation with an expert is advised {106}.


Therapy should be administered based on the following guidelines, published by the American Thoracic Society (ATS) and by the Centers for Disease Control and Prevention (CDC), and endorsed by the American Academy of Pediatrics (AAP) {84}.    • A 6-month regimen consisting of isoniazid, rifampin, and pyrazinamide given for 2 months followed by isoniazid and rifampin for 4 months is the preferred treatment for patients infected with fully susceptible organisms who adhere to the treatment course {82} {84}.
   • Ethambutol (or streptomycin in children too young to be monitored for visual acuity) should be included in the initial regimen until the results of drug susceptibility studies are available, and unless there is little possibility of drug resistance (i.e., there is less than 4% primary resistance to isoniazid in the community, and the patient has had no previous treatment with antituberculosis medications, is not from a country with a high prevalence of drug resistance, and has no known exposure to a drug-resistant case) {84}.
   • Alternatively, a 9-month regimen of isoniazid and rifampin is acceptable for persons who cannot or should not take pyrazinamide {84}. Ethambutol (or streptomycin in children too young to be monitored for visual acuity) should also be included until the results of drug susceptibility studies are available, unless there is little possibility of drug resistance {84}. If isoniazid resistance is demonstrated, rifampin and ethambutol should be continued for a minimum of 12 months {84}.
   • Consideration should be given to treating all patients with DOT {84}. DOT programs have been demonstrated to increase adherence in patients receiving antituberculosis chemotherapy in both rural and urban settings {95}.
   • Multidrug-resistant tuberculosis (i.e., resistance to at least isoniazid and rifampin) presents difficult treatment problems {84}. Treatment must be individualized and based on susceptibility studies. In such cases, consultation with an expert in tuberculosis is recommended {84}.
   • Children should be managed in essentially the same ways as adults, but doses of the medications must be adjusted appropriately and specific important differences between the management of adults and children addressed {84}. However, optimal therapy of tuberculosis in children with HIV infection has not been established {106}. The Committee on Infectious Diseases of the AAP recommends that therapy always should include at least three drugs initially, and should be continued for a minimum period of 9 months {106}. Isoniazid, rifampin, and pyrazinamide with or without ethambutol or an aminoglycoside should be given for at least the first 2 months {106}. A fourth drug may be needed for disseminated disease and whenever drug-resistant disease is suspected {106}.
   • Extrapulmonary tuberculosis should be managed according to the principles and with the drug regimens outlined for pulmonary tuberculosis, except in children who have miliary tuberculosis, bone/joint tuberculosis, or tuberculous meningitis. These children should receive a minimum of 12 months of therapy {84}.
   • A 4-month regimen of isoniazid and rifampin is acceptable therapy for adults who have active tuberculosis and who are sputum smear– and culture–negative, if there is little possibility of drug resistance {84}.


ATS, CDC, and AAP recommend preventive treatment of tuberculosis infection in the following patients:    • Preventive therapy with isoniazid given for 6 to 12 months is effective in decreasing the risk of future tuberculosis disease in adults and children with tuberculosis infection demonstrated by a positive tuberculin skin test reaction {84}.
   • Persons with a positive skin test and any of the following risk factors should be considered for preventive therapy regardless of age {84}:    —Persons with HIV infection {84}.
   —Persons at risk for HIV infection with unknown HIV status {84}.
   —Close contacts of sputum-positive persons with newly diagnosed infectious tuberculosis {84}.
   —Newly infected persons (recent skin test convertors) {84}.
   —Persons with medical conditions reported to increase the risk of tuberculosis (i.e., diabetes mellitus, corticosteroid therapy and other immunosuppressive therapy, intravenous drug users, hematologic and reticuloendothelial malignancies, end-stage renal disease, and clinical conditions associated with rapid weight loss or chronic malnutrition) {84}.
In some circumstances, persons with negative skin tests should be considered for preventive therapy {84}. These include children who are close contacts of infectious tuberculosis cases and anergic HIV-infected adults at increased risk of tuberculosis, tuberculin-positive adults with abnormal chest radiographs showing fibrotic lesions probably representing old healed tuberculosis, adults with silicosis, and persons who are known to be HIV-infected and who are contacts of patients with infectious tuberculosis {84}.
   • In the absence of any of the above risk factors, persons up to 35 years of age with a positive skin test who are in the following high-incidence groups should be also considered for preventive therapy {84}:    —Foreign-born persons from high-prevalence countries {84}.
   —Medically underserved low-income persons from high-prevalence populations (especially blacks, Hispanics, and Native Americans) {84}.
   —Residents of facilities for long-term care (e.g., correctional institutions, nursing homes, and mental institutions) {84}.

