Oxcarbazepine

Oxcarbazepine is the generic name for Trileptal.  There is also an extended release version of the drug sold by the brand name Oxtellar XR. Oxcarbazepine is available in many countries, including the United States, Canada, the UK, Australia, and the countries of the European Union.

Although oxcarbazepine has been used in the United States just since 2000, it has been used in some other countries since 1990 and has been tested in thousands of patients in many clinical trials around the world.

Oxtellar XR
Tablet
150mg Oxtellar

150 mg: yellow modified-oval shaped with “150” printed on one side

300mg Oxtellar

300 mg: brown modified-oval shaped with “300” printed on one side

600mg Oxtellar

600 mg: brownish red modified-oval shaped with “600” printed on one side

Trileptal

Trileptal is marketed in the United States by Novartis Pharmaceuticals. The name or appearance may differ in various countries, but the dose (measured in milligrams, abbreviated "mg") will usually be the same. These descriptions apply to the U.S. Versions:

Tablet

150-mg (pale gray-green, scored)
300-mg (yellow, scored)
600-mg (light pink, scored)

Liquid Solution

300 mg/5 mL suspension: off-white to slightly brown or slightly red liquid.

Indications

In 2000, oxcarbazepine was approved by the U.S. Food and Drug Administration (FDA) for the treatment of partial seizures. It is approved for use as either monotherapy or adjunctive therapy for adults and children as young as 4 years of age.

As the name suggests, oxcarbazepine is related to carbamazepine (Tegretol, Carbatrol) and appears to be similarly effective for controlling complex partial seizures and primary and secondarily generalized tonic-clonic seizures. It seems to cause fewer unwanted side effects in many (but not all) patients.

Oxcarbazepine is not effective against absence or myoclonic seizures.

Forms

The appearance, formulations and dosages of oxcarbazepine may vary from manufacturer to manufacturer.

How to take and store Oxcarbazepine?

 

 

Mechanisms of actions of Oxcarbazepine

The mechanism of action of oxcarbazepine is similar to that of carbamazepine.

Oxcarbazepine and its active metabolite, monohydroxy derivative (MHD), have effects on sodium channels and possibly potassium and calcium channels. Neither oxcarbazepine nor MHD has an effect at binding sites for GABA or other neurotransmitter receptors.

Clinical Pharmacology of Oxcarbazepine

Absorption peak plasma levels are reached approximately 4-5 hours after an oral dose. Nearly the entire administered dose is absorbed. Food appears to have almost no effect on the absorption of oxcarbazepine.

Distribution and metabolism: Oxcarbazepine is chemically and structurally similar to carbamazepine, but undergoes a different metabolic process. Carbamazepine is oxidized to the 10,11 epoxide and then hydrolyzed. Oxcarbazepine undergoes reduction of the carbonyl group to form MHD by a cytosolic, non-microsomal, non-inducible keto-reductase. MHD is the active metabolite of oxcarbazepine and accounts for its antiseizure activity. The half-life of MHD averages 8 to 10 hours and is stable during chronic oxcarbazepine therapy in co-medicated patients. MHD is approximately 40% protein-bound.

Because unchanged oxcarbazepine and its metabolites are nearly entirely excreted in the urine, hepatic impairment has no apparent affect on the pharmacokinetics of oxcarbazepine or MHD. However, because oxcarbazepine metabolites are cleared renally, MHD levels are significantly increased in patients with reduced creatinine clearances. Oxcarbazepine dosages in patients with renal impairment should be reduced by 50% and the titration phase should be prolonged.

Steady state: Steady state is achieved after 3 to 4 oxcarbazepine doses in a twice-daily regimen. The dose that a patient takes should not be increased until steady state has been reached (or some time later), so that the effects of the previous dosage can be assessed.

Efficacy of Oxcarbazepine

Monotherapy studies: Three international, randomized, double-blind, monotherapy trials of oxcarbazepine in patients with newly diagnosed or previously untreated partial-onset or primary generalized seizures have been performed. One study (Christe et al. 1997) compared oxcarbazepine to valproate, and the other two (Guerreiro et al.1997; Bill et al. 1997) compared oxcarbazepine to phenytoin—one in adults and one in children and adolescents. Blinded treatment was administered three times daily and titrated over 8 weeks based on clinical response. In the study of oxcarbazepine versus valproate, randomized patients were titrated to between 900 and 2,400 mg daily for both AEDs. In the other two studies, oxcarbazepine dosages were 450 to 2,400 mg daily and phenytoin dosages were 150 to 800 mg daily. Efficacy and tolerability were recorded during a 48-week maintenance period.

