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oxcarbazepine 600 mg tablet generic trileptal

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Uses

Seizure Disorders

Partial Seizures

Oxcarbazepine is used as monotherapy or adjunctive therapy (i.e., in combination with other anticonvulsants) in the management of partial seizures.

Monotherapy

Oxcarbazepine conventional (immediate-release) tablets and oral suspension are used as monotherapy of partial seizures in adults and pediatric patients 4 years of age or older.

Efficacy of oxcarbazepine monotherapy in patients with partial seizures has been established in several multicenter, randomized controlled studies using immediate-release preparations of the drug. In one placebo-controlled study in patients 11-62 years of age with refractory partial seizures (undergoing evaluation for epilepsy surgery) who had been withdrawn from anticonvulsants prior to randomization, oxcarbazepine at dosages up to 2.4 g daily for 10 days was more effective than placebo. Results of another placebo-controlled study in previously untreated patients 8-69 years of age with newly diagnosed or recent-onset partial seizures indicated that oxcarbazepine dosages up to 1.2 g daily for 84 days were more effective than placebo. In 2 conversion-to-monotherapy studies, therapy with oxcarbazepine 2.4 g daily for up to 126 days was substantially more effective than oxcarbazepine 300 mg daily in patients 11-66 years of age with partial seizures who had been withdrawn from previous therapy with 1 or 2 anticonvulsants because of inadequate control. An additional evaluator-blinded monotherapy trial was conducted in pediatric patients 1 month to 16 years of age with inadequately controlled or new-onset partial seizures. In this study, oxcarbazepine 40-60 mg/kg daily was not more effective than oxcarbazepine 10 mg/kg daily; however, due to several limitations in the study design, the results were considered uninterpretable. Efficacy of oxcarbazepine monotherapy in pediatric patients 4 years of age or older is based on pharmacokinetic and pharmacodynamic data.

Results of several multicenter, randomized, double-blind monotherapy trials in patients with newly diagnosed or previously untreated partial or generalized seizures indicate that oxcarbazepine exhibits anticonvulsant activity similar to carbamazepine, phenytoin, or valproic acid.

Adjunctive Therapy

Oxcarbazepine conventional (immediate-release) tablets and oral suspension are used as adjunctive therapy (i.e., in combination with other anticonvulsants) of partial seizures in adults and pediatric patients 2 years of age or older. Efficacy of oxcarbazepine for this use was established in 2 multicenter, randomized, double-blind, placebo-controlled studies (one in adults and one in children 3-17 years of age) and an additional evaluator-blinded study that compared 2 dosages of oxcarbazepine in infants and children 1 month to less than 4 years of age. In the placebo-controlled studies, patients initially were stabilized on optimum dosages of 1-3 anticonvulsants during an 8-week baseline period; those experiencing at least 8 (minimum 1-4 per month) partial seizures during this phase were randomized to receive oxcarbazepine (as an immediate-release preparation) or placebo during a dosage titration period of 2 weeks followed by a 14- or 24-week maintenance period in children or adults, respectively. Efficacy of oxcarbazepine in these studies was evaluated in terms of the change in seizure frequency (i.e., the median decrease [or increase] in average monthly [28-day] seizure rate). Adults receiving oxcarbazepine 600 mg, 1.2 g, or 2.4 g daily or placebo experienced a median decrease in seizure frequency of about 26, 40, 50, or 8%, respectively, while pediatric patients receiving oxcarbazepine dosages ranging from 30-46 mg/kg daily (depending on baseline body weight) or placebo experienced a median decrease in seizure frequency of about 35 or 9%, respectively. In the dose comparison study, infants and children who were receiving stable dosages of up to 2 anticonvulsants prior to study entry and who had experienced at least 2 partial seizures during a 72-hour baseline period were randomized to receive adjunctive therapy with low-dose oxcarbazepine (10 mg/kg daily with no titration period) or high-dose oxcarbazepine (60 mg/kg daily after a 26-day titration period) as an oral suspension. Patients in both groups received their target dosage for 9 days and seizures were assessed during the last 72 hours of the maintenance period with video electroencephalography (EEG). Oxcarbazepine 60 mg/kg daily was substantially more effective than oxcarbazepine 10 mg/kg daily in reducing seizure frequency. Efficacy of oxcarbazepine was not demonstrated in children younger than 2 years of age in this study.

