Carbamazepine Toxicity 

Carbamazepine Toxicity – 13 Interesting Facts

1. Carbamazepine is widely used in managing a variety of neurobehavioral conditions including epilepsy, bipolar disorder, and trigeminal neuralgia
2. Metabolism is reliant on CYP3A4 activity levels, which may be affected by a variety of medications and supplements
3. Intent and amount of ingestion should be elicited as well as duration of use and the identity of any other medications and supplements the patient takes
4. Clinical manifestations of acute carbamazepine toxicity include encephalopathy, coma, seizures, respiratory failure, tachycardia, hypotension, and cardiac conduction disturbances (QRS prolongation)
5. Treatment of acute carbamazepine toxicity is largely supportive and may include aggressive airway and ventilatory management
6. Carbamazepine clearance is enhanced by multiple-dose activated charcoal and intermittent hemodialysis; thorough risk-benefit analysis must be considered before initiation of these and is best done in consultation with toxicologist or poison control center
7. IV crystalloids or vasopressors may be needed to maintain appropriate blood pressure and systemic perfusion
8. Sodium bicarbonate is indicated to address ECG interval abnormalities to prevent and treat cardiac arrhythmias
9. Benzodiazepines are recommended for management of seizures
10. Discharge decisions should be made on a case-by-case basis and in consultation with a toxicology consultant or Poison Control Center; in general, patients may be considered for discharge when symptoms have resolved and 2 non-elevated sequential carbamazepine concentrations have resulted
11. Carbamazepine is a well-established cause of anticonvulsant hypersensitivity syndrome, which is a potentially life-threatening drug reaction
12. Prompt treatment and supportive care of carbamazepine toxicity allow for good outcomes
13. To prevent toxicity, patients should be evaluated for and educated regarding drug-drug interactions before initiation of carbamazepine therapy

Alarm Signs and Symptoms

• Respiratory depression
• Coma
• Seizure
• Cardiac dysrhythmia or ECG abnormalities (QRS/QTc prolongation)

Introduction

• Carbamazepine is a drug approved for seizure management and treatment of trigeminal neuralgia; it is also used to treat neuropathic pain, bipolar disorder, and psychosis
• Carbamazepine is structurally related to the cyclic antidepressants and shares many aspects of their toxicity
• Carbamazepine’s mechanism of action is multifaceted and incompletely understood
  • It inhibits activity of voltage-gated sodium channels and therefore stabilizes hyperexcited neurons, suppressing propagation of excitatory neurotransmission¹
  • It inhibits presynaptic reuptake of adenosine, enhancing presynaptic inhibition of excitatory neurotransmitter release (eg, glutamate) and thereby protecting against seizures²
  • An inhibitory effect on central dopaminergic and noradrenergic neurotransmission is hypothesized to be responsible for carbamazepine’s antipsychotic effects³
• Pharmacokinetic properties of carbamazepine are outlined in Table 1.

Table 1. Pharmacokinetic properties of carbamazepine.⁴

Absorption	LipophilicSlow and unpredictable absorption after oral administrationBoth peripheral and central nervous system peak concentrations can be delayed up to 100 hours after overdose ingestionBioavailability approaches 100% with immediate-release preparations, while extended-release formulations are absorbed more slowly and less completely
Distribution	Apparent volume of distribution is 0.8 to 1.8 L/kg and approximately 70% to 80% of carbamazepine is protein bound when used in therapeutic dosesRapid distribution to all tissuesSteady-state plasma concentrations are achieved in 3 to 4 days
Metabolism	Carbamazepine is metabolized primarily by CYP3A4 to carbamazepine 10,11-epoxide, which is also pharmacologically activeA reactive arene oxide intermediate is also formed, which is likely the cause of hypersensitivity reactions and teratogenic effects
Elimination	The elimination half-life is 25 to 65 hours at initiation of therapy and decreases to 12 to 17 hours with continued dosing (due to carbamazepine inducing its own metabolism)After an overdose, zero-order elimination kinetics are observed

Epidemiology

• The American Association of Poison Control Centers documented 2562 potentially toxic exposures to carbamazepine in 2020⁵
  • 12.4% were classified as moderate effect⁵
  • 2% were classified as major effect⁵

Etiology

• Carbamazepine toxicity can result from acute overdose, chronic usage, or medication interactions

Risk Factors

• Patients taking other substances metabolized by CYP34A4 or those patients with low 34A activity may be at higher risk for developing carbamazepine toxicity⁴

