This report was reviewed for medical and scientific accuracy by Roopal M. Karia, MD, Department of Neurology, UMDNJ-Robert Wood Johnson Medical School, New Brunswick, New Jersey

Editorial

James W. Wheless, MD, Professor of Neurology and Pediatrics, Director, Texas Comprehensive Epilepsy Program, University of Texas, Houston, Texas

Divalproex Sodium [Ed. valproate; valproic acid (VPA)] is an integral part of the neurologist's armamentarium for the treatment of persons with epilepsy, migraine headaches, or mania. VPA is FDA-approved for partial-onset seizures or absence seizures with or without other seizure types. However, VPA is recognized worldwide as the classic broad-spectrum antiepileptic drug (AED) with efficacy against absence, atonic, generalized tonic-clonic and primary generalized epilepsies, including juvenile myoclonic epilepsy (JME). Multiple formulations are commercially available to take advantage of VPA's efficacy and minimize potential side effects. This variety allows the clinician to individualize drug treatment for their patient and the neurologic condition being treated.

Critical understanding of the pharmacokinetics of each VPA formulation will allow the neurologist to better use this efficacious medicine. For example, in the teenager with JME whose seizures are easily controlled with VPA, the critical issue lies in choosing a formulation that will improve compliance. Divalproex sodium extended-release (ER) allows seizure control with improved compliance as reported by Thompson et al. in this report. McCabe et al report on their experience with converting patients from divalproex sodium delayed-release (DR) to divalproex sodium-ER. The ER formulation is currently limited to the availability of a 500 mg tablet. Dutta et al report the promising results of bioavailability testing of an investigational 250 mg ER tablet. The availability of a 250 mg ER tablet will allow easier titration of patients onto the ER formulation.

Acute seizure emergencies are often the most challenging to treat. Yu et al treated 25 children with acute seizures by rapidly administering intravenous VPA. This formulation is well tolerated and efficacious. While there are no comparative trials of intravenous VPA in the treatment of status epilepticus (SE), it appears reasonable at this time to advocate the drug's use for absence, myoclonic, and nonconvulsive SE. In the latter, it provides another non-sedating treatment option prior to consideration of the need for intubation or a drug-induced coma. Additionally, all data to date show no significant effect on blood pressure or pulse whether a loading dose (20-25 mg/kg) is given over 4, 8, or 16 minutes. Armed with this knowledge, the neurologist may infuse VPA as rapidly as the clinical situation dictates.

Finally, Dr. Christine Dean reminds us that not all broad-spectrum AEDs are therapeutically interchangeable and why VPA is still the comparator compound when treating generalized epilepsies. Valproate is the gold standard for treating JME. Lamotrigine or topiramate may be considered as alternative treatments for JME in certain patients. Both medicines are currently being compared to VPA in ongoing clinical trials of JME. Pending those results, VPA remains the most efficacious compound for treating primary generalized epilepsies.

Introduction

Divalproex sodium is a stable co-ordination compound comprised of sodium valproate and valproic acid in a 1:1 molar relationship. Divalproex sodium is commercially available in 3 oral formulations and one intravenous formulation. Food and Drug Administration (FDA) indications vary by formulation. Divalproex sodium delayed-release (Depakote-DR) tablets are indicated for sole or adjunctive treatment of patients with complex partial seizures, simple and complex absence seizures, and multiple seizure types that include absence seizures.¹ Additionally, Depakote-DR is FDA-approved for the treatment of manic episodes associated with bipolar disorder as well as for migraine prophylaxis. Divalproex sodium extended-release (Depakote-ER) tablets are indicated for migraine prophylaxis.² Divalproex sodium coated particles in capsules (Depakote Sprinkle) are indicated as sole or adjunctive treatment of patients with complex partial seizures, simple and complex absence seizures, and multiple seizure types that include absence seizures.³ The intravenous formulation is chemically known as sodium valproate (Depacon) and is indicated for complex partial seizures, simple and complex absence seizures, and multiple seizure types that include absence seizures where oral administration is not feasible.⁴

Divalproex sodium dissociates to the valproate ion in the gastrointestinal tract and is metabolized almost entirely by the liver. The plasma protein binding (90%) of valproate is concentration dependent and exhibits nonlinear binding. Consequently, valproate concentration does not increase proportionally with the dose, but to a lesser extent due to saturable plasma protein binding. Thus, monitoring of total serum valproate cannot provide a reliable index of bioactive valproate. Additionally, valproate may displace certain protein-bound drugs (e.g., phenytoin, carbamazepine, warfarin, and tolbutamide). However, unbound concentrations increase proportionally and conform to linear kinetics.

