Divalproex Sodium: Package Insert and Label Information (Page 6 of 8)

8.5 Geriatric Use

No patients above the age of 65 years were enrolled in double-blind prospective clinical trials of mania associated with bipolar illness. In a case review study of 583 patients, 72 patients (12%) were greater than 65 years of age. A higher percentage of patients above 65 years of age reported accidental injury, infection, pain, somnolence, and tremor. Discontinuation of valproate was occasionally associated with the latter two events. It is not clear whether these events indicate additional risk or whether they result from preexisting medical illness and concomitant medication use among these patients.
A study of elderly patients with dementia revealed drug related somnolence and discontinuation for somnolence [see Warnings and Precautions ( 5.14)] . The starting dose should be reduced in these patients, and dosage reductions or discontinuation should be considered in patients with excessive somnolence [see Dosage and Administration ( 2.4)] . There is insufficient information available to discern the safety and effectiveness of valproate for the prophylaxis of migraines in patients over 65.

10 OVERDOSAGE

Overdosage with valproate may result in somnolence, heart block, deep coma, and hypernatremia. Fatalities have been reported; however patients have recovered from valproate levels as high as 2,120 mcg/mL.
In overdose situations, the fraction of drug not bound to protein is high and hemodialysis or tandem hemodialysis plus hemoperfusion may result in significant removal of drug. The benefit of gastric lavage or emesis will vary with the time since ingestion. General supportive measures should be applied with particular attention to the maintenance of adequate urinary output.
Naloxone has been reported to reverse the CNS depressant effects of valproate overdosage. Because naloxone could theoretically also reverse the antiepileptic effects of valproate, it should be used with caution in patients with epilepsy.

11 DESCRIPTION

Divalproex sodium is a stable coordination compound comprised of sodium valproate and valproic acid in a 1:1 molar relationship. Chemically it is designated as sodium hydrogen bis(2-propylpentanoate). Divalproex sodium has the following structure:

spl-divalproex-structure
(click image for full-size original)

Divalproex sodium occurs as a white powder with a characteristic odor.
Divalproex sodium delayed-release tablets are for oral administration. Divalproex sodium delayed-release tablets, USP are supplied in three dosage strengths containing divalproex sodium USP equivalent to 125 mg, 250 mg, or 500 mg of valproic acid.

Inactive Ingredients

Divalproex sodium delayed-release tablets: colloidal silicon dioxide, corn starch, povidone, pregelatinized maize starch, hypromellose, titanium dioxide, triacetin, methacrylic acid copolymer type C, talc, triethyl citrate, colloidal anhydrous silica, sodium bicarbonate, and sodium lauryl sulfate.

Imprinting ink contains shellac glaze, iron oxide black, N-butyl alcohol, propylene glycol, and ammonium hydroxide.

In addition, individual tablets contain:

125 mg tablets: FD&C Red #40, and FD&C Blue #2

250 mg tablets: FD&C Yellow #6, and iron oxide yellow

500 mg tablets: D&C Red #30, FD&C Blue #2, and iron oxide red

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 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.
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.
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 and Administration ( 2.1)] .

12.3 Pharmacokinetics

Absorption/Bioavailability
Equivalent oral doses of divalproex sodium products and valproic acid 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 T max and C max 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 T max from 4 to 8 hours) than on the absorption of the sprinkle capsules (increase in T max 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 influences the efficacy of valproate as an antimanic or antimigraine agent is unknown.
Coadministration 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 and Administration (2.2)]. 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 Drug Interactions (7.2) 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).
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.
Elimination
Mean plasma clearance and volume of distribution for total valproate are 0.56 L/hr/1.73 m 2 and 11 L/1.73 m 2 , respectively. Mean plasma clearance and volume of distribution for free valproate are 4.6 L/hr/1.73 m 2 and 92 L/1.73 m 2. Mean terminal half-life for valproate monotherapy ranged from 9 to 16 hours following oral dosing regimens of 250 mg 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
Effect of Age
Neonates
Children within the first two months of life have a markedly decreased ability to eliminate valproate compared to older children and 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 2 months.
Children
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. Over the age of 10 years, children have pharmacokinetic parameters that approximate those of adults.
Elderly
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 years). 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)].
Effect of Sex
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 m 2 , respectively).
Effect of Race
The effects of race on the kinetics of valproate have not been studied.
Effect of Disease
Liver Disease
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)].
Renal Disease
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

