Vademecum

Description: Oxcarbazepine, the keto-analogue of carbamazepine, is an oral anticonvulsant which is indicated for the treatment of partial seizures with or without secondary generalization. Studies indicate that it is as effective as valproate, carbamazepine, and phenytoin. In addition, oxcarbazepine may be less likely than carbamazepine to cause CNS side effects such as dizziness or hematologic abnormalities such as leukopenia; however, further comparisons are needed. A major advantage of oxcarbazepine over carbamazepine is that monitoring of drug plasma levels and hematologic profiles is generally not necessary. In addition, drug interactions appear less significant with oxcarbazepine than carbamazepine. This anticonvulsant is now marketed in over 50 countries and is one of many initial treatment options, adjunct therapies, or alternatives for those with intolerance or nonresponsiveness to other anticonvulsants. Similar to carbamazepine, oxcarbazepine has been successfully used for the treatment of neuropathic pain such as trigeminal neuralgia. Oxcarbazepine received FDA approval on January 14, 2000. Mechanism of Action: The primary pharmacologic activity is attributed to the 10-monohydroxy metabolite (MHD) of oxcarbazepine because of the rapid systemic metabolism of the parent compound. Like most anticonvulsants, the exact mechanism of action is unknown; however, in vitro studies indicate that voltage-sensitive sodium channels are blocked thereby stabilizing neural membranes, inhibiting repetitive neuronal firing, and diminishing synaptic impulse activity. Modulation of potassium and calcium channels may also be involved. GABA receptors are not affected by oxcarbazepine or MHD. Pharmacokinetics: Following oral administration, oxcarbazepine is almost completely absorbed from the gastrointestinal tract. Food does not affect the rate or extent of absorption. Oxcarbazepine undergoes rapid reduction in the liver to MHD. Peak MHD plasma levels are reached in 4 to 6 hours while steady state levels are attained within 2�3 days of twice daily dosing. Maximum plasma levels and AUC values are 30�60% higher in the elderly. The half-lives of oxcarbazepine and MHD are 2 and 9 hours, respectively. MHD is metabolized primarily through conjugation to minor metabolites. About 4% of MHD is oxidized through hepatic CYP3A4/5 isoenzymes. Oxcarbazepine and MHD produce a dose-related inhibition of CYP2C19 and induction of CYP3A4/5. More than 95% of the dose is renally excreted; however, less than 1% is unchanged oxcarbazepine. Almost one-half of a dose is eliminated as metabolites of MHD. Less than 4% of a dose is excreted in the feces. Children < 8 years of age have a 30�40% increase in clearance compared to older children and adults. AUC values of MHD are 30�60% higher in the elderly. The renal clearance of MHD declines linearly with a decrease in creatinine clearance. The elimination half-life of MHD reaches 19 hours when the creatinine clearance falls below 30 ml/minute. The pharmacokinetics of the drug are not affected by mild to moderate liver impairment.

