Oxcarbazepine …

K K Jain MD†

Neuropharmacology & Neurotherapeutics

Updated 07.26.2021
Released 10.06.1999
Expires For CME 07.26.2024

Oxcarbazepine

Author: K K Jain MD†

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Oxcarbazepine

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Introduction

Historical note and terminology

Oxcarbazepine is a homologue of the well-known antiepileptic drug carbamazepine. It was developed as an alternative to carbamazepine for patients who had adverse reaction to carbamazepine or diphenylhydantoin. Despite its structural similarities, oxcarbazepine differs from carbamazepine in pharmacokinetic behavior, biotransformation profile, and interaction potential. Oxcarbazepine is like carbamazepine in its mechanisms of action and antiepileptic efficacy but has better tolerability and fewer interactions with other drugs. Most of the clinical development took place during the early 1990s, when it received approval in several countries. It was approved by the FDA in 1999. In 2003, the FDA approved oxcarbazepine as a monotherapy in children 4 years or older with partial epilepsy. This was the first epilepsy medication in 25 years to be approved for use as monotherapy in children.

Pharmacology

Pharmacology. The exact mechanism of action of oxcarbazepine is not well understood. Blockade of voltage-sensitive sodium channels could contribute to the antiepileptic efficacy of oxcarbazepine. Additional mechanisms of action, eg, an effect on potassium channels, might be clinically important. Oxcarbazepine also inhibits the release of glutamate.

Pharmacokinetics. Important pharmacokinetic features are as follows:

(1) Oxcarbazepine is the 10-keto derivative of carbamazepine. Absorption is about 95% following oral intake, and peak concentrations are reached within 4 to 6 hours.

(2) It is rapidly metabolized to 10,11-dihydro-10-hydroxycarbamepine, which is excreted in the urine as monohydroxy derivative that are in 2 enantiomeric forms: (R)-licarbazepine and (S)-licarbazepine (14).

(3) The elimination half-life of monohydroxy derivative is 8 to 13 hours, and kinetics are linear within the therapeutic dose range.

(4) Only 38% of the monohydroxy derivative is bound to serum proteins, as compared with 67% for the parent compound.

(5) As a neutral lipophilic substance, the active metabolite of oxcarbazepine is able to diffuse rapidly through the various membranes and the blood-brain barrier.

Oral loading of oxcarbazepine suspension was shown to be as effective as tablet and well-tolerated for rapidly achieving therapeutic levels of 10,11-dihydro-10-hydroxycarbazepine, the active metabolite of oxcarbazepine, in patients with epilepsy, particularly in those at high risk of recurrent seizures (13).

A model-based analysis predicted the comparable efficacy of OXC-XR (extended-release oxcarbazepine) qd versus OXC-IR (immediate-release oxcarbazepine) bid at monohydroxy derivative Cmin concentrations at a dose of 1200 to 2400 mg/day as monotherapy or adjunctive therapy (09). Based on this analysis, the U.S. Food and Drug Administration approved OXC-XR for use as monotherapy in adults and children 6 years of age or older with partial-onset seizures, with weight-based dosing in children.

Therapeutic drug monitoring. A bioanalytical method for the simultaneous determination of oxcarbazepine and its pharmacologically active metabolite -- 10, 11-dihydro-10-hydroxycarbamazepine -- in human plasma has been developed using a high-performance liquid chromatography with tandem mass spectrometry and successfully used to monitor plasma concentrations of the drug in a clinical study (19).

Pharmacogenetics/pharmacogenomics. The HLA-B*15:02 genotype is a predictor of the development of Stevens Johnson syndrome as well as toxic epidermal necrolysis as adverse reactions to carbamazepine or oxcarbazepine, and prescreening is recommended (31). The variant allele HLA-A*31:01 is associated with greater risk of maculopapular exanthema, drug reaction with eosinophilia and systemic symptoms, and Stevens Johnson syndrome or toxic epidermal necrolysis in patients treated with carbamazepine (25).