In each of these studies, the primary efficacy variable was the proportion of seizure-free patients who had at least one seizure assessment during the maintenance period. In the study comparing oxcarbazepine to valproate, slightly more than half of the patients in each treatment group remained seizure-free during the maintenance period; there was no statistically significant treatment difference. Similarly, there was no treatment difference in the percentage of patients with partial-onset seizures who were seizure-free (46% for oxcarbazepine and 48% for valproate) or the proportion of patients with primary generalized seizures who were seizure-free (72% for oxcarbazepine and 62% for valproate).

In the study testing oxcarbazepine versus phenytoin in adults, nearly 60% of patients in each treatment group were seizure-free during the maintenance period; there was no statistically significant treatment difference. Similarly, there was no treatment difference in the percentage of patients with partial-onset seizures who were seizure-free (56% with oxcarbazepine and 53% for phenytoin) or the proportion with primary generalized seizures who were seizure-free (64% with oxcarbazepine and 68% with phenytoin).

In the pediatric study of oxcarbazepine versus phenytoin, nearly 60% of the children in each treatment group were seizure-free during the maintenance period; there was no statistically significant difference in seizure frequency. Similarly, there was no treatment difference in the percentage of patients with partial-onset seizures who were seizure-free (60% for oxcarbazepine and 62% for phenytoin) or the proportion of patients with primary generalized seizures who were seizure-free (59% for oxcarbazepine and 54% for phenytoin).

An outpatient, double-blind oxcarbazepine monotherapy study compared seizure frequencies in patients maintained at oxcarbazepine 2,400 mg/day to seizure frequencies in patients taking tapering dosages down to 300 mg/day (Sachdeo et al. 2001). The primary efficacy measure, a survival analysis of the time to meet one of the exit criteria, was significantly in favor of the high-dose oxcarbazepine group.

Comparisons of oxcarbazepine and Tegretol (carbamazepine) have generally found them to be equally effective.

Adjunctive therapy studies: A summary of studies in which oxcarbazepine was used adjunctively for partial seizures reported that 41% of adults who took oxcarbazepine had their seizures reduced in frequency by at least half, compared to 13% of those who added a placebo to their previous medications (Cramer et al. 2001).

A comparable study of oxcarbazepine as adjunctive therapy for children also found that 41% of those who took oxcarbazepine had at least a 50% decrease in seizure frequency (Glauser et al. 2000). Of those who took a placebo, 22% had a similar reduction.

Common side effects of Oxcarbazepine

Dose-related side effects: Common side effects of oxcarbazepine include:

  • Sedation
  • Dizziness
  • Double vision
  • Nausea
  • Headache

If these problems do not diminish within several days, a reduction in the dose of oxcarbazepine often will solve the problem. Problems with sedation also may be helped by splitting the dose or giving the largest dose at bedtime. Patients taking oxcarbazepine and lamotrigine simultaneously may have fewer side effects if the pills are staggered by 1-2 hours.

Idiosyncratic reactions

Rash: Skin reactions occur less frequently with oxcarbazepine than with carbamazepine. In the Novartis safety database of Trileptal (oxcarbazepine), which includes data on 2,436 patients treated with Trileptal and 277 treated with carbamazepine, 2.8% of Trileptal-treated patients had hypersensitivity reactions compared with 6.5% of those on carbamazepine.

There is cross-sensitivity with skin reactions. In one study, 46 of 55 patients (84%) who were switched from carbamazepine to oxcarbazepine because of skin reactions did not experience a recurrence while taking oxcarbazepine. In another report, 37 of 51 patients (73%) with previous skin reactions to carbamazepine did not have a recurrence with oxcarbazepine.

Abnormal liver or bone marrow function: No clinically relevant fluctuations of white blood count have been observed in clinical studies and clinically relevant elevations of liver function tests appear to occur less often than with carbamazepine. In a large retrospective study, liver and bone marrow function tests became abnormal in no more than 2% of patients.

