What is the anti-tubercular (Anti-Tuberculosis) treatment regimen in patients with isoniazid (Isoniazid)-induced neurotoxicity?

From the Guidelines

In cases of isoniazid-induced neurotoxicity, the recommended approach is to discontinue isoniazid immediately and administer pyridoxine (vitamin B6) at a dose of 100-200 mg daily to reverse the neurotoxic effects, as supported by the most recent evidence from 1. The anti-tubercular regimen should be modified by replacing isoniazid with a fluoroquinolone, typically levofloxacin (750-1000 mg daily) or moxifloxacin (400 mg daily), as recommended by the World Health Organization and supported by studies such as 1. The modified regimen should include rifampin (600 mg daily), ethambutol (15-25 mg/kg daily), and pyrazinamide (20-25 mg/kg daily) for the initial 2 months, followed by rifampin and ethambutol with the fluoroquinolone for the continuation phase, as outlined in the treatment guidelines for isoniazid-resistant tuberculosis 1. Some key points to consider when modifying the regimen include:

• The total treatment duration remains 6-9 months depending on the site and severity of tuberculosis.
• Patients should be monitored closely for adverse effects of the new regimen, including QT prolongation with fluoroquinolones.
• Isoniazid causes neurotoxicity by depleting pyridoxine, which is essential for nerve function, and by inhibiting GABA synthesis.
• Patients with risk factors such as malnutrition, diabetes, HIV, alcoholism, pregnancy, or renal failure should receive prophylactic pyridoxine (25-50 mg daily) when taking isoniazid to prevent neurotoxicity, although the current evidence does not provide clear guidance on the use of high-dose isoniazid in such cases 1.

From the FDA Drug Label

Overdosage Signs and Symptoms Isoniazid overdosage produces signs and symptoms within 30 minutes to 3 hours after ingestion. ... Patients who acutely ingest > 80 mg/kg should be treated with intravenous pyridoxine on a gram per gram basis equal to the isoniazid dose ... If the dose of isoniazid is known, the patient should be treated initially with a slow intravenous bolus of pyridoxine, over 3 to 5 minutes, on a gram per gram basis, equal to the isoniazid dose.

The treatment for isoniazid-induced neurotoxicity involves administering intravenous pyridoxine on a gram per gram basis equal to the isoniazid dose. Key points include:

• Pyridoxine dosage: equal to the isoniazid dose, or an initial dose of 5 grams in adults or 80 mg/kg in children if the isoniazid dose is unknown
• Administration: slow intravenous bolus over 3 to 5 minutes
• Seizure management: repeat pyridoxine dosage if seizures continue, or consider administering diazepam if pyridoxine is ineffective 2

From the Research

Isoniazid Induced Neurotoxicity

• Isoniazid (INH) is a widely prescribed anti-tuberculosis drug that can cause peripheral neuropathy due to a disturbance of vitamin B6 metabolism 3.
• The metabolites of isoniazid, including hydrazine, have been found to be neurotoxic in cultured mouse dorsal root ganglion neurons and hybrid neuronal cell line 3.
• Pyridoxine, which is used to prevent or ameliorate isoniazid-induced neuropathy, did not consistently reverse the neurotoxicity of isoniazid metabolites in cell cultures, but some interaction with hydrazine cannot be ruled out 3.

Treatment of Isoniazid Induced Neurotoxicity

• Parenteral pyridoxine administration is an effective method in treating isoniazid intoxication, and it is recommended to have the intravenous form of pyridoxine available in emergency care units 4.
• Discontinuation of the therapeutic regimen and general supportive measures are also recommended for the treatment of acute intoxications with antituberculosis drugs, including isoniazid 5.
• In cases of isoniazid overdose, seizures, metabolic acidosis, and prolonged obtundation can occur, and prompt treatment with pyridoxine can reverse these symptoms 4, 6.

Determinants of Isoniazid Pharmacokinetics

• Several factors can influence the pharmacokinetics of isoniazid, including human immunodeficiency virus infection, formulation factors, patient sex, age, and history of previous antituberculosis treatment 7.
• The dose per kilogram of body weight is also associated with the concentrations of isoniazid, and further studies are required to assess the implications of variations in antituberculosis drug concentrations for efficacy and safety 7.