Oxcarbazepine 600 mg Tablet, Extended Release, 100-count — NDC 27241-239-01 (Billing 27241-0239-01)

12 CLINICAL PHARMACOLOGY

12.1Mechanism of Action The pharmacological activity of oxcarbazepine extended-release tablets are primarily exerted through the 10-monohydroxy metabolite (MHD) of oxcarbazepine [see Clinical Pharmacology ( 12.3 )]. 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.

12.2Pharmacodynamics 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.

12.3Pharmacokinetics 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 oxcarbazepine extended-release tablets, the elimination half-life of oxcarbazepine was between 7 hours and 11 hours; the elimination half-life of MHD is between 9 hours and 11 hours. In a mass balance study in humans, 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.

Absorption Oxcarbazepine extended-release tablets administered as a once daily dosage is not bioequivalent to the same total dosage of the immediate-release formulation given twice daily at steady state. Steady state plasma concentrations of MHD are reached within 5 days when oxcarbazepine extended-release tablets is given once daily. At steady state, when 1,200 mg oxcarbazepine extended-release tablets was given once daily, MHD C max occurred 7 hours post-dose.

At steady state, oxcarbazepine extended-release tablets given once daily produced MHD exposures (AUC and C max ) about 19% lower and MHD minimum concentrations (C min ) about 16% lower than the immediate-release oxcarbazepine given twice daily when administered at the same 1,200 mg total daily dosage. When oxcarbazepine extended-release tablets was administered at an equivalent 600 mg single dose (4 × 150 mg tablets, 2 × 300 mg tablets, or 1 × 600 mg tablet), equivalent MHD exposures (AUC) were observed. Following a single dose of oxcarbazepine extended-release tablets (1 × 150 mg tablets, 1 × 300 mg tablets, or 1 × 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 C max : AUC increases 2.4-fold and C max increases 1.9-fold with a 2-fold increase in dose.

Effect of Food: Single dose administration of 600 mg oxcarbazepine extended-release tablets following a high fat meal (800 calories to 1,000 calories) produced MHD exposure (AUC) equivalent to that produced under fasting conditions. Peak MHD concentration (C max ) was about 60% higher and occurred 2 hours earlier under fed conditions than under f… [Excerpted — this section continues on DailyMed.]

12.1Mechanism of Action The pharmacological activity of oxcarbazepine extended-release tablets are primarily exerted through the 10-monohydroxy metabolite (MHD) of oxcarbazepine [see Clinical Pharmacology ( 12.3 )]. 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.

12.3Pharmacokinetics 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 oxcarbazepine extended-release tablets, the elimination half-life of oxcarbazepine was between 7 hours and 11 hours; the elimination half-life of MHD is between 9 hours and 11 hours. In a mass balance study in humans, 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.

Absorption Oxcarbazepine extended-release tablets administered as a once daily dosage is not bioequivalent to the same total dosage of the immediate-release formulation given twice daily at steady state. Steady state plasma concentrations of MHD are reached within 5 days when oxcarbazepine extended-release tablets is given once daily. At steady state, when 1,200 mg oxcarbazepine extended-release tablets was given once daily, MHD C max occurred 7 hours post-dose.

At steady state, oxcarbazepine extended-release tablets given once daily produced MHD exposures (AUC and C max ) about 19% lower and MHD minimum concentrations (C min ) about 16% lower than the immediate-release oxcarbazepine given twice daily when administered at the same 1,200 mg total daily dosage. When oxcarbazepine extended-release tablets was administered at an equivalent 600 mg single dose (4 × 150 mg tablets, 2 × 300 mg tablets, or 1 × 600 mg tablet), equivalent MHD exposures (AUC) were observed. Following a single dose of oxcarbazepine extended-release tablets (1 × 150 mg tablets, 1 × 300 mg tablets, or 1 × 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 C max : AUC increases 2.4-fold and C max increases 1.9-fold with a 2-fold increase in dose.

Effect of Food: Single dose administration of 600 mg oxcarbazepine extended-release tablets following a high fat meal (800 calories to 1,000 calories) produced MHD exposure (AUC) equivalent to that produced under fasting conditions. Peak MHD concentration (C max ) was about 60% higher and occurred 2 hours earlier under fed conditions than under fasting conditions. The increase in C max , 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.

Distribution 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. Elimination Metabolism Oxcarbazepine is rapidly reduced by cytosolic enzymes in the liver to MHD, which is primarily responsible for the pharmacological effect of oxcarbazepine extended-release tablets. 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). Excretion 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-… [Excerpted — this section continues on DailyMed.]

12.2Pharmacodynamics 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.

