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Safety and tolerance of rapidly infused Depacon®
Epilepsy Research 52 (2003) 189 /201 www.elsevier.com/locate/epilepsyres
Safety and tolerance of rapidly infused Depacon† A randomized trial in subjects with epilepsy R.E. Ramsay a,*, D. Cantrell b, S.D. Collins c, J.K. Walch c, D.K. Naritoku d, J.C. Cloyd e, K. Sommerville c, The Depacon Rapid Infusion Study Group a
International Center for Epilepsy, University of Miami, Professional Arts Building, 1150 NW 14th Street, Suite 410, Miami, FL 33136, USA b North Texas Neuroscience Center, Irving, TX, USA c Abbott Laboratories, North Chicago, IL, USA d Southern Illinois University School of Medicine, Springfield, IL, USA e University of Minnesota College of Pharmacy, Minneapolis, MN, USA Received 22 March 2002; received in revised form 15 August 2002; accepted 28 August 2002
Abstract Background: Valproate sodium injection (Depacon† ) is an intravenous form of valproate for use in absence and complex partial seizures when circumstances preclude oral administration. Certain situations may warrant larger and more rapid infusions than permitted by the original labeling. This study evaluated the safety of more rapid infusions. Methods: Subjects with epilepsy were randomized in a 2:1 ratio to receive up to 15 mg/kg of valproate sodium infused at 3.0 or 1.5 mg/kg/min. Up to four infusions were allowed within 24 h to achieve target plasma valproate concentrations of 50 /100 mcg/ml. Primary safety endpoints were the changes in the 5-min and minimum post-first infusion blood pressures (BPs). Results: One hundred twelve subjects were treated, (3.0 mg/kg/min group: n /72, 1.5 mg/kg/min group: n /40). No significant treatment differences were detected for changes in the primary BP endpoints. Two subjects in the 3.0 mg/kg/min group had potentially clinically significant low systolic BP values during the study. Similar proportions of subjects in the two groups reported adverse events during or within 6 h following the first infusion. Conclusions: Valproate sodium injection dosages up to 15 mg/kg and rates of 1.5 and 3.0 mg/kg/min were well tolerated in this population. # 2002 Elsevier Science B.V. All rights reserved. Keywords: Valproate; Seizures; Epilepsy; Intravenous infusion; Safety
1. Introduction * Corresponding author. Tel.: /1-305-243-5944x4; fax: 1305-243-7668. E-mail address: [email protected] (R.E. Ramsay).
Valproate is an antiepilepsy drug (AED) with a broad spectrum of activity against simple and
0920-1211/02/$ - see front matter # 2002 Elsevier Science B.V. All rights reserved. PII: S 0 9 2 0 - 1 2 1 1 ( 0 2 ) 0 0 1 8 7 - 0
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complex absence and complex partial seizure types. It has also been reported to be useful against other seizure types, including myoclonic and tonic /clonic seizures (Bourgeois, 1995). Valproate sodium injection (Depacon† ), a preparation of valproate for intravenous (IV) administration, is approved for use when clinical factors make oral valproate administration difficult or impossible. Original labeling indicates that valproate sodium injection be administered over a period of 60 min at rates up to 20 mg/min and recommends, for adjunctive therapy, that doses exceeding 250 mg be given in divided doses (Abbott Laboratories, 2000). In certain clinical situations (e.g. drop in plasma drug levels, pre- and postsurgery, seizure clusters, status epilepticus, or rapid introduction of a new agent if seizures are uncontrolled on baseline medications), use of larger doses and more rapid delivery times have advantages. They would provide increases in plasma drug concentrations to attain steady-state or clinically necessary drug levels more quickly than with the original labeling. The effects of large valproate doses administered intravenously have been studied using animal models (Honack and Loscher, 1992; Turski et al., 1987; Walton and Treiman, 1992). Additionally, the pharmacokinetics of IV valproate have been studied in healthy adults, with rates of infusion up to 3.0 mg/kg/min and doses up to 1000 mg (Granneman et al., 1989; Hussein et al., 1993; Perucca et al., 1978). The studies demonstrated that IV valproate was well tolerated at these rates and doses; notably, no significant alterations in blood pressure, cardiac rhythm, state of consciousness, or respiratory rate occurred. Additionally, several studies have reported use of IV valproate infusions of approximately 30/50 mg/min (Ramsay et al., 2000; Venkataraman and Wheless, 1999) or 3 /6 mg/kg/min (Naritoku and Mueed, 1999; Sinha and Naritoku, 2000) in adults and children without clinically important safety concerns, such as significant changes in blood pressure or electrocardiographic (ECG) abnormalities. The present study was designed to evaluate the safety of two more rapid infusions of IV valproate in a larger group of subjects.
2. Methods 2.1. Protocol This study was an open-label, randomized, Phase IIIB, parallel-group, multicenter trial of valproate sodium injection administered intravenously to subjects with epilepsy. The study consisted of two phases: an infusion phase and an optional maintenance phase. Subjects were randomized in a 2:1 ratio to receive valproate sodium injection at a rate of either 3.0 or 1.5 mg/kg/min, for a total dose of up to 15 mg/kg per infusion. Up to four infusions of IV valproate (with at least 2 h separating each infusion) were allowed within the 24-h infusion phase. Once a target plasma valproate concentration of 50 /100 mcg/ ml was achieved or the investigator assessed the concentration to be adequate, the subject could be given an oral valproate product for use outside the protocol or continue on valproate sodium injection for up to 14 days during the maintenance phase of the study. Subjects were to return 1 week following the final infusion for a follow-up laboratory assessment and discussion of any adverse events. Subjects at least 2 years of age with a history of complex partial or absence seizures who had a clinical need for rapid valproate infusion were eligible for the study. The target sample size was 35 subjects in the 1.5 mg/kg/min group and 70 subjects in the 3.0 mg/kg/min group. This sample size allowed for the detection of a 10 mmHg difference between the treatment group means of the 5-min post-infusion systolic blood pressures with at least 80% power. Eligible subjects had no episodes of ‘serial seizures’ or ‘flurries’ within 24 h prior to the start of the study, had not experienced status epilepticus within 30 days prior to the start of the study, and had no prior history of Lennox / Gastaut syndrome or continuous spike waves in sleep. Subjects were excluded from the study if they had taken felbamate or experimental drugs within the previous 30 days. Subjects were also excluded if they had any significant history of cardiac, renal, neurological, psychiatric, oncologic, endocrine, hepatic, or metabolic disease that would have adversely affected their participation
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in the study, or if they displayed cardiac arrhythmias. Subjects with a clinical or serological history of hepatitis or thrombocytopenia were also excluded. Female subjects of childbearing potential were required to have a negative pregnancy test result prior to entering the study. Three categories of clinical need were targeted in this study: (1) patients with epilepsy best treated with valproate, with low or undetectable plasma valproate levels; (2) patients requiring re-introduction of valproate; and (3) patients who were unable to tolerate oral valproate delivery or who were temporarily restricted from taking oral medication. 2.2. Informed consent All subjects provided written informed consent prior to the initiation of any study procedures.
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Blood pressure was monitored during the infusion phase prior to each infusion and at 5, 10, 20, and 30 min post-infusion, or until baseline blood pressure was reached (if blood pressure reductions had occurred). Blood samples for free and total plasma valproate levels were obtained at various times throughout the infusion phase to assess whether there was a possible temporal relationship to adverse events. Free and total plasma valproate levels were measured using a commercially available Fluorescence Polarization Immunoassay (FPIA) on the TDx/TDxFLx system. Unbound drug was separated using ultrafiltration. Adverse events were collected throughout the study up to 30 days following discontinuation of valproate sodium injection and were categorized using COSTART V (Coding Symbols for a Thesaurus of Adverse Reaction Terms Dictionary). 2.5. Treatment administration
2.3. Patient assignment Eligible subjects were assigned subject numbers in ascending numerical order at each site. The subject number encoded the subject’s assignment to one of the two infusion rates (i.e. 1.5 or 3.0 mg/ kg/min). Randomization schedules were generated by the Statistics Department of Abbott Laboratories prior to study initiation. Blind-breaking envelopes containing the randomized rate were provided to study sites by Abbott Laboratories. Once a suitable subject was identified, the lowest subject-numbered envelope was opened, identifying to which of the two treatment groups the subject was assigned. 2.4. Data collected Subjects provided medical and seizure histories and underwent physical, neurological, and cardiac examinations. Vital signs were obtained, and blood samples were collected for the following laboratory tests: full chemistry panel, complete blood count, pregnancy, and total plasma valproate level. ECG recordings were obtained prior to drug administration, and ECG monitoring was maintained throughout each infusion and for 5 min post-infusion during the infusion phase.
