Abstract
Objective: To evaluate the efficacy and safety of extended-release divalproex sodium compared with placebo in prophylactic monotherapy treatment of migraine headache.
Methods: This was a double-blind, randomized, placebo-controlled, parallel-group study. Subjects with more than two migraine headache attacks during a 4-week baseline were randomly assigned in a 1:1 ratio at each center to receive either extended-release divalproex sodium or matching placebo once daily for 12 weeks. Subjects initiated treatment on 500 mg once daily for 1 week, and the dose was then increased to 1,000 mg once daily with an option, if intolerance occurred, to permanently decrease the dose to 500 mg during the second week. Reduction from baseline in 4-week migraine headache rate was the primary efficacy variable. Migraine headaches separated by a <24-hour headache-free interval were counted as single migraines in calculating migraine headache rates. Tolerance and safety were also evaluated.
Results: The mean reductions in 4-week migraine headache rate were 1.2 (from a baseline mean of 4.4) in the extended-release divalproex sodium group and 0.6 (from a baseline mean of 4.2) in the placebo group (p = 0.006); reductions with extended-release divalproex sodium were significantly greater than with placebo in all three 4-week segments of the treatment period. No significant differences were detected between treatment groups in either the overall incidence or in the incidence of any specific treatment-emergent adverse event; 8% of subjects treated with extended-release divalproex sodium and 9% of those treated with placebo discontinued for adverse events.
Conclusion: Extended-release divalproex sodium is an efficacious, well-tolerated, safe, and easy-to-use once-a-day prophylactic antimigraine medication.
The mechanism whereby valproate benefits migraine is unclear; valproate may affect many events in the migraine cascade.1 A γ-aminobutyric acid (GABA) receptor–mediated effect likely plays a role.1-7⇓⇓⇓⇓⇓⇓ Valproate increases GABA levels via activation of glutamic acid decarboxylase and inhibition of GABA aminotransferase, which degrades GABA.5,6⇓ In animal models of migraine, valproate has been shown to work through GABAA receptors on neurogenic inflammation by decreasing dural plasma protein extravasation4 and c-fos immunoreactivity in the trigeminal nucleus caudalis.7 There has also been speculation that GABA influences circadian rhythm via hormonal regulation of the anterior pituitary gland and that valproate could be a prophylactic agent by this mechanism.8
Previous double-blind placebo-controlled studies have documented the efficacy of sodium valproate and the marketed divalproex sodium delayed-release formulation in the prophylactic treatment of migraine headache.8-12⇓⇓⇓⇓ These studies were performed with twice-a-day and three-times-a-day dosing schedules. Because efficacy is directly related to compliance and because compliance diminishes rapidly with increasing dose frequency,13 a once-a-day extended-release formulation of divalproex sodium was developed. In the double-blind, randomized, placebo-controlled, parallel-group study described here, we evaluated the efficacy, tolerability, and safety of extended-release divalproex sodium compared with placebo in the prophylactic monotherapy treatment of subjects with migraine headache.
Methods.
This was a 17-week multicenter, double-blind, randomized, placebo-controlled, parallel-group study consisting of three phases: a 4-week baseline phase; a 12-week double-blind experimental phase; and a 1-week double-blind termination phase.
The study design was based on the International Headache Society (IHS) committee guidelines for controlled trials of drugs in migraine.14 Specifically, recommendations for patient selection, blinding, use of a placebo control, randomization, baseline recording of headaches, and durations of the baseline and treatment periods allowed concomitant drug usage, and visit timings were adopted from those set forth by the IHS. The classification of headaches as migraines with or without aura was according to IHS diagnostic criteria.15 This study was conducted in accordance with the Declaration of Helsinki (1996 revision), Good Clinical Practice guidelines, and all applicable local regulations.
Investigators were allowed to enroll men and women ≥12 years of age. Women of childbearing potential were required to practice contraception throughout the study. Inclusion criteria were initial onset of migraine headache ≥6 months before screening and an average of two or more migraine headaches per month during the 3 months before screening. Women who were lactating or pregnant were excluded, as were subjects who had headaches an average of ≥15 days per month; had ever experienced cluster headaches; had previously received an adequate course of treatment with valproate or divalproex sodium for migraine headaches; had a CNS neoplasm or infection, demyelinating disease, degenerative neurologic disease, or progressive CNS disease; had failed more than two adequate trials of prophylactic antimigraine regimens; or who had received prophylactic antimigraine medication within five half-lives of that medication before entering the baseline phase.