Oxcarbazepine also is commercially available as extended-release tablets for once-daily administration in the adjunctive management of partial seizures in adults and pediatric patients 6 years of age and older. Efficacy of the extended-release tablets in adults was evaluated in a randomized, double-blind, placebo-controlled study in patients 18-65 years of age with refractory partial epilepsy. Patients who experienced at least 3 partial seizures every 28 days during an 8-week baseline period despite receiving stable dosages of 1-3 anticonvulsants were randomized to receive adjunctive therapy with oxcarbazepine (1.2 or 2.4 g daily as extended-release tablets) or placebo. Patients receiving oxcarbazepine 1.2 g daily, oxcarbazepine 2.4 g daily, or placebo experienced a median decrease in seizure frequency of about 38, 43, or 29%, respectively. Although the comparison between the 1.2-g daily dosage and placebo did not reach statistical significance in this study, the effectiveness of this dosage is supported by exposure-response analyses. Efficacy of oxcarbazepine extended-release tablets in pediatric patients is based on a pharmacokinetic study in children 4-16 years of age and studies with the immediate-release preparation in pediatric patients in addition to clinical studies performed in the adult population with both immediate-release and extended-release preparations of the drug.(See Pediatric Use under Warnings/Precautions: Specific Populations, in Cautions.)

Bipolar Disorder

Oxcarbazepine has been used alone or in combination with other drugs (e.g., antipsychotic agents) for the treatment and prevention of acute manic or mixed episodes in patients with bipolar disorder. Limited data suggest that oxcarbazepine may have equivalent efficacy and better tolerability than carbamazepine for this indication. The American Psychiatric Association (APA) considers oxcarbazepine an alternative treatment option for patients who do not respond adequately to first-line therapies such as lithium, valproic acid, and antipsychotic agents (e.g., olanzapine). For additional information on the management of bipolar disorder,

Dosage and Administration

Administration

Oxcarbazepine is administered orally as conventional (immediate-release) tablets, oral suspension, or extended-release tablets.

Oxcarbazepine conventional tablets and oral suspension are administered twice daily without regard to meals. Oxcarbazepine extended-release tablets are administered once daily on an empty stomach (i.e., at least 1 hour before or 2 hours after a meal).(See Description.) The extended-release tablet should be swallowed whole with water or other liquid, and should not be cut, chewed, or crushed; because of these limitations, the extended-release tablet formulation is not recommended for use in children younger than 6 years of age.

Oxcarbazepine oral suspension should be shaken well immediately prior to administration. The appropriate dose should be administered using the oral dosing syringe supplied by the manufacturer. The oral suspension may be added to a small glass of water or swallowed directly from the syringe. After each use, the oral syringe should be rinsed with warm water and allowed to dry thoroughly.

The oral bioavailability of oxcarbazepine immediate-release tablets appears to be similar to that of the oral suspension and, therefore, these preparations can be used interchangeably on a mg-for-mg basis. At steady state, the extended-release tablets administered once daily are not bioequivalent to the immediate-release tablets administered twice daily; when converting from immediate-release preparations of oxcarbazepine to the extended-release tablets, a higher daily dosage may be required.

Patients currently receiving or beginning therapy with oxcarbazepine and/or any other anticonvulsant for any indication should be closely monitored for the emergence or worsening of depression, suicidal thoughts or behavior (suicidality), and/or any unusual changes in mood or behavior.(See Suicidality Risk under Cautions: Warnings/Precautions.)

Oxcarbazepine therapy should be withdrawn gradually to minimize the potential for increased seizure frequency and status epilepticus.

