Isoniazid

Isoniazid is a first-line anti-tuberculosis medication used to treat active tuberculosis (with other drugs) and to help prevent active disease in people with latent tuberculosis (TB) infection. Because proper dosing and monitoring are important, especially for liver safety, use this medication only as prescribed and follow your clinician's instructions.

Uses

Active Tuberculosis

Isoniazid is used with other anti-tuberculosis medications to treat clinical tuberculosis.

In Canada, treatment of culture-positive pulmonary tuberculosis generally follows several recommended multidrug regimens. These regimens have a minimum duration of 6 months (26 weeks) and include an initial intensive phase (2 months) followed by a continuation phase (usually 4 or 7 months). Isoniazid is considered a first-line anti-tuberculosis medication for treating all forms of tuberculosis caused by Mycobacterium tuberculosis known or presumed to be susceptible to the drug.

In Canada, isoniazid may be available on its own or as part of fixed-dose combination products with rifampin, or with rifampin and pyrazinamide, depending on local market availability. Although oral isoniazid is preferred for treating tuberculosis, the drug may be given IM for initial treatment or retreatment when it cannot be taken by mouth.

Latent Tuberculosis Infection

Isoniazid is commonly used on its own to treat tuberculosis infection and help reduce the risk of developing active tuberculosis disease. Terms such as “preventive therapy” and “chemoprophylaxis” have largely been replaced by “treatment of tuberculosis infection” or “tuberculosis preventive treatment,” which are considered more accurate and are used in current guidance.

People at risk of developing tuberculosis include those who have recently been infected with M. tuberculosis and those with medical conditions that increase the chance that latent tuberculosis infection will progress to active disease. The likelihood that a positive tuberculin test reflects a true infection with M. tuberculosis is influenced by how common infection is in the population being tested. In Canada, because the predictive value of tuberculin skin testing is lower in people without known risk factors or likely exposure, testing is generally targeted to higher-risk groups and discouraged in those at low risk. Canadian practice also defines positive tuberculin reactions using 3 cut-off points based on the individual's risk profile: 5 mm or more of induration for individuals at highest risk of developing clinical tuberculosis, 10 mm or more for those with an increased likelihood of infection or with medical conditions that raise the risk of progression to active tuberculosis, and 15 mm or more for individuals at low risk in whom tuberculin testing is generally not indicated.

Key Groups for Tuberculin Testing and Treatment

1. Individuals with HIV Infection
   • Those with an induration reaction of 5 mm or greater should receive LTBI treatment unless it is contraindicated.
   • Preventive therapy is recommended even with a negative tuberculin test if there is known exposure to active tuberculosis.
   • Isoniazid therapy may be helpful for tuberculin-negative children born to mothers with HIV infection.
2. Close Contacts of Tuberculosis Patients
   • Contacts with a significant reaction (≥5 mm) should be treated for LTBI, regardless of age.
   • Children under 5 years of age should be treated regardless of test results because they are more susceptible to disease.
3. Immunocompromised Individuals
   • Those receiving prolonged corticosteroid therapy or organ transplants should be treated if they have a significant tuberculin reaction.
   • Immunosuppressed individuals who are contacts of active tuberculosis cases should also receive treatment.
4. Individuals with a Prior Tuberculosis History
   • Those with healed but untreated tuberculosis should receive LTBI treatment, regardless of age.
5. High-Risk Population Groups
   • Recent immigrants from high-prevalence countries, residents of long-term care facilities, and healthcare personnel exposed to tuberculosis patients should be considered for treatment if they have significant tuberculin reactions.
6. Children and Adolescents
   • Infants and children exposed to high-risk adults should be treated if they have a significant tuberculin reaction.

Testing and Treatment Considerations

• Routine testing is not recommended for low-risk populations, but treatment may be considered for those with significant reactions.
• Before starting isoniazid therapy, patients must be screened for active tuberculosis and liver conditions to make sure there are no contraindications.

This streamlined approach helps ensure that vulnerable populations receive appropriate screening and treatment to prevent latent tuberculosis from progressing to active disease.

Isoniazid Monotherapy

Isoniazid monotherapy may be used for the treatment of tuberculosis infection in adults with HIV infection and those without HIV, with a 9-month regimen given daily or, in some situations, twice weekly under direct observation. For infants and children, a similar 9-month regimen may also be used. A 6-month regimen may be used in some adults, although a 9-month regimen has generally been regarded as more protective. Current guidance emphasizes the importance of adherence, and directly observed therapy is recommended when intermittent dosing is used. If treatment is interrupted for more than 2 months, a medical assessment is recommended before therapy is restarted.

