IV Levetiracetam for the Treatment of Neonatal Seizures: a Pharmacokinetic and Preliminary Efficacy and Safety Study

There is a pressing need to improve the treatment of seizures in the neonatal period. The
anticonvulsant agents currently in use may damage the developing brain and are quite
ineffective at controlling seizures in neonates. Newborn seizures are common (1 in 300
newborns) and are associated with very poor outcomes. 20-30% of infants with neonatal
seizures die, 20-30% develop epilepsy outside the neonatal period and 20-40% develop
cerebral palsy and/or mental retardation. Better treatments for neonatal seizures could
improve these outcomes.

An intravenous form of the anti-seizure medication levetiracetam has been released for use
in adults with epilepsy. Experience with oral levetiracetam has shown it to be a very safe
medication, with good efficacy in stopping seizures in other age groups. The intravenous
preparation could allow its use in neonates with seizures. Drug handling by the body is very
different in neonates to adults. Before we can use levetiracetam in this age group we need
to determine the correct dose and frequency by studying its absorption and distribution in
the body (pharmacokinetic profile).

This study is an add-on open label pharmacokinetic and preliminary safety study. Twenty-four
patients with neonatal seizures, who still experience clinical or electroencephalographic
seizures after treatment with Phenobarbital will be treated with intravenous levetiracetam,
and serial determinations of serum levetiracetam levels will be made to allow calculation of
pharmacokinetic parameters. We will also collect preliminary safety data. We will
specifically monitor for abnormalities of heart rate, respiratory rate and blood pressure,
unexpected death, the occurrence of hypotonia, sedation, poor feeding, irritability or
infection. Blood tests monitoring blood, liver and kidney function will be checked at
baseline, 48 hours and at completion of 7 days of treatment. We will also collect
preliminary descriptive data on the efficacy of levetiracetam in stopping neonatal seizures.

Inclusion Criteria:

- Newborns admitted with seizures to the UCSD, Children's Hospital or Sharp Mary Birch
NICUs in San Diego, CA, USA as well as Auckland City Hospital, Grafton,Auckland NZ :

- Term infants (gestational age greater than or equal to 37 weeks > 2460 grams (max
blood for study 6mL =3%)

- Postnatal age < 14 days.

- Received loading dose of phenobarbital 20mg/kg and/or phenytoin.

- Ongoing clinical or electroencephalographic seizures despite this therapy.

- For whom parental consent to participate in the study is obtained.

Exclusion Criteria:

- Serum creatinine greater than 1.2 at enrollment or greater than 2.0 at any time.

- Biochemical abnormality - hypoglycemia, hypocalcemia- that when treated result in
seizure cessation.

- Severe hypoxic ischemic injury likely to result in imminent death