OXCARBAZEPINE
Oxep Tablets
DESCRIPTION
Oxep® (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-5 H -dibenz[b, f ]azepine-5-carboxamide.
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.
Oxep film-coated tablets contain the following inactive ingredients: colloidal silicon dioxide, crospovidone, hydroxypropyl methylcellulose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, talc and titanium dioxide, yellow iron oxide.
CLINICAL PHARMACOLOGY
Mechanism of Action
The pharmacological activity of Oxep® (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 5 days and 4 weeks, respectively, with oxcarbazepine or MHD.
Pharmacokinetics
Following oral administration of Oxep, oxcarbazepine is completely absorbed and extensively metabolized to its pharmacologically active 10-monohydroxy metabolite (MHD). 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.
After single dose administration of Oxep to healthy male volunteers under fasted conditions, the median t max 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. Food has no effect on the rate and extent of absorption of oxcarbazepine.
Steady-state plasma concentrations of MHD are reached within 2-3 days in patients when Oxep 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 Oxep. 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 Oxep is recommended in patients with mild-to-moderate hepatic impairment. The pharmacokinetics of oxcarbazepine and MHD have not been evaluated in severe hepatic impairment.
Renal Impairment
There is a linear correlation between creatinine clearance and the renal clearance of MHD. When Oxep 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 Oxep is recommended in these patients (see PRECAUTIONS and DOSAGE AND ADMINISTRATION sections).
Pediatric Use
After a single-dose administration of 5 or 15 mg/kg of Oxep, the dose-adjusted AUC values of MHD were 30%-40% lower in children below the age of 8 years than in children above 8 years of age. The clearance in children greater than 8 years old approaches that of adults.
Geriatric Use
Following administration of single (300 mg) and multiple (600 mg/day) doses of Oxep 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 Oxep® (oxcarbazepine) as adjunctive and monotherapy for partial seizures in adults, and as adjunctive therapy in children aged 4-16 was established in 6 multicenter randomized, double-blind controlled trials.
Oxep Monotherapy Trials
Four randomized, double-blind, multicenter trials demonstrated the efficacy of Oxep as monotherapy. Two trials compared Oxep to placebo and two trials used a randomized withdrawal design to compare a high dose (2400 mg) with a low dose (300 mg) of Oxep, after substituting Oxep 2400 mg/day for one or more antiepileptic drugs (AEDs). All doses were administered on a BID schedule.
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 Oxep given as 1500 mg/day on Day 1 and 2400 mg/day thereafter for an additional 9 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 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 Oxep.
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 Oxep, initiated at 300 mg BID and titrated to 1200 mg/day (given as 600 mg BID) 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 two treatments was statistically significant in favor of Oxep.
A third trial substituted Oxep 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 Oxep dose for 56 days (baseline phase). Patients who were able to tolerate titration of Oxep to 2400 mg/day during simultaneous carbamazepine withdrawal were randomly assigned to either 300 mg/day of Oxep or 2400 mg/day Oxep. Patients were observed for 126 days or until one of the following 4 exit criteria occurred: 1) a doubling of the 28-day seizure frequency compared to baseline, 2) a two 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 Oxep 2400 mg/day group .
Another monotherapy substitution trial was conducted in 87 patients (11-66 years of age) whose seizures were inadequately controlled on 1 or 2 AEDs. Patients were randomized to either Oxep 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 one 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 Oxep 2400 mg/day group (14/34; 41.2%) compared to the Oxep 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 Oxep 2400 mg/day group.
Oxep Adjunctive Therapy Trials
The effectiveness of Oxep 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). Patients in these 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 Oxep 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 30-46 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 Oxep 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 1. 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 section), an outcome not seen in the monotherapy studies.
Subset analyses of the antiepileptic efficacy of Oxep 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.
INDICATIONS AND USAGE
Oxep® (oxcarbazepine) is indicated for use as monotherapy or adjunctive therapy in the treatment of partial seizures in adults with epilepsy and as adjunctive therapy in the treatment of partial seizures in children ages 4-16 with epilepsy.
CONTRAINDICATIONS
Oxep® (oxcarbazepine) should not be used in patients with a known hypersensitivity to oxcarbazepine or to any of its components.
WARNINGS
Hyponatremia
Clinically significant hyponatremia (sodium <125 mmol/L) can develop during Oxep® (oxcarbazepine) use. In the 14 controlled epilepsy studies 2.5% of Oxep treated patients (38/1524) 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 Oxep, 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 Oxep 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 Oxep 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 Oxep, 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, or obtundation).
