Study funded by Abbott, Abbott Park, IL.
Divalproex Sodium Extended-Release for the Prophylaxis of Migraine Headache in Adolescents: Results of a Stand-Alone, Long-Term Open-Label Safety Study
Article first published online: 19 NOV 2008
© 2008 the Authors. Journal compilation © 2008 American Headache Society
Headache: The Journal of Head and Face Pain
Volume 49, Issue 1, pages 45–53, January 2009
How to Cite
Apostol, G., Lewis, D. W., Laforet, G. A., Robieson, W. Z., Fugate, J. M., Abi-Saab, W. M. and Saltarelli, M. D. (2009), Divalproex Sodium Extended-Release for the Prophylaxis of Migraine Headache in Adolescents: Results of a Stand-Alone, Long-Term Open-Label Safety Study. Headache: The Journal of Head and Face Pain, 49: 45–53. doi: 10.1111/j.1526-4610.2008.01279.x
Conflict of Interest: All authors except Dr. Lewis are employees of Abbott.
- Issue published online: 5 JAN 2009
- Article first published online: 19 NOV 2008
- Accepted for publication August 20, 2008.
- pediatric migraine;
- divalproex sodium;
- migraine prophylaxis;
Objective.— The objective of this long-term open-label study in adolescents was to assess the safety and tolerability of divalproex sodium extended-release in the prophylaxis of migraine headaches.
Background.— Two formulations of divalproex sodium have demonstrated efficacy in the prevention of migraine headaches in adults. However, no medications are currently approved for this indication in adolescents, and long-term safety data on agents for migraine prevention are lacking for this younger population. Therefore, the current study was conducted to assess the long-term safety and tolerability of divalproex extended-release in adolescents with migraine headaches.
Methods.— This was a 12-month, phase 3, open-label, multicenter study of adolescents aged 12 to 17 years with migraine headaches diagnosed by International Headache Society criteria. Divalproex sodium extended-release was initiated at 500 mg/day for 15 days then increased to 1000 mg daily, with subsequent adjustments permitted within a dosing range of 250-1000 mg daily. Study visits were conducted at days 1 and 15 and months 1, 2, 3, 6, 9, and 12. Safety was evaluated by adverse event collection, laboratory assessments, physical and neurological examinations, vital signs, electrocardiograms, the Udvalg for Kliniske Undersøgelser Side Effect Rating Scale, the Wechsler Abbreviated Scale of Intelligence, and the Behavioral Assessment Scale for Children. Efficacy was evaluated by following the number of migraine headache days reported in subjects' headache diaries over sequential 4-week intervals for the duration of the trial.
Results.— A total of 241 subjects were enrolled and treated. The most frequently reported adverse events were nausea (19%), vomiting (18%), weight gain (12%), nasopharyngitis (11%), migraine (10%), and upper respiratory tract infection (10%). Ten (4%) subjects experienced serious adverse events, and 40 (17%) subjects discontinued because of an adverse event. Increases in ammonia levels were observed. No other clinically significant changes were observed in laboratory values, vital signs, rating scales, or electrocardiograms. Median 4-week migraine headache days decreased 75% between the first and the fourth months of the study (from 4.0 to 1.0) and remained at or below this level for the remainder of the study.
Conclusions.— In this long-term open-label study of adolescents with migraine, the safety and tolerability profile of divalproex sodium extended-release was consistent with findings from previous trials in adults, as well as 2 studies recently completed in adolescents. In general, divalproex sodium extended-release was well-tolerated in adolescents with migraine.
Behavior Assessment System for Children
- DVPX ER
divalproex sodium extended-release
serious adverse event
Udvalg for Kliniske Undersøgelser
Wechsler Abbreviated Scale of Intelligence
Migraine headache is a common and debilitating condition affecting an estimated 4.9% of males and 7.3% of females 12 to 17 years of age.1 Migraine exacts a significant toll on quality of life, including missed school days, reduced social activity,1 and disruptions in sleep and behavior.2 Despite this negative impact, only 10.7% of migraine patients under the age of 18 are currently using prophylactic medication for this condition,3 and there are currently no Food and Drug Administration (FDA)-approved agents for the prevention of migraines in children and adolescents.
