2.1 Adjunctive Therapy for Adults

Initiate oxcarbazepine tablets with a dose of 600 mg/day, given twice-a-day. If clinically indicated, the dose may be increased by a maximum of 600 mg/day at approximately weekly intervals; the maximum 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.

Dosage adjustment is recommended with concomitant use of strong CYP3A4 enzyme inducers or UGT inducers, which include certain antiepileptic drugs (AEDs) [see Drug Interactions ( 7.1, 7.2)].

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 The concomitant AEDs should be completely withdrawn over 3 to 6 weeks, while the maximum dose of oxcarbazepine tablets should be reached in about 2 to 4 weeks.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 maximum 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, initiate oxcarbazepine tablets at a dose of 600 mg/day (given twice-a-day); 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, initiate oxcarbazepine tablets at a daily dose of 8 to 10 mg/kg generally not to exceed 600 mg/day, given twice-a-day. The target maintenance dose of oxcarbazepine tablets should be achieved over 2 weeks, and is dependent upon patient weight, according to the following chart:

20 to 29 kg - 900 mg/day
29.1 to 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 to 51 mg/kg.

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

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.

Dosage adjustment is recommended with concomitant use of strong CYP3A4 enzyme inducers or UGT inducers, which include certain antiepileptic drugs (AEDs) [see Drug Interactions ( 7.1, 7.2)].

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 to 10 mg/kg/day given twice-a-day, while simultaneously initiating the reduction of the dose of the concomitant antiepileptic drugs. The concomitant antiepileptic drugs can be completely withdrawn over 3 to 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 Table 1.

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, initiate oxcarbazepine tablets at a dose of 8 to 10 mg/kg/day given twice-a-day. 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 Dosage Modification for Patients with Renal Impairment

In patients with impaired renal function (creatinine clearance <30 mL/min) initiate oxcarbazepine tablets at one-half the usual starting dose (300 mg/day, given twice-a-day) and increase slowly to achieve the desired clinical response [see Clinical Pharmacology ( 12.3)].

2.8 Administration Information

Oxcarbazepine tablets can be taken with or without food [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 3 months of treatment with oxcarbazepine tablets, although there were patients who first developed a serum sodium <125 mmol/L more than 1 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 and syndrome of inappropriate antidiuretic hormone secretion (SIADH) have been reported during postmarketing 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 (e.g., 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 Cross Hypersensitivity Reaction to Carbamazepine

Approximately 25% to 30% of patients who have had hypersensitivity reactions to carbamazepine 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 ( 5.2, 5.8)].

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. Such serious skin reactions may be life threatening, and some patients have required hospitalization with very rare reports of fatal outcome. The median time of onset for reported cases was 19 days after treatment initiation. 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 4 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 to 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 most antiepileptic drugs, oxcarbazepine tablets should generally be withdrawn gradually because of the risk of increased seizure frequency and status epilepticus [see Dosage and Administration ( 2.4) and Clinical Studies ( 14)]. But if withdrawal is needed because of a serious adverse event, rapid discontinuation can be considered.

5.7 Cognitive/Neuropsychiatric Adverse Reactions

Use of oxcarbazepine tablets has been associated with central nervous system-related adverse reactions. The most significant of these can be classified into 3 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.

Patients should be monitored for these signs and symptoms and advised not to drive or operate machinery until they have gained sufficient experience on oxcarbazepine tablets to gauge whether it adversely affects their ability to drive or operate machinery.

5.8 Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/Multi-Organ Hypersensitivity

Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), also known as multi-organ hypersensitivity, has occurred with oxcarbazepine tablets. Some of these events have been fatal or life-threatening. DRESS typically, although not exclusively, presents with fever, rash, lymphadenopathy and/or facial swelling, in association with other organ system involvement, such as hepatitis, nephritis, hematologic abnormalities, myocarditis, or myositis sometimes resembling an acute viral infection. Eosinophilia is often present. This disorder is variable in its expression, and other organ systems not noted here may be involved. It is important to note that early manifestations of hypersensitivity (e.g., fever, lymphadenopathy) may be present even though rash is not evident. If such signs or symptoms are present, the patient should be evaluated immediately. Oxcarbazepine tablets should be discontinued if an alternative etiology for the signs or symptoms cannot be established.