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 Oxep. 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 Oxep only if the potential benefit justifies the potential risk. If signs or symptoms of hypersensitivity develop, Oxep should be discontinued immediately.
Withdrawal of AEDs
As with all antiepileptic drugs, Oxep should be withdrawn gradually to minimize the potential of increased seizure frequency.
PRECAUTIONS
Cognitive/Neuropsychiatric Adverse Events
Use of Oxep® (oxcarbazepine) 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.
In one, large, fixed dose study, Oxep was added to existing AED therapy (up to three concomitant AEDs). By protocol, the dosage of the concomitant AEDs could not be reduced as Oxep was added, reduction in Oxep dosage was not allowed if intolerance developed, and patients were discontinued if unable to tolerate their highest target maintenance doses. In this trial, 65% of patients were discontinued because they could not tolerate the 2400 mg/day dose of Oxep on top of existing AEDs. The adverse events seen in this study were primarily CNS related and the risk for discontinuation was dose related.
In this trial, 7.1% of oxcarbazepine-treated patients and 4% of placebo-treated patients experienced a cognitive adverse event. The risk of discontinuation for these events was about 6.5 times greater on oxcarbazepine than on placebo. In addition, 26% of oxcarbazepine-treated patients and 12% of placebo-treated patients experienced somnolence. The risk of discontinuation for somnolence was about 10 times greater on oxcarbazepine than on placebo. Finally, 28.7% of oxcarbazepine-treated patients and 6.4% of placebo-treated patients experienced ataxia or gait disturbances. The risk for discontinuation for these events was about 7 times greater on oxcarbazepine than on placebo.
In a single placebo-controlled monotherapy trial evaluating 2400 mg/day of Oxep, no patients in either treatment group discontinued double-blind treatment because of cognitive adverse events, somnolence, ataxia, or gait disturbance.
In the two dose-controlled conversion to monotherapy trials comparing 2400 mg/day and 300 mg/day Oxep, 1.1% of patients in the 2400 mg/day group discontinued double-blind treatment because of somnolence or cognitive adverse events compared to 0% in the 300 mg/day group. In these trials, no patients discontinued because of ataxia or gait disturbances in either treatment group.
Information for Patients
Patients who have exhibited hypersensitivity reactions to carbamazepine should be informed that approximately 25%-30% of these patients may experience hypersensitivity reactions with Oxep. (See WARNINGS section.)
Female patients of childbearing age should be warned that the concurrent use of Oxep with hormonal contraceptives may render this method of contraception less effective (see Drug Interactions subsection) . Additional non-hormonal forms of contraception are recommended when using Oxep.
Caution should be exercised if alcohol is taken in combination with Oxep therapy, due to a possible additive sedative effect.
Patients should be advised that Oxep may cause dizziness and somnolence. Accordingly, patients should be advised not to drive or operate machinery until they have gained sufficient experience on Oxep to gauge whether it adversely affects their ability to drive or operate machinery.
Laboratory Tests
Serum sodium levels below 125 mmol/L have been observed in patients treated with Oxep (See WARNINGS section.) Experience from clinical trials indicates that serum sodium levels return toward normal when the Oxep dosage is reduced or discontinued, or when the patient was treated conservatively (e.g., fluid restriction).
Laboratory data from clinical trials suggest that Oxep use was associated with decreases in T 4 , without changes in T 3 or TSH.
Drug Interactions
Oxcarbazepine can inhibit CYP2C19 and induce CYP3A4/5 with potentially important effects on plasma concentrations of other drugs. In addition, several AEDs that are cytochrome P450 inducers can decrease plasma concentrations of oxcarbazepine and MHD.
Oxcarbazepine was evaluated in human liver microsomes to determine its capacity to inhibit the major cytochrome P450 enzymes responsible for the metabolism of other drugs. Results demonstrate that oxcarbazepine and its pharmacologically active 10-monohydroxy metabolite (MHD) have little or no capacity to function as inhibitors for most of the human cytochrome P450 enzymes evaluated (CYP1A2, CYP2A6, CYP2C9, CYP2D6, CYP2E1, CYP4A9 and CYP4A11) with the exception of CYP2C19 and CYP3A4/5. Although inhibition of CYP3A4/5 by oxcarbazepine and MHD did occur at high concentrations, it is not likely to be of clinical significance. The inhibition of CYP2C19 by oxcarbazepine and MHD, however, is clinically relevant (see below).