Divalproex sodium (DVPX) delayed-release tablets and DVPX extended-release (DVPX ER) tablets have been approved by the US FDA for migraine prophylaxis in adults. The efficacy and safety of DVPX for this indication was established in 3 randomized, placebo-controlled, double-blind, multicenter studies in adults, 2 using the delayed-release formulation4,5 and 1 conducted with DVPX ER.6 A subsequent pharmacokinetic (PK) study of DVPX ER in children and adolescents aged 8-17 years demonstrated a similar PK profile in children, adolescents, and historical adult controls,7 and several case reports and other uncontrolled studies have suggested that DVPX may be effective in the prevention of migraine headaches in children and adolescents.8-13 However, in a recent double-blind, placebo-controlled trial, DVPX ER failed to demonstrate efficacy in adolescent migraine prophylaxis when compared with placebo.14
The current trial complements 2 previous studies of DVPX ER use in adolescents with migraine, a 3-month double-blind, placebo-controlled efficacy and safety trial,14 and its 1-year, open-label safety extension.15 This report presents 12 months of safety and efficacy data collected during a free-standing, long-term open-label study of DVPX ER in the prophylaxis of migraine headaches in 241 adolescent subjects.
This was a phase 3, open-label, multicenter, long-term safety study of DVPX ER in adolescents with a diagnosis of migraine headaches consistent with International Headache Society criteria. Eligible subjects were 12 to 17 years of age, in general good health, at least 35 kg in weight, not pregnant or nursing, and using an effective method of birth control. Exclusion criteria included any history of valproate allergy/sensitivity, medication nonadherence, substance abuse in the past 6 months, or any serious medical or psychiatric disorder that would interfere with study participation. In addition, subjects who had taken part in a prior study of DVPX ER for migraine prophylaxis or had received an investigational agent within 30 days of enrollment were excluded. The study duration was approximately 12 months, with study visits occurring at days 1 and 15 and months 1, 2, 3, 6, 9, and 12. DVPX ER therapy was initiated at 500 mg daily for the first 15 days, then increased to 1000 mg daily, the recommended dose for migraine prophylaxis in adults.16 Based on clinical judgment, investigators had the option to change the dose at any time provided the total daily dose was between 250 mg and 1000 mg. The use of antidepressants, antiepileptic drugs aside from DVPX ER, products containing aspirin, anticoagulants, chronic use of systemic corticosteroids, clonazepam, diazepam, erythromycin, pemoline, rifampin, tolbutamide, and zidovudine were not allowed. Other medications could be prescribed by the investigator if necessary.
Safety assessments included adverse event (AE) collection, laboratory tests, vital signs, physical exams, brief neurological exams, and electrocardiograms (ECGs). The Udvalg for Kliniske Undersøgelser (UKU) Side Effect Rating Scale17 was used to assess movement-related side effects and was performed on day 1 (first day of study drug administration) and at months 1, 2, 3, 6, 9, and 12. In addition, cognitive and behavioral changes were evaluated using the Wechsler Abbreviated Scale of Intelligence (WASI)18 and Behavior Assessment System for Children (BASC),19 which were performed on day 1 and at months 6 and 12. At all visits except the final visit, subjects were given a migraine diary and were instructed to record all migraine headache activity during the study. Serum trough valproate concentrations were drawn at months 1, 2, 3, 6, 9, and 12, approximately 24 hours (±3 hours) after study drug dosing.
The intent-to-treat (ITT) dataset was defined as all subjects who received at least 1 dose of study drug and had ≥1 reliable headache evaluation during the study. Treatment-emergent AEs were coded according to the Medical Dictionary for Regulatory Activities. Mean changes from baseline in laboratory and vital signs were summarized, and laboratory and vital sign values meeting predefined criteria for potential clinical significance were identified. For the UKU Side Effect Rating Scale, the percentage of subjects with an individual side effect and the percentage of subjects with 1 or more of the side effects were summarized at each scheduled time point. The mean WASI and BASC scores at each scheduled time point and mean changes from baseline to each time point for the WASI and BASC were summarized. In addition, the number of migraine headache days was calculated for each 4-week interval over the course of the study for the ITT dataset.
