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Oxcarbazepine

Pronunciation

Class: Anticonvulsants, Miscellaneous
VA Class: CN400
Chemical Name: 10,11-Dihydro-10-oxo-5H-dibenz[b,f]azepine-5-carboxamide
Molecular Formula: C15H12N2O2
CAS Number: 28721-07-5
Brands: Trileptal

Introduction

Anticonvulsant agent;1 2 3 structurally related to carbamazepine.2 3 10 13

Uses for Oxcarbazepine

Partial Seizures

Management of partial seizures (alone or in combination with other anticonvulsants) in adults and children ≥4 years of age.1 2 4 10 13 14

Bipolar Disorder

Treatment and prevention of acute manic or mixed episodes in patients with bipolar disorder; used alone or in combination with other drugs (e.g., antipsychotic agents).16

American Psychiatric Association recommends that oxcarbazepine be reserved for patients who cannot tolerate or have had an inadequate response to first-line agents (e.g., lithium, valproate).16

Oxcarbazepine Dosage and Administration

General

  • Withdraw gradually to minimize the potential for increased seizure frequency.1 (See Discontinuance of Therapy under Cautions.)

  • Closely monitor for notable changes in behavior that could indicate emergence or worsening of suicidal thoughts or behavior or depression.18 19 22 23 (See Suicidality Risk under Cautions.)

Administration

Oral Administration

Administer orally twice daily without regard to meals.1 2

Tablets and suspension can be used interchangeably on a mg-for-mg basis.1

Suspension

Shake suspension well prior to administration of each dose.1

Measure and administer appropriate dose using an oral dosing syringe; dose may be added to a small glass of water or swallowed directly from the syringe.1 After each use, rinse the oral syringe with warm water and allowed to dry thoroughly.1

Dosage

Pediatric Patients

Partial Seizures
Monotherapy
Oral

Children 4–16 years of age: Initially, 8–10 mg/kg daily in 2 divided doses.1 Increase by 5 mg/kg every third day to recommended maintenance dosage.1 (See Table 1.)

Table 1. Recommended Range of Maintenance Dosages during Monotherapy For Management of Partial Seizures in Pediatric Patients1

Weight (kg)

Dosage Range (mg/day)

20

600–900

25

900–1200

30

900–1200

35

900–1500

40

900–1500

45

1200–1500

50

1200–1800

55

1200–1800

60

1200–2100

65

1200–2100

70

1500–2100

Combination Therapy
Oral

Children 4–16 years of age: Initially, 8–10 mg/kg daily (≤600 mg daily) in 2 divided doses.1 Increase to the target maintenance dosage over 2 weeks.1 (See Table 2.)

Table 2. Target Maintenance Dosage for Management of Partial Seizures in Combination with Other Anticonvulsant Agents in Pediatric Patients1

Weight (kg)

Target Dosage (mg/day)

20–29

900

29.1–39

1200

>39

1800

Conversion to Monotherapy
Oral

Children 4–16 years of age: Initially, 8–10 mg/kg daily in 2 divided doses.1 Increase dosage, based on patient response, by ≤10 mg/kg daily at weekly intervals to the recommended maintenance dosage for monotherapy.1 (See Table 1.) Observe patients closely during this transition phase.1

As oxcarbazepine replaces the existing anticonvulsant regimen, dosage of the other anticonvulsant(s) is simultaneously reduced and discontinued over 3–6 weeks.1 4 Observe patient closely during transition phase.1

Adults

Partial Seizures
Monotherapy
Oral

Initially, 600 mg daily administered in 2 equally divided doses.1 Increase dosage by 300-mg daily increments every third day up to a dosage of 1200 mg daily.1 4

Combination Therapy
Oral

Initially, 600 mg daily in 2 equally divided doses.1 Increase dosage by 600-mg daily increments at approximately weekly intervals to recommended daily dosage of 1200 mg.1 4 Efficacy may be somewhat higher in patients receiving dosages >1200 mg daily,1 3 4 10 but most patients cannot tolerate daily dosages of 2400 mg, mainly because of adverse CNS effects.1

