Levetiracetam Extended-release

LEVETIRACETAM EXTENDED-RELEASE- levetiracetam tablet, film coated, extended release
Par Pharmaceutical, Inc.

1 INDICATIONS AND USAGE

Extended-release levetiracetam tablets are indicated as adjunctive therapy in the treatment of partial onset seizures in patients 12 years of age and older with epilepsy.

2 DOSAGE AND ADMINISTRATION

2.1 Recommended Dosing

Extended-release levetiracetam tablets are administered once daily.

Initiate treatment with a dose of 1,000 mg once daily. The once daily dosage may be adjusted in increments of 1,000 mg every 2 weeks to a maximum recommended daily dose of 3,000 mg/day.

2.2 Dosage Adjustments in Adult Patients with Renal Impairment

Extended-release levetiracetam tablets dosing must be individualized according to the patient’s renal function status. Recommended dosage adjustments for adults are shown in Table 1. In order to calculate the dose recommended for patients with renal impairment, creatinine clearance adjusted for body surface area must be calculated. To do this, an estimate of the patient’s creatinine clearance (CLcr) in mL/min must first be calculated using the following formula:

[140-age (years)] x weight (kg) (x0.85 for female patients)

CLcr= —————————————————————————

72 x serum creatinine (mg/dL)

Then CLcr is adjusted for body surface area (BSA) as follows:

CLcr (mL/min)

CLcr (mL/min/1.73m²)= —————————- x 1.73

BSA subject (m²)

Table 1: Dosage Adjustment Regimen for Adult Patients with Renal Impairment
Group	Creatinine Clearance (mL/min/1.73m2)	Dosage (mg)	Frequency
Normal	> 80	1000 to 3000	Every 24 hours
Mild	50 to 80	1000 to 2000	Every 24 hours
Moderate	30 to 50	500 to 1500	Every 24 hours
Severe	< 30	500 to 1000	Every 24 hours

3 DOSAGE FORMS AND STRENGTHS

Levetiracetam extended-release tablets, 500 mg, are white to off-white, oval shaped, film coated tablets with A195 engraved on one side and plain on the other side.

Levetiracetam extended-release tablets, 750 mg, are pale yellow, film coated tablets with A214 engraved on one side and plain on the other side

4 CONTRAINDICATIONS

Extended-release levetiracetam tablets are contraindicated in patients with a hypersensitivity to levetiracetam. Reactions have included anaphylaxis and angioedema [see Warnings and Precautions (5.4)].

5 WARNINGS AND PRECAUTIONS

5.1 Behavioral Abnormalities and Psychotic Symptoms

Extended-release levetiracetam tablets may cause behavioral abnormalities and psychotic symptoms. Patients treated with extended-release levetiracetam tablets should be monitored for psychiatric signs and symptoms.

Behavioral abnormalities

Extended-Release Levetiracetam Tablets

A total of 7% of extended-release levetiracetam tablet-treated patients experienced non-psychotic behavioral disorders (reported as irritability and aggression) compared to 0% of placebo-treated patients. Irritability was reported in 7% of extended-release levetiracetam tablets-treated patients. Aggression was reported in 1% of extended-release levetiracetam tablet-treated patients.

No patient discontinued treatment or had a dose reduction as a result of these adverse reactions.

The number of patients exposed to extended-release levetiracetam tablets was considerably smaller than the number of patients exposed to immediate-release levetiracetam tablets in controlled trials. Therefore, certain adverse reactions observed in the immediate-release levetiracetam tablets controlled trials will likely occur in patients receiving extended-release levetiracetam tablets.

Immediate-Release Levetiracetam Tablets

A total of 13% of adult patients and 38% of pediatric patients (4 to 16 years of age) treated with immediate-release levetiracetam experienced non-psychotic behavioral symptoms (reported as aggression, agitation, anger, anxiety, apathy, depersonalization, depression, emotional lability, hostility, hyperkinesias, irritability, nervousness, neurosis, and personality disorder), compared to 6% and 19% of adult and pediatric patients on placebo. A randomized, double-blind, placebo-controlled study was performed to assess the neurocognitive and behavioral effects of immediate-release levetiracetam tablets as adjunctive therapy in pediatric patients (4 to 16 years of age). An exploratory analysis suggested a worsening in aggressive behavior in patients treated with immediate-release levetiracetam tablets in that study [see Use in Specific Populations (8.4)].

A total of 1.7% of adult patients treated with immediate-release levetiracetam discontinued treatment due to behavioral adverse reactions, compared to 0.2% of placebo-treated patients. The treatment dose was reduced in 0.8% of adult patients treated with immediate-release levetiracetam compared to 0.5% of placebo-treated patients. Overall, 11% of pediatric patients treated with immediate-release levetiracetam tablets experienced behavioral symptoms associated with discontinuation or dose reduction, compared to 6.2% of placebo-treated pediatric patients.

One percent of adult patients and 2% of pediatric patients (4 to 16 years of age) treated with immediate-release levetiracetam tablets experienced psychotic symptoms, compared to 0.2% and 2%, respectively, in adult and placebo-treated pediatric patients. In the controlled study that assessed the neurocognitive and behavioral effects of immediate-release levetiracetam tablets in pediatric patients 4 to 16 years of age, 1.6% immediate-release levetiracetam tablet-treated patients experienced paranoia, compared to no placebo-treated patients. There were 3.1% patients treated with immediate-release levetiracetam who experienced confusional state, compared to no placebo-treated patients [see Use in Specific Populations (8.4)].

Psychotic symptoms

Immediate-Release Levetiracetam tablets

One percent of immediate-release levetiracetam tablet-treated adult patients experienced psychotic symptoms compared to 0.2% of placebo-treated patients.

Two (0.3%) immediate-release levetiracetam tablet-treated adult patients were hospitalized and their treatment was discontinued due to psychosis. Both events, reported as psychosis, developed within the first week of treatment and resolved within 1 to 2 weeks following treatment discontinuation. There was no difference between drug and placebo-treated patients in the incidence of pediatric patients who discontinued treatment due to psychotic and non-psychotic adverse reactions.