Carbamazepine (5H-dibenzazepine-5-carboxamide) is an iminostilbene derivative with a tricyclic structure. It is an antiepileptic drug widely used for treatment of simple partial seizures and complex partial seizures, trigeminal neuralgia, and bipolar affective disorder.
Carbamazepine selectively inhibits high-frequency epileptic foci while normal neuronal activity remains undisturbed. Carbamazepine is absorbed erratically after oral administration because of its lipophilic nature. It has a large volume of distribution; peak plasma levels occur 4-8 hours postingestion but may take up to 24 hours to peak. The primary site of metabolism is the liver; its metabolite also is active, which may increase duration of the symptoms of toxicity.
Patients with carbamazepine toxicity may present with neurologic, ocular, cardiovascular, and cutaneous signs and symptoms (see Presentation). In addition to measurement of the serum carbamazepine level, the workup should include testing to detect organ system complications and rule out alternative diagnoses (see Workup). Treatment focuses on decontamination and supportive care (see Treatment and Medication).
Carbamazepine reduces the propagation of abnormal impulses in the brain by blocking sodium channels, thereby inhibiting the generation of repetitive action potentials in the epileptic focus. Carbamazepine is absorbed slowly and distributed erratically following oral administration. It enters the brain rapidly because of its high lipid solubility.
Carbamazepine is metabolized primarily in the liver by oxidative enzymes, then is conjugated with glucuronic acid, and finally is excreted in the urine. Its metabolite, carbamazepine-10,11-epoxide, is active and may achieve up to 50% concentration of the parent compound.
The elimination of carbamazepine increases over the first few weeks because of autoinduction. Carbamazepine also enhances the metabolism of phenytoin, causing its levels to fall. Erythromycin, isoniazid, and propoxyphene (withdrawn from the US market) inhibit the hepatic metabolism of carbamazepine; therefore, the dose of carbamazepine may need to be adjusted in patients taking multiple medications.
Carbamazepine induces the hepatic cytochrome P-450 system and its half-life decreases with chronic administration. The enhanced cytochrome P-450 system increases metabolism of other antiepileptic drugs.
According to the American Association of Poison Control Centers' National Poison Data System, 1811 carbamazepine single exposures were reported in 2016. Of those, 1337 were treated in a health care facility.[1]
Mortality/Morbidity
Of the single exposures to carbamazepine reported to the AAPCC in 2016, 304 resulted in no significant outcome and 54 had a major outcome. No deaths were reported.[1]
Montgomery et al reported that severity of symptoms at the time of initial contact with the poison control center correlates with outcome severity for children and adults. However, the amount of time between ingestion and poison control center contact did not alter the correlation between initial severity of symptoms and final outcome severity. Carbamazepine levels greater than 85 mg/L were associated with severe toxicity.[2]
Oxcarbazepine is structural derivative of carbamazepine. It is metabolized to 10-monohydrate derivate (MHD), which is the pharmacologically effective compound. van Optstal et al reported a case in which a patient ingested more than 100 tablets of oxcarbazepine.[3] The serum level of the parent compound was 10-fold higher than the therapeutic dosage of 31.6 mg/L. However, the concentration of MHD was only 2-fold higher. MHD levels peaked 7 hours after intake. The patient survived without an adverse outcome. The authors concluded that since oxcarbazepine is a prodrug, formation of the active MHD metabolite is a rate-limiting process contributing to low overall toxicity of this drug.
The AAPCC reported 1760 single exposures to oxcarbazepine in 2016, with no significant outcome in 369 cases, major outcomes in 17 cases, and no deaths.[1] A review of oxcarbazepine exposures reported to National Poison Data System from 2000 to 2012 found that less than 1% of cases resulted in severe outcomes. Of the 18,867 total cases, 68% of those with major outcomes, and all five deaths, were due to intentional exposure (ie, suicide attempt).[4]
Age
In 2016, 213 of the 1811 reported cases of carbamazepine exposures occurred in children younger than 6 years.[1] Pediatric patients with carbamazepine ingestion are at higher risk for dystonic reactions, coma, and apnea if serum levels exceed 28 mg/L. Children eliminate the drug more rapidly than adults.
