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Pharmacology: Pharmacodynamics: Valproic acid is a carboxylic acid. Other chemical names for this compound are 2-propylpentanoic acid, 2-propylvaleric acid and n-dipropylacetic acid. Valproic acid (pKa 4.8) is a colorless liquid with a characteristic odor. It is slightly soluble in water (1.3 mg/mL) and very soluble in organic solvents. Its empirical formula is C8H16O2 and has a molecular weight of 144.
Valproate sodium is the sodium salt of valproic acid and is chemically designated as sodium 2-propylpentanoate. Valproate sodium has a molecular weight of 166.2. It occurs as an essentially white and odorless, crystalline, deliquescent powder.
Divalproex sodium is a stable coordination compound comprised of sodium valproate and valproic acid in a 1:1 molar relationship and formed during the partial neutralization of valproic acid with 0.5 equivalent of sodium hydroxide. Divalproex sodium is chemically designated as sodium hydrogen bis (2-propylpentanoate). Divalproex sodium has a molecular weight of 310.41 and occurs as a white powder with a characteristic odor. Its empirical formula is C16H31NaO4.
Mechanism of action and Pharmacodynamic properties: Valproate/Valproic acid/Divalproex sodium dissociates to the valproate ion in the gastrointestinal tract. The mechanisms by which valproate exerts its therapeutic effects have not been established. It has been suggested that its activity in epilepsy is related to increased brain concentrations of gamma-aminobutyric acid (GABA).
Description of clinical studies: Epilepsy: Complex Partial Seizures (CPS): The studies described in the following section were conducted using divalproex sodium tablets.
The efficacy of divalproex sodium in reducing the incidence of complex partial seizures (CPS) that occur in isolation or in association with other seizure types was established in two controlled trials.
In one, multiclinic, placebo controlled study employing an add-on design (adjunctive therapy), 144 patients who continued to suffer eight or more CPS per eight weeks during an 8-week period of monotherapy with doses of either carbamazepine or phenytoin sufficient to assure plasma concentrations within the "therapeutic range", were randomized to receive, in addition to their original antiepilepsy drug (AED), either divalproex sodium or placebo. Randomized patients were to be followed for a total of 16 weeks. Table 1 presents the findings. (See Table 1).
Click on icon to see table/diagram/imageFigure 1 presents the proportion of patients (X-axis) whose percentage reduction from baseline in complex partial seizure rates was at least as great as that indicated on the Y-axis in the adjunctive therapy study. A positive percent reduction indicates an improvement (i.e., a decrease in seizure frequency), while a negative percent reduction indicates worsening. Thus, in a display of this type, the curve for an effective treatment is shifted to the left of the curve for placebo. This figure shows that the proportion of patients achieving any particular level of improvement was consistently higher for divalproex sodium than for placebo. For example, 45% of patients treated with divalproex sodium had a ≥50% reduction in complex partial seizure rate compared to 23% of patients treated with placebo. (See Figure 1.)
Click on icon to see table/diagram/imageThe second study assessed the capacity of divalproex sodium to reduce the incidence of CPS when administered as the sole AED. The study compared the incidence of CPS among patients randomized to either a high or low dose treatment arm. Patients qualified for entry into the randomized comparison phase of this study only if: 1) they continued to experience two or more CPS per four weeks during an 8 to 12 week long period of monotherapy with adequate doses of an AED (i.e., phenytoin, carbamazepine, phenobarbital, or primidone); and 2) they made a successful transition over a two week interval to divalproex sodium. Patients entering the randomized phase were then brought to their assigned target dose, gradually tapered off their concomitant AED and followed for an interval as long as 22 weeks. Less than 50% of the patients randomized, however, completed the study. In patients converted to divalproex sodium monotherapy, the mean total valproate concentrations during monotherapy were 71 and 123 mcg/mL in the low dose and high dose groups, respectively.
Table 2 presents the findings for all patients randomized who had at least one post-randomization assessment. (See Table 2.)
Click on icon to see table/diagram/imageFigure 2 presents the proportion of patients (X-axis) whose percentage reduction from baseline in complex partial seizure rates was at least as great as that indicated on the Y-axis in the monotherapy study. A positive percent reduction indicates an improvement (i.e., a decrease in seizure frequency), while a negative percent reduction indicates worsening. Thus, in a display of this type, the curve for a more effective treatment is shifted to the left of the curve for a less effective treatment. This figure shows that the proportion of patients achieving any particular level of reduction was consistently higher for high dose divalproex sodium than for low dose divalproex sodium. For example, when switching from carbamazepine, phenytoin, phenobarbital or primidone monotherapy to high dose divalproex sodium monotherapy, 63% of patients experienced no change or a reduction in complex partial seizure rates compared to 54% of patients receiving low dose divalproex sodium. (See Figure 2.)
