Carbamazepine …

K K Jain MD†

Neuropharmacology & Neurotherapeutics

Updated 09.12.2021
Released 12.15.1998
Expires For CME 09.12.2024

Carbamazepine

Author: K K Jain MD†

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Carbamazepine

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Introduction

Historical note and terminology

Carbamazepine is classified as an antiepileptic drug, although it is used for other indications as well. The era of antiepileptic drugs started with the introduction of bromides in 1857 and was followed by the discovery of the anticonvulsant effect of barbiturates in 1912 (12) and then by hydantoins a few years later (33). Several years elapsed without any further drug development in this area when, during the development of the antidepressant drug imipramine, carbamazepine (a related compound) was synthesized and shown to have antiepileptic properties (28). Efficacy in treating epilepsy was demonstrated by clinical trials (16). The beneficial effect of carbamazepine on trigeminal neuralgia was also demonstrated (03). The compound was developed and introduced into clinical practice as an antiepileptic drug in 1963 in the United Kingdom and Switzerland. It was initially used in the 1960s for the treatment of trigeminal neuralgia in the United States and was approved later for the treatment of epilepsy. Classical reviews of carbamazepine include 2 monographs (29; 14).

Pharmacology

Carbamazepine is a tricyclic compound that contains 2 benzene rings and 1 azepine ring with 1 double bond and 1 amide group.

Carbamazepine (chemical structure)

(Contributed by Dr. K K Jain.)

Pharmacodynamics. Concentrations of carbamazepine equal to those that are effective clinically inhibit sustained repetitive firing of cortical neurons in culture. This action is caused by reduction of currents through sodium channels.

Pharmacokinetics. Carbamazepine undergoes extensive biotransformation in humans, and the major pathway is epoxidation of the double bond of the azepine ring, which is catalyzed by hepatic cytochrome P450 3A4, leading to the formation of carbamazepine 10,11-epoxide.

Most studies indicate that 75% to 85% of orally ingested carbamazepine is absorbed and that the bioavailability varies according to the preparation. Half-life of carbamazepine ranges from 18 to 55 hours. Following multiple-dose treatment, the plasma half-life decreases considerably (6- to 12-hour range) because carbamazepine induces its own metabolism. Pharmacokinetic interactions with a wide range of drugs (listed in the Physicians Desk Reference) affect the metabolism of carbamazepine by either decreasing or increasing its serum concentration.

Formulations/delivery. Intravenous carbamazepine infusions at 70% of oral dose are bioequivalent to oral carbamazepine in patients with normal renal function (32). Intravenous carbamazepine has favorable pharmacokinetics and is well tolerated and safe when used as a short-term substitution for oral formulation and seizure control is unchanged (04).

A controlled-release formulation of carbamazepine delivers the same dose over a longer period as compared to a standard formulation, thereby reducing post-dose peaks of plasma levels as well as associated adverse events (23).

Therapeutic drug monitoring. A sensitive liquid chromatography-tandem mass spectrometry method to simultaneously analyze carbamazepine, oxcarbazepine, and their metabolites in human serum is available for routine analysis in clinical settings (15). An ultra-high-performance liquid chromatography-tandem mass spectrometry method enables simultaneous determination of carbamazepine and its 7 major metabolites in serum of epileptic patients within 5 minutes for effective individualized administration in clinical practice (13).

Pharmacogenetics. Genetic variants in microsomal epoxide hydrolase, a drug-metabolizing enzyme, can be used to predict maintenance doses of carbamazepine. Presence of the human leukocyte antigen (HLA-A)*31:01 allele is associated with carbamazepine-induced hypersensitivity reactions in persons of Northern European ancestry (17). HLA-B*15:02 and HLA-A*31:01 have also been identified as predictive genetic biomarkers for carbamazepine hypersensitivity in pediatric patients from North America with diverse ethnic backgrounds and recommendations for genetic testing have been described in clinical guidelines (01). A study has determined that routine screening for HLA-A*31:01 to reduce the incidence of cutaneous adverse drug reactions in patients being prescribed carbamazepine for epilepsy is cost effective (22). Carbamazepine should be avoided in individuals with positive HLA-B*1502 genotype to reduce the risk of drug-induced toxic epidermal necrolysis (31).