Alternative Regimens

While isoniazid monotherapy is generally the preferred treatment for latent tuberculosis infection, a 4-month course of daily rifampin monotherapy can be used as an alternative in both HIV-positive and HIV-negative patients, especially when isoniazid cannot be used because of resistance or intolerance.

Limited data suggest that a short-course (for example, 2-month) regimen of daily rifampin plus pyrazinamide is effective for treating latent tuberculosis infection in patients with HIV infection, and Canadian guidance indicates that this regimen is not expected to work differently in HIV-negative patients. However, liver toxicity, including some fatal cases, has been reported in patients receiving rifampin and pyrazinamide for latent tuberculosis. Although multidrug regimens containing rifampin and pyrazinamide are still recommended for active tuberculosis, current Canadian recommendations generally advise against offering regimens containing both rifampin and pyrazinamide for latent tuberculosis in either HIV-infected or HIV-negative individuals.

HIV-infected Individuals

Factors to consider when choosing the right regimen for latent tuberculosis infection in people with HIV infection include how likely it is that the infecting organism is susceptible to isoniazid (isoniazid is the preferred medication for isoniazid-susceptible M. tuberculosis), the potential for drug interactions with rifampin in patients taking HIV protease inhibitors or non-nucleoside reverse transcriptase inhibitors (NNRTIs), and the possibility of severe liver injury with pyrazinamide-containing regimens. If the infecting organism is resistant to both isoniazid and rifampin, treatment choice requires consultation with public health authorities.

Recommendations for treating tuberculosis infection in adults with HIV infection are generally similar to those for adults without HIV infection. However, the 6-month isoniazid monotherapy regimen is generally not preferred, and rifabutin may be used instead of rifampin when there are concerns about drug interactions with antiretroviral medications the patient may be receiving. Current guidance includes a 9-month regimen of isoniazid given daily, a 4-month regimen of rifampin given daily, and other rifamycin-based regimens in selected patients, depending on the clinical situation and potential drug interactions.

For infants and children with HIV infection, recommended regimens for 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.

Pregnant Women

For pregnant women who are at risk of tuberculosis infection progressing to active disease, particularly those with HIV infection or a recent infection, current guidance states that the potential risks of treatment must be weighed against the risk of progression to active tuberculosis. For women at lower risk of active disease, treatment is generally deferred until after delivery.

Patients with HIV infection or other factors associated with a very high risk of reactivation may still require treatment during pregnancy. However, current guidance states that, if tuberculosis preventive treatment is given during pregnancy, a 4-month regimen of rifampin given daily is the preferred option. Isoniazid-based regimens should generally be avoided until 3 months postpartum except in exceptional circumstances.

Current guidance also states that once-weekly rifapentine and isoniazid for 3 months should generally be avoided during pregnancy and in breastfeeding mothers until more data are available.

Drug-Resistant Latent Tuberculosis Infection

In individuals likely to be infected with M. tuberculosis organisms resistant to both isoniazid and rifampin and who are at high risk of developing tuberculosis, preventive treatment may be considered, although the choice of regimen requires expert consultation. A fluoroquinolone-based regimen, with or without a second drug such as ethambutol or ethionamide, may be used in selected contacts when the source strain is known to be susceptible to these drugs. Current guidance notes that observational data suggest a lower rate of progression to TB disease among multidrug-resistant contacts treated for 12 months with a fluoroquinolone with or without ethambutol or ethionamide, compared with those who refuse treatment. At present, there is insufficient evidence to make a recommendation for contacts of fluoroquinolone-resistant multidrug-resistant cases. Before starting treatment for tuberculosis infection in patients with suspected multidrug-resistant tuberculosis exposure, a careful assessment is required to rule out active disease.

Canadian pediatric guidance indicates that, until susceptibility test results are available, contacts likely to have been infected by an index case with isoniazid-resistant tuberculosis should receive both rifampin and isoniazid. If the index case is proven to be excreting organisms that are completely resistant to isoniazid, isoniazid should be stopped and rifampin should be given for at least six months. Expert consultation is recommended when making decisions about treatment for latent tuberculosis infection in children with isoniazid- and/or rifampin-resistant M. tuberculosis.

Dosage

Oral and IM doses of isoniazid are identical.

Active Tuberculosis

In the treatment of clinical tuberculosis, isoniazid should not be given alone. The drug is considered a first-line medication for treating all forms of tuberculosis. Tuberculosis therapy should continue long enough to help prevent relapse. In Canada, the minimum treatment duration generally 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 4 or 7 months). Completion of treatment is determined more accurately by the total number of doses and should not be based only on the length of therapy.