Clinical trials

Numerous clinical trials with oxcarbazepine have been reported during the past decade. Some of the trials in which oxcarbazepine has been used as monotherapy are listed in Table 1. The indication in these trials was partial epilepsy with or without secondarily generalized seizures and generalized tonic-clonic seizures without partial onset.

Table 1. Some Clinical Trials with Oxcarbazepine

Trial design	Results
Multicenter, randomized, 28-week, double-blind, placebo-controlled, dose-ranging (600, 1200, and 2400 mg/day), 4-arm, parallel-group trial (02).	Oxcarbazepine adjunctive therapy was found to be a safe and effective therapy in patients with uncontrolled partial seizures. Effectiveness increased with dose.
Multicenter, double-blind, randomized, parallel-group trial to assess the antiepileptic efficacy of oxcarbazepine as monotherapy in a refractory epilepsy patient population (03).	Oxcarbazepine was found to be safe and effective in the treatment of patients with partial epilepsy previously receiving treatment with other antiepileptic drugs.
Multicenter, randomized, placebo-controlled trial of oxcarbazepine as adjunctive therapy in children with inadequately controlled partial seizures on 1 or 2 concomitant antiepileptic drugs (11).	Oxcarbazepine adjunctive therapy was found to be safe, effective, and well tolerated in children with partial seizures.
Multicenter, double-blind, randomized, placebo-controlled, 2-arm parallel group, monotherapy design (29).	Oxcarbazepine monotherapy was effective and safe.
Double-blind, controlled clinical trial of oxcarbazepine vs. phenytoin as monotherapy in children and adolescents with epilepsy (12).	Oxcarbazepine showed efficacy and safety as first-line treatment and had significant advantages over phenytoin in terms of tolerability.
Double-blind, randomized, parallel-group comparison with phenytoin in adult patients with epilepsy (04).	These trials support the efficacy and safety of oxcarbazepine as first-line treatment. In addition, the results show that oxcarbazepine has significant advantages over phenytoin in terms of tolerability.
Double-blind, randomized, parallel-group comparison with sodium valproate in adult patients with epilepsy (06).	Efficacy and tolerability of oxcarbazepine was equivalent to that of valproic acid.
Double-blind, randomized, parallel-group, monotherapy trial compared oxcarbazepine at 2400 mg/day with oxcarbazepine at 300 mg/day in patients with uncontrolled partial-onset seizures (27).	Oxcarbazepine monotherapy at 2400 mg/day is well tolerated and efficacious in patients with uncontrolled partial onset seizures.
Prospective, open-label, multicenter study to evaluate the efficacy and tolerability of oxcarbazepine as monotherapy in patients with partial seizures who switched from their current antiepileptic drug monotherapy because of lack of efficacy or poor tolerability (20).	Oxcarbazepine as monotherapy may be a favorable treatment option for patients with partial seizures or those who show poor tolerability of their existing monotherapy regimen.

Indications

Oxcarbazepine is indicated as a monotherapy for the treatment of partial epilepsy with or without secondary generalization.