Click on icon to see table/diagram/imageIn a clinical trial of divalproex sodium as monotherapy in patients with epilepsy, 34/126 patients (27%) receiving approximately 50 mg/kg/day on average, had at least one value of platelets ≤75 x 109/L.
Approximately half of these patients had treatment discontinued, with return of platelet counts to normal. In the remaining patients, platelet counts normalized with continued treatment. In this study, the probability of thrombocytopenia appeared to increase significantly at total valproate concentrations of ≥110 mcg/mL (females) or ≥135 mcg/mL (males).
In a double-blind, multicenter trial of valproate in elderly patients with dementia (mean age was 83 years old), doses were increased by 125 mg/day to a target dose of 20 mg/kg/day. A significantly higher proportion of valproate patients had somnolence compared to placebo, and although not statistically significant, there was a higher proportion of patients with dehydration. Discontinuations for somnolence were also significantly higher than with placebo. In some patients with somnolence (approximately one-half), there was associated reduced nutritional intake and weight loss. There was a trend for the patients who experienced these events to have a lower baseline albumin concentration, lower valproate clearance, and a higher BUN.
Mania: The effectiveness of divalproex sodium for the treatment of acute mania was demonstrated in two 3-week, placebo controlled, parallel group studies.
Study 1: The first study enrolled adult patients who met DSM-III-R criteria for bipolar disorder and who were hospitalized for acute mania. In addition, they had a history of failing to respond to or not tolerating previous lithium carbonate treatment. Divalproex sodium was initiated at a dose of 250 mg t.i.d. and adjusted to achieve serum valproate concentrations in a range of 50 to 100 mcg/mL by day 7. Mean divalproex sodium doses for completers in this study were 1,118, 1,525, and 2,402 mg/kg/day at days 7, 14, and 21, respectively. Patients were assessed on the Young Mania Rating Scale (YMRS; score ranges from 0 to 60), an augmented Brief Psychiatric Rating Scale (BPRS-A), and the Global Assessment Scale (GAS). Baseline scores and change from baseline in the week 3 endpoint (last-observation-carry-forward) analysis were as follows: See Table 3.
Click on icon to see table/diagram/imageDivalproex sodium was statistically significantly superior to placebo on all three measures of outcome.
Study 2: The second study enrolled adult patients who met Research Diagnostic Criteria for manic disorder and who were hospitalized for acute mania. Divalproex sodium was initiated at a dose of 250 mg t.i.d. and adjusted within a dose range of 750 to 2,500 mg/day to achieve serum valproate concentrations in a range of 40 to 150 mcg/mL. Mean divalproex sodium doses for completers in this study were 1,116, 1,683, and 2,006 mg/day at days 7, 14, and 21, respectively.
Study 2 also included a lithium group for which lithium doses for completers were 1,312, 1,869, and 1,984 mg/day at days 7, 14, and 21, respectively. Patients were assessed on the Manic Rating Scale (MRS; score ranges from 11 to 63), and the primary outcome measures were the total MRS score, and scores for two subscales of the MRS, i.e., the Manic Syndrome Scale (MSS) and the Behavior and Ideation Scale (BIS). Baseline scores and change from baseline in the week 3 endpoint (last-observation-carry-forward) analysis were as follows: See Table 4.
Click on icon to see table/diagram/imageDivalproex sodium was statistically significantly superior to placebo on all three measures of outcome. An exploratory analysis for age and gender effects on outcome did not suggest any differential responsiveness on the basis of age or gender.
A comparison of the percentage of patients showing ≥30% reduction in the symptom score from baseline in each treatment group, separated by study, is shown in Figure 3. (See Figure 3.)
Click on icon to see table/diagram/imageMigraine: The results of two multicenter, randomized, double-blind, placebo-controlled clinical trials established the effectiveness of divalproex sodium in the prophylactic treatment of migraine headache.
Both studies employed essential identical designs and recruited patients with a history of migraine with or without aura (of at least six months in duration) who were experiencing at least two migraine headaches a month during the three months prior to enrollment. Patients with cluster headaches were excluded. Women of childbearing potential were excluded entirely from one study, but were permitted in the other if they were deemed to be practicing an effective method of contraception.