Indications...Dosage For the treatment of partial seizures: �for monotherapy treatment of partial seizures with or without secondary generalization: Oral dosage: Adults: Initiate at 300 mg PO twice daily. Increase as indicated by 300 mg/day every third day or 600 mg/day at weekly intervals up to 2400 mg/day in two divided doses. Some data indicate that 1200 mg/day may be effective in anticonvulsant-naive patients. When converting to oxcarbazepine from other anticonvulsants, initiate at 300 mg PO twice daily while beginning to reduce the dose of other anticonvulsants. Oxcarbazepine should be titrated upward by 600 mg/day at weekly intervals over 2 to 4 weeks to achieve the recommended dose of 2400 mg/day. The dosage(s) of concurrent anticonvulsants should be completely withdrawn over 3 to 6 weeks as tolerated. �for adjunct treatment of partial seizures with or without secondary generalization: Oral dosage: Adults: Initiate at 300 mg PO twice daily. The dose may be increased by a maximum of 600 mg/day at weekly intervals up to 1200 mg/day. Dosages above 1200 mg/day are considered more effective; however, in one large clinical trial, 65% of subjects withdrew from the study due to intolerable CNS effects from combined anticonvulsant therapy. Adolescents and children 4�16 years of age: Initiate at a daily dose of 8�10 mg/kg/day PO (generally <= 600 mg/day), given in two divided doses. The target dose should be achieved over 2 weeks, and is dependent upon weight. Dosage must be individualized. Suggested target dosages are listed. For 20�29 kg the target maintenance dose is 900 mg/day PO. For weight of 29.1�39 kg, the target dose is 1200 mg/day PO. If weight is > 39 kg, the target dose is 1800 mg/day PO. �conversion of patients from carbamazepine to oxcarbazepine: Adults and the elderly: Individualize dosage. The usual daily maintenance dose of oxcarbazepine is approximately 1.5 times that of carbamazepine in adults and 1.2 times that of carbamazepine in the elderly. For the treatment of trigeminal neuralgia�: Oral Dosage: Adults: Titrate as tolerated to effect, using recommended dosage titration schedules. Initiate at 300 mg PO twice daily. May be increased by no more than 600 mg/day at weekly intervals. Most patients respond to doses between 900 mg�2400 mg/day PO.[2758] [2759] Therapeutic Drug Monitoring: �Monitoring of plasma levels or hematologic profiles is generally not necessary. A target serum concentration of 12�30 mcg/ml has been suggested as an aid in assessing compliance or toxicity.[2757] Patients with hepatic impairment: Mild-to-moderate hepatic impairment does not appear to affect the metabolism of oxcarbazepine or the active metabolite (MHD); therefore, no dosage adjustments are recommended. The effects of severe hepatic impairment have not been evaluated. Patients with renal impairment: CrCl >= 30 ml/min: No dosage adjustments have been recommended, but renal clearance of MHD, the active metabolite, declines linearly with a decrease in creatinine clearance. CrCl < 30 ml/min: renal clearance of MHD, the active metabolite, is prolonged to 19 hours; therefore, initiate therapy with 50% of the usual starting dose and slowly titrate upward as necessary. �non-FDA-approved indication

Oral Administration �May be taken without regard to meals.

Contraindications In general, abrupt discontinuation of anticonvulsants may precipitate rebound seizures. Although this has not yet been documented with oxcarbazepine, withdrawal over several weeks is recommended if discontinuation is necessary. Oxcarbazepine should not be used in patients with a known hypersensitivity reaction to the drug or any of its components. Approximately 25�30% of patients with carbamazepine hypersensitivity will react to oxcarbazepine. This is likely due to the structural similarity of the two drugs. Clinically significant hyponatremia (sodium <125 mmol/L) may develop during treatment with oxcarbazepine. This typically occurs during the first 3 months; however, cases of symptomatic hyponatremia beginning more than 1 year after treatment initiation have been observed. Normalization of sodium levels usually occurs within a few days of discontinuing the drug. Monitoring of sodium levels should be considered if oxcarbazepine is used with other medications known to decrease sodium levels or in those with baseline hyponatremia. Oxcarbazepine should be used cautiously in those with renal impairment because the primary route of elimination of its metabolites is through the kidneys. The elimination half-life of MHD is prolonged to 19 hours when the creatinine clearance falls below 30 ml/min; therefore, dosage adjustments are recommended (see Dosage). There are no controlled studies evaluating the use of oxcarbazepine in children less than 2 years of age. Oxcarbazepine is classified as FDA pregnancy category C. Although there are no clinical trials documenting its effect in pregnant women, results of some animal studies indicate that oxcarbazepine may be teratogenic in humans. The documented cases of human teratogenicity of a related compound, carbamazepine, support this theory. Therefore, oxcarbazepine should only be used during pregnancy if the benefits of treatment clearly outweigh the risks to the fetus. Oxcarbazepine and its active metabolite MHD are excreted in human breast milk. A milk to plasma ratio of 0.5 has been reported. The decision to use the drug during breast-feeding should be carefully weighed, given the potential for adverse effects to the infant. Central nervous system effects, including somnolence and dizziness, are among the most frequently reported adverse effects of oxcarbazepine. Patients should be cautioned about engaging in tasks requiring mental alertness such as driving or operating machinery until they know how the drug will affect their cognition. Patients should also be informed about the additive central nervous system depressant effects of alcohol when used with anticonvulsants. Single and multiple dose studies indicate that the maximum plasma concentrations and AUC values of MHD are 30�60% higher in the elderly. This increase has been attributed to the decline in creatinine clearance associated with age. The significance of this finding has not been determined; however lower doses may be necessary in these patients.

