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Year : 2007  |  Volume : 10  |  Issue : 3  |  Page : 169-174

An assessment of the clinical equivalence of valproate chrono and extended release divalproex formulations

R. Madhavan Nayar Center for Comprehensive Epilepsy Care, Department of Neurology, Sree Chitra Tirunal Institute for Medical Sciences and Technology, Trivandrum, Kerala, India

Correspondence Address:
K Radhakrishnan
Department of Neurology, Sree Chitra Tirunal Institute for Medical Sciences and Technology, Trivandrum - 695 011, Kerala
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/0972-2327.34797

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Objective: No guideline currently exists to choose the clinically equivalent dose of divalproex extended release (ER) formulation while switching over from valproate chrono formulation. To address this issue, we evaluated the serum valproate concentration following switch over from valproate chrono to divalproex ER in persons with epilepsy. Materials and Methods: An open label study was conducted in two parts, each for a period of two months. During Part I, patients on regular twice-daily dose of valproate chrono were switched over to once daily divalproex ER (DESVAL ER ) based on the dose escalation recommended when switching over from divalproex DR to ER formulation as the guideline. During Part II, we switched from valproate chrono to divalproex ER with same dosage. Serum valproate concentration, seizure frequency and side effects were assessed serially for two months after changeover and compared with the preswitch data. Results: During Part I, compared to the baseline level, there was a significant increase in mean serum valproate level at two months (67.0 28.4 mg/ml versus 91.9 3.5 mg/ml, P 0.004). With the same dose conversion during Part II, the mean valproate level did not significantly differ before and after the switch (81.5 mg/dl versus 85.7 mg/dl, P 0.08). The mean monthly seizure frequencies and serum ammonia levels did not change during either part. No significant adverse effects occurred. Conclusion: The results of this open label study with small number of patients need to be replicated among larger patient sample through a randomized control design before recommending same dose conversion from valproate chrono to divalproex ER without change in efficacy and tolerability,

Keywords: Antiepileptic drugs, clinical equivalence, divalproex, extended release formulation, sodium valproate, valproate chrono

How to cite this article:
Rajesh B, Ashalatha R, Sarma SP, Radhakrishnan K. An assessment of the clinical equivalence of valproate chrono and extended release divalproex formulations. Ann Indian Acad Neurol 2007;10:169-74

How to cite this URL:
Rajesh B, Ashalatha R, Sarma SP, Radhakrishnan K. An assessment of the clinical equivalence of valproate chrono and extended release divalproex formulations. Ann Indian Acad Neurol [serial online] 2007 [cited 2022 Aug 18];10:169-74. Available from:

   Introduction Top

Valproic acid is a branched chain carboxylic acid and is chemically 2-propylpentanoic acid or N-dipropyl acetic acid. [1],[2] The term sodium valproate, valproic acid and divalproex refer to different forms of the same drug. Valproate ion is the pharmacologically active principle of these compounds. Sodium valproate is the sodium salt of valproic acid, whereas divalproex sodium (or simply divalproex) is a unique preparation consisting of sodium valproate and valproic acid in a 1:1 ratio. [1],[2]

Divalproex is available in different formulations: traditional, delayed release (DR), enteric coated, sprinkle capsule and extended release (ER) preparations. [1],[3] Another formulation, valproate chrono consists of sodium valproate and valproic acid in a 2:1 ratio in a sustained release formulation. [4] These molar ratios have been formulated based on the pharmocokinetic and pharmocodynamic properties of the respective combinations of valproic acid and its sodium salt which will in turn allow the slow release of drug in stomach, small intestine and large intestine over a 12-24h period. [1],[2],[3],[4] The rate of absorption and hence the time to reach peak plasma concentration of valproate ion depends on the specific formulation. Conventional sodium valproate tablets are usually administered in thrice daily dosages, valproate chrono and divalproex DR formulations are administered usually in twice-daily dosages, but ER formulations need be administered only once daily. [1],[2],[3],[4]

