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Carbamazepine poisoning

Carbamazepine poisoning
Literature review current through: Jan 2024.
This topic last updated: Nov 04, 2022.

INTRODUCTION — Carbamazepine has been used for many years for the treatment of both partial and generalized seizures, as well as trigeminal neuralgia. It has also been used as a mood stabilizer and for treatment of neuropathic pain syndromes.

In 2020, the American Association of Poison Control Centers reported 2562 toxic exposures to carbamazepine [1]. Of these, 1257 were isolated ingestions and 908 were treated in a health care facility. There was one death, and 52 patients experienced major toxicity, defined as life-threatening or resulting in significant disability [1].

The toxicology, diagnosis, and management of acute carbamazepine poisoning are discussed here. The clinical use of carbamazepine and chronic complications related to its use are reviewed separately.

(See "Overview of the management of epilepsy in adults".)

(See "Seizures and epilepsy in children: Initial treatment and monitoring".)

(See "Antiseizure medications: Mechanism of action, pharmacology, and adverse effects".)

PHARMACOLOGY AND CELLULAR TOXICOLOGY — Carbamazepine interacts with multiple receptors and ion channels. Its therapeutic effect results from binding to sodium channels in their inactivated state, which inhibits neuron depolarization and decreases glutamate release [2]. It is also anticholinergic, a property that is more relative in overdose than the therapeutic setting [3]. (See "Anticholinergic poisoning".)

In carbamazepine toxicity, sodium channel blockade may manifest as cardiovascular toxicity, particularly prolongation of the QRS interval. This conduction abnormality predisposes patients to ventricular dysrhythmias and hypotension [4].

Carbamazepine appears to have a paradoxical effect on adenosine receptors. In therapeutic doses, the drug inhibits presynaptic reuptake of adenosine, resulting in modulation and inhibition of glutamate neurotransmission [5,6]. In overdose, carbamazepine antagonizes adenosine receptors, resulting in a proconvulsant effect, which explains the seizure activity commonly seen in carbamazepine toxicity [6].

KINETICS — Carbamazepine is available in both immediate-release and controlled-release tablets and an immediate-release oral suspension. Absorption of therapeutic doses of an immediate-release formulation occurs in 3 to 12 hours [2,7]. In overdose, absorption is erratic and may be prolonged, with peak concentrations occurring over 96 hours after ingestion of a controlled-release formulation [8]. The volume of distribution ranges from 0.8 to 1.8 L/kg, and protein binding is estimated to be between 75 and 90 percent [9].

Carbamazepine undergoes hepatic metabolism, primarily through cytochrome P450 (CYP) 3A4 [10]. More than 30 metabolites have been identified [7,11]. The most important of these are carbamazepine-10,11-epoxide, which has intrinsic anticonvulsant activity, and trans-10-11-dihydroxy-10,11-dihydrocarbamazepine, an arene oxide metabolite believed to be responsible for the hypersensitivity reactions and teratogenic effects of carbamazepine [12,13].

Carbamazepine is a CYP 3A4 substrate as well as an inducer of multiple cytochrome P450 isoenzymes and may be subject to a number of drug-drug interactions (table 1). Toxic concentrations of carbamazepine may result from CYP 3A4 inhibition from erythromycin, fluoxetine, and cimetidine, among other drugs [2,14,15]. Conversely, CYP 3A4 inducers, such as phenytoin and phenobarbital, may decrease carbamazepine concentrations [10]. Plasma concentrations of many medications, including haloperidol and clozapine [16,17], are reduced in the setting of carbamazepine use. Carbamazepine induces its own metabolism, and dosage requirements increase with chronic use [11].

Carbamazepine's elimination half-life demonstrates significant variability with therapeutic dosing, ranging from 12 to 17 hours following chronic therapeutic use [2]. The half-life can be significantly prolonged following overdose and averages 35 hours following a single overdose and 20 hours after multiple dosages [18]. In overdose, carbamazepine's elimination is thought to display zero-order kinetics [18,19].

CLINICAL FEATURES — Clinicians should consider the diagnosis of carbamazepine toxicity in any patient with cerebellar symptoms, central nervous system (CNS) depression, and signs of the anticholinergic toxidrome, particularly if the patient is known to have a seizure disorder or access to anticonvulsants.

History — Important historical information in the patient with suspected carbamazepine poisoning includes:

Identity of any ingested pills, including dose and formulation (eg, immediate-release or controlled-release)

Approximate number of pills ingested

Time of ingestion

Whether the patient takes carbamazepine or any other medication chronically

Possible co-ingestants

Other helpful information includes symptoms prior to seeking medical care (such as vomiting, prolonged unconsciousness, or seizure activity) and whether any treatment was provided prior to arrival.

Examination and clinical manifestations — Carbamazepine toxicity frequently presents with neurologic, cardiovascular, and anticholinergic symptoms. Patients with mild carbamazepine toxicity or those presenting shortly after the ingestion when absorption remains incomplete may demonstrate drowsiness, nystagmus, and tachycardia [8,20-24]. More severe intoxication may manifest as lethargy, seizure, coma, hypotension, or dysrhythmia [21-25]. Signs and symptoms of anticholinergic toxicity are expected. Toxicity may be prolonged due to carbamazepine's delayed and erratic absorption. (See "Anticholinergic poisoning".)