Carcinogenesis
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/m 2 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.
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. Increased frequencies of sister chromatid exchange (SCE) have been reported in a study of epileptic children taking valproate; this association was not observed in another study conducted in adults.
Impairment of Fertility
In chronic toxicity studies in juvenile and adult rats and dogs, administration of valproate resulted in testicular atrophy and reduced spermatogenesis at oral doses of 400 mg/kg/day or greater in rats (approximately equal to or greater than the maximum recommended human dose (MRHD) on a mg/m 2 basis) and 150 mg/kg/day or greater in dogs (approximately equal to or greater than the MRHD on a mg/m 2 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/m 2 basis) for 60 days.

14 CLINICAL STUDIES

14.1 Mania

The effectiveness of divalproex sodium delayed-release tablets for the treatment of acute mania was demonstrated in two 3-week, placebo controlled, parallel group studies. (1) 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 delayed-release tablets were initiated at a dose of 250 mg tid and adjusted to achieve serum valproate concentrations in a range of 50 to 100 mcg/mL by day 7. Mean divalproex sodium delayed-release tablets doses for completers in this study were 1,118, 1,525, and 2,402 mg/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:

Table 6. Study 1
*
Mean score at baseline
Change from baseline to Week 3 (LOCF)
Difference in change from baseline to Week 3 endpoint (LOCF) between divalproex sodium delayed-release tablets and placebo
YMRS Total Score
Group Baseline *BL to Wk 3 Difference
Placebo 28.8 + 0.2
Divalproex sodium delayed-release tablets 28.5 – 9.5 9.7
BPRS-A Total Score
Group Baseline *BL to Wk 3 Difference
Placebo 76.2 + 1.8
Divalproex sodium delayed-release tablets 76.4 -17 18.8
GAS Score
Group Baseline *BL to Wk 3 Difference
Placebo 31.8 0
Divalproex sodium delayed-release tablets 30.3 + 18.1 18.1

Divalproex sodium delayed-release tablets were statistically significantly superior to placebo on all three measures of outcome. (2) 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 delayed-release tablets were initiated at a dose of 250 mg tid and adjusted within a dose range of 750 mg/day to 2,500 mg/day to achieve serum valproate concentrations in a range of 40 to 150 mcg/mL. Mean divalproex sodium delayed-release tablets 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:

Table 7. Study 2
*
Mean score at baseline
Change from baseline to Day 21 (LOCF)
Difference in change from baseline to Day 21 endpoint (LOCF) between divalproex sodium delayed-release tablets and placebo and lithium and placebo
MRS Total Score
Group Baseline *BL to Day 21 Difference
Placebo 38.9 – 4.4
Lithium 37.9 -10.5 6.1
Divalproex sodium delayed-release tablets 38.1 – 9.5 5.1
MSS Total Score
Group Baseline *BL to Day 21 Difference
Placebo 18.9 – 2.5
Lithium 18.5 – 6.2 3.7
Divalproex sodium delayed-release tablets 18.9 – 6.0 3.5
BIS Total Score
Group Baseline *BL to Day 21 Difference
Placebo 16.4 – 1.4
Lithium 16.0 – 3.8 2.4
Divalproex sodium delayed-release tablets 15.7 – 3.2 1.8

Divalproex sodium delayed-release tablets were 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 1.

spl-divalproex-figure-1
(click image for full-size original)

* p < 0.05
PBO = Placebo, DVPX = Divalproex sodium delayed-release tablets

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