CLINICAL PHARMACOLOGY

Mechanism of Action

The pharmacological activity of oxcarbazepine is primarily exerted through the 10-monohydroxy metabolite (MHD) of oxcarbazepine (see Metabolism and Excretion subsection). The precise mechanism by which oxcarbazepine and MHD exert their antiseizure effect is unknown; however, in vitro electrophysiological studies indicate that they produce blockade of voltage-sensitive sodium channels, resulting in stabilization of hyperexcited neural membranes, inhibition of repetitive neuronal firing, and diminution of propagation of synaptic impulses. These actions are thought to be important in the prevention of seizure spread in the intact brain. In addition, increased potassium conductance and modulation of high-voltage activated calcium channels may contribute to the anticonvulsant effects of the drug. No significant interactions of oxcarbazepine or MHD with brain neurotransmitter or modulator receptor sites have been demonstrated.

Pharmacodynamics

Oxcarbazepine and its active metabolite (MHD) exhibit anticonvulsant properties in animal seizure models. They protected rodents against electrically induced tonic extension seizures and, to a lesser degree, chemically induced clonic seizures, and abolished or reduced the frequency of chronically recurring focal seizures in Rhesus monkeys with aluminum implants. No development of tolerance (i.e., attenuation of anticonvulsive activity) was observed in the maximal electroshock test when mice and rats were treated daily for five days and four weeks, respectively, with oxcarbazepine or MHD.

Pharmacokinetics

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

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

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

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

Effect of Food: Food has no effect on the rate and extent of absorption of oxcarbazepine from Oxcarbazepine tablets. Although not directly studied, the oral bioavailability of the Oxcarbazepine suspension is unlikely to be affected under fed conditions. Therefore, Oxcarbazepine tablets and suspension can be taken with or without food.     

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

Distribution

The apparent volume of distribution of MHD is 49L.

      Approximately 40% of MHD is bound to serum proteins, predominantly to albumin. Binding is independent of the serum concentration within the therapeutically relevant range. Oxcarbazepine and MHD do not bind to alpha-1-acid glycoprotein.

Metabolism and Excretion

Oxcarbazepine is rapidly reduced by cytosolic enzymes in the liver to its 10-monohydroxy metabolite, MHD, which is primarily responsible for the pharmacological effect of Oxcarbazepine. MHD is metabolized further by conjugation with glucuronic acid. Minor amounts (4% of the dose) are oxidized to the pharmacologically inactive 10,11-dihydroxy metabolite (DHD).

      Oxcarbazepine is cleared from the body mostly in the form of metabolites which are predominantly excreted by the kidneys. More than 95% of the dose appears in the urine, with less than 1% as unchanged oxcarbazepine. Fecal excretion accounts for less than 4% of the administered dose. Approximately 80% of the dose is excreted in the urine either as glucuronides of MHD (49%) or as unchanged MHD (27%); the inactive DHD accounts for approximately 3% and conjugates of MHD and oxcarbazepine account for 13% of the dose.

Special Populations

Hepatic Impairment

The pharmacokinetics and metabolism of oxcarbazepine and MHD were evaluated in healthy volunteers and hepatically-impaired subjects after a single 900-mg oral dose. Mild-to-moderate hepatic impairment did not affect the pharmacokinetics of oxcarbazepine and MHD. No dose adjustment for Oxcarbazepine is recommended in patients with mild-to-moderate hepatic impairment. The pharmacokinetics of oxcarbazepine and MHD have not been evaluated in severe hepatic impairment and, therefore, caution should be exercised when dosing severely impaired patients.

Renal Impairment

There is a linear correlation between creatinine clearance and the renal clearance of MHD. When Oxcarbazepine is administered as a single 300-mg dose in renally-impaired patients (creatinine clearance <30 mL/min), the elimination half-life of MHD is prolonged to 19 hours, with a two-fold increase in AUC. Dose adjustment for Oxcarbazepine is recommended in these patients (see PRECAUTIONS and DOSAGE AND ADMINISTRATION sections).

Pediatric Use

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

Geriatric Use

Following administration of single (300 mg) and multiple (600 mg/day) doses of Oxcarbazepine to elderly volunteers (60-82 years of age), the maximum plasma concentrations and AUC values of MHD were 30%-60% higher than in younger volunteers (18-32 years of age). Comparisons of creatinine clearance in young and elderly volunteers indicate that the difference was due to age-related reductions in creatinine clearance.