Valproate sodium injection was supplied in 5-ml single-use vials. Each milliliter contained valproate sodium equivalent to 100 mg of valproic acid. Each vial was to be diluted with at least 50 ml of a compatible diluent. If, however, subjects (e.g. children with small catheters or elderly subjects) had clinical situations that required dilution volumes less than 50 ml in order to allow accurate delivery of either 1.5 or 3.0 mg/kg/min, the diluent volume could be reduced according to clinical judgment. In such cases, the volume of infusion could be reduced to allow accurate delivery, but the ratio of valproate sodium injection to the total volume of the infusion was not to be less than 1:5 (e.g. 5 ml of valproate sodium injection in 20 ml of compatible diluent), and in no instance was valproate sodium injection to be diluted with B/5 ml of diluent. Subjects were to receive an infusion at one of the aforementioned rates, for a total dose of up to 15 mg/kg per infusion (maximum dose /60 mg/kg in 24 h). In most cases, target plasma concentrations were attained after one infusion. However, if after the first infusion, plasma levels were below 50 mg/ l, up to three subsequent infusions (up to 15 mg/kg each) could be administered within 24 h. A minimum of a 2-h time lapse was required between
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infusions. The following equation, along with the results of the 1-h post-infusion plasma valproate level from the previous infusion, was used to determine the dosage for the subsequent infusion needed to attain the target plasma concentration: D W DCp Vd est; D /dose (mg), W /body mass (kg), DCp /desired change in plasma concentration (mg/l), and Vd est /estimated volume of distribution (l/kg). The volume of distribution for valproate has been estimated to range from 0.12 to 0.23 l/kg (Levy and Shen, 1989). For the purposes of this study, a value of 0.20 l/kg was used for the estimated volume of distribution. 2.6. Discontinuation from study Subjects were free to withdraw from the study of their own accord at any time. Subjects were removed from study participation if they experienced any of the following: status epilepticus, hypotension (blood pressure drop of /30 mmHg systolic and/or /20 mmHg diastolic) with symptoms, high-grade arrhythmia, chest pain, a need for a valproate sodium injection dosage /15 mg/kg in a single infusion or /60 mg/kg in a 24-h period during either phase of the study, a need for re-infusion during the infusion phase that was sooner than 2 h after the previous infusion, an IV maintenance phase of /14 days, or the need for a dosing interval of less than every 6 h during that phase. 2.7. Statistical methods Data were analyzed according to the infusion rate subjects came closest to matching (i.e. subjects whose first infusion was at a rate B/2.25 mg/kg/ min were grouped under the 1.5 mg/kg/min group, and those whose first infusion was at a rate /2.25 mg/kg/min were grouped under the 3.0 mg/kg/min group), and not necessarily according to their randomized treatment group. All subjects treated with study drug were evaluated. All statistical tests were two-tailed at the 0.05 level of significance. The primary safety endpoints were the changes from baseline in the 5-min and minimum post-first
infusion systolic and diastolic blood pressures. Changes from baseline in blood pressure to the end of the infusion, to the 10-, 20-, and 30-min post-first infusion measurements, and to the maximum value following the first infusion were also evaluated. A one-way analysis of variance (ANOVA) was used to compare treatment groups. The secondary endpoints were the proportions of subjects reporting treatment-emergent adverse events, for which treatment group differences were evaluated using Fisher’s exact test for each COSTART term. Ninety-five percent confidence intervals (CIs) for the treatment differences in these endpoints were also computed. In addition to the planned analyses, a regression analysis, which treated subjects’ actual infusion rate as a continuous predictor variable, was used to analyze the linear relationship between changes from baseline in blood pressure at each of the above-mentioned evaluation points and subjects’ actual infusion rate. Changes in laboratory variables from baseline to the 1-week follow-up visit were also analyzed by one-way ANOVA.
3. Results A total of 112 subjects were randomized at 12 investigational sites, and all received study drug; 37 were randomized to 1.5 mg/kg/min valproate sodium injection, and 75 were randomized to receive 3.0 mg/kg/min valproate sodium injection. Patient disposition during the study is depicted in Fig. 1. Three subjects randomized to receive 1.5 mg/kg/min and six subjects randomized to 3.0 mg/ kg/min received their first infusion at an infusion rate closer to the opposite treatment group. Therefore, for purposes of analysis, 72 subjects were included in the 3.0 mg/kg/min group (with an infusion rate of /2.25 mg/kg/min), and 40 subjects were included in the 1.5 mg/kg/min group (with an infusion rate of B/2.25 mg/kg/min). Fig. 2 depicts the distribution of valproate dosages (for the first infusion) administered in each treatment group. The mean age of all subjects was 36.3 years (range /13 months to 79 years). Sixty-one of 112 (54%) subjects were male; 78 (70%) were Cauca-
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Fig. 1. Patient disposition.
Fig. 2. Valproate dosages administered in each treatment group (first infusion, n /112).
sian, and 21 (19%) were African /American. No significant differences were noted between treatment groups in age, sex, race, weight, or height. No significant differences were noted between treatment groups for the following variables:
number of years with epilepsy, number of AEDs ever taken, reason for enrollment, epilepsy type, seizure types ever experienced, or types of status epilepticus ever experienced (Table 1). One hundred nine of the 112 subjects received a single infusion. The first infusion was within 0.1 mg/kg/min of the assigned 1.5 or 3.0 mg/kg/min rate for at least 70% of subjects in each treatment group. Two subjects in the 3.0 mg/kg/min group received a second infusion during the infusion phase, and one additional subject in the 3.0 mg/kg/ min group received two infusions during the maintenance phase. A summary of the dosage and distribution of infusion rates for the first infusion is presented in Table 2. Peak total and free valproate concentrations of approximately 94.4 and 14.3 mcg/ml (means across treatment groups), respectively, were observed, followed by a log-linear decay of plasma concentration. By 4/5 h following the first infusion,
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Table 1 Subject disease characteristics Disease characteristic
Treatment group 1.5 mg/kg/min (n / 40)
P value 3.0 mg/kg/min (n / 72)
Median (range) years with epilepsy
11.5 (1.0 /51.8)
11.5 (1.0 /47.4)
0.820
Mean (SD) number of antiepilepsy drugs ever taken
4.4 (2.92)
3.5 (2.69)
0.142
Reason for enrollment Epilepsy best treated with valproate, with low or 0 plasma levels of valproate Subject being reintroduced to valproate
27 (68%)
57 (79%)
13 (33%)
15 (21%)
Epilepsy type Focal Generalized Either
30 (75%) 9 (23%) 1 (3%)
49 (68%) 22 (31%) 1 (1%)
Seizure types ever experienceda,b Absence Complex partial evolving to generalized tonic /clonic Complex partial Generalized tonic /clonic Myoclonic Partial evolving to generalized tonic /clonic Simple partial Tonic Other
2 (5%) 5 (13%) 30 (75%) 22 (55%) 2 (5%) 1 (3%) 12 (30%) 0 (0%) 3 (8%)
9 (13%) 6 (8%) 47 (65%) 46 (64%) 7 (10%) 0 (0%) 22 (31%) 2 (3%) 3 (4%)
0.322 0.518 0.395 0.421 0.486 0.357 /0.999 0.537 0.665
Status epilepticus types ever experienced /30 days prior to studyb Generalized tonic /clonic Myoclonic Secondary generalized tonic /clonic Complex partial
1 0 4 3
0 1 5 2
0.570 0.357 /0.999 0.719 0.346
a b
0.181
0.570
(3%) (0%) (10%) (8%)
(0%) (1%) (7%) (3%)
75% of subjects had complex partial seizures and/or absence seizures. Some subjects had multiple seizure types.
plasma valproate concentrations had fallen below 50 mcg/ml for both infusion rates. Plasma concentration /time profiles for the two groups were similar. The mean plasma concentration /time profile for all subjects is presented in Fig. 3. Valproate concentrations declined more rapidly in hepatic enzyme-induced subjects (i.e. subjects receiving agents, such as phenobarbital, phenytoin, and carbamazepine, which increase valproate clearance). No significant differences in systolic or diastolic blood pressure were observed between treatment groups in the analysis of mean change from baseline to the primary protocol-specified endpoints of 5 min post-first infusion and the mini-
mum of all values post-infusion (Table 3). No significant differences in blood pressure were observed between treatment groups in the analysis of mean change from baseline to any of the other post-first infusion endpoints, with the exception of the 20-min post-first infusion measurement for diastolic blood pressure. This difference was not considered to be clinically important, as the diastolic blood pressure values for both groups at this time period were within the normal range. Mean systolic and diastolic blood pressure values following the first infusion for each group are shown in Figs. 4 and 5. Linear regression results indicated that the infusion rate did not significantly affect either the
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Table 2 Infusion phase valproate sodium injection administration Treatment group 1.5 mg/kg/min (n /40)a
3.0 mg/kg/min (n /72)b
Mean (SD ) valproate sodium dose for the first infusion mg 1184.4 (411.21) 1088.3 (363.10) mg/kg 14.4 (1.54) 14.7 (1.08) mg/kg/min 1.6 (0.24) 3.0 (0.20) Distribution of infusion More than 0.1 mg/kg/ min lessc Within 9/0.1 mg/kg/ minc More than 0.1 mg/kg/ min overc
rate for the first infusion , n (%) 3 (8%) 7 (10%) 28 (70%)
60 (83%)
9 (23%)
5 (7%)
Mean Vd (9/SD) for all subjects /0.179/0.04 l/kg; 69% of subjects had a Vd ranging from 0.14 to 0.2 l/kg. a Included subjects infused at a rate B/2.25 mg/kg/min. b Included subjects infused at a rate /2.25 mg/kg/min. c Versus the assigned 1.5 or 3.0 mg/kg/min rate.
Fig. 3. Mean total and free valproic acid plasma concentration /time (hours) profiles following the first infusion (n /109). Note: Error bars represent standard deviations. Suggested oral dose initiation indicates the optimum window of time for oral divalproex sodium to be started.
systolic or diastolic blood pressure changes from baseline at any of the post-first infusion endpoints evaluated. Three subjects had a vital sign value that met predefined criteria for potential clinical significance. While each of the values met the criteria, patients remained asymptomatic. Two subjects
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(Subject #109 and #803) in the 3.0 mg/kg/min group each had a systolic blood pressure measurement that was 5/90 mmHg and was decreased by ]/30 mmHg from baseline following the first valproate infusion. Subject #109 (age 39) had a systolic blood pressure of 83 mmHg 30 min after the infusion, a 32 mmHg decrease from the preinfusion recording. At the end of dosing through the 20-min post-infusion recording, systolic blood pressure ranged from 106 to 112 mmHg. At the 1week follow-up visit, the subject’s blood pressure was 126/70 mmHg. An adverse event of hypotension without clinical symptoms was recorded for Subject 803 (age 36), who had a systolic blood pressure of 74 mmHg at the end of the infusion, a 31 mmHg decrease from the pre-infusion recording. Hypotension resolved upon supine positioning of the subject. At 5 /30 min post-infusion, the subject’s systolic blood pressure ranged from 99 to 101 mmHg. The subject’s blood pressure was 112/ 68 mmHg at the follow-up visit. A third subject in the 3.0 mg/kg/min group (#719, age 64) had a diastolic blood pressure (120 mmHg) at the end of the first infusion that was ]/105 mmHg and was increased by ]/30 mmHg from a baseline of 74 mmHg. At 5 /30 min after dosing, diastolic blood pressure ranged from 82 to 86 mmHg. The subject’s blood pressure was 154/88 mmHg at the follow-up visit. Adverse events tended to occur in association with peak plasma valproate levels. The incidence of adverse events emerging during or within 6 h following the first infusion was similar between treatment groups (Table 4). The most common adverse events emerging during this time period were somnolence, paresthesia, dizziness, and nausea, which were all mild in severity, except for one case of nausea, which was moderate in severity. Additionally, the incidence of adverse events emerging during or within 1 h following the first infusion was similar between treatment groups (8/ 40 [20%] for the 1.5 mg/kg/min group; 14/72 [19%] for the 3.0 mg/kg/min group). No significant differences were noted between treatment groups in the incidence of any particular adverse event emerging during or within 1 or 6 h following the first infusion.
