Pediatric Carbamazepine Toxicity

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Practice Essentials

Carbamazepine (Tegretol) has been used for the treatment of trigeminal neuralgias since 1960. Since carbamazepine received approval for use as an antiepileptic agent in the United States in 1974, it became widely used for the management of partial or tonic-clonic epilepsy. Carbamazepine is also used as a treatment for patients with manic-depressive illness, postherpetic neuralgia, and phantom limb pain. Some of the available dosage forms for carbamazepine include 100-mg and 200-mg oral tablets and a 100 mg/5 mL oral suspension.

The therapeutic plasma concentration is 4-12 mg/L. A peak plasma level is achieved in 6-24 hours. Controlled-release formulation could result in peak levels as late as 4 days after administration. The volume of distribution is 1-2 L/kg. Carbamazepine is approximately 75-80% protein bound, and approximately 2-3% is excreted unchanged in the urine. Carbamazepine is oxidized by hepatic microsomal enzymes to produce its active metabolite, carbamazepine 10,11-epoxide. The serum concentration of the epoxide metabolite is approximately 20% in children and 10-15% in adults.

Autoinduction of microsomal enzyme results in a shorter carbamazepine half-life (10-20 h) in patients who use the drug long-term compared with those with a short-term exposure (31-35 h). The autoinduction process takes about 4 weeks.

Carbamazepine stimulates the synthesis of many monooxygenase and conjugating enzymes, which leads to the metabolism of many medications.[1]

In terms of drug interactions, carbamazepine induces the metabolism of other anticonvulsant drugs such as phenytoin, clonazepam, primidone, valproic acid, and ethosuximide. This may lead to subtherapeutic levels of these drugs, especially phenytoin.

In addition, carbamazepine reduces the duration and action of many therapeutic agents, including anticoagulants, cytotoxic drugs, analgesics, antiretrovirals, glucocorticoids, statins, antihypertensives, oral contraceptives, psychoactive drugs, and immunosuppressants. This can lead to patients on these drugs and carbamazepine being under treated. If carbamazepine is stopped while these drugs are continued, then the level of these drugs may rise, leading to toxicity. In addition, induction of enzymes can affect enzymes in endogenous metabolic pathways, which can subsequently affect bone, gonadal steroid, and lipid metabolism. This may lead to osteoporosis, sexual dysfunction, and vascular diseases.[1]

Inhibitors of hepatic microsomal enzymes, such as erythromycin, clarithromycin, and cimetidine, increase carbamazepine levels and may cause toxicity. Carbamazepine may increase the toxicity of adenosine and may increase the risk of heart block. Lower initial doses of adenosine should be used in patients who are taking carbamazepine.



View Image

Chemical structure of carbamazepine.

Carbamazepine can interfere with the action of low-dose oral contraceptives and may lead to breakthrough vaginal bleeding, ovulation, and even pregnancy in woman who are taking both medications.[2]

Armodafinil is a stimulant whose indications include obstructive sleep apnea, narcolepsy, and shift work sleep disorder, and like carbamazepine, it is an inducer of and substrate for cytochrome P450 (CYP3A4). A drug interaction study of the two agents found that systemic exposure to both carbamazepine and armodafinil was reduced after pretreatment with the other drug; A dose adjustment may be required when coadministering these compounds.[3]

On an interesting note, carbamazepine has been detected in the environment. Significant carbamazepine levels have been found in juvenile rainbow trout, probably due to pharmaceuticals that were discarded and contaminated the water.[4]

Pathophysiology

Carbamazepine is a complex drug that has both anticonvulsant properties in therapeutic doses and a proconvulsant property in overdose situations with supratherapeutic serum levels. Carbamazepine is chemically and stereospatially related to the tricyclic antidepressant (TCA) imipramine; it is spatially similar to phenytoin. The therapeutic anticonvulsant mechanism of carbamazepine is similar to phenytoin and is believed to be primarily related to the blockade of presynaptic voltage-gated sodium channels.

Blockage of sodium channels is believed to inhibit the release of synaptic glutamate and possibly other neurotransmitters. It also inhibits N -methyl-D-aspartate (NMDA) receptors and CNS adenosine receptors. Carbamazepine also has powerful anticholinergic properties through inhibition of the muscarinic and nicotinic acetylcholine receptors. The seizures that occur with carbamazepine toxicity are largely secondary to a central anticholinergic syndrome. The coma and respiratory depression associated with overdose may be related to sodium channel suppression of neurotransmission.