   • Twelve months of preventive therapy is recommended for adults and children with HIV infection and other conditions associated with immunosuppression {84}. Persons without HIV infection should receive preventive therapy for at least 6 months {84}.
   • In persons younger than 35 years of age, routine monitoring for adverse effects of isoniazid should consist of a monthly symptom review {84}. For persons 35 years of age and older, hepatic enzymes should be measured prior to starting isoniazid and monitored monthly throughout treatment, in addition to monthly symptom reviews {84}.
   • Persons who are presumed to be infected with isoniazid-resistant organisms should be treated with rifampin rather than with isoniazid {84}.
   • As with the treatment of active tuberculosis, the key to success of preventive treatment is patient adherence to the prescribed regimen {84}. Although not evaluated in clinical studies, directly observed, twice-weekly preventive therapy may be appropriate for adults and children at risk, who cannot or will not reliably self-administer therapy {84}.


The currently recommended regimen for treating tuberculosis is effective in treating HIV-infected patients with tuberculosis, and consists of isoniazid and rifampin for a minimum period of 6 months, plus pyrazinamide and either ethambutol or streptomycin for the first 2 months {79}.

Because of the common association of tuberculosis with HIV infection, an increasing number of patients probably will be considered candidates for combined therapy with rifampin and protease inhibitors {79}. Prompt initiation of appropriate pharmacologic therapy for patients with HIV infection who acquire tuberculosis is critical because tuberculosis may become rapidly fatal {79}. The management of these patients is complex, requires an individualized approach, and should be undertaken only by or in consultation with an expert {79}. In addition, all HIV-infected patients at risk for tuberculosis infection should be carefully evaluated and administered isoniazid preventive treatment if indicated, regardless of whether they are receiving protease inhibitor therapy {79}.

For HIV-infected patients diagnosed with drug-susceptible tuberculosis and for whom protease inhibitor therapy is being considered but has not been initiated, the suggested management strategy is to complete tuberculosis treatment with a regimen containing rifampin before starting therapy with a protease inhibitor {79}. The duration of the antituberculosis regimen is at least 6 months, and therapy should be administered according to the guidelines developed by ATS and CDC, including the recommendation to carefully assess clinical and bacteriologic response in patients coinfected with HIV and to prolong treatment if response is slow or suboptimal {79}.

Most infants £ 12 months of age with tuberculosis are asymptomatic at the time of diagnosis, and the gastric aspirate cultures in these patients have a high yield for M. tuberculosis {96}. When an infant is suspected of having tuberculosis, a thorough household investigation should be undertaken {96}. A 6-month regimen of isoniazid and rifampin supplemented during the first 2 months by pyrazinamide has been found to be well-tolerated and effective in infants with pulmonary tuberculosis {96}. Furthermore, twice-weekly DOT appears to be as effective as daily therapy, and is an essential alternative in patients for whom social issues prevent reliable daily therapy {96}.

Physicians caring for children should be familiar with the clinical forms of the disease in infants to enable them to make an early diagnosis {96}. Any child, especially one in a high-risk group or area, who has unexplained pneumonia, cervical adenitis, bone or joint infections, or aseptic meningitis should have a Mantoux tuberculin skin test performed, and a detailed epidemiologic history for tuberculosis should be obtained {96}.