Subject Characteristics and Disposition.— A total of 241 subjects were enrolled at 39 centers in the United States and took at least 1 dose of study drug. Subject demographics are presented in Table 1. Most subjects were white (78%), 53% were female, and the mean age was 14.5 years. Concomitant medications were taken by the majority (92%) of subjects, with analgesics and systemic anti-infective agents used most frequently. A total of 128 (53%) completed the study and 236 subjects were included in the ITT dataset. The most common reasons for withdrawing from the study (≥10% of subjects) were AEs (n = 40, 17%), lost to follow up (n = 32, 13%), withdrew consent (n = 29, 12%), and noncompliance (n = 25; 10%).
|Parameter||Total (n = 241)|
|Mean (SD)||14.5 (1.68)|
|Age distribution, n (%)|
|11† to 13 years||83 (34)|
|14 to 15 years||80 (33)|
|16 to 17 years||78 (32)|
|Gender, n (%)|
|Race, n (%)|
|American Indian/Alaska native||2 (<1)|
|Hispanic ethnicity¶, n (%)|
|Mean (SD)||63.2 (18.67)|
|Mean (SD)||23.4 (5.62)|
|Migraine headaches within 3 months of screening||N = 240††|
|Mean (SD)||24.4 (22.57)|
Exposure and Compliance.— A total of 154 subjects (64%) had ≥6 months of exposure to DVPX ER, and 97 subjects (40%) had ≥12 months of exposure to DVPX ER. Overall mean duration of DVPX ER exposure was 251 days. The DVPX ER mean modal dose was 847.5 mg (14.4 mg/kg) with a mean maximum daily dose of 951.2 mg (16.3 mg/kg) for the entire exposure period. Over the 12-month period, 54% of the subjects were ≥70% compliant with taking their study drug at each visit; an additional 24% were ≥70% compliant at all but 1 study visit. Eighteen subjects had missed their study medication for intervals of ≥7 days; the longest interval was 56 days. The mean (SD) serum trough valproate concentration at the final visit was 44.8 (35.5) µg/mL. One site had an unusually high rate (61%) of undetectable valproate levels, but an audit conducted by the study sponsor identified no significant problems with protocol compliance or Good Clinical Practice.
Headache History and Treatment Efficacy.— Subjects reported an average of 24.4 (SD = 22.57) migraine headaches (median = 18) within the 3 months prior to screening. Over the entire 12-month study, median (mean) 4-week headache days were 2.2 (3.8) and 1.0 (3.4) in the final 4-week period. DVPX ER treatment was associated with a 75% decrease (from 4.0 to 1.0) in median 4-week headache days between the first and fourth months of the study. This improvement was seen in both the last observation carried forward and observed cases datasets, and persisted for the duration of the trial. The Figure shows the median and mean 4-week migraine headache days over sequential 4 week intervals for observed cases in the ITT dataset.
Safety.— The most frequently reported (≥10%) treatment-emergent AEs were nausea (19%), vomiting (18%), weight gain (12%), nasopharyngitis (11%), migraine (10%), and upper respiratory tract infection (10%, Table 2). Migraines classified as AEs included worsening of pre-existing migraine headaches, new headache types, and/or migraine-associated symptoms that had not previously been experienced by the subject. AEs that led to premature discontinuation for 2 or more subjects included weight gain (n = 6), alopecia (n = 5), nausea (n = 4), increased ammonia (n = 3), migraine (n = 3), upper abdominal pain (n = 2), depressed mood (n = 2), depression (n = 2), and irritability (n = 2).
|Adverse event†||DVPX ER (N = 241) N (%)|
|Any adverse event||203 (84)|
|Weight gain||29 (12)|
|Upper respiratory tract infection||25 (10)|
A total of 10 subjects (4%) had 1 or more serious AEs (SAEs, Table 3). Six subjects experienced the following nonpsychiatric SAEs: abdominal pain/anorexia/nausea, wrist fracture, pneumonitis/elective abortion, postprocedural vomiting/pain, worsening migraine, and elective abortion. In addition, 4 subjects experienced psychiatric SAEs. One subject with a family history of depression and history of untreated attention-deficit hyperactivity disorder was hospitalized for depression following a suicide attempt with study drug. Another subject with a family history of bipolar disorder and schizophrenia was hospitalized for major depression and suicidal thoughts; her depression was thought to be related to the stress of her parents' divorce. A third subject was hospitalized because of suicidal ideation related to a recent sexual assault. A fourth subject with a history of impulsive aggression and attention-deficit hyperactivity disorder was hospitalized after a violent outburst at home. None of the SAEs experienced by these 10 subjects was classified by the investigator as being related to study drug.
