Carbamazepine Toxicity
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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 Erythromycin, isoniazid, and propoxyphene (withdrawn from the US market) inhibit the hepatic metabolism of carbamazepine; therefore, the dose of carbamazepine may need to be adjusted in patients taking multiple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.
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]
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]
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.
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]
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. [Medline]. [Full Text].
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. [Medline].
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. [Medline]. [Full Text].
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. [Medline].
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. [Medline].
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. [Medline].
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. [Medline].
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. [Medline].
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. [Medline].
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. [Medline].
Kumar R, Chivukula S, Katukuri GR, Chandrasekhar UK, Shivashankar KN. Carbamazepine Induced Thrombocytopenia. J Clin Diagn Res. 2017 Sep. 11 (9):OD12-OD13. [Medline]. [Full Text].
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. [Medline].
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.
Nidhi Kapoor, MD Clinical Assistant Professor, Department of Emergency Medicine, The Warren Alpert Medical School of Brown University
Nidhi Kapoor, MD is a member of the following medical societies: American College of Emergency Physicians, Rhode Island Medical Society, Society for Academic Emergency Medicine, Wilderness Medical Society
Disclosure: Nothing to disclose.
Richard J Hamilton, MD, FAAEM, FACMT, FACEP Professor and Chair, Department of Emergency Medicine, Drexel University College of Medicine
Richard J Hamilton, MD, FAAEM, FACMT, FACEP is a member of the following medical societies: American Academy of Emergency Medicine, American College of Medical Toxicology, Society for Academic Emergency Medicine
Disclosure: Nothing to disclose.
John T VanDeVoort, PharmD Regional Director of Pharmacy, Sacred Heart and St Joseph’s Hospitals
John T VanDeVoort, PharmD is a member of the following medical societies: American Society of Health-System Pharmacists
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
John G Benitez, MD, MPH is a member of the following medical societies: American Academy of Clinical Toxicology, American Academy of Emergency Medicine, American College of Medical Toxicology, American College of Preventive Medicine, Undersea and Hyperbaric Medical Society, Wilderness Medical Society, American College of Occupational and Environmental Medicine
Disclosure: Nothing to disclose.
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
Gil Z Shlamovitz, MD, FACEP is a member of the following medical societies: American College of Emergency Physicians, American Medical Informatics Association
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
David C Lee, MD is a member of the following medical societies: American Academy of Emergency Medicine, American College of Emergency Physicians, American College of Medical Toxicology, Society for Academic Emergency Medicine
Disclosure: Nothing to disclose.
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.
Carbamazepine Toxicity
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