5.9 Hematologic Events

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

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 Risk of Seizure Aggravation

Exacerbation of or new onset primary generalized seizures has been reported with oxcarbazepine tablets. The risk of aggravation of primary generalized seizures is seen especially in children but may also occur in adults. In case of seizure aggravation, oxcarbazepine tablets should be discontinued.

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 Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Most Common Adverse Reactions in All Clinical Studies

6.2 Postmarketing Experience

The following adverse reactions have been identified during postapproval use of oxcarbazepine tablets. Because these reactions are reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

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

Cardiovascular System: atrioventricular block

Immune System Disorders: anaphylaxis [see Warnings and Precautions ( 5.2)]

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

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

Metabolism and Nutrition Disorders: hypothyroidism and syndrome of inappropriate antidiuretic hormone secretion (SIADH)

Skin and Subcutaneous Tissue Disorders: erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis [see Warnings and Precautions ( 5.4)], Acute Generalized Exanthematous Pustulosis (AGEP)

Musculoskeletal, Connective Tissue and Bone Disorders: There have been reports of decreased bone mineral density, osteoporosis and fractures in patients on long-term therapy with oxcarbazepine tablets.

Injury, Poisoning, and Procedural Complications: fall

Nervous System Disorders: dysarthria

7.1 Effect of Oxcarbazepine Tablets on Other Drugs

Phenytoin levels have been shown to increase with concomitant use of oxcarbazepine tablets at doses greater than 1200 mg/day [see Clinical Pharmacology ( 12.3)]. Therefore, it is recommended that the plasma levels of phenytoin be monitored during the period of oxcarbazepine tablets titration and dosage modification. A decrease in the dose of phenytoin may be required.

7.2 Effect of Other Drugs on Oxcarbazepine Tablets

Strong inducers of cytochrome P450 enzymes and/or inducers of UGT (e.g., rifampin, carbamazepine, phenytoin and phenobarbital) have been shown to decrease the plasma/serum levels of MHD, the active metabolite of oxcarbazepine tablets (25% to 49%) [see Clinical Pharmacology ( 12.3)]. If oxcarbazepine tablets and strong CYP3A4 inducers or UGT inducers are administered concurrently, it is recommended that the plasma levels of MHD be monitored during the period of oxcarbazepine tablets titration. Dose adjustment of oxcarbazepine tablets may be required after initiation, dosage modification, or discontinuation of such inducers.

7.3 Hormonal Contraceptives

Concurrent use of oxcarbazepine tablets with hormonal contraceptives may render these contraceptives less effective [see Clinical Pharmacology ( 12.3)]. Studies with other oral or implant contraceptives have not been conducted.

8.1 Pregnancy

Pregnancy Exposure Registry
There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to AEDs, such as oxcarbazepine tablets, during pregnancy. Encourage women who are taking oxcarbazepine tablets during pregnancy to enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry by calling 1-888-233-2334 or visiting http://www.aedpregnancyregistry.org/.

Risk Summary
There are no adequate data on the developmental risks associated with the use of oxcarbazepine tablets in pregnant women; however, oxcarbazepine tablets is closely related structurally to carbamazepine, which is considered to be teratogenic in humans. Data on a limited number of pregnancies from pregnancy registries suggest that oxcarbazepine tablets monotherapy use is associated with congenital malformations (e.g., craniofacial defects such as oral clefts, and cardiac malformations such as ventricular septal defects). Increased incidences of fetal structural abnormalities and other manifestations of developmental toxicity (embryolethality, growth retardation) were observed in the offspring of animals treated with either oxcarbazepine or its active 10-hydroxy metabolite (MHD) during pregnancy at doses similar to the maximum recommended human dose (MRHD).