Tachycardia is common following carbamazepine overdose. Hypotension is observed in moderate to severe poisoning and may be due to direct negative inotropic effects. Hyperthermia may be a result of anticholinergic effects (impaired heat dissipation) or from seizure activity [21,24].

Neurologic examination typically reveals altered mental status. The patient may be agitated, but CNS depression, ranging from drowsiness to coma, is more common [20-26]. Coma is often cyclical and consciousness may fluctuate abruptly from alert (although encephalopathic) to comatose [20,25]. Ataxia and dysmetria (loss of coordinated movement) are common [22,25]. Choreoathetosis or dyskinesia may be seen with therapeutic use or in overdose.

Seizures may occur, particularly in patients with underlying epilepsy [21-25]. Seizures are often self-limited but may rarely progress to status epilepticus [21,25]. Myoclonus, hypertonia, hypotonia, and choreoathetosis have all been described in the setting of acute carbamazepine toxicity [23,24,27]. A single case report has described sensorineural hearing loss [28].

Ocular examination frequently reveals nystagmus and mydriasis, and occasionally ophthalmoplegia [8,19,23,27]. Oropharyngeal examination often reveals dry mucus membranes, and may show signs of trauma, which can occur from a fall due to a depressed level of consciousness or seizure activity.

Abdominal examination may reveal hypoactive or absent bowel sounds and the urinary bladder may be palpable from urinary retention, both due to the anticholinergic effects of the drug. Abdominal tenderness is rare. Pancreatitis is rare, but has been described [29].

The skin may be hot, dry, and flushed and the axillae dry due to anticholinergic effects. One case report describes bullous eruptions following carbamazepine poisoning [30].

Chronic use of carbamazepine has been associated with leukopenia, agranulocytosis, and rarely, aplastic anemia. Other chronic side effects can include drug hypersensitivity, Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). Patients with Asian ancestry or carriers of the HLA-B*15:02 gene are at increased risk of carbamazepine-associated SJS/TEN. The US Food and Drug Administration recommends that patient populations at risk should be screened for the presence of the HLA-B*15:02 allele prior to starting carbamazepine [31]. Chronic side effects from carbamazepine therapy are discussed separately. (See "Antiseizure medications: Mechanism of action, pharmacology, and adverse effects", section on 'Carbamazepine' and "Aplastic anemia: Pathogenesis, clinical manifestations, and diagnosis", section on 'Drugs' and "Drug hypersensitivity: Classification and clinical features" and "Stevens-Johnson syndrome and toxic epidermal necrolysis: Pathogenesis, clinical manifestations, and diagnosis".)

DIFFERENTIAL DIAGNOSIS — Carbamazepine toxicity may present in a similar fashion to other poisonings as well as metabolic, infectious, or structural central nervous system (CNS) disorders.

The toxicologic differential diagnosis is based largely on the presenting symptoms. If anticholinergic toxicity is present, anticholinergic agents (eg, tricyclic antidepressants, antihistamines, phenothiazines, and cyclobenzaprine) should be considered. Cerebellar abnormalities and CNS depression should prompt consideration of sedative-hypnotic toxicity or toxic effects from other anticonvulsants, such as phenytoin, valproic acid, or topiramate. Serum drug testing may help refine the differential diagnosis. (See "Anticholinergic poisoning" and "Tricyclic antidepressant poisoning" and "Phenytoin poisoning" and "Valproic acid poisoning" and "Benzodiazepine poisoning".)

Signs of carbon monoxide (CO) poisoning include those occurring from cardiotoxicity and neurotoxicity, which are also prominent in carbamazepine poisoning. If CO poisoning is considered, a carboxyhemoglobin concentration should be obtained. (See "Carbon monoxide poisoning".)

CNS pathology, especially cerebellar disease, can present with findings similar to acute carbamazepine poisoning. Hypoglycemia, encephalitis-meningitis, status epilepticus, hepatic encephalopathy, subarachnoid hemorrhage, and stroke all may resemble carbamazepine toxicity. Hypoglycemia can be quickly excluded by finger-stick glucose testing. Neurologic imaging and analysis of the cerebrospinal fluid can distinguish many of these conditions from carbamazepine toxicity. (See "Hypoglycemia in adults without diabetes mellitus: Clinical manifestations, causes, and diagnosis" and "Clinical features and diagnosis of acute bacterial meningitis in adults" and "Convulsive status epilepticus in adults: Classification, clinical features, and diagnosis" and "Hepatic encephalopathy in adults: Clinical manifestations and diagnosis" and "Initial assessment and management of acute stroke".)

LABORATORY EVALUATION

General diagnostic testing in overdose — Routine laboratory evaluation of the poisoned patient should include the following:

Fingerstick glucose, to rule out hypoglycemia as the cause of any alteration in mental status

Acetaminophen and salicylate concentrations, to rule out these common co-ingestions

Pregnancy test in women of childbearing age

Serum carbamazepine concentration — Serum carbamazepine concentrations should be followed serially in an acute overdose. Serum concentrations may not peak for over 96 hours; concentrations should be obtained every four to six hours until there is a definite downward trend and the patient is improving clinically [8]. Therapeutic concentrations of carbamazepine range from 4 to 12 mcg/mL (17 to 51 micromol/L).

