2.1 Adjunctive Therapy for Adults

Treatment with oxcarbazepine tablets should be initiated with a dose of 600 mg/day, given in a twice-a-day regimen. If clinically indicated, the dose may be increased by a maximum of 600 mg/day at approximately weekly intervals; the recommended daily dose is 1200 mg/day. Daily doses above 1200 mg/day show somewhat greater effectiveness in controlled trials, but most patients were not able to tolerate the 2400 mg/day dose, primarily because of CNS effects. It is recommended that the patient be observed closely and plasma levels of the concomitant AEDs be monitored during the period of oxcarbazepine tablets titration, as these plasma levels may be altered, especially at oxcarbazepine tablets doses greater than 1200 mg/day [see ]. Drug Interactions (7.1)

2.2 Conversion to Monotherapy for Adults

Patients receiving concomitant AEDs may be converted to monotherapy by initiating treatment with oxcarbazepine tablets at 600 mg/day (given in a twice-a-day regimen) while simultaneously initiating the reduction of the dose of the concomitant AEDs. The concomitant AEDs should be completely withdrawn over 3-6 weeks, while the maximum dose of oxcarbazepine tablets should be reached in about 2-4 weeks. Oxcarbazepine tablets may be increased as clinically indicated by a maximum increment of 600 mg/day at approximately weekly intervals to achieve the recommended daily dose of 2400 mg/day. A daily dose of 1200 mg/day has been shown in one study to be effective in patients in whom monotherapy has been initiated with oxcarbazepine tablets. Patients should be observed closely during this transition phase.

2.3 Initiation of Monotherapy for Adults

Patients not currently being treated with AEDs may have monotherapy initiated with oxcarbazepine tablets. In these patients, oxcarbazepine tablets should be initiated at a dose of 600 mg/day (given in a twice-a-day regimen); the dose should be increased by 300 mg/day every third day to a dose of 1200 mg/day. Controlled trials in these patients examined the effectiveness of a 1200 mg/day dose; a dose of 2400 mg/day has been shown to be effective in patients converted from other AEDs to oxcarbazepine tablets monotherapy (see above).

2.4 Adjunctive Therapy for Pediatric Patients (Aged 2-16 Years)

In pediatric patients aged 4-16 years, treatment should be initiated at a daily dose of 8-10 mg/kg generally not to exceed 600 mg/day, given in a twice-a-day regimen. The target maintenance dose of oxcarbazepine tablets should be achieved over two weeks, and is dependent upon patient weight, according to the following chart:

20-29 kg - 900 mg/day

29.1-39 kg - 1200 mg/day

>39 kg - 1800 mg/day

In the clinical trial, in which the intention was to reach these target doses, the median daily dose was 31 mg/kg with a range of 6-51 mg/kg.

In pediatric patients aged 2 to <4 years, treatment should also be initiated at a daily dose of 8-10 mg/kg generally not to exceed 600 mg/day, given in a twice-a-day regimen. For patients under 20 kg, a starting dose of 16-20 mg/kg may be considered [see ]. The maximum maintenance dose of oxcarbazepine tablets should be achieved over 2-4 weeks and should not exceed 60 mg/kg/day in a twice-a-day regimen. Clinical Pharmacology (12.3)

In the clinical trial in pediatric patients (2 to 4 years of age) in which the intention was to reach the target dose of 60 mg/kg/day, 50% of patients reached a final dose of at least 55 mg/kg/day.

Under adjunctive therapy (with and without enzyme-inducing AEDs), when normalized by body weight, apparent clearance (L/hr/kg) decreased when age increased such that children 2 to <4 years of age may require up to twice the oxcarbazepine dose per body weight compared to adults; and children 4 to ≤12 years of age may require a 50% higher oxcarbazepine dose per body weight compared to adults.