Management of a newborn infant whose mother, or other household contact, is suspected of having tuberculosis is based on individual considerations {106}. If possible, separation of the mother, or contact, and infant should be minimized {106}. The Committee on Infectious Diseases of the AAP offers the following recommendations in the management of the newborn infant whose mother, or any other household contact, has tuberculosis {96}:    • Mother, or any other household contact, with a positive tuberculin skin test reaction but no evidence of current disease: Investigation of other members of the household or extended family to whom the infant may later be exposed is indicated {106}. If no evidence of current disease is found in the mother or in members of the extended family, the infant should be tested with a Mantoux tuberculin skin test at 3 to 4 months of age {106}. When the family members cannot be promptly tested, consideration should be given to administering isoniazid (10 mg per kg of body weight a day) to the infant until skin testing and other evaluation of the family members have excluded contact with a case of active tuberculosis {106}. The infant does not need to be hospitalized during this time if adequate follow-up can be arranged, but adherence to medication administration should be closely monitored {106}. The mother also should be considered for isoniazid therapy {106}.
   • Mother with untreated (newly diagnosed) disease or disease that has been treated for 2 or more weeks and who is judged to be noncontagious at delivery: Careful investigation of household members and extended family is mandatory {106}. A chest radiograph and Mantoux tuberculin skin test should be performed on the infant at 3 to 4 months and at 6 months of age {106}. Separation of the mother and infant is not necessary if adherence to treatment for the mother and infant is assured {106}. The mother can breast-feed {106}. The infant should receive isoniazid even if the tuberculin skin test and chest radiograph do not suggest clinical tuberculosis, since cell-mediated immunity of a degree sufficient to mount a significant reaction to tuberculin skin testing may develop as late as 6 months of age in an infant infected at birth {106}. Isoniazid can be discontinued if the Mantoux skin test is negative at 3 to 4 months of age, the mother is adherent to treatment and has a satisfactory clinical response, and no other family members have infectious tuberculosis {106}. The infant should be examined carefully at monthly intervals {106}. If nonadherence is documented, the mother has an acid-fast bacillus (AFB)–positive sputum or smear, and supervision is impossible, the infant should be separated from the ill family member and Bacillus Calmette-Guérin (BCG) vaccine may be considered for the infant {106}. However, the response to the vaccine in infants may be delayed and inadequate for prevention of tuberculosis {106}.
   • Mother has current disease and is suspected of having been contagious at the time of delivery: The mother and infant should be separated until the infant is receiving therapy or the mother is confirmed to be noncontagious {106}. Otherwise, management is the same as when the disease is judged to be noncontagious to the infant at delivery {106}.
   • Mother has hematogenously spread tuberculosis (e.g., meningitis, miliary disease, or bone involvement): The infant should be evaluated for congenital tuberculosis {106}. If clinical and radiographic findings do not support the diagnosis of congenital tuberculosis, the infant should be separated from the mother until she is judged to be noncontagious {106}. The infant should be given isoniazid until 3 or 4 months of age, at which time the Mantoux skin test should be repeated {106}. If the skin test is positive, isoniazid should be continued for a total of 12 months {106}. If the skin test is negative and the chest radiograph is normal, isoniazid may be discontinued, depending on the status of the mother and whether there are other cases of infectious tuberculosis in the family {106}. The infant should continue to be examined carefully at monthly intervals {106}.


Health care or correctional institutions experiencing outbreaks of tuberculosis that are resistant to isoniazid and rifampin, or that are resuming therapy for a patient with a prior history of antitubercular therapy, may need to begin five- or six-drug regimens as initial therapy. These regimens should include the four-drug regimen and at least three medications to which the suspected multidrug-resistant strain may be susceptible {64}.

Patients with impaired renal function do not generally require a reduction in dose if the plasma creatinine concentration is less than 6 mg per 100 mL. If renal impairment is more severe or if patients are slow acetylators, a reduction in dose and/or serum determinations may be required. Slow acetylators may require dosage adjustments to ensure isoniazid serum concentrations of less than 1 mcg per mL measured 24 hours after the preceding dose. In anuric patients, one-half the usual maintenance dose is recommended {04}.

For oral dosage forms only
Isoniazid may be taken with meals if gastrointestinal irritation occurs. Antacids may also be taken. However, isoniazid should be taken at least 1 hour before aluminum-containing antacids.

Oral absorption may be decreased if isoniazid is taken with food or antacids {18}.


Oral Dosage Forms

ISONIAZID SYRUP USP

Usual adult and adolescent dose
Tuberculosis {08} {15} {48} {64}
Treatment, latent infection{109}{110}: Oral, 300 mg once a day.

Treatment: In combination with other antituberculosis medications—Oral, 300 mg of isoniazid once a day for the entire treatment period; or 15 mg per kg of body weight, up to 900 mg, two or three times a week, as specified by the treatment regimen.