Diagnosis

Approach to Diagnosis

• Diagnosis is suggested by history, physical examination, and laboratory assessment
• In all cases of suspected carbamazepine toxicity, laboratory tests should be ordered, including carbamazepine concentration, electrolyte panel, CBC, concentrations of any other medications the patient takes, and pregnancy test (if applicable) I⁴
  • In cases of intentional ingestions or ingestions involving unknown substances, acetaminophen and salicylate concentrations should be assessed
• ECG is imperative to assess intervals⁴

Workup

History

• History is key in making the diagnosis of carbamazepine toxicity; the clinician should attempt to determine the following:
  • The intent of overdose (intentional versus unintentional)
  • Total amount of drug ingested
  • Timing and duration of drug ingestion
  • Identity and quantity of any co-ingestants
• Acute toxicity from carbamazepine overdose is dose dependent
  • Carbamazepine dosage varies based on age and indication; typical maximum daily doses are as follows:⁶
    • Epilepsy
      • Aged younger than 6 years: 35 mg/kg/24 hours
      • Aged 6 to 15 years: 1000 mg/24 hours
      • Aged older than 15 years: 1200 mg/24 hours
        • In rare instances, up to 1500 mg/24 hours
    • Trigeminal neuralgia
      • Adult: 1200 mg/24 hours
  • Acute ingestion of more than 20 mg/kg is often associated with an antimuscarinic toxidrome, nystagmus, and ataxia⁷
  • Ingestions greater than 50 mg/kg are associated with ECG abnormalities and neurotoxicity, which may be manifested as coma or seizures⁷
  • These dosages are general guidelines, and additional factors should be elucidated:
    • Chronic carbamazepine usage, which predisposes the patient to developing toxicity due to drug accumulation
    • Off-label dosing and usage for conditions such as psychosis, bipolar disorder, and cocaine use disorder⁹
  • A complete medication review and search for CYP3A4 substrates is imperative
    • Notable medications include:
      • Clarithromycin and azole antifungals inhibit CYP3A4 and increase carbamazepine concentrations¹⁰
      • Barbiturates and phenytoin are inducers of CYP3A4 and reduce carbamazepine concentrations¹⁰
    • Nondrug substrates of note include: grapefruit juice (inhibits CYP3A4) and Saint John’s wort (induces CYP3A4)

Physical Examination

• An antimuscarinic toxidrome is often present in the early stages of carbamazepine toxicity, characterized by:¹¹
  • Elevated temperature
  • Tachycardia
  • Delirium
  • Dry mucous membranes
  • Cutaneous flushing
  • Urinary retention
• These effects may be responsible for delayed or prolonged gastrointestinal tract absorption and fluctuating signs of toxicity in some cases⁷
• Toxicity manifests primarily as neurologic findings
  • Mental status
    • Somnolence or coma with respiratory depression is reported in 21% to 48% of carbamazepine overdose cases¹²
    • Waxing and waning mental status is common in large ingestions¹²
    • Massive carbamazepine ingestion is associated with deep coma, fixed pupils, and absent dolls eye and oculovestibular reflexes, which commonly improves after several days¹²
  • Seizures⁷
  • Abnormal movements
    • Dystonia or choreoathetosis is occasionally seen with therapeutic usage of carbamazepine, as well as with toxicity¹³

Laboratory Tests

• Serum carbamazepine concentration
  • Therapeutic serum concentrations of carbamazepine are 4 to 12 mg/L (approximately 20-50 mmol/L)⁴
  • Although no consensus guidelines exist, experts agree that serial measurements of carbamazepine concentration aid in risk assessment and may help guide management and disposition planning
    • Initial carbamazepine concentration should be obtained on patient arrival
    • A second carbamazepine concentration should be obtained 2 to 4 hours after the initial concentration to assess the initial concentration trajectory
    • Levels may subsequently be trended every 4 to 6 hours until a clear downward trajectory is observed
    • Thereafter, assessing carbamazepine concentrations every 8 to 12 hours is likely sufficient
    • Consultation with a toxicology specialist or Poison Control Center is recommended to help interpret findings and guide management
• Electrolytes panel should be obtained to identify carbamazepine-induced hyponatremia, which has a 1.8% to 40% incidence¹⁵
  • Increased sensitivity of peripheral osmoreceptors to antidiuretic hormone or the syndrome of inappropriate antidiuretic hormone secretion are proposed mechanisms for carbamazepine-induced hyponatremia¹⁵
• CBC to evaluate for carbamazepine-associated leukopenia¹
• Acetaminophen and salicylate concentrations for screening purposes in the setting of intentional or unknown ingestions
• Pregnancy test
  • Associated fetal complications include neural tube defects, cleft palate, rib abnormalities, and spina bifida¹⁶
• Drug screening
  • Carbamazepine cross-reacts with some toxicology screening for cyclic antidepressants, given its structural similarity to those compounds¹⁷