Interactions NOTE: Some studies in which oxcarbazepine drug interactions have been reported involve crossover from other anticonvulsant treatment. This factor may complicate interpretation of the data and assessment of the clinical significance of some drug interactions occurring with oxcarbazepine. Given the complex nature of anticonvulsant drug interactions, careful monitoring is recommended during polytherapy with these agents. The coadministration of oxcarbazepine with medications metabolized through the hepatic CYP2C19 isoenzyme may produce clinically significant drug interactions with phenytoin or fosphenytoin. This occurs from dose-related CYP2C19 inhibition by oxcarbazepine and its active metabolite, MHD. In one adult study, phenytoin plasma levels increased up to 40% when > 1200 mg/day of oxcarbazepine was concurrently administered. There was less than a 10% mean change in phenytoin levels observed in pediatric patients studied. The mean MHD concentration decreased by 30% in one study, likely due to the induction of CYP3A4 by phenytoin. The CYP3A4 isoenzyme is a minor metabolic pathway of MHD. Oxcarbazepine and its active metabolite, MHD, are dose-dependent inducers of the hepatic CYP3A4/5 isoenzymes thereby having the potential to lower the plasma levels of medications metabolized through these pathways. The effectiveness of CNS medications such as alprazolam, galantamine, triazolam, quetiapine, could theoretically be decreased. Oxcarbazepine and its active metabolite, MHD, are dose-dependent inducers of the hepatic CYP3A4/5 isoenzymes thereby having the potential to lower the plasma levels of medications metabolized through these pathways. The effectiveness of imunosuppressive medications such as cyclosporine, sirolimus, and tacrolimus could theoretically be decreased. The results of one study demonstrated that the mean AUC of ethinylestradiol/levonorgestrel was decreased by 52% when co-administered with oxcarbazepine. A high percentage of breakthrough bleeding has been reported in the literature from the combined use of oxcarbazepine and oral contraceptives. A similar interaction can be expected with other hormonal contraceptives since the CYP3A subgroup is responsible for the metabolism of sex hormones. Patients should be instructed about the importance of alternative birth control methods if this combination is necessary. The AUC of felodipine was decreased by 28% during repeated administration with oxcarbazepine. This interaction can be anticipated because felodipine is metabolized through the CYP3A4 isoenzyme which is induced by oxcarbazepine and its active metabolite, MHD. In one study, verapamil reportedly produced a 20% decrease in the plasma levels of MHD, the active metabolite of oxcarbazepine. The mechanism is not clear since it is contrary to the typical interactions seen with verapamil which are the result of its hepatic CYP3A4 inhibition. In pre-marketing clinical trials, carbamazepine produced a mean decrease of 40% in the plasma concentration of MHD, the active metabolite of oxcarbazepine. The potent CYP3A4 induction effect of carbamazepine was likely a factor because CYP3A4 is a minor metabolic pathway of MHD. Although oxcarbazepine is a CYP3A4 inducer, autoinduction has not been observed because reduction is its primary metabolic route. Pre-marketing studies demonstrated a minor interaction between valproic acid and MHD, the active metabolite of oxcarbazepine. Although valproic acid produced only a mean decrease of 18% in MHD concentrations, careful monitoring is still indicated due to the variable and unpredictable effects of valproic acid on the CYP450 system. An interaction is possible when oxcarbazepine is co-administered with phenobarbital. The mean concentration of MHD, the active metabolite of oxcarbazepine, was decreased by 25% in one study, whereas the mean phenobarbital concentration was increased by 14%. This interaction likely involves the effects of phenobarbital as an inducer of the CYP3A4 isoenzyme and MHD as an inhibitor of CYP2C19. De-induction from previous anticonvulsant therapy may be a contributor to the elevated phenobarbital levels in these studies. Complex interactions exist among anticonvulsants. Because primidone is metabolized to phenobarbital, primidone can stimulate the metabolism of other anticonvulsants, including oxcarbazepine. A retrospective evaluation indicates that the clearance of lamotrigine is increased by 29% when given concurrently with oxcarbazepine. This is significantly less than the effect of carbamazepine, which reduced lamotrigine levels by 54%. This interaction may be attributable to CYP450 induction by oxcarbazepine. If oxcarbazepine is discontinued, lamotrigine doses may need to be adjusted downward. An additive CNS depressant effect can be expected during the concurrent use of ethanol and oxacarbazepine. This combination should be avoided. No change in the kinetics of MHD, the active metabolite of oxcarbazepine, was observed when oxcarbazepine was co-administered with cimetidine, erythromycin, or dextropropoxyphene. Limited data suggest that oxcarbazepine does not significantly alter the effects of warfarin.