Observe patients closely and monitor plasma concentrations of concomitantly administered anticonvulsants during dosage titration of oxcarbazepine; plasma concentrations of these drugs may be altered when dosage of oxcarbazepine exceeds 1200 mg daily.1 4

Conversion to Monotherapy
Oral

Initially, 600 mg daily in 2 equally divided doses.1 Increase dosage by 600-mg daily increments at approximately weekly intervals to recommended daily dosage of 2400 mg, usually within 2–4 weeks.1 4

As oxcarbazepine replaces the existing anticonvulsant regimen, dosage of the other anticonvulsant(s) is simultaneously reduced and discontinued over 3–6 weeks.1 4 Observe patient closely during transition phase.1

Special Populations

Hepatic Impairment

No dosage adjustment required in patients with mild to moderate hepatic impairment.1

Renal Impairment

Initially, 300 mg daily in patients with CLcr <30 mL/minute; increase dosage slowly based on patient response.1

Geriatric Patients

Manufacturer makes no specific dosage recommendations.1

Cautions for Oxcarbazepine

Contraindications

  • Known hypersensitivity to oxcarbazepine or any ingredient in the formulation.1 4

Warnings/Precautions

Warnings

Hyponatremia

Possible hyponatremia (serum sodium concentrations <125 mEq/L),1 4 5 generally during first 3 months of therapy, but has been reported >1 year after initiation of therapy.1 4 Serum sodium concentrations have returned to baseline values a few days after discontinuance of the drug.1 4

Consider monitoring serum sodium concentrations during maintenance therapy with oxcarbazepine, particularly in patients receiving drugs known to decrease serum sodium concentrations (e.g., drugs associated with inappropriate antidiuretic hormone secretion [SIADH]) or in those with symptoms of hyponatremia (e.g., nausea, malaise, headache, lethargy, confusion, obtundation, increase in seizure frequency or severity).1 4

Discontinuance of Therapy

Possibility of increased seizure frequency following discontinuance of oxcarbazepine.1 Reduce dosage, discontinue drug, or make drug substitution gradually.1

Sensitivity Reactions

History of Carbamazepine Hypersensitivity

Approximately 25–30% of patients with a history of carbamazepine hypersensitivity will develop hypersensitivity to oxcarbazepine.1 2 4 Use in patients with a history of such hypersensitivity only if potential benefits justify possible risks.1 4 If hypersensitivity reaction develops, discontinue oxcarbazepine immediately.1

Dermatologic and Hypersensitivity Reactions

Severe dermatologic reactions (e.g., toxic epidermal necrolysis, Stevens-Johnson syndrome), sometimes fatal, reported rarely.1 Recurrence of serious skin reactions following rechallenge with oxcarbazepine reported.1 Consider discontinuance if skin reaction develops.1

Multiorgan hypersensitivity reactions occurring days to weeks or months (range: 4–60 days) after initiating therapy reported rarely.1 May present with fever and rash accompanied by manifestations of other organ system involvement (e.g., lymphadenopathy, hepatitis, abnormal liver function test results, hematologic abnormalities [eosinophilia, thrombocytopenia, neutropenia], pruritus, nephritis, oliguria, hepatorenal syndrome, arthralgia, asthenia, other signs and symptoms).1 Discontinue oxcarbazepine if such a hypersensitivity reaction is suspected.1

Possible cross-sensitivity with other drugs that produce multiorgan hypersensitivity reactions (e.g., carbamazepine).1

General Precautions

Nervous System Effects

Possible neuropsychiatric effects: impaired cognitive or psychomotor performance (e.g., difficulties in concentrating, language, and speech), somnolence or fatigue, and coordination difficulties (e.g., ataxia, gait disturbances).1 3 4 5