In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. The background risk of major birth defects and miscarriage for the indicated population is unknown.

Clinical Considerations
An increase in seizure frequency may occur during pregnancy because of altered levels of the active metabolite of oxcarbazepine. Monitor patients carefully during pregnancy and through the postpartum period [see Warnings and Precautions ( 5.10)].

Data
Human Data
Data from published registries have reported craniofacial defects such as oral clefts and cardiac malformations such as ventricular septal defects in children with prenatal oxcarbazepine exposure.

Animal Data
When pregnant rats were given oxcarbazepine (0, 30, 300, or 1000 mg/kg/day) orally throughout the period of organogenesis, increased incidences of fetal malformations (craniofacial, cardiovascular, and skeletal) and variations were observed at the intermediate and high doses (approximately 1.2 and 4 times, respectively, the MRHD on a mg/m 2 basis). Increased embryofetal death and decreased fetal body weights were seen at the high dose. Doses ≥300 mg/kg/day were also maternally toxic (decreased body weight gain, clinical signs), but there is no evidence to suggest that teratogenicity was secondary to the maternal effects.

In a study in which pregnant rabbits were orally administered MHD (0, 20, 100, or 200 mg/kg/day) during organogenesis, embryofetal mortality was increased at the highest dose (1.5 times the MRHD on a mg/m 2 basis). This dose produced only minimal maternal toxicity.

In a study in which female rats were dosed orally with oxcarbazepine (0, 25, 50, or 150 mg/kg/day) during the latter part of gestation and throughout the lactation period, a persistent reduction in body weights and altered behavior (decreased activity) were observed in offspring exposed to the highest dose (less than the MRHD on a mg/m2 basis). Oral administration of MHD (0, 25, 75, or 250 mg/kg/day) to rats during gestation and lactation resulted in a persistent reduction in offspring weights at the highest dose (equivalent to the MRHD on a mg/m 2 basis).

8.2 Lactation

Risk Summary
Oxcarbazepine and its active metabolite (MHD) are present in human milk after oxcarbazepine tablets administration. The effects of oxcarbazepine and its active metabolite (MHD) on the breastfed infant or on milk production are unknown. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for oxcarbazepine tablets and any potential adverse effects on the breastfed infant from oxcarbazepine tablets or from the underlying maternal condition.

8.3 Females and Males of Reproductive Potential

Contraception
Use of oxcarbazepine tablets with hormonal contraceptives containing ethinylestradiol or levonorgestrel is associated with decreased plasma concentrations of these hormones and may result in a failure of the therapeutic effect of the oral contraceptive drug. Advise women of reproductive potential taking oxcarbazepine tablets who are using a contraceptive containing ethinylestradiol or levonorgestrel to use additional or alternative non-hormonal birth control [see Drug Interactions ( 7.3) and Clinical Pharmacology ( 12.3)].

8.4 Pediatric Use

Oxcarbazepine tablets is indicated for use as adjunctive therapy for partial-onset seizures in patients aged 2 to 16 years.

The safety and effectiveness for use as adjunctive therapy for partial-onset seizures in pediatric patients below the age of 2 have not been established.

Oxcarbazepine tablets is also indicated as monotherapy for partial-onset seizures in patients aged 4 to 16 years.

The safety and effectiveness for use as monotherapy for partial-onset seizures in pediatric patients below the age of 4 have not been established.

Oxcarbazepine tablets has been given to 898 patients between the ages of 1 month to 17 years in controlled clinical trials (332 treated as monotherapy) and about 677 patients between the ages of 1 month to 17 years in other trials [see Warnings and Precautions ( 5.11), Adverse Reactions ( 6.1), Clinical Pharmacology ( 12.3), and Clinical Studies ( 14)].

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 to 82 years of age), the maximum plasma concentrations and AUC values of MHD were 30% to 60% higher than in younger volunteers (18 to 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. Close monitoring of sodium levels is required in elderly patients at risk for hyponatremia [see Warnings and Precautions ( 5.1)].