Carbamazepine causes antagonism at the adenosine subtype A1 receptor and agonism at the adenosine subtype A2 receptor. In lower therapeutic doses, this may be partially responsible for the anticonvulsant effect, whereas, in overdose situations, it may increase sedation or precipitate coma.

Cardiac arrhythmias due to carbamazepine are related to its sodium channel and anticholinergic effects. In therapeutic doses, the cardiovascular sodium channels are only minimally affected, and carbamazepine does not appear to be proarrhythmic. However, in overdose situations, carbamazepine produces sodium channel blockade effects similar to those of TCAs.

In 2004, HLA-B*1502 was found to be strongly associated with carbamazepine-induced Stevens-Johnson syndrome in people of Han-Chinese ethnicity, increasing the risk by about 100-fold. As a result, screening for HLA-B*1502 before carbamazepine prescription is routinely performed in the South-East Asian population.[5]

Epidemiology

The incidence of carbamazepine toxicity has decreased over the course of the 21st century. The American Association of Poison Control Centers (AAPCC) reported 6096 cases of carbamazepine exposure in 2000,[6] 4255 case mentions and 2352 single exposures in 2007,[7] and 3447 case mentions and 1674 single exposures in 2017.[8]

From 2000 to 2012, there were 18,867cases, with a mean of 1451 exposures/year. The patients were predominantly adults, with 5,464 exposures in children younger than 6 years (29%). The most commonly reported clinical effects were drowsiness (N = 4703, 25%), vomiting (N = 1559, 8%), tachycardia (N = 590, 3%), agitation (N = 342, 1.8%), hypotension (N = 178, 0.9%), electrolyte disturbance (N = 153, 0.8%), coma (N = 156, 0.8%), and seizures (n = 121, 0.6%). Fifty-three percent of adults and 38% of children were managed in a health-care facility.[9]

In 2017, among 1674 single exposures to carbamazepine, 59 patients experienced major toxicity and one death was reported.[8] Complications of severe poisoning include coma, respiratory depression, seizures, hypotension, and GI hypomotility. Cardiac toxicity is uncommon in children, especially in those who have a structurally normal heart.

No specific sex predilection has been noted. Most pediatric patients are younger than 6 years. Of the 1674 cases of carbamazepine toxicity reported by the AAPCC in 2017, 179 were in children younger than 6 years, 38 were in children aged 6-12, and 109 in patients 13-19 years old; 1285 were in individuals older than 19 years.[8]

Patient Education

A discussion regarding the prevention of unintentional ingestion is an important component of the routine care of the child.

The patient's parents should be taught how to safely store medications.

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.

History

Ingestion history

In children younger than 6 years, ingestions of carbamazepine are commonly unintentional. Suicidal ingestions typically occur in adolescents.

Other causes of carbamazepine poisoning include iatrogenic overdose; dosage errors; and interactions with drugs such as erythromycin, cimetidine, and isoniazid. All these drugs increase the levels of carbamazepine by competitively inhibiting its metabolism.

The medication source is usually the patient or another family member who is taking carbamazepine for seizure control or the treatment of other illness.

An important cause of toxicity in children who are using the suspension is failure to adequately shake the bottle. Because the drug settles to the bottom of the bottle, if the full bottle is not shaken, the patient actually receives a low dose of the drug, which may lead to subtherapeutic levels and seizures. However, if the child is subsequently given doses of the drug from the bottom of the unshaken bottle, the patient may develop toxicity because the active drug has been concentrated there.

Symptom history

Symptoms usually appear within 6 hours of ingestion but significat symptoms may be delayed as long as 24 hours after the ingestion. Case reports indicate the possibility of delayed absorption, which causes levels to peak as late as 72 hours.

Mild toxic ingestions cause vomiting, drowsiness, ataxia, slurred speech, nystagmus, dystonic reactions, and hallucinations.

Severe intoxications may produce coma, seizures, respiratory depression, and hypotension. Neurologic symptoms are the most common symptoms seen with severe overdoses. In a letter to the Editor of the Journal of Emergency Medicine, the case of a 7 year-old boy who took an overdose of carbamazepine that was equivalent to 100 mg/kg and presented to the emergency department in a coma is reported.[10]

Physical

Carbamazepine toxicity should be considered in any child who presents with seizures, apnea, or an unexplained change in mental status, particularly when the child has access to the drug. The serum concentration may not always directly correlate with the clinical picture. The severity of toxicity is assessed on the basis of the clinical status and not the serum carbamazepine concentration.