In vitro , the UDP-glucuronyl transferase level was increased, indicating induction of this enzyme. Increases of 22% with MHD and 47% with oxcarbazepine were observed. As MHD, the predominant plasma substrate, is only a weak inducer of UDP-glucuronyl transferase, it is unlikely to have an effect on drugs that are mainly eliminated by conjugation through UDP-glucuronyl transferase (e.g., valproic acid, lamotrigine).
In addition, oxcarbazepine and MHD induce a subgroup of the cytochrome P450 3A family (CYP3A4 and CYP3A5) responsible for the metabolism of dihydropyridine calcium antagonists and oral contraceptives, resulting in a lower plasma concentration of these drugs.
As binding of MHD to plasma proteins is low (40%), clinically significant interactions with other drugs through competition for protein binding sites are unlikely.
Antiepileptic Drugs
In vivo , the plasma levels of phenytoin increased by up to 40% when Oxep was given at doses above 1200 mg/day. Therefore, when using doses of Oxep 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 Oxep.
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 Oxep.
Hormonal Contraceptives
Co-administration of Oxep 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 Oxep with hormonal contraceptives may render these contraceptives less effective (see Drug Interactions subsection) . Studies with other oral or implant contraceptives have not been conducted.
Calcium Antagonists
After repeated co-administration of Oxep, 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.
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 Oxep.
Drug/Laboratory Test Interactions
There are no known interactions of Oxep with commonly used laboratory tests.
Carcinogenesis/Mutagenesis/Impairment of Fertility
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 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.
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.
In a fertility study in which rats were administered MHD (50, 150, 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 2 times the MRHD on a mg/m 2 basis
Pregnancy Category C
Increased incidences of fetal structural abnormalities and other manifestations of developmental toxicity (embryo-lethality, 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.
When pregnant rats were given oxcarbazepine (30, 300, or 1000 mg/kg) 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 maximum recommended human dose [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 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 (20, 100, or 200 mg/kg) 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 (25, 50, or 150 mg/kg) 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 (0.6 times the MRHD on a mg/m 2 basis). Oral administration of MHD (25, 75, or 250 mg/kg) 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
There are no adequate and well-controlled clinical studies of Oxep in pregnant women; however, Oxep is closely related structurally to carbamazepine, which is considered to be teratogenic in humans. Given this fact, and the results of the animal studies described, it is likely that Oxep is a human teratogen. Oxep should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Labor and Delivery
The effect of Oxep on labor and delivery in humans has not been evaluated.
Nursing Mothers
Oxcarbazepine and its active metabolite (MHD) are excreted in human breast milk. A milk-to-plasma concentration ratio of 0.5 was found for both. Because of the potential for serious adverse reactions to Oxep 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.
Patients with 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 CLINICAL PHARMACOLOGY , Pharmacokinetics subsection ). Oxep 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.
Pediatric Use
Oxep has been shown to be effective as adjunctive therapy for partial seizures in patients aged 4-16 years old. Oxep has been given to about 623 patients between the ages of 3-17 in controlled clinical trials (185 treated as monotherapy) and about 615 patients between the ages of 3-17 in other trials. (See ADVERSE REACTIONS for a description of the adverse events associated with Oxep use in this population.)
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 Oxep 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.
ADVERSE REACTIONS
Most Common Adverse Events in All Clinical Studies
Adjunctive Therapy/Monotherapy in Adults Previously Treated with other AEDs: The most commonly observed (>/=5%) adverse experiences seen in association with Oxep® (oxcarbazepine) and substantially more frequent than in placebo-treated patients were: Dizziness, somnolence, diplopia, fatigue, nausea, vomiting, ataxia, abnormal vision, abdominal pain, tremor, dyspepsia, abnormal gait.
Approximately 23% of these 1537 adult patients discontinued treatment because of an adverse experience. The adverse experiences most commonly associated with discontinuation were: Dizziness (6.4%), diplopia (5.9%), ataxia (5.2%), vomiting (5.1%), nausea (4.9%), somnolence (3.8%), headache (2.9%), fatigue (2.1%), abnormal vision (2.1%), tremor (1.8%), abnormal gait (1.7%), rash (1.4%), hyponatremia (1.0%).
Monotherapy in Adults not Previously Treated with other AEDs: The most commonly observed (>/=5%) adverse experiences seen in association with Oxep in these patients were similar to those in previously treated patients.