The relationship between carbamazepine concentrations and particular toxicities varies. Carbamazepine concentrations above 40 mcg/mL (170 micromol/L) correlate with an increased risk for seizures, apnea, dystonia, hypotension, and coma [22,25,27,32]. The relationship between the serum carbamazepine concentration and seizure risk is less consistent, but one small retrospective case series reported that seizures occurred exclusively in epileptic patients and with a serum carbamazepine concentration greater than 25 mcg/mL [32].

Oxcarbazepine can produce a false positive result with both serum carbamazepine immunoassay testing and gas chromatography/mass spectrometry. Oxcarbazepine is not metabolized to carbamazepine in vivo [33]. It is likely that a structurally similar or a common metabolite (10,11-dihydroxycarbamazepine) causes this interference. It is unclear if such interference occurs only following overdose of oxcarbazepine or if it is possible after therapeutic use.

Ancillary testing — Rarely, severe carbamazepine toxicity can cause QRS prolongation and dysrhythmia. Patients should be placed on continuous cardiac monitoring and a 12-lead electrocardiogram (ECG) should be obtained. Should QRS prolongation develop, sodium bicarbonate should be administered and a repeat ECG obtained. (See 'QRS interval prolongation' below.)

Sinus tachycardia is the most frequently observed cardiac effect of carbamazepine, but bradycardia, atrioventricular block, premature ventricular contractions, ventricular tachycardia, and junctional escape rhythms have all been attributed to carbamazepine toxicity [25].

Rhabdomyolysis may be present following an acute overdose of carbamazepine, if the patient has seized or experienced a prolonged period of unconsciousness. Creatine phosphokinase should be obtained initially and followed serially if elevated or if the history suggests the patient is at risk for rhabdomyolysis. (See "Rhabdomyolysis: Clinical manifestations and diagnosis" and "Clinical features and diagnosis of heme pigment-induced acute kidney injury".)

Imaging is not routinely needed following carbamazepine ingestion. However, if the diagnosis is in question, concomitant pathology is suspected, or the patient is encephalopathic or has signs of head trauma, computed tomography of the head is indicated. Also, if history or examination suggests aspiration or pulmonary edema, a chest radiograph should be obtained.

If urine toxicology testing is performed, carbamazepine may trigger a false positive result for tricyclic antidepressants on immunoassay because of structural similarities among these drugs [34-36].

Laboratory tests may reveal evidence of chronic toxicity. Examples include leukopenia, or rarely agranulocytosis, on a complete blood count [37], or hyponatremia on a basic metabolic profile [38]. Liver function tests (LFTs) are elevated in up to 30 percent of patients using carbamazepine chronically [20,39]. Hyperammonemia, although more common with valproic acid toxicity, has been reported in carbamazepine poisoning [40-42]. (See "Valproic acid poisoning", section on 'Hyperammonemia'.)

MANAGEMENT

Airway, breathing, and circulation — Patients with significant CNS depression may lose protective airway reflexes and should be intubated, particularly in light of their lower seizure threshold. Short-acting neuromuscular blocking agents (eg, succinylcholine) are preferable, so as not to mask subsequent seizure activity. Induction agents with GABA agonist activity (eg, midazolam) may be preferable depending upon the patient's hemodynamic status.

Hypotension is initially treated with isotonic crystalloid. Caution should be exercised in patients at risk for volume overload, such as those with underlying heart disease or carbamazepine-induced myocardial dysfunction. Direct-acting vasopressors (eg, norepinephrine) are used if intravenous (IV) fluids fail to correct the hypotension.

QRS interval prolongation — Sodium channel blockade may cause QRS interval prolongation and in other poisonings has been shown to predispose patients to ventricular dysrhythmias [43,44]. QRS prolongation due to carbamazepine toxicity is treated with sodium bicarbonate. A clear treatment threshold based upon the QRS duration has not been established; however, a reasonable practice is to give a bolus of 100 to 150 meq of sodium bicarbonate IV for QRS intervals longer than 110 milliseconds, particularly in patients with hypotension. Repeat boluses may be required. Treatment of drug-induced QRS prolongation with sodium bicarbonate is described in detail separately. (See "Tricyclic antidepressant poisoning", section on 'Sodium bicarbonate for cardiac toxicity'.)

We suggest avoiding class 1A (eg, procainamide) and 1C (eg, flecainide) antiarrhythmics in patients with acute carbamazepine poisoning, although no studies have documented adverse effects from such treatment.

Seizures — Seizures caused by carbamazepine overdose should be treated with gamma-aminobutyric acid (GABA) agonists, such as benzodiazepines (eg, diazepam). Propofol administered as a continuous infusion for the sedation of intubated patients also functions as an effective anticonvulsant. There is no role for phenytoin in the management of carbamazepine-induced seizures [45]. Electroencephalogram monitoring may be necessary in some patients.

