Divalproex Sodium Extended-Release: Package Insert and Label Information (Page 6 of 8)
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
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).
12.2 Pharmacodynamics
The relationship between plasma concentration and clinical response is not well documented. One contributing factor is the nonlinear, concentration dependent protein binding of valproate which affects the clearance of the drug. Thus, monitoring of total serum valproate may not 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.
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.
In placebo-controlled clinical trials of acute mania, patients were dosed to clinical response with trough plasma concentrations between 85 and 125 mcg/mL [see Dosage and Administration (2.1)].
12.3 Pharmacokinetics
The absolute bioavailability of divalproex sodium extended-release tablets administered as a single dose after a meal was approximately 90% relative to intravenous infusion.
When given in equal total daily doses, the bioavailability of divalproex sodium extended-release tablets are less than that of divalproex sodium tablets. In five multiple-dose studies in healthy subjects (N=82) and in subjects with epilepsy (N=86), when administered under fasting and nonfasting conditions, divalproex sodium extended-release tablets given once daily produced an average bioavailability of 89% relative to an equal total daily dose of divalproex sodium tablets given BID, TID, or QID. The median time to maximum plasma valproate concentrations (Cmax ) after divalproex sodium extended-release tablets administration ranged from 4 to 17 hours. After multiple once-daily dosing of divalproex sodium extended-release tablets, the peak-to-trough fluctuation in plasma valproate concentrations was 10-20% lower than that of regular divalproex sodium tablets given BID, TID, or QID.
Conversion from Divalproex Sodium Tablets to Divalproex Sodium Extended-Release Tablets
When divalproex sodium extended-release tablets are given in doses 8 to 20% higher than the total daily dose of divalproex sodium tablets, the two formulations are bioequivalent. In two randomized, crossover studies, multiple daily doses of divalproex sodium tablets were compared to 8 to 20% higher once-daily doses of divalproex sodium extended-release tablets. In these two studies, divalproex sodium extended-release tablets and divalproex sodium tablets regimens were equivalent with respect to area under the curve (AUC; a measure of the extent of bioavailability). Additionally, valproate Cmax was lower, and Cmin was either higher or not different, for divalproex sodium extended-release tablets relative to divalproex sodium tablets regimens (see Table 9).
| Table 9. Bioavailability of Divalproex Sodium Extended-ReleaseTablets Relative to Divalproex Sodium Tablets When Divalproex Sodium Extended-Release Tablets Dose is 8 to 20% Higher | ||||
| Study Population | Regimens | Relative Bioavailability | ||
| Divalproex sodium extended-release tablets vs. Divalproex sodium tablets | AUC24 | Cmax | Cmin | |
| Healthy Volunteers (N=35) | 1000 & 1500 mgDivalproex sodium extended-release tablets vs.875 & 1250 mg Divalproex sodium tablets | 1.059 | 0.882 | 1.173 |
| Patients with epilepsy on concomitant enzyme-inducing antiepilepsy drugs (N = 64) | 1000 to 5000 mgDivalproex sodium extended-release tablets vs.875 to 4250 mgDivalproex sodium tablets | 1.008 | 0.899 | 1.022 |
Concomitant antiepilepsy drugs (topiramate, phenobarbital, carbamazepine, phenytoin, and lamotrigine were evaluated) that induce the cytochrome P450 isozyme system did not significantly alter valproate bioavailability when converting between divalproex sodium tablets and divalproex sodium extended-release tablets.
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 Drug Interactions (7.2) for more detailed information on the pharmacokinetic interactions of valproate with other drugs].
Valproate concentrations in cerebrospinal fluid (CSF) approximate unbound concentrations in plasma (about 10% of total concentration).
Valproate is metabolized almost entirely by the liver. In adult patients on monotherapy, 30-50% 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 15-20% 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.
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 1000 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.
The valproate pharmacokinetic profile following administration of divalproex sodium extended-release tablets was characterized in a multiple-dose, non-fasting, open label, multi-center study in children and adolescents. Divalproex sodium extended-release tablets once daily doses ranged from 250-1750 mg. Once daily administration of divalproex sodium extended-release tablets in pediatric patients (10-17 years) produced plasma VPA concentration-time profiles similar to those that have been observed in adults.
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 is increased by 44%. Accordingly, the initial dosage should be reduced in the elderly [see Dosage and Administration (2.4)].
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).
The effects of race on the kinetics of valproate have not been studied.
Liver disease impairs the capacity to eliminate valproate. In one study, the clearance of free valproate was decreased by 50% in 7 patients with cirrhosis and by 16% in 4 patients with acute hepatitis, compared with 6 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 [see Boxed Warning, Contraindications (4), and Warnings and Precautions (5.1)].
A slight reduction (27%) in the unbound clearance of valproate has been reported in patients with renal failure (creatinine clearance < 10 mL/minute); however, hemodialysis typically reduces valproate concentrations by about 20%. Therefore, no dosage adjustment appears to be necessary in patients with renal failure. Protein binding in these patients is substantially reduced; thus, monitoring total concentrations may be misleading.