All subjects gave informed consent after the nature of the study was explained and before any study-specific procedure was performed. Each subject entering the baseline phase was assigned a baseline subject number. During the baseline phase, subjects maintained a headache diary in which headache activity was recorded. Subjects compliant in maintaining a headache diary and who had at least two migraine headache attacks (separated by a headache-free interval of at least 24 hours) during the 4-week baseline phase were eligible to be randomized. Following the 4-week baseline phase, eligible subjects were randomly assigned in a 1:1 ratio at each center to receive either extended-release divalproex sodium (Depakote Extended-Release Tablets, Abbott Laboratories, Abbott Park, IL) or identical gray ovaloid placebo tablets, assigned a randomized subject number, and entered into the 12-week experimental phase.
The randomization schedule, which assigned a unique series of randomized subject numbers to each center, was computer generated by Abbott Laboratories Department of Clinical Statistics prior to study initiation. The schedule was used by the Abbott Laboratories Investigational Drug Services Department to package and label the study medication containers. Randomization was accomplished by instructing investigators to assign the subject numbers in ascending numerical sequence as subjects qualified for randomization. Treatment assignments were provided to the clinical sites in sealed envelopes that could have been opened if needed in an emergency. The integrity of these envelopes was verified at each clinical monitoring visit.
The experimental phase consisted of a 2-week dose titration/adjustment period followed by a 10-week fixed-dose treatment period. During the first week of the dose titration/adjustment period, each subject received one tablet of extended-release divalproex sodium 500 mg or matching placebo per day beginning with the evening meal on Day 1. After 1 week, subjects received the 1,000-mg/d dose with the evening meal, as two tablets of extended-release divalproex sodium 500 mg, or matching placebo. During the second week of treatment, the investigator had the option to decrease the subject’s dose to 500 mg/d for the remainder of the experimental phase, if deemed necessary because of intolerance. The physician or coordinator maintained contact with the subject by telephone on days 8 and 15 and by office visit on days 29, 57, and 85.
Headache diaries were used to collect information regarding the start and end times, characteristics, and symptomatic medication usage associated with each headache attack. Headache attacks separated by any headache-free interval were to be reported separately. Based on review of the diaries, the headache type of each attack was determined by the investigator per the IHS diagnostic criteria. The tolerability and safety of study medication were monitored through adverse event reporting and assessments of prior and concurrent medication, physical and brief neurologic examinations, routine laboratory evaluations, and serum pregnancy tests for women of childbearing potential.
Statistics.
The study was designed to randomly allocate 105 subjects per treatment group, based on reductions in migraine headache rates observed during fixed-dose treatment with 500 or 1,000 mg/d of delayed-release Depakote or placebo in a previous double-blind, dose-response study.11 Under the assumption that no more than 25% of the subjects would reduce their dose back to 500 mg during the 2nd week of the study, the signal-to-noise ratio (the difference between treatment means divided by the SD, based on reductions in square-root transformed 4-week migraine headache rates) for this study was estimated to be at least 0.46. Using a significance level of 0.05, the power to detect a treatment difference between extended-release Depakote and placebo was 0.91.
The primary and secondary efficacy variables chosen for the current study were specified in the protocol and were based on (or were slight modifications of) variables included in the IHS committee guidelines for controlled trials of drugs in migraine,14 including the committee’s recommended use of the 4-week migraine headache rate as the primary efficacy variable and the 24-hour headache-free rule in calculating the migraine headache rates. Per this rule, migraine headache attacks separated by a <24-hour headache-free interval were combined and considered as a single migraine headache in calculations of 4-week migraine headache rates.
The efficacy data set was an intent-to-treat data set that included all data from randomized subjects who received study drug and provided at least one headache evaluation during the experimental phase. The primary efficacy variable was the experimental phase reduction from baseline (i.e., the baseline phase) in 4-week migraine headache rate. The 4-week rates for the experimental and baseline phases were calculated for each subject as the number of migraine headaches during the study phase multiplied by the ratio of 28 days to the actual number of days in the phase.
