Nervous System Effects
Peripheral neuritis, usually preceded by paresthesia of the feet and hands, is the most common adverse effect of isoniazid and occurs most frequently in malnourished patients and those predisposed to neuritis (e.g., alcoholics, diabetics). Rarely, other adverse nervous system effects have also occurred including seizures, toxic encephalopathy, muscle twitching, ataxia, stupor, tinnitus, euphoria, memory impairment, separation of ideas and reality, loss of self-control, dizziness, and toxic psychosis.
Neurotoxic effects may be prevented or relieved by the administration of 10-50 mg of pyridoxine hydrochloride daily during isoniazid therapy, and pyridoxine should be administered in malnourished patients, pregnant women, and those predisposed to neuritis (e.g., HIV-infected individuals). In addition, optic neuritis and atrophy have been reported with isoniazid.
Hepatic Effects
Mild hepatic dysfunction, as evidenced by mild and transient increases in serum AST (SGOT), ALT (SGPT), and bilirubin concentrations, has occurred in approximately 10-20% of patients receiving isoniazid, usually during the first 4-6 months of therapy. In most cases, enzyme concentrations return to pretreatment values despite continuation of isoniazid, but progressive liver dysfunction, bilirubinuria, jaundice, and severe and sometimes fatal hepatitis have occurred rarely.
The incidence of isoniazid-associated hepatitis is lowest in patients younger than 20 years of age and greatest in daily users of alcohol and patients 35 years of age or older. The American Academy of Pediatrics (AAP) states that the incidence of hepatitis during isoniazid therapy in otherwise healthy infants, children, and adolescents is rare and that routine determination of serum aminotransferase concentrations are not recommended.
The manufacturers state that progressive liver damage may occur in up to 2.3% of patients older than 50 years of age who receive isoniazid. However, data from one study suggest that hepatitis occurs in approximately 4.5% of patients older than 65 years of age who receive the drug. If symptoms of hepatitis or signs suggestive of hepatic damage occur during isoniazid therapy, the drug should be discontinued promptly.
Sensitivity Reactions
Hypersensitivity reactions, including fever, skin eruptions (morbilliform, maculopapular, purpuric, or exfoliative), lymphadenopathy, vasculitis, and, rarely, hypotension, have occurred rarely with isoniazid, usually 3-7 weeks following initiation of therapy.
At the first sign of a hypersensitivity reaction, all drugs should be discontinued. If isoniazid is reinstituted, the drug should be restarted in small and gradually increasing doses only after symptoms have cleared. If there is any indication of recurrence of hypersensitivity, isoniazid should be discontinued immediately.
Hematologic Effects
Adverse hematologic effects, including agranulocytosis, eosinophilia, thrombocytopenia, methemoglobinemia, and hemolytic, sideroblastic, or aplastic anemia, have occurred in patients receiving isoniazid.
Other Adverse Effects
Other reported adverse effects of isoniazid include nausea, vomiting, epigastric distress, dryness of the mouth, pyridoxine deficiency, pellagra, hyperglycemia, metabolic acidosis, and urinary retention and gynecomastia in males. A systemic lupus erythematosus-like syndrome and a rheumatic syndrome with arthralgia have also occurred. IM administration of isoniazid has caused irritation at the site of injection.
Precautions and Contraindications
Liver function tests should be performed periodically in patients receiving isoniazid. In addition, patients should be questioned monthly for signs and symptoms of liver disease and should be instructed to report to their physician any of the prodromal symptoms of hepatitis (e.g., persistent fatigue, weakness or fever exceeding 3 days, malaise, nausea, vomiting, unexplained anorexia). If these symptoms appear or if signs suggestive of hepatic damage occur, isoniazid should be discontinued promptly, since continued use of the drug in these patients has been reported to cause a more severe form of liver damage.
Some clinicians recommend discontinuing isoniazid therapy if serum aminotransferase concentrations are more than 3-5 times higher than the upper limit of the normal range or if patients develop manifestations of hepatitis. Patients who have had signs or symptoms of hepatic damage during isoniazid therapy generally should receive alternative antituberculosis agents, but if isoniazid must be reinstituted, the drug should be restarted only after hepatic symptoms and laboratory abnormalities have cleared. Isoniazid should be restarted in very small and gradually increasing dosages and should be discontinued immediately if there is any indication of recurrent liver involvement.