Vital signs

Tachycardia is common.  Hypothermia may occur after an acute overdose and may last as long as 10 hours. 

Neurologic effects

Common neurologic effects include ataxia, slurred speech, nystagmus, dystonia and other extrapyramidal movements, and various degrees of CNS depression. A waxing and waning delirium is commonly seen with carbamazepine toxicity.  Seizures are common in children with an underlying epileptic disorder. In severe cases, coma and status epilepticus may occur.

Syndrome of inappropriate antidiuretic hormone secretion has also been reported though this complication is much more common with chronic use.[45]

Respiratory effects

Respiratory depression or apnea that requires mechanical ventilation may be observed within first 24 hours of the patient's presentation. Pulmonary edema or aspiration pneumonia may occur. Fulminant interstitial pneumonitis may also be noted.[11]

Cardiovascular effects

Cardiovascular effects are rarely observed in children. Hypotension, bradycardia, and conduction disorders may occur in patients with an abnormal myocardium or a preexisting conduction defect. A 2:1 atrioventricular (AV) block due to carbamazepine has been reported, which may occur even in therapeutic serum carbamazepine levels, and can be reversible after discontinuation of carbamazepine therapy.[12]

GI and hepatic effects

Antimuscarinic effects include delayed gastric emptying and decreased intestinal motility.

With acute carbamazepine toxicity, chemical pancreatitis without accompanying pain or abnormalities may be present.

Hepatitis and, rarely, hepatic failure may occur. This is usually due to an idiosyncratic reaction rather than an overdose. Studies in mice demonstrate that liver injury due to carbamazepine is probably due to metabolic activation of enzymes followed by the stimulation of immune responses. Prostaglandin E administration appeared to ameliorate the liver toxicity caused by carbamazepine in mice.[13]

Hematologic effects

Neutropenia, agranulocytosis, thrombocytopenia, and aplastic anemia may occur with therapeutic doses or chronic intoxication but not after an acute overdose. Carbamazepine has also been reported to have induced immunoglobulin deficiency in some cases in therapeutic doses;[14] however, this has not been reported in acute intoxication.

Thrombocytopenia or aplastic anemia can result in bleeding. However, this effect is rarely seen with acute poisoning.

Dermatologic effects

Dermatologic effects are due to idiosyncratic reactions rather than to an overdose of carbamazepine. Severe cutaneous adverse reactions (SCARS) such as the following may occur:

Patients of Asian descent, especially Han Chinese, are particularly at risk for SCARS. This sensitivity is linked to having the HLA-B*1502 allele.[18] Some authorities recommend that patients of Asian descent be screened for this allele before being started on carbamazepine.[19] In Europeans, the HLA-A*3101 allele has been associated with carbamazepine-induced hypersensitivity reactions, but this is much less common than that seen in Asians who have the HLA-B*1502 allele.[20]

Endocrine effects

Long-term use of carbamazepine may decrease free T4 levels. Usually this is compensated for by increasing thyrotropin levels. Therefore, thyroid function tests should be monitored in patients on carbamazepine, and thyroid hormone supplementation can be given if clinically indicated.[21]

Hyponatremia

Hyponatremia is not usually seen after acute overdoses but is known complication of chronic use.  There are several risk factors for hyponatremia associated with carbamazepine use:  age greater than 40 years, concomitant use of drugs associated with hyponatremia, menstruation, psychiatric conditions, surgery, (psychogenic) polydipsia, and female gender. Symptoms such as unsteadiness, dizziness, difficulty concentrating, reduced attention span, mild confusion, and lethargy should alert the physician to check the sodium levels. In patients with multiple risk factors, hyponatremia may occur much faster and can even cause life-threatening symptoms. In such cases, preventive fluid restriction can be of great value.[5]

Fatalities

Death may result from any of the following:

Laboratory Studies

The workup in a patient with suspected carbamazepine poisoning should include appropriate comprehensive serum and urine drug screening, plus analysis of the following:

Serum drug testing should be based on the history of ingestion and/or the patient’s toxidrome.