Adult Dosage

When isoniazid is used with other anti-tuberculosis drugs, current guidance recommends that adults and children 15 years of age or older receive isoniazid 5 mg/kg once daily, up to a maximum of 300 mg. When an intermittent multidrug regimen is used to treat tuberculosis, the recommended isoniazid dose for adults and children 15 years of age or older is 15 mg/kg once, twice, or three times weekly, up to a maximum of 900 mg.

Pediatric Dosage

Infants and children tolerate larger doses of isoniazid than adults and may be given isoniazid in a dose of up to 10-20 mg/kg once daily, depending on disease severity. The maximum dose of isoniazid recommended by the manufacturers for children is 300-500 mg daily. Canadian tuberculosis guidance recommends that when isoniazid is used in daily multidrug regimens in pediatric patients, an isoniazid dose of 10-15 mg/kg (up to 300 mg) daily should be used. Pediatric experts also caution that using an isoniazid dose greater than 10 mg/kg daily together with rifampin may increase the incidence of liver toxicity.

When an intermittent multidrug regimen is used to treat tuberculosis in paediatric patients, current guidance recommends an isoniazid dose of 20-30 mg/kg twice weekly, up to a maximum of 900 mg.

Fixed-Combination Preparations

When isoniazid is given as a fixed-dose combination containing isoniazid and rifampin as part of a multidrug regimen for pulmonary tuberculosis, the usual adult dose is equivalent to 600 mg of rifampin and 300 mg of isoniazid once daily. Current guidance continues to favour daily dosing when possible.

Although fixed-dose combination products were developed for daily regimens, intermittent regimens are not generally preferred in current practice. If an intermittent regimen is used, it should be used only in selected circumstances under directly observed therapy, and twice-weekly continuation-phase regimens are specifically discouraged because they are associated with higher rates of failure and relapse.

When used in an intermittent multidrug regimen, these experts state that 2 capsules of Rifamate® (600 mg of rifampin and 300 mg of isoniazid) plus an additional 600 mg of isoniazid (900 mg of isoniazid total) may be given twice weekly using directly observed therapy (DOT).

The manufacturer states that Rifamate® should not be used for the initial treatment of tuberculosis, but only after the effectiveness of the rifampin and isoniazid doses in the fixed-combination product has been established by titrating the individual components in the patient.

When isoniazid is given as the fixed combination containing isoniazid, rifampin, and pyrazinamide (Rifater®) in the initial phase (for example, the initial 2 months) of multidrug therapy for pulmonary tuberculosis, the manufacturer states that the adult dose 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. In individuals weighing more than 90 kg, additional pyrazinamide may need to be given with the fixed-combination product to achieve an adequate dose of this drug.

The ratio of rifampin, isoniazid, and pyrazinamide in Rifater® may not be appropriate in children or adolescents under 15 years of age because children usually receive higher mg/kg doses of isoniazid than adults.

Latent Tuberculosis Infection

Isoniazid has traditionally been used as the only anti-tuberculosis drug for at least 6 months to treat tuberculosis infection. Every effort should be made to support adherence for at least 6 months, since preventive therapy of shorter duration appears to provide little benefit. If doses cannot be directly observed, adherence should be carefully assessed throughout treatment. Current guidance more often prefers shorter rifamycin-based regimens when appropriate, although isoniazid remains an accepted alternative.

Current guidance includes a 9-month daily isoniazid regimen or, in certain situations, a 9-month twice-weekly observed isoniazid regimen for adults and children. Continuing isoniazid therapy for tuberculosis infection for longer than 12 months does not generally provide additional benefit. In infants and children, 9 months of daily isoniazid remains an acceptable alternative regimen, and in some situations 9 months of observed, twice-weekly isoniazid may be more appropriate.

Current guidance also states that completion of therapy for tuberculosis infection is determined more accurately by the total number of doses and should not be based only on treatment duration. For a 9-month daily isoniazid regimen, at least 270 doses should be given within 12 months, and for a 6-month daily regimen, at least 180 doses should be given within 9 months. For regimens in which isoniazid is given twice weekly, at least 76 doses should be given within 12 months for the 9-month regimen, or at least 52 doses within 9 months for the 6-month regimen.

Administration

Isoniazid is usually taken by mouth. The drug may be given by IM injection when oral therapy is not possible. The fixed-combination product containing isoniazid and rifampin (Rifamate®) and the fixed-combination product containing isoniazid, rifampin, and pyrazinamide (Rifater®) should be taken either 1 hour before or 2 hours after a meal. The manufacturer states that Rifater® should be taken with a full glass of water.