In addition to its role as a broad-spectrum antiepileptic drug, [1],[2] valproate is being increasingly prescribed in the treatment of psychiatric disorders [5] and as an antimigraine prophylactic agent. [6] Studies have suggested that noncompliance with pharmacological treatment of chronic disorders necessitating daily regular medication is as high as 50%. [7],[8] This may be especially important in the treatment of individuals with epilepsy, for whom noncompliance not only is a common cause of poor seizure control, but also may precipitate life-threatening status epilepticus. [7],[9] Once daily-dosing has been shown to improve patient compliance and, consequently, may improve treatment outcomes. [10]

For these reasons, more and more patients receiving valproate therapy are now a days being changed to divalproex ER formulations. Because the extent of valproate absorption from divalproex ER depends on the gastrointestinal transit time, the intrinsic variability of gastrointestinal transit time may contribute to slightly lower bioavailability of divalproex ER compared to divalproex DR. [11] In order to cover this problem, while switching over from divalproex DR to divalproex ER, an increase in the daily dosage by up to 8% to 20% is recommended to achieve clinically equivalent serum levels. [11],[12]

Valproate chrono, the sustained release formulation of valproate popular in India, constitute a different molar ratio of sodium valproate and valproic acid (2:1) compared to the equimolar ratio for divalproex DR, popular in Europe and the Unites States. To our knowledge, no dosage schedule currently exists to guide the clinician while switching over from chrono formulation to divalproex ER. In order to understand the clinically equivalent dosages, we estimated the serum valproate concentration following switch over from valproate chrono to divalproex ER in a group of persons with epilepsy.

   Materials and Methods Top

Patient selection

Persons with epilepsy attending the R. Madavan Nayar Center for Comprehensive Epilepsy Care, Sree Chitra Tirunal Institute for Medical Sciences and Technology, Trivandrum, India, aged between 15 and 65 years, on chrono formulation of valproate, in a twice-daily dosage schedule were eligible for the study. Excluded from the study were patients with a history of hypersensitivity to valproate, pregnant or lactating females, patients with hepatic or renal impairment, patients with medical or neurological disorder other than epilepsy, patients with a progressive neurological disease, patients requiring frequent medication changes and patients unwilling or unable to comply with the study protocols. Written informed consent was obtained from each subject. The institutional review board approved the study.

Study design

This was an open label study conducted in two parts (Part I and Part II), each for a period of two months. Patients on a regular twice-daily dose of valproate chrono were switched over to once daily divalproex ER (DESVAL ER , Solus - Ranbaxy, Mumbai, India). On the day of switch (day zero), patients took the morning dose of their usual chrono formulation and from that night started divalproex ER as a single dose. Subsequently, patients were continued on once daily dosage of divalproex ER administered at night.

Clinic visits

Patients visited the clinic on eight occasions. The first visit was five days prior to switch (day -five). Subsequently, patients visited the clinic on day zero (day of switch), days 1, 4, 7, 14, 30 and 60 after the switch.

Dosing schedule

We computed the dose conversion for Part I trial based on the dose escalation of 8% to 20% recommended when switching over from divalproex DR to ER formulation as the guideline. [11],[12] In India, while valproate chrono is available as 200 mg, 300 mg and 500 mg tablets, divalproex ER is marketed as 250 mg, 500 mg, 750 mg and 1000 mg tablets, which also influenced the dose conversion [Table - 1]. During Part II Trial, we switched patients from valproate chrono to divalproex ER with the same dosage.

Clinical and laboratory evaluation

During pre-recruitment visit (day -5), patients were evaluated with a detailed history (including present and past illnesses and concomitant medications), review of the carefully maintained seizure frequency diary during the previous two months, physical examination for nervous and other systems and for the presence of any adverse effects due to valproate. Laboratory assessment included hemogram, serum ammonia, transaminases, alkaline phosphatase, blood urea and creatinine. Only patients with normal laboratory parameters were recruited for the study. Patients maintained a record containing relevant details about the occurrence of seizures, adverse effects or other ailments, which was reviewed during each visit.