Suicidality Risk

Increased risk of suicidality (suicidal behavior or ideation) observed in an analysis of studies using various anticonvulsants in patients with epilepsy, psychiatric disorders (e.g., bipolar disorder, depression, anxiety), and other conditions (e.g., migraine, neuropathic pain); risk in patients receiving anticonvulsants (0.43%) was approximately twice that in patients receiving placebo (0.24%).18 19 22 23 Increased suicidality risk was observed ≥1 week after initiation of anticonvulsant therapy and continued through 24 weeks.18 19 23 Relative risk was higher for patients with epilepsy compared with those receiving anticonvulsants for other conditions.18 23

Closely monitor all patients currently receiving or beginning anticonvulsant therapy for changes in behavior that may indicate emergence or worsening of suicidal thoughts or behavior or depression.18 19 22 23 Anxiety, agitation, hostility, insomnia, and mania may be precursors to emerging suicidality.18

Balance risk of suicidality with risk of untreated illness.18 23 Epilepsy and other illnesses treated with anticonvulsants are themselves associated with morbidity and mortality and an increased risk of suicidality.22 23 If suicidal thoughts or behavior emerges during anticonvulsant therapy, consider whether these symptoms may be related to the illness itself.22 23 (See Advice to Patients.)

Specific Populations

Pregnancy

Category C.1

Lactation

Oxcarbazepine and its active 10-monohydroxy metabolite (MHD) distributed into milk.1 Discontinue nursing or the drug.1

Pediatric Use

Safety and efficacy not established in children <4 years of age.1

Children <2 years of age not studied in controlled clinical trials.1

Severe dermatologic reactions (e.g., toxic epidermal necrolysis, Stevens-Johnson syndrome) and multiorgan hypersensitivity reactions reported rarely.1 (See Dermatologic and Hypersensitivity Reactions under Cautions.)

Geriatric Use

Systemic exposure to MHD may be increased (see Absorption: Special Populations, under Pharmacokinetics).1 4 Consider age-related decreases in renal function when selecting dosage; adjust dosage if necessary.1 (See Renal Impairment under Dosage and Administration.)

Common Adverse Effects

Dizziness, somnolence, diplopia, fatigue, nausea, vomiting, ataxia, abnormal vision, abdominal pain, tremor, dyspepsia, abnormal gait.1 2 3 10 13 14

Interactions for Oxcarbazepine

May inhibit CYP2C191 2 4 and induce CYP3A4 and CYP3A5.1 4 Weakly induces UDP-glucuronyl transferase.1

Drugs Metabolized by Hepatic Microsomal Enzymes

CYP2C19 substrates: Potential pharmacokinetic interaction (increased plasma concentrations of CYP2C19 substrate).1

CYP3A4 and CYP3A5 substrates: Potential pharmacokinetic interaction (decreased plasma concentrations of CYP3A4 or CYP3A5 substrate).1

Specific Drugs

Drug

Interaction

Comments

Calcium-channel blocking agents (felodipine, verapamil)

Increased metabolism of the calcium-channel blocking agent1 4

Carbamazepine

Possible decreased plasma concentrations of oxcarbazepine and metabolite, MHD1

Cimetidine

Pharmacokinetic interaction unlikely1

Contraceptives, oral

Increased metabolism of oral estrogen-progestin contraceptives1 2 4

Possible decreased contraceptive efficacy1 2 4

Dextropropoxyphene

Pharmacokinetic interaction unlikely1

Erythromycin

Pharmacokinetic interaction unlikely1

Lamotrigine

Clinically important effect on lamotrigine elimination is unlikely1

Phenobarbital

Possible increased plasma concentrations of phenobarbital;1 2 4 possible decreased plasma concentrations of oxcarbazepine and metabolite, MHD1

Phenytoin

Possible increased plasma phenytoin concentrations;1 2 4 possible decreased plasma concentrations of oxcarbazepine and metabolite, MHD1

Reduction of phenytoin dosage may be required if administered concomitantly with oxcarbazepine dosages >1200 mg daily1

