CLINICAL PHARMACOLOGY
Pharmacodynamics
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).
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), the 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 4-8 hours) than on the absorption of the sprinkle
capsules (increase in Tmax from 3.3-4.8)
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.
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
AND 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 DRUG 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).
Metabolism
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
b-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.
Elimination
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/hr/1.73
m2. Mean terminal half-life for valproate monotherapy
ranged from 9-16 hours following oral dosing regimens
of 250-1000 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.
Special Populations
Effect of Age
Neonates: Children within the
first 2 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 ten days ranged
from 10-67 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: 69-89 years) to eliminate valproate
has been shown to be reduced compared to younger adults
(age range: 22-26 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)
Effect of 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 1.73m2, respectively).
Effect of Race
The effects of race on the kinetics of valproate have
not been studied.
Effect of Disease
Liver Disease: See BOXED WARNING,
CONTRAINDICATIONS, and WARNINGS. 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
12-18 hours. Liver disease is also associated with decreased
albumin concentrations and larger unbound fractions (2-2.6
fold increases) 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.
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.
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 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 50-100 mcg/ml
of total valproate, although some patients may be controlled
with lower or higher plasma concentrations.
Mania: In placebo-controlled
trials of acute mania, patients were dosed to clinical
response with trough plasma concentrations between 50
and 125 mcg/ml (see DOSAGE AND ADMINISTRATION).
CLINICAL STUDIES
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 tid and adjusted to achieve
serum valproate concentrations in a range of 50-100 mcg/ml
by day 7. Mean divalproex sodium doses for completers in
this study were 1118, 1525, and 2402 mg/day at days 7,14,
and 21, respectively. Patients were assessed on the Young
Mania Rating Scale (YMRS; score ranges from 0-60), 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 can be seen in TABLE 1.
| TABLE 1 Study
1 |
| Group |
Baseline* |
BL to Wk 3† |
Difference‡ |
| YMRS Total
Score |
|
|
28.8 |
+0.2 |
|
|
|
28.5 |
-9.5 |
9.7 |
| BPRS-A Total
Score |
|
|
76.2 |
+1.8 |
|
|
|
76.4 |
-17.0 |
18.8 |
| GAS Total
Score |
|
|
31.8 |
0.0 |
|
|
|
30.3 |
+18.1 |
18.1 |
| * Mean score
at baseline. |
| † Change
from baseline to week 3 (LOCF). |
| ‡ Difference
in change from baseline to week 3 endpoint (LOCF)
between divalproex sodium and placebo. |
Divalproex Sodium was statistically significantly superior
to placebo on all 3 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 tid and adjusted
within a dose range of 750-2500 mg/day to achieve serum
valproate concentrations in a range of 40-150 mcg/ml. Mean
divalproex sodium doses for completers in this study were
1116, 1683, and 2006 mg/day at days 7, 14, and 21, respectively.
Study 2 also included a lithium group for which lithium
doses for completers were 1312, 1869, and 1984 mg/day at
days 7, 14, and 21, respectively. Patients were assessed
on the Manic Rating Scale (MRS; score ranges from 11-63),
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 is
shown in TABLE 2.
|
TABLE 2 Study 2
|
|
Group
|
Baseline*
|
BL to Day 21†
|
Difference‡
|
| MRS Total
Score |
|
|
38.9 |
-4.4 |
|
|
|
37.9 |
-10.5 |
6.1 |
|
|
38.1 |
-9.5 |
5.1 |
| MSS Total
Score |
|
|
18.9 |
-2.5 |
|
|
|
18.5 |
-6.2 |
3.7 |
|
|
18.9 |
-6.0 |
3.5 |
| BIS Total
Score |
|
|
16.4 |
-1.4 |
|
|
|
16.0 |
-3.8 |
2.4 |
|
|
15.7 |
-3.2 |
1.8 |
| * Mean score
at baseline. |
| † Change
from baseline to day 21 (LOCF). |
| ‡ Difference
in change from baseline to day 21 endpoint (LOCF)
between divalproex sodium, lithium, and placebo. |
Divalproex 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.
Migraine
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 essentially identical designs and
recruited patients with a history of migraine with or
without aura (of at least 6 months in duration) who were
experiencing at least 2 migraine headaches a month during
the 3 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 male,
83 female), ranging in age from 26-73 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 2500 mg a day. Doses over 500 mg were given
in 3 divided doses (tid). The mean dose during the treatment
phase was 1087 mg/day resulting in a mean trough total
valproate level of 72.5 mcg/ml, with a range of 31-133
mg/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. These rates were significantly
different.
In the second study, a total of 176 patients (19 males
and 157 females), ranging in age from 17-76 years, were
randomized equally to one of three divalproex sodium dose
groups (500, 1000, or 1500 mg/day) or placebo. The treatments
were given in 2 divided doses. 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 1000/1500 mg/day group and
placebo group.
The initial dose was 250 mg daily. The regimen was advanced
by 250 mg every 4 days (8 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,
1000, and 1500 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, 1000, and 1500 mg/day groups,
respectively, based on intent-to-treat results. Migraine
headache rates in the combined divalproex sodium 1000/1500
mg group were significantly lower than in the placebo
group.
Epilepsy
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, a multiclinic, placebo controlled study employing
an add-on design, (adjunctive therapy) 144 patients who
continued to suffer 8 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, or placebo. Randomized
patients were to be followed for a total of 16 weeks. TABLE
3 presents the findings.
| TABLE 3 Adjunctive
Therapy Study |
| Median Incidence
of CPS Per 8 Weeks |
| Add-On Treatment |
Number of Patients |
Baseline Incidence |
Experimental Incidence |
| Divalproex Sodium |
75 |
16.0 |
8.9* |
| Placebo |
69 |
14.5 |
11.5 |
| * Reduction
from baseline statistically significantly greater
for divalproex sodium than placebo at p £0.05
level. |
The proportion of patients achieving any particular level
of reduction was consistently higher for high dose divalproex
sodium than for low dose divalproex sodium. 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.
|
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