Trileptal

Pronunciation

Generic Name: Oxcarbazepine
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

Warning(s)

Special Alerts:

[UPDATE 05/05/2009] FDA notified healthcare professionals that it approved updated labeling for antiepileptic drugs used to treat epilepsy, psychiatric disorders, and other conditions (e.g., migraine and neuropathic pain syndromes). FDA also required development of a medication guide, to be issued to patients each time the product is dispensed. Since issuing safety alerts on December 16, 2008 and January 31, 2008, FDA has been working with the manufacturers of drugs in this class to better understand the suicidality risk. Eleven antiepileptic drugs were included in a pooled analysis of placebo-controlled clinical studies in which these drugs were used to treat epilepsy as well as psychiatric disorders and other conditions. The increased risk of suicidal thoughts or behavior was generally consistent among the eleven drugs, with varying mechanisms of action and across a range of indications. This observation suggests that the risk applies to all antiepileptic drugs used for any indication.

The drugs included in the analyses include (some of these drugs are also available in generic form):

  • Carbamazepine (marketed as Carbatrol, Equetro, Tegretol, Tegretol XR)

  • Felbamate (marketed as Felbatol)

  • Gabapentin (marketed as Neurontin)

  • Lamotrigine (marketed as Lamictal)

  • Levetiracetam (marketed as Keppra)

  • Oxcarbazepine (marketed as Trileptal)

  • Pregabalin (marketed as Lyrica)

  • Tiagabine (marketed as Gabitril)

  • Topiramate (marketed as Topamax)

  • Valproate (marketed as Depakote, Depakote ER, Depakene, Depacon)

  • Zonisamide (marketed as Zonegran)

For more information visit the FDA website at: and .

[UPDATE 12/16/2008] The FDA has completed its analysis of reports of suicidality (suicidal behavior or ideation [thoughts]) from placebo-controlled clinical trials of drugs used to treat epilepsy, psychiatric disorders, and other conditions. Based on the outcome of this review, FDA is requiring that all manufacturers of drugs in this class include a Warning in their labeling and develop a Medication Guide to be provided to patients prescribed these drugs to inform them of the risks of suicidal thoughts or actions.

For more information visit the FDA website at: and .

[Posted 01/31/2008] FDA informed healthcare professionals that the Agency has analyzed reports of suicidality (suicidal behavior or ideation) from placebo-controlled clinical studies of eleven drugs used to treat epilepsy as well as psychiatric disorders, and other conditions. In the FDA’s analysis, patients receiving antiepileptic drugs had approximately twice the risk of suicidal behavior or ideation (0.43%) compared to patients receiving placebo (0.22%). The increased risk of suicidal behavior and suicidal ideation was observed as early as one week after starting the antiepileptic drug and continued through 24 weeks. The results were generally consistent among the eleven drugs. The relative risk for suicidality was higher in patients with epilepsy compared to patients who were given one of the drugs in the class for psychiatric or other conditions.

Healthcare professionals should closely monitor all patients currently taking or starting any antiepileptic drug for notable changes in behavior that could indicate the emergence or worsening of suicidal thoughts or behavior or depression.

The drugs included in the analyses include (some of these drugs are also available in generic form):

  • Carbamazepine (marketed as Carbatrol, Equetro, Tegretol, Tegretol XR)

  • Felbamate (marketed as Felbatol)

  • Gabapentin (marketed as Neurontin)

  • Lamotrigine (marketed as Lamictal)

  • Levetiracetam (marketed as Keppra)

  • Oxcarbazepine (marketed as Trileptal)

  • Pregabalin (marketed as Lyrica)

  • Tiagabine (marketed as Gabitril)

  • Topiramate (marketed as Topamax)

  • Valproate (marketed as Depakote, Depakote ER, Depakene, Depacon)

  • Zonisamide (marketed as Zonegran)

Although the 11 drugs listed above were the ones included in the analysis, FDA expects that the increased risk of suicidality is shared by all antiepileptic drugs and anticipates that the class labeling changes will be applied broadly. For more information visit the FDA website at: and .

Introduction

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

Uses for Trileptal

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

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

Slideshow: Flashback: FDA Drug Approvals 2013

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

Trileptal Dosage and Administration

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

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

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 Trileptal

Contraindications

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

Warnings/Precautions

Warnings

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

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 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 Oxcarbazepine

Possibility of increased seizure frequency following discontinuance of oxcarbazepine.1 Reduce dosage, discontinue drug, or make drug substitution gradually.1 If a hypersensitivity reaction occurs, discontinue oxcarbazepine and initiate alternative therapy.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

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

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

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 Trileptal

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

Trileptal 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

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

  • 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

  • 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.

Oxcarbazepine

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Suspension

300 mg/5 mL

Trileptal (with alcohol and propylene glycol)

Novartis

Tablets, film-coated

150 mg

Trileptal (scored)

Novartis

300 mg

Trileptal (scored)

Novartis

600 mg

Trileptal (scored)

Novartis

Comparative Pricing

This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 10/2014. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.

OXcarbazepine 150MG Tablets (GLENMARK PHARMACEUTICALS): 30/$39.99 or 90/$109.97

OXcarbazepine 300MG/5ML Suspension (SANDOZ): 250/$147.99 or 750/$425.96

OXcarbazepine 300MG Tablets (GLENMARK PHARMACEUTICALS): 60/$131.00 or 180/$378.98

OXcarbazepine 600MG Tablets (GLENMARK PHARMACEUTICALS): 60/$259.98 or 180/$742.97

Trileptal 150MG Tablets (NOVARTIS): 60/$134.99 or 180/$389.96

Trileptal 300MG Tablets (NOVARTIS): 60/$245.99 or 180/$700.00

Trileptal 600MG Tablets (NOVARTIS): 60/$450.01 or 180/$1,283.02

AHFS DI Essentials. © Copyright, 2004-2014, Selected Revisions October 3, 2014. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, 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. [IDIS 465709] [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. [IDIS 424300] [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. [IDIS 450497] [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. [IDIS 449303] [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. [IDIS 456941] [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. [IDIS 449302] [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.

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