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, and Impairment of Fertility
Valproate was administered orally to rats and mice at doses of 80 and 170 mg/kg/day (less than the maximum recommended human dose on a mg/m2 basis) for two years. The primary findings were an increase in the incidence of subcutaneous fibrosarcomas in high-dose male rats receiving valproate and a dose-related trend for benign pulmonary adenomas in male mice receiving valproate. The significance of these findings for humans is unknown.
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. Increased frequencies of sister chromatid exchange (SCE) have been reported in a study of epileptic children taking valproate, but this association was not observed in another study conducted in adults. There is some evidence that increased SCE frequencies may be associated with epilepsy. The biological significance of an increase in SCE frequency is not known.
Chronic toxicity studies of valproate in juvenile and adult rats and dogs demonstrated reduced spermatogenesis and testicular atrophy at oral doses of 400 mg/kg/day or greater in rats (approximately equivalent to or greater than the maximum recommended human dose (MRHD) on a mg/m2 basis) and 150 mg/kg/day or greater in dogs (approximately 1.4 times the MRHD or greater on a mg/m2 basis). Fertility studies in rats have shown no effect on fertility at oral doses of valproate up to 350 mg/kg/day (approximately equal to the MRHD on a mg/m2 basis) for 60 days. The effect of valproate on testicular development and on sperm production and fertility in humans is unknown.
14 CLINICAL STUDIES
14.1 Mania
The effectiveness of divalproex sodium extended-release tablets for the treatment of acute mania is based in part on studies establishing the effectiveness of divalproex sodium tablets for this indication. Divalproex sodium extended-release tablets effectiveness was confirmed in one randomized, double-blind, placebo-controlled, parallel group, 3-week, multicenter study. The study was designed to evaluate the safety and efficacy of divalproex sodium extended-release tablets in the treatment of bipolar I disorder, manic or mixed type, in adults. Adult male and female patients who had a current DSM-IV TR primary diagnosis of bipolar I disorder, manic or mixed type, and who were hospitalized for acute mania, were enrolled into this study. Divalproex sodium extended-release tablets were initiated at a dose of 25 mg/kg/day given once daily, increased by 500 mg/day on Day 3, then adjusted to achieve plasma valproate concentrations in the range of 85-125 mcg/mL. Mean daily divalproex sodium extended-release tablets doses for observed cases were 2362 mg (range: 500-4000), 2874 mg (range: 1500-4500), 2993 mg (range: 1500-4500), 3181 mg (range: 1500-5000), and 3353 mg (range: 1500-5500) at Days 1, 5, 10, 15, and 21, respectively. Mean valproate concentrations were 96.5 mcg/mL, 102.1 mcg/mL, 98.5 mcg/mL, 89.5 mcg/mL at Days 5, 10, 15 and 21, respectively. Patients were assessed on the Mania Rating Scale (MRS; score ranges from 0-52).
Divalproex sodium extended-release tablets were significantly more effective than placebo in reduction of the MRS total score.
14.2 Epilepsy
The efficacy of valproate 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, multi-clinic, placebo controlled study employing an add-on design, (adjunctive therapy) 144 patients who continued to suffer eight or more CPS per 8 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 tablets or placebo. Randomized patients were to be followed for a total of 16 weeks. The following Table presents the findings.
| Table 10. Adjunctive Therapy Study Median Incidence of CPS per 8 Weeks | |||
| Add-onTreatment | Numberof Patients | BaselineIncidence | ExperimentalIncidence |
| Divalproex sodium tablets | 75 | 16.0 | 8.9* |
| Placebo | 69 | 14.5 | 11.5 |
| * Reduction from baseline statistically significantly greater for valproate than placebo at p ≤ 0.05 level. | |||
Figure 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 valproate than for placebo. For example, 45% of patients treated with valproate had a ≥ 50% reduction in complex partial seizure rate compared to 23% of patients treated with placebo.
The second study assessed the capacity of valproate 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 2 or more CPS per 4 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 valproate. 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 tablets monotherapy, the mean total valproate concentrations during monotherapy were 71 and 123 mcg/mL in the low dose and high dose groups, respectively.
The following Table presents the findings for all patients randomized who had at least one post-randomization assessment.
| Table 11. Monotherapy Study Median Incidence of CPS per 8 Weeks | |||
| Treatment | Numberof Patients | BaselineIncidence | RandomizedPhase Incidence |
| High dose Valproate | 131 | 13.2 | 10.7* |
| Low dose Valproate | 134 | 14.2 | 13.8 |
| * Reduction from baseline statistically significantly greater for high dose than low dose at p ≤ 0.05 level. | |||
Figure 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 valproate than for low dose valproate. For example, when switching from carbamazepine, phenytoin, phenobarbital or primidone monotherapy to high dose valproate monotherapy, 63% of patients experienced no change or a reduction in complex partial seizure rates compared to 54% of patients receiving low dose valproate.
Information on pediatric studies are presented in section 8.
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