In one, multi-clinic, placebo controlled study employing an add-on design (adjunctive therapy), 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 divalproex sodium delayed-release tablets or placebo. Randomized patients were to be followed for a total of 16 weeks. The following table presents the findings.
|Add – on Treatment||Number of Patients||Baseline Incidence||Experimental Incidence|
|Divalproex sodium delayed-release tablets||75||16.0||8.9*|
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 valproate than for placebo. For example, 45% of patients treated with valproate had a ≥ 50% reduction in complex partial seizure rate compared to 23% of patients treated with placebo.
The second study assessed the capacity of valproate 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 valproate. 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 divalproex sodium delayed-release tablets monotherapy, the mean total valproate concentrations during monotherapy were 71 and 123 mcg/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.
|Treatment||Number of Patients||Baseline Incidence||Randomized Phase Incidence|
|High dose Divalproex sodium delayed-release tablets||131||13.2||10.7*|
|Low dose Divalproex sodium delayed-release tablets||134||14.2||13.8|
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 valproate than for low dose valproate. For example, when switching from carbamazepine, phenytoin, phenobarbital or primidone monotherapy to high dose valproate monotherapy, 63% of patients experienced no change or a reduction in complex partial seizure rates compared to 54% of patients receiving low dose valproate.
The results of two multicenter, randomized, double-blind, placebo-controlled clinical trials established the effectiveness of divalproex sodium delayed-release tablets in the prophylactic treatment of migraine headache.
Both studies employed essentially identical designs and recruited patients with a history of migraine with or without aura (of at least 6 months in duration) who were experiencing at least 2 migraine headaches a month during the 3 months prior to enrollment. Patients with cluster headaches were excluded. Women of childbearing potential were excluded entirely from one study, but were permitted in the other if they were deemed to be practicing an effective method of contraception.
In each study following a 4-week single-blind placebo baseline period, patients were randomized, under double blind conditions, to divalproex sodium delayed-release tablets or placebo for a 12-week treatment phase, comprised of a 4-week dose titration period followed by an 8-week maintenance period. Treatment outcome was assessed on the basis of 4-week migraine headache rates during the treatment phase.
In the first study, a total of 107 patients (24 M, 83 F), ranging in age from 26 to 73 were randomized 2:1, divalproex sodium delayed-release tablets to placebo. Ninety patients completed the 8-week maintenance period. Drug dose titration, using 250 mg tablets, was individualized at the investigator’s discretion. Adjustments were guided by actual/sham trough total serum valproate levels in order to maintain the study blind. In patients on divalproex sodium delayed-release tablet doses ranged from 500 to 2,500 mg a day. Doses over 500 mg were given in three divided doses (TID). The mean dose during the treatment phase was 1,087 mg/day resulting in a mean trough total valproate level of 72.5 mcg/mL, with a range of 31 to 133 mcg/mL.
The mean 4-week migraine headache rate during the treatment phase was 5.7 in the placebo group compared to 3.5 in the divalproex sodium delayed-release tablets group (see Figure 4). These rates were significantly different.
In the second study, a total of 176 patients (19 males and 157 females), ranging in age from 17 to 76 years, were randomized equally to one of three divalproex sodium delayed-release tablets dose groups (500, 1,000, or 1,500 mg/day) or placebo. The treatments were given in two divided doses (BID). One hundred thirty-seven patients completed the 8-week maintenance period. Efficacy was to be determined by a comparison of the 4-week migraine headache rate in the combined 1,000/1,500 mg/day group and placebo group.
The initial dose was 250 mg daily. The regimen was advanced by 250 mg every 4 days (8 days for 500 mg/day group), until the randomized dose was achieved. The mean trough total valproate levels during the treatment phase were 39.6, 62.5, and 72.5 mcg/mL in the divalproex sodium delayed-release tablets 500, 1,000, and 1,500 mg/day groups, respectively.
The mean 4-week migraine headache rates during the treatment phase, adjusted for differences in baseline rates, were 4.5 in the placebo group, compared to 3.3, 3.0, and 3.3 in the divalproex sodium delayed-release tablets 500, 1,000, and 1,500 mg/day groups, respectively, based on intent-to-treat results (see Figure 4). Migraine headache rates in the combined divalproex sodium delayed-release tablets 1,000/1,500 mg group were significantly lower than in the placebo group.
Figure 4 Mean 4-week Migraine Rates
- Mean dose of divalproex sodium delayed-release tablets were 1,087 mg/day.
- Dose of divalproex sodium delayed-release tablets were 500 or 1,000 mg/day.
1. Meador KJ, Baker GA, Browning N, et al. Fetal antiepileptic drug exposure and cognitive outcomes at age 6 years (NEAD study): a prospective observational study. Lancet Neurology 2013; 12 (3):244-252.
125 mg (as valproic acid) pink colored, oval shaped, biconvex, enteric coated tablets, imprinted with “L005” (in black ink) on one side and plain on the other side.
Bottles of 100 NDC 68180-265-01
Bottles of 500 NDC 68180-265-02
Box containing 10 x 10’s unit dose tablets NDC 68180-265-13
250 mg (as valproic acid) pink colored, oval shaped, biconvex, enteric coated tablets, imprinted with “L006” (in black ink) on one side and plain on the other side.
Bottles of 100 NDC 68180-266-01
Bottles of 500 NDC 68180-266-02
Bottles of 1000 NDC 68180-266-03
Box containing 10 x 10’s unit dose tablets NDC 68180-266-13
500 mg (as valproic acid) pink colored, oval shaped, biconvex, enteric coated tablets, imprinted with “L007” (in black ink) on one side and plain on the other side.
Bottles of 100 NDC 68180-267-01
Bottles of 500 NDC 68180-267-02
Bottles of 1000 NDC 68180-267-03
Box containing 10 x 10’s unit dose tablets NDC 68180-267-13
Store at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature].
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