Carbamazepine Toxicity

Carbamazepine has a therapeutic range of 4 to 12 mg/L (17 to 51 micromol/L), erratic and delayed absorption (peak up to 24 to 72 hours in overdose), and an active metabolite (carbamazepine-10,11-epoxide). It induces its own metabolism. Toxicity follows acute overdose (ingestion of over 20 mg/kg is toxic and over 100 mg/kg severe), or chronic accumulation from drug interactions.

Interacting inhibitors of CYP3A4 raise levels: erythromycin, clarithromycin, fluconazole, verapamil, diltiazem, isoniazid, valproate (epoxide) and grapefruit juice.

Mechanisms: sodium channel blockade (cardiac conduction and neurotoxicity), anticholinergic and structural similarity to tricyclic antidepressants, and vasopressin-like effect (hyponatremia). Complications: seizures, coma, respiratory depression, cardiac conduction abnormality, hyponatremia, rhabdomyolysis and, over days, delayed deterioration from sustained absorption.

• Nystagmus, diplopia, ataxia, dysarthria, drowsiness
• Dystonia, myoclonus, choreoathetosis, hyperreflexia
• Tachycardia, anticholinergic features (dry mouth, urinary retention, ileus, mydriasis)
• Seizures, coma, apnea (levels over 40 mg/L)
• ECG: sinus tachycardia, QRS and QT prolongation, atrioventricular block (levels over 40 mg/L)
• Hyponatremia with confusion
• Red flags: coma, seizures, respiratory depression, QRS widening and bradyarrhythmia

1. Serum carbamazepine level at presentation and every 4 to 6 hours until two falling values (the peak may be delayed to 72 hours with large or sustained-release ingestions).
2. ECG and continuous monitoring.
3. Electrolytes (sodium), glucose, creatinine, creatine kinase, liver tests, full blood count, arterial blood gas.
4. Paracetamol and salicylate levels.
5. Urine tricyclic screen often gives a false positive with carbamazepine.

Differentials: tricyclic antidepressant poisoning, phenytoin and other anticonvulsant toxicity, anticholinergic toxicity, cerebellar disease, other sedative overdose.

1. Airway and supportive care: intubate for coma, with IV crystalloid.
2. Activated charcoal: 50 g orally (children 1 g/kg, maximum 50 g) within 1 to 2 hours, then repeated doses of 25 to 50 g every 4 hours (children 0.5 g/kg every 4 hours) for 24 to 48 hours in alert patients with intact bowel sounds, a protected airway and no ileus. Stop for ileus or falling levels. Use an antiemetic (ondansetron 4 to 8 mg IV).
3. Seizures: lorazepam 4 mg IV (children 0.1 mg/kg, maximum 4 mg), repeated once, then phenobarbital 15 to 20 mg/kg IV over 20 minutes if refractory. Avoid phenytoin.
4. QRS widening above 100 ms or ventricular arrhythmia: sodium bicarbonate 1 to 2 mmol/kg IV (1 to 2 mL/kg of 8.4%), repeated until QRS narrows, with a target pH of 7.50 to 7.55.
5. Hypotension: crystalloid 20 mL/kg and norepinephrine 0.05 to 0.5 micrograms/kg/min.
6. Hyponatremia: fluid restriction to 800 mL daily, and 3% saline 100 mL IV over 10 minutes only for seizures, with correction not faster than 8 mmol/L in 24 hours.
7. Extracorporeal removal (haemodialysis or haemoperfusion): recommended for a level over 60 mg/L (254 micromol/L), or prolonged coma, recurrent seizures or life-threatening arrhythmia. Suggested for a level over 40 mg/L with these features in a patient on optimal management. Stop when the level is under 10 mg/L.
8. Observation: at least 24 hours for sustained-release products, with repeated levels.

Prevention: check levels after any change in interacting drugs, and test sodium, liver function and blood count periodically. Counsel on severe rash risk (Stevens-Johnson syndrome) in the first 8 weeks, particularly in people carrying certain HLA types.