In each study following a 4-week single-blind placebo baseline period, patients were randomized, under double blind conditions, to divalproex sodium or placebo for a 12-week treatment phase, comprised of a 4-week dose titration period followed by an 8-week maintenance period. Treatment outcome was assessed on the basis of 4-week migraine headache rates during the treatment phase.
In the first study, a total of 107 patients (24 M, 83 F), ranging in age from 26 to 73 were randomized 2:1, divalproex sodium to placebo. Ninety patients completed the 8-week maintenance period.
Drug dose titration, using 250 mg tablets, was individualized at the investigator's discretion. Adjustments were guided by actual/sham trough total serum valproate levels in order to maintain the study blind. In patients on divalproex sodium, doses ranged from 500 to 2,500 mg a day. Doses over 500 mg were given in three divided doses (t.i.d.). The mean dose during the treatment phase was 1,087 mg/day resulting in a mean trough total valproate level of 72.5 mcg/mL, with a range of 31 to 133 mcg/mL.
The mean 4-week migraine headache rate during the treatment phase was 5.7 in the placebo group compared to 3.5 in the divalproex sodium group (see Figure 4). These rates were significantly different.
In the second study, a total of 176 patients (19 males and 157 females), ranging in age from 17 to 76 years, were randomized equally to one of three divalproex sodium dose groups (500, 1,000, or 1,500 mg/day) or placebo. The treatments were given in two divided doses (b.i.d.). One hundred thirty-seven patients completed the 8-week maintenance period. Efficacy was to be determined by a comparison of the 4-week migraine headache rate in the combined 1,000/1,500 mg/day group and placebo group.
The initial dose was 250 mg daily. The regimen was advanced by 250 mg every four days (eight days for 500 mg/day group), until the randomized dose was achieved. The mean trough total valproate levels during the treatment phase were 39.6, 62.5, and 72.5 mcg/mL in the divalproex sodium 500, 1,000, and 1,500 mg/day groups, respectively.
The mean 4-week migraine headache rates during the treatment phase, adjusted for differences in baseline rates, were 4.5 in the placebo group, compared to 3.3, 3.0, and 3.3 in the divalproex sodium 500, 1,000, and 1,500 mg/day groups, respectively, based on intent-to-treat results (see Figure 4). Migraine headache rates in the combined divalproex sodium 1,000/1,500 mg group were significantly lower than in the placebo group. (See Figure 4.)
Click on icon to see table/diagram/imagePharmacokinetics: Absorption/Bioavailability: Equivalent oral doses of divalproex sodium (Depakote) products and valproic acid (Depakene) capsules deliver equivalent quantities of valproate ion systemically. Although the rate of valproate ion absorption may vary with the formulation administered (liquid, solid, or sprinkle), conditions of use (e.g., fasting or postprandial) and the method of administration (e.g., whether the contents of the capsule are sprinkled on food or the capsule is taken intact), these differences should be of minor clinical importance under the steady state conditions achieved in chronic use in the treatment of epilepsy. However, it is possible that differences among the various valproate products in Tmax and Cmax could be important upon initiation of treatment. For example, in single dose studies, the effect of feeding had a greater influence on the rate of absorption of the tablet (increase in Tmax from 4 to 8 hours) than on the absorption of the sprinkle capsules (increase in Tmax from 3.3 to 4.8 hours).
While the absorption rate from the G.I. tract and fluctuation in valproate plasma concentrations vary with dosing regimen and formulation, the efficacy of valproate as an anticonvulsant in chronic use is unlikely to be affected. Experience employing dosing regimens from once-a-day to four-times-a-day, as well as studies in primate epilepsy models involving constant rate infusion, indicate that total daily systemic bioavailability (extent of absorption) is the primary determinant of seizure control and that differences in the ratios of plasma peak to trough concentrations between valproate formulations are inconsequential from a practical clinical standpoint.
(Whether or not rate of absorption of divalproex sodium enteric coated tablets influences the efficacy of valproate as an antimanic or antimigraine agent is unknown.)
Co-administration of oral valproate products with food and substitution among the various divalproex sodium and valproic acid formulations should cause no clinical problems in the management of patients with epilepsy (see Dosage & Administration). Nonetheless, any changes in dosage administration, or the addition or discontinuance of concomitant drugs should ordinarily be accompanied by close monitoring of clinical status and valproate plasma concentrations.