The principal secondary variables were the experimental phase percent reduction from baseline in 4-week migraine headache rate, assessing both actual percentages and the proportion of subjects achieving at least a 50% reduction, and the experimental phase reduction from baseline in the number of migraine headache days per 4 weeks. Other secondary variables included the experimental phase changes from baseline in the proportions of migraine headaches treated with particular classes of symptomatic medications (e.g., triptans). In addition to the overall analyses of the primary and principal secondary variables, analyses were performed separately for the three 28-day periods of the experimental phase. For these across-time analyses, the last observation carried-forward method was employed for subjects who prematurely discontinued before entering a 28-day period, such that the value for the subject’s last available period was used as an estimate of the subject’s value for the period(s) containing no data. In addition to these planned analyses, analyses of changes in efficacy during the last 4 weeks of each subject’s experimental phase (or during the entire experimental phase for subjects treated for <4 weeks) were performed.
The nonparametric van Elteren16 method of linearly combining Wilcoxon test results from individual investigators, using weights recommended by Lehmann,17 was the protocol-specified primary analysis method for the continuous variables. This weighted treatment comparison assigned weight 1/(n1+n2+1) to the Wilcoxon rank sum statistic computed for each investigator, where n1 and n2 were the sample sizes of the two treatment groups at the investigator site. Ninety-five percent CI of weighted treatment differences in means for these variables (except for the nonnormal experimental phase percent reduction) were derived using the analogous protocol-specified alternative analysis method, an analysis of variance (ANOVA) model that weighted treatment differences at each investigator site inversely proportional to the variance of the estimated treatment group difference. Because the study results indicated that the distribution of migraine headache rates did not depart greatly from the Gaussian distribution, means and CI of weighted mean treatment differences have been used to describe the nonparametric analysis results. The proportions of subjects achieving at least a 50% reduction in 4-week migraine headache rate were analyzed using Cochran–Mantel–Haenszel statistics with center as the stratification factor.
Baseline differences between treatment groups were assessed by the Fisher’s exact test for discrete variables; by one-way ANOVA for age, weight, and height; and by the Wilcoxon rank sum test for the other continuous variables. Baseline phase differences between treatment groups in 4-week migraine headache rates and number of days per 4 weeks with migraine headaches were assessed using the methods outlined here for reductions in these variables. Differences in the baseline phase and change-from-baseline proportions of migraine headaches treated with particular classes of symptomatic medications were assessed by the Wilcoxon rank sum test.
All randomized subjects who received study drug were evaluated for safety. Treatment groups were compared with respect to the proportion of subjects reporting treatment-emergent adverse events during the experimental phase using the Fisher’s exact test and were also compared during the experimental phase with respect to changes from baseline in laboratory variables and body weight using a one-way ANOVA.
All tests were two-tailed and values of p ≤ 0.050 were considered significant.
Results.
A flow diagram for all subjects enrolled in the trial appears in figure 1. Two subjects were randomly allocated but did not take study medication, one due to transportation issues and one randomly allocated in error who had ≥15 headache days during the baseline phase. A total of 237 subjects (122 receiving extended-release divalproex sodium, 115 receiving placebo) from 24 American investigators were randomly allocated and treated. The average age of these subjects was 40.5 years (range, 16 to 69 years); 79% (187/237) were women and 88% (208/237) were white. The median number of years with migraine headaches was 19.7 (range, 1 to 59 years). No significant differences were detected between treatment groups with respect to age, sex, race, weight, or height (table 1), the number of years with migraine headaches, the particular types of headaches ever experienced, the maximum severity of any migraine headache without aura (categories rated by subjects as either mild, moderate, severe, or excruciating), the particular associated symptoms of migraine headaches, the number of migraine headaches within 3 months before screening, the number of prophylactic antimigraine medication regimens ever used, or the number of failed adequate trials of prophylactic antimigraine regimens (table 2).
Figure. 1. Flow diagram for subjects enrolled in the trial.
Demographic characteristics*
Baseline disease characteristics*
A total of 234 (119 receiving extended-release divalproex sodium, 115 receiving placebo) of the treated subjects provided at least one experimental phase headache evaluation and comprised the efficacy dataset, and all 237 treated subjects were evaluated for safety. No significant differences were detected between treatment groups during the baseline phase in 4-week migraine headache rate, in the number of migraine headache days per 4 weeks, or in the proportions of migraine headaches treated with particular classes of symptomatic medications. A total of 101 subjects (82.8%) on extended-release divalproex sodium and 101 on placebo (87.8%) completed the experimental phase of the trial.