Pharmacogenetic Testing

Because of a strong association between the presence of the variant HLA-B*1502 allele and risk of developing oxcarbazepine-induced Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), pharmacogenetic testing for HLA-B*1502 should be considered prior to initiating oxcarbazepine therapy.(See Pharmacogenomics of Oxcarbazepine-induced Cutaneous Reactions under Warnings/Precautions: Serious Dermatologic Reactions, in Cautions.) The test is considered positive if 1 or 2 copies of HLA-B*1502 are detected and negative if no copies of the variant allele are detected. Patients who test positive for HLA-B*1502 should not be initiated on oxcarbazepine therapy unless the benefits clearly outweigh the risks. Application of HLA-B*1502 genotyping as a screening tool has important limitations and must never substitute for appropriate clinical vigilance and patient management. For additional information and guidance on how to interpret and apply the results of HLA-B*1502 testing, the Clinical Pharmacogenetics Implementation Consortium (CPIC) guideline for HLA genotype and use of carbamazepine and oxcarbazepine should be consulted.

Dosage

Partial Seizures

Monotherapy

In adults with partial seizures who are being transferred from other anticonvulsant drug therapy to monotherapy with oxcarbazepine, the recommended initial dosage of oxcarbazepine as conventional preparations is 600 mg daily (administered as 300 mg twice daily). Dosage may be increased in increments of up to 600 mg daily at approximately weekly intervals to the maximum recommended dosage of 2.4 g daily (administered as 1.2 g twice daily), usually within 2-4 weeks. As oxcarbazepine is being initiated, dosage of the other anticonvulsant(s) should be simultaneously reduced and discontinued over 3-6 weeks. Patients should be closely observed during this transition phase.

In adults with partial seizures who are not currently receiving any anticonvulsant drug therapy, the recommended initial dosage of oxcarbazepine as conventional preparations is 600 mg daily (administered as 300 mg twice daily). Dosage should be increased in increments of 300 mg daily every third day to a dosage of 1.2 g daily (administered as 600 mg twice daily).

In children 4-16 years of age with partial seizures who are being transferred from other anticonvulsant drug therapy to monotherapy with oxcarbazepine, the recommended initial dosage of oxcarbazepine as conventional preparations is approximately 8-10 mg/kg daily (administered as 4-5 mg/kg twice daily). Dosage may be increased in increments of up to 10 mg/kg daily at approximately weekly intervals to achieve the recommended maintenance dosage based on weight (see Table 1). As oxcarbazepine is being initiated, dosage of the other anticonvulsant(s) should be simultaneously reduced and discontinued over 3-6 weeks. Patients should be closely observed during this transition phase.

Children 4-16 years of age with partial seizures who are not currently receiving any anticonvulsant drug therapy may initiate oxcarbazepine therapy as conventional preparations at a dosage of 8-10 mg/kg daily (administered as 4-5 mg/kg twice daily). Dosage should be increased in increments of 5 mg/kg daily every third day until the recommended maintenance dosage based on weight is achieved (see Table 1).

Table 1. Recommended Maintenance Dosages in Pediatric Patients Receiving Oxcarbazepine Monotherapy (as Conventional Preparations)[1 ]
Weight (kg) Dosage Range
20 600-900 mg daily
25 900 mg to 1.2 g daily
30 900 mg to 1.2 g daily
35 900 mg to 1.5 g daily
40 900 mg to 1.5 g daily
45 1.2-1.5 g daily
50 1.2-1.8 g daily
55 1.2-1.8 g daily
60 1.2-2.1 g daily
65 1.2-2.1 g daily
70 1.5-2.1 g daily

Adjunctive Therapy

For adjunctive therapy of partial seizures in adults, the initial dosage of oxcarbazepine as conventional preparations is 600 mg daily (administered as 300 mg twice daily). Subsequent dosage may be increased in increments of up to 600 mg daily at approximately weekly intervals; the maximum recommended dosage is 1.2 g daily (administered as 600 mg twice daily). Although efficacy was somewhat greater in patients receiving dosages exceeding 1.2 g daily in clinical studies, most patients were not able to tolerate a dosage of 2.4 g daily, mainly because of adverse CNS effects.

