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Manufacturer
GLENMARK PHARMA
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68462013901

oxcarbazepine 600 mg tablet (generic trileptal)

Generic
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Uses

Seizure Disorders

Partial Seizures

Oxcarbazepine is used as monotherapy or in combination with other anticonvulsants in the management of partial seizures in adults and children 4 years of age and older.

Monotherapy

Efficacy of oxcarbazepine monotherapy in patients with partial seizures has been established in several multicenter, randomized, double-blind clinical trials. These studies have included adults and children 8 years of age or older. In one placebo-controlled, randomized clinical trial in patients with refractory partial seizures (undergoing evaluation for epilepsy surgery) who had been withdrawn from anticonvulsants prior to randomization, oxcarbazepine at dosages up to 2400 mg daily for 10 days was more effective than placebo. Results of another placebo-controlled clinical trial in patients with newly diagnosed or recent-onset partial seizures indicate that oxcarbazepine dosages up to 1200 mg daily for 84 days were more effective than placebo. In addition, therapy with oxcarbazepine 2400 mg daily for up to 126 days was substantially more effective than oxcarbazepine 300 mg daily in 2 other clinical trials in patients with partial seizures who had been withdrawn from therapy with 1 or 2 anticonvulsants because of inadequate control.

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 valproate sodium.

Combination Therapy

Efficacy of oxcarbazepine as adjunctive therapy in patients with partial seizures was established in 2 multicenter, placebo-controlled, randomized, double-blind clinical trials in patients with partial seizures (one in adults and one in children 3-17 years of age). In both studies, patients initially were stabilized with 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 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). Adult patients receiving oxcarbazepine 600, 1200, or 2400 mg daily or placebo experienced a median decrease in seizure frequency of about 26, 40, 50, or 8%, respectively, while pediatric patients receiving oxcarbazepine maintenance 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.

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. However, the American Psychiatric Association (APA) currently recommends that oxcarbazepine be reserved for patients unable to tolerate or who had an inadequate therapeutic response to first-line agents such as lithium and valproate (e.g., valproic acid, divalproex). For further information on the management of bipolar disorder,

Dosage and Administration

General

Oxcarbazepine tablets and suspension are administered orally twice daily without regard to meals.

Oxcarbazepine suspension should be shaken well prior to administration of each dose. The appropriate measured dose of the suspension should be administered using an oral dosing syringe. 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 manufacturer of Trileptal states that oral bioavailability of oxcarbazepine tablets appears to be similar to that of the suspension and, therefore, these preparations can be used interchangeably on a mg-for-mg basis.

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 Warnings/Precautions: Warnings, in Cautions.)

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

Partial Seizures

Monotherapy

In adults and children older than 16 years of age with partial seizures being transferred from other anticonvulsant drug therapy to monotherapy with oxcarbazepine, the recommended initial dosage of oxcarbazepine is 600 mg daily given in 2 equally divided doses. Oxcarbazepine dosage may be increased by 600-mg daily increments at approximately weekly intervals to a recommended daily dosage of 2400 mg, usually within 2-4 weeks. As oxcarbazepine replaces the existing anticonvulsant therapeutic regimen, dosage of the other anticonvulsant(s) is simultaneously reduced and discontinued over 3-6 weeks. Patients should be observed during this transition phase.

In adults not receiving anticonvulsant drug therapy, the recommended initial daily dosage of oxcarbazepine as initial monotherapy is 600 mg daily administered in 2 equally divided doses. Dosage should be increased by 300-mg daily increments every third day to a maximum daily dosage of 1200 mg.

In children 4-16 years of age with partial seizures being transferred from other anticonvulsant drug therapy to monotherapy with oxcarbazepine, the recommended initial dosage of oxcarbazepine is 8-10 mg/kg daily given in 2 equally divided doses. Oxcarbazepine dosage may be increased in increments of up to 10 mg/kg daily at weekly intervals to achieve the recommended maintenance dosage.(See Table 1.) As oxcarbazepine replaces the existing anticonvulsant therapeutic regimen, dosage of the other anticonvulsant(s) is simultaneously reduced and discontinued over 3-6 weeks.

Children 4-16 years of age not receiving anticonvulsant drug therapy may initiate therapy with oxcarbazepine at a dosage of 8-10 mg/kg daily given in 2 equally divided doses. Dosage may be increased in increments of 5 mg/kg daily every third day until the recommended maintenance dosage is achieved.(See Table 1.)

