Usual Adult Dose for Epilepsy

Monotherapy:

• Initial dose: 1200 mg orally daily in 3 to 4 divided doses
• Maintenance dose: Titrate previously untreated patients by increasing the dose in 600 mg increments every 2 weeks to 2400 mg orally daily in 3 to 4 divided doses based on clinical response and thereafter to 3600 mg orally daily in 3 to 4 divided doses if clinically indicated
• Maximum dose: 3600 mg orally daily in 3 to 4 divided doses

Conversion to monotherapy:

• Initial dose: 1200 mg orally daily in 3 to 4 divided doses; reduce the dose of concomitant antiepileptic drugs (AEDs) by 33% at the initiation of this drug
• Maintenance dose: At week 2, increase the dose to 2400 mg orally daily in 3 to 4 divided doses and reduce the dosage of other AEDs up to an additional 33% of the original dose; at week 3, increase the dose to 3600 mg orally daily in 3 to 4 divided doses and continue to reduce the dose of other AEDs as clinically indicated
• Maximum dose: 3600 mg orally daily in 3 to 4 divided doses

Adjunctive therapy:

• Initial dose: 1200 mg orally daily in 3 to 4 divided doses; reduce the dose of other AEDs by 20%; further dose reductions of concomitant AEDs may be necessary to minimize side effects
• Maintenance dose: Increase dose by 1200 mg increments at weekly intervals to 3600 mg orally daily in 3 to 4 divided doses
• Maximum dose: 3600 mg orally daily in 3 to 4 divided doses

Comments:

• In some patients, titration to a 3600 mg/day dose has been achieved in as little as 3 days with appropriate adjustment of other AEDs.

Use: For use as monotherapy or adjunctive therapy in children 14 years of age and older and adults in the treatment of partial seizures, with and without generalization (only in those patients who respond inadequately to alternative treatments and whose epilepsy is so severe that a substantial risk of aplastic anemia and/or liver failure is deemed acceptable in light of the benefits conferred by its use)

Usual Pediatric Dose for Lennox-Gastaut Syndrome

Children 2 to 14 years with Lennox-Gastaut Syndrome:
Adjunctive therapy:

• Initial dose: 15 mg/kg/day orally in 3 to 4 divided doses; reduce the dose of concomitant AEDs by 20%; further dose reductions of concomitant AEDs may be necessary to minimize side effects
• Maintenance dose: Increase the dose by 15 mg/kg/day increments at weekly intervals as tolerated to desired clinical response
• Maximum dose: 45 mg/kg/day orally in 3 to 4 divided doses

Children 14 years of age and older:
Use adult dosing.

Use: For use as adjunctive therapy in the treatment of partial seizures and generalized seizures associated with Lennox-Gastaut syndrome in children (only in those patients who respond inadequately to alternative treatments and whose epilepsy is so severe that a substantial risk of aplastic anemia and/or liver failure is deemed acceptable in light of the benefits conferred by its use)

Renal Dose Adjustments

Use with caution.

Liver Dose Adjustments

Contraindicated

Precautions

US BOXED WARNINGS:
APLASTIC ANEMIA:

• This drug is associated with a marked increase in the incidence of aplastic anemia; therefore, use only in patients with epilepsy so severe that the risk is acceptable because of the benefit of its use.
• Obtain an expert hematologic consultation before therapy is initiated.
• Aplastic anemia (pancytopenia in the presence of a bone marrow largely depleted of hematopoietic precursors) occurs at more than a 100-fold greater incidence in patients taking this drug is than in untreated patients (i.e., 2 to 5 per million persons per year).
• The risk of death in patients with aplastic anemia generally varies as a function of its severity and etiology; current estimates of the overall fatality rate are in the range of 20% to 30%, but rates as high as 70% have been reported in the past.
• There are too few cases, and too little known about them to provide a reliable estimate of the syndrome's incidence or its case fatality rate or to identify the factors, if any, that might conceivably be used to predict who is at greater or lesser risk.
• Aplastic anemia may not be seen until after a patient has been on this drug for several months (e.g., 5 to 30 weeks); however, the injury to bone marrow stem cells may occur weeks to months earlier. Patients who discontinue therapy remain at risk for developing anemia for an unknown period afterwards.
• It is not safe to assume that a patient who has been on this drug without signs of hematologic abnormality for long periods of time is without risk of developing aplastic anemia.
• It is not known whether or not the dose affects the incidence of aplastic anemia.
• It is not known whether or not concomitant use of AEDs and/or other drugs affects the incidence of aplastic anemia.
• Aplastic anemia typically develops without warning, the full blown syndrome presenting with signs of infection, bleeding, or anemia.
• Routine blood testing cannot reliably be used to reduce the incidence of aplastic anemia; however, in some cases, it allows the detection of the hematologic changes before the syndrome presents clinically.
• Therapy should be discontinued if any evidence of bone marrow depression occurs.

HEPATIC FAILURE

• This drug is associated with acute liver failure. The reported incidence is about 6 cases leading to death or transplant per 75,000 patient years of use; this rate is an underestimate because of under reporting, and the true rate could be considerably greater than this (e.g., if the reporting rate is 10%, the true rate would be one case per 1250 patient years of use).
• About 67% of cases resulted in death or liver transplantation, usually within 5 weeks of the onset of liver failure.
• The earliest onset of severe hepatic dysfunction followed by liver failure was 3 weeks after initiation of therapy; however, some reports described dark urine and nonspecific warning symptoms (e.g., anorexia, malaise, GI symptoms). In other reports it was not clear if any warning symptoms preceded the onset of jaundice.
• It is not known if the risk of developing hepatic failure changes with duration of exposure.
• It is not known if the dosage of this drug affects the incidence of hepatic failure.
• It is not known if concomitant use of other AEDs and/or other drugs affect the incidence of hepatic failure.
• Do not prescribe this drug to anyone with a history of hepatic dysfunction.
• Initiate therapy only in patients without active liver disease and with normal baseline serum transaminases.
• It is unknown if periodic serum transaminase testing will prevent serious injury but early detection of drug-induced hepatic injury along with immediate withdrawal of therapy enhances the likelihood for recovery.
• It is unknown how rapidly patients can progress from normal liver function to liver failure, but other drugs known to be hepatotoxins can cause liver failure rapidly (e.g., from normal enzymes to liver failure in 2 to 4 weeks).
• Monitor serum transaminase levels (AST and ALT) at baseline and periodically thereafter; the schedule for monitoring is a matter of clinical judgement.
• Discontinue therapy if serum AST or ALT levels increase 2 times the upper limit of normal (ULN) or more, or if signs of liver failure are apparent.
• Patients who develop hepatocellular injury while on this drug and are withdrawn from therapy for any reason should be presumed to be at increased risk for liver injury if therapy is reintroduced; therefore, such patients should not be considered for retreatment.

• Safety and efficacy have not been established in patients younger than 2 years for any indication.
• Safety and efficacy in patients younger than 14 years (other than those with Lennox-Gastaut syndrome) has not been established.

Consult WARNINGS section for additional precautions.

Dialysis

Data not available

Other Comments

Patient advice:

• Patients should be informed that this drug is associated with aplastic anemia and hepatic failure (potentially fatal conditions) either acutely or over the long term.
• Patients should be instructed to read the Medication Guide each time this drug is dispensed.
• Patients, their caregivers, and families should be counseled that AEDs may increase the risk of suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or worsening of symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts about self-harm. Behaviors of concern should be reported immediately to healthcare providers.