Levetiracetam

LEVETIRACETAM — levetiracetam tablet, film coated, extended release
Sun Pharmaceutical Industries, Inc.

1 INDICATIONS AND USAGE

Levetiracetam extended-release tablets are indicated for the treatment of partial-onset seizures in patients 12 years of age and older.

2 DOSAGE AND ADMINISTRATION

2.1 Recommended Dosing

For adults and adolescent patients, the recommended dosing for monotherapy and adjunctive therapy is the same; as outlined below.
Adults and Adolescents 12 Years of Age and Older Weighing 50 kg or More

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 once daily.Administration

Levetiracetam extended-release tablets are administered once daily. Levetiracetam extended-release tablets should be swallowed whole. The tablets should not be chewed, broken, or crushed.

2.2 Dosage Adjustments in Adult Patients with Renal Impairment

Levetiracetam extended-release 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:

levetiracetam-formula1
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Then CLcr is adjusted for body surface area (BSA) as follows:

levetiracetam-formula2
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Table 1: Dosage Adjustment Regimen for Adult Patients with Renal Impairment
Group Creatinine Clearance (mL/min/1.73m2)Dosage (mg)Frequency
Normal > 801,000 to 3,000Every 24 hours
Mild 50 to 801,000 to 2,000Every 24 hours
Moderate 30 to 50500 to 1,500Every 24 hours
Severe < 30500 to 1,000Every 24 hours

levetiracetam-formula1levetiracetam-formula2

2.3 Discontinuation of Levetiracetam Extended-Release Tablets

Avoid abrupt withdrawal from levetiracetam extended-release tablets in order to reduce the risk of increased seizure frequency and status epilepticus [see Warnings and Precautions (5.7)].

3 DOSAGE FORMS AND STRENGTHS

Levetiracetam extended-release tablets, 500 mg are oval, blue and white to off-white colored, biconvex, bilayer, film-coated, extended-release tablets having laser drill on blue layer and imprinted with “573” with black ink on one side and plain on other side. Levetiracetam extended-release tablets, 750 mg are oval, blue and white to off-white colored, biconvex, bilayer, film-coated, extended-release tablets having laser drill on blue layer and imprinted with “576” with black ink on one side and plain on other side.

4 CONTRAINDICATIONS

Levetiracetam extended-release 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

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

Behavioral abnormalities
Levetiracetam Extended-Release Tablets
A total of 7% of levetiracetam extended-release tablets-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 levetiracetam extended-release tablets-treated patients. Aggression was reported in 1% of levetiracetam extended-release tablets-treated patients.
No patient discontinued treatment or had a dose reduction as a result of these adverse reactions.
The number of patients exposed to levetiracetam extended-release 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 levetiracetam extended-release 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 tablets 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 tablets 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 tablets, 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% levetiracetam tablets-treated patients experienced paranoia, compared to no placebo-treated patients. There were 3.1% patients treated with immediate-release levetiracetam tablets 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 levetiracetam tablets-treated adult patients experienced psychotic symptoms compared to 0.2% of placebo-treated patients.
Two (0.3%) levetiracetam tablets-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.

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