If oxcarbazepine extended-release tablets are used for adjunctive therapy of partial seizures in adults, the manufacturer recommends an initial dosage of 600 mg once daily for 1 week. In patients receiving concomitant enzyme-inducing anticonvulsants (e.g., carbamazepine, phenobarbital, phenytoin), a higher initial dosage of 900 mg once daily may be considered. Subsequent dosage may be increased in increments of 600 mg daily at weekly intervals up to the recommended dosage of 1.2-2.4 g once daily. Although efficacy was somewhat greater with a daily dosage of 2.4 g compared with 1.2 g in clinical studies, the higher dosage was associated with an increased incidence of adverse effects.

Dosage requirements for adjunctive oxcarbazepine therapy in pediatric patients may be increased compared with adults because of increased clearance of the drug.(See Pediatric Use under Warnings/Precautions: Specific Populations, in Cautions.) For adjunctive therapy of partial seizures in children 2 to less than 4 years of age, the recommended initial dosage of oxcarbazepine as conventional preparations is 8-10 mg/kg (generally not exceeding 600 mg) daily (administered as 4-5 mg/kg twice daily). For children weighing less than 20 kg, an initial dosage of 16-20 mg/kg daily (administered as 8-10 mg/kg twice daily) may be considered. Dosage should be increased over 2-4 weeks to achieve the maximum maintenance dosage. In clinical trials in children 2-4 years of age, the target dosage was 60 mg/kg daily; however, only 50% of patients reached a final dosage of at least 55 mg/kg daily.

For adjunctive therapy of partial seizures in children 4-16 years of age, the recommended initial dosage of oxcarbazepine as conventional preparations is 8-10 mg/kg (generally not exceeding 600 mg) daily (administered as 4-5 mg/kg twice daily). Dosage should be increased over 2 weeks to the recommended target maintenance dosage based on weight (900 mg daily in children weighing 20-29 kg, 1.2 g daily in children weighing 29.1-39 kg, and 1.8 g daily in children weighing more than 39 kg).

If oxcarbazepine extended-release tablets are used for adjunctive therapy of partial seizures in children 6 years of age or older, the recommended initial dosage is 8-10 mg/kg once daily (not to exceed 600 mg once daily in the first week). Dosage may be increased over 2-3 weeks in increments of 8-10 mg/kg daily at weekly intervals up to the recommended target dosage based on weight (900 mg daily in children weighing 20-29 kg, 1.2 g daily in children weighing 29.1-39 kg, and 1.8 g daily in children weighing more than 39 kg).

Dosage adjustments may be required in patients receiving concomitant therapy with enzyme-inducing drugs.(See Drug Interactions.)

Special Populations

The manufacturers make no specific dosage recommendations for patients with hepatic impairment. Use of oxcarbazepine is not recommended for patients with severe hepatic impairment.(See Hepatic Impairment under Warnings/Precautions: Specific Populations, in Cautions.)

In patients with severe renal impairment (creatinine clearance less than 30 mL/minute), the initial dosage of oxcarbazepine should be reduced to 300 mg daily (given in divided doses twice daily as conventional preparations or once daily as extended-release tablets); dosage should be increased slowly to achieve the desired clinical response.(See Renal Impairment under Warnings/Precautions: Specific Populations, in Cautions.) The manufacturer of oxcarbazepine extended-release tablets recommends that dosage be increased in increments of 300-450 mg daily at weekly intervals in patients with severe renal impairment. Use of conventional oxcarbazepine preparations (instead of the extended-release tablets) is recommended in patients with end-stage renal disease on dialysis.

The manufacturer of conventional oxcarbazepine preparations makes no specific dosage recommendations for geriatric patients. The manufacturer of oxcarbazepine extended-release tablets recommends that a lower initial dosage of 300 or 450 mg daily be considered in geriatric patients, with subsequent dosage increases made in increments of 300-450 mg daily at weekly intervals to achieve the desired response.

Cautions

Contraindications

Known hypersensitivity to oxcarbazepine or any ingredient in the formulation, or to eslicarbazepine acetate.

