Mechanism of Action
The pharmacological activity of Oxtellar XR™ is primarily exerted through the 10-monohydroxy metabolite (MHD) of oxcarbazepine. The precise mechanism by which oxcarbazepine and MHD exert their antiseizure effect is unknown; however, in vitro electrophysiological studies indicate that they produce blockade of voltage-sensitive sodium channels, resulting in stabilization of hyperexcited neural membranes, inhibition of repetitive neuronal firing, and diminution of propagation of synaptic impulses. These actions are thought to be important in the prevention of seizure spread in the intact brain. In addition, increased potassium conductance and modulation of high-voltage activated calcium channels may contribute to the anticonvulsant effects of the drug. No significant interactions of oxcarbazepine or MHD with brain neurotransmitter or modulator receptor sites have been demonstrated.
Oxcarbazepine and its active metabolite (MHD) exhibit anticonvulsant properties in animal seizure models. They protected rodents against electrically induced tonic extension seizures and, to a lesser degree, chemically induced clonic seizures, and abolished or reduced the frequency of chronically recurring focal seizures in Rhesus monkeys with aluminum implants. No development of tolerance (i.e., attenuation of anticonvulsive activity) was observed in the maximal electroshock test when mice and rats were treated daily for five days and four weeks, respectively, with oxcarbazepine or MHD.
Following oral administration, oxcarbazepine is absorbed and extensively metabolized to its pharmacologically active 10-monohydroxy metabolite (MHD), which is responsible for most antiepileptic activity.
In clinical studies of Oxtellar XR™, the elimination half-life of oxcarbazepine was between 7 and 11 hours; the elimination half-life of MHD is between 9 and 11 hours.
In a mass balance study in human, only 2% of total radioactivity in plasma after administration of immediate-release oxcarbazepine was due to unchanged oxcarbazepine, with approximately 70% present as MHD, and the remainder attributable to minor metabolites.
Oxtellar XR™ administered as a once daily dose is not bioequivalent to the same total dose of the immediate release formulation given twice daily at steady state. Steady state plasma concentrations of MHD are reached within 5 days when Oxtellar XR™ is given once daily. At steady state, when 1200 mg Oxtellar XR™ was given once daily, MHD Cmax occurred 7 hours post-dose. At steady state, Oxtellar XR™ given once daily produced MHD exposures (AUC and Cmax) about 19% lower and MHD minimum concentrations (Cmin) about 16% lower than the immediate-release oxcarbazepine given twice daily when administered at the same 1200 mg total daily dose. When Oxtellar XR™ was administered at an equivalent 600 mg single dose (4 x 150 mg tablets, 2 x 300 mg tablets, or 1 x 600 mg tablet), equivalent MHD exposures (AUC) were observed.
Following a single dose of Oxtellar XR™ (1 x 150 mg tablets, 1 x 300 mg tablets, or 1 x 600 mg tablet), the pharmacokinetics of MHD are not linear and show greater than dose proportional increase in AUC and less than proportional increase in Cmax: AUC increases 2.4-fold and Cmax increases 1.9-fold with a 2-fold increase in dose.
Effect of Food: Single dose administration of 600 mg Oxtellar XR™ following a high fat meal (800 – 1000 calories) produced MHD exposure (AUC) equivalent to that produced under fasting conditions. Peak MHD concentration (Cmax) was about 60% higher and occurred 2 hours earlier under fed conditions than under fasting conditions.
The increase in Cmax, even without a significant change in the overall exposure, should be considered by the prescriber especially during the titration phase, when some adverse reactions are most likely to occur coincidentally with peak levels.
The apparent volume of distribution of MHD is 49 L. Approximately 40% of MHD is bound to serum proteins, predominantly to albumin. Binding is independent of the serum concentration within the therapeutically relevant range. Oxcarbazepine and MHD do not bind to alpha-1-acid glycoprotein.
Oxcarbazepine is rapidly reduced by cytosolic enzymes in the liver to MHD, which is primarily responsible for the pharmacological effect of TRADENAME. MHD is metabolized further by conjugation with glucuronic acid. Minor amounts (4% of the dose) are oxidized to the pharmacologically inactive 10,11-dihydroxy metabolite (DHD).
Oxcarbazepine is cleared from the body mostly in the form of metabolites which are predominantly excreted by the kidneys. More than 95% of a dose of immediate-release oxcarbazepine appears in the urine, with less than 1% as unchanged oxcarbazepine. Fecal excretion accounts for less than 4% of an administered dose. Approximately 80% of the dose is excreted in the urine either as glucuronides of MHD (49%) or as unchanged MHD (27%); the inactive DHD accounts for approximately 3% and conjugates of MHD and oxcarbazepine account for 13% of the dose.