The average dose of study drug during the experimental phase was 871 mg/d in the extended-release divalproex sodium–treated group and 907 mg equivalents/day in the placebo-treated group. The average duration of the ex-perimental phase was 76 days in the extended-release divalproex sodium–treated group and 79 days in the placebo-treated group. A total of 224 subjects (114 receiving extended-release divalproex sodium, 110 receiving placebo) entered the fixed-dose period of the experimental phase. Ninety-eight (86%) of these subjects treated with extended-release divalproex sodium and 100 (91%) of these placebo-treated subjects maintained the 1,000-mg dose (two extended-release divalproex sodium or two matching placebo tablets) for the duration of their treatment periods. The proportion of subjects who generally took study drug as directed at all visits was comparable between the placebo-treated (74%) and extended-release divalproex sodium–treated (75%) groups.
The proportion of migraine headaches treated with a symptomatic medication decreased during the experimental phase by 0.2% in the placebo-treated group and by 2.4% in the extended-release divalproex sodium–treated group. Reductions in the proportions of migraine headaches treated with nonsteroidal anti-inflammatory drugs (0% vs −2.4%), non–nonsteroidal anti-inflammatory drugs (11% vs 7.2%), and isometheptene (15.6% vs 4.0%) were slightly greater in the extended-release divalproex sodium group. Subjects in the placebo group had slightly greater reductions in the proportions of migraine headaches treated with opiates (1.1% vs −2.2%) and triptans (2.3% vs 0.6%). None of these treatment differences were significant, however.
Efficacy.
Overall results.
The primary efficacy variable was the experimental phase reduction from baseline in the 4-week migraine headache rate. The baseline phase mean 4-week migraine headache rate was 4.4 in the extended-release divalproex sodium–treated group and 4.2 in the placebo-treated group. The experimental phase reduction from baseline in the 4-week migraine headache rate was greater in the extended-release divalproex sodium–treated group (mean 1.2) than in the placebo-treated group (mean 0.6, 95% CI of treatment difference, 0.2 to 1.2; p = 0.006).
The experimental phase reduction from baseline in the number of migraine headache days per 4 weeks was greater in the extended-release divalproex sodium group (mean 1.7, from a baseline mean of 6.3) compared with the placebo group (mean 0.7, from a baseline mean of 5.8; 95% CI of treatment difference, 0.2 to 2.0; p = 0.009).
The experimental phase percent reduction from baseline in the 4-week migraine headache rate was greater in the extended-release divalproex sodium group (median = 32%; 25th to 75th percentiles, 3 to 56%) than in the placebo group median (22%; 25th to 75th percentiles, 11 to 48%) (p = 0.013). The proportion of subjects achieving at least 50% reduction in their experimental phase migraine headache rate was higher in the extended-release divalproex sodium group (36/119; 30%) than in the placebo group (28/115; 24%), but the difference was not significant (p = 0.251).
Results across time.
Changes from baseline were also analyzed within each of the three 4-week segments of the experimental phase using the last observation carried-forward method so that all subjects were considered in each period.
Significant differences in reductions in 4-week migraine headache rates favoring extended-release divalproex sodium were noted in the first 4 weeks of therapy (p = 0.035) and also in the second (p = 0.006) and third 28-day periods (p = 0.045; figure 2), per the primary analysis method.
Figure 2. Migraine headache rates during each 4-week interval. *Significant treatment difference in reduction from baseline p = 0.035 (days 1 to 28), p = 0.006 (days 29 to 56), and p = 0.045 (days 57 to 84). +Ninety-five percent CI of the treatment differences (extended-release divalproex sodium − placebo) in reductions from baseline were 0.0 to 1.1 (days 1 to 28), 0.0 to 1.2 (days 29 to 56), and 0.1 to 1.4 (days 57 to 84). Triangles = placebo (n = 115); squares = extended-release divalproex sodium (n = 119).