|Gender/age||Preferred Term(s)||Reason serious||Onset (study day)||Severity||Relationship|
|Female/15||Depression†||Hospitalization||255||Severe||Probably not related|
|Female/17||Abdominal pain lower||Hospitalization||118||All severe||Not related|
|Male/14||Wrist fracture||Required intervention||384||Mild||Not related|
|Induced abortion||Required intervention||299||Severe||Not related|
|Female/17||Major depression†||Hospitalization||110||Severe||Probably not related|
|Female/16||Injury†||Hospitalization||200||Both severe||Both not related|
|Male/12||Impulse-control disorder†||Hospitalization||112 (1 day after last dose of study drug)||Severe||Probably not related|
|Female/14||Induced abortion||Required intervention||32||Severe||Not related|
|Male/16||Migraine||Hospitalization||20 days after last dose of study drug||Severe||Not related|
|Female/16||Postprocedural vomiting||Hospitalization||91||Severe||Both not related|
Laboratory changes in this study were consistent with prior studies of DVPX.14,15,20-26 Mean laboratory values that decreased ≥5% from baseline to final included platelet count (−29.0 × 109/L, SD = 47.9, baseline = 292.5 × 109/L), white blood cell count (−0.49 × 109/L, SD = 1.70, baseline = 6.82 × 109/L), percent basophils (−0.02%, SD = 0.20%, baseline = 0.33%), alkaline phosphatase (−23.7 U/L, SD = 46.3, baseline = 173.8 U/L), and cholesterol (−0.24 mmol/L, SD = 0.56, baseline = 4.33 mmol/L). Mean increases of ≥5% from baseline to final were observed for percent monocytes (0.42%, SD = 2.3, baseline = 5.4%), uric acid (37.8 µM/L, SD = 59.7, baseline = 271.3 µM/L), and ammonia (9.9 µM/L, SD = 24.9, baseline = 41.1 µM/L). In 43 subjects (18%), at least 1 ammonia level was classified as “very high” (≥90 µM/L). In most cases, these elevations were transient; ammonia levels returned to <90 µM/L at the final visit in 34 of 43 subjects (79%). None of the subjects with elevated ammonia levels were symptomatic. Some subjects prematurely discontinued from the study because of abnormal laboratory values, including 2 subjects with increased ammonia, 1 with elevated ammonia and increased bilirubin, 1 with leukopenia, and 1 with elevated liver enzymes and prolonged coagulation times.
Vital sign changes from baseline to final were minimal. Mean changes from baseline to final values for body weight and height were 3.43 kg and 2.26 cm, respectively. Mean body mass index increased 0.66 kg/m2; 6 (2%) subjects discontinued from the study because of an AE of weight gain. There were no clinically significant abnormalities in physical examinations or ECGs during the study.
Irregular menses were reported as an AE in 2 out of 119 postmenarchal female subjects and contributed to the premature discontinuation of one of these subjects from the study. In addition, although use of adequate birth control was required for study participation, 5 subjects became pregnant during the 1-year trial. Two delivered healthy babies, 2 had elective abortions, and the remaining subject was lost to follow up.
The UKU assessment indicated no DVPX ER-related increases in neurological, movement-related side effects over the 12-month study period. Parent ratings from the BASC demonstrated incremental improvement in subjects' adaptive and problem behaviors from baseline to months 6 and 12; final BASC scores for hyperactivity, aggression, anxiety, depression, somatization, atypicality, withdrawal, and attention problems were 0.1 to 7.0 points better than baseline. In addition, all WASI subtest T-scores (ie, vocabulary, matrix reasoning, similarities, block design) and IQ scores (ie, verbal, performance, and full) showed small numerical improvement from baseline to the end of treatment.
The present study evaluated the safety, tolerability, and efficacy of DVPX ER over a 1-year period in 241 adolescents with migraine. More than half of the subjects were ≥70% compliant with study medication for the extent of the trial, and another 24% were ≥70% compliant at all but 1 study visit. Overall, 53% of subjects completed the trial.
The most common AEs in this study (nausea, vomiting, weight gain, nasopharyngitis, migraine, upper respiratory tract infection) are consistent with those reported in previous controlled studies of DVPX in adults with migraine headache,4-6 as well as controlled14 and open-label DVPX ER migraine trials in adolescents.15 In addition, the laboratory parameters with the greatest degree of change from baseline (decreased platelets, increased uric acid, alkaline phosphatase, and ammonia) displayed similar changes in a previous, smaller long-term open-label safety study of DVPX ER in adolescents.15
Thrombocytopenia is known to be associated with DVPX treatment in children,23,24 adolescents,20 and adults22 and is described in the product labeling16. In addition, symptomatic and asymptomatic elevations in ammonia are recognized side effects of DVPX in pediatric and adult patients.21,25,26 In the present study, no subject with elevated ammonia was symptomatic.