Usual adult prescribing limits
300 mg daily. {08} {15}

Usual pediatric dose
Tuberculosis {08} {11} {64}
Treatment, latent infection{109}{110}: Oral, 10 mg per kg of body weight, up to 300 mg, once a day.

Treatment: In combination with other antituberculosis medications—Oral, 10 to 20 mg of isoniazid per kg of body weight, up to 300 mg, once a day; or 20 to 40 mg per kg of body weight, up to 900 mg, two or three times a week, as specified by the treatment regimen {16} {64}.


Strength(s) usually available
U.S.—


50 mg per 5 mL (Rx) [Laniazid][Generic]{10}{14}

Canada—


50 mg per 5 mL (Rx) [Isotamine] [PMS Isoniazid]{12}{13}

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), unless otherwise specified by the manufacturer. Store in a tight, light-resistant container. Protect from freezing.

Auxiliary labeling:
   • Continue medicine for full time of treatment.
   • Avoid alcoholic beverages.

Note: When dispensing, include a calibrated liquid-measuring device.



ISONIAZID TABLETS USP

Usual adult and adolescent dose
See Isoniazid Syrup USP .

Usual adult prescribing limits
See Isoniazid Syrup USP . {08} {15}

Usual pediatric dose
See Isoniazid Syrup USP . {08} {11}

Strength(s) usually available
U.S.—


50 mg (Rx) [Laniazid][Generic]


100 mg (Rx) [Laniazid][Generic]


300 mg (Rx) [Laniazid][Generic]{10}{11}

Canada—


50 mg (Rx) [PMS Isoniazid]


100 mg (Rx) [PMS Isoniazid]


300 mg (Rx) [PMS Isoniazid]{12}{13}

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), unless otherwise specified by the manufacturer. Store in a well-closed, light-resistant container.

Auxiliary labeling:
   • Continue medicine for full time of treatment.
   • Avoid alcoholic beverages.



Parenteral Dosage Forms

ISONIAZID INJECTION USP

Usual adult and adolescent dose
Tuberculosis {11} {64}
Treatment, latent infection{109}{110}: Intramuscular, 300 mg once a day.

Treatment: In combination with other antituberculosis medications—Intramuscular, 5 mg of isoniazid per kg of body weight, up to 300 mg, once a day for the entire treatment period; or 15 mg per kg of body weight, up to 900 mg, two or three times a week, as specified by the treatment regimen.


Usual adult prescribing limits
300 mg daily. {11}

Usual pediatric dose
Tuberculosis {11}
Treatment, latent infection{109}{110}: Intramuscular, 10 mg per kg of body weight, up to 300 mg, once a day.

Treatment: In combination with other antituberculosis medications—Intramuscular, 10 to 20 mg of isoniazid per kg of body weight, up to 300 mg, once a day; or 20 to 40 mg per kg of body weight, up to 900 mg, two or three times a week, as specified by the treatment regimen.


Strength(s) usually available
U.S.—


100 mg per mL (Rx) [Nydrazid]{10}{11}

Canada—
Not commercially available.

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), unless otherwise specified by the manufacturer. Protect from light. Protect from freezing.

Note: Crystallization may occur at low temperatures. Upon warming to room temperature, the crystals will redissolve.