Gender

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

Race

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

INDICATIONS AND USAGE

Oxcarbazepine is indicated for use as monotherapy or adjunctive therapy in the treatment of partial seizures in adults and as monotherapy in the treatment of partial seizures in children aged 4 years and above with epilepsy, and as adjunctive therapy in children aged 2 years and above with epilepsy.

CONTRAINDICATIONS

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 Oxcarbazepine use. In the 14 controlled epilepsy studies 2.5% of Oxcarbazepine-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, 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 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 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, 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).

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. Angioedema associated with laryngeal edema can be fatal. If a patient develops any of these reactions after treatment with Oxcarbazepine, the drug should be discontinued and an alternative treatment started. These patients should not be rechallenged with the drug (see WARNINGS, Patients with a Past History of Hypersensitivity Reaction to Carbamazepine subsection).

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. 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 only if the potential benefit justifies the potential risk. If signs or symptoms of hypersensitivity develop, Oxcarbazepine should be discontinued immediately (see WARNINGS, Anaphylactic Reactions and Angioedema subsection; see PRECAUTIONS, Multi-Organ Hypersensitivity subsection).

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 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 has also been reported.

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

Withdrawal of AEDs

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

PRECAUTIONS

Cognitive/Neuropsychiatric Adverse Events

Use of 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.

Adult Patients

      In one large, fixed-dose study, Oxcarbazepine was added to existing AED therapy (up to three concomitant AEDs). By protocol, the dosage of the concomitant AEDs could not be reduced as Oxcarbazepine was added, reduction in Oxcarbazepine 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 Oxcarbazepine 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 seven times greater on oxcarbazepine than on placebo.

      In a single placebo-controlled monotherapy trial evaluating 2400 mg/day of Oxcarbazepine, 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 Oxcarbazepine, 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.

Pediatric Patients

      A study was conducted in pediatric patients (3 to 17 years old) with inadequately controlled partial seizures in which Oxcarbazepine was added to existing AED therapy (up to two concomitant AEDs). By protocol, the dosage of concomitant AEDs could not be reduced as Oxcarbazepine was added. Oxcarbazepine was titrated to reach a target dose ranging from 30 mg/kg to 46 mg/kg (based on a patient’s body weight with fixed doses for predefined weight ranges).

      Cognitive adverse events occurred in 5.8% of oxcarbazepine-treated patients (the single most common event being concentration impairment, 4 of 138 patients) and in 3.1% of patients treated with placebo.  In addition, 34.8% of oxcarbazepine-treated patients and 14.0% of placebo-treated patients experienced somnolence. (No patient discontinued due to a cognitive adverse event or somnolence.). Finally, 23.2% of oxcarbazepine-treated patients and 7.0% of placebo-treated patients experienced ataxia or gait disturbances. Two (1.4%) oxcarbazepine-treated patients and 1 (0.8%) placebo-treated patient discontinued due to ataxia or gait disturbances.

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 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. Other associated manifestations included lymphadenopathy, hepatitis, liver function test abnormalities, hematological abnormalities (e.g., eosinophilia, thrombocytopenia, neutropenia), pruritis, nephritis, oliguria, hepatorenal syndrome, arthralgia and asthenia. 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 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, Patients with a Past History of Hypersensitivity Reaction to Carbamazepine subsection).

Information for Patients

Anaphylactic reactions and angioedema may occur during treatment with Oxcarbazepine. Patients should be advised to report immediately signs and symptoms suggesting angioedema (swelling of the face, eyes, lips, tongue or difficulty in swallowing or breathing) and to stop taking the drug until they have consulted with their physician (see WARNINGS, Anaphylactic Reactions and Angioedema subsection).

      Patients who have exhibited hypersensitivity reactions to carbamazepine should be informed that approximately 25%-30% of these patients may experience hypersensitivity reactions with Oxcarbazepine. Patients should be advised that if they experience a hypersensitivity reaction while taking Oxcarbazepine they should consult with their physician immediately (see WARNINGS, Patients with a Past History of Hypersensitivity Reaction to Carbamazepine subsection).

      Patients should be advised that serious skin reactions have been reported in association with Oxcarbazepine. In the event a skin reaction should occur while taking Oxcarbazepine, patients should consult with their physician immediately (see WARNINGS, Serious Dermatological Reactions subsection).