Imaging Studies

• Imaging is not required for diagnosis of carbamazepine toxicity, but may be used in specific scenarios for further evaluation of sequelae or other sources of pathology
  • Chest radiography should be obtained for patients who are obtunded in order to investigate the possibility of aspiration pneumonitis
  • Neuroimaging (CT scanning) should be considered in patients with profound altered mental status or refractory seizures to exclude other etiologies

Diagnostic Procedures

• ECG should be obtained in all cases of suspected carbamazepine toxicity¹⁸
  • QRS and QTc prolongation can be seen¹⁸

Differential Diagnosis

Table 2. Differential Diagnosis: Carbamazepine toxicity.

Condition	Description	Differentiated by
Cyclic antidepressant toxicity	Antimuscarinic effects; cardiovascular toxicity (conduction delays, dysrhythmias); altered mental status (delirium, somnolence, coma)	Known access to cyclic antidepressant
Sedative-hypnotic toxicity	Somnolence, coma	ECG abnormalities are absent
Anticholinergic toxicity	Hyperthermia, tachycardia, delirium, seizure, mydriasis, dry mucous membranes/axillae, cutaneous flushing, urinary retention, QRS/QTc prolongation	Anticholinergic effects generally more pronounced and prolonged
Serotonin toxicity (serotonin syndrome)	Hyperthermia, tachycardia, autonomic instability, diaphoresis, shivering, tremor, clonus, seizure	Autonomic instability is more commonQRS prolongation is uncommonDoes not cause ataxia, nystagmus, or dysmetria
Lamotrigine toxicity	Tachycardia, hypertension, somnolence, ataxia, nystagmus, seizures, nausea/vomiting, QRS prolongation	Oculogyric crisis is possible20
Phenytoin toxicity	Ataxia, nystagmus, somnolence, slurred speech, extrapyramidal symptoms	Cardiotoxicity is uncommon21
Valproic acid toxicity	Somnolence, encephalopathy, respiratory depression, hypernatremia, anion gap–associated metabolic acidosis, pancytopenia, liver injury22	Often involves elevated AST/ALT and hyperammonemia
Anticonvulsant hypersensitivity syndrome	Fever, morbilliform cutaneous rash, and multiorgan manifestations23	Not dose dependentOccurs most frequently within first 2 months of therapyAbnormalities in test results can include eosinophilia, positive rheumatoid factor, cold agglutinins, hypo- or hypergammaglobulinemia, and antinuclear antibodies

Treatment

Approach to Treatment

• Goals of treatment include:
  • Airway protection and escalating respiratory support
  • Decontamination to limit gastrointestinal absorption of carbamazepine
  • Correction of drug-associated hypotension
  • Correction of cardiac conduction abnormalities
  • Treatment of seizure activity

Nondrug and Supportive Care

• Given the progressive clinical effects of carbamazepine, patients should be closely monitored for clinical deterioration
  • Frequent neurologic checks, including ability to protect airway
  • Continuous cardiopulmonary monitoring
• Airway/breathing
  • Head of patient’s bed should be elevated to 30° in order to minimize aspiration risk if somnolence develops
  • Tracheal intubation and mechanical ventilation are indicated in severe toxicity if accompanied by:
    • Respiratory failure
    • Active vomiting with risk or evidence of aspiration pneumonitis

Drug Therapy

• No antidote exists for carbamazepine toxicity
• Decontamination
  • Multiple-dose activated charcoal²⁴
    • Associated with improved outcomes (eg, decreased length of stay, decreased intubation duration, decreased duration of coma) and should be considered in patients presenting with large overdoses
    • Risk of aspiration due to progressive somnolence and neurotoxicity (such as seizure) should be carefully weighed against the benefit of activated charcoal administration
    • Consult with a medical toxicologist at the bedside or with a Poison Control Center to determine if patient is an appropriate candidate
  • Whole-bowel irrigation²⁶
    • Generally not recommended as it has not been shown to change outcome in carbamazepine-poisoned patients
    • Discuss with toxicologist or Poison Control Center to weigh risks and benefits in specific patient scenarios (eg, extended release formulation overdose, severe overdose)
• Medications are indicated to counteract specific signs and symptoms of carbamazepine toxicity
  • Seizure
    • Carbamazepine-associated seizures should be treated with benzodiazepines²⁷
  • Hypotension
    • Direct-acting vasopressors such as norepinephrine or epinephrine should be used for hypotension refractory to crystalloid administration²⁷
  • QRS interval prolongation
    • Sodium bicarbonate should be employed if the QRS interval is prolonged²⁷
      • Treatment with sodium bicarbonate is recommended for QRS durations of 120 milliseconds or longer; some experts suggest duration of 100 milliseconds as the threshold for intervention¹⁸
        • Discuss patient-specific scenarios with toxicologist or Poison Control Center for further guidance
      • Sodium bicarbonate boluses should be used until the QRS interval normalizes
      • Bicarbonate infusion can then be initiated for maintenance of appropriate interval duration