Divalproex sodium reaches peak plasma concentrations 3-6 hours after ingestion. Mean terminal half-life for epilepsy monotherapy ranges from 9 to 16 hours. In epilepsy monotherapy, therapy for adults and children age 10 years of age and older is initiated at 10-15 mg/kg/day and increased by 5-10 mg/kg/week to achieve optimal clinical response. Ordinarily, optimal clinical response is achieved at daily doses below 60 mg/kg/day. The dosing schedule for adjunctive therapy is essentially the same up to a maximum dose of 60 mg/kg/day.

Many patients with epilepsy suffer seizures due to inadequate compliance with antiepileptic medications. The FDA recently approved the ER formulation for migraine prophylaxis. This formulation was specifically designed for once daily administration compared to the traditional DR formulation that must be taken two to four times a day for optimal seizure control. In addition, high peak serum valproic acid (VPA) concentrations can cause side effects and low trough concentrations allow breakthrough seizures. Once daily administration of an antiepileptic medication has the potential to improve compliance, decrease side effects, and enhance efficacy. In an effort to determine whether divalproex sodium ER is effective for epilepsy patients, investigators presented a number of pilot studies at the recent American Epilepsy Society Meeting in Philadelphia, PA.

Pharmacokinetics of Divalproex Sodium Extended Release (ER)

Divalproex sodium-ER is a hydrophilic matrix formulation that delivers active drug throughout the gastrointestinal tract at a constant zero-order rate [maintenance of plasma concentration within desired therapeutic range over extended time] over 18 hours. It is currently available only as a 500 mg tablet. In order to provide greater flexibility in dosing the ER formulation, researchers have compared the bioavailability of two novel 250 mg ER tablet formulations (designated formulations A and B) to the current 500 mg ER tablet. Both are hydrophilic matrix tablets that utilize the rate-controlling polymer, Methocel K15M (Dow Chemical) and have similar in vitro dissolution rates to the 500 mg ER tablet.

The comparison was conducted in a Phase I, single dose, fasting and nonfasting, randomized, open label, three-period, complete-crossover study⁵ in 39 health subjects. One group (n = 15) was dosed after a 10-hour fast and the other (n = 24) dosed after breakfast. Dosing regimens consisted of 3 treatments: two 250 mg ER-formulation A, two 250 mg ER-formulation B and one 500 mg ER reference tablet (formulation C) with a washout interval of 7 days between regimens. Bioequivalence assessments were made via a 90% confidence interval (CI) for maximum plasma concentration (C_max) and area-under-the-curve (AUC_∞).

Formulation A produced a higher fasting C_max (32.3 mg/mL, p ≤ 0.05) and AUC_∞ (959 mg·h/mL) and nonfasting C_max (35.1 mg/mL, p ≤ 0.05) and AUC_∞ (945 mg·h/mL) compared to the divalproex sodium-ER 500 mg tablet (23.5 mg/mL, 859 mg·h/mL, 27.5 mg/mL, 903 mg·h/mL, respectively). Therefore, formulation A did not meet the bioequivalence criterion since CI exceeded established limits. Formulation B produced a fasting C_max (25.3 mg/mL) and AUC_∞ (831 mg·h/mL) and nonfasting C_max (28.3 mg/mL) and AUC_∞ (898 mg·h/mL). Formulation B met the bioequivalence criterion relative to the reference formulation as is being further developed for patient use.

The formulations tested were generally well tolerated. The most frequently reported events (> 3 subjects) were headache, diarrhea, somnolence, and pain and were judged mild in severity. Formulations B and C (reference) were comparably tolerated.

Rapid Conversion from Divalproex sodium DR to ER

McCabe et al.⁶ reported serum VPA concentrations on 53 patients stabilized on divalproex sodium-DR who converted to divalproex sodium-ER in an overnight fashion. In converting, 9 patients chose once daily administration while 42 patients chose twice daily dosing on the ER formulation. Compared to the DR formulation, the mg/day dosage of the ER formulation was unchanged in 22 patients, increased in 26 patients, and decreased in 5 patients. All patients tolerated the rapid conversion to the ER formulation. Of the patients on twice daily dosing converting to ER (same mg/day), there was an average VPA plasma concentration change of 0.9%. However, more significant changes were seen in 2 patients switched from the sprinkle formulation and in one patient switched from twice daily dosing with the DR formulation. Investigators noted in 3 patients switched to once daily administration of the ER formulation that serum VPA levels had greater fluctuation depending upon the time of day that blood levels were drawn. Clinically, no patient had worsening of his or her seizures. Of 20 patients who had complained of tremor while taking the DR formulation, 5 (25%) reported significant improvement in the tremor.