Warnings/Precautions

Hyponatremia

Clinically important hyponatremia (serum sodium concentrations less than 125 mEq/L) has been reported in 2.5% of patients receiving oxcarbazepine (as conventional preparations) in clinical studies, compared with 0% in patients receiving placebo or active controls (i.e., carbamazepine, phenobarbital, phenytoin, valproic acid). Generally, hyponatremia occurred during the first 3 months of oxcarbazepine therapy, although this adverse effect was reported in some patients more than 1 year after initiation of such therapy. In clinical studies, most patients with hyponatremia were asymptomatic. However, it should be considered that these patients were monitored frequently, and in some patients dosage of oxcarbazepine was reduced or discontinued or the fluid intake restricted. It is not known whether these measures prevented development of hyponatremia. Symptomatic hyponatremia and syndrome of inappropriate antidiuretic hormone secretion (SIADH) were reported in some patients during postmarketing experience with oxcarbazepine. In clinical trials in which patients developed hyponatremia, serum sodium concentrations returned to baseline values a few days after discontinuance of the drug.

The manufacturers state that monitoring serum sodium concentrations should be considered during maintenance therapy with oxcarbazepine, particularly in patients concurrently receiving other drugs known to decrease serum sodium concentrations (e.g., drugs associated with SIADH) or in those with symptoms of hyponatremia (e.g., nausea, malaise, headache, lethargy, confusion, obtundation, increase in seizure frequency or severity).

Serious Dermatologic Reactions

Serious and sometimes fatal dermatologic reactions, including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), have been reported in adults and children receiving oxcarbazepine. The incidence of SJS and TEN in patients receiving oxcarbazepine exceeds the rate in the general population by threefold to tenfold. The median time to onset of these reactions was 19 days after initiation of the drug.

If a skin reaction develops during oxcarbazepine therapy, consideration should be given to discontinuing the drug and initiating an alternative anticonvulsant agent.

Pharmacogenomics of Oxcarbazepine-induced Cutaneous Reactions

Studies have found that the risk of developing SJS and TEN with carbamazepine (a drug that is closely related to oxcarbazepine) is strongly associated with the presence of human leukocyte antigen (HLA)-B*1502, an inherited allelic variant of the HLA-B gene. The HLA-B*1502 allele is found almost exclusively in patients with ancestry across broad areas of Asia, although marked variation exists in its prevalence among specific Asian populations. The frequency of this allele ranges from 2-12% in the Han Chinese population to more than 15% in the Philippines and some Malaysian populations; lower frequencies of about 1-6% have been reported in the Korean, Indian, and Japanese populations. HLA-B*1502 is largely absent in individuals not of Asian origin (e.g., Caucasians, African-Americans, Hispanics, Native Americans). Although data are more limited, the available evidence also suggests that the HLA-B*1502 allele is a risk factor for the development of SJS and TEN in patients receiving oxcarbazepine.

The manufacturers recommend that testing for the presence of HLA-B*1502 be considered in patients with ancestry in genetically at-risk populations prior to initiating oxcarbazepine therapy.(See Pharmacogenetic Testing under Dosage and Administration: Administration.) Screening generally is not recommended in populations with low prevalence of HLA-B*1502 or in patients who are currently receiving oxcarbazepine therapy since the risk of SJS and TEN usually develops within the first 4-28 days of therapy, regardless of HLA-B*1502 status. Patients testing positive for HLA-B*1502 should not receive oxcarbazepine therapy unless the benefits clearly outweigh the risks.

Application of HLA genotyping as a screening tool has important limitations and must never substitute for appropriate clinical vigilance and patient management. The role of other possible factors, such as anticonvulsant drug dosage, compliance, concomitant medications and illnesses, in the development of, and morbidity from, these reactions and the level of dermatologic monitoring have not been adequately studied to date.