There was a greater reduction in the number of migraine headache days per 4 weeks in the extended-release divalproex sodium group than in the placebo group during days 29 to 56 (means 1.9 vs 0.8; p = 0.001) and days 57 to 84 (means 1.8 vs 0.6; p = 0.021). The 95% CI of the treatment difference was 0.2 to 2.4 for both periods. The reduction during the first 28 days (means 1.2 vs 0.6) favored extended-release divalproex sodium but was not significant (95% CI of treatment difference, −0.2 to 1.7; p = 0.123). Experimental phase percent reductions and the proportions of subjects achieving at least 50% reduction in migraine headache rate were greater in the extended-release divalproex sodium group in all three 28-day periods. There was no difference in experimental phase percent reductions in the first 28-day period (medians 26% vs 25%; 25th to 75th percentiles, −10 to 50% vs −5 to 42%; p = 0.169), but the experimental phase percent reductions were greater during days 29 to 56 (medians 41% vs 20%; 25th to 75th percentiles, 0 to 67% vs −11 to 50%; p = 0.005) and days 57 to 84 (medians 33% vs 25%; 25th to 75th percentiles, 0 to 64% vs −16 to 50%; p = 0.035). The proportion of subjects achieving at least a 50% reduction was greater during days 1 to 28 (29% vs 18%; p = 0.039) and days 29 to 56 (45% vs 26%; p = 0.001), but not during the final period (37% vs 27%; p = 0.077).
During the last 4 weeks of each patient’s treatment period (or during the entire treatment period for subjects who received <4 weeks of treatment) there was a mean reduction of 1.5 migraine headaches per 4 weeks in the extended-release divalproex sodium group vs 0.6 in the placebo group (95% CI, 0.3 to 1.5; p = 0.003). Migraine headache days per 4 weeks were also reduced by extended-release divalproex sodium treatment (mean 2.0 vs 0.7 for placebo; 95% CI of treatment difference, 0.4 to 2.6; p = 0.006). The proportion of subjects with at least a 50% reduction in migraine headache rate was 41% in the extended-release divalproex sodium group vs 28% in the placebo group (p = 0.024).
Adverse events.
Eighty-three of the 122 extended-release divalproex sodium–treated subjects (68%) and 81 of the 115 placebo-treated subjects (70%) experienced at least one treatment-emergent adverse event during the experimental phase. No significant differences were detected between treatment groups in either the overall incidence or in the incidence of any specific treatment-emergent adverse event (table 3).
Summary of treatment-emergent adverse events reported by at least 5% of subjects in either treatment group*
Weight gain was observed in both treatment groups. Among the 99 subjects in each treatment group with weight recordings, 63% of extended-release divalproex sodium–treated subjects, and 64% of placebo-treated subjects showed some weight gain at the end of the experimental phase. There was no appreciable difference in mean increases from baseline in the extended-release divalproex sodium group (1.22 kg from a baseline mean of 74.66 kg) when compared with the placebo group (0.68 kg from a baseline mean of 74.11 kg; p = 0.148). Median weight gains were 1.3% (range, −7.4 to 15.4%) in the extended-release divalproex sodium group and 0.9% (range, −7.1 to 13.2%) in the placebo group. Forty-two percent of extended-release divalproex sodium–treated subjects and 32% of placebo-treated subjects showed weight gains of at least 2%. Six of 122 subjects (5%) in the extended-release divalproex sodium group reported weight gain as an adverse event (all were mild or moderate in severity) compared with two of 115 subjects (2%) in the placebo group (both were of moderate severity).
Serious adverse events were experienced by 2% (2/122) of extended-release divalproex sodium–treated subjects and 3% (4/115) of placebo-treated subjects. Two subjects reported a serious adverse event (gastrointestinal hemorrhage in a placebo subject and nausea in a subject taking extended-release divalproex sodium) considered by the investigator to be related to study drug. The gastrointestinal hemorrhage on placebo resolved 11 days after treatment, and the nausea on extended-release divalproex sodium resolved 1 day after treatment.
Eight percent (10/122) of extended-release divalproex sodium–treated subjects and 9% (10/115) of placebo-treated subjects prematurely discontinued from the experimental phase for adverse events. Adverse events leading to discontinuation in the extended-release divalproex sodium group included somnolence (three subjects), nausea (two subjects), and ventricular arrhythmia, cholecystitis, agitation, increased nonprotein nitrogen, and asthenia (one subject each). Of these, somnolence, nausea (in one subject), and asthenia were judged by the investigator to be probably related to the study medication; whereas agitation, increased nonprotein nitrogen, and nausea (one subject) were judged to be possibly related. Adverse events leading to discontinuation in the placebo group included dyspepsia (two subjects) and nausea, breast carcinoma, gastrointestinal hemorrhage, flu syndrome, lymphadenopathy, rash, chest pain, and urticaria (one subject each). Of these, dyspepsia (two subjects), gastrointestinal hemorrhage, and rash were judged by the investigator to be probably related to the study medication; lymphadenopathy and nausea were judged to be possibly related; and chest pain and urticaria were judged to be probably not related.