2.5 Conversion to Monotherapy for Pediatric Patients (Aged 4-16 Years)

Patients receiving concomitant antiepileptic drugs may be converted to monotherapy by initiating treatment with oxcarbazepine tablets at approximately 8-10 mg/kg/day given in a twice-a-day regimen, while simultaneously initiating the reduction of the dose of the concomitant antiepileptic drugs. The concomitant antiepileptic drugs can be completely withdrawn over 3-6 weeks while oxcarbazepine tablets may be increased as clinically indicated by a maximum increment of 10 mg/kg/day at approximately weekly intervals to achieve the recommended daily dose. Patients should be observed closely during this transition phase.

The recommended total daily dose of oxcarbazepine tablets is shown in the table below.

2.6 Initiation of Monotherapy for Pediatric Patients (Aged 4-16 Years)

Patients not currently being treated with antiepileptic drugs may have monotherapy initiated with oxcarbazepine tablets. In these patients, oxcarbazepine tablets should be initiated at a dose of 8-10 mg/kg/day given in a twice-a-day regimen. The dose should be increased by 5 mg/kg/day every third day to the recommended daily dose shown in the table below.

2.7 Patients with Hepatic Impairment

In general, dose adjustments are not required in patients with mild-to-moderate hepatic impairment [see .] Clinical Pharmacology (12.3)

2.8 Patients with Renal Impairment

In patients with impaired renal function (creatinine clearance <30 mL/min) oxcarbazepine tablets therapy should be initiated at one-half the usual starting dose (300 mg/day) and increased slowly to achieve the desired clinical response [see ] Clinical Pharmacology (12.3)

5.1 Hyponatremia

Clinically significant hyponatremia (sodium <125 mmol/L) can develop during oxcarbazepine tablets use. In the 14 controlled epilepsy studies 2.5% of oxcarbazepine tablets-treated patients (38/1,524) had a sodium of less than 125 mmol/L at some point during treatment, compared to no such patients assigned placebo or active control (carbamazepine and phenobarbital for adjunctive and monotherapy substitution studies, and phenytoin and valproate for the monotherapy initiation studies). Clinically significant hyponatremia generally occurred during the first three months of treatment with oxcarbazepine tablets, although there were patients who first developed a serum sodium <125 mmol/L more than one year after initiation of therapy. Most patients who developed hyponatremia were asymptomatic but patients in the clinical trials were frequently monitored and some had their oxcarbazepine tablets dose reduced, discontinued, or had their fluid intake restricted for hyponatremia. Whether or not these maneuvers prevented the occurrence of more severe events is unknown. Cases of symptomatic hyponatremia have been reported during post-marketing use. In clinical trials, patients whose treatment with oxcarbazepine tablets was discontinued due to hyponatremia generally experienced normalization of serum sodium within a few days without additional treatment.

Measurement of serum sodium levels should be considered for patients during maintenance treatment with oxcarbazepine tablets, particularly if the patient is receiving other medications known to decrease serum sodium levels (for example, drugs associated with inappropriate ADH secretion) or if symptoms possibly indicating hyponatremia develop (e.g., nausea, malaise, headache, lethargy, confusion, obtundation, or increase in seizure frequency or severity).

5.2 Anaphylactic Reactions 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 tablets. Angioedema associated with laryngeal edema can be fatal. If a patient develops any of these reactions after treatment with oxcarbazepine tablets, the drug should be discontinued and an alternative treatment started. These patients should not be rechallenged with the drug [see ]. Warnings and Precautions (5.3)

5.3 Patients with a Past History of Hypersensitivity Reaction to Carbamazepine

Patients who have had hypersensitivity reactions to carbamazepine should be informed that approximately 25%-30% of them will experience hypersensitivity reactions with oxcarbazepine tablets. For this reason patients should be specifically questioned about any prior experience with carbamazepine, and patients with a history of hypersensitivity reactions to carbamazepine should ordinarily be treated with oxcarbazepine tablets only if the potential benefit justifies the potential risk. If signs or symptoms of hypersensitivity develop, oxcarbazepine tablets should be discontinued immediately [see , ]. Warnings and Precautions (5.25.8)

5.4 Serious Dermatological Reactions

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 tablets use. The median time of onset for reported cases was 19 days. Such serious skin reactions may be life threatening, and some patients have required hospitalization with very rare reports of fatal outcome. Recurrence of the serious skin reactions following rechallenge with oxcarbazepine tablets has also been reported.