Suicidality Risk

An increased risk of suicidality (suicidal behavior or ideation) was observed in an analysis of studies using various anticonvulsants, including oxcarbazepine, compared with placebo. The analysis of suicidality reports from 199 placebo-controlled studies involving 11 anticonvulsants (i.e., carbamazepine, felbamate, gabapentin, lamotrigine, levetiracetam, oxcarbazepine, pregabalin, tiagabine, topiramate, valproate, and zonisamide) in patients with epilepsy, psychiatric disorders (e.g., bipolar disorder, depression, anxiety), and other conditions (e.g., migraine, neuropathic pain) found that patients receiving anticonvulsants had approximately twice the risk of suicidal behavior or ideation (0.43%) compared with patients receiving placebo (0.24%). This increased suicidality risk was observed as early as one week after beginning therapy and continued through 24 weeks. Although patients treated with an anticonvulsant for epilepsy, psychiatric disorders, and other conditions were all found to have an increased suicidality risk compared with those receiving placebo, the relative suicidality risk was higher for patients with epilepsy compared with those receiving anticonvulsants for other conditions.

Clinicians should inform patients, their families, and caregivers about the potential for an increase in the risk of suicidality with anticonvulsant therapy; all patients currently receiving or beginning therapy with any anticonvulsant for any indication be closely monitored for the emergence or worsening of depression, suicidal thoughts or behavior (suicidality), and/or unusual changes in mood or behavior. Clinicians who prescribe oxcarbazepine or any other anticonvulsant should balance the risk of suicidality with the risk of untreated illness. Epilepsy and many other illnesses for which anticonvulsants are prescribed are themselves associated with an increased risk of morbidity and mortality and an increased risk of suicidal thoughts and behavior. If suicidal thoughts and behavior emerge during anticonvulsant therapy, the clinician should consider whether these symptoms may be related to the illness being treated.(See Advice to Patients.)

Discontinuance of Therapy

Because of the possibility of increased seizure frequency and status epilepticus, anticonvulsant drugs, including oxcarbazepine, should be withdrawn gradually. The manufacturer of oxcarbazepine conventional preparations states that if withdrawal is necessary because of a serious adverse event, rapid discontinuance can be considered.

Cognitive and Neuropsychiatric Effects

Neuropsychiatric effects reported during oxcarbazepine treatment are classified into 3 categories: impaired cognitive or psychomotor performance including difficulties in concentrating, language, and speech; somnolence or fatigue; and coordination difficulties (e.g., ataxia, gait disturbances).Patients should be monitored for such effects during oxcarbazepine therapy.(See Advice to Patients.)

Hematologic Effects

Pancytopenia, agranulocytosis, and leukopenia have been reported rarely during postmarketing experience with oxcarbazepine. Discontinuance of therapy should be considered if such hematologic abnormalities develop.

Seizure Control During Pregnancy

Plasma concentrations of the active metabolite of oxcarbazepine may decrease during pregnancy. Patients should be monitored for possible loss of seizure control during pregnancy and throughout the postpartum period.(See Pregnancy under Warnings/Precautions: Specific Populations, in Cautions.)

Risk of Seizure Exacerbation

Seizure exacerbation or new-onset primary generalized seizures have been reported during oxcarbazepine therapy; this has been observed particularly in children. If seizure aggravation occurs, oxcarbazepine should be discontinued.

Sensitivity Reactions

Hypersensitivity

Anaphylaxis and angioedema involving the larynx, glottis, lips, and eyelids, sometimes fatal, have been reported rarely following administration of the first or subsequent doses of oxcarbazepine (as conventional preparations). If anaphylaxis or angioedema occurs during oxcarbazepine therapy, the drug should be discontinued and alternative therapy initiated. Patients who experience these hypersensitivity reactions should not be rechallenged with the drug.

Approximately 25-30% of patients with a history of carbamazepine hypersensitivity will develop hypersensitivity to oxcarbazepine. Oxcarbazepine should only be used in patients with previous hypersensitivity to carbamazepine if the potential benefits outweigh the risks. If a hypersensitivity reaction develops, oxcarbazepine should be discontinued immediately.

