INDICATIONS
Mania
Divalproex sodium is indicated for the treatment of the
manic episodes associated with bipolar disorder. A manic
episode is a distinct period of abnormally and persistently
elevated, expansive, or irritable mood. Typical symptoms
of mania include pressure of speech, motor hyperactivity,
reduced need for sleep, flight of ideas, grandiosity,
poor judgement, aggressiveness, and possible hostility.
The efficacy of divalproex sodium was established in
3-week trials with patients meeting DSM-III-R criteria
for bipolar disorder who were hospitalized for acute mania
(See CLINICAL STUDIES.)
The safety and effectiveness of divalproex sodium for
long-term use in mania (i.e., more than 3 weeks) has not
been systematically evaluated in controlled clinical trials.
Therefore, physicians who elect to use divalproex sodium
for extended periods of time should continually re-evaluate
the long term usefulness of the drug for the individual
patient.
Epilepsy
Divalproex sodium is indicated as monotherapy and adjunctive
therapy in the treatment of patients with complex partial
seizures that occur either in isolation or in association
with other types of seizures. Divalproex sodium is also
indicated for use as sole and adjunctive therapy in the
treatment of simple and complex absence seizures, and
adjunctively in patients with multiple seizure types that
include absence seizures.
Simple absence is defined as very brief clouding of the
sensorium or loss of consciousness, accompanied by certain
generalized epileptic discharges without other detectable
clinical signs. Complex absence is the term used when
other signs are also present.
Migraine
Divalproex sodium is indicated for the prophylaxis of
migraine headaches. There is no evidence that divalproex
sodium is useful in the acute treatment of migraine headaches.
Because valproic acid may be a hazard to the fetus, divalproex
sodium should be considered for women of childbearing
potential only after this risk has been thoroughly discussed
with the patient and weighed against the potential benefits
of treatment (see WARNINGS, Usage in Pregnancy and Information
for the Patient).
See WARNINGS (FOR STATEMENT REGARDING FATAL HEPATIC DYSFUNCTION.)
DOSAGE AND ADMINISTRATION
Mania
Divalproex sodium tablets are administered orally. The
recommended initial dose is 750 mg daily in divided doses.
The dose should be increased as rapidly as possible to
achieve the lowest therapeutic dose which produces the
desired clinical effect or the desired range of plasma
concentrations. In placebo-controlled clinical trials
of acute mania, patients were dosed to a clinical response
with a trough plasma concentration between 50 and 125
mcg/ml. Maximum concentrations were generally achieved
within 14 days. The maximum recommended dose is 60 mg/kg/day.
There is no body of evidence available from controlled
trials to guide a clinician in the longer term management
of a patient who improves during divalproex sodium treatment
of an acute manic episode. While it is generally agreed
that pharmacological treatment beyond an acute response
in mania is desirable, both for maintenance of the initial
response and for prevention of new manic episodes, there
are no systematically obtained data to support the benefits
of divalproex sodium in such longer-term treatment. Although
there are no efficacy data that specifically address longer-term
antimanic treatment with divalproex sodium, the safety
of divalproex sodium in long-term use is supported by
data from record reviews involving approximately 360 patients
treated with divalproex sodium for greater than 3 months.
Epilepsy
Divalproex sodium tablets are administered orally. Divalproex
sodium has been studied as monotherapy and adjunctive
therapy in complex partial seizures, and in simple and
complex absence seizures in adults and adolescents. As
the divalproex sodium dosage is titrated upward, concentrations
of phenobarbital, carbamazepine, and/or phenytoin may
be affected (see DRUG INTERACTIONS).
Complex Partial Seizures: For
adults and children 10 years of age and older.
Monotherapy (Initial Therapy): Divalproex
sodium has not been systematically studied as initial
therapy. Patients should initiate therapy at 10-15 mg/kg/day.
The dosage should be increased by 5-10 mg/kg/week to achieve
optimal clinical response. Ordinarily, optimal clinical
response is achieved at daily doses below 60 mg/kg/day.
If unsatisfactory clinical response has not been achieved,
plasma levels should be measured to determine whether
or not they are in the usually accepted therapeutic range
(50-100 mcg/ml). No recommendation regarding the safety
of valproate for use at doses above 60 mg/kg/day can be
made.