The reporting rate of TEN and SJS associated with oxcarbazepine tablets 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 tablets, consideration should be given to discontinuing oxcarbazepine tablets use and prescribing another antiepileptic medication.

5.5 Suicidal Behavior and Ideation

Antiepileptic drugs (AEDs), including oxcarbazepine tablets, increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication. Patients treated with any AED for any indication should be monitored for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior.

Pooled analyses of 199 placebo-controlled clinical trials (mono- and adjunctive therapy) of 11 different AEDs showed that patients randomized to one of the AEDs had approximately twice the risk (adjusted Relative Risk 1.8, 95% CI:1.2, 2.7) of suicidal thinking or behavior compared to patients randomized to placebo. In these trials, which had a median treatment duration of 12 weeks, the estimated incidence rate of suicidal behavior or ideation among 27,863 AED-treated patients was 0.43%, compared to 0.24% among 16,029 placebo-treated patients, representing an increase of approximately one case of suicidal thinking or behavior for every 530 patients treated. There were four suicides in drug-treated patients in the trials and none in placebo-treated patients, but the number is too small to allow any conclusion about drug effect on suicide.

The increased risk of suicidal thoughts or behavior with AEDs was observed as early as one week after starting drug treatment with AEDs and persisted for the duration of treatment assessed. Because most trials included in the analysis did not extend beyond 24 weeks, the risk of suicidal thoughts or behavior beyond 24 weeks could not be assessed.

The risk of suicidal thoughts or behavior was generally consistent among drugs in the data analyzed. The finding of increased risk with AEDs of varying mechanisms of action and across a range of indications suggests that the risk applies to all AEDs used for any indication. The risk did not vary substantially by age (5-100 years) in the clinical trials analyzed. Table 2 shows absolute and relative risk by indication for all evaluated AEDs.

The relative risk for suicidal thoughts or behavior was higher in clinical trials for epilepsy than in clinical trials for psychiatric or other conditions, but the absolute risk differences were similar for the epilepsy and psychiatric indications.

Anyone considering prescribing oxcarbazepine tablets or any other AED must balance the risk of suicidal thoughts or behavior with the risk of untreated illness. Epilepsy and many other illnesses for which AEDs are prescribed are themselves associated with morbidity and mortality and an increased risk of suicidal thoughts and behavior. Should suicidal thoughts and behavior emerge during treatment, the prescriber needs to consider whether the emergence of these symptoms in any given patient may be related to the illness being treated.

Patients, their caregivers, and families should be informed that AEDs increase the risk of suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or worsening of the signs and symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts about self-harm. Behaviors of concern should be reported immediately to healthcare providers.

5.6 Withdrawal of AEDs

As with all antiepileptic drugs, oxcarbazepine tablets should be withdrawn gradually to minimize the potential of increased seizure frequency.

5.7 Cognitive/Neuropsychiatric Adverse Events

Use of oxcarbazepine tablets has been associated with central nervous system-related adverse events. The most significant of these can be classified into three general categories: 1) cognitive symptoms including psychomotor slowing, difficulty with concentration, and speech or language problems, 2) somnolence or fatigue, and 3) coordination abnormalities, including ataxia and gait disturbances.

5.8 Multi-Organ Hypersensitivity

Multi-organ hypersensitivity reactions have occurred in close temporal association (median time to detection 13 days: range 4-60) to the initiation of oxcarbazepine tablets therapy in adult and pediatric patients. Although there have been a limited number of reports, many of these cases resulted in hospitalization and some were considered life threatening. Signs and symptoms of this disorder were diverse; however, patients typically, although not exclusively, presented with fever and rash associated with other organ system involvement. These may include hematologic and lymphatic (e.g., eosinophilia, thrombocytopenia, lymphadenopathy, leukopenia, neutropenia, splenomegaly), hepatobiliary (e.g., hepatitis, liver function test abnormalities), renal (e.g., proteinuria, nephritis, oliguria, renal failure), muscles and joints (e.g., joint swelling, myalgia, arthralgia, asthenia), nervous system (e.g., hepatic encephalopathy), respiratory (e.g., dyspnea, pulmonary edema, asthma, bronchospasm, interstitial lung disease), hepatorenal syndrome, pruritus, and angioedema. Because the disorder is variable in its expression, other organ system symptoms and signs, not noted here, may occur. If this reaction is suspected, oxcarbazepine tablets should be discontinued and an alternative treatment started. Although there are no case reports to indicate cross sensitivity with other drugs that produce this syndrome, the experience amongst drugs associated with multi-organ hypersensitivity would indicate this to be a possibility [see ]. Warnings and Precautions (5.3)