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Table 3 Changes from baseline in systolic and diastolic blood pressure Endpoint (first infusion)
End of infusion Systolic Diastolic
Mean changea (SD) 1.5 mg/kg/min
3.0 mg/kg/min
0.5 (10.79) 0.0 (8.27)
0.8 (10.70) 2.1 (9.11)
Treatment differenceb
95% CI (L, U) treatment difference
P value
0.3 2.1
/4.0, 4.5 /1.4, 5.7
0.907 0.236
5 min post-infusion Systolic Diastolic
1.0 (9.9) /0.3 (8.41)
/1.6 (7.76) 1.5 (8.06)
/2.6 1.7
/6.1, 1.0 /1.6, 5.1
0.153 0.305
10 min post-infusion Systolic Diastolic
/0.9 (12.05) /0.5 (8.56)
/0.8 (8.87) /0.7 (8.05)
0.1 /0.2
/4.0, 4.2 /3.6, 3.1
0.967 0.900
20 min post-infusion Systolic Diastolic
0.8 (11.92) /2.7 (9.47)
/1.1 (11.45) 0.9 (8.46)
/1.9 3.6
/6.7, 2.9 0.0, 7.3
0.429 0.049*
30 min post-infusion Systolic Diastolic
0.7 (11.77) /1.3 (10.01)
/1.3 (10.45) 0.6 (8.71)
/1.9 2.0
/6.3, 2.5 /1.7, 5.7
0.388 0.292
Minimum post-infusion value Systolic /6.2 (9.02) Diastolic /6.1 (9.10)
/8.2 (10.03) /4.4 (6.93)
/2.0 1.6
/5.8, 1.8 /1.5, 4.7
0.291 0.300
Maximum post-infusion value Systolic 6.8 (12.50) Diastolic 4.7 (8.48)
6.6 (8.79) 6.6 (9.26)
/0.2 1.9
/4.2, 3.9 /1.7, 5.4
0.939 0.299
CI (L, U) /lower and upper limits. a Mean baseline blood pressure values were 124.9 (systolic) and 75.3 mmHg (diastolic) for the 1.5 mg/kg/min group and 125.0 (systolic) and 71.9 mmHg (diastolic) for the 3.0 mg/kg/min group. b Mean change from baseline for the 3.0 mg/kg/min group minus the mean change from baseline for the 1.5 mg/kg/min group at the time point indicated. * Significant difference between treatment groups (P B/0.05).
Treatment-emergent adverse events, including all events reported up to 30 days following the last infusion, occurred with similar incidence in the 1.5 and 3.0 mg/kg/min groups (17/40 [42.5%] and 37/ 72 [51.4%] of subjects, respectively; P /0.432). The most commonly reported treatment-emergent adverse events in the 1.5 mg/kg/min group (n /40) included somnolence in six patients (15%), nausea in four patients (10%), dyspepsia in three patients (8%), dizziness in three patients (8%), asthenia in two patients (5%), paresthesia in two patients (5%), and vomiting in two patients (5%). Similarly, in the 3.0 mg/kg/min group (n /72), reports of somnolence were noted in seven patients (10%), nausea in six patients (8%), dyspepsia in one patient (1%), dizziness in seven patients (10%),
asthenia in six patients (8%), paresthesia in six patients (8%), and vomiting in two patients (3%). In both treatment groups, most of these treatmentemergent adverse events were mild or moderate in severity, and none occurred with significantly greater incidence in either treatment group. Serious treatment-emergent adverse events were reported by three subjects. Two events were reported by one subject in the 1.5 mg/kg/min group (stupor and dyspnea) 7 days post-treatment. The subject died on the same day, and this death was believed to be from breast cancer, metastatic to the brain, and unrelated to the study drug. Serious adverse events were reported in two subjects in the 3.0 mg/kg/min group (hostility, increased drug level, and confusion in one subject;
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Fig. 4. Mean systolic blood pressure following the first infusion. Note: Error bars represent standard deviations. For the 1.5 mg/kg/min group: n /40 (baseline), n /39 (end of infusion), n /38 (5 min), n /37 (10 min), n /36 (20 min), and n / 38 (30 min). For the 3.0 mg/kg/min group: n /71 (baseline), n /67 (end of infusion), n /64 (5 min), n /67 (10 min), n /67 (20 min), and n /68 (30 min).
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encephalopathy in another subject). The hostility, increased drug level, and confusion occurred 6 days post-infusion, were considered to be unrelated to the IV valproate infusion. The events resolved within 8 days, and the investigator thought they were related to oral AED therapy (carbamazepine, lamotrigine, and divalproex sodium). The one serious adverse event that was considered by the investigator as possibly related to the study drug was encephalopathy, which occurred 4 days following a single infusion of 3.0 mg/kg/min and a peak plasma valproate concentration of 123 mcg/ml. Oral valproate was discontinued in this subject, and the adverse event resolved within 3 days. No significant differences were noted between the treatment groups in the change from baseline to the 1-week follow-up evaluation for any hematology or clinical chemistry variables, with the exception of blood urea nitrogen (BUN). A significant difference between the treatment groups in the mean change from baseline for BUN was observed ( /1.5 mg/dl from a mean baseline value of 14.3 mg/dl for the 1.5 mg/kg/min group, and 1.5 mg/dl from a mean baseline value of 13.0 mg/dl for the 3.0 mg/kg/min group, P B/ 0.05); however, this treatment difference was not considered clinically significant. No adverse events, such as thrombocytopenia or increased liver function tests, were reported in either treatment group, and no subjects had platelet values that met predefined criteria for potential clinical significance. 3.1. Protocol deviations
Fig. 5. Mean diastolic blood pressure following the first infusion. Note: Error bars represent standard deviations. For the 1.5 mg/kg/min group: n /40 (baseline), n /39 (end of infusion), n /38 (5 min), n /37 (10 min), n /36 (20 min), and n /38 (30 min). For the 3.0 mg/kg/min group: n /71 (baseline), n /66 (end of infusion), n /64 (5 min), n /67 (10 min), n /67 (20 min), and n /68 (30 min).
As previously mentioned, the evaluation of nine subjects who received their first infusion at a rate closer to the opposite randomized treatment group, and their subsequent recategorization into the treatment group most closely resembling their actual infusion rate, deviated from the original study protocol. Other protocol deviations included 24 subjects (including six of those nine whose treatment group was recategorized) in whom the first infusion was not administered at a rate that was within 0.1 mg/kg/min of either the 1.5 or 3.0 mg/kg/min rates, 28 subjects who received an
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Table 4 Summary of most frequently reported adverse events emerging during or within 6 h following the first infusion COSTART terma
Treatment differenceb, 95% Cl (L, U)c
Treatment group 1.5 mg/kg/min (n /40) Severity
3.0 mg/kg/min (n /72) Total
Mild Moderate
Severe n (%)
Somnolence Dizziness Nausea Paresthesia
3 2 2 2
0 0 0 0
0 0 0 0
Total
9
0
0
3 2 2 2
(7.5%) (5.0%) (5.0%) (5.0%)
Severity
Total
Mild Moderate
n (%)
4 5 2 5
0 0 1 0
9 (22.5%) 18
1
4 5 3 5
(5.6%) (6.9%) (4.2%) (6.9%)
19 (26.4%)
/1.9% 1.9% /0.8% 1.9%
( /22.3, ( /13.7, ( /20.8, ( /13.7,
11.4%) 21.6%) 11.4%) 21.6%)
3.9% ( /15.4, 24.3%)
Cl (L, U) /lower and upper limits of exact confidence interval. a Adverse events occuring in ]/5.0% of subjects in either treatment group. b Total incidence for the 3.0 mg/kg/min group minus the total incidence for the 1.5 mg/kg/min group. c Exact confidence interval.
infusion in which the volume was B/50 ml, 20 subjects who did not meet all admission criteria (including one subject who was less than 2 years of age /subject was 13 months old), four subjects who were administered oral valproate B/6 h postinfusion, and three subjects at one site who were not assigned subject numbers in ascending numerical order. For the 24 subjects (12 in each treatment group) whose actual first infusion rate varied by more than 0.1 mg/kg/min from the protocoldefined rates, the mean infusion rates in the 1.5 and 3.0 mg/kg/min groups were 1.74 (range: 1.00 / 2.15 mg/kg/min) and 2.92 mg/kg/min (range: 2.34 / 3.72 mg/kg/min), respectively. Of these other protocol deviations, none were considered to have had a clinically important impact on the study’s outcome.