Distribution: Protein Binding: The plasma protein binding of valproate is concentration dependent and the free fraction increases from approximately 10% at 40 mcg/mL to 18.5% at 130 mcg/mL. Protein binding of valproate is reduced in the elderly, in patients with chronic hepatic diseases, in patients with renal impairment, and in the presence of other drugs (e.g., aspirin). Conversely, valproate may displace certain protein-bound drugs (e.g., phenytoin, carbamazepine, warfarin, and tolbutamide) (see Interactions for more detailed information on the pharmacokinetic interactions of valproate with other drugs).
CNS Distribution: Valproate concentrations in cerebrospinal fluid (CSF) approximate unbound concentrations in plasma (about 10% of total concentration).
Placental transfer (see Use in Pregnancy & Lactation): Valproate crosses the placental barrier in animal species and in humans: In animal species, valproate crosses the placenta, to a similar extent as in humans; In humans, several publications assessed the concentration of valproate in the umbilical cord of neonates at delivery. Valproate serum concentration in the umbilical cord, representing that in the fetuses, was similar to or slightly higher than that in the mothers.
Metabolism: Valproate is metabolized almost entirely by the liver. In adult patients on monotherapy, 30 to 50% of an administered dose appears in urine as a glucuronide conjugate. Mitochondrial β-oxidation is the other major metabolic pathway, typically accounting for over 40% of the dose. Usually, less than 15 to 20% of the dose is eliminated by other oxidative mechanisms. Less than 3% of an administered dose is excreted unchanged in urine.
The relationship between dose and total valproate concentration is nonlinear; concentration does not increase proportionally with the dose, but rather, increases to a lesser extent due to saturable plasma protein binding. The kinetics of unbound drug are linear.
Excretion: Mean plasma clearance and volume of distribution for total valproate are 0.56 L/hr/1.73 m2 and 11 L/1.73 m2, respectively. Mean plasma clearance and volume of distribution for free valproate are 4.6 L/hr/1.73 m2 and 92 L/1.73 m2. Mean terminal half-life for valproate monotherapy ranged from 9 to 16 hours following oral dosing regimens of 250 to 1,000 mg.
The estimates cited apply primarily to patients who are not taking drugs that affect hepatic metabolizing enzyme systems. For example, patients taking enzyme-inducing antiepileptic drugs (carbamazepine, phenytoin, and phenobarbital) will clear valproate more rapidly. Because of these changes in valproate clearance, monitoring of antiepileptic concentrations should be intensified whenever concomitant antiepileptics are introduced or withdrawn.
Special Populations: Neonates: In neonates and infants up to 2 months of age, valproate clearance is decreased when compared to adults. This is a result of reduced clearance (perhaps due to delay in development of glucuronosyltransferase and other enzyme systems involved in valproate elimination) as well as increased volume of distribution (in part due to decreased plasma protein binding). For example, in one study, the half-life in children under 10 days ranged from 10 to 67 hours compared to a range of 7 to 13 hours in children greater than two months.
Geriatric: The capacity of elderly patients (age range: 68 to 89 years) to eliminate valproate has been shown to be reduced compared to younger adults (age range: 22 to 26). Intrinsic clearance is reduced by 39%; the free fraction of valproate is increased by 44%. Accordingly, the initial dosage should be reduced in the elderly (see Dosage & Administration).
Pediatric: Pediatric patients (i.e., between 3 months and 10 years) have 50% higher clearances expressed on weight (i.e., mL/min/kg) than do adults.
Above the age of 10 years, children and adolescents have valproate clearances similar to those reported in adults. Based on published literature, in pediatric patients below the age of 10 years, the systemic clearance of valproate varies with age. In children aged 2-10 years, valproate clearance is 50% higher than in adults.
Gender: There are no differences in the body surface area adjusted unbound clearance between males and females (4.8±0.17 and 4.7±0.07 L/hr per 1.73 m2, respectively).
Ethnicity: The effects of ethnicity on the kinetics of valproate have not been studied.
Renal impairment: A slight reduction (27%) in the clearance of unbound valproate has been reported in patients with renal failure (creatinine clearance <10 mL/minute); however, hemodialysis typically reduces valproate concentrations by about 20%. Protein binding in these patients is substantially reduced; thus, monitoring total concentrations may be misleading. For further guidance refer to Dosage & Administration.
Hepatic impairment: See Contraindications and Hepatotoxicity under Precautions.
Liver disease impairs the capacity to eliminate valproate. In one study, the clearance of free valproate was decreased by 50% in seven patients with cirrhosis and by 16% in four patients with acute hepatitis, compared to six healthy subjects. In that study, the half-life of valproate was increased from 12 to 18 hours. Liver disease is also associated with decreased albumin concentrations and larger unbound fractions (2 to 2.6 fold increase) of valproate. Accordingly, monitoring of total concentrations may be misleading since free concentrations may be substantially elevated in patients with hepatic disease whereas total concentrations may appear to be normal.