Approximately 9% of these 295 adult patients discontinued treatment because of an adverse experience. The adverse experiences most commonly associated with discontinuation were: Dizziness (1.7%), nausea (1.7%), rash (1.7%), headache (1.4%).
Adjunctive Therapy/Monotherapy in Pediatric Patients Previously Treated with other AEDs: The most commonly observed (>/=5%) adverse experiences seen in association with Oxep in these patients were similar to those seen in adults.
Approximately 11% of these 456 pediatric patients discontinued treatment because of an adverse experience. The adverse experiences most commonly associated with discontinuation were: Somnolence (2.4%), vomiting (2.0%), ataxia (1.8%), diplopia (1.3%), dizziness (1.3%), fatigue (1.1%), nystagmus (1.1%).
Incidence in Controlled Clinical Studies: The prescriber should be aware that the figures in Tables 3, 4, 5 and 6 cannot be used to predict the frequency of adverse experiences in the course of usual medical practice where patient characteristics and other factors may differ from those prevailing during clinical studies. Similarly, the cited frequencies cannot be directly compared with figures obtained from other clinical investigations involving different treatments, uses, or investigators. An inspection of these frequencies, however, does provide the prescriber with one basis to estimate the relative contribution of drug and nondrug factors to the adverse event incidences in the population studied.
Controlled Clinical Studies of Adjunctive Therapy/Monotherapy in Adults Previously Treated with other AEDs: Table 3 lists treatment-emergent signs and symptoms that occurred in at least 2% of adult patients with epilepsy treated with Oxep or placebo as adjunctive treatment and were numerically more common in the patients treated with any dose of Oxep. Table 4 lists treatment-emergent signs and symptoms in patients converted from other AEDs to either high dose Oxep or low dose (300 mg) Oxep. Note that in some of these monotherapy studies patients who dropped out during a preliminary tolerability phase are not included in the tables.
Table 3: Treatment-Emergent Adverse Event Incidence in a Controlled Clinical Study of Adjunctive Therapy in Adults (Events in at least 2% of patients treated with 2400 mg/day of Oxep and numerically more frequent than in the placebo group)
Oxcarbazepine Dosage (mg/day)
Body System/
Adverse Event OXC 600 OXC 1200 OXC 2400 Placebo
N=163 N=171 N=126 N=166
% % % %
Body as a Whole
Fatigue 15 12 15 7
Asthenia 6 3 6 5
Edema Legs 2 1 2 1
Weight Increase 1 2 2 1
Feeling Abnormal 0 1 2 0
Cardiovascular System
Hypotension 0 1 2 0
Digestive System
Nausea 15 25 29 10
Vomiting 13 25 36 5
Pain Abnormal 10 13 11 5
Diarrhea 5 6 7 6
Dyspepsia 5 5 6 2
Constipation 2 1 6 4
Gastritis 2 1 2 1
Metabolic and Nutritional Disorders
Hyponatremia 3 1 2 1
Musculoskeletal System
Muscle Weakness 1 2 2 0
Sprains and Strains 0 2 2 1
Nervous System
Headache 32 28 26 23
Dizziness 26 32 49 13
Somnolence 20 28 36 12
Ataxia 9 17 31 5
Nystagmus 7 20 26 5
Gait Abnormal 5 10 17 1
Insomnia 4 2 3 1
Tremor 3 8 16 5
Nervousness 2 4 2 1
Agitation 1 1 2 1
Coordination Abnormal 1 3 2 1
EEG Abnormal 0 0 2 0
Speech Disorder 1 1 3 0
Confusion 1 1 2 1
Cranial Injury NOS 1 0 2 1
Dysmetria 1 2 3 0
Thinking Abnormal 0 2 4 0
Respiratory System
Rhinitis 2 4 5 4
Skin and Appendages
Acne 1 2 2 0
Special Senses
Diplopia 14 30 40 5
Vertigo 6 12 15 2
Vision Abnormal 6 14 13 4
Accommodation Abnormal 0 0 2 0
Table 4: Treatment-Emergent Adverse Event Incidence in Controlled Clinical Studies of Monotherapy in Adults Previously Treated with Other AEDs (Events in at least 2% of patients treated with 2400 mg/day of Oxep and numercially more frequent than in the low dose control group) Oxcarbazepine Dosage (mg/day)