A serum and urine drug screen may not detect carbamazepine; therefore, the serum carbamazepine level should also be determined if the patient has access to carbamazepine. Structural similarity between carbamazepine and tricyclic antidepressants (TCAs) may cause false-positive results with immunoassay for TCAs. Patients who are taking carbamazepine should have therapeutic drug monitoring using serum carbamazepine levels.[24]

Because carbamazepine absorption varies, the serum concentration may not peak for as long as 24-72 hours. With controlled-release formulation, levels may continue to rise until 4 days postingestion. In fact, the initial carbamazepine level may be misleading. For this reason, serial measurements documenting a declining carbamazepine level and prolonged observation are recommended when managing these overdoses.[25]

Initial serum levels of more than 35 mg/L (127 µmol/L) suggest serious toxicity. However, lower initial serum levels do not necessarily indicate a benign course and the patient still needs to be closely monitored for signs and symptoms of significant toxicity.

The serum concentration may not always directly correlate with the clinical picture. The severity of toxicity is assessed on the basis of the clinical status and not only the serum carbamazepine concentration.

Toxicity may result from carbamazepine itself or its active epoxide metabolite. However, measuring epoxide levels along with the carbamazepine level provides no additional advantage.

The complete blood cell count (CBC) with a differential should be obtained. Rarely, hematologic adverse effects, including agranulocytosis, thrombocytopenia, and aplastic anemia, have been reported with long-term carbamazepine use.[26]

Although in utero exposure to carbamazepine has not been associated with adverse neuropsychological function, it has been associated with reduced verbal abilities.Therefore, a urine pregnancy test should be obtained on adolescent girls and if they are pregnant they should be counseled as to the possible effects of carbamazepine on the development of the fetus.[27]

Imaging Studies

Computed tomography of the head maybe warranted as part of evaluation for altered mental status.

With acute carbamazepine toxicity, ultrasonography may reveal chemical pancreatitis. These patients may have no accompanying pain or other signs and symptoms.

 

Other Tests

Other tests to consider include the following:

Medical Care

General and supportive measures in carbamazepine toxicity are as follows[30] :

Discharge patients with carbamazepine toxicity if the following conditions are met:

Activated charcoal and lavage

After the patient's airway, breathing, and circulation are stabilized, therapy with multiple-dose activated charcoal can be considered and should be directed by a medical toxicologist or poison control center.  Multi-dose activated charcoal may be of benefii due to the enterohepatic circulation that occurs with carbamazepine overdose. Carbamazepine is one of several important drugs that have enterohepatic circulation (others are phenobarbital and theophylline), which allows treatment of overdose with multiple doses of charcoal, even after all of the drug has been absorbed. This procedure is often referred to as "gut dialysis" because drug levels may rapidly fall after this treatment. Multi-dose activated charcoal should only be given in cases where there airway is secure.   In patients with an impaired gag reflex, this will require a nasogastric tube be inserted after the airway has been protected by endotracheal intubation.  In patients with unsecured airways, multi-dose activated charcoal should not be given.  Sorbitol should not be used.

It is important to note that serious carbamazepine poisoning is often complicated by drug-induced GI hypomotility. Severe ileus may interfere with the administration of multiple-dose charcoal and with decontamination of the GI tract. GI hypomotility may result in ongoing drug absorption and prolongation of symptoms.

Whole bowel irrigation

Whole bowel irrigation may be used to treat carbamazepine overdoses with sustained-released preparations or in patients who had a massive ingestion. It can also be used if the formation of concretions or pharmacobezoars is suspected. If the carbamazepine level is not decreasing or is even rising despite repeated doses of activated charcoal, the use of whole bowel irrigation should be strongly considered.  The use of whole bowel irrigation should be guided by a medical toxicologist or poison control center.

Whole bowel irrigation uses preparations that contain polyethylene glycol (PEG), such as Colyte or Go-lightly. PEG decreases the amount of the toxin in the digestive tract without causing dehydration or electrolyte depletion. The dose is 20-40 mL/kg/h until the patient has clear diarrhea. It is contraindicated in children younger than 9 months and in patients with an acute abdominal problem. In young children, the PEG solution should not be cooled, as that could result in hypothermia.[31]

Charcoal hemoperfusion

Charcoal hemoperfusion has been used to treat patients with life-threatening carbamazepine poisoning.[32] Activated charcoal imbedded in the hemoperfusion cartridge competes with plasma proteins for binding of the drug.

Hemoperfusion is limited to the removal of substances from the blood compartment; therefore, patients receiving drugs with a large volume of distribution may require prolonged hemoperfusion.