Adverse Reactions Central nervous system effects are among the most commonly observed adverse reactions with oxcarbazepine. Dizziness is the side effect most commonly associated with discontinuation of the drug in adult trials. Many CNS effects are dose-related including dizziness (22�49%), sedation (19�36%), headache (13�32%), ataxia (5�31%), nystagmus (7�26%), gait abnormalities (5�17%), and tremor (3�16%). In general, low-dose oxcarbazepine is better tolerated than high-dose oxcarbazepine, but effectiveness may be diminished. There is also a high incidence of CNS effects in pediatric patients including headache (31%), sedation (31%), dizziness (28%), and ataxia (13%). Sedation is the side effect most commonly associated with discontinuation of the drug in pediatric trials. Other CNS effects observed in pediatrics include nystagmus (9%), emotional lability (8%), gait abnormalities (8%), tremor (6%), impaired concentration (2%), and involuntary muscle contractions (2%). The most common gastrointestinal complaints among adults and children are nausea/vomiting. Nausea occurs in 15�29% of adults and 19% of children. Vomiting reportedly occurs in 7�36% of adults depending upon dose. In pediatric studies, vomiting was the most commonly observed of all adverse reactions (33%). Less frequently reported gastrointestinal effects in adults include diarrhea (7%), dyspepsia (6%), constipation (5%), and abdominal pain (5%). Less common adverse gastrointestinal effects observed in pediatric patients include constipation (4%) and dyspepsia (2%). Other adverse effects occurring more frequently with oxcarbazepine than placebo include fatigue (12�15%), vertigo (6�15%), diplopia (14�40%) and abnormal vision (6�14%). Ophthalmic effects which have been reported in open trials include mydriasis, photophobia, eye edema, accommodation abnormalities, and conjunctival hemorrhage; although, causality to oxcarbazepine has not been established. Although uncommon, allergic skin reactions such as rash (unspecified) may occur with oxcarbazepine. Rarely, this may become as severe as exfoliative dermatitis. Other skin conditions reportedly include erythema multiforme, Stevens-Johnson syndrome, and toxic epidermal necrolysis. Hypersensitivity reactions may also manifest as fever, lymphadenopathy, eosinophilia or arthralgia. Cross-sensitivity between carbamazepine and oxcarbazepine is approximately 25�30%. This is likely due to the structural similarity of the two drugs. Significant hyponatremia (sodium <125 mmol/L) may develop during treatment with oxcarbazepine and has been reported in 2.5% of patients in pre-marketing trials. Sodium levels <135 mmol/L may occur more frequently in those treated with oxcarbazepine than with carbamazepine. This reaction typically occurs during the first 3 months; however, cases of symptomatic hyponatremia beginning more than 1 year after treatment initiation have been observed. Normalization of sodium levels usually occurs within a few days of discontinuing the drug. A mechanism other than SIADH may be partially responsible since some cases of hyponatremia without abnormal ADH levels have been observed. Monitoring of sodium levels should be considered if oxcarbazepine is used with other medications known to decrease sodium levels or in those with baseline hyponatremia. Infection, inclusive of the respiratory tract, urinary tract, chest, sinuses, and ear, were reported in 2�10% of patients receiving oxcarbazepine in clinical trials. Leukopenia and thrombocytopenia have been reported in open label and uncontrolled trials; however, a causal relationship to oxcarbazepine has not been established.

Oxcarbazepine Trileptal�

2758. Grant SM, Faulds D. Oxcarbazepine: a review of its pharmacology and therapeutic potential in epilepsy, trigeminal neuralgia and affective disorders. Drugs 1992;43:873�88.

2759. Remillard G. Oxcarbazepine and intractable trigeminal neuralgia. Epilepsia 1994;35(suppl 3):28�29.

2757. Tecoma, ES. Oxcarbazepine. Epilepsia 1999;40(suppl 5):37�46.