Multi-organ Hypersensitivity

Multi-organ hypersensitivity (also known as drug reaction with eosinophilia and systemic symptoms [DRESS]), a potentially fatal or life-threatening reaction, has been reported with oxcarbazepine. The clinical presentation is variable, but typically includes eosinophilia, fever, rash, lymphadenopathy, and/or facial swelling associated with other organ system involvement such as hepatitis, nephritis, hematologic abnormalities, myocarditis, or myositis. However, signs and symptoms associated with other organ systems also may occur.

If manifestations of multi-organ hypersensitivity occur during oxcarbazepine therapy, patients should be evaluated immediately; if an alternative cause cannot be identified, the drug should be discontinued.

Specific Populations

Pregnancy

Category C.

There are no adequate and well-controlled studies of oxcarbazepine in pregnant women; however, the drug is closely related to carbamazepine, which has been associated with teratogenic effects in humans. Limited data from pregnancy registries suggest that use of oxcarbazepine during pregnancy may be associated with congenital malformations. The drug should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Because of physiologic changes that occur during pregnancy, plasma concentrations of the active metabolite of oxcarbazepine (MHD) may gradually decrease during pregnancy; patients should be monitored during pregnancy and throughout the postpartum period.

Women who are pregnant while receiving oxcarbazepine should be encouraged to enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry at 888-233-2334 (for patients); registry information also can be found on the website http://www.aedpregnancyregistry.org.

Lactation

Both oxcarbazepine and its active MHD metabolite are distributed into milk in humans. Because of the potential for serious adverse reactions to oxcarbazepine in nursing infants, a decision should be made whether to discontinue nursing or the drug, taking into account the importance of the drug to the woman.

Pediatric Use

Safety and efficacy of oxcarbazepine conventional preparations as monotherapy of partial seizures have not been established in children younger than 4 years of age.

Safety and efficacy of oxcarbazepine conventional preparations as adjunctive therapy of partial seizures have not been established in children younger than 2 years of age.

Oxcarbazepine extended-release tablets are not recommended for use in children younger than 6 years of age because of administration difficulties and lack of studies in children younger than 4 years of age.(See Dosage and Administration: Administration.)

Clearance of the active MHD metabolite of oxcarbazepine decreases as age and weight increase. In children 2 to younger than 4 years of age, mean weight-adjusted clearance is approximately 80% higher than that of adults. In children 4-12 years of age, mean weight-adjusted clearance is approximately 40% higher than that of adults. In children 13 years of age or older, weight-adjusted MHD clearance is expected to be similar to that of adults.

Oxcarbazepine has been studied as adjunctive therapy and monotherapy for partial seizures in children 1 month to 17 years of age in controlled clinical trials.

As in adults, severe dermatologic and other sensitivity reactions have been reported in pediatric patients.

Geriatric Use

Peak plasma concentrations of MHD and the area under the plasma concentration-time curve (AUC) may be 30-60% higher in geriatric patients 60 years of age or older than in younger adults (possibly related to decreases in renal function with age).

Close monitoring of serum sodium concentrations is recommended in geriatric patients at risk for hyponatremia.

Hepatic Impairment

In patients with mild to moderate hepatic impairment, the pharmacokinetics of oxcarbazepine and its active MHD metabolite were unaffected based on studies with immediate-release oxcarbazepine.

Renal Impairment

In patients with renal impairment (creatinine clearance less than 30 mL/min), half-life of the active MHD metabolite of oxcarbazepine is increased to 19 hours and systemic exposure is increased twofold based on studies with immediate-release formulations of the drug. Dosage modification is necessary in patients with renal impairment.(See Dosage and Administration: Special Populations.)

Common Adverse Effects

Adverse effects occurring in 10% or more of patients receiving conventional oxcarbazepine include dizziness, somnolence, diplopia, fatigue, nausea, vomiting, ataxia, abnormal vision, abdominal pain, nystagmus, tremor, dyspepsia, and abnormal gait.

Adverse effects occurring in 5% or more of patients receiving oxcarbazepine extended-release tablets include dizziness, somnolence, headache, balance disorder, tremor, vomiting, diplopia, asthenia, and fatigue.