Off-label uses

	(1) Manic depressive illness. Antimanic effect of oxcarbazepine has been demonstrated in uncontrolled studies. It is recommended for use predominantly as an add-on treatment for patients with bipolar disorder who have not improved with well-established treatments.
	(2) Use of oxcarbazepine in patients with trigeminal neuralgia has been approved in some countries. A retrospective, real-world study of the effectiveness and tolerability of carbamazepine and oxcarbazepine in a large cohort of patients with classical, secondary, and idiopathic trigeminal neuralgia has shown their effectiveness, but their side effects are still a major issue (08). Oxcarbazepine monotherapy has been shown to be effective in postherpetic neuralgia.
	(3) Attention-deficit hyperactivity disorder
	(4) Treatment of alcohol withdrawal
	(5) Essential tremor
	(6) Migraine headache
	(7) Restless legs syndrome
	(8) Paroxysmal dyskinesia
	(9) Improving mood in patients with epilepsy
	(10) Treatment of trichotillomania (16).
	(11) Switching from immediate-release to extended-release oxcarbazepine in epilepsy patients on high dosages increases the safety and quality of life of epilepsy patients.
	(12) Treatment of seizures after intrathecal baclofen for multiple sclerosis (07).
	(13) In a retrospective study, use of carbamazepine or oxcarbazepine monotherapy was equally effective in the treatment of paroxysmal kinesigenic dyskinesia (33).
	(14) In a systematic review of randomized trials, oxcarbazepine was reported to be effective in reducing pain in diabetic peripheral neuropathy in one trial but was ineffective for painful neuropathies from other causes (34).
	(15) A patient with epilepsy and central diabetes insipidus who developed oxcarbazepine-induced hyponatremia had appropriately concentrated urine for 5 years on just oxcarbazepine, despite undetectable antidiuretic hormone levels, suggesting that oxcarbazepine (or 1 of its metabolites) may stimulate collecting tubule V2 receptor-G protein complex independent of antidiuretic hormone, resulting in increased renal tubular water reabsorption (01). Thus, oxcarbazepine may be useful as an alternative therapy for patients with central diabetes insipidus.
	(16) Gambling disorder (17).

Special considerations

Serum sodium estimation should be done at the start of therapy and repeated periodically to detect hyponatremia.

Oxcarbazepine, like other carbamazepine derivatives, should be used with caution for generalized epilepsy as it can exacerbate seizures. Its metabolite (S)-licarbazepine has been shown to exacerbate spike and wave discharges in experimental studies in mice harboring the human γ-aminobutyric acid A receptor γ2(R43Q) mutation (14).

Pregnancy. A significant decrease of plasma concentration of 10-monohydroxy derivate of oxcarbazepine is associated with deterioration of seizure control during treatment of pregnant women (24). A potential risk to the fetus exists during pregnancy. Oxcarbazepine should be used only if the benefits outweigh the risks. The mother should receive supplementation with folic acid during pregnancy to reduce the risk of neural tube malformations of the offspring. Because oxcarbazepine and its active metabolite are secreted in the mother's milk, breast feeding of the newborn should be avoided.

Pediatric. Safety in pediatric use has been demonstrated by clinical trials. A prospective study has shown that oxcarbazepine can be considered an effective and well-tolerated first-line drug for long-term monotherapy in children with epilepsy, both for idiopathic and symptomatic/cryptogenic forms (10).

The “Warnings and Precautions” section of the prescribing information for oxcarbazepine tablets and oral suspension, indicated for use as monotherapy or adjunctive therapy in the treatment of partial seizures in adults and children ages 4 to 16 years with epilepsy, describes serious dermatological reactions, including Stevens-Johnson syndrome and toxic epidermal necrolysis that have been reported in both children and adults in association with oxcarbazepine use.

Geriatric. In elderly patients with renal insufficiency, the dose may need to be reduced. The elderly show a higher frequency of adverse effects.

Anesthesia. There are no special precautions for anesthesia.

Hepatic porphyria. Most antiepileptic drugs, except gabapentin, are known to precipitate clinically latent porphyria by inducing hepatic metabolism. Because of low induction of hepatic enzymes, oxcarbazepine can also be successfully administered to patients with hepatic porphyria and focal epilepsy who do not respond to treatment with gabapentin.

Adverse effects

A meta-analysis of literature and systematic review of clinical studies reveals no evidence that oxcarbazepine administration has any significant effect on serum levels of homocysteine, vitamin B12, and folate in epileptic patients (26).

Although oxcarbazepine has a lower risk of cutaneous adverse drug reactions than carbamazepine, an association of HLA-B*40:02 and HLA-DRB1*04:03 alleles with oxcarbazepine hypersensitivity, manifesting as susceptibility to maculopapular eruption or more severe Stevens-Johnson syndrome and toxic epidermal necrolysis has been demonstrated in Korean patients (23).