Hematology and blood chemistry assessments were performed at initial screening, at the end of the baseline phase, after 4 weeks and at the end of the experimental phase, and following the termination phase. Significant differences were observed between treatment groups with respect to experimental phase changes from baseline to minimum, maximum, and final values of platelet count, neutrophil percentage, lymphocyte percentage (final value only), and monocyte percentage; however, none of these differences were considered clinically significant. Significant differences were also observed between the placebo-treated and extended-release divalproex–treated groups in mean experimental phase changes from baseline to minimum, maximum, and final values of creatinine, uric acid (minimum and maximum values only), calcium, inorganic phosphorus (minimum value only), total protein, alkaline phosphatase, and cholesterol (minimum and maximum values only); however, none of these differences were considered clinically significant.
Urinalysis was performed on each subject at initial screening and at the end of the baseline and experimental phases. No significant differences were observed between treatment groups in changes from baseline to minimum, maximum, or final value for pH or specific gravity.
Discussion.
In this double-blind, placebo-controlled study, extended-release divalproex sodium given once daily demonstrated significant improvement vs placebo in multiple measures of efficacy, including the protocol-defined primary measure, 4-week migraine headache rate. The major findings in this study include the early onset of action of extended-release divalproex sodium in reducing headache frequency and headache days, the near-equivalent proportions of extended-release divalproex sodium and placebo-treated subjects who discontinued the study due to adverse events or who had treatment-emergent adverse events, and the simplicity of dose initiation and convenience provided by this once-a-day formulation.
Early onset of significant clinical action has been a hallmark of the marketed delayed-release formulation of divalproex sodium. Similarly, the onset of activity for extended-release divalproex sodium in this study began in the first 4 weeks of treatment, which included a 2-week dose adjustment period. Headache frequency in the extended-release divalproex sodium group decreased from 4.4 to 3.5 migraines per 4 weeks during this period compared with a decrease from 4.2 to 3.7 for placebo (p = 0.035). Improvements with extended-release divalproex sodium continued in the second (p = 0.006) and third (p = 0.045) 4-week periods, with headache frequencies decreasing by 1.2 migraines per 4 weeks compared with decreases of 0.6 to 0.7 for placebo. A critical measure of migraine impact for the patient, family, and employer is the number of days the patient has migraine. Extended-release divalproex sodium showed some effect early by reducing the number of migraine headache days from 6.3 to 5.1 in the first 4 weeks compared with a reduction from 5.8 to 5.1 for placebo. Significant differences vs placebo were seen in the second (p = 0.001) and third (p = 0.021) 4-week periods when reductions of 1.8 to 1.9 days per 4 weeks were achieved with extended-release divalproex sodium compared with reductions of 0.6 to 0.8 days per 4 weeks for placebo.
In the prior two large, placebo-controlled trials of delayed-release divalproex sodium, the baseline frequencies of headaches were generally higher than in the present study, averaging close to six migraine headaches per 4 weeks.9,11⇓ The use of the IHS-recommended 24-hour rule in the current study, in which two or more migraine headache attacks not separated by a 24-hour headache-free interval are counted as a single migraine, may account for most of this difference. This change in method limits comparison of efficacy between this study and the previous controlled studies of delayed-release divalproex sodium in the prophylaxis of migraine. Another factor may be the different doses used across the studies as well as the different formulations. Both formulations of divalproex sodium (delayed and extended release) are effective in migraine prophylaxis, but the magnitude of the effect of extended release compared with delayed release remains unclear. The current study used a placebo comparator to show the degree of efficacy, which would be difficult if the comparison were with another formulation of divalproex.