Isoniazid solutions should be sterilized by autoclaving.

Important Safety Information

Liver function tests should be done regularly in patients taking isoniazid. Patients should also be asked every month about signs and symptoms of liver disease and told to report any early symptoms of hepatitis to their doctor (for example, ongoing fatigue, weakness, or fever lasting more than 3 days; malaise; nausea; vomiting; unexplained loss of appetite). If these symptoms appear, or if there are signs of liver damage, isoniazid should be stopped right away, since continued use in these patients has been reported to cause a more severe form of liver injury.

Some clinicians recommend stopping isoniazid if serum aminotransferase levels are more than 3-5 times the upper limit of normal or if the patient develops signs of hepatitis. Patients who have had signs or symptoms of liver damage during isoniazid therapy should generally be treated with alternative antituberculosis agents. If isoniazid has to be started again, it should be restarted only after liver symptoms and lab abnormalities have cleared. Isoniazid should be restarted at very small doses that are increased gradually, and it should be stopped immediately if there is any sign of recurrent liver involvement.

The AAP states that hepatitis during isoniazid therapy is rare in children and that routine testing of serum aminotransferase levels is not recommended. However, liver function tests should be monitored about once a month during the first several months of treatment in children with severe tuberculosis, especially meningitis and disseminated disease.

The AAP also states that liver function tests should be monitored in patients with current or recent liver disease; those receiving a high daily dose of isoniazid (more than 10 mg/kg/day) together with rifampin and/or pyrazinamide; those who are pregnant or within 6 weeks postpartum; those with clinical evidence of hepatotoxicity; those with hepatobiliary disease from other causes; and those taking other hepatotoxic drugs at the same time, especially anticonvulsants. In most other patients, monthly clinical assessments for 3 months, followed by assessment every 1-3 months to watch for signs of hepatitis or other side effects of treatment, are appropriate.

Isoniazid should be used with caution in people who use alcohol daily, people who inject illicit drugs, patients with chronic liver disease or severe renal impairment, and those with a history of previous therapy in whom isoniazid was stopped because of side effects (for example, headache, dizziness, nausea) that were possibly, but not definitely, related to the drug. Minor dose adjustments may be needed in patients with severe renal impairment. Limited data from a retrospective analysis of deaths from isoniazid-associated hepatitis suggest that the risk of fatal hepatitis may be higher in women, particularly Black and Hispanic women, and during the postpartum period.

Regular eye examinations should be done in patients who develop visual symptoms while taking the drug. The manufacturers recommend that eye examinations, including ophthalmoscopy, be done before starting isoniazid and periodically during treatment even if no visual symptoms occur. However, some clinicians question whether this precaution is necessary.

Isoniazid should be used with caution in patients who are malnourished or at risk of neuropathy (for example, people with diabetes or alcohol use disorder), and pyridoxine should generally be given at the same time. In Canadian practice, pyridoxine is generally recommended for children and adolescents with unusually low milk and meat intake, those with nutritional deficiencies (including all children with symptomatic HIV infection), breast-feeding infants and their mothers, and pregnant women.

Isoniazid is contraindicated in patients with acute liver disease or a history of previous isoniazid-associated liver injury. Although preventive treatment should generally be deferred in these patients, a positive hepatitis B surface antigen test is not considered a contraindication to this 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.

Side Effects

Isoniazid is generally well tolerated at the currently recommended doses. However, patients who are slow acetylators of isoniazid and those with advanced HIV disease appear to have a higher rate of some side effects. Patients with poor nutrition are also at risk of peripheral neuritis, one of the most common side effects of isoniazid. Other neurologic side effects include psychotic reactions and seizures. Pyridoxine may be given to prevent or treat these side effects. Optic neuritis has also been reported. Temporary increases in liver enzymes occur in 10 to 20% of patients during the first few months of treatment and usually return to normal despite continued treatment. Symptomatic hepatitis occurs in about 0.1 to 0.15% of patients given isoniazid alone, but the risk can increase with age, regular alcohol use, and chronic liver disease. The effect of acetylator status remains uncertain.

Raised liver enzymes together with clinical signs of hepatitis, such as nausea, vomiting, or fatigue, may indicate liver damage. In these situations, isoniazid should be stopped while the patient is being assessed and should only be restarted cautiously once liver function has recovered. Deaths due to liver necrosis have occurred.

Interactions

The risk of hepatotoxicity may be higher in patients taking isoniazid with a rifamycin or other potentially hepatotoxic drugs, including alcohol. Isoniazid can inhibit the liver metabolism of a number of drugs, sometimes leading to increased toxicity. These include the antiepileptics carbamazepine, ethosuximide, primidone, and phenytoin; the benzodiazepines diazepam and triazolam; chlorzoxazone; theophylline; and disulfiram. Isoniazid has also been associated with increased concentrations and enhanced effects or toxicity of clofazimine, cycloserine, and warfarin.