Gastrointestinal decontamination

Activated charcoal — Activated charcoal (AC) remains the most common method of gastrointestinal (GI) decontamination for acute carbamazepine poisoning, although its effectiveness in improving clinical outcomes has not been proven [46]. The role of GI decontamination in the management of acute overdose is discussed separately. (See "Gastrointestinal decontamination of the poisoned patient".)

It is acceptable to give a single dose of AC (1 g/kg; maximum dose 50 g) to patients with a normal mental status who present within one to two hours of an acute overdose and are able to protect their airway [47,48]. AC should be withheld in spontaneously breathing patients with CNS sedation who may not be able to protect their airway. We do NOT recommend that endotracheal intubation be performed solely for the purpose of giving charcoal.

Multidose activated charcoal — We do not empirically recommend multiple dose activated charcoal (MDAC) in the treatment of carbamazepine toxicity, as this implies scheduled administration of more than two doses of activated charcoal. Although some literature suggests a benefit in giving MDAC for severe carbamazepine toxicity [46,49-52], there is little data to suggest improved outcomes and we do not believe that the benefits of this therapy outweigh the risks. (See "Gastrointestinal decontamination of the poisoned patient", section on 'Multidose activated charcoal'.)

However, a second dose of activated charcoal may be given to patients who are not at risk for aspiration and in whom the therapy is not contraindicated by evidence of decreased intestinal motility noted on physical examination (eg, decreased bowel sounds) or imaging studies (eg, dilated bowel loops with air fluid concentrations). Care should always be taken to ascertain normal intestinal motility prior to administering activated charcoal. The anticholinergic effects of carbamazepine cause decreased bowel motility and predispose patients to the development of an ileus, which often precludes MDAC therapy. We suggest that any administration of activated charcoal beyond the initial dose be given in consultation with a medical toxicologist or poison control center. (See 'Additional resources' below.)

Although both the American Academy of Clinical Toxicologists and the European Association of Poisons Centres and Clinical Toxicologists recommend that treatment with MDAC be "considered" following carbamazepine ingestions resulting in serious or life-threatening signs and symptoms, the authors note that there is no convincing evidence that MDAC reduces morbidity or mortality [49].

Other methods — There is no role for other types of GI decontamination for acute carbamazepine poisoning. Whole bowel irrigation after ingestion of sustained release tablets failed to reduce absorption in several reported cases [8,53,54], and we do not advocate its use. Gastric emptying (by syrup of ipecac or gastric lavage) is not recommended [55,56].

Extracorporeal elimination — We suggest that extracorporeal removal of carbamazepine be reserved for severely poisoned patients who continue to deteriorate (as manifest by signs such as multiple refractory seizures, hemodynamic instability requiring vasopressors, or life-threatening dysrhythmias) despite maximum supportive care [57]. Decisions regarding hemodialysis in the setting of carbamazepine intoxication should be made, whenever possible, in conjunction with a medical toxicologist. (See 'Additional resources' below.)

It remains questionable whether hemodialysis and related techniques enhance the elimination of carbamazepine. At therapeutic concentrations, carbamazepine is highly protein bound, limiting the effectiveness of extracorporeal elimination.

When extracorporeal elimination is used, high-flux hemodialysis is the preferred approach. The clearance rate for hemodialysis is superior to continuous venovenous hemodialysis (CVVHD), but the technique may not be feasible in hemodynamically unstable patients and the effect on clinical outcome remains unknown [58,59]. Data regarding clearance rates for CVVHD with or without albumin dialysate are underwhelming.

Charcoal hemoperfusion can be effective but is often difficult to obtain [8,60-64], and the procedure entails risks (eg, thrombocytopenia, coagulopathy, hypothermia, hypocalcemia, hypophosphatemia, and hypoglycemia) [61-64]. In a small retrospective study, patients managed with early charcoal hemoperfusion experienced lower peak carbamazepine concentrations, fewer cases of respiratory depression, fewer seizures, and shorter hospitalizations compared with patients not treated with extracorporeal elimination [65]. Plasmapheresis and plasma exchange have been used to enhance carbamazepine elimination [66], but outcome data are limited and use of these techniques cannot be recommended, pending further study. (See "Continuous kidney replacement therapy in acute kidney injury", section on 'Definition of CKRT modality'.)

Despite substantial improvement in hemodialysis and continuous renal replacement therapy (CRRT) technology, most of the evidence supporting extracorporeal elimination of carbamazepine in the setting of overdose remains limited to case reports and case series [58-60,67-71]. Many of these reports use serum carbamazepine concentrations before and after hemodialysis or CRRT to gauge effectiveness, but this approach can be misleading. To judge carbamazepine clearance accurately, the concentration of carbamazepine in the dialysate should be measured. In addition, some authors hypothesize that the active metabolite carbamazepine-10,11 epoxide (CBZ–E), with its lower degree of protein binding, can be effectively cleared via extracorporeal modalities thereby limiting toxicity. However, quantitative concentrations of this metabolite are rarely measured.

Physostigmine — We do not recommend the use of physostigmine to treat patients suffering anticholinergic effects from acute carbamazepine toxicity. Physostigmine's half-life is significantly shorter than carbamazepine's, and its therapeutic effects are transient compared to carbamazepine's toxicity. Moreover, carbamazepine's toxicity is not due solely to anticholinergic effects [72]. The use of physostigmine for anticholinergic poisoning is found separately. (See "Anticholinergic poisoning", section on 'Antidotal therapy with physostigmine for severe toxicity'.)