Plasma level of the metabolite carbamazepine-10,11-epoxide is an important biomarker of carbamazepine-induced adverse drug reactions (Fricke-Galindo et al 2018).

Asian patients with epilepsy and the SCN1A rs2298771 polymorphism, especially the GG genotype, may be at risk of carbamazepine resistance (37).

Interactions

Drugs that inhibit CYP3A4 metabolism inhibit carbamazepine metabolism and, thus, increase its serum concentrations. Some of these drugs are:

• cimetidine
• danazol
• diltiazem
• macrolide antibiotics
• fluoxetine
• loratadine
• terfenadine
• isoniazid
• doxorubicin
• felbamate
• propoxyphene
• verapamil
• valproate

Drugs that induce CYP3A4 can increase the rate of carbamazepine metabolism and decrease plasma carbamazepine concentrations. These include the following:

• cisplatin
•doxorubicin
• phenobarbital
• phenytoin
• primidone
• theophylline

Carbamazepine can also affect the pharmacokinetics of other drugs. Carbamazepine greatly reduces the serum concentrations of simvastatin, probably by inducing its metabolism. Concomitant administration of carbamazepine and simvastatin should be avoided. Carbamazepine significantly decreases plasma concentrations of fexofenadine, an antihistaminic, probably due to P-glycoprotein induction in the small intestine (35). Adjunctive treatment with carbamazepine reduces the serum concentration of paliperidone in a dose-dependent manner during treatment of schizophrenia (36).

A double-blind, randomized, crossover study of healthy young women found that carbamazepine decreases levels of low-dose oral contraceptive steroids, resulting in increased breakthrough bleeding, and permits ovulation (07). Therefore, women on carbamazepine therapy are not adequately protected from pregnancy by oral contraceptives.

Long-term carbamazepine therapy leads to increased clearance of the analgesic fentanyl resulting in decreased duration of therapeutic plasma concentrations of fentanyl and an increased dose requirement (20).

Current guidelines recommend caution in prescribing concomitant use of direct-acting oral anticoagulants and antiepileptic drugs due to drug-drug interactions leading to potential risk of subtherapeutic anticoagulant concentration and treatment failure. A significant interaction between carbamazepine and apixaban, causing subtherapeutic concentration of the drug, has been reported in a patient with atrial fibrillation who had a transient ischemic attack (08). Measurement of plasma concentration of the anticoagulant can help guide a personalized management and avoid adverse clinical outcomes.

Adverse effects

Carbamazepine is generally a safe drug, but as with any drug that has been in use for over half a century, it has accumulated a long list of adverse events reported to both the manufacturer and health authorities. A number of these have been published in the literature and are included in the Physician's Desk Reference. Absence and myoclonic seizures are known to be aggravated by carbamazepine, but this may occur in some focal epilepsies as well. One case of aggravation of seizures in childhood occipital epilepsy, with posterior sharp and slow-wave high amplitude complexes recorded by EEG, has been reported when carbamazepine was added to valproate (30). Clinical condition and EEG findings improved following withdrawal of carbamazepine.

The adverse events may be idiosyncratic or due to dose-related toxicity. The latter can be managed by lowering the dose and does not necessarily require discontinuation of the medication.

Rapid oral loading of carbamazepine in the emergency department, although effective, is associated with a high rate of adverse effects. Most of the dose-related adverse effects involve the nervous system. The most commonly reported of these are ataxia and nystagmus. Lesions in splenium of corpus callosum have been demonstrated by MRI. There are usually no clinical neurologic manifestations, and the lesions clear up on discontinuation of carbamazepine. Hyponatremia has been reported in 26% of carbamazepine-treated patients and was severe and persistent in 7% of patients (02).

A pro-convulsive carbamazepine metabolite, quinolinic acid, has been detected in drug-resistant epileptic human brain specimen removed at surgery (11). The explanation for this is that a drug-resistant blood-brain-barrier not only impedes drug access to the brain but also may allow the formation of neurotoxic metabolites.

Other systems frequently involved are the skin, the hematopoietic system, and the cardiovascular system. Severe drug eruptions and life-threatening events are rare. Other rare complications include Stevens-Johnsons syndrome and toxic epidermal necrolysis.