Most of the adverse effects are minor and transient. These usually occur at the start of the therapy and subside during the therapy. Ataxia, dizziness, fatigue, nausea, somnolence, and diplopia have been significantly associated with oxcarbazepine. Analysis of a drug safety database shows that the occurrence of adverse events in patients on oxcarbazepine therapy is significantly dependent on the serum level of mono-hydroxy-carbazepine, the main metabolite of oxcarbazepine, rather than the dosage of the drug (28).

Hyponatremia associated with oxcarbazepine is usually benign and can be managed with water restriction. Acute water intoxication may occur rarely and may require drug discontinuation. Possible mechanisms of hyponatremia include a direct effect of oxcarbazepine on the renal collecting tubules or an enhancement of their responsiveness to circulating antidiuretic hormone. Serum sodium level should be monitored during oxcarbazepine therapy.

Oxcarbazepine-induced oculogyric crises occur rarely and can be relieved by vagus nerve stimulation, which has been used as a treatment for epilepsy.

Psychotic side effects have been reported following oxcarbazepine therapy in a patient with coexistent Parkinson disease and epilepsy, possibly because of its dopaminergic effect, and caution is recommended in its use in such patients (15).

Oxcarbazepine has been reported to aggravate seizures in Jeavons syndrome, which is a distinct clinical syndrome manifested by eyelid myoclonia, photosensitivity, and EEG paroxysms, which may be associated with absence (22). A child with complex partial seizures developed infantile spasms, developmental regression, and hypsarrhythmia (West syndrome) during the 2 weeks directly following initiation of oxcarbazepine, and the symptoms resolved within a few days after discontinuation of therapy (32). A patient with Rasmussen syndrome with seizures resistant to valproic acid developed frequent absence seizures after starting oxcarbazepine as add-on therapy but disappeared after oxcarbazepine was discontinued (05).

Retrospective analysis of adverse effects of ingestions of oxcarbazepine overdose reported to United States poison centers over a period of 13 years showed that serious outcomes were infrequent (less than 1% in the pediatric patients) (30). Even in adults with intentional ingestion of oxcarbazepine, there were few neurologic and cardiovascular complications.