Drug Interactions

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

In vitro studies indicate that oxcarbazepine and its active MHD metabolite can inhibit cytochrome P-450 (CYP) isoenzyme 2C19 and can therefore potentially increase plasma concentrations of drugs metabolized by this isoenzyme. Oxcarbazepine and MHD do not appear to inhibit other CYP isoenzymes, including CYP3A4/5, 1A2, 2A6, 2C9, 2D6, 2E1, 4A9, and 4A11, at clinically relevant concentrations.

In vitro studies indicate that oxcarbazepine can induce CYP3A4/5 and can therefore potentially reduce plasma concentrations of drugs metabolized by this isoenzyme (e.g., dihydropyridine calcium-channel blocking agents, oral contraceptives, cyclosporine).

Potent inducers of CYP3A4 (e.g., carbamazepine, phenytoin, phenobarbital, rifampin) may decrease plasma concentrations of MHD. If oxcarbazepine is used concomitantly with a potent CYP3A4 inducer, the manufacturer recommends that plasma MHD concentrations be monitored during titration of oxcarbazepine therapy; dosage adjustment of oxcarbazepine may be required when initiating, discontinuing, or modifying dosage of potent CYP3A4 inducers.

Drugs Affecting or Metabolized by Uridine Diphosphate Glucuronosyltransferase

In vitro studies indicate that MHD exhibits only weak induction of uridine diphosphate glucuronosyltransferase (UGT) and is therefore not likely to interact with drugs that are metabolized by UGT (e.g., valproic acid, lamotrigine).

Potent inducers of UGT may decrease plasma concentrations of MHD. If oxcarbazepine is used concomitantly with a potent UGT inducer, the manufacturer recommends that plasma MHD concentrations be monitored during titration of oxcarbazepine therapy; dosage adjustment of oxcarbazepine may be required when initiating, discontinuing, or modifying dosage of potent UGT inducers.

Drugs Associated with Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis

Because of the risk of Stevens-Johnson syndrome and toxic epidermal necrolysis in HLA-B*1502-positive patients receiving oxcarbazepine, avoidance of other drugs associated with these serious dermatologic reactions should be considered in such patients when alternative therapies are available.

Alcohol

Additive sedative effects may occur with concomitant use of alcohol and oxcarbazepine. Caution is advised.

Anticonvulsants

CYP-inducing anticonvulsants (e.g., carbamazepine, phenytoin, phenobarbital) may decrease plasma concentrations of MHD. In clinical studies, MHD concentrations were decreased by approximately 40, 25, or 30% with concomitant administration of carbamazepine, phenobarbital, or phenytoin, respectively. Dosage adjustments may be necessary. Oxcarbazepine dosages exceeding 1.2 g daily have been shown to increase plasma phenytoin concentrations by up to 40%; dosage reduction of phenytoin may be necessary.

With regard to other anticonvulsants evaluated, lamotrigine did not affect plasma MHD concentrations and valproic acid reduced plasma MHD concentrations by only 18%.

Calcium-channel Blocking Agents

Concomitant administration of oxcarbazepine and felodipine resulted in a 28% decrease in systemic exposure of felodipine.

Concomitant administration of oxcarbazepine and verapamil resulted in a 20% decrease in plasma concentrations of MHD.

Cimetidine

When cimetidine and oxcarbazepine were administered concomitantly, no effect on the pharmacokinetics of MHD was observed.

Erythromycin

When erythromycin and oxcarbazepine were administered concomitantly, no effect on the pharmacokinetics of MHD was observed.

Oral Contraceptives

Oxcarbazepine may reduce the efficacy of hormonal contraceptives. When oxcarbazepine was administered concomitantly with an oral contraceptive, systemic exposures of the estrogen and progestin components were decreased by 48-52 and 32-52%, respectively. Women of childbearing potential should use additional nonhormonal methods of contraception during oxcarbazepine therapy.

Protein-bound Drugs

Clinically important interactions are not likely to occur when oxcarbazepine is administered concomitantly with protein-bound drugs.

Warfarin

An interaction between oxcarbazepine and warfarin is not likely.

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