Body System/
Adverse Event 2400 300
N=86 N=86
% %
Body as a Whole
Fatigue 21 5
Fever 3 0
Allergy 2 0
Edema Generalized 2 1
Pain Chest 2 0
Digestive System
Nausea 22 7
Vomiting 15 5
Diarrhea 7 5
Dyspepsia 6 1
Anorexia 5 3
Pain Abdominal 5 3
Mouth Dry 3 0
Hemorrhage Rectum 2 0
Toothache 2 1
Hemic and Lymphatic System
Lymphadenopathy 2 0
Infections and Infestations
Infection Viral 7 5
Infection 2 0
Metabolic and Nutritional Disorders
Hyponatremia 5 0
Thirst 2 0
Nervous System
Headache 31 15
Dizziness 28 8
Somnolence 19 5
Anxiety 7 5
Ataxia 7 1
Confusion 7 0
Nervousness 7 0
Insomnia 6 3
Tremor 6 3
Amnesia 5 1
Convulsions Aggravated 5 2
Emotional Lability 3 2
Hypoesthesia 3 1
Coordination Abnormal 2 1
Nystagmus 2 0
Speech Disorder 2 0
Respiratory System
Upper Respiratory Tract Infection 10 5
Coughing 5 0
Bronchitis 3 0
Pharyngitis 3 0
Skin and Appendages
Hot Flushes 2 1
Purpura 2 0
Special Senses
Vision Abnormal 14 2
Diplopia 12 1
Taste Perversion 5 0
Vertigo 3 0
Ear Ache 2 1
Ear Infection NOS 2 0
Urogenital and Reproductive System
Urinary Tract Infection 5 1
Micturition Frequency 2 1
Vaginitis 2 0
Controlled Clinical Study of Monotherapy in Adults not Previously Treated with other AEDs: Table 5 lists treatment-emergent signs and symptoms in a controlled clinical study of monotherapy in adults not previously treated with other AEDs that occurred in at least 2% of adult patients with epilepsy treated with Oxep or placebo and were numerically more common in the patients treated with Oxep.
Table 5: Treatment-Emergent Adverse Event Incidence in a Controlled Clinical Study of Monotherapy in Adults not Previously Treated with Other AEDs (Events in at least 2% of patients treated with Oxep and numerically more frequent than in the placebo group)
Body System/ Oxcarbazepine Placebo
Adverse Event N=55 N=49
% %
Body as a Whole
Falling Down NOS 4 0
Digestive System
Nausea 16 12
Diarrhea 7 2
Vomiting 7 6
Constipation 5 0
Dyspepsia 5 4
Musculoskeletal System
Pain Back 4 2
Nervous System
Dizziness 22 6
Headache 13 10
Ataxia 5 0
Nervousness 5 2
Amnesia 4 2
Coordination Abnormal 4 2
Tremor 4 0
Respiratory System
Upper Respiratory Tract Infection 7 0
Epistaxis 4 0
Infection Chest 4 0
Sinusitis 4 2
Skin and Appendages
Rash 4 2
Special Senses
Vision Abnormal 4 0
Controlled Clinical Studies of Adjunctive Therapy/Monotherapy in Pediatric Patients Previously Treated with other AEDs: Table 6 lists treatment-emergent signs and symptoms that occurred in at least 2% of pediatric patients with epilepsy treated with Oxep or placebo as adjunctive treatment and were numerically more common in the patients treated with Oxep.
Table 6: Treatment-Emergent Adverse Event Incidence in Controlled Clinical Studies of Adjunctive Therapy/Monotherapy in Pediatric Patients Previously Treated with Other AEDs (Events in at least 2% of patients treated with Oxep and numerically more frequent than in the placebo group)
Body System/ Oxcarbazepine Placebo
Adverse Event N=171 N=139
% %
Body as a Whole
Fatigue 13 9
Allergy 2 0
Asthenia 2 1
Digestive System
Vomiting 33 14
Nausea 19 5
Constipation 4 1
Dyspepsia 2 0
Nervous System
Headache 31 19
Somnolence 31 13
Dizziness 28 8
Ataxia 13 4
Nystagmus 9 1
Emotional Lability 8 4
Gait Abnormal 8 3
Tremor 6 4
Speech Disorder 3 1
Concentration Impaired 2 1
Convulsions 2 1
Muscle Contractions Involuntary 2 1
Respiratory System
Rhinitis 10 9
Pneumonia 2 1
Skin and Appendages
Bruising 4 2
Sweating Increased 3 0
Special Senses
Diplopia 17 1
Vision Abnormal 13 1
Vertigo 2 0