References

01: Abdallah B, Hodgins S, Landry D, O'shea M, Braden G. Oxcarbazepine therapy for complete central diabetes insipidus. Case Rep Nephrol Dial 2018;8(1):20-4.** PMID 29594147
02: Barcs G, Walker EB, Elger CE, et al. Oxcarbazepine placebo-controlled, dose-ranging trial in refractory partial epilepsy. Epilepsia 2000;41(12):1597-607. PMID 11114219
03: Beydoun A, Sachdeo RC, Rosenfeld WE, et al. Oxcarbazepine monotherapy for partial-onset seizures: a multicenter, double-blind, clinical trial. Neurology 2000;54(12):2245-51. PMID 10881247
04: Bill PA, Vigonius U, Pohlmann H, et al. A double-blind controlled clinical trial of oxcarbazepine versus phenytoin in adults with previously untreated epilepsy. Epilepsy Res 1997;27(3):195-204. PMID 9237054
05: Caraballo RH, Cachia P, Valenzuela GR, Calvo A. Rasmussen syndrome: absence seizures may be induced by oxcarbazepine. Epileptic Disord 2019;21(1):108-11.** PMID 30767898
06: Christe W, Kramer G, Vigonius U, et al. A double-blind controlled clinical trial: oxcarbazepine versus sodium valproate in adults with newly diagnosed epilepsy. Epilepsy Res 1997;26(3):451-60. PMID 9127726
07: D'Aleo G, Rifici C, Kofler M, Sessa E, Saltuari L, Bramanti P. Seizure after intrathecal baclofen bolus in a multiple sclerosis patient treated with oxcarbazepine. Neurol Sci 2011;32(2):293-5. PMID 20607336
08: Di Stefano G, De Stefano G, Leone C, et al. Real-world effectiveness and tolerability of carbamazepine and oxcarbazepine in 354 patients with trigeminal neuralgia. Eur J Pain 2021;25(5):1064-71. PMID 33428801
09: Faison S, Gomeni R, Mendes S, O'Neal W, Schwabe S, Nasser A. Predicted efficacy of once-daily extended-release oxcarbazepine (Oxtellar XR®) monotherapy in adults and children with partial-onset seizures: exposure-response modeling and simulation. Clin Pharmacol 2020;12:135-47.** PMID 33061671
10: Franzoni E, Gentile V, Pellicciari A, et al. Prospective study on long-term treatment with oxcarbazepine in pediatric epilepsy. J Neurol 2009;256(9):1527-32. PMID 19597919
11: Glauser TA, Nigro M, Sachdeo R, et al. Adjunctive therapy with oxcarbazepine in children with partial seizures. The Oxcarbazepine Pediatric Study Group. Neurology 2000;54(12):2237-44. PMID 10881246
12: Guerreiro MM, Vigonius U, Pohlmann H, et al. A double-blind controlled clinical trial of oxcarbazepine versus phenytoin in children and adolescents with epilepsy. Epilepsy Res 1997;27(3):205-13. PMID 9237055
13: Kim DW, Gu N, Lee H, et al. Usefulness of oral loading of oxcarbazepine suspension in selected patients with epilepsy. Int J Clin Pharmacol Ther 2013;51(10):780-6. PMID 23849326
14: Kim TH, Reid CA, Petrou S. Oxcarbazepine and its active metabolite, (S)-licarbazepine, exacerbate seizures in a mouse model of genetic generalized epilepsy. Epilepsia 2015;56(1):e6-9.** PMID 25489632
15: Kovacs N, Nagy F, Balas I, Komoly S, Janszky J. Oxcarbazepine may induce psychotic symptoms in Parkinson's disease. Epilepsy Behav 2008;12(3):492-3. PMID 18222110
16: Leombruni P, Gastaldi F. Oxcarbazepine for the treatment of trichotillomania. Clin Neuropharmacol 2010;33(2):107-8. PMID 20375658
17: Lin CC, Chao CY, Chang HA, Kao YC, Chang CC, Tzeng NS. Oxcarbazepine for gambling disorder. Am J Ther 2020;27(5):e524-5. PMID 32769391
18: Liu WT, Yan XX, Cheng DZ, et al. Oxcarbazepine monotherapy in children with benign epilepsy with centrotemporal spikes improves quality of life. Chin Med J (Engl) 2020;133(14):1649-54. PMID 32649517
19: Mano Y. LC-MS-MS determination of oxcarbazepine and an active metabolite in human plasma for clinical application. J Chromatogr Sci 2018;56(8):687-94. PMID 29733349
20: Martinez W, Ingenito A, Blakeslee M, Barkley GL, McCague K, D’Souza J. Efficacy, safety, and tolerability of oxcarbazepine monotherapy. Epilepsy Behav 2006;9(3):448-56. PMID 16962380
21: Mazza M, Della Marca G, Di Nicola M, et al. Oxcarbazepine improves mood in patients with epilepsy. Epilepsy Behav 2007;10(3):397-401. PMID 17300991
22: Menon R, Baheti NN, Cherian A, Iyer RS. Oxcarbazepine induced worsening of seizures in Jeavons syndrome: lessons learnt from an interesting presentation. Neurol India 2011;59(1):70-2. PMID 21339665
23: Moon J, Kim TJ, Lim JA, et al. HLA-B*40:02 and DRB1*04:03 are risk factors for oxcarbazepine-induced maculopapular eruption. Epilepsia 2016;57(11):1879-86. PMID 27666425
24: Petrenaite V, Sabers A, Hansen-Schwartz J. Seizure deterioration in women treated with oxcarbazepine during pregnancy. Epilepsy Res 2009;84(2-3):245-9. PMID 19231139
25: Phillips EJ, Sukasem C, Whirl-Carrillo M, et al. Clinical pharmacogenetics implementation consortium guideline for hla genotype and use of carbamazepine and oxcarbazepine: 2017 Update. Clin Pharmacol Ther 2018;103(4):574-81.** PMID 29392710
26: Rezaei S, Shab-Bidar S, Abdulahi Abdurahman A, Djafarian K. Oxcarbazepine administration and the serum levels of homocysteine, vitamin B12 and folate in epileptic patients: a systematic review and meta-analysis. Seizure 2017;45:87-94. PMID 27978484
27: Sachdeo R, Beydoun A, Schachter S, et al. Oxcarbazepine (Trileptal) as monotherapy in patients with partial seizures. Neurology 2001;57(5):864-71. PMID 11552018
28: Sattler A, Schaefer M, May TW. Relationship between mono-hydroxy-carbazepine serum concentrations and adverse effects in patients on oxcarbazepine monotherapy. Seizure 2015;31:149-54. PMID 26362393
29: Schachter SC, Vazquez B, Fisher RS, et al. Oxcarbazepine: double-blind, randomized, placebo-control, monotherapy trial for partial seizures. Neurology 1999;52(4):732-7. PMID 10078718
30: 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;35(10):1055-9. PMID 26612556
31: Teh LK, Selvaraj M, Bannur Z, et al. Coupling genotyping and computational modeling in prediction of anti-epileptic drugs that cause Stevens Johnson syndrome and toxic epidermal necrolysis for carrier of HLA-B*15:02. J Pharm Pharm Sci 2016;19(1):147-60.** PMID 27096699
32: Veerapandiyan A, Singh P, Mikati MA. Possible induction of West syndrome by oxcarbazepine therapy in a patient with complex partial seizures. Epileptic Disord 2012;14(1):99-103. PMID 22425652
33: Yang Y, Su Y, Guo Y, et al. Oxcarbazepine versus carbamazepine in the treatment of paroxysmal kinesigenic dyskinesia. Int J Neurosci 2012;122(12):719-22. PMID 22856516
34: Zhou M, Chen N, He L, Yang M, Zhu C, Wu F. Oxcarbazepine for neuropathic pain. Cochrane Database Syst Rev 2013;3:CD007963. PMID 23543558