4. Discussion In this study, valproate sodium injection was safe and well tolerated at infusion rates of 1.5 and 3.0 mg/kg/min at doses of up to 15 mg/kg per infusion. It has been suggested that in certain clinical situations, infusion at a rate greater than 1.5 mg/kg/min may be justified (Alfonso et al., 1999; Alvarez et al., 1999; Edwards et al., 1999; Kriel et al., 1999; Leniger and Hufnagel, 1999;
Limdi and Faught, 1999; Peters and Pohlmann, 1999; Peters and Pohlmann-Eden, 1999; Sherman, 1999; Short et al., 1999; Venkataraman and Wheless, 1999; Wheless and Venkataraman, 1998). In general, these situations involve subjects for whom the risk for the occurrence of frequent and many seizures is high and immediate action is necessary. For example, in patients with a history of frequent seizures awaiting surgery or presenting in an emergency department in a post-ictal state after one or more seizures, the oral route of medication may be unavailable or would be associated with an unacceptable delay in attaining therapeutic drug concentrations. In many patients with refractory epilepsy, frequent daily seizures occur, even in the setting of the best available therapy. Evidence for this is demonstrated by data from several previous clinical trials of divalproex sodium and tiagabine HCl (Beydoun et al., 1997; Mattson et al., 1985; Sachdeo et al., 1997; Uthman et al., 1998; Willmore et al., 1996). Baseline evaluation of subjects showed that 25% experienced complex partial seizures at frequencies of at least 3.1 /4.7 per week (maximum 417 per week). From this evaluation, one can conclude that a significant proportion of patients with refractory epilepsy, in the situations outlined above, are at risk of morbidity and mortality associated with frequent seizures and need a timely means of
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intervention available to increase AED concentrations to therapeutic levels. In such instances, IV valproate infusion rates of 20 mg/min over 60-min time periods may not provide adequate seizure protection in a timely fashion. Previous smaller studies of valproate sodium injection have demonstrated that larger doses and/ or more rapid infusions were well tolerated (Naritoku and Mueed, 1999; Ramsay et al., 2000; Sinha and Naritoku, 2000; Venkataraman and Wheless, 1999; Wheless and Venkataraman, 1998). The present study included a larger subject base than the previously mentioned studies of high-dose and/or rapidly infused valproate, including both children and adults with a range of clinical conditions. The infusion rates chosen for the study, 1.5 and 3.0 mg/kg/min, were considered clinically appropriate (for an epilepsy population with complex partial or absence seizures requiring a rapid infusion of valproic acid), but sufficiently different to assess whether infusion rate affected important safety parameters. Analysis of safety parameters demonstrated no significant differences between the infusion rates of 1.5 and 3.0 mg/kg/min that were considered clinically important. The pharmacokinetics of valproate after a single 15 mg/kg infusion were consistent with previous studies in healthy volunteers (Cavanaugh et al., 1994; Hussein et al., 1994, 1993). Doses were calculated according to standard pharmacokinetic formula. The peak concentrations attained matched predicted values. Peak valproate concentrations were within 22% of 50 /100 mcg/ml in all subjects with both infusion rates, suggesting that valproate concentrations are predictable following rapid infusion, and therapeutic levels are quickly attained. Plasma concentration decay times were log-linear for both total and free valproate and fell below 50 mcg/ml within 4/5 h post-dose for both infusion rates. These data suggest oral dosing with the standard divalproex sodium (not the extendedrelease formulation) may need to start from 1 to 3 h post-infusion in order to maintain concentrations above 50 mcg/ml. Given the longer Tmax of the new, once-a-day, extended-release formulation of divalproex sodium (Depakote† ER), dosing with this formulation may need to start concurrent
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with the infusion, although it is important to note that Depakote† ER is not yet approved for use in epilepsy. There was no difference between the two infusion rates in changes in laboratory tests. There was also a relative lack of respiratory depression, arrhythmias, and hypotension noted in this study. This is in contrast to other commonly used parenteral AEDs, such as lorazepam, phenobarbital, diazepam, and phenytoin, which have been variably associated with hypoventilation, cardiacrhythm disturbances, and/or hypotension (Treiman et al., 1998). Notably, in this study, only two subjects (1.8%) had potentially clinically significant low blood pressure values; this is in contrast to fosphenytoin and phenytoin, which have been associated with hypotension in 7.7 and 9.1% of patients, respectively (Parke-Davis, 1999). No infusion rate-related safety issues and no new safety issues associated with valproate sodium injection were noted in this study. Overall, data obtained from this trial indicate that valproate sodium injection is well tolerated in subjects with epilepsy when it is administered in dosages up to 15 mg/kg per infusion at rates up to 3.0 mg/kg/ min. The results of this controlled trial support previous studies and anecdotal reports of high infusion rates of valproate that are well tolerated among patients with epilepsy who are otherwise healthy or in patients who are unstable from other conditions (Czapinski and Terczynski, 1998; Sinha and Naritoku, 2000; Wheless and Venkataraman, 1998). The rapid infusion rate and good tolerability make valproate sodium injection a likely candidate for future study in acute seizure management.
5. Participating investigators Deborah T. Combs Cantrell, MD, North Texas Neuroscience Center, Irving, TX; James C. Cloyd, PharmD, University of Minnesota College of Pharmacy, Minneapolis, MN; John R. Gates, MD, Minnesota Epilepsy Group, PA, St. Paul, MN; Andres M. Kanner, MD, Rush-PresbyterianSt. Luke’s Medical Center, Chicago, IL; Ruben I. Kuzniecky, MD, University of Alabama Epilepsy
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Center, Birmingham, AL; David M. Labiner, MD, University of Arizona Department of Neurology, Tucson, Az; Georgia D. Montouris, MD, The Comprehensive Epilepsy Center, Chesterfield, Missouri; George L. Morris, MD, Medical College of Wisconsin Department of Neurology, Milwaukee, Wi; Dean K. Naritoku, MD, SIU School of Medicine Department of Neurology, Springfield, IL; John M. Pellock, MD, Medical College of Virginia/Virginia Commonwealth University, Richmond, VA; R. Eugene Ramsay, MD, University of Miami International Center for Epilepsy, Miami, FL; Blanca Vasquez, MD, NYUMt. Sinai School of Medicine, New York, NY; James W. Wheless, MD, The University of Texas Medical School at Houston, Houston, TX.
Acknowledgements This research was supported by Abbott Laboratories. The authors would like to thank Guoliang Cao, Roger Deaton, Sandeep Dutta, PhD, Yihua Giu, and David Morris, PhD, for their technical expertise in the development and analysis of this study.
References Abbott Laboratories, 2000. Depacon† [valproate sodium injection package insert]. North Chicago, IL. Alfonso, I., Perea, A., Paez, J.C., Dunoyer, C., Yelin, K., Alvarez, L., 1999. Intravenous valproic acid dose in neonates [abstract]. Epilepsia 40 (Suppl. 7), 143. Alvarez, L., Dunoyer, C., Gilman, J., Alfonso, I., Resnick, T., Duchowny, M., Jayakar, P., 1999. Safety and dose/level relationship in rapid intravenous loading of valproic acid in children under age 12 years [abstract]. Epilepsia 40 (Suppl. 7), 143. Beydoun, A., Sackellares, J.C., Shu, V., 1997. Safety and efficacy of divalproex sodium monotherapy in partial epilepsy: a double-blind, concentration-response design clinical trial. Neurology 48, 182 /188. Bourgeois, B.F.D., 1995. Valproic acid-clinical use. In: Levy, R.H., Mattson, R.H., Meldrum, B.S. (Eds.), Antiepileptic Drugs, 4th ed.. Raven Press, New York. Cavanaugh, J.H., Hussein, Z., Lamm, J., Granneman, G.R., 1994. Pharmacokinetics of multiple oral dose divalproex sodium after intravenous loading dose administration in healthy volunteers. Drug Invest. 7, 1 /7.
Czapinski, P., Terczynski, A., 1998. Intravenous valproic acid administration in status epilepticus [in Polish]. Neurol. Neurochir. 32, 11 /22. Edwards, K.R., Shea, P., Behnke, M., 1999. Acute treatment of migraine headache with intravenous valproate (Depacon) [abstract]. Epilepsia 40 (Suppl. 7), 143. Granneman, G.R., Lamm, J.E., Cavanaugh, J.H., 1989. Assessment of pharmacokinetics of sodium valproate injectable [abstract]. Epilepsia 30, 668. Honack, D., Loscher, W., 1992. Intravenous valproate: onset and duration of anticonvulsant activity against a series of electroconvulsions in comparison with diazepam and phenytoin. Epilepsy Res. 13, 215 /221. Hussein, Z., Mukherjee, D., Lamm, J., Cavanaugh, J.H., Granneman, G.R., 1994. Pharmacokinetics of valproate after multiple-dose oral and intravenous infusion administration: gastrointestinal-related diurnal variation. J. Clin. Pharmacol. 34, 754 /759. Hussein, Z., Patterson, K.J., Lamm, J.E., Cavanaugh, J.H., Granneman, G.R., 1993. Effect of infusion duration on valproate pharmacokinetics. Biopharm. Drug Dispos. 14, 389 /399. Kriel, R.L., Birnbaum, A.K., Norberg, S.K., Wical, B.S., Le, D.N., Cloyd, J.C., 1999. Pharmacokinetics of total and unbound valproate after rapid infusion of Depacon [abstract]. Epilepsia 40 (Suppl. 7), 232. Leniger, T., Hufnagel, A., 1999. Nonconvulsive status epilepticus treated with intravenous valproate [abstract]. Epilepsia 40 (Suppl. 7), 149. Levy, R.H., Shen, D.D., 1989. Valproate Absorption, Distribution, and Excretion. Antiepileptic Drugs, 3rd ed.. Raven Press, Ltd, New York. Limdi, N.A., Faught, E., 1999. Safety of rapid infusion of intravenous valproic acid [abstract]. Epilepsia 40 (Suppl. 7), 144. Mattson, R.H., Cramer, J.A., Collins, J.F., 1985. A comparison of valproate with carbamazepine for the treatment of complex partial and secondarily generalized tonic /clonic seizures. N. Engl. J. Med. 313, 145 /151. Naritoku, D.K., Mueed, S., 1999. Intravenous loading of valproate for epilepsy. Clin. Neuropharmacol. 22, 102 /106. Parke-Davis, 1999. Cerebyx [fosphenytoin sodium injection package insert]. Morris Plains, New Jersey. Perucca, E., Gatti, G., Frigo, G.M., Crema, A., 1978. Pharmacokinetics of valproic acid after oral and intravenous administration. Br. J. Clin. Pharmacol. 5, 313 /318. Peters, C.N.A., Pohlmann, B., 1999. Preliminary experiences with intravenous valproate with special regard to status epilepticus [abstract]. Neurology 52 (Suppl. 2), A249. Peters, C.N.A., Pohlmann-Eden, B., 1999. Efficacy and safety of intravenous valproate in status epilepticus [abstract]. Epilepsia 40 (Suppl. 7), 149 /150. Ramsay, R.E., Cantrell, D.E., Johnson, M.E., DeToledo, J., Rogue, H., Lowe, M.R., Pryor, F.M., 2000. Safety of highdose rapid infusion of intravenous valproic acid [abstract]. Neurology 54, A11.