Valproate

Clinically important effect on valproate elimination is unlikely1

Warfarin

Interaction unlikely1

Oxcarbazepine Pharmacokinetics

Absorption

Bioavailability

Completely absorbed following oral administration.1 2 3 4

Oral bioavailabilities of tablets and suspension appear to be similar.1

Food

Food does not affect rate or extent of absorption.1

Special Populations

In adults >65 years of age, peak plasma concentrations and AUC for MHD may be 30–60% higher than values in younger adults.1 4

In children <8 years of age, systemic exposure to MHD may be decreased by 30–40% compared with values in adults and children >8 years of age.1

Distribution

Plasma Protein Binding

40% (primarily albumin).1

Elimination

Metabolism

Extensively metabolized in the liver by cytosolic enzymes to MHD (10,11-dihydro-10-hydroxy-5H-dibenz[b, f]azepine-5-carboxamide),1 6 10 13 14 which is believed to be responsible for the pharmacologic activity of oxcarbazepine.1 3 4 10 13 14

Elimination Route

Excreted in urine (>95%), mainly as metabolites, and in feces (<4%).1 2 4

Half-life

Oxcarbazepine: 2 hours.1

MHD: 9 hours.1

Special Populations

In patients with mild to moderate hepatic impairment, pharmacokinetics of oxcarbazepine and MHD unaffected; not evaluated to date in patients with severe hepatic impairment.1

In patients with renal impairment (Clcr <30 mL/min), half-life is increased to 19 hours and AUC is increased twofold.1

Stability

Storage

Oral

Tablets

Tight container at 25°C (may be exposed to 15–30°C).1

Suspension

Original container at 25°C (may be exposed to 15–30°C).1 Use within 7 weeks of opening container.1

Actions

  • Exact mechanism of action is unknown; may prevent spread of epileptic seizures by stabilizing excitatory neuronal membranes, inhibiting repetitive neuronal firing, and decreasing propagation of synaptic impulses (by blocking voltage-sensitive sodium channels).1 2 3 4

  • Increased potassium conductance and modulation of high-voltage activated calcium channels also may contribute to anticonvulsant activity.1 4

  • Protects against electrically induced tonic extension seizures and, to a lesser degree, chemically induced clonic seizures; may abolish or reduce frequency of chronically recurring focal seizures.1 4

Advice to Patients

  • Risk of hypersensitivity reaction; patients who have had previous hypersensitivity reaction to carbamazepine at increased risk.1 4 Importance of immediately reporting hypersensitivity reactions, skin reactions, or fever accompanied by signs and/or symptoms of other organ system involvement (e.g., rash, lymphadenopathy).1

  • Risk of dizziness and somnolence; avoid driving or operating machinery until effects on individual are known.1 20 21

  • Risk of suicidality (anticonvulsants may increase risk of suicidal thoughts or actions in about 1 in 500 people).18 22 23 Importance of patients, family members, and caregivers being alert to day-to-day changes in mood, behavior, and actions and immediately informing clinician of any new or worrisome behaviors (e.g., talking or thinking about wanting to hurt oneself or end one's life, withdrawing from friends and family, becoming depressed or experiencing worsening of existing depression, becoming preoccupied with death and dying, giving away prized possessions).18 23

  • Risk of low sodium concentrations in the blood; manifestations may include nausea, extreme drowsiness and/or fatigue, discomfort, headache, confusion, increase in seizure frequency or severity, or dullness.1 20 21

  • Caution if alcohol is used concomitantly, because additive sedative effects may occur.1

  • Importance of not abruptly discontinuing therapy.1

  • Importance of women informing their clinician if they are or plan to become pregnant or plan to breast-feed.1 Importance of informing women of childbearing age that concomitant use of oxcarbazepine with oral contraceptives may result in decreased efficacy of the contraceptives.1 4

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses.1

  • Importance of advising patients of other important precautionary information.1 (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

OXcarbazepine

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Suspension

300 mg/5 mL*

Oxcarbazepine Oral Suspension

Trileptal

Novartis

Tablets, film-coated

150 mg*

Oxcarbazepine Tablets

Trileptal (scored)

