Isoniazid is used to treat mycobacterial infections, including Mycobacterium tuberculosis. Due to its specific and therefore limited use, overdose is uncommon.

The hallmarks of toxicity are seizures, coma and metabolic acidosis. Pyridoxine, given in a dose proportional to the ingested dose of isoniazid, is used as an antidote.

The toxicity of isoniazid results from functional pyridoxine toxicity. This occurs through two mechanisms 1) Isoniazid metabolites inhibiting the action of pyridoxine phosphokinase, which converts pyridoxine to its active form and 2) Isoniazid directly combining with pyridoxal phosphate, forming inactive hydrazone.

Functional pyridoxine deficiency leads to deficiency of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA), resulting in seizures.

Isoniazid also acts as a weak monoamine oxidase inhibitor (MAOi) and has potential to cause serotonin toxicity (if taken with another serotonergic agent) and tyramine reactions.

Severe toxicity has been reported with ingestion of greater than 20mg/kg and are common with ingestions over 6g.

Isoniazid is well absorbed with a high bioavailability (90%). In therapeutic use, peak plasma concentrations occur at 1-2 hours post ingestion.

Isoniazid has good tissue penetration with a volume of distribution of 0.7-0.8L/kg. Protein binding is low.

Metabolism is primarily hepatic, predominantly by cytochrome CYP2E1. The rate of metabolism varies depending on if the patient is a slow (common in those of Asian and Scandinavian descent) or fast acetylator (common in those of African and Caucasian descent).

Elimination if primarily via the kidneys. The elimination half life ranges from 1-4 hours but can be prolonged in slow acetylators.

Acute toxicity results in seizures, coma and metabolic acidosis, generally occurring within 2 hours of ingestion.

In patients presenting with seizures, coma or unexplained metabolic acidosis, who have a history of tuberculosis (or have contact with those with tuberculosis) isoniazid toxicity should be considered.

• Bloods gas analysis – looking for metabolic acidosis
• Serum creatine kinase – likely to be elevated in the setting of seizures
• Renal and liver panels

Patients who have compromise of airway or breathing, secondary to coma on refractory seizures, should be intubated and ventilated.

Ensure adequate intravenous hydration to patients with seizures especially if they have evidence of rhabdomyolysis.

First line management of seizures is with pyridoxine (see below), if this is unavailable, or if seizures are refractory, then treat with an intravenous benzodiazepine, and rapidly escalate to a barbiturate if unresponsive to benzodiazepines.

Offer activated charcoal to all patient presenting within 2 hours of an intentional overdose of isoniazid. If the patient is intubated this can be given by nasogastric or orogastric tube.

Isoniazid is dialysable, but its use as a treatment should be considered second line, after antidotal treatment with pyridoxine.

Consider haemodialysis if:
• Seizures or metabolic acidosis are refractory to pyridoxine
• Seizures or metabolic acidosis with inadequate supplies of pyridoxine

Intravenous pyridoxine (vitamin B6) is indicated for isoniazid toxicity complicated by seizures or metabolic acidosis. Give:

In those ingesting 5g or less of isoniazid:
Pyridoxine in a gram for gram dose with the ingested dose of isoniazid (i.e. if 3g of isoniazid has been ingested, give 3g intravenous Pyridoxine).

In those ingesting >5g or with an unknown dose:
Pyridoxine 5g.

Infuse the required dose at a rate of 500mg/minute. If seizures stop during infusion, give the remainder of the infusion over 4hr. Dose can be repeated at 30 minutes if seizures or metabolic acidosis do not resolve.

Intravenous pyridoxine is not always readily available (or an adequate dose may not be available). In this situation an oral dose of pyridoxine equivalent to the ingested dose of isoniazid can be given, noting that if activated charcoal has been given the bioavailability of this will be reduced.

Pyridoxine is cleared by dialysis, so the dose will have to be adjusted in patients who are being dialysed – discuss with a clinical toxicologist.

Observe asymptomatic patients following acute isoniazid overdose for 12 hours post ingestion.

Patients who develop severe isoniazid toxicity (seizures, coma, metabolic acidosis) require management in an intensive care unit.

Given the risk of tyramine reactions, at discharge, patients should be advised to follow a tyramine-free diet for 3 days.

1. Bateman DN, Page CB. Antidotes to coumarins, isoniazid, methotrexate and thyroxine, toxins that work via metabolic processes. Br J Clin Pharmacol 2016;81(3):437–45. PDF
2. Dilrukshi M, Ratnayake CAP, Gnanathasan CA. Oral pyridoxine can substitute for intravenous pyridoxine in managing patients with severe poisoning with isoniazid and rifampicin fixed dose combination tablets: a case report. BMC Res Notes 2017;10(1):370. PDF
3. Morrow LE, Wear RE, Schuller D, Malesker M. Acute isoniazid toxicity and the need for adequate pyridoxine supplies. Pharmacotherapy 2006;26(10):1529–32. PDF
4. Mowry JB, Shepherd G, Hoffman RS, Lavergne V, Gosselin S, Nolin TD, et al. Extracorporeal treatments for isoniazid poisoning: Systematic review and recommendations from the EXTRIP workgroup. Pharmacotherapy 2021;41(5):463-78. EXTRIP
5. Skinner K, Saiao A, Mostafa A, Soderstrom J, Medley G, Roberts MS, et al. Isoniazid poisoning: Pharmacokinetics and effect of hemodialysis in a massive ingestion. Hemodial Int 2015;19(4):E37–40. PDF
6. Wason S, Lacouture PG, Lovejoy FH Single high-dose pyridoxine treatment for isoniazid overdose. JAMA 1981;246(10):1102–4. PDF