Revised: 06/30/2000



References
  1. Wallach J, editor. Interpretation of diagnostic tests. 4th ed. Boston: Little Brown and Company; 1986. p. 661.
  1. Laniazid package insert (Lannett—US), Rev 1/86, Rec 5/86.
  1. Peloquin CA, MacPhee AA, Berning SE. Malabsorption of antimycobacterial medications. N Engl J Med 1993; 329(15): 1122-3.
  1. Panel comments, 6/84.
  1. Alfentanil package insert (Alfenta, Janssen—US), Rev 12/86, Rec 12/86.
  1. Epstein MM. Inhibition of the metabolism of paracetamol by isoniazid. Br J Clin Pharmacol 1991; 31: 130-42.
  1. I.N.H. (Ciba). In: PDR Physicians" desk reference. 42nd ed. 1988. Oradell, NJ: Medical Economics Company; 1988. p. 869-70.
  1. Panel comments, 3/87.
  1. USP DI, VA Medication Classification System. 9th ed. Rockville, MD: The United States Pharmacopeial Convention, Inc., 1989: 2472.
  1. Red book 1989. Montvale, NJ: Medical Economics Data; 1989. p. 408, 428-9.
  1. Nydrazid injection package insert (Squibb—US), Rev 11/87, Rec 3/89.
  1. Isotamine (ICN). In: Krogh CME, editor. CPS Compendium of pharmaceuticals and specialties. 24th ed. Ottawa: Canadian Pharmaceutical Association; 1988. p. 447.
  1. PMS Isoniazid (Pharmascience). In: Krogh CME, editor. CPS Compendium of pharmaceuticals and specialties. 24th ed. Ottawa: Canadian Pharmaceutical Association; 1988. p. 726.
  1. Laniazid (Lannett). In: PDR Physicians" desk reference. 43rd ed. 1989. Oradell, NJ: Medical Economics Company; 1989. p. 1097.
  1. I.N.H. package insert (Ciba—US), Rev 8/87, Rec 1/89.
  1. Committee on Infectious Diseases, American Academy of Pediatrics. Chemotherapy for tuberculosis in infants and children. Pediatrics 1992; 89(1): 161-5.
  1. Berning SE, Huitt GA, Iseman MD, Peloquin CA. Malabsorption of antituberculosis medications by a patient with AIDS. N Engl J Med 1992; 327(25): 1817-8.
  1. Baciewicz AM, Self TH. Isoniazid interactions. South Med J 1985; 78(6): 714-8.
  1. Reed MD, Blumer JL. Clinical pharmacology of antitubercular drugs. Ped Clin N Am 1983; 30(1): 177-93.
  1. Hansten PD. Isoniazid drug interactions. Drug Interactions Newsletter 1983; 3(2): 7-11.
  1. Snavely SR, Hodges GR. The neurotoxicity of antibacterial agents. Ann Intern Med 1984; 101(1): 92-104.
  1. Engelhard D, Stutman HR, Marks MI. Interaction of ketoconazole with rifampin and isoniazid. N Engl J Med 1984; 311(26): 1681-3.
  1. Wright JM, Stokes EF, Sweeney VP. Isoniazid-induced carbamazepine toxicity and vice versa. N Engl J Med 1982; 307(21): 1325-7.
  1. Valsalan VC, Cooper GL. Carbamazepine intoxication caused by interaction with isoniazid. BMJ 1982; 285: 261-2.
  1. Salpeter S. Tuberculosis chemoprophylaxis. West J Med 1992; 157: 421-4.
  1. Panel comment, 6/84.
  1. Panel comment, 3/87.
  1. Panel comment, 3/87.
  1. Panel comment, 3/87.
  1. Panel comment, 2/87.
  1. Panel comment, 10/88.
  1. AMA Drug evaluations. 6th ed. Chicago: American Medical Association; September 1986. p. 1542.
  1. Holdiness MR. Clinical pharmacokinetics of the antituberculosis drugs. Clin Pharmacokinet 1984; 9: 511-44.
  1. Kergueris MF. Acetylation character of isoniazid in the rabbit and in man. Eur J Drug Metab Pharmacokinet 1983; 8(2): 133-6.
  1. Horai Y. Isoniazid disposition, comparison of isoniazid phenotyping methods in and acetylator distribution of Japanese patients with idiopathic systemic lupus erythematosus and control subjects. Br J Clin Pharmacol 1982; 13: 361-74.
  1. Wyngaarden JB, Smith LH, editors. Cecil"s textbook of medicine. Philadelphia: WB Saunders Company; 1990. p. 117.
  1. Mannisto P. Influence of various diets on the bioavailability of isoniazid. J Antimicrob Chemother 1982; 10: 427-34.