Serum valproate and ammonia levels

Two baseline blood samples for valproate levels were obtained for each patient on day -five and on the morning of switch (day zero), to ensure consistency. Blood samples for valproate were drawn during each subsequent visit between 8 am and 9 am. Serum valproate concentration was estimated by the chemiluminescence method. Serum ammonia levels were assessed on day -five, day 30 and day 60.

Statistical analyses

We compared the serum valproate levels on day zero (while on valproate chrono) and day 60 (while on divalproex ER) to decide clinical equivalence and for efficacy comparison, we considered the mean seizure frequency during two months prior to switch with the mean monthly seizure frequency during the 2-month trial period. We used median and mean standard deviation to define the dispersion. In addition to mean, we computed the 5 th and 95 th percentiles of serum valpraote levels. To compare the group means, we used a paired t -test in Part I study and Wilcoxon Signed Ranks test to account for the small number of patients in Part II study. A P value of ≤0.05 was considered to be significant.

   Results Top

Part I trial

A total of 25 patients were enrolled and all of them completed the study adhering to the protocols. Their clinical and demographic characteristics are shown in [Table - 2]. Twenty-two patients had primary generalized epilepsy, while three had complex partial seizures. All except three patients received valproate as monotherapy. The dose of divalproex ER administered ranged from 500 -1750 mg/day (mean 890 mg/day).

Serum valproate levels: [Figure - 1] shows the serum valproate levels before and after switch. In addition, we have provided the fifth and 95 th percentiles of serum valproate levels during the study period [Table - 3] . The mean serum valproate levels at base line were 61.8 g/ml (on day -5) and 67 g/ml (on day zero). The levels rose immediately after the switch and remained at a significantly higher level than baseline throughout the study. Compared to the baseline level, there was a 37% increase in mean serum valproate levels at the end of the study, which was highly significant (67.0 28.4 g/ml versus 91.9 3.5 g/ml, P 0.004). Compared to the base line 95 th level of 125.2 g/ml, the 60 th day value rose to 151.9 g/ml [Table - 3].

Adverse effects: While on valproate chrono, one patient had a mild postural tremor, two had weight gain and one female patient had excessive hair loss. Three patients complained of increased somnolence during the first week following switch over to divalproex ER, which resolved by the next week. One patient had nausea and vomiting related to an intercurrent febrile illness. Gastrointestinal symptoms in the form of abdominal discomfort and constipation were reported by one patient, which improved after one month. The nondisabling, postural tremor present in one patient before the switch did not change after the switch over from chrono to ER formulation.

Serum ammonia levels: The baseline mean serum ammonia level of 76.7 g/dl (normal laboratory value 15 to 50 g/dl) increased to 88.6 g/dl at the end of the study, which was statistically insignificant ( P 0.31).

Seizure outcome: The mean monthly seizure frequency of 0.8 1.5 did not significantly differ from the mean monthly seizure frequency of 0.3 1.1 after being on divalproex ER for 2 months ( P 0.10). None had break though seizures.

Part II trial

Because of the significantly higher level of serum valproate observed during Part I study following conversion from chrono to ER formulation (with an increased dose), we studied five patients with same dose conversion [Table - 1]. Their age ranged from 28 to 35 (median 30) years. All had primary generalized epilepsy. While four patients were switched from 1000 mg of valproate chrono to 1000 mg of divalproex, one patient was switched from 1500 mg to 1500 mg. The higher dose of valproate in Part II trial compared to Part I Trial is due to the selection of patients receiving 1000 or 1500 mg of valproate chrono for Part II trial to achieve conversion to same dose of divalproex ER.