Other complications — Rhabdomyolysis requires aggressive hydration with intravenous fluids. Aspiration may warrant antibiotic therapy; mechanical ventilation may be necessary for respiratory failure. Hyponatremia may require urgent correction depending upon the rate and degree of the fall in the serum sodium concentration. (See "Aspiration pneumonia in adults" and "Overview of the treatment of hyponatremia in adults" and "Prevention and treatment of heme pigment-induced acute kidney injury (including rhabdomyolysis)", section on 'Prevention'.)

PEDIATRIC CONSIDERATIONS — Of the carbamazepine exposures reported in 2020, 218 involved children less than 20 years old. Nearly half of these were in patients under six years old [1].

Most pediatric ingestions produce only mild toxicity due to their accidental nature, and are characterized by ataxia, nystagmus, drowsiness, and emesis [19,27,73,74]. Peripheral anticholinergic signs are frequently absent [27,73]. The serum carbamazepine concentration at which more severe manifestations of toxicity develop is estimated to be lower than that of adults [27,74]. According to one case series, children with a serum carbamazepine concentration above 28 mcg/mL (117 micromol/L) are at highest risk of coma and apnea [27].

ADDITIONAL RESOURCES

Regional poison control centers — Regional poison control centers in the United States are available at all times for consultation on patients with known or suspected poisoning, and who may be critically ill, require admission, or have clinical pictures that are unclear (1-800-222-1222). In addition, some hospitals have medical toxicologists available for bedside consultation. Whenever available, these are invaluable resources to help in the diagnosis and management of ingestions or overdoses. Contact information for poison centers around the world is provided separately. (See "Society guideline links: Regional poison control centers".)

Society guideline links — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Treatment of acute poisoning caused by specific agents other than drugs of abuse".)

SUMMARY AND RECOMMENDATIONS

PharmacologyCarbamazepine binds to sodium channels in their inactivated state, inhibiting neuron depolarization and decreasing glutamate release. It is also anticholinergic and antagonizes adenosine receptors in overdose, resulting in a proconvulsant effect. Toxicity may be prolonged due to carbamazepine's delayed and erratic absorption. (See 'Pharmacology and cellular toxicology' above and 'Kinetics' above.)

History – Important historical information in the patient with suspected carbamazepine poisoning includes (see 'History' above):

Identity of any ingested pills, including dose and formulation (eg, immediate release or controlled release)

Time of ingestion

Whether the patient takes carbamazepine or any other medication chronically

Possible co-ingestants

Clinical featuresCarbamazepine toxicity frequently presents with neurologic and cardiovascular symptoms. (See 'Examination and clinical manifestations' above.)

Patients with mild carbamazepine toxicity, or those presenting shortly after ingestion, may demonstrate signs such as drowsiness, nystagmus, and tachycardia. After acute overdose, tachycardia is common.

Severe intoxication may manifest as lethargy, seizure, coma, hypotension, or dysrhythmia. Signs and symptoms of anticholinergic toxicity are expected.

Sodium channel blockade from carbamazepine overdose may cause QRS prolongation and predispose to ventricular dysrhythmias.

Hyperthermia may result from anticholinergic effects or seizure activity.

The patient may be agitated, but central nervous system (CNS) depression, ranging from drowsiness to coma, is more common. Fluctuations in consciousness are classically encountered in carbamazepine toxicity.

Differential diagnosisCarbamazepine toxicity may present in a similar fashion to other poisonings (eg, anticholinergics, anticonvulsants, sedative hypnotics) as well as metabolic and other non-toxicologic disorders. Considerations include carbon monoxide poisoning, hypoglycemia, CNS infection, intracranial hemorrhage, and stroke. (See 'Differential diagnosis' above.)

Laboratory evaluation – Serum carbamazepine concentrations should be followed serially in an acute overdose. Concentrations may not peak for a few days; concentrations should be obtained every four to six hours until there is a definite downward trend and the patient is improving clinically. Other useful diagnostic tests include fingerstick glucose, acetaminophen and salicylate concentrations, blood count, serum electrolytes, creatine phosphokinase, liver function tests, pregnancy test, and an electrocardiogram. (See 'Laboratory evaluation' above.)

Management

Airway control – Patients with significant CNS depression may lose protective airway reflexes and should be intubated. Short-acting neuromuscular blocking agents are preferable so as not to mask subsequent seizure activity. Induction agents with antiepileptic effects (eg, midazolam) may be preferable depending upon the patient's hemodynamic status. (See 'Airway, breathing, and circulation' above.)

Hypotension – Hypotension is treated initially with intravenous (IV) boluses of isotonic crystalloid. Direct-acting vasopressors (eg, norepinephrine) are used if IV fluids fail to correct the hypotension. (See 'Airway, breathing, and circulation' above.)

QRS prolongation – In a patient with QRS prolongation caused by carbamazepine overdose, we suggest treating with sodium bicarbonate (Grade 2C). Our approach is to give boluses of 100 to 150 meq of sodium bicarbonate IV for QRS intervals longer than 110 milliseconds. (See 'QRS interval prolongation' above.)