Charcoal hemoperfusion may have a more important role in patients with acute toxicity because of the low intrinsic clearance (see Background). Hemoperfusion may effectively remove the parent drug and its epoxide metabolite; thus, charcoal hemoperfusion is an important adjuvant therapy in patients with life-threatening carbamazepine poisoning complicated by drug-induced gastrointestinal hypomotility. Repeat hemoperfusion treatments may by necessary until GI motility returns to its previous level.

To the author's knowledge, no written guidelines address the use of charcoal hemoperfusion in carbamazepine poisoning. Hence, a common-sense approach is to use charcoal hemoperfusion in the following situations:

Dialysis

Peritoneal dialysis is ineffective in eliminating carbamazepine from the serum because of the drug's insolubility in water, high protein binding, and relatively large volume of distribution. It had been thought that hemodialysis is also ineffective in treating carbamazepine toxicity for the same reasons. However, several case reports have documented successful management of severe carbamazepine toxicity with hemodialysis. Askenazi et al reported a 10-year old girl with carbamazepine poisoning who was treated successfully using albumin-enhanced continuous venovenous hemodialysis.[33]

Yildiz et al reported successful use of continuous venovenous hemodiafiltration (CVVHDF) for the treatment of carbamazepine poisoning in a 2-year old patient after ingestion of controlled-release tablets.[34] These authors claim that, although more difficult and more expensive, CVVHDF combines both diffusion and convection principles, thus enhancing the clearance of the drug.

Bek et al used conventional low-flux hemodialysis in the management of acute carbamazepine overdose in three adolescent patients.[35] They conclude that standard low-flux hemodialysis may be used for treatment of mild carbamazepine overdose or when hemoperfusion is not available.

Harder et al reported a case in an adult with acute carbamazepine overdose who was successfully treated with hemodialysis followed by continuous venovenous hemodialysis. The patient’s clinical status and her levels of carbamazepine and its epoxide metabolite markedly and rapidly improved with this treatment.[36]

Prabahar et al successfully treated an adult with severe carbamazepine toxicity using “simple hemodialysis” because hemoperfusion was not available at their facility. Their report also included a review of the available literature on this subject. They concluded that hemodialysis was an effective and relatively safe way of managing severe carbamazepine toxicity, especially when charcoal hemoperfusion is not available.[37]

A systematic review of extracorporeal treatment of carbemazepine poisoning by Ghannoum et al concluded that intermittent hemodialysis is the preferred extracorporeal treatment, but intermittent hemoperfusion or continuous renal replacement therapies are alternatives if hemodialysis is not available.[38]

Ghannoum et al recommend extracorporeal treatment for patients with multiple seizures refractory to treatment or with life-threatening dysrhythmias. They suggest it for patients with prolonged coma or respiratory depression requiring mechanical ventilation and for those with significant, persistent toxicity, particularly when multiple-dose activated charcoal and supportive measures fail to reduce carbamazepine concentrations. Extracorporeal treatment should be continued until clinical improvement becomes apparent or the serum carbamazepine concentration falls below 10 mg/L.[38]

Consultations

If the patient's history suggests suicidal intent, consult a child psychiatrist. In all cases involving an accidental ingestion, personnel from social services or child protective services should be notified to evaluate the patient's home situation.

Consultation with a medical toxicologist or with poison control center personnel should be considered.

Consultation with a nephrologist should be obtained early if charcoal hemoperfusion may be needed.

Prevention

Patients should follow up with their primary care provider within 24-48 hours after their discharge. The physician should reevaluate the patient's condition and discuss the prevention of future episodes.

A discussion with the patient's parents concerning the safe storage and dosage of medications is essential. Parents should be provided the toll-free telephone number for the American Association of Poison Control Centers (800-222-1222).

Guidelines Summary

The Extracorporeal Treatments in Poisoning (EXTRIP) workgroup performed a systematic review and provided the following clinical recommendations for ECTR in carbamazepine poisoning[38] :

Activated charcoal (Actidose-Aqua, Liqui-Char, Insta-Char)

Clinical Context:  Emergency treatment in poisoning caused by drugs and chemicals. Network of pores present in activated charcoal absorbs 100-1000 mg of drug per gram of charcoal. Prevents absorption by adsorbing drug in the intestine. Multidose charcoal may interrupt enterohepatic recirculation and enhance elimination by enterocapillary exsorption. Theoretically, by constantly bathing the GI tract with charcoal, the intestinal lumen serves as a dialysis membrane for reverse absorption of drug from intestinal villous capillary blood into intestine. Does not dissolve in water.