Investigators concluded that conversion to twice daily dosing of the ER formulation produced little variation in plasma VPA levels but urged closer follow up of blood levels in patients who convert to once daily administration. Blood levels should be drawn in a consistent manner [same daily time] prior to dosing for patients on once daily administration (generally 1-2 hours before dosing).

Efficacy of Divalproex sodium ER in Pediatric Epilepsy

Adolescents present special challenges when it comes to medication compliance. Thompson et al.⁷ identified 20 adolescent patients, ages 12-17, being treated for epilepsy with divalproex sodium DR. Seizure types included complex partial, generalized tonic-clonic, myoclonic, and absence. The average breakthrough seizure frequency was once a month, all due to subtherapeutic valproate levels. Using a ratio of 1 mg divalproex sodium DR to 1.25 mg divalproex sodium ER, the investigators immediately switched the patients to the ER formulation given on a once daily basis.

After beginning the divalproex sodium ER (October 2000 to date), there have been no reported breakthrough seizures. Serum valproate levels have ranged from 70-110 µg/dL. As would be expected, the patients reported that once daily dosing of their medication was easier to remember. Interestingly, they reported less gastrointestinal complaints such as nausea, dyspepsia, and abdominal pain.

The investigators concluded that divalproex sodium ER produced better patient compliance with once daily dosing and decreased plasma level fluctuations leading to 1) potentially fewer peak serum-related side effects and hence, better patient tolerance and 2) improvement in seizure control due to fewer subtherapeutic serum levels.

Safety and Efficacy of Intravenous Valproate in Status Epilepticus

Parenteral antiepileptic medications are often required for the acute treatment of status epilepticus and acute repetitive seizures. The FDA for seizures recently approved intravenous valproate where oral administration of mediation is not feasible. Phenobarbital undergoes less rapid penetration of the blood-brain barrier and may be associated with sedation and respiratory depression.⁸ Hypotension and cardiac arrhythmia are associated with phenytoin,⁹ in addition to injection site tissue damage. Fosphenytoin circumvents the adverse effects of phenytoin¹⁰ but still has limited value in the treatment of myoclonic, atonic and absence seizures. Intravenous valproate may facilitate administration of loading doses in the emergent treatment of seizures.

Yu et al.¹¹ administered intravenous valproate to 25 children, ages one month to 15 years, with acute uncontrolled seizures (18 with status epilepticus and 7 with acute repetitive seizures). The children received intravenous valproate at an infusion rate of 3 mg/kg/min for a total loading dose of 25 mg/kg. The solution was diluted in a 1:1 ratio with Dextrose 5% in Water.

Rapid intravenous loading of valproate stopped status epilepticus within 20 minutes and also arrested acute repetitive seizures. Blood pressure and heart rate remained stable among all patients. Only one patient noted transient tremors. Serum valproate levels were drawn after one hour of infusion and ranged from 90-120 ug/mL. Investigators concluded that intravenous valproate loading is safe and effective in the treatment of acute seizure emergencies.

Lamotrigine or Divalproex Sodium for Generalized Seizures?

Recent literature suggests that lamotrigine may be effective in the treatment of generalized seizures,¹² a condition for which divalproex sodium has traditionally been the drug of choice. Dean et al.¹³ presented the results of a large, retrospective study that included 340 patients (129 male, 211 female), ages 16-48 years with generalized seizures who were converted from divalproex sodium to lamotrigine over a 12-week period. Although all of the patients had complete seizure control with divalproex sodium, adverse effects associated with divalproex sodium prompted the switch. Seizure types included generalized tonic-clonic seizures (GTCS), absence seizures (AS), juvenile myoclonic epilepsy (JME), myoclonic seizures, and atonic seizures.