5.9 Hematologic Events

Rare reports of pancytopenia, agranulocytosis, and leukopenia have been seen in patients treated with oxcarbazepine tablets during post-marketing experience. Discontinuation of the drug should be considered if any evidence of these hematologic events develop.

5.10 Seizure Control During Pregnancy

Due to physiological changes during pregnancy, plasma levels of the active metabolite of oxcarbazepine, the 10-monohydroxy derivative (MHD), may gradually decrease throughout pregnancy. It is recommended that patients be monitored carefully during pregnancy. Close monitoring should continue through the postpartum period because MHD levels may return after delivery.

5.11 Laboratory Tests

Serum sodium levels below 125 mmol/L have been observed in patients treated with oxcarbazepine tablets [see ]. Experience from clinical trials indicates that serum sodium levels return toward normal when the oxcarbazepine tablets dosage is reduced or discontinued, or when the patient was treated conservatively (e.g., fluid restriction). Warnings and Precautions (5.1)

Laboratory data from clinical trials suggest that oxcarbazepine tablets use was associated with decreases in T , without changes in T or TSH. 43

5.12 FD&C Yellow No. 5 (Tartrazine)

This product contains FD&C Yellow No. 5 (tartrazine) which may cause allergic type reactions (including bronchial asthma) in certain susceptible persons. Although the overall incidence of FD&C Yellow No. 5 (tartrazine) sensitivity in the general population is low, it is frequently seen in patients who also have aspirin sensitivity.

6.1 Clinical Studies Experience

6.2 Post-Marketing and Other Experience

The following adverse events not seen in controlled clinical trials have been observed in named patient programs or post- marketing experience:

multi-organ hypersensitivity disorders characterized by features such as rash, fever, lymphadenopathy, abnormal liver function tests, eosinophilia and arthralgia [see ] Body as a Whole:Warnings and Precautions (5.8)

[see ] Anaphylaxis:Warnings and Precautions (5.2)

pancreatitis and/or lipase and/or amylase increase Digestive System:

Systems: aplastic anemia [see ] Hematologic and LymphaticWarnings and Precautions (5.9)

hypothyroidism Metabolism:

erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis [see ] Skin and Appendages:Warnings and Precautions (5.4)

7.1 Antiepileptic Drugs

Potential interactions between oxcarbazepine tablets and other AEDs were assessed in clinical studies. The effect of these interactions on mean AUCs and C are summarized in Table 7. min

, the plasma levels of phenytoin increased by up to 40% when oxcarbazepine tablets was given at doses above 1200 mg/day. Therefore, when using doses of oxcarbazepine tablets greater than 1200 mg/day during adjunctive therapy, a decrease in the dose of phenytoin may be required. The increase of phenobarbital level, however, is small (15%) when given with oxcarbazepine tablets. In vivo

Strong inducers of cytochrome P450 enzymes (i.e., carbamazepine, phenytoin and phenobarbital) have been shown to decrease the plasma levels of MHD (29%-40%).

No autoinduction has been observed with oxcarbazepine tablets.

7.2 Hormonal Contraceptives

Coadministration of oxcarbazepine tablets with an oral contraceptive has been shown to influence the plasma concentrations of the two hormonal components, 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 tablets with hormonal contraceptives may render these contraceptives less effective. Studies with other oral or implant contraceptives have not been conducted.

7.3 Calcium Antagonists

After repeated coadministration of oxcarbazepine tablets, 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.