Study data highly relevant to clinical practice include assessing efficacy at the end of treatment in all subjects. Analyzing changes in efficacy during the last 4 weeks of each patient’s treatment period (or during the entire treatment period for subjects treated for <4 weeks) showed significant reductions in migraine frequency and migraine headache days and in the proportion of subjects with at least a 50% reduction in migraine frequency. The pharmacoeconomic consequences of these reductions in migraine headache frequency are unknown. Future studies addressing this issue may be helpful.
Similar proportions of extended-release divalproex sodium- and placebo-treated subjects had treatment-emergent adverse events, and similar proportions discontinued treatment prematurely due to adverse events. The release parameters of the new formulation were designed to produce both lower and delayed peak serum levels. Although the delay of release generated by the enteric coating decreases these effects substantially, the further decreases in peak levels and delay of delivery produced by the extended-release formulation were designed to lead to further improvements in peak serum level–related events. Multidose pharmacokinetic studies of equivalent milligram doses of the two forms demonstrate higher plasma concentration with the enteric-coated form (delayed release) than with the extended-release form and generally higher bioavailability. In healthy subjects, when it was administered either fasting or immediately before small meals, extended-release divalproex sodium produced an average bioavailability of 81 to 89% relative to delayed-release divalproex sodium given twice daily. Maximum plasma concentrations of valproate (Cmax) were attained in 7 to 14 hours with the extended-release formulation, compared with 3.3 to 4 hours for delayed-release Depakote enteric-coated tablets after administration of a single 500-mg dose (figure 3). Relative to delayed release, the Cmax of extended-release formulations given with subjects fasting or with small meals to healthy subjects ranged from 74 to 81% and Cmin ranged from 82 to 85%.18 This combination of delayed Tmax and diminished Cmax may be the physiologic basis for the similar adverse event rates and discontinuation rates compared with placebo in this study. It is also possible, given the reduced bioavailability of the extended-release formulation, that a lower effective dose of the extended-release formulation was used in this study than in previous studies. The lower bioavailability under conditions of fasting or small meals is important to note.
Figure 3. Mean plasma valproate concentrations after administration of a single 500-mg dose of extended-release divalproex sodium in healthy volunteers. Diamonds = divalproex sodium–enteric coated (DR) tablet; squares = divalproex sodium–extended release (ER) tablet. Data on file, Abbott Laboratories.
Appendix
Participating investigators: Sheena K. Aurora, Department of Neurology, Henry Ford Hospital, Detroit, MI; Raymond Brewer, TX Headache Institute, San Antonio, TX; Roger Cady, Headache Care Center, Springfield, MO; John W. Cochran, VA Neuroscience Center PLC, Alexandria, VA; James J. Corbett, Department of Neurology, University of Mississippi Medical Center, Jackson, MS; Keith B. Edwards, Neurologic Consultant PC, Bennington, VT; Frederick G. Freitag, Diamond Headache Clinic, Chicago, IL; Jerome Goldstein, The San Francisco Headache Clinic, San Francisco, CA; Robert G. Kaniecki, Allegheny Neurologist Associates, Pittsburgh, PA; Jack A. Klapper, CO Neurology & Headache Center, Denver, CO; David Kudrow, CA Medical Clinical for Headache, Encino, CA; Robert Kunkel, Headache Center, Cleveland Clinic Foundation, Cleveland, OH; Herbert G. Markley, UMass Memorial Health Care, Worcester, MA; Ninan T. Mathew, Houston Headache Clinic, Houston, TX; Joseph A. Nicolas, Cincinnati Headache Center, Cincinnati, OH; John Rothrock, Department of Neurology, University of South Alabama, Mobile, AL; Joel R. Saper, MI Head Pain & Neurologic Institute, Ann Arbor, MI; Fred D. Sheftell, The New England Center for Headache, Stanford, CT; Stephen Silberstein, Jefferson Headache Center, Philadelphia, PA; Egilius L.H. Spierings, Boston Clinical Research Center, Wellesley Hill, MA; Jerome M. Walker, Neurologist and Headache Specialists of Atlanta, LLC, Decatur, GA; Edward Westbrook, Division of Clinical Research, University Hospitals of Cleveland, Cleveland, OH; Paul K. Winner, Palm Beach Headache Center, Palm Beach, FL; Alberto Yataco, Innovative Medical Research, Towson, MD.
Acknowledgments
Supported by Abbott Laboratories, Abbott Park, IL.
- Received May 11, 2001.
- Accepted February 15, 2002.
References
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