R.E. Ramsay et al. / Epilepsy Research 52 (2003) 189 /201 The Tiagabine Study Group, Sachdeo, R.C., Leroy, R.F., Krauss, G.L., Drake, M.E., Green, P.M., Leppik, I.E., Shu, V.S., Ringham, G.L., Sommerville, K.W., 1997. Tiagabine therapy for complex partial seizures. A dosefrequency study. Arch. Neurol. 54, 595 /601. Sherman, S.J., 1999. A retrospective review of the use of intravenous valproic acid in a university-based tertiary-care hospital including use for status epilepticus [abstract]. Epilepsia 40 (Suppl. 7), 95. Short, D.W., Pack, A.M., Brazil, C.W., 1999. Depacon administration, safety, and efficacy in a hospital setting [abstract]. Epilepsia 40 (Suppl. 7), 226. Sinha, S., Naritoku, D., 2000. Intravenous valproate is well tolerated in unstable patients with status epilepticus. Neurology 55, 422 /424. Veterans Affairs Status Epilepticus Cooperative Study Group, Treiman, D.M., Meyers, P.D., Walton, N.Y., Collins, J.F., Colling, C., Rowan, J., Handforth, A., Faught, E., Calabrese, V.P., Uthman, B.M., Ramsay, E., Mamdani, M.B., 1998. A comparison of four treatments for generalized convulsive status epilepticus. N. Engl. J. Med. 339, 792 / 798.
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Turski, W.A., Cavalheiro, E.A., Coimbra, C., da Penha Berzaghi, M., Ikonomidou-Turski, C., Turski, L., 1987. Only certain antiepileptic drugs prevent seizures induced by pilocarpine. Brain Res. 434, 281 /305. Uthman, B.M., Rowan, A.J., Ahmann, P.A., Leppik, I.E., Schacter, S.C., Sommerville, K.W., Shu, V., 1998. Tiagabine for complex partial seizures: a randomized, add-on, doseresponse trial. Arch. Neurol. 55, 56 /62. Venkataraman, V., Wheless, J.W., 1999. Safety of rapid intravenous infusion of valproate loading doses in epilepsy patients. Epilepsy Res. 35, 147 /153. Walton, N.Y., Treiman, D.M., 1992. Valproic acid treatment of experimental status epilepticus. Epilepsy Res. 12, 199 /205. Wheless, J., Venkataraman, V., 1998. Safety of high intravenous valproate doses in epilepsy patients. J. Epilepsy 11, 319 /324. The M88-194 Study Group, Willmore, L.J., Shu, V., Wallin, B., 1996. Efficacy and safety of add-on divalproex sodium in the treatment of complex partial seizures. Neurology 46, 49 /53.
Safety and tolerance of rapidly infused Depacon† A randomized trial in subjects with epilepsy R.E. Ramsay a,*, D. Cantrell b, S.D. Collins c, J.K. Walch c, D.K. Naritoku d, J.C. Cloyd e, K. Sommerville c, The Depacon Rapid Infusion Study Group a
International Center for Epilepsy, University of Miami, Professional Arts Building, 1150 NW 14th Street, Suite 410, Miami, FL 33136, USA b North Texas Neuroscience Center, Irving, TX, USA c Abbott Laboratories, North Chicago, IL, USA d Southern Illinois University School of Medicine, Springfield, IL, USA e University of Minnesota College of Pharmacy, Minneapolis, MN, USA Received 22 March 2002; received in revised form 15 August 2002; accepted 28 August 2002
Abstract Background: Valproate sodium injection (Depacon† ) is an intravenous form of valproate for use in absence and complex partial seizures when circumstances preclude oral administration. Certain situations may warrant larger and more rapid infusions than permitted by the original labeling. This study evaluated the safety of more rapid infusions. Methods: Subjects with epilepsy were randomized in a 2:1 ratio to receive up to 15 mg/kg of valproate sodium infused at 3.0 or 1.5 mg/kg/min. Up to four infusions were allowed within 24 h to achieve target plasma valproate concentrations of 50 /100 mcg/ml. Primary safety endpoints were the changes in the 5-min and minimum post-first infusion blood pressures (BPs). Results: One hundred twelve subjects were treated, (3.0 mg/kg/min group: n /72, 1.5 mg/kg/min group: n /40). No significant treatment differences were detected for changes in the primary BP endpoints. Two subjects in the 3.0 mg/kg/min group had potentially clinically significant low systolic BP values during the study. Similar proportions of subjects in the two groups reported adverse events during or within 6 h following the first infusion. Conclusions: Valproate sodium injection dosages up to 15 mg/kg and rates of 1.5 and 3.0 mg/kg/min were well tolerated in this population. # 2002 Elsevier Science B.V. All rights reserved. Keywords: Valproate; Seizures; Epilepsy; Intravenous infusion; Safety
1. Introduction * Corresponding author. Tel.: /1-305-243-5944x4; fax: 1305-243-7668. E-mail address: [email protected] (R.E. Ramsay).
Valproate is an antiepilepsy drug (AED) with a broad spectrum of activity against simple and
0920-1211/02/$ - see front matter # 2002 Elsevier Science B.V. All rights reserved. PII: S 0 9 2 0 - 1 2 1 1 ( 0 2 ) 0 0 1 8 7 - 0
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complex absence and complex partial seizure types. It has also been reported to be useful against other seizure types, including myoclonic and tonic /clonic seizures (Bourgeois, 1995). Valproate sodium injection (Depacon† ), a preparation of valproate for intravenous (IV) administration, is approved for use when clinical factors make oral valproate administration difficult or impossible. Original labeling indicates that valproate sodium injection be administered over a period of 60 min at rates up to 20 mg/min and recommends, for adjunctive therapy, that doses exceeding 250 mg be given in divided doses (Abbott Laboratories, 2000). In certain clinical situations (e.g. drop in plasma drug levels, pre- and postsurgery, seizure clusters, status epilepticus, or rapid introduction of a new agent if seizures are uncontrolled on baseline medications), use of larger doses and more rapid delivery times have advantages. They would provide increases in plasma drug concentrations to attain steady-state or clinically necessary drug levels more quickly than with the original labeling. The effects of large valproate doses administered intravenously have been studied using animal models (Honack and Loscher, 1992; Turski et al., 1987; Walton and Treiman, 1992). Additionally, the pharmacokinetics of IV valproate have been studied in healthy adults, with rates of infusion up to 3.0 mg/kg/min and doses up to 1000 mg (Granneman et al., 1989; Hussein et al., 1993; Perucca et al., 1978). The studies demonstrated that IV valproate was well tolerated at these rates and doses; notably, no significant alterations in blood pressure, cardiac rhythm, state of consciousness, or respiratory rate occurred. Additionally, several studies have reported use of IV valproate infusions of approximately 30/50 mg/min (Ramsay et al., 2000; Venkataraman and Wheless, 1999) or 3 /6 mg/kg/min (Naritoku and Mueed, 1999; Sinha and Naritoku, 2000) in adults and children without clinically important safety concerns, such as significant changes in blood pressure or electrocardiographic (ECG) abnormalities. The present study was designed to evaluate the safety of two more rapid infusions of IV valproate in a larger group of subjects.
2. Methods 2.1. Protocol This study was an open-label, randomized, Phase IIIB, parallel-group, multicenter trial of valproate sodium injection administered intravenously to subjects with epilepsy. The study consisted of two phases: an infusion phase and an optional maintenance phase. Subjects were randomized in a 2:1 ratio to receive valproate sodium injection at a rate of either 3.0 or 1.5 mg/kg/min, for a total dose of up to 15 mg/kg per infusion. Up to four infusions of IV valproate (with at least 2 h separating each infusion) were allowed within the 24-h infusion phase. Once a target plasma valproate concentration of 50 /100 mcg/ ml was achieved or the investigator assessed the concentration to be adequate, the subject could be given an oral valproate product for use outside the protocol or continue on valproate sodium injection for up to 14 days during the maintenance phase of the study. Subjects were to return 1 week following the final infusion for a follow-up laboratory assessment and discussion of any adverse events. Subjects at least 2 years of age with a history of complex partial or absence seizures who had a clinical need for rapid valproate infusion were eligible for the study. The target sample size was 35 subjects in the 1.5 mg/kg/min group and 70 subjects in the 3.0 mg/kg/min group. This sample size allowed for the detection of a 10 mmHg difference between the treatment group means of the 5-min post-infusion systolic blood pressures with at least 80% power. Eligible subjects had no episodes of ‘serial seizures’ or ‘flurries’ within 24 h prior to the start of the study, had not experienced status epilepticus within 30 days prior to the start of the study, and had no prior history of Lennox / Gastaut syndrome or continuous spike waves in sleep. Subjects were excluded from the study if they had taken felbamate or experimental drugs within the previous 30 days. Subjects were also excluded if they had any significant history of cardiac, renal, neurological, psychiatric, oncologic, endocrine, hepatic, or metabolic disease that would have adversely affected their participation
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in the study, or if they displayed cardiac arrhythmias. Subjects with a clinical or serological history of hepatitis or thrombocytopenia were also excluded. Female subjects of childbearing potential were required to have a negative pregnancy test result prior to entering the study. Three categories of clinical need were targeted in this study: (1) patients with epilepsy best treated with valproate, with low or undetectable plasma valproate levels; (2) patients requiring re-introduction of valproate; and (3) patients who were unable to tolerate oral valproate delivery or who were temporarily restricted from taking oral medication. 2.2. Informed consent All subjects provided written informed consent prior to the initiation of any study procedures.