Serum valproate level: The mean valproate level prior to switch of 81.5 g/dl did not significantly differ from the level of 85.7 g/dl at two months after change over to divalproex ER ( P 0.08) [Figure - 1]. Similarly, the 95 th percentile levels between baseline and 60 th day (109 g/dl versus 104 g/dl) did not significantly differ [Table - 3].

Efficacy and tolerability: The mean monthly seizure frequencies (0.4 0.6 versus 0.3 0.5, P 0.31) and serum ammonia levels (87.8 13.2 versus 87.6 15.0, P 0.79) did not differ. None had break though seizures. No adverse effects occurred.

   Discussion Top

We wish to emphasize that the objective of this study was, by utilizing serum valproate levels, to find out the clinically equivalent dosage conversion while switching over from valproate chrono to divalproex ER formulation. We acknowledge that the a duration of eight weeks study period and the small number of patients in Part II trial do not permit us to reliably evaluate the safety and efficacy of divalproex ER. However, all our patients had well-controlled epilepsy with minimal side effects, which did not worsen during the study period. None had break through seizures while switching over from valproate chrono to divalproex ER.

Novel drug delivery methods like slow-release oral formulations improve the therapeutic/toxic ratio of antiepileptic drugs and therefore the drug compliance and seizure control. [1],[2],[3],[4] The divalproex used in this study, DESVAL ER is based on Diffusion Expansion Soluble Polymer Matrix Technology (Ranbaxy Laboratories, Mumbai, India), which relies on a hydrophilic soluble polymer, hydroxypropyl methyl cellulose. This matrix undergoes wetting, hydration, expansion and erosion in the gut. The drug is released slowly and continuously over a 24h period, provides more prolonged stable serum concentration without marked peak-to-trough fluctuations and allows once daily dosing. A pooled data analysis showed that divalproex ER achieved superior tolerability with less frequent tremor, weight gain and gastrointestinal complaints than divalproex DR preparation. [13] Divalproex ER also improved seizure control and was greatly preferred by patients over divalproex DR. [13] A missed dose of divalproex ER can be replaced up to 12h later without any clinically significant perturbation in plasma valproic acid concentrations in the majority of patients with epilepsy. [14]

Patients on conventional sodium valproate can be switched over to twice-daily chrono formulation directly, with the same total daily dosage, without loss of seizure control. [15] No guideline currently exists to choose the clinically equivalent dose of divalproex extended release (ER) formulation while switching over from valproate chrono formulation. To our knowledge, ours is the first study, which addressed the issues related to a switch over from chrono to ER formulation of valproate. When we used an increment in dose of divalproex ER in Part I study as perceived from divalproex DR to ER conversion data, there was a 37% increase in the serum valproate level at two months of treatment with divalproex ER compared to the serum valproate level while on valproate chrono therapy. The initial higher level could be ascribed to the single dose of divalproex ER at bedtime, in addition to the morning dose of valproate chrono, on the day of the switch over [Figure - 1]. To confirm that while switching over from valproate chrono to divalproex ER formulation a dosage hike is unnecessary, we undertook the Part II study, which revealed that the serum valproate level was maintained with same dose conversion. Twenty-two out of 25 patients in Part I study and all patients in Part II study received valproate as monotherapy; therefore, drug interaction did not influence the results. The ideal time to draw blood for plasma valproate concentration is 24h after the last dose of diavalproex ER, [16] but for logistic reasons, we administered the drug at night and measured serum drug level in the morning. To overcome this problem, we compared the serum valproate concentrations of the 60 th day of administration after steady levels have been achieved. [17]

The adverse effects observed in this study were mild and self-limiting. Valproate is known to cause elevation in serum ammonia levels. [1],[2],[18] The baseline serum ammonia levels in our patients were above the normal range, which did not change during the study period. Most of our patients had well-controlled epilepsy as suggested by the low preswitch monthly mean seizure frequency, which showed no change after switch over indicating that the efficacy of divalproex ER and valproate chrono are similar. Thibault et al . [19] compared the therapeutic profile of divalproex ER versus the original divalproex formulation and found that divalproex ER was similar to conventional divalproex in the treatment of well-controlled, primary generalized epilepsy in terms of overall safety and efficacy parameters.