Over a 6-week period, the patients slowly titrated lamotrigine (200 mg/day) to their divalproex sodium (10-20 mg/kg/day). At week 6, when they had reached lamotrigine 200 mg/day, they began to taper the divalproex sodium and discontinued it at week 12. At week 8, the lamotrigine dose was increased to 250 mg/day, and at week 12 were converted to lamotrigine monotherapy at 300 mg/day. Two hundred and two of the 340 patients (59%) who had been seizure free on divalproex sodium therapy failed successful conversion to lamotrigine monotherapy. One hundred and twenty (59%) had JME, 72 (36%) had GTCS, 6 (3%) had atonic seizures, and 4 (2%) had myoclonic jerks.

The results indicated a variable response to drug treatment and suggest a substantial number of patients with generalized epilepsy may not adequately be controlled with conversion to lamotrigine monotherapy after previous seizure control on divalproex sodium; particularly patients with JME. Investigators advised that switch therapy be cautiously approached in patients who were clinically stabilized.

References

1. Depakote Delayed-Release Prescribing Information. Abbott Labs. Available at http://www.rxabbott.com. Accessed December 11, 2001.

2. Depakote Extended-Release Prescribing Information. Abbott Labs. Available at http://www.rxabbott.com. Accessed December 11, 2001.

3. Depakote Sprinkle Prescribing Information. Abbott Labs. Physician's Desk Reference 2001. Medical Economics Company, Montvale, NJ.

4. Depacon Prescribing Information. Abbott Labs. Available at http://www.rxabbott.com. Accessed December 11, 2001.

5. Dutta S et al. Comparison of the Bioavailability of Two Novel 250 mg Depakote Extended-Release Formulations Relative to a 500 mg Depakote Extended-Release Reference Formulation in Healthy Volunteers. Epilepsia 2001; 42 (suppl 7), p 88-9.

6. McCabe et al. Rapid Conversion from Delayed Release Valproic Acid (VPA) to Extended Release VPA: Clinical and Pharmacokinetic Observations. Epilepsia 2001;42 (suppl), p 90.

7. Thompson NM et al. Efficacy of Depakote ER in pediatric epilepsy. Epilepsia 2001;42 (suppl), p 87.

8. Crawley et al. Effect of Phenobarbital on Seizure Frequency and Mortality in Childhood Cerebral Malaria: A Randomized, Controlled Intervention Study. Lancet 2000 Feb 26;355(9205):701-706.

9. Donovan PJ, Cline D. Phenytoin Administration by Constant Intravenous Infusion: Selective Rates of Administration. Ann Emerg Med 1991 Feb;20(2):139-142.

10. Wheless JW. Pediatric Use of Intravenous and Intramuscular Phenytoin: Lessons Learned. J Child Neurol 1998 Oct; 13 Suppl 1:S11-S14; discussion S30-S32.

11. Yu KTT et al. Safety and Efficacy of Intravenous Valproate Loading in Pediatric Status Epilepticus and Acute Repetitive Seizures. Epilepsia 2001;42 (suppl), p 188-9.

12. French JA. The Role of New Antiepileptic Drugs. Am J Manag Care 2001 Jul;7(7 Suppl):S209-S214.

13. Dean JC et al. Outcomes of switch therapy in seizure patients: divalproex sodium to lamotrigine. Epilepsia 2001;42 (suppl), p 178.

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Disclosure

Roopal M. Karia, MD
Has no significant relationships to disclose.

James W. Wheless, MD
Consultant, Research Grants, Speaker's Bureau: Abbott Laboratories

David C. Howard
Has no significant relationships to disclose.

This report contains information on commercial products that are unlabeled for use or investigational uses of products not yet approved. Depakote ER is not included in the labeling approved by the US FDA for the treatment of epilepsy.

This report is supported by an educational grant from Abbott Laboratories.

Medical Writer: David C. Howard, B.S. Pharmacy, Director of Research, Millennium Medical Communications, Hampton, NH

The opinions expressed in this publication are those of the participating faculty and do not necessarily reflect the opinions or the recommendations of their affiliated institutions: University of Medicine & Dentistry of New Jersey; MMC, Inc.; or any other persons. Any procedures, medications, or other courses of diagnosis or treatment discussed or suggested in this publication should not be used by clinicians without evaluation of their patients' conditions, assessment of possible contraindications or dangers in use, review of any applicable manufacturer's product information, and comparison with the recommendation of other authorities. This Epilepsy Express Report includes discussion of treatment and indications outside of current approved labeling. This Epilepsy Express Report was made possible through an unrestricted educational grant from Abbott Laboratories.

© 2001 Millennium Medical Communications, Inc. and UMDNJ - Center for Continuing and Outreach Education