Serious Side effects of Oxcarbazepine

SJS and TEN: As of April 19, 2005 the FDA and Novartis pharmaceuticals (the manufacturer of Trileptal) issued a new warning regarding oxcarbazepine. Serious dermatological reactions, including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), have been reported in both children and adults in association with oxcarbazepine use. The most common time of onset after first dosage of oxcarbazepine was 19 days. Such serious skin reactions may be life-threatening, and some patients have required hospitalization with very rare reports of fatal outcome.

The reporting rate of TEN and SJS associated with oxcarbazepine use, which is generally accepted to be an underestimate due to underreporting, exceeds the background incidence rate estimates by a factor of 3 to 10 fold. Estimates of the background incidence rate for these serious skin reactions in the general population range between 0.5 to 6 cases per million person years. Therefore, if a patient develops a skin reaction while taking oxcarbazepine, consideration should be given to discontinuing oxcarbazepine use and prescribing another anti-epileptic medication.

Hyponatremia: Hyponatremia occurs more commonly with oxcarbazepine than with carbamazepine. While isolated cases of hyponatremic coma have been reported, oxcarbazepine-induced hyponatremia is seldom clinically significant.

Anaphylaxis and angioedema: Rare cases of anaphylaxis and angioedema involving the larynx, glottis, lips and eyelids have been reported in patients after taking the first or subsequent doses of oxcarbazepine. Angioedema associated with laryngeal edema can be fatal. If a patient develops any of these reactions after treatment with oxcarbazepine, the drug should be discontinued and an alternative treatment started. These patients should not be rechallenged with the drug

On July 10, 2008, an advisory panel was convened by the Food and Drug Administration (FDA) to review data that the FDA had previously collected from drug studies showing an association between many of the antiepileptic drugs (AEDs) and suicidal ideation and behavior, which together are called suicidality. According to the FDA’s Alert, among the patients with epilepsy in these drug studies, 1 out of 1000 people taking the placebo (inactive substance) showed suicidality compared to approximately 3.5 out of 1000 people who took an AED. The FDA advisory panel voted to accept the FDA's data at its meeting on July 10.

  • Taking antiepileptic medicines may increase the risk of having suicidal thoughts or actions;
  • Do not make any changes to the medication regimen without first talking with the responsible healthcare professional;
  • Pay close attention to any day-to-day changes in mood, behavior and actions. These changes can happen very quickly so it is important to be mindful of any sudden differences.
  • Be aware of common warning signs that might be a signal for risk of suicide. Some of these are:
    • Talking or thinking about wanting to hurt yourself or end your life
    • Withdrawing from friends and family
    • Becoming depressed or having your depression get worse
    • Becoming preoccupied with death and dying
    • Giving away prized possessions

We again urge patients and families to contact their doctor before stopping an epilepsy medication because this may possibly lead to seizures and worsening of mood.

Other Uses of Oxcarbazepine

Open trials of oxcarbazepine in patients with carbamazepine-resistant trigeminal neuralgia have shown positive results. In one study, all cases responded within 24 hours.

A limited number of other studies evaluated oxcarbazepine in patients with affective disorders, especially bipolar disorder, with mixed results.

Oxcarbazepine Interactions with other medications

Effects of other drugs on oxcarbazepine: The metabolism of oxcarbazepine and MHD is unaffected by induction or inhibition of the cytochrome P450 system. This reduces the potential for interactions with anti-epileptic drugs (AEDs) and other drugs that inhibit the metabolism of carbamazepine, such as erythromycin, cimetidine, and propoxyphene.

Effects of oxcarbazepine on other drugs: Studies in non-epileptic women taking oral contraceptives found that oxcarbazepine reduced ethinylestradiol and levonorgestrel concentrations. It may therefore reduce the potency of oral contraceptives and other hormonal forms of birth control.

Oxcarbazepine can inhibit the hepatic isoenzyme CYP 2C19 and thereby increase phenytoin concentrations by up to 40%.

AED Interaction Sheets: Seizure drugs are often affected by drug-drug interactions. Print these informative sheets for practical help.