Race
Increased risk for carbamazepine-induced Stevens-Johnson syndrome and toxic epidermal necrolysis has been linked to carriage of the HLA-B*1502, which is common in Han-Chinese, Thai, and Malaysian populations.The US Food and Drug Administration has recommended screening for the HLA-B*1502 allele before starting carbamazepine therapy in patients of Asian ancestry.[5]
Carbamazepine toxicity should be considered in differential diagnosis of patients presenting with ataxia. Query about whether the patient has been taking carbamazepine on an acute or chronic basis, the time of ingestion, formulation (immediate vs extended release) and the approximate dose ingested. The symptoms of carbamazepine toxicity may include the following:
Cardiovascular findings may include the following:
Tachycardia
Hypotension
Neurologic findings may include the following:
Ataxia
Slurred speech
Dystonia, myoclonic activity
Varying degrees of CNS depression progressing to coma
Seizures, headache, confusion, and athetosis
Increased or decreased deep tendon reflexes
Respiratory depression, apnea
Delayed gastric emptying, abdominal pain
Oliguria, urinary retention
Skin findings may include the following:
Bullous skin eruptions: Toxic epidermal necrolysis (TEN) has been reported with use of this drug. Severe drug eruptions are rare, and life-threatening events occur in 4 per million persons a year. TEN can trigger a life-threatening systemic inflammatory reaction leading to respiratory failure.[6]
Rash, dermatitis: Drug rash with eosinophilia and systemic symptoms, also known as DRESS syndrome, reflects a serious hypersensitivity reaction to drugs. Clinically, a diffuse maculopapular rash, exfoliative dermatitis, facial edema, lymphadenopathy, fever, and multivisceral involvement may be observed. All of these symptoms are associated with a high mortality rate.[7] A cross-reactivity between carbamazepine and phenytoin occurs, which may lead to or worsen DRESS syndrome. Discontinuation of the anticonvulsants and topical steroids should ameliorate the rash.
Carbamazepine toxicity may result from acute overdose or chronic therapy.
Therapeutic levels are 4-12 mg/L, but individual variation exists.
Patients on multiple anticonvulsants may not tolerate high levels and can be maintained at 4-8 mg/L, while others can achieve levels of 8-12 mg/L without adverse effects.
Ataxia and nystagmus may occur at levels greater than 10 mg/L.
Cardiovascular effects are usually seen at levels greater than 12 mg/L. The drug interferes with action potentials in Purkinje fibers and the His bundle, which may lead to atrioventricular blocks and arrhythmias.[8]
Peak serum levels with controlled-release formulations of carbamazepine can result in delayed presentations of toxicity. Levels may not peak for 96 hours from the time of ingestion. Continuing repeat dosing of activated charcoal and whole-bowel irrigation is important. Hemoperfusion may be necessary if end-organ toxicity becomes evident.
Drug-drug interactions are known to occur. Vander et al reported a case of carbamazepine toxicity that occurred after administration of oxybutynin and an increase in the dose of dantrolene.[9] The combination of these drugs elevated the level of carbamazepine, leading to toxicity.
Obtain a fingerstick glucose measurement for possible explanation of altered mental status.
Measure serum carbamazepine level to verify that symptoms are due carbamazepine toxicity. Symptomatic patients may require multiple serum levels (q4-6h) until downtrend is documented. In overdose with controlled-release carbamazepine, levels may peak as late as 96 hours after ingestion.[10]
Obtain serum acetaminophen level in every intentional overdose.
Perform liver function tests to ascertain if liver damage has occurred.
Obtain a complete blood count with differential (rarely, hematologic adverse effects, including agranulocytosis, thrombocytopenia, and aplastic anemia, have been reported with long-term carbamazepine use[11] )
Measure electrolyte levels; hyponatremia is not uncommon with chronic dosing[12] but rarely is noted in acute overdose.
Perform blood urea nitrogen and creatinine tests to ascertain if renal damage has occurred.
Measure arterial blood gas level if pulse oximetry reads less than 90-95% or if any respiratory compromise is evident.
Obtain a pregnancy test in females of childbearing age.
Obtain an abdominal radiograph, because patients with rising serum levels may have a bezoar of undigested tablets that may be visualized radiographically.
Obtain a chest radiograph if crackles or rales are heard on physical examination and pulmonary edema is suspected or to confirm endotracheal (ET) placement if respiratory depression occurs.
For carbamazepine toxicity, the following ED care may be indicated[13] :
Place the patient on a cardiac monitor
Administer intravenous fluids as needed for hypotension
Administer intravenous diazepam (5-10 mg, repeat q10-15min prn) or other suitable benzodiazepine to control seizures
Gastric lavage may be helpful if performed within 1 hour of ingestion
Protect the patient’s airway by placing the patient in left lateral decubitus position or by intubating
Induction of emesis is not recommended because of the risk of CNS depression and seizures
Administer activated charcoal if the patient is able to protect his or her airway
Multiple doses of activated charcoal (1 g/kg) can be administered every 2-4 hours to enhance total body clearance and elimination in the patient with significant toxicity
A saline cathartic or sorbitol may be given with the first dose of charcoal, although evidence for their effectiveness is lacking. Do not repeat activated charcoal administration if ileus is present
Perform whole-bowel irrigation (WBI) after ingestion of extended-release drug formulation: Adults and adolescents are treated with 1.5-2 L/h (20-30 mL/min) of polyethylene glycol electrolyte lavage solution (PEG-ELS); small children are given 0.5 L/h (25 mL/kg/h)
Administer sodium bicarbonate when QRS is wider than 100 msec due to carbamazepine toxicity (sodium channel blockade)
The clinician should be aware of the marginal clinical effect of extracorporal carbamazepine removal. High-efficiency hemodialysis and venovenous hemodialysis may have a similar effect as charcoal hemoperfusion. Peritoneal dialysis is not useful for carbamazepine removal.