7.4 Other Drug Interactions

Cimetidine, erythromycin and dextropropoxyphene had no effect on the pharmacokinetics of MHD. Results with warfarin show no evidence of interaction with either single or repeated doses of oxcarbazepine tablets.

7.5 Drug/Laboratory Test Interactions

There are no known interactions of oxcarbazepine tablets with commonly used laboratory tests.

8.1 Pregnancy

Oxcarbazepine tablets levels may decrease during pregnancy [see ]. Warnings and Precautions (5.10)

8.2 Labor and Delivery

The effect of oxcarbazepine tablets on labor and delivery in humans has not been evaluated.

8.3 Nursing Mothers

Oxcarbazepine and its active metabolite (MHD) are excreted in human milk. A milk-to-plasma concentration ratio of 0.5 was found for both. Because of the potential for serious adverse reactions to oxcarbazepine tablets in nursing infants, a decision should be made about whether to discontinue nursing or to discontinue the drug in nursing women, taking into account the importance of the drug to the mother.

8.4 Pediatric Use

Oxcarbazepine tablets is indicated for use as adjunctive therapy for partial seizures in patients aged 2-16 years. Oxcarbazepine tablets is also indicated as monotherapy for partial seizures in patients aged 4-16 years. Oxcarbazepine tablets has been given to 898 patients between the ages of 1 month-17 years in controlled clinical trials (332 treated as monotherapy) and about 677 patients between the ages of 1 month-17 years in other trials [see for a description of the adverse events associated with oxcarbazepine tablets use in this population]. Adverse Reactions (6.1)

8.5 Geriatric Use

There were 52 patients over age 65 in controlled clinical trials and 565 patients over the age of 65 in other trials. Following administration of single (300 mg) and multiple (600 mg/day) doses of oxcarbazepine tablets in 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.

8.6 Renal Impairment

In renally-impaired patients (creatinine clearance <30 mL/min), the elimination half-life of MHD is prolonged with a corresponding two-fold increase in AUC [see ]. Oxcarbazepine tablets therapy should be initiated at one-half the usual starting dose and increased, if necessary, at a slower than usual rate until the desired clinical response is achieved. Clinical Pharmacology (12.3)

9.2 Abuse

The abuse potential of oxcarbazepine tablets has not been evaluated in human studies.

9.3 Dependence

Intragastric injections of oxcarbazepine to four cynomolgus monkeys demonstrated no signs of physical dependence as measured by the desire to self-administer oxcarbazepine by lever pressing activity.

Human Overdose Experience

Isolated cases of overdose with oxcarbazepine tablets have been reported. The maximum dose taken was approximately 24,000 mg. All patients recovered with symptomatic treatment.

Treatment and Management

There is no specific antidote. Symptomatic and supportive treatment should be administered as appropriate. Removal of the drug by gastric lavage and/or inactivation by administering activated charcoal should be considered.

12.1 Mechanism of Action

The pharmacological activity of oxcarbazepine tablets is primarily exerted through the 10-monohydroxy metabolite (MHD) of oxcarbazepine [see ]. The precise mechanism by which oxcarbazepine and MHD exert their antiseizure effect is unknown; however, 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. Clinical Pharmacology (12.3)in vitro

12.2 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.

12.3 Pharmacokinetics

Following oral administration of oxcarbazepine tablets, oxcarbazepine is completely absorbed and extensively metabolized to its pharmacologically active 10-monohydroxy metabolite (MHD). 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.

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.