The divalproex ER has the following disadvantages as well. The increased tablet size may preclude ingestion by young children and elderly with swallowing difficulties. Divalproex ER tablets should not be split, crushed or chewed, since that would destroy the extended-release attributes of the formulation. [20] In patients on a combination of multiple antiepileptic drugs, because many of them such as carbamazepine, lamotrigine, topiramate, levetiracetam are prescribed 12 hourly, divalproex ER with a once daily dosage schedule may create two different dosing schedules and may adversely influence patient compliance. In such instances, twice daily dosing of divalproex ER is often a preferred option. [21] Similarly, patients on high dose of valproate may experience side effects after a single dose and prefer a twice daily dosing regimen. Especially in patients with altered gastrointestinal transit time (as in gastric or intestinal bypass surgery), premature release of the contents of divalproex ER tablet may result in rapid rise in serum valproate level ("dose dumping") and early fall to subtherapeutic levels ("bottom out") during once daily dose administration. [21]

In conclusion, patients on valproate chrono can be safely switched over to a same dose of divalproex ER. The currently available strengths of valproate chrono (200 mg, 300 mg and 500 mg) and divalproex ER (250 mg, 500 mg, 750 mg and 1000 mg) in our country causes difficulties in same dose conversion. The result of the present study is limited by the relatively small number of study subjects, especially in Part II and the open nature of the study design. Furthermore, since we studied only subjects aged between 15 to 55 years, the relevance of this finding to children and elderly remains uncertain. The study design does not permit us to decide in the routine management of epilepsy whether patients can be initiated on divalproex ER without first achieving seizure control with chrono preparation. If our results are replicated through randomized control studies involving larger number of patients and longer duration of follow-up, pharmaceutical companies may have to consider manufacturing tablet strengths of valproate chrono and divalproex ER that facilitate same dose conversion. A change over to divalproex ER should not be viewed as a measure to improve efficacy or tolerability, but rather as a method to overcome the disadvantages of twice daily administration of the chrono preparation for patients in whom once daily dosing is preferred.

   Acknowledgement Top

The authors acknowledge the receipt of fi nancial support from Ranbaxy Laboratories, Mumbai to conduct this study.