  1. INH package insert (Lilly—US), Rev 9/88, Rec 1/89.
  1. Miceli JN, Olson WA, Cohen SN. Elimination kinetics of isoniazid in the newborn infant. Dev Pharmacol Ther 1981; 2: 235-9.
  1. Hauser MJ, Baier H. Interactions of isoniazid with foods. Drug Intell Clin Pharm 1982; 16: 617-8.
  1. Smith CK, Durack DT. Isoniazid and reaction to cheese. Ann Intern Med 1978; 88(4): 520-1.
  1. Shinn AF, Shrewsbury RP. EDI, evaluation of drug interactions. 3rd ed. St Louis: Mosby; l985. p. 222, 446.
  1. Theuer CP. Tuberculosis in patients with human immunodeficiency virus infection. West J Med 1989; 150: 700-4.
  1. Centers for Disease Control and Prevention (CDC). Recommendations of the Advisory Committee for the Elimination of Tuberculosis (ACET): tuberculosis and human immunodeficiency virus infection. MMWR Morb Mortal Wkly Rep 1989; 38(14): 236-50.
  1. Young LY, Koda-Kimble MA, editors. Applied therapeutics. The clinical use of drugs. 4th ed. Vancouver, WA: Applied Therapeutics, Inc; 1988. p. 836.
  1. Brown LS, Felton CP. Drug abuse, HIV infection, and tuberculosis. JAMA 1989; 262(5): 615-6.
  1. Torrent J. Theophylline-isoniazid interaction. Drug Intell Clin Pharm 1989; 23: 143-4.
  1. The use of preventive therapy for tuberculous infection in the United States. MMWR Morb Mortal Wkly Rep 1990; 39(RR-8): 9-12.
  1. Panel comments, 3/90.
  1. Combs DL, O"Brien RJ, Geiter LJ. USPHS tuberculosis short-course chemotherapy trial 21: effectiveness, toxicity, and acceptability. Ann Intern Med 1990; 112(6): 397-406.
  1. Cohn DL. A 62-dose, 6-month therapy for pulmonary and extrapulmonary tuberculosis. Ann Intern Med 1990; 112(6): 407-15.
  1. Panel comments, 5/90.
  1. Isoniazid package insert, (Lilly—US), Rev 4/90, Rec 6/90.
  1. Murphy R, Swartz R, Watkins PB. Severe acetaminophen toxicity in a patient receiving isoniazid. Ann Intern Med 1990; 113(10): 799-800.
  1. Moulding TS, Redeker AG, Kanel GC. Acetaminophen, isoniazid, and hepatic toxicity. Ann Intern Med 1991; 114(5): 431.
  1. Blumberg AE, Gil RA. Cerebellar syndrome caused by isoniazid. Ann Pharmacother 1990; 24: 829-31.
  1. Visudhiphan P, Chiemchanya S. Tuberculous meningitis in children: treatment with isoniazid and rifampin for twelve months. J Pediatr 1989; 114: 875-9.
  1. Chaisson RE, Slutkin G. Tuberculosis and human immunodeficiency virus infection. J Infect Dis 1989; 159(1): 96-100.
  1. Small PM. Treatment of tuberculosis in patients with advanced human immunodeficiency virus infection. N Engl J Med 1991; 324(5): 289-94.
  1. Haddad LM, Winchester JF, editors. Clinical management of poisoning and drug overdose. Philadelphia: WB Saunders Company; 1983. p. 615-8.
  1. Ellenhorn MJ, Barceloux DG. Medical toxicology. Diagnosis and treatment of human poisoning. New York: Elsevier; 1988. p. 364-72.
  1. Bredemann JA, Krechel SW, Eggers GWN. Treatment of refractory seizures in massive isoniazid overdose. Anesth Analg 1990; 71: 554-7.
  1. American Academy of Pediatrics (AAP). Committee on Infectious Disease. Screening for tuberculosis in infants and children. Pediatrics 1994; 93(1): 131-4.
  1. Centers for Disease Control and Prevention (CDC). Recommendations of the Advisory Council for the Elimination of Tuberculosis: initial therapy for tuberculosis in the era of multidrug resistance. MMWR Morb Mortal Wkly Rep 1993; 42(RR-7): 1-8.
  1. Sarma GR, Kailasam S, Nair NGK, et al. Effect of prednisolone and rifampin on isoniazid metabolism in slow and rapid inactivators of isoniazid. Antimicrob Agents Chemother 1980; 18(5): 661-6.
  1. Witmer DR, Ritschel WA. Phenytoin-isoniazid interaction: a kinetic approach to management. Drug Intell Clin Pharm 1984; 18: 483-6.