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Oxcarbazepine

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antiepileptic drugs
carbamazepine
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Oxcarbazepine …

Oxcarbazepine

Introduction

Historical note and terminology

Pharmacology

Clinical trials

Table 1. Some Clinical Trials with Oxcarbazepine

Indications

Off-label uses

Contraindications

Goals and duration of treatment

Dosing

Special considerations

Interactions

Adverse effects

References

Contributors

Author

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Questions or Comment?

Also in This Category

Anti-LGI1 encephalitis

Self-limited (familial) neonatal epilepsy

Alcohol withdrawal seizures

Acupuncture

Epileptic lesions due to malformation of cortical development

Epileptic spasms

Sleep and epilepsy

Neocortical temporal lobe seizures

Oxcarbazepine

Introduction

Historical note and terminology

Pharmacology

Clinical trials

Table 1. Some Clinical Trials with Oxcarbazepine

Indications

Off-label uses

Contraindications

Goals and duration of treatment

Dosing

Special considerations

Interactions

Adverse effects

References

Contributors

Author

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

Questions or Comment?

Also in This Category

Anti-LGI1 encephalitis

Self-limited (familial) neonatal epilepsy

Alcohol withdrawal seizures

Acupuncture

Epileptic lesions due to malformation of cortical development

Epileptic spasms

Sleep and epilepsy

Neocortical temporal lobe seizures

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