The half-life of the parent was about two hours, while the half-life of MHD was about nine hours after the immediate release formulation. A population pharmacokinetic model for Oxtellar XR™ was developed in healthy normal adults and applied to pharmacokinetic data in patients with epilepsy. For oxcarbazepine, systemic parameters were scaled allometrically, suggesting that steady state oxcarbazepine exposure will vary inversely with weight.
No studies with Oxtellar XR™ in elderly patients have been completed [see Use In Specific Populations].
Following administration of single (300 mg) and multiple (600 mg/day) doses of immediate-release oxcarbazepine to elderly volunteers (60-82 years of age), the maximum plasma concentrations and AUC values of MHD were 30%-60% higher than in younger volunteers (18-32 years of age).
Comparisons of creatinine clearance in young and elderly volunteers indicate that the difference was due to age-related reductions in creatinine clearance.
Oxtellar XR™ is not approved for pediatric patients less than 6 years of age because the size of the tablets are inappropriate for younger children, and has not been studied in patients younger than 4 years of age. A pharmacokinetic study of Oxtellar XR™ was performed in 18 pediatric patients with epilepsy, 4 to 16 years of age, after multiple doses. The population pharmacokinetic model suggested that dosing of pediatric patients with Oxtellar XR™ can be determined based on body weight. Weight-normalized doses in pediatric patients should produce MHD exposures (AUC) comparable to that in typical adults, with oxcarbazepine exposures ~40% higher in children than in adults [see Use In Specific Populations].
The effects of gender have not been studied for Oxtellar XR™.
No gender-related pharmacokinetic differences have been observed in children, adults, or the elderly with immediate-release oxcarbazepine.
The effects of race have not been studied for Oxtellar XR™.
Renal or Hepatic Impairment
The effects of renal or hepatic impairment have not been studied for Oxtellar XR™ [see Use In Specific Populations].
Based on investigations with immediate-release oxcarbazepine, there is a linear correlation between creatinine clearance and the renal clearance of MHD. When immediate-release oxcarbazepine is administered as a single 300 mg dose in renallyimpaired patients (creatinine clearance < 30 mL/min), the elimination half-life of MHD is prolonged to 19 hours, with a two-fold increase in AUC. Dose adjustment is recommended in these patients [see DOSAGE AND ADMINISTRATION and Use in Special Populations].
The pharmacokinetics and metabolism of immediate-release oxcarbazepine and MHD were evaluated in healthy volunteers and hepatically impaired subjects after a single 900 mg oral dose. Mild-to-moderate hepatic impairment did not affect the pharmacokinetics of immediate-release oxcarbazepine and MHD. The pharmacokinetics of oxcarbazepine and MHD have not been evaluated in severe hepatic impairment, and therefore it is not recommended in these patients [see Use in Specific Populations].
Due to physiological changes during pregnancy, MHD plasma levels may gradually decrease throughout pregnancy [see Use In Specific Populations]
Drug Interaction Studies
Oxcarbazepine can inhibit CYP2C19 and induce CYP3A4/5 with potentially important effects on plasma concentrations of other drugs. In addition, several AEDs that are cytochrome P450 inducers can decrease plasma concentrations of oxcarbazepine and MHD.
Oxcarbazepine was evaluated in human liver microsomes to determine its capacity to inhibit the major cytochrome P450 enzymes responsible for the metabolism of other drugs. Results demonstrate that oxcarbazepine and its pharmacologically active 10-monohydroxy metabolite (MHD) have little or no capacity to function as inhibitors for most of the human cytochrome P450 enzymes evaluated (CYP1A2, CYP2A6, CYP2C9, CYP2D6, CYP2E1, CYP4A9 and CYP4A11) with the exception of CYP2C19 and CYP3A4/5.
Although inhibition of CYP3A4/5 by oxcarbazepine and MHD did occur at high concentrations, it is not likely to be of clinical significance. The inhibition of CYP2C19 by oxcarbazepine and MHD, is clinically relevant.
In vitro, the UDP-glucuronyl transferase level was increased, indicating induction of this enzyme. Increases of 22% with MHD and 47% with oxcarbazepine were observed. As MHD, the predominant plasma substrate, is only a weak inducer of UDP-glucuronyl transferase, it is unlikely to have an effect on drugs that are mainly eliminated by conjugation through UDPglucuronyl transferase (e.g., valproic acid, lamotrigine).
In addition, oxcarbazepine and MHD induce a subgroup of the cytochrome P450 3A family (CYP3A4 and CYP3A5) responsible for the metabolism of dihydropyridine calcium antagonists, oral contraceptives and cyclosporine resulting in a lower plasma concentration of these drugs.
Several AEDs that are cytochrome P450 inducers can decrease plasma concentrations of oxcarbazepine and MHD. No autoinduction has been observed with immediate-release oxcarbazepine.