Cardiac rhythm disturbances have been reported in patients on carbamazepine within therapeutic doses. A patient with trigeminal neuralgia, who presented with syncope due to atrioventricular block, recovered following discontinuation of carbamazepine and resumption of normal sinus rhythm (05). In another patient with recurrent attacks of dizziness and syncope electrocardiogram revealed 2:1 AV block, and the arrhythmia completely resolved following withdrawal of carbamazepine therapy (06).

Interaction with oral contraceptives may reduce contraceptive efficacy, so an alternative method of contraception should be recommended to women of childbearing age.

A controlled, cross-sectional study showed that epileptic men taking carbamazepine present with changes in hormonal levels, altered semen quality, erectile dysfunction, and a reduction in coital frequency (25). Erectile dysfunction has been reported improved by switching treatment carbamazepine to oxcarbazepine in men with epilepsy (26).

Cases of drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome have been reported with carbamazepine (10). DRESS syndrome is a potentially life-threatening multisystem adverse drug reaction, and reexposure or drug provocation tests must be avoided.

Acute carbamazepine intoxication with neurologic manifestations can be treated with hemodialysis, which is simple, cheap, widespread, and easier to apply compared to hemoperfusion (21).

Several prospective studies involving exposure during pregnancy have shown that carbamazepine therapy increases the rate of congenital anomalies, mainly neural tube defects, cardiovascular and urinary tract anomalies, and cleft palate. Pregnant epileptic women on carbamazepine therapy should be monitored by ultrasound and fetal echocardiography.

Measures for safer use of carbamazepine include monotherapy prescription where possible, an adequate dose titration, knowledge of previous adverse drug reactions in the patient, and routine monitoring of plasma carbamazepine concentrations in symptomatic patients (Fricke-Galindo et al 2018).