While hyperammonemic encephalopathy should be considered in any patient who develops unexplained lethargy and vomiting or changes in mental status on DVPX, the clinical significance of asymptomatic elevated ammonia is unclear. A 2007 meta-analysis showed that asymptomatic elevations in ammonia are remarkably common in association with valproic acid or DVPX use in adults, with a mean prevalence of 90.3% in prospective studies and 47.3% in cross-sectional studies.27 In addition, a recent report suggests that a high proportion of elevated ammonia false positives are observed in pediatric patients (up to 48%).28 Ammonia measurements are greatly influenced by pre-analytical factors, including sampling technique, temperature, and time elapsed before analysis.28,29 The current study utilized venous blood, which is associated with greater assay variability than arterial samples.
Recently, concerns have been raised regarding a potential relationship between the use of antiepileptic drugs and suicidality.30 A 2008 meta-analysis conducted by the FDA on 11 antiepileptic drugs used for a variety of indications (epilepsy, bipolar disorder, migraine, etc.) in children and adults found a 1.8-fold increased risk of suicidal behavior or ideation among patients receiving antiepileptic drugs compared with those receiving placebo (0.43% vs 0.22%, estimated odds ratio 1.80, 95% CI 0.29, 1.84).31 This finding prompted an FDA alert emphasizing the need for careful monitoring for signs of suicidality among patients receiving this class of medication.30 The estimated odds ratio for suicidality associated with DVPX vs placebo in this meta-analysis was 0.72 (95% CI 0.29, 1.84).31 Although the DVPX studies analyzed by the FDA included primarily adult subjects, the overall analysis for all 11 antiepileptic drugs showed no pattern in drug effect with respect to age subgroups.31 During the present study of DVPX ER in adolescents with migraine, there were 2 suicide attempts and 1 occurrence of suicidal ideation. However, none of these events were considered related to DVPX ER treatment, but rather to traumatic life events and family histories of psychiatric illness.
Some reports have suggested that treatment with anticonvulsants for the prevention of migraine headache may adversely affect cognition and behavior.32-35 In the present study, there was no evidence of deleterious cognitive or behavioral effects in adolescents taking DVPX ER. It is also well-established that treatment with anticonvulsants may be associated with adverse motor effects.36 In a previous placebo-controlled trial of DVPX ER in adults with migraine, abnormal gait, tremor, and hypertonia were reported by >1% but less than 5% of DVPX ER-treated patients, and at higher frequency than the placebo group.16 However, in the present open-label study, no DVPX ER-associated movement disorders were detected in adolescent subjects with migraine, as assessed by the UKU Side Effect Scale.
Divalproex sodium has been implicated in the development of reproductive complications in female patients, including polycystic ovary syndrome37,38 and teratogenicity.16 In the present study, out of 119 postmenarchal female subjects, 2 reported irregular menses, and neither displayed any clinical evidence of hyperandrogenism. With regard to teratogenicity, for the 2 live births for which information is available, there was no evidence of any adverse outcome in the infants exposed to DVPX ER in utero.
Previous open-label9,13 and retrospective12 studies involving relatively small numbers of subjects have suggested that DVPX may be effective in the prevention of migraine in children and adolescents. In the current trial of 241 adolescents, median 4-week migraine headache days improved 75% between the first and the fourth 28-day period, with this effect persisting to the end of the 12-month study. However, interpretation of these results is limited by the open-label, nonplacebo-controlled conditions of the trial. Similar improvements were seen in an earlier 3-month double-blind, placebo-controlled study, but there was no statistically significant difference between groups treated with DVPX ER vs placebo.14
Along with the previous placebo-controlled trial14 and its open-label extension,15 the present 241-subject study extends and refines our understanding of the safety and tolerability of DVPX ER in adolescents with migraine. Although these results must be considered in the context of the study's open-label design, the AE, laboratory, and other safety findings are consistent with previous results from both adult4-6 and adolescent14,15 DVPX migraine studies, as well as with established experience with DVPX for other indications in adults.16 In the first of the 3 adolescent migraine trials, DVPX ER failed to demonstrate efficacy compared with placebo,14 but, taken together, safety results from the 3 studies14,15 support the conclusion that DVPX ER is generally well-tolerated in adolescents with migraine headaches.