   References Top

1.Perucca E. Pharmacological and therapeutic properties of valproate: A summary after 35 years of clinical experience. CNS Drugs 2002;16:695-714.  Back to cited text no. 1  [PUBMED]  
2.DeVane CL. Pharmacokinetics, drug interactions and tolerability of valproate. Psychopharmacol Bull 2003;37:25-42.  Back to cited text no. 2  [PUBMED]  [FULLTEXT]
3.Genton P. Progress in pharmaceutical development presentation with improved pharmacokinetics: A new formulation for valproate. Acta Neurol Scand Suppl 2005;182:26-32.  Back to cited text no. 3  [PUBMED]  
4.Roberts D, Easter D, O'Bryan-Tear G. Epilim chrono: A multidose, crossover comparison of two formulations of valproate in healthy volunteers. Biopharm Drug Dispos 1996;17:175-82.  Back to cited text no. 4  [PUBMED]  
5.Bowden CL, Singh V. Valproate in bipolar disorder: 2000 onwards. Acta Psychiatr Scand Suppl 2005;426:13-20.  Back to cited text no. 5  [PUBMED]  
6.Ramadan NM. Migraine headache prophylaxis: Current options and advances on the horizon. Curr Neurol Neurosci Rep 2006;6:95-9.  Back to cited text no. 6  [PUBMED]  
7.Leppik IE, Schmidt D. Summary of the First International Workshop on Compliance in Epilepsy. Epilepsy Res 1988;2:179-82.  Back to cited text no. 7    
8.Keck PE Jr, McElroy SL, Strakowski SM, Boune ML, West SA. Compliance with maintenance treatment in bipolar disorder. Psychopharmacol Bull 1997;33:87-91.  Back to cited text no. 8    
9.Gopinath B, Radhakrishnan K, Sarma PS, Jayachandran D, Alexander A. A questionnaire survey about doctor-patient communication, compliance and locus of control among South Indian people with epilepsy. Epilepsy Res 2000;39:73-82.  Back to cited text no. 9  [PUBMED]  [FULLTEXT]
10.Cramer JA, Mattson RH, Prevey ML, Scheyer RD, Ouellette VL. How often is medication taken as prescribed? A novel assessment technique. JAMA 1989;261:3273-7.  Back to cited text no. 10    
11.Dutta S, Zhang Y. Bioavailability of divalproex extended-release formulation relative to the divalproex delayed-release formulation. Biopharm Drug Dispos 2004;25:345-52.  Back to cited text no. 11  [PUBMED]  [FULLTEXT]
12.Dutta S, Zhang Y, Selness DS, Lee LL, Williams LA, Sommerville KW. Comparison of the bioavailability of unequal doses of divalproex sodium extended-release formulation relative to the delayed-release formulation in healthy volunteers. Epilepsy Res 2002;49:1-10.  Back to cited text no. 12  [PUBMED]  [FULLTEXT]
13.Smith MC, Centorrino F, Welge JA, Collins MA. Clinical comparison of extended-release divalproex versus delayed-release divalproex: Pooled data analyses from nine trials. Epilepsy Behav 2004;5:746-51.  Back to cited text no. 13  [PUBMED]  [FULLTEXT]
14.Reed RC, Dutta S. Predicted serum valproic acid concentrations in patients missing and replacing a dose of extended-release divalproex sodium. Am J Health Syst Pharm 2004;61:2284-9.  Back to cited text no. 14  [PUBMED]  [FULLTEXT]
15.Despland PA. A retrospective study of 113 epileptic patients treated with sustained-release valproate. Epilepsia 1994;35:S99-100.  Back to cited text no. 15  [PUBMED]  
16.Reed RC, Dutta S. Does it really matter when a blood sample for valproaic acid concentration is taken following once-daily administration of divalproex-ER? Ther Drug Monit 2006;28:413-8.  Back to cited text no. 16  [PUBMED]  [FULLTEXT]
17.Dutta S, Reed RC, Cavansugh JH. Pharmacokinetics and safety of extended-release divalproex sodium tablets: Morning versus evening administration. Am J Health Syst Pharm 2004;61:2280-3.  Back to cited text no. 17    
18.Panda S, Radhakrishnan K. Two cases of valproate-induced hyperammonemic encephalopathy without hepatic failure. J Assoc Physicians India 2004;52:746-8.  Back to cited text no. 18  [PUBMED]  
19.Thibault M, Blume WT, Saint-Hilaire JM, Zakhari R, Sommerville KW. Divalproex extended-release versus the original divalproex tablet: Results of a randomized, crossover study of well-controlled epileptic patients with primary generalized seizures. Epilepsy Res 2002;50:243-9.  Back to cited text no. 19  [PUBMED]  
20.Dutta S, Reed RC, O'Dea RF. Comparative absorption profiles of divalproex sodium delayed-release vesus extended-release tablets - clinical implications. Ann Pharmacother 2006;40:619-25.  Back to cited text no. 20  [PUBMED]  [FULLTEXT]
21.Reed RC, Dutta S, Cavanaugh JH, Locke C, Granneman GR. Every-12-hour administration of extended-release divalproex in patients with epilepsy: Impact on plasma valproic acid concentrations. Epilepsy Behav 2006;8:391-6.  Back to cited text no. 21  [PUBMED]  [FULLTEXT]


  [Figure - 1]

  [Table - 1], [Table - 2], [Table - 3]

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