Oxcarbazepine effects on Children

The starting dose for children is usually 8 to 10 mg/kg per day, divided into two doses. Children under 8 may need a higher dose relative to weight than older children. Dosage increases should be done slowly to minimize side effects, with a target dose of 10-50 mg/kg per day.

The concentrations of the active metabolite, MHD, in children aged 6 to 18 are similar to those observed in adults, but those reported in children aged 2 to 5 are lower due to faster clearance.

Oxcarbazepine and Pregnancy

The U.S. Food and Drug Administration (FDA) lists oxcarbazepine in Pregnancy Category C. This indicates that caution is advised, but the benefits of the medication may outweigh the potential risks. Studies in animals have shown some harm to the fetus.

Information about the safety of oxcarbazepine in pregnancy is limited. In one retrospective study, 3 of 12 women treated with oxcarbazepine as monotherapy or polytherapy during the first trimester had spontaneous abortions; the other 9 delivered normal babies.

Women who are capable of becoming pregnant should take at least 400 mcg (0.4 mg) of folic acid (folate) daily to help prevent neural tube defects. Women at high risk, such as those with a history of a neural tube defect in a previous pregnancy, should take 4,000 mcg (4 mg) daily, beginning before they become pregnant.

The risk of defects is generally higher for women who take more than one AED and for women with a family history of birth defects.

About 20% to 35% of women have seizures more often during pregnancy because of changes in hormones or changes in how their AED is metabolized. It is not known if this is true for oxcarbazepine.

Oxcarbazepine and MHD cross the placenta and are excreted in breast milk, with a milk-to-plasma concentration ratio of 0.5.

Oxcarbazepine effects on Seniors

Lower initial doses and caution in titration are required. Maintenance doses should be reduced, dosing intervals increased, or both in seniors with reduced creatinine clearance.

Some common side effects of oxcarbazepine, such as sedation, may exacerbate pre-existing problems of seniors, and their greater risk of injury from falls or other accidents makes this an area of concern.

Oxcarbazepine Dosing and titration

Adults usually are started with 300 to 600 mg per day, divided into two doses. The dose can be increased after about a week. The recommended dosage as monotherapy in adults is 600 to 1,200 mg per day, in two doses. Higher dosages may be necessary when used as polytherapy in patients with refractory seizures. MHD levels of 10-30 mcg/mL are usually attained.

Doses should be reduced by half for patients with renal insufficiency.

Oxcarbazepine Package insert

In the United States, companies that manufacture medicines are required to publish certain kinds of information about each product. This document is commonly known as a “package insert” because it is usually included with each package of the medicine.

You can also read these documents (also called "prescribing information") online. The U.S. package insert for Trileptal (oxcarbazepine) is found at:

Some of the information may differ in other countries.

Learn how to read a package insert here.

Oxcarbazepine References for Professionals

Abstracts of articles relevant to this topic are available through PubMed, a service of the National Library of Medicine:

Here are links to some articles relevant to this subject:

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 Jun;27(3):195-204. PMID: 9237054    

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 Mar;26(3):451-60. PMID: 9127726.

Cramer JA, Ben Menachem E, French J. Review of treatment options for refractory epilepsy: new medications and vagal nerve stimulation. Epilepsy Res 2001 Nov;47(1-2):17-25. PMID: 11673017.

Friis ML, Kristensen O, Boas J, et al: Therapeutic experiences with 947 epileptic out-patients in oxcarbazepine treatment. Acta Neurol Scand 87: 224-7, 1993. PMID 8475694.

Glauser TA, Nigro M, Sachdeo R, et al. Adjunctive therapy with oxcarbazepine in children with partial seizures. The Oxcarbazepine Pediatric Study Group. Neurology 2000 Jun 27;54(12):2237-44. PMID: 10881246.

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 Jun;27(3):205-13. PMID: 9237055.

Sachdeo R, Beydoun A, Schachter S, et al: Oxcarbazepine (Trileptal) as monotherapy in patients with partial seizures. Neurology 2001 Sep 11;57(5):864-71.

Schachter SC, Vazquez B, Fisher RS, et al: Oxcarbazepine: double-blind, randomized, placebo-control, monotherapy trial for partial seizures. Neurology 52: 732-7, 1999. PMID 10078718.

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