14 CLINICAL STUDIES Oxcarbazepine extended-release tablets has been evaluated as adjunctive therapy for partial-onset seizures in adults. The use of oxcarbazepine extended-release tablets for the treatment of partial-onset seizures in pediatric patients 6 years of age and older is based on adequate and well-controlled studies of oxcarbazepine extended-release tablets in adults, along with clinical trials of immediate-release oxcarbazepine in pediatric patients, and on pharmacokinetic evaluations of the use of oxcarbazepine extended-release tablets in pediatric patients.

14.1Oxcarbazepine Extended-Release Tablets Primary Trial A multicenter, randomized, double-blind, placebo-controlled, three-arm, parallel-group study (Study 1) in male and female adults with refractory partial-onset seizures (18 years to 65 years of age, inclusive) was performed to examine the safety and efficacy of oxcarbazepine extended-release tablets. Patients had at least three partial-onset 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-onset seizures 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 oxcarbazepine extended-release tablets (1,200 mg/day or 2,400 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-Onset Seizure Frequency in the 16-week Treatment Period *Wilcoxon rank-sum test of the median percentage change in partial-onset seizure frequency per 28 days during the 16-week Treatment Phase (Titration + Maintenance Periods) relative to the 8-week Baseline Phase. Median seizure frequency during 8-week 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* Placebo (N=121) 7.0 5.0 -28.7 % Oxcarbazepine Extended-Release Tablets 1,200 mg/day (N=122) 6.0 4.3 -38.2 % 9.5% 0.078 Oxcarbazepine Extended-Release Tablets 2,400 mg/day (N=123) 6.0 3.7 -42.9 % 14.2% 0.003 Although the 1,200 mg/day-placebo contrast did not reach statistical significance, concentration-response analyses reveal that the 1,200 mg/day dosage is an effective dosage.

14.2Immediate-Release Oxcarbazepine Adjunctive Therapy Trials The effectiveness of immediate-release oxcarbazepine as an adjunctive therapy for partial-onset seizures in adults was demonstrated at dosages of 600 mg/day, 1,200 mg/day, and 2,400 mg/day (divided twice daily) in a randomized, double-blind, placebo-controlled trial. All dosages resulted in a statistically significant reduction in seizure frequency when compared to placebo (p < 0.05). The effectiveness of immediate-release oxcarbazepine in dosages of 30 mg/kg/day to 46 mg/kg/day, depending on baseline weight, as an adjunctive therapy for partial-onset seizures in pediatric patients, including patients 6 to less than 17 years of age, was studied in a randomized, double-blind, placebo-controlled trial.

Oxcarbazepine in the single weight-based dosage group resulted in a statistically significant reduction in seizure frequency when compared to placebo (p < 0.05).

13 NONCLINICAL TOXICOLOGY

13.1Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis In two-year carcinogenicity studies, oxcarbazepine was administered in the diet at doses of up to 100 mg/kg/day to mice and by gavage at doses of up to 250 mg/kg/day to rats, and the pharmacologically active 10-hydroxy metabolite (MHD) was administered orally at doses of up to 600 mg/kg/day to rats. In mice, a dose-related increase in the incidence of hepatocellular adenomas was observed at oxcarbazepine doses ≥ 70 mg/kg/day or approximately 0.1 times the maximum recommended human dose (MRHD) on a mg/m 2 basis.

In rats, the incidence of hepatocellular carcinomas was increased in females treated with oxcarbazepine at doses ≥ 25 mg/kg/day (0.1 times the MRHD on a mg/m 2 basis), and incidences of hepatocellular adenomas and/or carcinomas were increased in males and females treated with MHD at doses of 600 mg/kg/day (2.4 times the MRHD on a mg/m 2 basis) and ≥ 250 mg/kg/day (equivalent to the MRHD on a mg/m 2 basis), respectively. There was an increase in the incidence of benign testicular interstitial cell tumors in rats at 250 mg oxcarbazepine/kg/day and at ≥ 250 mg MHD/kg/day, and an increase in the incidence of granular cell tumors in the cervix and vagina in rats at 600 mg MHD/kg/day.

Mutagenesis Oxcarbazepine increased mutation frequencies in the Ames test in vitro in the absence of metabolic activation in one of five bacterial strains. Both oxcarbazepine and MHD produced increases in chromosomal aberrations and polyploidy in the Chinese hamster ovary assay in vitro in the absence of metabolic activation. MHD was negative in the Ames test, and no mutagenic or clastogenic activity was found with either oxcarbazepine or MHD in V79 Chinese hamster cells in vitro.

Oxcarbazepine and MHD were both negative for clastogenic or aneugenic effects (micronucleus formation) in an in vivo rat bone marrow assay. Impairment of Fertility In a fertility study in which rats were administered MHD (50 mg/kg, 150 mg/kg, or 450 mg/kg) orally prior to and during mating and early gestation, estrous cyclicity was disrupted and numbers of corpora lutea, implantations, and live embryos were reduced in females receiving the highest dose (approximately two times the MRHD on a mg/m 2 basis).