Seizure – In a patient who seizes after a carbamazepine overdose, we suggest treating with GABA agonists such as benzodiazepines (eg, diazepam) instead of phenytoin or other anticonvulsants (Grade 2C).

Gastrointestinal decontamination – It is acceptable to give a single dose of activated charcoal (AC; 1 g/kg; maximum dose 50 g) to patients with a normal mental status who present within one to two hours of an acute carbamazepine overdose and are able to protect their airway. AC should be withheld in unintubated patients with CNS depression. We do not recommend that tracheal intubation be performed solely for the purpose of giving charcoal. (See 'Gastrointestinal decontamination' above.)

Extracorporeal elimination – Extracorporeal removal of carbamazepine with hemodialysis can be used in severely poisoned patients with signs of continued deterioration (eg, refractory seizures; hemodynamic instability requiring vasopressors; life-threatening dysrhythmias) despite maximum supportive care. Decisions regarding hemodialysis in the setting of carbamazepine intoxication should be made, whenever possible, in conjunction with a medical toxicologist. (See 'Extracorporeal elimination' above.)

  1. Gummin DD, Mowry JB, Beuhler MC, et al. 2020 Annual Report of the American Association of Poison Control Centers' National Poison Data System (NPDS): 38th Annual Report. Clin Toxicol (Phila) 2021; 59:1282.
  2. Novartis Pharmaceuticals USA. Prescribing information for Tegretol CR400(R) tablets www.pharma.us.novartis.com/product/pi/pdf/tegretol.pdf (Accessed on August 27, 2008).
  3. Spiller HA. Management of carbamazepine overdose. Pediatr Emerg Care 2001; 17:452.
  4. Starmer CF, Lastra AA, Nesterenko VV, Grant AO. Proarrhythmic response to sodium channel blockade. Theoretical model and numerical experiments. Circulation 1991; 84:1364.
  5. Fujiwara Y, Sato M, Otsuki S. Interaction of carbamazepine and other drugs with adenosine (A1 and A2) receptors. Psychopharmacology (Berl) 1986; 90:332.
  6. Van Calker D, Steber R, Klotz KN, Greil W. Carbamazepine distinguishes between adenosine receptors that mediate different second messenger responses. Eur J Pharmacol 1991; 206:285.
  7. Kanarkowski R, Rybakowski J. [Clinical pharmacokinetics of carbamazepine]. Psychiatr Pol 1989; 23:379.
  8. Graudins A, Peden G, Dowsett RP. Massive overdose with controlled-release carbamazepine resulting in delayed peak serum concentrations and life-threatening toxicity. Emerg Med (Fremantle) 2002; 14:89.
  9. Vree TB, Janssen TJ, Hekster YA, et al. Clinical pharmacokinetics of carbamazepine and its epoxy and hydroxy metabolites in humans after an overdose. Ther Drug Monit 1986; 8:297.
  10. Spina E, Martines C, Fazio A, et al. Effect of phenobarbital on the pharmacokinetics of carbamazepine-10,11-epoxide, an active metabolite of carbamazepine. Ther Drug Monit 1991; 13:109.
  11. Kanarkowski R, Wankiewicz G, Lehmann W, Rybakowski J. Pharmacokinetics of carbamazepine in psychiatric patients. Pol J Pharmacol Pharm 1988; 40:55.
  12. Yoo JH, Kang DS, Chun WH, et al. Anticonvulsant hypersensitivity syndrome with an epoxide hydrolase defect. Br J Dermatol 1999; 140:181.
  13. Hundt HK, Aucamp AK, Müller FO. Pharmacokinetic aspects of carbamazepine and its two major metabolites in plasma during overdosage. Hum Toxicol 1983; 2:607.
  14. Goulden KJ, Camfield P, Dooley JM, et al. Severe carbamazepine intoxication after coadministration of erythromycin. J Pediatr 1986; 109:135.
  15. Tagawa T, Mimaki T, Ono J, et al. Erythromycin-induced carbamazepine intoxication in two epileptic children. Jpn J Psychiatry Neurol 1989; 43:513.
  16. Jerling M, Lindström L, Bondesson U, Bertilsson L. Fluvoxamine inhibition and carbamazepine induction of the metabolism of clozapine: evidence from a therapeutic drug monitoring service. Ther Drug Monit 1994; 16:368.
  17. Iwahashi K, Miyatake R, Suwaki H, et al. The drug-drug interaction effects of haloperidol on plasma carbamazepine levels. Clin Neuropharmacol 1995; 18:233.
  18. Winnicka RI, Topaciński B, Szymczak WM, Szymańska B. Carbamazepine poisoning: elimination kinetics and quantitative relationship with carbamazepine 10,11-epoxide. J Toxicol Clin Toxicol 2002; 40:759.
  19. Perez A, Wiley JF. Pediatric carbamazepine suspension overdose-clinical manifestations and toxicokinetics. Pediatr Emerg Care 2005; 21:252.