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Blood pressure was monitored during the infusion phase prior to each infusion and at 5, 10, 20, and 30 min post-infusion, or until baseline blood pressure was reached (if blood pressure reductions had occurred). Blood samples for free and total plasma valproate levels were obtained at various times throughout the infusion phase to assess whether there was a possible temporal relationship to adverse events. Free and total plasma valproate levels were measured using a commercially available Fluorescence Polarization Immunoassay (FPIA) on the TDx/TDxFLx system. Unbound drug was separated using ultrafiltration. Adverse events were collected throughout the study up to 30 days following discontinuation of valproate sodium injection and were categorized using COSTART V (Coding Symbols for a Thesaurus of Adverse Reaction Terms Dictionary). 2.5. Treatment administration
2.3. Patient assignment Eligible subjects were assigned subject numbers in ascending numerical order at each site. The subject number encoded the subject’s assignment to one of the two infusion rates (i.e. 1.5 or 3.0 mg/ kg/min). Randomization schedules were generated by the Statistics Department of Abbott Laboratories prior to study initiation. Blind-breaking envelopes containing the randomized rate were provided to study sites by Abbott Laboratories. Once a suitable subject was identified, the lowest subject-numbered envelope was opened, identifying to which of the two treatment groups the subject was assigned. 2.4. Data collected Subjects provided medical and seizure histories and underwent physical, neurological, and cardiac examinations. Vital signs were obtained, and blood samples were collected for the following laboratory tests: full chemistry panel, complete blood count, pregnancy, and total plasma valproate level. ECG recordings were obtained prior to drug administration, and ECG monitoring was maintained throughout each infusion and for 5 min post-infusion during the infusion phase.
Valproate sodium injection was supplied in 5-ml single-use vials. Each milliliter contained valproate sodium equivalent to 100 mg of valproic acid. Each vial was to be diluted with at least 50 ml of a compatible diluent. If, however, subjects (e.g. children with small catheters or elderly subjects) had clinical situations that required dilution volumes less than 50 ml in order to allow accurate delivery of either 1.5 or 3.0 mg/kg/min, the diluent volume could be reduced according to clinical judgment. In such cases, the volume of infusion could be reduced to allow accurate delivery, but the ratio of valproate sodium injection to the total volume of the infusion was not to be less than 1:5 (e.g. 5 ml of valproate sodium injection in 20 ml of compatible diluent), and in no instance was valproate sodium injection to be diluted with B/5 ml of diluent. Subjects were to receive an infusion at one of the aforementioned rates, for a total dose of up to 15 mg/kg per infusion (maximum dose /60 mg/kg in 24 h). In most cases, target plasma concentrations were attained after one infusion. However, if after the first infusion, plasma levels were below 50 mg/ l, up to three subsequent infusions (up to 15 mg/kg each) could be administered within 24 h. A minimum of a 2-h time lapse was required between
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infusions. The following equation, along with the results of the 1-h post-infusion plasma valproate level from the previous infusion, was used to determine the dosage for the subsequent infusion needed to attain the target plasma concentration: D W DCp Vd est; D /dose (mg), W /body mass (kg), DCp /desired change in plasma concentration (mg/l), and Vd est /estimated volume of distribution (l/kg). The volume of distribution for valproate has been estimated to range from 0.12 to 0.23 l/kg (Levy and Shen, 1989). For the purposes of this study, a value of 0.20 l/kg was used for the estimated volume of distribution. 2.6. Discontinuation from study Subjects were free to withdraw from the study of their own accord at any time. Subjects were removed from study participation if they experienced any of the following: status epilepticus, hypotension (blood pressure drop of /30 mmHg systolic and/or /20 mmHg diastolic) with symptoms, high-grade arrhythmia, chest pain, a need for a valproate sodium injection dosage /15 mg/kg in a single infusion or /60 mg/kg in a 24-h period during either phase of the study, a need for re-infusion during the infusion phase that was sooner than 2 h after the previous infusion, an IV maintenance phase of /14 days, or the need for a dosing interval of less than every 6 h during that phase. 2.7. Statistical methods Data were analyzed according to the infusion rate subjects came closest to matching (i.e. subjects whose first infusion was at a rate B/2.25 mg/kg/ min were grouped under the 1.5 mg/kg/min group, and those whose first infusion was at a rate /2.25 mg/kg/min were grouped under the 3.0 mg/kg/min group), and not necessarily according to their randomized treatment group. All subjects treated with study drug were evaluated. All statistical tests were two-tailed at the 0.05 level of significance. The primary safety endpoints were the changes from baseline in the 5-min and minimum post-first
infusion systolic and diastolic blood pressures. Changes from baseline in blood pressure to the end of the infusion, to the 10-, 20-, and 30-min post-first infusion measurements, and to the maximum value following the first infusion were also evaluated. A one-way analysis of variance (ANOVA) was used to compare treatment groups. The secondary endpoints were the proportions of subjects reporting treatment-emergent adverse events, for which treatment group differences were evaluated using Fisher’s exact test for each COSTART term. Ninety-five percent confidence intervals (CIs) for the treatment differences in these endpoints were also computed. In addition to the planned analyses, a regression analysis, which treated subjects’ actual infusion rate as a continuous predictor variable, was used to analyze the linear relationship between changes from baseline in blood pressure at each of the above-mentioned evaluation points and subjects’ actual infusion rate. Changes in laboratory variables from baseline to the 1-week follow-up visit were also analyzed by one-way ANOVA.
3. Results A total of 112 subjects were randomized at 12 investigational sites, and all received study drug; 37 were randomized to 1.5 mg/kg/min valproate sodium injection, and 75 were randomized to receive 3.0 mg/kg/min valproate sodium injection. Patient disposition during the study is depicted in Fig. 1. Three subjects randomized to receive 1.5 mg/kg/min and six subjects randomized to 3.0 mg/ kg/min received their first infusion at an infusion rate closer to the opposite treatment group. Therefore, for purposes of analysis, 72 subjects were included in the 3.0 mg/kg/min group (with an infusion rate of /2.25 mg/kg/min), and 40 subjects were included in the 1.5 mg/kg/min group (with an infusion rate of B/2.25 mg/kg/min). Fig. 2 depicts the distribution of valproate dosages (for the first infusion) administered in each treatment group. The mean age of all subjects was 36.3 years (range /13 months to 79 years). Sixty-one of 112 (54%) subjects were male; 78 (70%) were Cauca-
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Fig. 1. Patient disposition.
Fig. 2. Valproate dosages administered in each treatment group (first infusion, n /112).
sian, and 21 (19%) were African /American. No significant differences were noted between treatment groups in age, sex, race, weight, or height. No significant differences were noted between treatment groups for the following variables:
number of years with epilepsy, number of AEDs ever taken, reason for enrollment, epilepsy type, seizure types ever experienced, or types of status epilepticus ever experienced (Table 1). One hundred nine of the 112 subjects received a single infusion. The first infusion was within 0.1 mg/kg/min of the assigned 1.5 or 3.0 mg/kg/min rate for at least 70% of subjects in each treatment group. Two subjects in the 3.0 mg/kg/min group received a second infusion during the infusion phase, and one additional subject in the 3.0 mg/kg/ min group received two infusions during the maintenance phase. A summary of the dosage and distribution of infusion rates for the first infusion is presented in Table 2. Peak total and free valproate concentrations of approximately 94.4 and 14.3 mcg/ml (means across treatment groups), respectively, were observed, followed by a log-linear decay of plasma concentration. By 4/5 h following the first infusion,
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Table 1 Subject disease characteristics Disease characteristic
Treatment group 1.5 mg/kg/min (n / 40)
P value 3.0 mg/kg/min (n / 72)
Median (range) years with epilepsy
11.5 (1.0 /51.8)
11.5 (1.0 /47.4)
0.820
Mean (SD) number of antiepilepsy drugs ever taken
4.4 (2.92)
3.5 (2.69)
0.142
Reason for enrollment Epilepsy best treated with valproate, with low or 0 plasma levels of valproate Subject being reintroduced to valproate
27 (68%)
57 (79%)
13 (33%)
15 (21%)
Epilepsy type Focal Generalized Either
30 (75%) 9 (23%) 1 (3%)
49 (68%) 22 (31%) 1 (1%)
Seizure types ever experienceda,b Absence Complex partial evolving to generalized tonic /clonic Complex partial Generalized tonic /clonic Myoclonic Partial evolving to generalized tonic /clonic Simple partial Tonic Other
2 (5%) 5 (13%) 30 (75%) 22 (55%) 2 (5%) 1 (3%) 12 (30%) 0 (0%) 3 (8%)
9 (13%) 6 (8%) 47 (65%) 46 (64%) 7 (10%) 0 (0%) 22 (31%) 2 (3%) 3 (4%)
0.322 0.518 0.395 0.421 0.486 0.357 /0.999 0.537 0.665
Status epilepticus types ever experienced /30 days prior to studyb Generalized tonic /clonic Myoclonic Secondary generalized tonic /clonic Complex partial
1 0 4 3
0 1 5 2
0.570 0.357 /0.999 0.719 0.346
a b
0.181
0.570
(3%) (0%) (10%) (8%)
(0%) (1%) (7%) (3%)
75% of subjects had complex partial seizures and/or absence seizures. Some subjects had multiple seizure types.