Mechanism of Action

Isoniazid may be bacteriostatic or bactericidal, depending on the concentration reached at the site of infection and the susceptibility of the infecting organism.

Although the exact way isoniazid works has not been fully established, several mechanisms have been proposed, including interference with the metabolism of bacterial proteins, nucleic acids, carbohydrates, and lipids.

One of the drug's main actions appears to be inhibition of mycolic acid synthesis in susceptible bacteria, leading to loss of acid-fastness and disruption of the bacterial cell wall. Isoniazid is active against susceptible bacteria only when they are dividing. Susceptible bacteria may undergo 1 or 2 divisions before multiplication is stopped. 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.

Resistance

Natural and acquired resistance to isoniazid has been demonstrated in vitro and in vivo in strains of M. tuberculosis. In vitro, resistance to isoniazid develops stepwise. The mechanism of resistance may be related to the drug's failure to penetrate or be taken up by resistant bacteria.

Resistant strains can develop quickly from initially susceptible bacteria if isoniazid is used alone to treat clinical tuberculosis. However, resistance does not appear to be a major problem when the drug is used alone for preventive therapy. When isoniazid is combined with other antituberculosis agents to treat clinical tuberculosis, the emergence of resistant strains may be delayed or prevented.

Pharmacokinetics

Isoniazid is readily absorbed from the gastrointestinal tract and after intramuscular injection. Peak concentrations of about 3 to 7 micrograms/mL appear in the blood 1 to 2 hours after an oral fasting dose of 300 mg. Food reduces the rate and extent of absorption of isoniazid. Isoniazid is not considered to bind appreciably to plasma proteins and is distributed into all body tissues and fluids, including the cerebrospinal fluid (CSF). It appears in fetal blood if given during pregnancy and is distributed into breast milk. The plasma half-life of isoniazid ranges from about 1 to 6 hours, with shorter half-lives in fast acetylators. The main metabolic route is acetylation of isoniazid to acetyl isoniazid by N-acetyltransferase in the liver and small intestine. In patients with normal renal function, more than 75% of a dose appears in the urine within 24 hours, mainly as metabolites. Small amounts of the drug are also excreted in the feces. Isoniazid is removed by hemodialysis.

Distribution

Therapeutic concentrations of isoniazid have been detected in CSF and synovial fluid several hours after an oral dose. Diffusion into saliva is good, and it has been suggested that salivary concentrations could be used instead of serum concentrations in pharmacokinetic studies.

HIV-infected Patients

Malabsorption of isoniazid and other antituberculous drugs may occur in patients with HIV infection and tuberculosis and may contribute to acquired drug resistance and reduced effectiveness of tuberculosis treatment.

Pregnancy

Isoniazid crosses the placenta, and average fetal concentrations of 61.5 and 72.8% of the maternal serum or plasma concentration have been reported. The half-life of isoniazid may be prolonged in neonates.

Storage

Isoniazid preparations should be protected from light, air, and excessive heat. Isoniazid tablets should be stored in tightly closed, light-resistant containers at a temperature below 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. Isoniazid injection should be protected from light and stored at a temperature below 40°C, preferably between 15-30°C; avoid freezing. At low temperatures, isoniazid in solution tends to crystallize, and the injection should be warmed to room temperature to redissolve the crystals before use.

Overdosage

An overdose of isoniazid has caused nausea, vomiting, dizziness, slurred speech, blurred vision, and visual hallucinations, including bright colours and strange designs. Symptoms of overdose usually occur within 30 minutes to 3 hours after taking the drug. After marked overdose, respiratory distress and CNS depression, progressing rapidly from stupor to coma, severe intractable seizures, metabolic acidosis, acetonuria, and hyperglycemia have occurred. If untreated or inadequately treated, an isoniazid overdose may be fatal.

Treatment of Overdose

When managing isoniazid overdose, the airway should be secured and adequate breathing established immediately. Seizures may be controlled with IV diazepam or short-acting barbiturates and a dose 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 full dose has been given. If seizures are controlled and the overdose is recent, within 2-3 hours, the stomach should be emptied by gastric lavage.

Blood gases and serum electrolyte, glucose, and BUN levels should be measured. Blood should be typed and cross-matched in case hemodialysis is required. IV sodium bicarbonate should be given to control metabolic acidosis and repeated as needed; the dose should be adjusted based on lab test results.