For maximum effect, administer within 30 min after poison ingestion. The usual dose is 1 g/kg but never less than 30 g. It can be repeated in a dose of 0.5 g/kg q2h or 1 g/kg q4h when indicated, until the patient is asymptomatic and/or toxic drug levels have decreased to safe levels if measurable.

Sorbitol may be added to activated charcoal to improve its palatability. However, as mentioned above, it should never be used with multiple doses of charcoal, and never in children younger than 1 y.

Class Summary

Consider activated charcoal decontamination in any patient who presents within 4 hours of ingestion, or even later if the patient has an overdose with a sustained release preparation or has evidence of significant toxicity.  Activated charcaol should only be given to patients who are alert, have an intact airway and are not at risk of having seizures.

Author

Muhammad Waseem, MBBS, MS, FAAP, FACEP, FAHA, Professor of Emergency Medicine in Clinical Pediatrics, Weill Cornell Medical College; Attending Physician, Departments of Emergency Medicine and Pediatrics, Lincoln Medical and Mental Health Center; Adjunct Professor of Emergency Medicine, Adjunct Professor of Pediatrics, St George's University School of Medicine, Grenada

Disclosure: Nothing to disclose.

Coauthor(s)

Joel R Gernsheimer, MD, FACEP, Visiting Associate Professor, Department of Emergency Medicine, Attending Physician and Director of Geriatric Emergency Medicine, State University of New York Downstate Medical Center

Disclosure: Nothing to disclose.

Nicholas D Caputo, MD, House Staff, Department of Emergency Medicine, Lincoln Medical and Mental Health Center/Weill Cornell Medical College

Disclosure: Nothing to disclose.

Specialty Editors

Mary L Windle, PharmD, Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Nothing to disclose.

Jeffrey R Tucker, MD, Assistant Professor, Department of Pediatrics, Division of Emergency Medicine, University of Connecticut School of Medicine, Connecticut Children's Medical Center

Disclosure: Received salary from Merck for employment.

Chief Editor

Stephen L Thornton, MD, Associate Clinical Professor, Department of Emergency Medicine (Medical Toxicology), University of Kansas Hospital; Medical Director, University of Kansas Hospital Poison Control Center; Staff Medical Toxicologist, Children’s Mercy Hospital

Disclosure: Nothing to disclose.

Additional Contributors

Timothy E Corden, MD, Associate Professor of Pediatrics, Co-Director, Policy Core, Injury Research Center, Medical College of Wisconsin; Associate Director, PICU, Children's Hospital of Wisconsin

Disclosure: Nothing to disclose.

William T Zempsky, MD, Associate Director, Assistant Professor, Department of Pediatrics, Division of Pediatric Emergency Medicine, University of Connecticut and Connecticut Children's Medical Center

Disclosure: Nothing to disclose.

Acknowledgements

The authors and editors of Medscape Reference gratefully acknowledge the contributions of previous author Girish G Deshpande, MD, to the original writing and development of this article.

