PDP-LEVETIRACETAM

1 Adverse Reaction Overview In well-controlled clinical studies, the most frequently reported adverse events associated with the use of levetiracetam in combination with other AEDs, not seen at an equivalent frequency among placebo-treated patients, were somnolence, asthenia, dizziness, infection; and most notably in pediatrics, altered mood and behaviour, as well as decreased appetite.

Of the most frequently reported adverse events, asthenia, somnolence and dizziness appeared to occur predominantly during the first four weeks of treatment with levetiracetam. 2 Clinical Trial Adverse Reactions Because clinical trials are conducted under very specific conditions, the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug.

Adverse reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates. Adults The partial onset seizure data below are representative of the adverse event findings from other seizure types.

Product Monograph - pdp-LEVETIRACET AM Page 20 of 56 Central Nervous System Adverse Reactions Levetiracetam use is associated with the occurrence of central nervous system (CNS) adverse events; the most significant of these can be classified into 3 main categories: 1) somnolence and fatigue 2) behavioural/psychiatric, and 3) coordination difficulties.

There was no clear dose response relationship for any of the three categories of CNS adverse events, within the recommended dose range of up to 3000 mg/day. Somnolence/asthenia and coordination difficulties occurred most frequently within the first 4 weeks of treatment, a nd usually resolved while patients remained on treatment.

In the case of behavioural/psychiatric symptoms (including such adverse events as aggression, agitation, anger, anxiety, emotional lability, hostility, and irritability), approximately half of the patients reported these events within the first 4 weeks, with the remaining events occurring throughout the duration of the trials.

See Table 7 for the incidence rate of individual adverse events contained within each category. ) have been reported approximately equally in patients with and without a psychiat ric history. Table 7 Total combined incidence rate for each of the three categories of CNS adverse events in placebo-controlled add-on clinical trials.

Category of CNS Adverse Events Levetiracetam* + Anti-epileptic Therapy (n=672) Placebo + Antiepileptic Therapy (N=351) Somnolence and Fatigue Somnolence 15% 10% Fatigue 14% 10% Behavioural / Psychological Symptoms Non-psychotic (1) 14% 6% Psychotic (2) 1% 0% Coordination Difficulties Coordination Difficulties (3) 3% 2% *Reflects levetiracetam doses of 1000 mg, 2000 mg, 3000 mg, and 4000 mg per day.

, Immune). Product Monograph - pdp-LEVETIRACET AM Page 5 of 56 4. 1 Dosing Considerations pdp-levetiracetam is available in the form of an oral solution and an IV solution for injection. d). Depending on the clinical response and tolerability, the daily dose may be increased every two weeks by increments of 1000 mg, to a maximum recommended daily dose of 3000 mg daily.

In clinical trials, daily doses of 1000 mg, 2000 mg, and 3000 mg, given as twice daily dosing were shown to be effective. Although there was a tendency toward s a greater response rate with higher doses, a consistent statistically significant increase in response with increased dose has not been shown.

There are limited safety data from controlled clinical trials at doses higher than 3000 mg/day (approximately 40 patients), therefore these doses are not recommended. pdp-levetiracetam IV Solution is for intravenous use only as an alternative for patients when oral administration is temporarily not feasible.

There is no experience with administration of intravenous levetiracetam for a period longer than 4 days. Elderly Patients (65 years and older) Dose selection and titration should proceed cautiously in elderly patients, as renal function decreases with age.

Accordingly, adjustment of the dose is recommended in elderly patients with compromised renal function (see below). Dosage Adjustments in Adult Patients with Impaired Renal Function Renal excretion of unchanged drug accounts for approximately 66% of administered levetiracetam dose.

Consistent with this, pdp-levetiracetam dosage should be reduced in patients with impaired renal function (see Table 1 below). Patients with end stage renal disease should receive supplemental doses following dialysis. To use this dosing table, an estimate of the patient’s creatinine clearance (CLcr) in mL/mi n is needed.

The CLcr in mL/min may be estimated from serum creatinine (mg/dL). 73 m2) Dosage and Frequency Normal ≥80 500 to 1500 mg twice daily Mild 50-79 500 to 1000 mg twice daily Moderate 30-49 250 to 750 mg twice daily Severe* <30 250 to 500 mg twice daily End-stage renal disease patients undergoing dialysis (1) (2) - 500 to 1000 mg once daily (1) A 750 mg loading dose is recommended on the first day of treatment w ith levetiracetam.