References

01: Amstutz U, Shear NH, Rieder MJ, et al. Recommendations for HLA-B15:02 and HLA-A31:01 genetic testing to reduce the risk of carbamazepine-induced hypersensitivity reactions. Epilepsia 2014;55(4):496-506. PMID 24597466
02: Berghuis B, van der Palen J, de Haan GJ, et al. Carbamazepine- and oxcarbazepine-induced hyponatremia in people with epilepsy. Epilepsia 2017;58(7):1227-33. PMID 28542738
03: Blom S. Trigeminal neuralgia. Its treatment with a new anticonvulsant drug (G32883). Lancet 1962;1:839-40. PMID 13870089
04: Brigo F, Leo A, Russo E, Striano P, Belcastro V. Intravenous carbamazepine for the treatment of epilepsy. Expert Opin Pharmacother 2018;19(7):743-7. PMID 29648925
05: Can I, Tholakanahalli V. Carbamazepine-induced atrioventricular block in an elderly woman. Turk Kardiyol Dern Ars 2016;44(1):68-70. PMID 26875133
06: Celik IE, Akyel A, Colgecen M, Ozeke O. A rare cause of 2:1 atrioventricular block: carbamazepine. Am J Emerg Med 2015;33(10):1541.e3-4. PMID 26306438
07: Davis AR, Westhoff CL, Stanczyk FZ. Carbamazepine coadministration with an oral contraceptive: effects on steroid pharmacokinetics, ovulation, and bleeding. Epilepsia 2011;52(2):243-7. PMID 21204827
08: Di Gennaro L, Lancellotti S, De Cristofaro R, De Candia E. Carbamazepine interaction with direct oral anticoagulants: help from the laboratory for the personalized management of oral anticoagulant therapy. J Thromb Thrombolysis 2019;48(3):528-31. PMID 31041653
09: Fricke-Galindo I, LLerena A, Jung-Cook H, López-López M. Carbamazepine adverse drug reactions. Expert Rev Clin Pharmacol 2018;11(7):705-718. PMID 29898616 **
10: Ganeva M, Gancheva T, Lazarova R, et al. Carbamazepine-induced drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome: report of four cases and brief review. Int J Dermatol 2008;47(8):853-60. PMID 18717872
11: Ghosh C, Marchi N, Hossain M, et al. A pro-convulsive carbamazepine metabolite: quinolinic acid in drug resistant epileptic human brain. Neurobiol Dis 2012;46(3):692-700. PMID 22426401
12: Hauptman A. Luminal bei epilepsie. München Med Wochenschr 1912;59:1907-9.
13: Jiang W, Xia T, Yun Y, et al. UHPLC-MS/MS method for simultaneous determination of carbamazepine and its seven major metabolites in serum of epileptic patients. J Chromatogr B Analyt Technol Biomed Life Sci 2019;1108:17-24.** PMID 30660838
14: Kramer G, Hopf C, editors. Carbamazepine in der neurologie. Stuttgart: Thieme, 1987.
15: Lionetto L, Casolla B, Cavallari M, Tisei P, Buttinelli C, Simmaco M. High-performance liquid chromatography-tandem mass spectrometry method for simultaneous quantification of carbamazepine, oxcarbazepine, and their main metabolites in human serum. Ther Drug Monit 2012;34(1):53-8. PMID 22210100
16: Lustig B. On treatment results with the new antiepileptic agent G 32883. Med Welt 1964;4:203-4. PMID 14124164
17: McCormack M, Alfirevic A, Bourgeois S, et al. HLA-A3101 and carbamazepine-induced hypersensitivity reactions in Europeans. N Engl J Med 2011;364(12):1134-43. PMID 21428769
18: Nolan SJ, Sudell M, Tudur Smith C, Marson AG. Topiramate versus carbamazepine monotherapy for epilepsy: an individual participant data review. Cochrane Database Syst Rev 2016a;12:CD012065. PMID 27922722
19: Nolan SJ, Tudur Smith C, Weston J, Marson AG. Lamotrigine versus carbamazepine monotherapy for epilepsy: an individual participant data review. Cochrane Database Syst Rev 2016b;11:CD001031. PMID 27841445
20: Nozari A, Akeju O, Mirzakhani H, et al. Prolonged therapy with the anticonvulsant carbamazepine leads to increased plasma clearance of fentanyl. J Pharm Pharmacol 2019;71(6):982-7. PMID 30793320
21: Ozhasenekler A, Gökhan S, Güloğlu C, Orak M, Ustündağ M. Benefit of hemodialysis in carbamazepine intoxications with neurological complications. Eur Rev Med Pharmacol Sci 2012;16 Suppl 1:43-7. PMID 22582484
22: Plumpton CO, Yip VL, Alfirevic A, Marson AG, Pirmohamed M, Hughes DA. Cost-effectiveness of screening for HLA-A*31:01 prior to initiation of carbamazepine in epilepsy. Epilepsia 2015;56(4):556-63. PMID 26046144
23: Powell G, Saunders M, Marson AG. Immediate-release versus controlled-release carbamazepine in the treatment of epilepsy. Cochrane Database Syst Rev 2010;(1):CD007124. PMID 20091617
24: Powell G, Saunders M, Rigby A, Marson AG. Immediate-release versus controlled-release carbamazepine in the treatment of epilepsy. Cochrane Database Syst Rev 2014;12:CD007124. PMID 25470302
25: Reis RM, de Angelo AG, Sakamoto AC, Ferriani RA, Lara LA. Altered sexual and reproductive functions in epileptic men taking carbamazepine. J Sex Med 2013;10(2):493-9. PMID 23057419
26: Sachdeo R, Sathyan RR. Amelioration of erectile dysfunction following a switch from carbamazepine to oxcarbazepine: recent clinical experience. Curr Med Res Opin 2005;21(7):1065-8. PMID 16004674
27: Sands TT, Balestri M, Bellini G, et al. Rapid and safe response to low-dose carbamazepine in neonatal epilepsy. Epilepsia 2016;57(12):2019-30. PMID 27888506
28: Schindler W, Hafliger F. Über derivate des iminodibenzyls. Helv Chim Acta 1954;37:472-83.
29: Sillanpaa M. Carbamazepine. Pharmacology and clinical use. Acta Neurol Scand 1981;64:1-202. PMID 6952742
30: Skrijelj FE, Mulić M. Aggravation of symptomatic occipital epilepsy of childhood by carbamazepine. Vojnosanit Pregl 2014;71(4):404-7. PMID 24783423
31: Tan JC, Murrell DF, Hersch MI. Genetic screening for human leukocyte antigen alleles prior to carbamazepine treatment. J Clin Neurosci 2015;22(12):1992-3. PMID 26319500
32: Tolbert D, Cloyd J, Biton V, et al. Bioequivalence of oral and intravenous carbamazepine formulations in adult patients with epilepsy. Epilepsia 2015;56(6):915-23. PMID 25982590
33: Werdnecke E. Phenyläthylhydantoin (Nirvanol), ein neues Schlaf- und Beruhigungsmittel. Deutsch Med Wochenschr 1916;42:1193.
34: Wiffen PJ, Derry S, Moore RA, McQuay HJ. Carbamazepine for acute and chronic pain in adults. Cochrane Database Syst Rev 2011;(1):CD005451. PMID 21249671
35: Yamada S, Yasui-Furukori N, Akamine Y, Kaneko S, Uno T. Effects of the P-glycoprotein inducer carbamazepine on fexofenadine pharmacokinetics. Ther Drug Monit 2009;31(6):764-8. PMID 19855315
36: Yasui-Furukori N, Kubo K, Ishioka M, Tsuchimine S, Inoue Y. Interaction between paliperidone and carbamazepine. Ther Drug Monit 2013;35(5):649-52. PMID 24052066
37: Zhang X, Liu J, Ye J. Association between SCN1A polymorphism and carbamazepine responsiveness in epilepsy: a meta-analysis. Epilepsy Res 2021;176:106627. PMID 34218210

