Tolerability and Efficacy of Depakote-extended Release in the Elderly

There is a bimodal distribution to the new onset seizures with one peak occurring in the very
young and the second peak occurring in persons over age 65 years. The presentation of
seizures in the elderly may vary from that of younger patients and the diagnosis may be
confused with other conditions such as transient ischemic attacks. However, the consequences
of epilepsy in the elderly can be severe leading to impaired cognition, increased falls, and
a decreased quality of life. The treatment of epilepsy may be complicated by pharmacokinetic
and pharmacodynamic changes occurring in the elderly.

Three Veterans Cooperative trials evaluating antiepileptic drug (AED) therapy in the elderly
demonstrated that the ability to tolerate the AED is a more determining factor for long term
success than the ability to suppress seizure activity. In general, elderly patients appear
more intolerable to medications. This may stem from co-morbid conditions, concurrent
medications, pharmacokinetic changes, and/or pharmacodynamic changes. Therefore, it is
important to study the efficacy and tolerability of AEDs in the elderly.

Valproic acid has been available for the treatment of partial and generalized seizures since
1978. Sodium divalproex is metabolized in the gut to valproic acid. Depakote and Depakote-ER
(extended release)are among the dosage forms of sodium divalproex. Depakote is an enteric
coated tablet that is designed to dissolve in the more alkaline milieu of the small intestine
rather than the more acidic milieu of the stomach. This helps the drug to bypass the stomach
and reduces gastrointestinal distress. Once the enteric coating dissolves, the sodium
divalproex is metabolized to valproic acid and rapidly absorbed. Depakote is administered
twice a day. Depakote-ER is a controlled release drug delivery system designed to release
drug over a 22 hour period which allows for once a day dosing. The efficacy and tolerability
of Depakote-ER has not been described in elderly patients with epilepsy.

Inclusion Criteria:

- Is > 60 years of age (male or female)

- Has a confirmed diagnosis of epilepsy with partial seizures

- Has one of the following

1. newly diagnosed partial seizures

2. has inadequately controlled partial seizures, i.e. continues to have seizure
activity while on his/her medication regimen

3. is taking Depakote twice a day for partial seizures but is having side effects or
problems with adherence and may benefit from once a day dosing

- Is able and willing to maintain an accurate, complete, written daily seizure diary

- Is able and willing to complete the QOLIE, the Beck Depression Inventory, and the SSQ

- Is able to given written informed consent

- Is compliant with clinic visits

- Is able to swallow Depakote-ER

Exclusion Criteria:

- Has had status epilepticus in the 24 weeks prior to the Baseline Phase of the Study

- Is taking three or more AEDs chronically

- Is currently abusing alcohol and/or any other substance

- Has taken an investigational drug within the previous 30 days or plans to take an
investigational drug anytime during the study

- Is receiving any medication that could influence seizure control

- Is currently following the ketogenic diet

- Is planning surgery or the insertion of the vagal nerve stimulator for seizure control
during the course of the study.

- Is suffering from acute or progressive neurologic disease, severe psychiatric disease,
or severe mental abnormality that are likely to interfere with the objectives of the
study

- Has any clinically significant cardiac, renal, hepatic condition, or a condition that
affects the absorption, distribution, metabolism or excretion of drugs.

- Baseline elevations of LFTs more than 3 times normal, clinically elevated amylase, and
clinically significant thrombocytopenia