Oxcarbazepine

OXCARBAZEPINE- oxcarbazepine tablet, film coated
Ascend Laboratories

Rx only

Prescribing Information

DESCRIPTION

Oxcarbazepine is an antiepileptic drug available as 150 mg, 300 mg and 600 mg film-coated tablets for oral administration. Oxcarbazepine is 10,11-Dihydro-10-oxo-5H -dibenz[b,f ]azepine-5-carboxamide, and its structural formula is

Chemical Structure

Oxcarbazepine is a white to faintly orange crystalline powder. It is slightly soluble in chloroform, dichloromethane, acetone, and methanol and practically insoluble in ethanol, ether and water. Its molecular weight is 252.27.

Oxcarbazepine film-coated tablets contain the following inactive ingredients: microcrystalline cellulose, crospovidone, hypromellose, colloidal silicon dioxide, magnesium stearate, talc. Coating: polyvinyl alcohol, talc, titanium dioxide, polyethylene glycol, 1FD&C Yellow No. 6 aluminum lake, lecithin, FD&C Blue No. 2 aluminum lake, 2FD&C Yellow No. 5 aluminum lake. Allergen Statement: This product contains soy.


1
Contains FD&C Yellow No. 6 as a color additive.
2
Contains FD&C Yellow No. 5 as a color additive. (See PRECAUTIONS).

CLINICAL PHARMACOLOGY

Mechanism of Action

The pharmacological activity of Oxcarbazepine is primarily exerted through the 10-monohydroxy metabolite (MHD) of oxcarbazepine (see Metabolism and Excretion subsection). 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.

Pharmacodynamics

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.

Pharmacokinetics

Following oral administration of Oxcarbazepine tablets, oxcarbazepine is completely absorbed and extensively metabolized to its pharmacologically active 10-monohydroxy metabolite (MHD). The half-life of the parent is about two hours, while the half-life of MHD is about nine hours, so that MHD is responsible for most antiepileptic activity.

Based on MHD concentrations, Oxcarbazepine tablets and suspension were shown to have similar bioavailability.

After single-dose administration of Oxcarbazepine tablets to healthy male volunteers under fasted conditions, the median tmax was 4.5 (range 3 to 13) hours.

In a mass balance study in people, only 2% of total radioactivity in plasma was due to unchanged oxcarbazepine, with approximately 70% present as MHD, and the remainder attributable to minor metabolites.

Effect of Food

Food has no effect on the rate and extent of absorption of oxcarbazepine from Oxcarbazepine tablets. Therefore, Oxcarbazepine tablets can be taken with or without food.

Steady-state plasma concentrations of MHD are reached within 2-3 days in patients when Oxcarbazepine is given twice a day. At steady-state the pharmacokinetics of MHD are linear and show dose proportionality over the dose range of 300 to 2400 mg/day.

Distribution

The apparent volume of distribution of MHD is 49L.

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.

Metabolism and Excretion

Oxcarbazepine is rapidly reduced by cytosolic enzymes in the liver to its 10-monohydroxy metabolite, MHD, which is primarily responsible for the pharmacological effect of Oxcarbazepine. 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 the dose appears in the urine, with less than 1% as unchanged oxcarbazepine. Fecal excretion accounts for less than 4% of the 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.

Special Populations

Hepatic Impairment

The pharmacokinetics and metabolism of 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 oxcarbazepine and MHD. No dose adjustment for Oxcarbazepine is recommended in patients with mild-to-moderate hepatic impairment. The pharmacokinetics of oxcarbazepine and MHD have not been evaluated in severe hepatic impairment and, therefore, caution should be exercised when dosing severely impaired patients.

Renal Impairment

There is a linear correlation between creatinine clearance and the renal clearance of MHD. When Oxcarbazepine is administered as a single 300-mg dose in renally-impaired 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 for Oxcarbazepine is recommended in these patients (see PRECAUTIONS and DOSAGE AND ADMINISTRATION sections).

Pediatric Use

Weight-adjusted MHD clearance decreases as age and weight increases, approaching that of adults. The mean weight-adjusted clearance in children 2 years-<4 years of age is approximately 80% higher on average than that of adults. Therefore, MHD exposure in these children is expected to be about one-half that of adults when treated with a similar weight-adjusted dose. The mean weight-adjusted clearance in children 4–12 years of age is approximately 40% higher on average than that of adults. Therefore, MHD exposure in these children is expected to be about three-quarters that of adults when treated with a similar weight-adjusted dose. As weight increases, for patients 13 years of age and above, the weight-adjusted MHD clearance is expected to reach that of adults.

Geriatric Use

Following administration of single (300 mg) and multiple (600 mg/day) doses of 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.

Gender

No gender-related pharmacokinetic differences have been observed in children, adults, or the elderly.

Race

No specific studies have been conducted to assess what effect, if any, race may have on the disposition of oxcarbazepine.

CLINICAL STUDIES

The effectiveness of Oxcarbazepine as adjunctive and monotherapy for partial seizures in adults, and as adjunctive therapy in children aged 2-16 years was established in seven multicenter, randomized, controlled trials.

The effectiveness of Oxcarbazepine as monotherapy for partial seizures in children aged 4-16 years was determined from data obtained in the studies described, as well as by pharmacokinetic/pharmacodynamic considerations.