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Carbamazepine

Other Pertinent Drugs

Lamotrigine
Oxcarbazepine
Phenytoin
Primidone
Vigabatrin

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	(1) Epilepsy. Generalized tonic-clonic (grand mal) seizures and complex partial seizures. Carbamazepine is not effective in absence-type seizures and may even aggravate the occurrence of absence seizures.
	(2) Trigeminal and glossopharyngeal neuralgias.
	(3) Equetro, an extended-release capsule formulation of carbamazepine, is approved for use in adult patients experiencing an acute manic or mixed episode associated with bipolar I disorder.
	(4) An intravenous preparation of carbamazepine is approved by the United States Food and Drug Administration as a short-term replacement therapy for oral carbamazepine formulations when oral administration is temporarily not feasible.

	(1) Paroxysmal kinesigenic choreoathetosis
	(2) Alcohol withdrawal
	(3) Agitation and aggressive behavior following severe closed-head injury
	(4) Kleine-Levin syndrome
	(5) Cocaine addiction
	(6) Primary nocturnal enuresis
	(7) Management of psychosis in Alzheimer disease patients.
	(8) Myotonia congenita
	(9) Treatment of pathologic gambling
	(10) Unipolar depression
	(11) Carbamazepine is used as an effective drug for vestibular paroxysmia as a manifestation of VIIIth nerve vascular compression syndrome.
	(12) Posttraumatic stress disorder

Carbamazepine …

Carbamazepine

Introduction

Historical note and terminology

Pharmacology

Clinical trials

Indications

Off-label uses

Contraindications

Goals and duration of treatment

Dosing

Special considerations

Interactions

Adverse effects

Media

References

Contributors

Author

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Also in This Category

Photosensitive occipital lobe epilepsy

Intermittent explosive disorder

Serotonin syndrome

Pyridoxine/P5P-dependent developmental epileptic encephalopathy

Reflex seizures

Anti-LGI1 encephalitis

Self-limited (familial) neonatal epilepsy

Drug-induced myasthenic syndromes

Carbamazepine

Introduction

Historical note and terminology

Pharmacology

Clinical trials

Indications

Off-label uses

Contraindications

Goals and duration of treatment

Dosing

Special considerations

Interactions

Adverse effects

Media

References

Contributors

Author

This is an article preview. Start a Free Account to access the full version.

Questions or Comment?

Also in This Category

Photosensitive occipital lobe epilepsy

Intermittent explosive disorder

Serotonin syndrome

Pyridoxine/P5P-dependent developmental epileptic encephalopathy

Reflex seizures

Anti-LGI1 encephalitis

Self-limited (familial) neonatal epilepsy

Drug-induced myasthenic syndromes

This is an article preview.
Start a Free Account
to access the full version.