  20. Durelli L, Massazza U, Cavallo R. Carbamazepine toxicity and poisoning. Incidence, clinical features and management. Med Toxicol Adverse Drug Exp 1989; 4:95.
  21. Spiller HA, Carlisle RD. Status epilepticus after massive carbamazepine overdose. J Toxicol Clin Toxicol 2002; 40:81.
  22. Tibballs J. Acute toxic reaction to carbamazepine: clinical effects and serum concentrations. J Pediatr 1992; 121:295.
  23. O'Neal W Jr, Whitten KM, Baumann RJ, et al. Lack of serious toxicity following carbamazepine overdosage. Clin Pharm 1984; 3:545.
  24. Fisher RS, Cysyk B. A fatal overdose of carbamazepine: case report and review of literature. J Toxicol Clin Toxicol 1988; 26:477.
  25. Hojer J, Malmlund HO, Berg A. Clinical features in 28 consecutive cases of laboratory confirmed massive poisoning with carbamazepine alone. J Toxicol Clin Toxicol 1993; 31:449.
  26. Seymour JF. Carbamazepine overdose. Features of 33 cases. Drug Saf 1993; 8:81.
  27. Stremski ES, Brady WB, Prasad K, Hennes HA. Pediatric carbamazepine intoxication. Ann Emerg Med 1995; 25:624.
  28. de la Cruz M, Bance M. Carbamazepine-induced sensorineural hearing loss. Arch Otolaryngol Head Neck Surg 1999; 125:225.
  29. Tsao CY, Wright FS. Acute chemical pancreatitis associated with carbamazepine intoxication. Epilepsia 1993; 34:174.
  30. Godden DJ, McPhie JL. Bullous skin eruption associated with carbamazepine overdosage. Postgrad Med J 1983; 59:336.
  31. Leckband SG, Kelsoe JR, Dunnenberger HM, et al. Clinical Pharmacogenetics Implementation Consortium guidelines for HLA-B genotype and carbamazepine dosing. Clin Pharmacol Ther 2013; 94:324.
  32. Brahmi N, Kouraichi N, Abderrazek H, et al. Clinical experience with carbamazepine overdose: relationship between serum concentration and neurological severity. J Clin Psychopharmacol 2008; 28:241.
  33. Garg U, Johnson L, Wiebold A, et al. False-Positive Carbamazepine Results by Gas Chromatography-Mass Spectrometry and VITROS 5600 Following a Massive Oxcarbazepine Ingestion. J Appl Lab Med 2018; 3:135.
  34. George S, Braithwaite RA. A preliminary evaluation of five rapid detection kits for on site drugs of abuse screening. Addiction 1995; 90:227.
  35. Fleischman A, Chiang VW. Carbamazepine overdose recognized by a tricyclic antidepressant assay. Pediatrics 2001; 107:176.
  36. Saidinejad M, Law T, Ewald MB. Interference by carbamazepine and oxcarbazepine with serum- and urine-screening assays for tricyclic antidepressants. Pediatrics 2007; 120:e504.
  37. Sobotka JL, Alexander B, Cook BL. A review of carbamazepine's hematologic reactions and monitoring recommendations. DICP 1990; 24:1214.
  38. Kuz GM, Manssourian A. Carbamazepine-induced hyponatremia: assessment of risk factors. Ann Pharmacother 2005; 39:1943.
  39. Mayoral W, Lewis JH. Drug-induced liver disease. Curr Opin Gastroenterol 2000; 16:231.
  40. Adams EN, Marks A, Lizer MH. Carbamazepine-induced hyperammonemia. Am J Health Syst Pharm 2009; 66:1468.
  41. Chopra A, Kolla BP, Mansukhani MP, et al. Valproate-induced hyperammonemic encephalopathy: an update on risk factors, clinical correlates and management. Gen Hosp Psychiatry 2012; 34:290.
  42. Schwarz E, Thoelke M. Altered Mental Status and Hyperammonemia after Overdose of Valproic Acid with Therapeutic Valproic Acid Concentrations. International Journal of Clinical Medicine 2014; 5:546.
  43. Bradberry SM, Thanacoody HK, Watt BE, et al. Management of the cardiovascular complications of tricyclic antidepressant poisoning : role of sodium bicarbonate. Toxicol Rev 2005; 24:195.
  44. Liebelt EL. Targeted management strategies for cardiovascular toxicity from tricyclic antidepressant overdose: the pivotal role for alkalinization and sodium loading. Pediatr Emerg Care 1998; 14:293.
  45. Cave G, Sleigh JW. ECG features of sodium channel blockade in rodent phenytoin toxicity and effect of hypertonic saline. Vet Hum Toxicol 2003; 45:254.
  46. Mise S, Jukić I, Tonkić A, et al. Multidose activated charcoal in the treatment of carbamazepine overdose with seizures: a case report. Arh Hig Rada Toksikol 2005; 56:333.
  47. Chyka PA, Seger D, Krenzelok EP, et al. Position paper: Single-dose activated charcoal. Clin Toxicol (Phila) 2005; 43:61.
  48. Greene S, Harris C, Singer J. Gastrointestinal decontamination of the poisoned patient. Pediatr Emerg Care 2008; 24:176.