Oxcarbazepine Monotherapy Trials

Four randomized, controlled, double-blind, multicenter trials, conducted in a predominately adult population, demonstrated the efficacy of Oxcarbazepine as monotherapy. Two trials compared Oxcarbazepine to placebo and two trials used a randomized withdrawal design to compare a high dose (2400 mg) with a low dose (300 mg) of Oxcarbazepine, after substituting Oxcarbazepine 2400 mg/day for one or more antiepileptic drugs (AEDs). All doses were administered on a BID schedule. A fifth randomized, controlled, rater-blind, multicenter study, conducted in a pediatric population, failed to demonstrate a statistically significant difference between low and high dose Oxcarbazepine treatment groups.

One placebo-controlled trial was conducted in 102 patients (11-62 years of age) with refractory partial seizures who had completed an inpatient evaluation for epilepsy surgery. Patients had been withdrawn from all AEDs and were required to have 2-10 partial seizures within 48 hours prior to randomization. Patients were randomized to receive either placebo or Oxcarbazepine given as 1500 mg/day on Day 1 and 2400 mg/day thereafter for an additional nine days, or until one of the following three exit criteria occurred: 1) the occurrence of a fourth partial seizure, excluding Day 1, 2) two new-onset secondarily generalized seizures, where such seizures were not seen in the one-year period prior to randomization, or 3) occurrence of serial seizures or status epilepticus. The primary measure of effectiveness was a between-group comparison of the time to meet exit criteria. There was a statistically significant difference in favor of Oxcarbazepine (see Figure 1), p=0.0001.

Figure 1: Kaplan-Meier Estimates of Exit Rate by Treatment Group

Figure 1
(click image for full-size original)

The second placebo-controlled trial was conducted in 67 untreated patients (8-69 years of age) with newly-diagnosed and recent-onset partial seizures. Patients were randomized to placebo or Oxcarbazepine, initiated at 300 mg BID and titrated to 1200 mg/day (given as 600 mg BID) in six days, followed by maintenance treatment for 84 days. The primary measure of effectiveness was a between-group comparison of the time to first seizure. The difference between the two treatments was statistically significant in favor of Oxcarbazepine (see Figure 2), p=0.046.

Figure 2: Kaplan-Meier Estimates of First Seizure Event Rate by Treatment Group

Figure 2
(click image for full-size original)

A third trial substituted Oxcarbazepine monotherapy at 2400 mg/day for carbamazepine in 143 patients (12-65 years of age) whose partial seizures were inadequately controlled on carbamazepine (CBZ) monotherapy at a stable dose of 800 to 1600 mg/day, and maintained this Oxcarbazepine dose for 56 days (baseline phase). Patients who were able to tolerate titration of Oxcarbazepine to 2400 mg/day during simultaneous carbamazepine withdrawal were randomly assigned to either 300 mg/day of Oxcarbazepine or 2400 mg/day Oxcarbazepine. Patients were observed for 126 days or until one of the following four exit criteria occurred: 1) a doubling of the 28-day seizure frequency compared to baseline, 2) a two-fold increase in the highest consecutive two-day seizure frequency during baseline, 3) a single generalized seizure if none had occurred during baseline, or 4) a prolonged generalized seizure. The primary measure of effectiveness was a between-group comparison of the time to meet exit criteria. The difference between the curves was statistically significant in favor of the Oxcarbazepine 2400 mg/day group (see Figure 3), p=0.0001.

Figure 3: Kaplan-Meier Estimates of Exit Rate by Treatment Group

Figure 3
(click image for full-size original)

Another monotherapy substitution trial was conducted in 87 patients (11-66 years of age) whose seizures were inadequately controlled on one or two AEDs. Patients were randomized to either Oxcarbazepine 2400 mg/day or 300 mg/day and their standard AED regimen(s) were eliminated over the first six weeks of double-blind therapy. Double-blind treatment continued for another 84 days (total double-blind treatment of 126 days) or until one of the four exit criteria described for the previous study occurred. The primary measure of effectiveness was a between-group comparison of the percentage of patients meeting exit criteria. The results were statistically significant in favor of the Oxcarbazepine 2400 mg/day group (14/34; 41.2%) compared to the Oxcarbazepine 300 mg/day group (42/45; 93.3%) (p<0.0001). The time to meeting one of the exit criteria was also statistically significant in favor of the Oxcarbazepine 2400 mg/day group (see Figure 4), p=0.0001.

Figure 4: Kaplan-Meier Estimates of Exit Rate by Treatment Group

Figure 4
(click image for full-size original)

A monotherapy trial was conducted in 92 pediatric patients (1 month to 16 years of age) with inadequately-controlled or new-onset partial seizures. Patients were hospitalized and randomized to either Oxcarbazepine 10 mg/kg/day or were titrated up to 40-60 mg/kg/day within three days while withdrawing the previous AED on the second day of Oxcarbazepine therapy. Seizures were recorded through continuous video-EEG monitoring from Day 3 to Day 5. Patients either completed the 5-Day treatment or met one of the two exit criteria: 1) three study-specific seizures (i.e. electrographic partial seizures with a behavioral correlate), 2) a prolonged study-specific seizure. The primary measure of effectiveness was a between-group comparison of the time to meet exit criteria in which the difference between the curves was not statistically significant (p=0.904). The majority of patients from both dose groups completed the 5-day study without exiting.

Although this study failed to demonstrate an effect of oxcarbazepine as monotherapy in pediatric patients, several design elements, including the short treatment and assessment period, the absence of a true placebo, and the likely persistence of plasma levels of previously administered AEDs during the treatment period, make the results uninterpretable. For this reason, the results do not undermine the conclusion, based on pharmacokinetic/pharmacodynamic considerations, that oxcarbazepine is effective as monotherapy in pediatric patients 4 years old and older.

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