Depakote

[Divalproex]

Patients (50 male, 187 female) ranging in age from 16 to 69 were treated with DEPAKOTE ER (N= 122) or placebo (N= 115). Four patients were below the age of 18 and 3 were above the age of 65. Two hundred and two patients (101 in each treatment group) completed the treatment period. The mean reduction in 4-week migraine headache rate was 1.2 from a baseline mean of 4.4 in the DEPAKOTE ER group, versus 0.6 from a baseline mean of 4.2 in the placebo group. The treatment difference was statistically significant (see Figure 1).

Figure 1 Mean Reduction In 4-Week
Migraine Headache Rates 1.2

0.6
1.2

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0
0.2
0.4
0.6
0.8
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1.2

Placebo Depakote ER

DN0829V1 CR23-03583 August 14, 2003
Page 6 of 2828 * p= 0.006

Epilepsy The efficacy of DEPAKOTE in reducing the incidence of complex partial seizures (CPS) that occur in isolation or in association with other seizure types was established in two controlled trials using DEPAKOTE (divalproex sodium delayed-release tablets).

In one, multiclinic, placebo controlled study employing an add-on design, (adjunctive therapy) using DEPAKOTE, 144 patients who continued to suffer eight or more CPS per 8 weeks during an 8 week period of monotherapy with doses of either carbamazepine or phenytoin sufficient to assure plasma concentrations within the "therapeutic range" were randomized to receive, in addition to their original antiepilepsy drug (AED), either DEPAKOTE or placebo. Randomized patients were to be followed for a total of 16 weeks. The following table presents the findings.

Adjunctive Therapy Study Median Incidence of CPS per 8 Weeks
Add-on Treatment Number of Patients Baseline Incidence Experimental Incidence
DEPAKOTE 75 16. 0 8.9 *
Placebo 69 14.5 11.5
* Reduction from baseline statistically signficantly greater for DEPAKOTE than placebo at p 0.05 level.

Figure 2 presents the proportion of patients (X axis) whose percentage reduction from baseline in complex partial seizure rates was at least as great as that indicated on the Y axis in the adjunctive therapy study. A positive percent reduction indicates an improvement (i. e., a decrease in seizure frequency), while a negative percent reduction indicates worsening. Thus, in a display of this type, the curve for an effective treatment is shifted to the left of the curve for placebo. This figure shows that the proportion of patients achieving any particular level of improvement was consistently higher for DEPAKOTE than for placebo. For example, 45% of patients treated with DEPAKOTE had a 50% reduction in complex partial seizure rate compared to 23% of patients treated with placebo.

Figure 2

The second study assessed the capacity of DEPAKOTE to reduce the incidence of CPS when administered as the sole AED. The study compared the incidence of CPS among patients randomized to either a high or low dose treatment arm. Patients qualified for entry into the randomized comparison phase of this study only if 1) they continued to experience 2 or more CPS per 4 weeks during an 8 to 12 week long period of monotherapy with adequate doses of an AED (i. e., phenytoin, carbamazepine, phenobarbital, or primidone) and 2) they made a successful transition over a two week interval to DEPAKOTE. Patients entering the randomized phase were then brought to their assigned target dose, gradually tapered off their concomitant AED and followed for an interval as long as 22 weeks. Less than 50% of the patients randomized, however, completed the study. In patients converted to DEPAKOTE monotherapy, the mean total valproate concentrations during monotherapy were 71 and 123 µg/ mL in the low dose and high dose groups, respectively.

The following table presents the findings for all patients randomized who had at least one post-randomization assessment.

Monotherapy Study Median Incidence of CPS per 8 Weeks

Treatment Number of Patients Baseline Incidence Randomized Phase Incidence
High dose DEPAKOTE 131 13. 2 10. 7 *

Low dose DEPAKOTE 134 14. 2 13. 8
* Reduction from baseline statistically significantly greater for high dose than low dose at p 0.05 level.

Figure 3 presents the proportion of patients (X axis) whose percentage reduction from baseline in complex partial seizure rates was at least as great as that indicated on the Y axis in the monotherapy study. A positive percent reduction indicates an improvement (i. e., a decrease in seizure frequency), while a negative percent reduction indicates worsening. Thus, in a display of this type, the curve for a more effective treatment is shifted to the left of the curve for a less effective treatment.

This figure shows that the proportion of patients achieving any particular level of reduction was consistently higher for high dose DEPAKOTE than for low dose DEPAKOTE. For example, when switching from carbamazepine, phenytoin, phenobarbital or primidone monotherapy to high dose DEPAKOTE monotherapy, 63% of patients experienced no change or a reduction in complex partial seizure rates compared to 54% of patients receiving low dose DEPAKOTE.

DN0829V1 CR23-03583 August 14, 2003

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