Divalproex Sodium (Page 12 of 15)

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, and Impairment of Fertility

Carcinogenesis

Valproate was administered orally to rats and mice at doses of 80 and 170 mg/kg/day (less than the maximum recommended human dose on a mg/m ² basis) for two years. The primary findings were an increase in the incidence of subcutaneous fibrosarcomas in high-dose male rats receiving valproate and a dose-related trend for benign pulmonary adenomas in male mice receiving valproate.

Mutagenesis

Valproate was not mutagenic in an in vitro bacterial assay (Ames test), did not produce dominant lethal effects in mice, and did not increase chromosome aberration frequency in an in vivo cytogenetic study in rats. Increased frequencies of sister chromatid exchange (SCE) have been reported in a study of epileptic children taking valproate; this association was not observed in another study conducted in adults.

Impairment of Fertility

In chronic toxicity studies in juvenile and adult rats and dogs, administration of valproate resulted in testicular atrophy and reduced spermatogenesis at oral doses of 400 mg/kg/day or greater in rats (approximately equal to or greater than the maximum recommended human dose (MRHD) on a mg/m2 basis) and 150 mg/kg/day or greater in dogs (approximately equal to or greater than the MRHD on a mg/m2 basis). Fertility studies in rats have shown no effect on fertility at oral doses of valproate up to 350 mg/kg/day (approximately equal to the MRHD on a mg/m2 basis) for 60 days.

14 CLINICAL STUDIES

14.1 Mania

The effectiveness of divalproex sodium for the treatment of acute mania was demonstrated in two 3-week, placebo controlled, parallel group studies.

(1) Study 1: The first study enrolled adult patients who met DSM-III-R criteria for bipolar disorder and who were hospitalized for acute mania. In addition, they had a history of failing to respond to or not tolerating previous lithium carbonate treatment. Divalproex sodium was initiated at a dose of 250 mg tid and adjusted to achieve serum valproate concentrations in a range of 50-100 mcg/mL by day 7. Mean divalproex sodium doses for completers in this study were 1,118, 1,525, and 2,402 mg/day at Days 7, 14, and 21, respectively. Patients were assessed on the Young Mania Rating Scale (YMRS; score ranges from 0-60), an augmented Brief Psychiatric Rating Scale (BPRS-A), and the Global Assessment Scale (GAS). Baseline scores and change from baseline in the Week 3 endpoint (last-observation-carry-forward) analysis were as follows:

Table 6. Study 1

1 Mean score at baseline
2 Change from baseline to Week 3 (LOCF)
3 Difference in change from baseline to Week 3 endpoint (LOCF) between divalproex sodium and placebo
YMRS Total Score
Group	Baseline 1	BL to Wk 3 2	Difference 3
Placebo	28.8	+ 0.2
Divalproex sodium	28.5	— 9.5	9.7
BPRS-A Total Score
Group	Baseline 1	BL to Wk 3 2	Difference 3
Placebo	76.2	+ 1.8
Divalproex sodium	76.4	-17.0	18.8
GAS Score
Group	Baseline 1	BL to Wk 3 2	Difference 3
Placebo	31.8	0.0
Divalproex sodium	30.3	+ 18.1	18.1

Divalproex sodium was statistically significantly superior to placebo on all three measures of outcome.

(2) Study 2: The second study enrolled adult patients who met Research Diagnostic Criteria for manic disorder and who were hospitalized for acute mania. Divalproex sodium was initiated at a dose of 250 mg tid and adjusted within a dose range of 750-2,500 mg/day to achieve serum valproate concentrations in a range of 40-150 mcg/mL. Mean divalproex sodium doses for completers in this study were 1,116, 1,683, and 2,006 mg/day at Days 7, 14, and 21, respectively. Study 2 also included a lithium group for which lithium doses for completers were 1,312, 1,869, and 1,984 mg/day at Days 7, 14, and 21, respectively. Patients were assessed on the Manic Rating Scale (MRS; score ranges from 11-63), and the primary outcome measures were the total MRS score, and scores for two subscales of the MRS, i.e., the Manic Syndrome Scale (MSS) and the Behavior and Ideation Scale (BIS). Baseline scores and change from baseline in the Week 3 endpoint (last-observation carry-forward) analysis were as follows:

Table 7. Study 2

1 Mean score at baseline
2 Change from baseline to Day 21 (LOCF)
3 Difference in change from baseline to Day 21 endpoint (LOCF) between divalproex sodium and placebo and lithium and placebo
MRS Total Score
Group	Baseline 1	BL to Day 21 2	Difference 3
Placebo	38.9	— 4.4
Lithium	37.9	-10.5	6.1
Divalproex sodium	38.1	— 9.5	5.1
MSS Total Score
Group	Baseline 1	BL to Day 21 2	Difference 3
Placebo	18.9	— 2.5
Lithium	18.5	— 6.2	3.7
Divalproex sodium	18.9	— 6.0	3.5
BIS Store Score
Group	Baseline 1	BL to Day 21 2	Difference 3
Placebo	16.4	— 1.4
Lithium	16.0	— 3.8	2.4
Divalproex sodium	15.7	— 3.2	1.8

Divalproex sodium was statistically significantly superior to placebo on all three measures of outcome. An exploratory analysis for age and gender effects on outcome did not suggest any differential responsiveness on the basis of age or gender.

A comparison of the percentage of patients showing ≥ 30% reduction in the symptom score from baseline in each treatment group, separated by study, is shown in Figure 1.

Figure 1

* p < 0.05

PBO = placebo, DVPX = Divalproex sodium