  1. Peloquin CA. Controversies in the management of Mycobacterium avium complex infection in AIDS patients. Ann Pharmacother 1993; 27: 928-37.
  1. Behrman RE, Vaughan VC III, editors. Nelson textbook of pediatrics. 13th ed. Philadelphia: W.B. Saunders Company; 1987. p. 635-6.
  1. Yaffe SJ, Aranda JV. Pediatric pharmacology. Therapeutic principles in practice. 2nd ed. Philadelphia: WB Saunders Company; 1992. p. 17.
  1. Yaffe SJ, Aranda JV. Pediatric pharmacology. Therapeutic principles in practice. 2nd ed. Philadelphia: WB Saunders Company; 1992. p. 218.
  1. Panel comments, 3/21/94.
  1. Wolinsky E. Statement of the Tuberculosis Committee of the Infectious Diseases Society of America. Clin Infect Dis 1993; 16: 627-8.
  1. Humma LM. Prevention and treatment of drug-resistant tuberculosis. Am J Health Syst Pharm 1996; 53: 2291-8.
  1. Goletti D, Weissman D, Jackson RW, et al. Effect of Mycobacterium tuberculosis on HIV replication: role of immune activation. J Immunol 1996; 157: 1271-8.
  1. Nardell EA, Brickner BW. Tuberculosis in New York City—focal transmission of an often fatal disease. JAMA 1996; 276(15): 1259-60.
  1. Centers for Disease Control and Prevention (CDC). Recommendations of the Advisory Council for the Elimination of Tuberculosis (ACET). Essential components of a tuberculosis prevention and control program. MMWR Morb Mortal Wkly Rep 1995; 44(RR-11): 1-16.
  1. Centers for Disease Control and Prevention (CDC). Recommendations of the Advisory Council for the Elimination of Tuberculosis (ACET). Screening for tuberculosis and tuberculosis infection in high-risk populations. MMWR Morb Mortal Wkly Rep 1995; 44(RR-11): 19-34.
  1. Centers for Disease Control and Prevention (CDC). Recommendations of the Advisory Council for the Elimination of Tuberculosis (ACET). Prevention and control of tuberculosis in correctional facilities. MMWR Morb Mortal Wkly Rep 1996; 45(RR-8): 1-27.
  1. Centers for Disease Control and Prevention (CDC). Clinical update: impact of HIV protease inhibitors on the treatment of HIV-infected tuberculosis patients with rifampin. MMWR Morb Mortal Wkly Rep 1996; 45(42): 921-5.
  1. Centers for Disease Control and Prevention (CDC). Multidrug-resistant tuberculosis outbreak on an HIV ward—Madrid, Spain, 1991-1995. MMWR Morb Mortal Wkly Rep 1996; 45(16): 330-3.
  1. Centers for Disease Control and Prevention (CDC). Characteristics of foreign-born hispanic patients with tuberculosis—eight U.S. counties bordering Mexico. MMWR Morb Mortal Wkly Rep 1996; 45(47): 1032-6.
  1. Centers for Disease Control and Prevention (CDC). Tuberculosis morbidity—United States, 1995. MMWR Morb Mortal Wkly Rep 1996; 45(18): 365-70.
  1. Peloquin CA, Nitta AT, Burman WJ, et al. Low antituberculosis drug concentrations in patients with AIDS. Ann Pharmacother 1996; 30: 919-25.
  1. The American Thoracic Society (ATS). Ad Hoc Committee on the Scientific Assembly on Microbology, Tuberculosis, and Pulmonary Infections. Treatment of tuberculosis and tuberculosis infection in adults and children. Clin Infect Dis 1995; 21: 9-27.
  1. Khan EJ, Starke JR. Diagnosis of tuberculosis in children: increased need for better methods. Emerg Infect Dis 1995; 1(4): 115-23.
  1. Rullán JV, Herrera D, Cano R, et al. Nosocomial transmission of multidrug-resistant Mycobacterium tuberculosis in Spain. Emerg Infect Dis 1996; 2(2): 125-9.
  1. Centers for Disease Control and Prevention (CDC). The Division of Tuberculosis Elimination (DTBE). The use of HIV protease inhibitors with rifampin. TB Notes 1996; 3: 15-9.
  1. Frieden TR, Sherman LF, Maw KL, et al. A multi-institutional outbreak of highly drug-resistant tuberculosis—epidemiology and clinical outcomes. JAMA 1996; 276(15): 1229-35.
