Regulatory Decision Summary for Pdp-Levetiracetam

The submission consisted of scientific literature and foreign reviews. In Canada, only the tablet formulation of levetiracetam was marketed, and only for use as adjunctive therapy in adults. All of the safety and efficacy studies were conducted with Keppra tablets, oral or intravenous (IV) solutions. The products proposed for the Canadian market are subsequent entry versions of the solutions, and the sponsor has linked these versions to Keppra.

The following pharmacokinetic (PK) characteristics of levetiracetam minimize the risks associated with treatment: The oral solution of levetiracetam (LEV) is essentially 100% bioequivalent to the IV solution; it is highly soluble in water; the extent of absorption is not affected by food; it has linear pharmacokinetics; steady state is achieved within 48 hours; it is <10% protein bound; its metabolism is not dependent on hepatic cytochrome p450 enzyme system, and therefore there is reduced likelihood of drug interactions.

The literature and foreign reviews assessed, supported the approval of the following indications:

1. Pediatric Indication for partial onset seizure (POS) for patients ≥4 years of age

Oral solution. The pivotal safety and efficacy study was a 28-week, double blind, controlled study with 159 patients with POS, 3-17 years of age. The primary outcomes, the median percent reduction in seizures (LEV: 43% vs. Placebo: 24%) and responder rate (LEV: 45% vs. Placebo: 20%) were both clinically and statistically significant. In addition, data from 3 PK studies and one Population PK study (total number [n]=197) revealed that pediatric patients required a 30-40% higher dose than adults to achieve similar drug exposure, with body weight as the pivotal factor in determining the proper dosage regimen in children; this is reflected in the dosing instructions in the Product Monograph (PM). The primary safety signal was a higher level of behavioural/psychiatric adverse events in this age group compared to older age groups, which has been labelled in the PM.

IV solution. The approval of the I.V. solution in this age group was based on a simulation population PK study. The IV exposure in children was based on a 4-day PK study in 4-16 year olds (n=33), plus 5 additional scientific reports from the literature describing its use in children. No new safety signals were identified to what was already known with LEV.

2. Pediatric Indication for POS >1 month to <4 years of age

Oral solution: The pivotal safety and efficacy study for children aged >1 month to <4 years of age was a 6 day, double-blind, controlled trial with 116 children. Patients were titrated to 40 or 50 mg/kg/day. The primary endpoint of responder rates was clinically and statistically significant (LEV: 43% vs. Placebo: 20%). In addition, a pharmacokinetic as well as a population PK study were also performed for a total exposure of 168 patients aged >1 month to <4 years of age. The population PK model validated the dosing regimen suggesting that children aged 1-6 months require about 70% of the dose used in children >4 years of age, and children >6 months of age should use the same dosing regimen as older children. The safety results demonstrated that irritability and psychotic symptoms were increased in this age group compared to older children, and there was an increased risk of high diastolic blood pressure. This has also been included in the PM.

IV solution. The pivotal study used to support the approval of the IV solution for use in children >1 month to <4 years of age was a 4-day PK trial (n=19). This data, together with data from a population PK analysis did not reveal any new safety signals with this formulation. Based on the totality of the evidence provided for this age group, together with the PK characteristics that support general IV use, the extension of the indication for the IV solution down to 1 month of age was acceptable.

3. Seizures other than POS

The approved indication of LEV for myoclonic seizures was based on a 24-week, double-blind, controlled clinical trial (n=122) in patients >12 years of age. The primary endpoint of responder rate was clinically and statistically significant (LEV: 58% vs. Placebo: 23%). There were no additional safety signals identified in that trial.

The approved indication of LEV for primary generalized tonic-clonic (PGCT) was based on a 24-week, double-blind, controlled trial (n=229) in patients aged 4 to 65 years old. The primary endpoint of percent reduction in seizure rate was both statistically and clinically significant (LEV: 57% vs. Placebo: 28%), and no additional safety signals were detected.

Health Canada has granted the indication for PGTC for ages 12 and up.