Table 1. Recommended Range of Maintenance Dosages in Children Receiving Oxcarbazepine Monotherapy[1 ]
Weight (kg) Dosage Range (mg/day)
20 600-900
25 900-1200
30 900-1200
35 900-1500
40 900-1500
45 1200-1500
50 1200-1800
55 1200-1800
60 1200-2100
65 1200-2100
70 1500-2100

Combination Therapy

For adjunctive therapy in the management of partial seizures in adults and children older than 16 years of age, the initial dosage of oxcarbazepine is 600 mg daily administered in 2 equally divided doses. Oxcarbazepine dosage may be increased by 600-mg daily increments at approximately weekly intervals to a recommended daily dosage of 1200 mg. Although efficacy may be somewhat higher in patients receiving oxcarbazepine dosages exceeding 1200 mg daily, most patients cannot tolerate daily dosages of 2400 mg, mainly because of adverse CNS effects. The manufacturers recommend that patients be observed closely and that plasma concentrations of concomitantly administered anticonvulsants be monitored during dosage titration of oxcarbazepine since plasma concentrations of these drugs may be altered when dosage of oxcarbazepine exceeds 1200 mg daily.

For adjunctive therapy in the management of partial seizures in children 4-16 years of age, the recommended initial dosage of oxcarbazepine (administered in 2 equally divided doses) is 8-10 mg/kg daily, generally not exceeding 600 mg daily. The target daily maintenance dosage of 900-1800 mg depends on patient weight (900, 1200, or 1800 mg in children weighing 20-29, 29.1-39, or more than 39 kg, respectively) and should be reached within 2 weeks. Since clearance of the drug appears to be increased (by 30-40%) in children younger than 8 years of age compared with that in adults, such children received the highest maintenance dosage in controlled clinical trials.

Special Populations

The manufacturers state that the initial dosage of oxcarbazepine should be 300 mg daily (one-half of the usual starting dosage) in patients with renal impairment (creatinine clearance less than 30 mL/minute); dosage should be increased slowly to achieve the desired clinical response.

In general, no dosage adjustments are necessary in patients with mild to moderate hepatic impairment.

Cautions

Contraindications

Known hypersensitivity to oxcarbazepine or any ingredient in the formulation.

Warnings/Precautions

Warnings

Hyponatremia

Clinically important hyponatremia (serum sodium concentrations less than 125 mEq/L) has been reported in 2.5% of patients receiving oxcarbazepine in clinical studies, versus 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 was reported in some patients during postmarketing surveillance. In clinical trials in patients developing 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 inappropriate antidiuretic hormone secretion [SIADH]) or in those with symptoms of hyponatremia (e.g., nausea, malaise, headache, lethargy, confusion, obtundation, increase in seizure frequency or severity).

Suicidality Risk

The US Food and Drug Administration (FDA) has alerted healthcare professionals about an increased risk of suicidality (suicidal behavior or ideation) observed in an analysis of studies using various anticonvulsants, including oxcarbazepine, compared with placebo. The analysis of suicidality reports from placebo-controlled studies involving 11 anticonvulsants (i.e., carbamazepine, felbamate, gabapentin, lamotrigine, levetiracetam, oxcarbazepine, pregabalin, tiagabine, topiramate, valproate, 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.

Based on the current analysis of the available data, FDA recommends that clinicians inform patients, their families, and caregivers about the potential for an increase in the risk of suicidality with anticonvulsant therapy and that 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. Symptoms such as anxiety, agitation, hostility, insomnia, and mania may be precursors to emerging suicidality. 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, anticonvulsant drugs, including oxcarbazepine, should be withdrawn gradually.

Sensitivity Reactions

History of Carbamazepine Hypersensitivity

Approximately 25-30% of patients with a history of carbamazepine hypersensitivity will develop hypersensitivity to oxcarbazepine. Therefore, oxcarbazepine should only be used in patients with a history of such hypersensitivity if the potential benefits justify the potential risk to the patient. If a hypersensitivity reaction develops, oxcarbazepine should be discontinued immediately.