  1. Mendez AP, Sterling TR, Frieden TR. The relationship between delayed or incomplete treatment and all-cause mortality in patients with tuberculosis. JAMA 1996; 276(15): 1223-28.
  1. Raviglione MC, Snider DE, Kochi A. Global epidemiology of tuberculosis—morbidity mortality of a worldwide epidemic. JAMA 1995; 273(3): 220-6.
  1. National Institute of Allergy and Infectious Diseases (NIAID). Tuberculosis increases HIV replication in HIV-infected people. NIAID news for release, Thursday, Aug. 1, 1996.
  1. Horn DL, Hewlett D, Haas WH, et al. Superinfection with rifampin-isoniazid-streptomycin-ethambutol (RISE)-resistant tuberculosis in three patients with AIDS: confirmation by polymerase chain reaction fingerprinting. Ann Intern Med 1994; 121(2): 115-6.
  1. Bishai WR, Graham NMH, Harrington S, et al. Brief report: rifampin-resistant tuberculosis in a patient receiving rifabutin prophylaxis. N Engl J Med 1996; 334(24): 1573-6.
  1. Allos BM, Gensheimer KF, Bloch AB, et al. Management of an outbreak of tuberculosis in a small community. Ann Intern Med 1996; 125(2): 114-7.
  1. Hoffmann ND, Kelly C, Futterman D. Tuberculosis infection in human immunodeficiency virus-positive adolescents and young adults: a New York City cohort. Pediatrics 1996; 97(2): 198-203.
  1. Vallejo JG, Ong LT, Strake JR. Clinical features, diagnosis, and treatment of tuberculosis in infants. Pediatrics 1994; 94(1): 1-7.
  1. Telzak EE, Sepkowitz K, Alpert P, et al. Multidrug-resistant tuberculosis in patients without HIV infection. N Engl J Med 1995; 333(14): 907-11.
  1. Goble M, Iseman MD, Madsen LA, et al. Treatment of 171 patients with pulmonary tuberculosis resistant to isoniazid and rifampin. N Engl J Med 1993; 328(8): 527-32.
  1. Small PM, Shafer RW, Hopewell PC, et al. Exogenus reinfection with multidrug-resistant Mycobacterium tuberculosis in patients with advanced HIV infection. N Engl J Med 1993; 328 (16): 1137-44.
  1. Bradford WZ, Martin JN, Reingold AL, et al. The changing epidemiology of acquired drug-resistant tuberculosis in San Francisco, USA. Lancet 1996; 348: 928-31.
  1. Snider GL. Tuberculosis then and now: a personal perspective on the last 50 years. Ann Intern Med 1997; 126(3): 237-43.
  1. Piscitelli SC, Flexner C, Minor JR, et al. Drug interactions in patients infected with human immunodeficiency virus. Clin Infect Dis 1996; 23: 685-93.
  1. Friedman LN, Williams MT, Singh TP, et al. Tuberculosis, AIDS, and death among substance abusers on welfare in New York City. N Engl J Med 1996; 334(13): 828-33.
  1. Antonucci G, Girardi E, Raviglione MC, et al. Risk factors for tuberculosis in HIV-infected persons: a prospective cohort study. JAMA 1995; 274(2): 143-8.
  1. Libraty DH, Byrd TF. Cutaneous miliary tuberculosis in the AIDS era: case report and review. Clin Infect Dis 1996; 23: 706-10.
  1. American Academy of Pediatrics (AAP). Tuberculosis. In: Peter G, editor. 1994 Red book: report of the Committee on Infectious Disaeases. 23rd ed. Elk Grove Village, IL: American Academy of Pediatrics; 1994. p. 480-500.
  1. Nakata K, Rom WN, Honda Y, et al. Mycobacterium tuberculosis enhances human immunodeficiency virus-1 replication in the lung. Am J Crit Care Med 1997; 155: 996-1003.
  1. Fujiwara PI, Cook SV, Rutherford CM, et al. A continuing survey of drug-resistant tuberculosis, New York City, April 1994. Arch Intern Med 1997; 157: 531-6.
  1. Panel comments, 4/2000.
  1. American Thoracic Society (ATS) and Centers for Disease Control and Prevention (CDC). Targeted tuberculin testing and treatment of latent tuberculoisis infection. Am J Respir Crit Care Med 2000; 161: s221-s247.
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