Consult a medical toxicologist or a certified poison control center. Nephrology consultation is indicated if charcoal hemoperfusion is being considered.
Clinical Context:
Network of pores present in activated charcoal adsorbs 100-1000 mg of drug per gram of charcoal. Does not dissolve in water.
For maximum effect, administer within 30 min of ingestion of poison. May administer as aqueous suspension or combine with cathartic (usually sorbitol 70%) in the presence of active bowel sounds.
Repeat dose, if necessary (without cathartic), to adsorb large pill masses or drug packages.
With superactivated forms, use of doses of 0.5 g/kg PO may be possible.
These agents are used to adsorb drugs or poisons after acute ingestion and to limit absorption into systemic circulation. Charcoal is not beneficial for other routes of exposure (eg, IV, inhalation, injection). Clinician should be aware of potential risk of charcoal aspiration and death due to aspiration pneumonia, especially in patients with altered mental status and/or those having seizures. Prudent airway control is recommended in such populations.
Clinical Context:
DOC for treatment of status epilepticus because persists in the CNS longer than diazepam. Rate of injection should not exceed 2 mg/min. May be administered IM if unable to obtain vascular access.
Monitoring patient's blood pressure after administering dose is important. Adjust prn.
Clinical Context:
Depresses all levels of CNS (eg, limbic and reticular formation), possibly by increasing activity of GABA. Third-line agent for agitation or seizures because of shorter duration of anticonvulsive effects and accumulation of active metabolites that may prolong sedation.
Clinical Context:
Used as alternative in termination of refractory status epilepticus. Because water soluble, takes approximately 3 times longer than diazepam to peak EEG effects. Thus, clinician must wait 2-3 min to fully evaluate sedative effects before initiating procedure or repeating dose. Has twice the affinity for benzodiazepine receptors than diazepam. May be administered IM if unable to obtain vascular access.
These agents are important for sedation and may act in the spinal cord to induce muscle relaxation. These actions may help counteract the CNS effects caused by carbamazepine toxicity.
Clinical Context:
Used to correct arrhythmias if patient is diagnosed with bicarbonate-responsive acidosis, hyperkalemia, or overdose resulting in an acidotic state. Routine use for arrhythmia is not recommended.
Carefully explain the proper method of taking anticonvulsants to avoid adverse reactions.
Educate to keep all medications and poisons in a locked cabinet or on high shelves to prevent pediatric accidental ingestions.
Instruct patients and parents to ensure that suspensions of carbamazepine should be shaken vigorously before administration. Otherwise, the drug settles in its container and early doses will contain less carbamazepine and subsequent underdosing will occur; later doses may contain more drug and lead to toxicity.
For patient education resources, see the Drug Overdose Center and Poisoning - First Aid and Emergency Center, as well as Poisoning, Drug Overdose, Activated Charcoal, and Poison Proofing Your Home.
Nidhi Kapoor, MD, Clinical Assistant Professor, Department of Emergency Medicine, The Warren Alpert Medical School of Brown University
Disclosure: Nothing to disclose.
Coauthor(s)
Richard J Hamilton, MD, FAAEM, FACMT, FACEP, Professor and Chair, Department of Emergency Medicine, Drexel University College of Medicine
Disclosure: Nothing to disclose.
Specialty Editors
John T VanDeVoort, PharmD, Regional Director of Pharmacy, Sacred Heart and St Joseph's Hospitals
Disclosure: Nothing to disclose.
John G Benitez, MD, MPH, Associate Professor, Department of Medicine, Medical Toxicology, Vanderbilt University Medical Center; Managing Director, Tennessee Poison Center
Disclosure: Nothing to disclose.
Chief Editor
Gil Z Shlamovitz, MD, FACEP, Associate Professor of Clinical Emergency Medicine, Keck School of Medicine of the University of Southern California; Chief Medical Information Officer, Keck Medicine of USC
Disclosure: Nothing to disclose.
Additional Contributors
Asim Tarabar, MD, Assistant Professor, Director, Medical Toxicology, Department of Emergency Medicine, Yale University School of Medicine; Consulting Staff, Department of Emergency Medicine, Yale-New Haven Hospital
Disclosure: Nothing to disclose.
David C Lee, MD, Research Director, Department of Emergency Medicine, Associate Professor, North Shore University Hospital and New York University Medical School