8.6 Renal Impairment

Dose adjustment is recommended for renally impaired patients (CLcr <30 mL/min) [see Dosage and Administration ( 2.7) and 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 4 cynomolgus monkeys demonstrated no signs of physical dependence as measured by the desire to self-administer oxcarbazepine by lever pressing activity.

10.1 Human Overdose Experience

Isolated cases of overdose with oxcarbazepine tablets have been reported. The maximum dose taken was approximately 48,000 mg. All patients recovered with symptomatic treatment. Nausea, vomiting, somnolence, aggression, agitation, hypotension, and tremor each occurred in more than one patient. Coma, confusional state, convulsion, dyscoordination, depressed level of consciousness, diplopia, dizziness, dyskinesia, dyspnea, QT prolongation, headache, miosis, nystagmus, overdose, decreased urine output, blurred vision also occurred.

10.2 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 Clinical Pharmacology ( 12.3)]. The precise mechanism by which oxcarbazepine and MHD exert their anti-seizure 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.

12.2 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 5 days and 4 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 2 hours, while the half-life of MHD is about 9 hours, so that MHD is responsible for most antiepileptic activity.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis
In 2-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 which is less than 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 (less than 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 in vitro Ames test in the absence of metabolic activation. 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 study in which male and female rats were administered oxcarbazepine (0, 25, 75 and 150 mg/kg/day) orally prior to and during mating and continuing in females during gestation, no adverse effects on fertility or reproductive performance were observed. The highest dose tested is less than the MRHD on a mg/m 2 basis. In a fertility study in which rats were administered MHD (0, 50, 150, or 450 mg/kg/day) 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 2 times the MRHD on a mg/m 2 basis).

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 2 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 1 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 to 62 years of age) with refractory partial-onset seizures who had completed an inpatient evaluation for epilepsy surgery. Patients had been withdrawn from all AEDs and were required to have 2 to 10 partial-onset 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 9 days, or until 1 of the following 3 exit criteria occurred: 1) the occurrence of a fourth partial-onset seizure, excluding Day 1, 2) 2 new-onset secondarily generalized seizures, where such seizures were not seen in the 1-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 Figure 1), p=0.0001.

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

The second placebo-controlled trial was conducted in 67 untreated patients (8 to 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 6 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 2 treatments was statistically significant in favor of oxcarbazepine tablets (see Figure 2), p=0.046.

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 to 65 years of age) whose partial-onset 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 1 of the following 4 exit criteria occurred: 1) a doubling of the 28-day seizure frequency compared to baseline, 2) a 2-fold increase in the highest consecutive 2-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 Figure 3), p=0.0001.

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

Another monotherapy substitution trial was conducted in 87 patients (11 to 66 years of age) whose seizures were inadequately controlled on 1 or 2 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 6 weeks of double-blind therapy. Double-blind treatment continued for another 84 days (total double-blind treatment of 126 days) or until 1 of the 4 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 Figure 4), p=0.0001.

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 to 60 mg/kg/day within 3 days while withdrawing the previous AED on the second day of oxcarbazepine tablets. Seizures were recorded through continuous video-EEG monitoring from Day 3 to Day 5. Patients either completed the 5-day treatment or met 1 of the 2 exit criteria: 1) three study-specific seizures (i.e., electrographic partial-onset 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-onset seizures was established in 2 multicenter, randomized, double-blind, placebo-controlled trials, one in 692 patients (15 to 66 years of age) and one in 264 pediatric patients (3 to 17 years of age), and in one multicenter, rater-blind, randomized, age-stratified, parallel-group study comparing 2 doses of oxcarbazepine in 128 pediatric patients (1 month to <4 years of age).

Patients in the 2 placebo-controlled trials were on 1 to 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 to 4 per month) partial-onset 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 2-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 to 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-onset 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 Adverse Reactions ( 6)], an outcome not seen in the monotherapy studies.

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 years 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-onset seizures on 1 to 2 concomitant AEDs. Patients who experienced at least 2 study-specific seizures (i.e., electrographic partial-onset 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).

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