      Patients should be instructed that a fever associated with other organ system involvement (rash, lymphadenopathy, etc.) may be drug related and should be reported to the physician immediately (see PRECAUTIONS, Multi-Organ Hypersensitivity subsection).

      Female patients of childbearing age should be warned that the concurrent use of Oxcarbazepine 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 Oxcarbazepine.

      Caution should be exercised if alcohol is taken in combination with Oxcarbazepine therapy, due to a possible additive sedative effect.

      Patients should be advised that Oxcarbazepine may cause dizziness and somnolence. Accordingly, patients should be advised not to drive or operate machinery until they have gained sufficient experience on Oxcarbazepine 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 Oxcarbazepine (see WARNINGS section). Experience from clinical trials indicates that serum sodium levels return toward normal when the Oxcarbazepine dosage is reduced or discontinued, or when the patient was treated conservatively (e.g., fluid restriction).

      Laboratory data from clinical trials suggest that Oxcarbazepine use was associated with decreases in T4, without changes in T3 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

Potential interactions between Oxcarbazepine and other AEDs were assessed in clinical studies. The effect of these interactions on mean AUCs and Cmin are summarized in Table 2.

1 nc denotes a mean change of less than 10%

2 Pediatrics

3 Mean increase in adults at high Oxcarbazepine doses

      In vivo, the plasma levels of phenytoin increased by up to 40% when Oxcarbazepine was given at doses above 1200 mg/day. Therefore, when using doses of Oxcarbazepine 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.

      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.

Hormonal Contraceptives

Coadministration of Oxcarbazepine 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 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 coadministration of Oxcarbazepine, 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 Oxcarbazepine.

Drug/Laboratory Test Interactions

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

Carcinogenesis/Mutagenesis/Impairment of Fertility

In two-year carcinogenicity studies, oxcarbazepine was administered in the diet at doses of up to 100 mg/kg/day to mice and by gavage at doses of up to 250 mg/kg 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/m2 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/m2 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/m2 basis) and ≥250 mg/kg/day (equivalent to the MRHD on a mg/m2 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 two times the MRHD on a mg/m2 basis).

Pregnancy Category C

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.

      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/m2 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/m2 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/m2 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/m2 basis).

      There are no adequate and well-controlled clinical studies of Oxcarbazepine in pregnant women; however, Oxcarbazepine 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 Oxcarbazepine is a human teratogen. Oxcarbazepine should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Labor and Delivery

The effect of Oxcarbazepine 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 Oxcarbazepine 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). Oxcarbazepine 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

Oxcarbazepine is indicated for use as adjunctive therapy for partial seizures in patients aged 2-16 years. Oxcarbazepine is also indicated as monotherapy for partial seizures in patients aged 4-16 years. Oxcarbazepine 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 ADVERSE REACTIONS section for a description of the adverse events associated with Oxcarbazepine 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 Oxcarbazepine 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 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 1,537 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 Oxcarbazepine 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 4 Years Old and Above Previously Treated with other AEDs: The most commonly observed (≥5%) adverse experiences seen in association with Oxcarbazepine 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%).

Monotherapy in Pediatric Patients 4 Years Old and Above Not Previously Treated with other AEDs: The most commonly observed (≥5%) adverse experiences seen in association with Oxcarbazepine in these patients were similar to those in adults.

      Approximately 9.2% of 152 pediatric patients discontinued treatment because of an adverse experience. The adverse experiences most commonly associated (≥1%) with discontinuation were rash (5.3%) and maculopapular rash (1.3%).

Adjunctive Therapy/Monotherapy in Pediatric Patients 1 Month to <4 Years Old Previously Treated or Not Previously Treated with other AEDs: The most commonly observed (≥5%) adverse experiences seen in association with Oxcarbazepine in these patients were similar to those seen in older children and adults except for infections and infestations which were more frequently seen in these younger children.

      Approximately 11% of these 241 pediatric patients discontinued treatment because of an adverse experience. The adverse experiences most commonly associated with discontinuation were: Convulsions (3.7%), status epilepticus (1.2%), and ataxia (1.2%).

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 Oxcarbazepine or placebo as adjunctive treatment and were numerically more common in the patients treated with any dose of Oxcarbazepine. Table 4 lists treatment-emergent signs and symptoms in patients converted from other AEDs to either high dose Oxcarbazepine or low dose (300 mg) Oxcarbazepine. Note that in some of these monotherapy studies patients who dropped out during a preliminary tolerability phase are not included in the tables.