Plasma Levels and Clinical Effect: The relationship between plasma concentration and clinical response is not well documented. One contributing factor is the nonlinear, concentration dependent protein binding of valproate that affects the clearance of the drug. Thus, monitoring of total serum valproate cannot provide a reliable index of the bioactive valproate species.
For example, because the plasma protein binding of valproate is concentration dependent, the free fraction increases from approximately 10% at 40 mcg/mL to 18.5% at 130 mcg/mL. Higher than expected free fractions occur in the elderly, in hyperlipidemic patients, and in patients with hepatic and renal diseases.
Mania: In placebo-controlled clinical trials of acute mania, patients were dosed to clinical response with trough plasma concentrations between 50 and 125 mcg/mL (see Dosage & Administration).
Epilepsy: The therapeutic range in epilepsy is commonly considered to be 50 to 100 mcg/mL of total valproate, although some patients may be controlled with lower or higher plasma concentrations.
Equivalent doses of valproate sodium and divalproex sodium yield equivalent plasma levels of the valproate ion.
Toxicology: Preclinical safety data: Carcinogenesis, Mutagenesis, Reproductive and Developmental Toxicity and Impairment of Fertility: Carcinogenesis: The 2-year carcinogenicity studies were conducted in mice and rats given oral valproate doses of approximately 80 and 160 mg/kg/day (which are the maximum tolerated doses in these species but less than the maximum recommended human dose based on body surface area). Subcutaneous fibrosarcomas were observed in male rats and hepatocellular carcinomas and bronchiolo-alveolar adenomas were observed in male mice at incidences slightly higher than concurrent study controls but comparable to historical control data.
Mutagenesis: Valproate was not mutagenic in an in vitro bacterial assay (Ames test), did not produce dominant lethal effects in mice, and did not increase chromosome aberration frequency in an in vivo cytogenetic study in rats. Valproate was not mutagenic in bacteria (Ames test) or mouse lymphoma L5178Y cells at thymidine kinase locus (mouse lymphoma assay) and did not induce DNA repair activity in primary culture of rat hepatocytes. It did not induce either chromosome aberrations in rat bone marrow or dominant lethal effects in mice after oral administration.
In literature, after intraperitoneal exposure to valproate, increased incidences of DNA and chromosome damage (DNA strand-breaks, chromosomal aberrations or micronuclei) have been reported in rodents. However, the relevance of the results obtained with the intraperitoneal route of administration is unknown.
Statistically significant higher incidences of sister-chromatid exchange (SCE) have been observed in patients exposed to valproate as compared to healthy subjects not exposed to valproate. However, these data may have been impacted by confounding factors. Two published studies examining SCE frequency in epileptic patients treated with valproate versus untreated epileptic patients, provided contradictory results. The biological significance of an increase in SCE frequency is not known.
Reproductive and Developmental Toxicity: Teratogenic effects (malformations of multiple organ systems) have been demonstrated in mice, rats, and rabbits.
In published literature, behavioral abnormalities have been reported in first generation offspring of mice and rats after in utero exposure to clinically relevant doses/exposures of valproate.
In mice, behavioral changes have also been observed in the 2nd and 3rd generations, albeit less pronounced in the 3rd generation, following an acute in utero exposure of the first generation. The relevance of these findings for humans is unknown.
Impairment of fertility: In sub-chronic/chronic toxicity studies, testicular degeneration/atrophy or spermatogenesis abnormalities and a decrease in testes weight were reported in adult rats and dogs after oral administration starting at doses of 400 mg/kg/day and 150 mg/kg/day, respectively with associated NOAELs for testis findings of 270 mg/kg/day in adult rats and 90 mg/kg/day in adult dogs.
In a fertility study in rats, valproate at doses up to 350 mg/kg/day did not alter male reproductive performance.
In juvenile rats, a decrease in testes weight was only observed at doses exceeding the maximum tolerated dose (from 240 mg/kg/day by intraperitoneal or intravenous route) and with no associated histopathological changes. No effects on the male reproductive organs were noted at tolerated doses (up to 90 mg/kg/day). Relevance of the testicular findings to pediatric population is unknown.
However, male infertility has been identified as an undesirable effect in humans (see Use in Pregnancy & Lactation and Adverse Reactions).
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