12.6 Special Populations

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

14.1 Oxcarbazepine Tablets Monotherapy Trials

Four randomized, controlled, double-blind, multicenter trials, conducted in a predominately adult population, demonstrated the efficacy of oxcarbazepine tablets as monotherapy. Two trials compared oxcarbazepine tablets 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 tablets, after substituting oxcarbazepine tablets 2400 mg/day for one or more antiepileptic drugs (AEDs). All doses were administered on a twice-a-day 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 tablets 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 tablets 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 tablets (see ), p=0.0001. Figure 1

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

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 tablets, initiated at 300 mg twice a day and titrated to 1200 mg/day (given as 600 mg twice a day) 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 tablets (see ), p=0.046. Figure 2

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

A third trial substituted oxcarbazepine tablets 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 tablets dose for 56 days (baseline phase). Patients who were able to tolerate titration of oxcarbazepine tablets to 2400 mg/day during simultaneous carbamazepine withdrawal were randomly assigned to either 300 mg/day of oxcarbazepine tablets or 2400 mg/day oxcarbazepine tablets. 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 tablets 2400 mg/day group (see ), p=0.0001. Figure 3

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

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 tablets 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 tablets 2400 mg/day group (14/34; 41.2%) compared to the oxcarbazepine tablets 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 tablets 2400 mg/day group (see ), p=0.0001. Figure 4

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

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 tablets 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 tablets 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.

14.2 Oxcarbazepine Tablets Adjunctive Therapy Trials

The effectiveness of oxcarbazepine tablets as an adjunctive therapy for partial seizures was established in two multicenter, randomized, double-blind, placebo-controlled trials, one in 692 patients (15-66 years of age) and one in 264 pediatric patients (3-17 years of age), and in one multicenter, rater-blind, randomized, age-stratified, parallel-group study comparing two doses of oxcarbazepine in 128 pediatric patients (1 month to <4 years of age).

Patients in the two placebo-controlled trials were on 1-3 concomitant AEDs. In both of the trials, patients were stabilized on optimum dosages of their concomitant AEDs during an 8-week baseline phase. Patients who experienced at least 8 (minimum of 1-4 per month) partial seizures during the baseline phase were randomly assigned to placebo or to a specific dose of oxcarbazepine tablets in addition to their other AEDs.

In these studies, the dose was increased over a two-week period until either the assigned dose was reached, or intolerance prevented increases. Patients then entered a 14- (pediatrics) or 24-week (adults) maintenance period.

In the adult trial, patients received fixed doses of 600, 1200 or 2400 mg/day. In the pediatric trial, patients received maintenance doses in the range of 30-46 mg/kg/day, depending on baseline weight. The primary measure of effectiveness in both trials was a between-group comparison of the percentage change in partial seizure frequency in the double-blind treatment phase relative to baseline phase. This comparison was statistically significant in favor of oxcarbazepine tablets at all doses tested in both trials (p=0.0001 for all doses for both trials). The number of patients randomized to each dose, the median baseline seizure rate, and the median percentage seizure rate reduction for each trial are shown in Table 8. It is important to note that in the high-dose group in the study in adults, over 65% of patients discontinued treatment because of adverse events; only 46 (27%) of the patients in this group completed the 28-week study [see ], an outcome not seen in the monotherapy studies. Adverse Reactions(7)

Subset analyses of the antiepileptic efficacy of oxcarbazepine tablets with regard to gender in these trials revealed no important differences in response between men and women. Because there were very few patients over the age of 65 in controlled trials, the effect of the drug in the elderly has not been adequately assessed.

The third adjunctive therapy trial enrolled 128 pediatric patients (1 month to <4 years of age) with inadequately-controlled partial seizures on 1-2 concomitant AEDs. Patients who experienced at least 2 study-specific seizures (i.e., electrographic partial seizures with a behavioral correlate) during the 72-hour baseline period were randomly assigned to either oxcarbazepine tablets 10 mg/kg/day or were titrated up to 60 mg/kg/day within 26 days. Patients were maintained on their randomized target dose for 9 days and seizures were recorded through continuous video-EEG monitoring during the last 72 hours of the maintenance period. The primary measure of effectiveness in this trial was a between-group comparison of the change in seizure frequency per 24 hours compared to the seizure frequency at baseline. For the entire group of patients enrolled, this comparison was statistically significant in favor of oxcarbazepine tablets 60 mg/kg/day. In this study, there was no evidence that oxcarbazepine tablets were effective in patients below the age of 2 years (N=75).

Store at 20°-25°C (77°F); excursions permitted to 15°-30°C (59°-86°F) [See USP Controlled Room Temperature].

Dispense in tight container (USP).