  49. Position statement and practice guidelines on the use of multi-dose activated charcoal in the treatment of acute poisoning. American Academy of Clinical Toxicology; European Association of Poisons Centres and Clinical Toxicologists. J Toxicol Clin Toxicol 1999; 37:731.
  50. Wason S, Baker RC, Carolan P, et al. Carbamazepine overdose--the effects of multiple dose activated charcoal. J Toxicol Clin Toxicol 1992; 30:39.
  51. Brahmi N, Kouraichi N, Thabet H, Amamou M. Influence of activated charcoal on the pharmacokinetics and the clinical features of carbamazepine poisoning. Am J Emerg Med 2006; 24:440.
  52. Montoya-Cabrera MA, Sauceda-García JM, Escalante-Galindo P, et al. Carbamazepine poisoning in adolescent suicide attempters. Effectiveness of multiple-dose activated charcoal in enhancing carbamazepine elimination. Arch Med Res 1996; 27:485.
  53. Thanacoody R, Caravati EM, Troutman B, et al. Position paper update: whole bowel irrigation for gastrointestinal decontamination of overdose patients. Clin Toxicol (Phila) 2015; 53:5.
  54. Lurie Y, Bentur Y, Levy Y, et al. Limited efficacy of gastrointestinal decontamination in severe slow-release carbamazepine overdose. Ann Pharmacother 2007; 41:1539.
  55. Vale JA, Kulig K, American Academy of Clinical Toxicology, European Association of Poisons Centres and Clinical Toxicologists. Position paper: gastric lavage. J Toxicol Clin Toxicol 2004; 42:933.
  56. Position paper: Ipecac syrup. J Toxicol Clin Toxicol 2004; 42:133.
  57. Ghannoum M, Yates C, Galvao TF, et al. Extracorporeal treatment for carbamazepine poisoning: systematic review and recommendations from the EXTRIP workgroup. Clin Toxicol (Phila) 2014; 52:993.
  58. Harder JL, Heung M, Vilay AM, et al. Carbamazepine and the active epoxide metabolite are effectively cleared by hemodialysis followed by continuous venovenous hemodialysis in an acute overdose. Hemodial Int 2011; 15:412.
  59. Choi JS, Kim CS, Bae EH, et al. Enhanced clearance of carbamazepine using albumin-containing dialysate during CVVHDF. Intensive Care Med 2013; 39:159.
  60. Bek K, Koçak S, Ozkaya O, et al. Carbamazepine poisoning managed with haemodialysis and haemoperfusion in three adolescents. Nephrology (Carlton) 2007; 12:33.
  61. Deshpande G, Meert KL, Valentini RP. Repeat charcoal hemoperfusion treatments in life threatening carbamazepine overdose. Pediatr Nephrol 1999; 13:775.
  62. Leslie PJ, Heyworth R, Prescott LF. Cardiac complications of carbamazepine intoxication: treatment by haemoperfusion. Br Med J (Clin Res Ed) 1983; 286:1018.
  63. Cameron RJ, Hungerford P, Dawson AH. Efficacy of charcoal hemoperfusion in massive carbamazepine poisoning. J Toxicol Clin Toxicol 2002; 40:507.
  64. Pilapil M, Petersen J. Efficacy of hemodialysis and charcoal hemoperfusion in carbamazepine overdose. Clin Toxicol (Phila) 2008; 46:342.
  65. Yang X, Xin S, Zhang Y, Li T. Early hemoperfusion for emergency treatment of carbamazepine poisoning. Am J Emerg Med 2018; 36:926.
  66. Duzova A, Baskin E, Usta Y, Ozen S. Carbamazepine poisoning: treatment with plasma exchange. Hum Exp Toxicol 2001; 20:175.
  67. Ram Prabahar M, Raja Karthik K, Singh M, et al. Successful treatment of carbamazepine poisoning with hemodialysis: a case report and review of the literature. Hemodial Int 2011; 15:407.
  68. Chetty M, Sarkar P, Aggarwal A, Sakhuja V. Carbamazepine poisoning: treatment with haemodialysis. Nephrol Dial Transplant 2003; 18:220.
  69. Schuerer DJ, Brophy PD, Maxvold NJ, et al. High-efficiency dialysis for carbamazepine overdose. J Toxicol Clin Toxicol 2000; 38:321.
  70. Li TG, Yan Y, Wang NN, Zhao M. Acute carbamazepine poisoning treated with resin hemoperfusion successfully. Am J Emerg Med 2011; 29:518.
  71. Garlich FM, Goldfarb DS. Have advances in extracorporeal removal techniques changed the indications for their use in poisonings? Adv Chronic Kidney Dis 2011; 18:172.
  72. Burns MJ, Linden CH, Graudins A, et al. A comparison of physostigmine and benzodiazepines for the treatment of anticholinergic poisoning. Ann Emerg Med 2000; 35:374.
  73. Macnab AJ, Birch P, Macready J. Carbamazepine poisoning in children. Pediatr Emerg Care 1993; 9:195.
  74. Lifshitz M, Gavrilov V, Sofer S. Signs and symptoms of carbamazepine overdose in young children. Pediatr Emerg Care 2000; 16:26.
Topic 332 Version 23.0

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