Acknowledgments: The participation of the following investigators is gratefully acknowledged:
Jay L. Adler, MD, Clinicos, LLC, Colorado Springs, CO; Paul Aguillard, MD, Lake Ascension Physicians, Gonzales, LA; Sheena K. Aurora, MD, Swedish Headache Clinic, Seattle, WA; Roger Cady, MD, Clinvest/Headache Care Center, Springfield, MO; Richard V. Colan, MD, Milwaukee, WI; Robert Egel, MD, Advocate Hope Children's Hospital, Oak Lawn, IL; Arthur H. Elkind, M.D., P.C., Elkind Headache Center, Mount Vernon, NY; Joseph M. Elser, MD, Arkansas Children's Hospital Research Institute, Little Rock, AR; Jose A. Ferreira, MD, Pediatric Epilepsy & Neurology Specialists, Tampa, FL; Marvin Fishman, MD, Texas Children's Hospital, Houston, TX; Edward Goldstein, MD, Child Neurology Associates, PC, Atlanta, GA; Julie Jacques, DO, Healthstar Physicians, Morristown, TN; Azimuddin K. Kazi, MD, Neurological Specialists, PC, Stratford, CT; Siriwan Kriengkrairut, MD, St. Alexius Medical Center Clinical Research, Bismarck, ND; John Claude Krusz, MD, Dallas, TX; Donald Lewis, MD, Monarch Medical Research, Norfolk, VA; Steve Linder, MD, Dallas Pediatric Neurology Associates, Dallas, TX; Edwin Liu, MD, Pediatric Neurology and Epilepsy Center, Loxahatchee, FL; Cosme Lozano, MD, Joliet, IL; Michael Mann, MD, Bulverde, TX; Charles K. Powers, MD, Wilker/Powers Center for Clinical Studies, St. Cloud, FL; Alan D. Purdy, MD, Spokane, WA; Keith Reisinger, MD, Primary Physicians Research, Pittsburgh, PA; Harvey Resnick, MD, R/D Clinical Research, Lake Jackson, TX; Tonia Sabo, MD, Clinical Trials Organization, Denver, CO; Joel R. Saper, MD, Michigan Head Pain & Neurological Institute, Ann Arbor, MI; Elias H. Sarkis, MD, Sarkis Clinical Trials, Gainesville, FL; Nishant Shah, MD, Advocate Lutheran General Children's Hospital, Park Ridge, IL; Timothy R. Smith, MD, Mercy Health Research/Ryan Headache Center, St Louis, MO; Philip A. Snell, MD, Mountain View Clinical Research, Greer, SC; James Voirin, DO, Physician Associates, LLC, Oviedo, FL; Wendy Waldman, MD, Iowa Health Physicians, Des Moines, IA; Victoria D. Woods, MD, DMI Research, Largo, FL; John Wooten, MD, Raleigh Neurology, Raleigh, NC.
Special thanks to Alyssa O'Neill, Clinical Project Manager, for ensuring the careful and timely completion of this study, and to Muriel Cunningham for her medical writing and editing expertise.
- 10Low dose of sodium divalproate for the treatment of migraine. MedGenMed. 2003;5:32..
- 15Safety and tolerability of divalproex sodium extended-release in the prophylaxis of migraine headaches: Results of an open-label extension trial in adolescents. Headache. (submitted)., , , et al.
- 16Abbott Laboratories. Depakote ER (divalproex sodium extended-release tablets) prescribing information. North Chicago, IL 60064, USA. October 2006.
- 18Wechsler Abbreviated Scale of Intelligence. San Antonio, TX: The Psychological Corporation; 1999..
- 29Tietz Clinical Guide to Laboratory Tests, 4th edn. St Louis, MO: Saunders/Elsevier; 2006..
- 30United States Food and Drug Administration, Center for Drug Evaluation and Research. Information for Healthcare Professionals: Suicidality and Antiepileptic Drugs. 1/31/2008; Available at: http://www.fda.gov/cder/drug/InfoSheets/HCP/antiepilepticsHCP.htm (accessed May 2, 2008).
- 31United States Food and Drug Administration, Center for Drug Evaluation and Research. Statistical Review and Evaluation: Antiepileptic Drugs and Suicidality 5/23/2008; Available at: http://www.fda.gov/ohrms/dockets/ac/08/briefing/2008-4372b1-01-FDA.pdf (accessed August 7, 2008).
- 32Analysis of pooled data from two pivotal controlled trials on the efficacy of topiramate in the prevention of migraine. J Am Osteopath Assoc. 2007;107:251-258., , , et al.