Carbamazepine Toxicity

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Practice Essentials

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).

Pathophysiology

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 Erythromycin, isoniazid, and propoxyphene (withdrawn from the US market) inhibit the hepatic metabolism of carbamazepine; therefore, the dose of carbamazepine may need to be adjusted in patients taking multiple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.

Epidemiology

Frequency

United States

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]

History

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:

Physical

Ocular findings may include the following:

Cardiovascular findings may include the following:

Neurologic findings may include the following:

Skin findings may include the following:

Blood dyscrasias may involve the following:

Causes

See the list below:

Laboratory Studies

See the list below:

Imaging Studies

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.

Other Tests

Obtain a 12-lead electrocardiogram (ECG). Abnormalties found may include the following[8] :

Prehospital Care

Prehospital care may include the following:

Emergency Department Care

For carbamazepine toxicity, the following ED care may be indicated[13] :

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.

Consultations

Consult a medical toxicologist or a certified poison control center. Nephrology consultation is indicated if charcoal hemoperfusion is being considered.

Medication Summary

The goals of pharmacotherapy are to reduce morbidity and to prevent complications. Other than activated charcoal, no antidotes are available.

Activated charcoal

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.

Class Summary

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.

Lorazepam (Ativan)

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.

Diazepam (Valium, Diastat, Diazepam Intensol)

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.

Midazolam

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.

Class Summary

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.

Sodium bicarbonate

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.

Class Summary

Indicated for widened QRS resulting from acidosis.

Polyethylene glycol-electrolyte solution (Colyte, GoLytely, MoviPrep, NuLytely)

Clinical Context:  Laxative with strong electrolyte and osmotic effects that has cathartic actions in GI tract.

Class Summary

If extended-release carbamazepine has been ingested, consider using whole-bowel irrigation with a PEG-electrolyte solution.

Further Inpatient Care

See the list below:

Transfer

Transfer the patient if appropriate monitoring facilities or critical care areas are not available.

Deterrence/Prevention

Education and communication between the primary care physician and the patient is important for prevention of carbamazepine overdose.

Complications

Complications of carbamazepine toxicity may include the following:

Prognosis

See the list below:

Patient Education

See the list below:

Author

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

Disclosure: Nothing to disclose.

References

  1. Gummin DD, Mowry JB, Spyker DA, Brooks DE, Fraser MO, Banner W. 2016 Annual Report of the American Association of Poison Control Centers' National Poison Data System (NPDS): 34th Annual Report. Clin Toxicol (Phila). 2017 Dec. 55 (10):1072-1252. [View Abstract]
  2. Montgomery VL, Richman BJ, Goldsmith LJ, Rodgers GC Jr. Severity and carbamazepine level at time of initial poison center contact correlate with outcome in carbamazepine poisoning. J Toxicol Clin Toxicol. 1995. 33(4):311-23. [View Abstract]
  3. van Opstal JM, Janknegt R, Cilissen J, L'Ortije WH, Nel JE, De Heer F. Severe overdosage with the antiepileptic drug oxcarbazepine. Br J Clin Pharmacol. 2004 Sep. 58(3):329-31. [View Abstract]
  4. Spiller HA, Strauch J, Essing-Spiller SJ, Burns G. Thirteen years of oxcarbazepine exposures reported to US poison centers: 2000 to 2012. Hum Exp Toxicol. 2015 Nov 26. [View Abstract]
  5. Tangamornsuksan W, Chaiyakunapruk N, Somkrua R, Lohitnavy M, Tassaneeyakul W. Relationship between the HLA-B*1502 allele and carbamazepine-induced Stevens-Johnson syndrome and toxic epidermal necrolysis: a systematic review and meta-analysis. JAMA Dermatol. 2013 Sep. 149 (9):1025-32. [View Abstract]
  6. Fischer M, Hamm H, Wirbelauer J. [Severe drug-related skin reaction: toxic epidermal necrolysis caused by carbamazepine]. Klin Padiatr. 2004 Sep-Oct. 216(5):288-93. [View Abstract]
  7. Allam JP, Paus T, Reichel C, Bieber T, Novak N. DRESS syndrome associated with carbamazepine and phenytoin. Eur J Dermatol. 2004 Sep-Oct. 14(5):339-42. [View Abstract]
  8. Apfelbaum JD, Caravati EM, Kerns WP 2nd, Bossart PJ, Larsen G. Cardiovascular effects of carbamazepine toxicity. Ann Emerg Med. 1995 May. 25(5):631-5. [View Abstract]
  9. Vander T, Odi H, Bluvstein V, Ronen J, Catz A. Carbamazepine toxicity following Oxybutynin and Dantrolene administration: a case report. Spinal Cord. 2005 Apr. 43(4):252-5. [View Abstract]
  10. 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 Mar. 14(1):89-94. [View Abstract]
  11. Kumar R, Chivukula S, Katukuri GR, Chandrasekhar UK, Shivashankar KN. Carbamazepine Induced Thrombocytopenia. J Clin Diagn Res. 2017 Sep. 11 (9):OD12-OD13. [View Abstract]
  12. Berghuis B, van der Palen J, de Haan GJ, Lindhout D, Koeleman BPC, Sander JW, et al. Carbamazepine- and oxcarbazepine-induced hyponatremia in people with epilepsy. Epilepsia. 2017 Jul. 58 (7):1227-1233. [View Abstract]
  13. Doyon S. Antiepileptics. In: Hoffman RS, Howland MA, Lewin NA, Nelson LS, Goldfrank LR, eds. Goldfrank's Toxicologic Emergencies. 10th ed. New York: McGraw-Hill Education; 2015. Chapter 48.