Treatment Procedures

• Extracorporeal drug removal via intermittent hemodialysis is reasonable in severe cases associated with intractable seizures, life-threatening dysrhythmias, or refractory hypotension²⁹
  • Hemodialysis improves level of consciousness and decreases seizure activity as carbamazepine concentrations fall²⁹
  • Continuous renal replacement therapy and peritoneal dialysis are much less effective than intermittent hemodialysis²⁹

Persistent or Recurrent Disease

• Although not studied specifically in the context of carbamazepine toxicity, ECMO (extracorporeal membrane oxygenation) may be considered in refractory cases based on its utility in severe poisoning as a whole³⁰

Admission Criteria

• Patients with cardiac conduction abnormalities, coma, or seizures should be admitted to an ICU
• Patients with mild symptoms (eg, somnolence, ataxia) or asymptomatic carbamazepine concentration elevations may be admitted to a monitored setting
• Discharge decisions should be made on a case-by-case basis and in consultation with a toxicology consultant or Poison Control Center
  • Although no specific guidelines exist, experts agree that completely asymptomatic patients may be considered for discharge following two normal carbamazepine concentrations, separated by 4 hours

Special Considerations

Pediatrics

• Endogenous elimination of carbamazepine is more rapid in children, making toxicity less common¹³
• Incidence of seizures and movement disorders such as dystonia and choreoathetosis may be higher when toxicity does occur in children¹³

Anticonvulsant Hypersensitivity Syndrome

• Also termed drug-induced hypersensitivity syndrome
• Potentially fatal drug reaction characterized by fever, morbilliform cutaneous rash, and multiorgan manifestations²³
• The most commonly implicated anticonvulsants are carbamazepine, phenytoin, phenobarbital, and lamotrigine
• Occurs most frequently within the first 2 months of therapy
• Not related to dosage or serum concentration (in contrast to carbamazepine toxicity)
• Pathophysiology is thought to be secondary to the accumulation of reactive arene oxide intermediates resulting from decreased epoxide hydrolase enzymatic activity
  • Arene oxides form neoantigens that trigger type IV hypersensitivity reactions, similar to Stevens-Johnson syndrome and toxic epidermal necrolysis
• Initial symptoms include:
  • Fever (typically 38°-40° C) for 1 to 2 weeks
  • Diffuse, pruritic macular rash that spreads from face to trunk to extremities
    • Mucositis is present in 30% and lymphadenopathy in 75% of cases²³
  • Multiorgan involvement typically occurs several weeks into the syndrome
    • The liver is the most frequently affected organ (80% of cases involve hepatitis); hepatic necrosis is the most common cause of death³⁴
    • Nephritis, myocarditis, pneumonitis, pancreatitis, thyroiditis, and encephalitis are also seen
  • Eosinophilia is common²³
• Laboratory abnormalities can include positive rheumatoid factor, cold agglutinins, hypo- or hypergammaglobulinemia, and antinuclear antibodies
• There is no reliable standard for diagnosis of this syndrome
• This syndrome is often mistaken for sepsis
• Prompt discontinuation of the offending anticonvulsant is critical
• Patients should be admitted to the ICU or burn unit
  • Fluid replacement, electrolyte optimization, nutritional support, prevention of superinfection, and skin care are critical supportive care measures
  • Methylprednisolone 30 mg/kg IV for 3 days is recommended; IV immunoglobulin 2 g/kg over 5 days is recommended if the patient does not respond quickly to methylprednisolone³⁴
• Fatality rates are as high as 10%³⁴

Follow-up

Complications

• The clinician should be aware of and investigate the following possible complications, which are similar to those of other sedating drugs and drugs that can cause seizures:
  • Aspiration pneumonitis
  • Rhabdomyolysis
  • Compartment syndrome
  • Trauma

Prognosis

• In the setting of prompt treatment and appropriate supportive care, full recovery is expected

Referral

• Consultation with medical toxicology specialists or a Poison Control Center is advised
• Patients whose toxicity is determined to be intentional should be evaluated by psychiatry

Screening and Prevention

Prevention

• Patients being initiated on carbamazepine therapy should be evaluated for and educated regarding drug-drug interactions that would predispose them to the development of toxicity (ie, CYP3A4 substrates)

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