Dermatologic and Hypersensitivity Reactions

Serious dermatologic reactions, including Stevens-Johnson syndrome and toxic epidermal necrolysis, have been reported in adults and children receiving oxcarbazepine; reactions have been life-threatening, have required hospitalization, and rarely have been fatal. The incidence of Stevens-Johnson syndrome and toxic epidermal necrolysis reported 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. Recurrence of serious dermatologic reactions following rechallenge with oxcarbazepine has occurred. If a skin reaction develops in a patient receiving oxcarbazepine, discontinuance of the drug should be considered and another anticonvulsant agent initiated.

Multiorgan hypersensitivity reactions occurring days to weeks or months (range 4-60 days) after initiation of oxcarbazepine therapy have been reported in adults and pediatric patients. Although these reactions have been reported rarely, many of these patients required hospitalization, and some reactions were considered life-threatening. Manifestations may include (but are not limited to) fever, rash, lymphadenopathy, hepatitis, abnormal liver function test results, eosinophilia, thrombocytopenia, neutropenia, pruritus, nephritis, oliguria, hepatorenal syndrome, arthralgia, and asthenia. If a multiorgan hypersensitivity reaction is suspected, oxcarbazepine should be discontinued and an alternative therapy initiated. There is a possibility of cross-sensitivity with other drugs that produce multiorgan hypersensitivity reactions.

General Precautions

Nervous System 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).(See Suicidality Risk under Warnings/Precautions: Warnings, in Cautions.)

Specific Populations

Pregnancy

Category C.

North American Antiepileptic Drug (NAAED) Pregnancy Registry at 888-233-2334 (for patients); registry information also available on the website http://www.aedpregnancyregistry.org.

The effect of oxcarbazepine on labor and delivery is unknown.

Lactation

Both oxcarbazepine and its active 10-monohydroxy metabolite (MHD) are distributed into milk in humans. 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 as monotherapy or adjunctive therapy for partial seizures in children younger than 4 years of age have not been established.

Efficacy of oxcarbazepine as adjunctive therapy for partial seizures in children 4-16 years of age has been established in clinical studies. Efficacy as monotherapy for partial seizures in children 4-16 years of age is based on clinical studies and pharmacokinetic and pharmacodynamic considerations.

Oxcarbazepine has not been evaluated in clinical studies in children younger than 2 years of age.

Severe dermatologic and other sensitivity reactions have been reported in pediatric patients.(See Dermatologic and Hypersensitivity Reactions under Warnings/Precautions: Sensitivity Reactions, in Cautions.)

Geriatric Use

Although peak plasma concentrations of MHD and the area under the plasma concentration-time curve (AUC) may be 30-60% higher in adults 60 years of age or older than in younger adults (possibly related to decreases in renal function with age), the manufacturers do not make specific recommendations for dosage adjustment in such patients.

Common Adverse Effects

Adverse effects occurring in 5% or more of patients and more frequently than placebo include dizziness, somnolence, diplopia, fatigue, nausea, vomiting, ataxia, abnormal vision, abdominal pain, tremor, dyspepsia, and abnormal gait.

Drug Interactions

Drugs Affecting Hepatic Microsomal Enzymes

Anticonvulsants

Oxcarbazepine may inhibit metabolism of other anticonvulsants (e.g., phenobarbital, phenytoin), possibly via inhibition of the cytochrome P-450 (CYP) isoenzyme 2C19, resulting in increased plasma concentrations of these drugs. Oxcarbazepine dosages exceeding 1200 mg daily may increase plasma phenytoin concentrations by 40% and, therefore, when such dosages of oxcarbazepine are used concomitantly with phenytoin, dosage reduction of phenytoin may be required.

Potent inducers of CYP isoenzymes (e.g., carbamazepine, phenytoin, phenobarbital) may decrease plasma concentrations of oxcarbazepine and its active 10-monohydroxy metabolite (MHD).

Oral Contraceptives

Oxcarbazepine may induce metabolism of oral estrogen-progestin contraceptives, possibly via induction of CYP3A4 and CYP3A5, resulting in decreased area under the plasma concentration-time curve (AUC) and consequent decreased efficacy of the contraceptives.

Calcium-channel Blocking Agents

Oxcarbazepine may induce metabolism of some calcium-channel blocking agents (e.g., felodipine, verapamil), possibly via induction of CYP3A4 and CYP3A5 isoenzymes, resulting in decreased AUC of the calcium-channel blocking agents.

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