plasma valproate concentrations had fallen below 50 mcg/ml for both infusion rates. Plasma concentration /time profiles for the two groups were similar. The mean plasma concentration /time profile for all subjects is presented in Fig. 3. Valproate concentrations declined more rapidly in hepatic enzyme-induced subjects (i.e. subjects receiving agents, such as phenobarbital, phenytoin, and carbamazepine, which increase valproate clearance). No significant differences in systolic or diastolic blood pressure were observed between treatment groups in the analysis of mean change from baseline to the primary protocol-specified endpoints of 5 min post-first infusion and the mini-
mum of all values post-infusion (Table 3). No significant differences in blood pressure were observed between treatment groups in the analysis of mean change from baseline to any of the other post-first infusion endpoints, with the exception of the 20-min post-first infusion measurement for diastolic blood pressure. This difference was not considered to be clinically important, as the diastolic blood pressure values for both groups at this time period were within the normal range. Mean systolic and diastolic blood pressure values following the first infusion for each group are shown in Figs. 4 and 5. Linear regression results indicated that the infusion rate did not significantly affect either the
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Table 2 Infusion phase valproate sodium injection administration Treatment group 1.5 mg/kg/min (n /40)a
3.0 mg/kg/min (n /72)b
Mean (SD ) valproate sodium dose for the first infusion mg 1184.4 (411.21) 1088.3 (363.10) mg/kg 14.4 (1.54) 14.7 (1.08) mg/kg/min 1.6 (0.24) 3.0 (0.20) Distribution of infusion More than 0.1 mg/kg/ min lessc Within 9/0.1 mg/kg/ minc More than 0.1 mg/kg/ min overc
rate for the first infusion , n (%) 3 (8%) 7 (10%) 28 (70%)
60 (83%)
9 (23%)
5 (7%)
Mean Vd (9/SD) for all subjects /0.179/0.04 l/kg; 69% of subjects had a Vd ranging from 0.14 to 0.2 l/kg. a Included subjects infused at a rate B/2.25 mg/kg/min. b Included subjects infused at a rate /2.25 mg/kg/min. c Versus the assigned 1.5 or 3.0 mg/kg/min rate.
Fig. 3. Mean total and free valproic acid plasma concentration /time (hours) profiles following the first infusion (n /109). Note: Error bars represent standard deviations. Suggested oral dose initiation indicates the optimum window of time for oral divalproex sodium to be started.
systolic or diastolic blood pressure changes from baseline at any of the post-first infusion endpoints evaluated. Three subjects had a vital sign value that met predefined criteria for potential clinical significance. While each of the values met the criteria, patients remained asymptomatic. Two subjects
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(Subject #109 and #803) in the 3.0 mg/kg/min group each had a systolic blood pressure measurement that was 5/90 mmHg and was decreased by ]/30 mmHg from baseline following the first valproate infusion. Subject #109 (age 39) had a systolic blood pressure of 83 mmHg 30 min after the infusion, a 32 mmHg decrease from the preinfusion recording. At the end of dosing through the 20-min post-infusion recording, systolic blood pressure ranged from 106 to 112 mmHg. At the 1week follow-up visit, the subject’s blood pressure was 126/70 mmHg. An adverse event of hypotension without clinical symptoms was recorded for Subject 803 (age 36), who had a systolic blood pressure of 74 mmHg at the end of the infusion, a 31 mmHg decrease from the pre-infusion recording. Hypotension resolved upon supine positioning of the subject. At 5 /30 min post-infusion, the subject’s systolic blood pressure ranged from 99 to 101 mmHg. The subject’s blood pressure was 112/ 68 mmHg at the follow-up visit. A third subject in the 3.0 mg/kg/min group (#719, age 64) had a diastolic blood pressure (120 mmHg) at the end of the first infusion that was ]/105 mmHg and was increased by ]/30 mmHg from a baseline of 74 mmHg. At 5 /30 min after dosing, diastolic blood pressure ranged from 82 to 86 mmHg. The subject’s blood pressure was 154/88 mmHg at the follow-up visit. Adverse events tended to occur in association with peak plasma valproate levels. The incidence of adverse events emerging during or within 6 h following the first infusion was similar between treatment groups (Table 4). The most common adverse events emerging during this time period were somnolence, paresthesia, dizziness, and nausea, which were all mild in severity, except for one case of nausea, which was moderate in severity. Additionally, the incidence of adverse events emerging during or within 1 h following the first infusion was similar between treatment groups (8/ 40 [20%] for the 1.5 mg/kg/min group; 14/72 [19%] for the 3.0 mg/kg/min group). No significant differences were noted between treatment groups in the incidence of any particular adverse event emerging during or within 1 or 6 h following the first infusion.
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Table 3 Changes from baseline in systolic and diastolic blood pressure Endpoint (first infusion)
End of infusion Systolic Diastolic
Mean changea (SD) 1.5 mg/kg/min
3.0 mg/kg/min
0.5 (10.79) 0.0 (8.27)
0.8 (10.70) 2.1 (9.11)
Treatment differenceb
95% CI (L, U) treatment difference
P value
0.3 2.1
/4.0, 4.5 /1.4, 5.7
0.907 0.236
5 min post-infusion Systolic Diastolic
1.0 (9.9) /0.3 (8.41)
/1.6 (7.76) 1.5 (8.06)
/2.6 1.7
/6.1, 1.0 /1.6, 5.1
0.153 0.305
10 min post-infusion Systolic Diastolic
/0.9 (12.05) /0.5 (8.56)
/0.8 (8.87) /0.7 (8.05)
0.1 /0.2
/4.0, 4.2 /3.6, 3.1
0.967 0.900
20 min post-infusion Systolic Diastolic
0.8 (11.92) /2.7 (9.47)
/1.1 (11.45) 0.9 (8.46)
/1.9 3.6
/6.7, 2.9 0.0, 7.3
0.429 0.049*
30 min post-infusion Systolic Diastolic
0.7 (11.77) /1.3 (10.01)
/1.3 (10.45) 0.6 (8.71)
/1.9 2.0
/6.3, 2.5 /1.7, 5.7
0.388 0.292
Minimum post-infusion value Systolic /6.2 (9.02) Diastolic /6.1 (9.10)
/8.2 (10.03) /4.4 (6.93)
/2.0 1.6
/5.8, 1.8 /1.5, 4.7
0.291 0.300
Maximum post-infusion value Systolic 6.8 (12.50) Diastolic 4.7 (8.48)
6.6 (8.79) 6.6 (9.26)
/0.2 1.9
/4.2, 3.9 /1.7, 5.4
0.939 0.299
CI (L, U) /lower and upper limits. a Mean baseline blood pressure values were 124.9 (systolic) and 75.3 mmHg (diastolic) for the 1.5 mg/kg/min group and 125.0 (systolic) and 71.9 mmHg (diastolic) for the 3.0 mg/kg/min group. b Mean change from baseline for the 3.0 mg/kg/min group minus the mean change from baseline for the 1.5 mg/kg/min group at the time point indicated. * Significant difference between treatment groups (P B/0.05).
Treatment-emergent adverse events, including all events reported up to 30 days following the last infusion, occurred with similar incidence in the 1.5 and 3.0 mg/kg/min groups (17/40 [42.5%] and 37/ 72 [51.4%] of subjects, respectively; P /0.432). The most commonly reported treatment-emergent adverse events in the 1.5 mg/kg/min group (n /40) included somnolence in six patients (15%), nausea in four patients (10%), dyspepsia in three patients (8%), dizziness in three patients (8%), asthenia in two patients (5%), paresthesia in two patients (5%), and vomiting in two patients (5%). Similarly, in the 3.0 mg/kg/min group (n /72), reports of somnolence were noted in seven patients (10%), nausea in six patients (8%), dyspepsia in one patient (1%), dizziness in seven patients (10%),
asthenia in six patients (8%), paresthesia in six patients (8%), and vomiting in two patients (3%). In both treatment groups, most of these treatmentemergent adverse events were mild or moderate in severity, and none occurred with significantly greater incidence in either treatment group. Serious treatment-emergent adverse events were reported by three subjects. Two events were reported by one subject in the 1.5 mg/kg/min group (stupor and dyspnea) 7 days post-treatment. The subject died on the same day, and this death was believed to be from breast cancer, metastatic to the brain, and unrelated to the study drug. Serious adverse events were reported in two subjects in the 3.0 mg/kg/min group (hostility, increased drug level, and confusion in one subject;
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Fig. 4. Mean systolic blood pressure following the first infusion. Note: Error bars represent standard deviations. For the 1.5 mg/kg/min group: n /40 (baseline), n /39 (end of infusion), n /38 (5 min), n /37 (10 min), n /36 (20 min), and n / 38 (30 min). For the 3.0 mg/kg/min group: n /71 (baseline), n /67 (end of infusion), n /64 (5 min), n /67 (10 min), n /67 (20 min), and n /68 (30 min).