References

  1. Brodie MJ, Mintzer S, Pack AM, Gidal BE, Vecht CJ, Schmidt D. Enzyme induction with antiepileptic drugs: cause for concern?. Epilepsia. 2013 Jan. 54(1):11-27. [View Abstract]
  2. Davis AR, Westhoff CL, Stanczyk FZ. Carbamazepine coadministration with an oral contraceptive: effects on steroid pharmacokinetics, ovulation, and bleeding. Epilepsia. 2011 Feb. 52(2):243-7. [View Abstract]
  3. Darwish M, Bond M, Yang R, Hellriegel ET, Robertson P Jr. Evaluation of the potential for pharmacokinetic drug-drug interaction between armodafinil and carbamazepine in healthy adults. Clin Ther. 2015 Feb 1. 37 (2):325-37. [View Abstract]
  4. Li ZH, Zlabek V, Velisek J, et al. Acute toxicity of carbamazepine to juvenile rainbow trout (Oncorhynchus mykiss): effects on antioxidant responses, hematological parameters and hepatic EROD. Ecotoxicol Environ Saf. March 2011. 74(3):319-27. [View Abstract]
  5. Berghuis B, de Haan GJ, van den Broek MP, Sander JW, Lindhout D, Koeleman BP. Epidemiology, pathophysiology and putative genetic basis of carbamazepine- and oxcarbazepine-induced hyponatremia. Eur J Neurol. 2016 Sep. 23 (9):1393-9. [View Abstract]
  6. Litovitz TL, Klein-Schwartz W, White S, Cobaugh DJ, Youniss J, Omslaer JC, et al. 2000 Annual report of the American Association of Poison Control Centers Toxic Exposure Surveillance System. Am J Emerg Med. 2001 Sep. 19(5):337-95. [View Abstract]
  7. Bronstein AC, Spyker DA, Cantilena LR Jr, Green JL, Rumack BH, Heard SE. 2007 Annual Report of the American Association of Poison Control Centers' National Poison Data System (NPDS): 25th Annual Report. Clin Toxicol (Phila). 2008 Dec. 46(10):927-1057. [View Abstract]
  8. Gummin DD, Mowry JB, Spyker DA, Brooks DE, Osterthaler KM, Banner W. 2017 Annual Report of the American Association of Poison Control Centers' National Poison Data System (NPDS): 35th Annual Report. Clin Toxicol (Phila). 2018 Dec. 56 (12):1213-1415. [View Abstract]
  9. 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. 2016 Oct. 35 (10):1055-9. [View Abstract]
  10. Dogan M, Yilmaz C, Temel H, Çaksen H, Taskin G. A case of carbamazepine intoxication in a young boy. J Emerg Med. 2010 Nov. 39(5):655-6. [View Abstract]
  11. Narita H, Ozawa T, Nishiyama T, et al. An atypical case of fulminant interstitial pneumonitis induced by carbamazepine. Curr Drug Saf. 2009 Jan. 4(1):30-3. [View Abstract]
  12. Celik IE, Akyel A, Colgecen M, Ozeke O. A rare cause of 2:1 atrioventricular block: carbamazepine. Am J Emerg Med. 2015 Oct. 33 (10):1541.e3-4. [View Abstract]
  13. Higuchi S, Yano A, Takai S, Tsuneyama K, Fukami T, Nakajima M, et al. Metabolic activation and inflammation reactions involved in carbamazepine-induced liver injury. Toxicol Sci. 2012 Nov. 130(1):4-16. [View Abstract]
  14. Go T. Carbamazepine-induced IgG1 and IgG2 deficiency associated with B cell maturation defect. Seizure. 2004 Apr. 13(3):187-90. [View Abstract]
  15. Sevketoglu E, Hatipoglu S, Akman M, Bicer S. Toxic epidermal necrolysis in a child after carbamazepine dosage increment. Pediatr Emerg Care. 2009 Feb. 25(2):93-5. [View Abstract]
  16. Suzuki Y, Fukuda M, Tohyama M, et al. Carbamazepine-induced drug-induced hypersensitivity syndrome in a 14-year-old Japanese boy. Epilepsia. 2008 Dec. 49(12):2118-21. [View Abstract]
  17. Locharernkul C, Loplumlert J, Limotai C, et al. Carbamazepine and phenytoin induced Stevens-Johnson syndrome is associated with HLA-B*1502 allele in Thai population. Epilepsia. 2008 Dec. 49(12):2087-91. [View Abstract]
  18. Zhang Y, Wang J, Zhao LM, Peng W, Shen GQ, Xue L, et al. Strong association between HLA-B*1502 and carbamazepine-induced Stevens-Johnson syndrome and toxic epidermal necrolysis in mainland Han Chinese patients. Eur J Clin Pharmacol. September 2011. 67(9):885-887. [View Abstract]
  19. Chen P, Lin JJ, Lu CS, et al. Carbamazepine-induced toxic effects and HLA-B*1502 screening in Taiwan. N Engl J Med. March 2011. 364(12):1126-33. [View Abstract]
  20. McCormack M, Alfirevic A, Bourgeois S et al. HLA-A*3101 and carbamazepine-induced hypersensitivity reactions in Europeans. N Engl J Med. March 2011. 364(12):1134-43. [View Abstract]
