Levetiracetam Extended-release

LEVETIRACETAM EXTENDED-RELEASE- levetiracetam tablet, film coated, extended release
Trupharma, LLC

1 INDICATIONS AND USAGE

Levetiracetam extended-release tablets is indicated as adjunctive therapy in the treatment of partial onset seizures in patients >16 years of age with epilepsy.

2 DOSAGE AND ADMINISTRATION

Treatment should be initiated with a dose of 1000 mg once daily. The daily dosage may be adjusted in increments of 1000 mg every 2 weeks to a maximum recommended daily dose of 3000 mg.

2.1 Adult Patients With Impaired Renal Function

Levetiracetam extended-release tablet dosing must be individualized according to the patients renal function status. Recommended doses and adjustment for dose for adults are shown in Table 1. To use this dosing table, an estimate of the patients creatinine clearance (CLcr) in mL/min is needed. CLcr in mL/min may be estimated from serum creatinine (mg/dL) determination using the following formula:

calculation
(click image for full-size original)
Table 1: Dosing Adjustment Regimen For Adult Patients With Impaired Renal Function
GroupCreatinine Clearance (mL/min/1.73m 2) Dosage (mg) Frequency
Normal> 801000 to 3000 Every 24 h
Mild50 to 801000 to 2000 Every 24 h
Moderate30 to 50500 to 1500Every 24 h
Severe< 30500 to 1000Every 24 h

3 DOSAGE FORMS AND STRENGTHS

Levetiracetam 500 mg extended-release tablets are white, oblong-shaped, film-coated imprinted in green with “P46” on one side.

Levetiracetam 750 mg extended-release tablets are white, oblong-shaped, film-coated imprinted in green with “P47” on one side.

4 CONTRAINDICATIONS

None

5 WARNINGS AND PRECAUTIONS

5.1 Suicidal Behavior and Ideation

Antiepileptic drugs (AEDs), including levetiracetam extended-release tablets, increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication. Patients treated with any AED for any indication should be monitored for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior.

Pooled analyses of 199 placebo-controlled clinical trials (mono- and adjunctive therapy) of 11 different AEDs showed that patients randomized to one of the AEDs had approximately twice the risk (adjusted Relative Risk 1.8, 95% CI:1.2, 2.7) of suicidal thinking or behavior compared to patients randomized to placebo. In these trials, which had a median treatment duration of 12 weeks, the estimated incidence rate of suicidal behavior or ideation among 27,863 AED-treated patients was 0.43%, compared to 0.24% among 16,029 placebo-treated patients, representing an increase of approximately one case of suicidal thinking or behavior for every 530 patients treated. There were four suicides in drug-treated patients in the trials and none in placebo-treated patients, but the number is too small to allow any conclusion about drug effect on suicide.

The increased risk of suicidal thoughts or behavior with AEDs was observed as early as one week after starting drug treatment with AEDs and persisted for the duration of treatment assessed. Because most trials included in the analysis did not extend beyond 24 weeks, the risk of suicidal thoughts or behavior beyond 24 weeks could not be assessed.

The risk of suicidal thoughts or behavior was generally consistent among drugs in the data analyzed. The finding of increased risk with AEDs of varying mechanisms of action and across a range of indications suggests that the risk applies to all AEDs used for any indication. The risk did not vary substantially by age (5-100 years) in the clinical trials analyzed. Table 2 shows absolute and relative risk by indication for all evaluated AEDs.

Table 2: Risk by indication for antiepileptic drugs in the pooled analysis
Indication Placebo patients with Events Per 1000 Patients Drug patients with Events Per 1000 Patients Relative Risk: Incidence of Events in Drug Patients/Incidence in Placebo Patients Risk difference: Additional Drug Patients with Events Per 1000 patients
Epilepsy 1.0 3.4 3.5 2.4
Psychiatric 5.7 8.5 1.5 2.9
Other 1.0 1.8 1.9 0.9
Total 2.4 4.3 1.8 1.9

The relative risk for suicidal thoughts or behavior was higher in clinical trials for epilepsy than in clinical trials for psychiatric or other conditions, but the absolute risk differences were similar for the epilepsy and psychiatric indications.

Anyone considering prescribing levetiracetam extended-release tablets or any other AED must balance the risk of suicidal thoughts or behavior with the risk of untreated illness. Epilepsy and many other illnesses for which AEDs are prescribed are themselves associated with morbidity and mortality and an increased risk of suicidal thoughts and behavior. Should suicidal thoughts and behavior emerge during treatment, the prescriber needs to consider whether the emergence of these symptoms in any given patient may be related to the illness being treated.

Patients, their caregivers, and families should be informed that AEDs increase the risk of suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or worsening of the signs and 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.

5.2 Neuropsychiatric Adverse Reactions

Levetiracetam extended-release tablets

In some patients experiencing partial onset seizures, levetiracetam extended-release causes somnolence, dizziness, and behavioral abnormalities.

In the levetiracetam extended-release tablet double-blind, controlled trial in patients experiencing partial onset seizures, 7.8% of levetiracetam extended-release tablet treated patients experienced somnolence compared to 2.5% of placebo-treated patients. Dizziness was reported in 5.2% of levetiracetam extended-release tablet treated patients compared to 2.5% of placebo-treated patients.

A total of 6.5% of levetiracetam extended-release tablet-treated patients experienced non-psychotic behavioral disorders (reported as irritability and aggression) compared to 0% of placebo-treated patients. Irritability was reported in 6.5% of levetiracetam extended-release tablet treated patients. Aggression was reported in 1.3% oflevetiracetam extended-release 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 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 may also occur in patients receiving levetiracetam extended-release tablets.

Immediate-Release Levetiracetam Tablets

In controlled trials of immediate-release levetiracetam tablets in patients experiencing partial onset seizures, immediate-release levetiracetam tablets cause the occurrence of central nervous system adverse reactions that can be classified into the following categories: 1) somnolence and fatigue, 2) coordination difficulties, and 3) behavioral abnormalities.

In controlled trials of adult patients with epilepsy experiencing partial onset seizures, 14.8% of immediate-release levetiracetam tablet-treated patients reported somnolence, compared to 8.4% of placebo patients. There was no clear dose response up to 3000 mg/day.

In controlled trials of adult patients with epilepsy experiencing partial onset seizures, 14.7% of treated patients reported asthenia, compared to 9.1% of placebo patients.

A total of 3.4% of immediate-release levetiracetam tablet-treated patients experienced coordination difficulties, (reported as either ataxia, abnormal gait, or incoordination) compared to 1.6% of placebo patients.

Somnolence, asthenia and coordination difficulties occurred most frequently within the first 4 weeks of treatment.

In controlled trials of patients with epilepsy experiencing partial onset seizures, 5 (0.7%) immediate-release levetiracetam tablet-treated patients experienced psychotic symptoms compared to 1 (0.2%) placebo patient.

A total of 13.3% of immediate-release levetiracetam tablet patients experienced other behavioral symptoms (reported as aggression, agitation, anger, anxiety, apathy, depersonalization, depression, emotional lability, hostility, irritability, etc.) compared to 6.2% of placebo patients.

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