Novartis

300 mg*

Oxcarbazepine Tablets

Trileptal (scored)

Novartis

600 mg*

Oxcarbazepine Tablets

Trileptal (scored)

Novartis

AHFS DI Essentials. © Copyright 2017, Selected Revisions April 10, 2017. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

References

1. Novartis. Trileptal (oxcarbazepine) tablets and oral suspension prescribing information. East Hanover, NJ; 2005 Mar.

2. Anon. Two new drugs for epilepsy. Med Lett Drugs Ther. 2000; 42:33-5. [PubMed 10803174]

3. Scachter SC. The next wave of anticonvulsants: focus on levetiracetam, oxcarbazepine, and zonisamide. CNS Drugs. 2000; 14:229-49.

4. Novartis. Trileptal (oxcarbazepine) tablets product monograph. East Hanover, NJ; 2000 Mar.

5. Isojarvi JI, Huuskonen UE, Pakarinen AJ et al. The regulation of serum sodium after replacing carbamazepine with oxcarbazepine. Epilepsia. 2001; 42:741-5. [PubMed 11422328]

6. Scachter SC, Vazquez B, Fisher RS et al. Oxcarbazepine: double-blind, randomized, placebo-control, monotherapy trial for partial seizures. Neurology. 1999; 52:732-7. [PubMed 10078718]

7. Dam M, Ekberg R, Loyning Y et al. A double-blind study comparing oxcarbazepine and carbamazepine in patients with newly diagnosed, previously untreated epilepsy. Epilepsy Res. 1989; 3:70-6. [PubMed 2645120]

8. 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; 27:195-204. [PubMed 9237054]

9. 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; 26:451-60. [PubMed 9127726]

10. Beydoun A. Safety and efficacy of oxcarbazepine: results of randomized, double-blind trials. Pharmacotherapy. 2000; 20(8 Part 2):S152-8. [PubMed 10937814]

11. 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; 27:205-13. [PubMed 9237055]

12. Novartis, East Hanover, NJ: Personal communication.

13. Beydoun A, Sachdeo RC, Rosenfeld WE et al. Oxcarbazepine monotherapy for partial-onset seizures: a multicenter, double-blind, clinical trial. Neurology. 2000; 54:2245-51. [PubMed 10881247]

14. Barcs G, Walker EB, Elger CE et al. Oxcarbazepine placebo-controlled, dose-ranging trial in refractory partial epilepsy. Epilepsia. 2000; 41:1597-607. [PubMed 11114219]

15. Glauser TA, Nigro M, Sachdeo R et al. (The Oxcarbazepine Pediatric Study Group). Adjunctive therapy with oxcarbazepine in children with partial seizure. Neurology. 2000; 54:2237-44. [PubMed 10881246]

16. American Psychiatric Association. Practice guideline for the treatment of patients with bipolar disorder (revision). Am J Psychiatry. 2002; 159(Suppl):1-50.

18. Food and Drug Administration. FDA Alert: Information for healthcare professionals: suicidality and antiepileptic drugs. Rockville, MD; 2008 Jan 31. From the FDA website.

19. Food and Drug Administration. FDA News: FDA alerts health care providers to risk of suicidal thoughts and behavior with antiepileptic medications. Rockville, MD; 2008 Jan 31. From the FDA website.

20. Teva Pharmaceuticals USA. Oxcarbazepine (oxcarbazepine) film-coated tablets prescribing information. Sellersville, PA; 2007 Sep.

21. Food and Drug Administration. Patient information sheet: Oxcarbazepine (marketed as Trileptal). 2007 Mar 16. From the FDA website.

22. Food and Drug Administration. Suicidal behavior and ideation and antiepileptic drugs: update 5/5/2009. Rockville, MD; 2009 May 5. From the FDA website.

23. Novartis. Trileptal (oxcarbazepine) tablets and oral suspension prescribing information. East Hanover, NJ; 2009 Apr 23.

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