  21. Aggarwal A, Rastogi N, Mittal H, et al. Thyroid hormone levels in children receiving carbamazepine or valproate. Pediatr Neurol. Sep 2011. 45(3):159-62. [View Abstract]
  22. Spiller HA, Carlisle RD. Status epilepticus after massive carbamazepine overdose. J Toxicol Clin Toxicol. 2002. 40(1):81-90. [View Abstract]
  23. 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]
  24. Lucas C, Donovan P. Just a repeat' - When drug monitoring is indicated. Aust Fam Physician. Jan-Feb 2013. 42(1-2):18-22. [View Abstract]
  25. Patel VH, Schindlbeck MA, Bryant SM. Delayed elevation in carbamazepine concentrations after overdose: a retrospective poison center study. Am J Ther. Nov-Dec 2013. 20(6):602-6. [View Abstract]
  26. 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]
  27. Baker GA, Bromley RL, Briggs M, Cheyne CP, Cohen MJ, García-Fiñana M, et al. IQ at 6 years after in utero exposure to antiepileptic drugs: a controlled cohort study. Neurology. 2015 Jan 27. 84 (4):382-90. [View Abstract]
  28. De Rubeis DA, Young GB. Continuous EEG monitoring in a patient with massive carbamazepine overdose. J Clin Neurophysiol. 2001 Mar. 18(2):166-8. [View Abstract]
  29. Mantzouranis EC, Bertsias GK, Pallis EG, Tsatsakis AM. Hair analysis differentiates chronic from acute carbamazepine intoxication. Pediatr Neurol. 2004 Jul. 31(1):73-5. [View Abstract]
  30. Doyon S. Antiepileptics. Hoffman RS, Howland MA, Lewin NA, Nelson LS, Goldfrank LR. Goldfrank's Toxicologic Emergencies. 10th ed. New York, NY: McGraw-Hill Education; 2015.
  31. [Guideline] Benson BE, Hoppu K, Troutman WG, Bedry R, Erdman A, Höjer J, et al. Position paper update: gastric lavage for gastrointestinal decontamination. Clin Toxicol (Phila). 2013 Mar. 51 (3):140-6. [View Abstract]
  32. Deshpande G, Meert KL, Valentini RP. Repeat charcoal hemoperfusion treatments in life threatening carbamazepine overdose. Pediatr Nephrol. 1999 Nov. 13(9):775-7. [View Abstract]
  33. Askenazi DJ, Goldstein SL, Chang IF, et al. Management of a severe carbamazepine overdose using albumin-enhanced continuous venovenous hemodialysis. Pediatrics. 2004 Feb. 113(2):406-9. [View Abstract]
  34. Yildiz TS, Toprak DG, Arisoy ES, Solak M, Toker K. Continuous venovenous hemodiafiltration to treat controlled-release carbamazepine overdose in a pediatric patient. Paediatr Anaesth. 2006 Nov. 16(11):1176-8. [View Abstract]
  35. Bek K, Kocak S, Ozkaya O, et al. Carbamazepine poisoning managed with haemodialysis and haemoperfusion in three adolescents. Nephrology (Carlton). 2007 Feb. 12(1):33-5. [View Abstract]
  36. 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. July 2011. 15(3):412-5. [View Abstract]
  37. 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. July 2011. 15(3):407-11. [View Abstract]
  38. [Guideline] Ghannoum M, Yates C, Galvao TF, Sowinski KM, Vo TH, Coogan A, et al. Extracorporeal treatment for carbamazepine poisoning: systematic review and recommendations from the EXTRIP workgroup. Clin Toxicol (Phila). 2014 Dec. 52 (10):993-1004. [View Abstract]
  39. Andersohn F, Konzen C, Garbe E. Systematic review: agranulocytosis induced by nonchemotherapy drugs. Ann Intern Med. 2007 May 1. 146(9):657-65. [View Abstract]
  40. Fleischman A, Chiang VW. Carbamazepine overdose recognized by a tricyclic antidepressant assay. Pediatrics. 2001 Jan. 107(1):176-7. [View Abstract]
  41. 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]
  42. Marini AM, Choi JY, Labutta RJ. Transient neurologic deficits associated with carbamazepine-induced hypertension. Clin Neuropharmacol. 2003 Jul-Aug. 26(4):174-6. [View Abstract]
  43. Morselli PL, Frigerio A. Metabolism and Pharmacolinetics of Carbamazepine. Drug Metab Rev. 1975. 4(1):97-113. [View Abstract]
  44. Spiller HA. Management of carbamazepine overdose. Pediatr Emerg Care. 2001 Dec. 17(6):452-6. [View Abstract]
  45. Van Amelsvoort T, Bakshi R, Devaux CB, Schwabe S. Hyponatremia associated with carbamazepine and oxcarbazepine therapy: a review. Epilepsia. 1994 Jan-Feb. 35 (1):181-8. [View Abstract]

Chemical structure of carbamazepine.

Chemical structure of carbamazepine.