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encephalopathy in another subject). The hostility, increased drug level, and confusion occurred 6 days post-infusion, were considered to be unrelated to the IV valproate infusion. The events resolved within 8 days, and the investigator thought they were related to oral AED therapy (carbamazepine, lamotrigine, and divalproex sodium). The one serious adverse event that was considered by the investigator as possibly related to the study drug was encephalopathy, which occurred 4 days following a single infusion of 3.0 mg/kg/min and a peak plasma valproate concentration of 123 mcg/ml. Oral valproate was discontinued in this subject, and the adverse event resolved within 3 days. No significant differences were noted between the treatment groups in the change from baseline to the 1-week follow-up evaluation for any hematology or clinical chemistry variables, with the exception of blood urea nitrogen (BUN). A significant difference between the treatment groups in the mean change from baseline for BUN was observed ( /1.5 mg/dl from a mean baseline value of 14.3 mg/dl for the 1.5 mg/kg/min group, and 1.5 mg/dl from a mean baseline value of 13.0 mg/dl for the 3.0 mg/kg/min group, P B/ 0.05); however, this treatment difference was not considered clinically significant. No adverse events, such as thrombocytopenia or increased liver function tests, were reported in either treatment group, and no subjects had platelet values that met predefined criteria for potential clinical significance. 3.1. Protocol deviations
Fig. 5. Mean diastolic blood pressure following the first infusion. Note: Error bars represent standard deviations. For the 1.5 mg/kg/min group: n /40 (baseline), n /39 (end of infusion), n /38 (5 min), n /37 (10 min), n /36 (20 min), and n /38 (30 min). For the 3.0 mg/kg/min group: n /71 (baseline), n /66 (end of infusion), n /64 (5 min), n /67 (10 min), n /67 (20 min), and n /68 (30 min).
As previously mentioned, the evaluation of nine subjects who received their first infusion at a rate closer to the opposite randomized treatment group, and their subsequent recategorization into the treatment group most closely resembling their actual infusion rate, deviated from the original study protocol. Other protocol deviations included 24 subjects (including six of those nine whose treatment group was recategorized) in whom the first infusion was not administered at a rate that was within 0.1 mg/kg/min of either the 1.5 or 3.0 mg/kg/min rates, 28 subjects who received an
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Table 4 Summary of most frequently reported adverse events emerging during or within 6 h following the first infusion COSTART terma
Treatment differenceb, 95% Cl (L, U)c
Treatment group 1.5 mg/kg/min (n /40) Severity
3.0 mg/kg/min (n /72) Total
Mild Moderate
Severe n (%)
Somnolence Dizziness Nausea Paresthesia
3 2 2 2
0 0 0 0
0 0 0 0
Total
9
0
0
3 2 2 2
(7.5%) (5.0%) (5.0%) (5.0%)
Severity
Total
Mild Moderate
n (%)
4 5 2 5
0 0 1 0
9 (22.5%) 18
1
4 5 3 5
(5.6%) (6.9%) (4.2%) (6.9%)
19 (26.4%)
/1.9% 1.9% /0.8% 1.9%
( /22.3, ( /13.7, ( /20.8, ( /13.7,
11.4%) 21.6%) 11.4%) 21.6%)
3.9% ( /15.4, 24.3%)
Cl (L, U) /lower and upper limits of exact confidence interval. a Adverse events occuring in ]/5.0% of subjects in either treatment group. b Total incidence for the 3.0 mg/kg/min group minus the total incidence for the 1.5 mg/kg/min group. c Exact confidence interval.
infusion in which the volume was B/50 ml, 20 subjects who did not meet all admission criteria (including one subject who was less than 2 years of age /subject was 13 months old), four subjects who were administered oral valproate B/6 h postinfusion, and three subjects at one site who were not assigned subject numbers in ascending numerical order. For the 24 subjects (12 in each treatment group) whose actual first infusion rate varied by more than 0.1 mg/kg/min from the protocoldefined rates, the mean infusion rates in the 1.5 and 3.0 mg/kg/min groups were 1.74 (range: 1.00 / 2.15 mg/kg/min) and 2.92 mg/kg/min (range: 2.34 / 3.72 mg/kg/min), respectively. Of these other protocol deviations, none were considered to have had a clinically important impact on the study’s outcome.
4. Discussion In this study, valproate sodium injection was safe and well tolerated at infusion rates of 1.5 and 3.0 mg/kg/min at doses of up to 15 mg/kg per infusion. It has been suggested that in certain clinical situations, infusion at a rate greater than 1.5 mg/kg/min may be justified (Alfonso et al., 1999; Alvarez et al., 1999; Edwards et al., 1999; Kriel et al., 1999; Leniger and Hufnagel, 1999;
Limdi and Faught, 1999; Peters and Pohlmann, 1999; Peters and Pohlmann-Eden, 1999; Sherman, 1999; Short et al., 1999; Venkataraman and Wheless, 1999; Wheless and Venkataraman, 1998). In general, these situations involve subjects for whom the risk for the occurrence of frequent and many seizures is high and immediate action is necessary. For example, in patients with a history of frequent seizures awaiting surgery or presenting in an emergency department in a post-ictal state after one or more seizures, the oral route of medication may be unavailable or would be associated with an unacceptable delay in attaining therapeutic drug concentrations. In many patients with refractory epilepsy, frequent daily seizures occur, even in the setting of the best available therapy. Evidence for this is demonstrated by data from several previous clinical trials of divalproex sodium and tiagabine HCl (Beydoun et al., 1997; Mattson et al., 1985; Sachdeo et al., 1997; Uthman et al., 1998; Willmore et al., 1996). Baseline evaluation of subjects showed that 25% experienced complex partial seizures at frequencies of at least 3.1 /4.7 per week (maximum 417 per week). From this evaluation, one can conclude that a significant proportion of patients with refractory epilepsy, in the situations outlined above, are at risk of morbidity and mortality associated with frequent seizures and need a timely means of
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intervention available to increase AED concentrations to therapeutic levels. In such instances, IV valproate infusion rates of 20 mg/min over 60-min time periods may not provide adequate seizure protection in a timely fashion. Previous smaller studies of valproate sodium injection have demonstrated that larger doses and/ or more rapid infusions were well tolerated (Naritoku and Mueed, 1999; Ramsay et al., 2000; Sinha and Naritoku, 2000; Venkataraman and Wheless, 1999; Wheless and Venkataraman, 1998). The present study included a larger subject base than the previously mentioned studies of high-dose and/or rapidly infused valproate, including both children and adults with a range of clinical conditions. The infusion rates chosen for the study, 1.5 and 3.0 mg/kg/min, were considered clinically appropriate (for an epilepsy population with complex partial or absence seizures requiring a rapid infusion of valproic acid), but sufficiently different to assess whether infusion rate affected important safety parameters. Analysis of safety parameters demonstrated no significant differences between the infusion rates of 1.5 and 3.0 mg/kg/min that were considered clinically important. The pharmacokinetics of valproate after a single 15 mg/kg infusion were consistent with previous studies in healthy volunteers (Cavanaugh et al., 1994; Hussein et al., 1994, 1993). Doses were calculated according to standard pharmacokinetic formula. The peak concentrations attained matched predicted values. Peak valproate concentrations were within 22% of 50 /100 mcg/ml in all subjects with both infusion rates, suggesting that valproate concentrations are predictable following rapid infusion, and therapeutic levels are quickly attained. Plasma concentration decay times were log-linear for both total and free valproate and fell below 50 mcg/ml within 4/5 h post-dose for both infusion rates. These data suggest oral dosing with the standard divalproex sodium (not the extendedrelease formulation) may need to start from 1 to 3 h post-infusion in order to maintain concentrations above 50 mcg/ml. Given the longer Tmax of the new, once-a-day, extended-release formulation of divalproex sodium (Depakote† ER), dosing with this formulation may need to start concurrent
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with the infusion, although it is important to note that Depakote† ER is not yet approved for use in epilepsy. There was no difference between the two infusion rates in changes in laboratory tests. There was also a relative lack of respiratory depression, arrhythmias, and hypotension noted in this study. This is in contrast to other commonly used parenteral AEDs, such as lorazepam, phenobarbital, diazepam, and phenytoin, which have been variably associated with hypoventilation, cardiacrhythm disturbances, and/or hypotension (Treiman et al., 1998). Notably, in this study, only two subjects (1.8%) had potentially clinically significant low blood pressure values; this is in contrast to fosphenytoin and phenytoin, which have been associated with hypotension in 7.7 and 9.1% of patients, respectively (Parke-Davis, 1999). No infusion rate-related safety issues and no new safety issues associated with valproate sodium injection were noted in this study. Overall, data obtained from this trial indicate that valproate sodium injection is well tolerated in subjects with epilepsy when it is administered in dosages up to 15 mg/kg per infusion at rates up to 3.0 mg/kg/ min. The results of this controlled trial support previous studies and anecdotal reports of high infusion rates of valproate that are well tolerated among patients with epilepsy who are otherwise healthy or in patients who are unstable from other conditions (Czapinski and Terczynski, 1998; Sinha and Naritoku, 2000; Wheless and Venkataraman, 1998). The rapid infusion rate and good tolerability make valproate sodium injection a likely candidate for future study in acute seizure management.
5. Participating investigators Deborah T. Combs Cantrell, MD, North Texas Neuroscience Center, Irving, TX; James C. Cloyd, PharmD, University of Minnesota College of Pharmacy, Minneapolis, MN; John R. Gates, MD, Minnesota Epilepsy Group, PA, St. Paul, MN; Andres M. Kanner, MD, Rush-PresbyterianSt. Luke’s Medical Center, Chicago, IL; Ruben I. Kuzniecky, MD, University of Alabama Epilepsy
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Center, Birmingham, AL; David M. Labiner, MD, University of Arizona Department of Neurology, Tucson, Az; Georgia D. Montouris, MD, The Comprehensive Epilepsy Center, Chesterfield, Missouri; George L. Morris, MD, Medical College of Wisconsin Department of Neurology, Milwaukee, Wi; Dean K. Naritoku, MD, SIU School of Medicine Department of Neurology, Springfield, IL; John M. Pellock, MD, Medical College of Virginia/Virginia Commonwealth University, Richmond, VA; R. Eugene Ramsay, MD, University of Miami International Center for Epilepsy, Miami, FL; Blanca Vasquez, MD, NYUMt. Sinai School of Medicine, New York, NY; James W. Wheless, MD, The University of Texas Medical School at Houston, Houston, TX.
Acknowledgements This research was supported by Abbott Laboratories. The authors would like to thank Guoliang Cao, Roger Deaton, Sandeep Dutta, PhD, Yihua Giu, and David Morris, PhD, for their technical expertise in the development and analysis of this study.
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