The AAP states that the incidence of hepatitis during isoniazid therapy in children is rare and that routine determination of serum aminotransferase concentrations is not recommended. However, liver function tests should be monitored approximately monthly during the first several months of treatment in children with severe tuberculosis, especially meningitis and disseminated disease.
The AAP states that monitoring of liver function tests should also be performed in patients with concurrent or recent liver disease, those receiving a high daily dose of isoniazid (more than 10 mg/kg daily) in combination with rifampin and/or pyrazinamide, those who are pregnant or within 6 weeks postpartum, those with clinical evidence of hepatotoxicity, and those with hepatobiliary tract disease from other causes, and those receiving other hepatotoxic drugs concomitantly (especially anticonvulsants). In most other patients, monthly clinical evaluations for 3 months, followed by evaluation every 1-3 months to observe for manifestations of hepatitis or other adverse effects of drug therapy, is appropriate.
Isoniazid should be used with caution in daily users of alcohol, individuals who inject illicit drugs, patients with chronic liver disease or severe renal impairment, and those with a history of prior therapy in whom isoniazid was discontinued because of adverse effects (e.g., headache, dizziness, nausea) possibly, but not definitely, related to the drug. Minor dosage adjustments may be necessary in patients with severe renal impairment. Limited data based on a retrospective analysis of isoniazid-associated hepatitis deaths suggest that the risk of fatal hepatitis associated with the drug may be increased in women, particularly black and Hispanic women, and during the postpartum period.
Periodic ophthalmologic examinations should be performed in patients who develop visual symptoms while receiving the drug. The manufacturers recommend that ophthalmologic examinations (including ophthalmoscopy) be performed prior to initiation of isoniazid therapy and periodically during therapy with the drug, even without the occurrence of visual symptoms; however, some clinicians question the necessity of this precaution.
Isoniazid should be used with caution in patients who are malnourished or predisposed to neuropathy (e.g., diabetics, alcoholics), and pyridoxine generally should be administered concomitantly.The American Academy of Pediatrics (AAP) recommends concomitant pyridoxine therapy in children and adolescents who have an abnormally low milk and meat intake, in those with nutritional deficiencies (including all symptomatic HIV-infected children), in breast-feeding infants and their mothers, and pregnant women.
Isoniazid is contraindicated in patients with acute liver disease or a history of previous isoniazid-associated hepatic injury. Isoniazid preventive therapy should be deferred in patients with acute liver disease; however, the ATS and CDC state that seropositivity for hepatitis B surface antigen is not in itself a contraindication for such therapy. Isoniazid is also contraindicated in patients with a history of severe adverse reactions to the drug, including severe hypersensitivity reactions or drug fever, chills, and arthritis.
Carcinogenicity
Isoniazid has been reported to induce pulmonary tumors in animals; however, there is no evidence to date to support carcinogenic effects in humans.
Pregnancy and Lactation
No isoniazid-related congenital abnormalities have been observed in mammalian reproductive studies; however, it has been reported that isoniazid may exert an embryocidal effect when the drug is administered orally in pregnant rats and rabbits.
Although safe use of the drugs during pregnancy has not been definitely established, isoniazid (combined with rifampin and/or ethambutol) has been used to treat clinical tuberculosis in pregnant women. The American Thoracic Society (ATS), US Centers for Disease Control and Prevention (CDC), and Infectious Diseases Society of America (IDSA) state that isoniazid is considered safe for use in pregnant women, but the risk of hepatitis may be increased in the peripartum period.
The manufacturers state that the potential benefits of isoniazid therapy for latent tuberculosis infection during pregnancy should be weighed against the possible risks to the fetus. Use of antituberculosis agents for the treatment of latent tuberculosis infection in pregnant women is controversial.
Some experts prefer to delay treatment until after delivery because pregnancy itself does not increase the risk for progression to disease and 2 studies suggest that there may be an increased risk of hepatotoxicity during pregnancy and the early postpartum period. However, the American Academy of Pediatrics (AAP) and other experts state that pregnant women who have positive tuberculin skin tests without evidence of clinical tuberculosis should receive therapy with isoniazid for latent tuberculosis infection if they are likely to have been infected recently or have high-risk medical conditions, especially human immunodeficiency virus (HIV) infection. The AAP recommends that such therapy begin after the first trimester.
If isoniazid is administered during pregnancy, concomitant administration of pyridoxine (25 mg daily) is recommended.
Because isoniazid crosses the placenta and is distributed into milk, neonates and breast-fed infants of isoniazid-treated mothers should be carefully observed for evidence of adverse effects.