As binding of MHD to plasma proteins is low (40%), clinically significant interactions with other drugs through competition for protein binding sites are unlikely.
Coadministration of immediate-release oxcarbazepine with an oral contraceptive has been shown to influence the plasma concentrations of two components of hormonal contraceptives, ethinylestradiol (EE) and levonorgestrel (LNG). The mean AUC values of EE were decreased by 48% [90% CI: 22-65] in one study and 52% [90% CI: 38-52] in another study. The mean AUC values of LNG were decreased by 32% [90% CI: 20-45] in one study and 52% [90% CI: 42-52] in another study. Therefore, concurrent use of oxcarbazepine with hormonal contraceptives may render these contraceptives less effective.
Calcium Channel Antagonists
After repeated coadministration of immediate-release oxcarbazepine, the AUC of felodipine was lowered by 28% [90% CI: 20-33]. Verapamil produced a decrease of 20% [90% CI: 18-27] of the plasma levels of MHD after coadministration with immediate-release oxcarbazepine.
Cimetidine, erythromycin and dextropropoxyphene had no effect on the pharmacokinetics of MHD after coadministration with immediate-release oxcarbazepine. Results with warfarin show no evidence of interaction with either single or repeated doses of immediate-release oxcarbazepine.
Oxtellar XR™ has been evaluated as adjunctive therapy for partial seizures in adults. The use of Oxtellar XR™ for the treatment of partial seizures in children is based on adequate and well-controlled studies of Oxtellar XR™ in adults, along with clinical trials of immediate-release oxcarbazepine in children, and on pharmacokinetic evaluations of the use of Oxtellar XR™ in children.
Oxtellar XR™ Primary Trial
A multicenter, randomized, double-blind, placebo-controlled, three-arm, parallel-group study (Study 1) in male and female adults with refractory partial epilepsy (18 to 65 years of age, inclusive) was performed to examine the safety and efficacy of Oxtellar XR™.
Patients had at least three partial seizures per 28 days during an 8 week Baseline Period. Subjects were receiving treatment with at least one to three antiepileptic drugs and were on stable treatment for a minimum of 4 weeks. Subjects with a diagnosis other than partial epilepsy were excluded.
The study included an 8 week Baseline Period, followed by a Treatment Period, which included a 4 week Titration Phase followed by a 12 week Maintenance Phase. The primary endpoint of the study was median percentage change from baseline in seizure frequency per 28 days during the treatment period relative to the baseline period. The criterion for statistical significance was p < 0.05. A total of 366 patients were enrolled at 88 sites in North America and Eastern Europe. Subjects were randomized to one of three treatment groups and took Oxtellar XR™ (1200 or 2400 mg/day) or placebo.
Table 6 presents the primary efficacy results by treatment group.
Table 6: Primary Efficacy Results in Study 1: Percent Change from
Baseline in Partial Seizure Frequency in the 16-week Treatment Period
|Median seizure frequency during 8week baseline period (per 28 days)||Median seizure frequency during 16-week treatment period (per 28 days)||Median percent change in seizure frequency||Seizure frequency percent change effect size||P value vs placebo*|
|Oxtellar XR™ 1200mg/day (N=122)||6.0||4.3||-38.20%||9.50%||0.078|
|Oxtellar XR™ 2400mg/day (N=123)||6.0||3.7||-42.90%||14.20%||0.003|
|* Wilcoxon rank-sum test of the median percentage change in partial seizure frequency per 28 days during the 16-week Treatment Phase (Titration + Maintenance Periods) relative to the 8-week Baseline Phase.|
Although the 1200 mg/day-placebo contrast did not reach statistical significance, concentration-response analyses reveal that the 1200 mg/day dose is an effective dose.
Immediate-Release Oxcarbazepine Adjunctive Therapy Trials
The effectiveness of immediate-release oxcarbazepine as an adjunctive therapy for partial seizures in adults was demonstrated at doses of 600mg per day, 1200mg per day and 2400mg per day (divided twice daily) in a randomized, double-blind, placebo-controlled trial. All doses resulted in a statistically significant reduction in seizure frequency when compared to placebo (p < 0.05).
The effectiveness of immediate-release oxcarbazepine in doses of 30-46 mg/kg/day, depending on baseline weight, as an adjunctive therapy for partial seizures in children 3 years to 17 years of age was studied in a randomized, double-blind, placebo-controlled trial. Oxcarbazepine in the single weight based dose group resulted in a statistically significant reduction in seizure frequency when compared to placebo (p < 0.05).
Last reviewed on RxList: 11/9/2012
This monograph has been modified to include the generic and brand name in many instances.
Additional Oxtellar XR Information
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