The probability of thromocytopenia increases significantly
at total trough valproate plasma concentrations above
100 mcg/ml in females and 135 mcg/ml in males. The benefit
of improved seizure control with higher doses should be
weighed against the possibility of a greater incidence
of adverse reactions.
Conversion to Monotherapy: Patients
should initiate therapy at 10-15 mg/kg/day. The dosage
should be increased by 5-10 mg/kg/week to achieve optimal
clinical response. Ordinarily, optimal clinical response
is achieved at daily doses below 60 mg/kg/day. If satisfactory
clinical response has not been achieved, plasma levels
should be measured to determine whether or not they are
in the usually accepted therapeutic range (50-100 mcg/ml).
No recommendation regarding the safety of valproate for
use at doses above 60 mg/kg/day can be made. Concomitant
antiepilepsy drug (AED) dosage can ordinarily be reduced
by approximately 25% every 2 weeks. This reduction may
be started at initiation of divalproex sodium therapy,
or delayed by 1-2 weeks if there is a concern that seizures
are likely to occur with a reduction. The speed and duration
of withdrawal of the concomitant AED can be highly variable,
and patients should be monitored closely during his period
for increased seizure frequency.
Adjunctive Therapy: Divalproex
sodium may be added to the patient's regimen at a dosage
of 10-15 mg/kg/day. The dosage may be increased by 5-10
mg/kg/week to achieve optimal clinical response. Ordinarily,
optimal clinical response is achieved at daily doses below
60 mg/kg/day. If satisfactory clinical response has not
been achieved, plasma levels should be measured to determine
whether or not they are in the usually accepted therapeutic
range (50-100 mcg/ml). No recommendation regarding the
safety of valproate for the use at doses above 60 mg/kg/day
can be made. If the total daily dose exceeds 250 mg, it
should be given in divided doses.
In a study of adjunctive therapy for complex partial
seizures in which patients were receiving either carbamazepine
or phenytoin in addition to divalproex sodium, no adjustment
of carbamazepine or phenytoin dosage was needed (see CLINICAL
STUDIES.) However, since valproate may interact with these
or other concurrently administered AEDs as well as other
drugs (see DRUG INTERACTIONS), periodic plasma concentration
determinations of concomitant AEDs are recommended during
the early course of therapy (see DRUG INTERACTIONS.)
Simple and Complex Absence Seizures: The
recommended initial dose is 15 mg/kg/day, increasing at
one week intervals by 5-10 mg/kg/day until seizures are
controlled or side effects preclude further increases.
The maximum recommended dosage is 60 mg/kg/day. If the
total daily dose exceeds 250 mg, it should be given in
divided doses.
A good correlation has not been established between daily
dose, serum concentrations, and therapeutic effect. However,
therapeutic valproate serum concentrations for most patients
with absence seizures is considered to range from 50-100
mcg/ml. Some patients may be controlled with lower or
higher serum concentrations (see CLINICAL PHARMACOLOGY.)
As the divalproex sodium dosage is titrated upward, blood
concentrations of phenobarbital and/or phenytoin may be
affected (see PRECAUTIONS.)
Antiepilepsy drugs should not be abruptly discontinued
in patients in whom the drug is administered to prevent
major seizures because of the strong possibility of precipitating
status elipticus with attendant hypoxia and threat to
life.
In epileptic patients previously receiving divalproex
sodium (valproic acid) therapy, divalproex sodium tablets
should be initiated at the same daily dose and dosing
schedule.
After the patient is stabilized on divalproex sodium
tablets, a dosing schedule of 2 or 3 times daily may be
elected in selected patients.
Migraine
Divalproex sodium tablets are administered orally. The
recommended starting dose is 250 mg twice daily. Some
patients may benefit from doses up to 1000 mg/day. In
the clinical trials, there was no evidence that higher
doses led to greater efficacy.
General Dosing Advice
Dosing in Elderly Patients: Due
to a decrease in unbound clearance of valproate, the starting
dose should be reduced; the ultimate therapeutic dose
should be achieved on the basis of clinical response.
Dose-Related Adverse Events:
The frequency of adverse effected (particularly elevated
liver enzymes and thrombocytopenia) may be dose-related.
The probability of thrombocytopenia appears to increase
significantly at total valproate concentrations of ³110
mcg/ml (females) or ³135 mcg/ml (males) (see PRECAUTIONS).
The benefit of improved therapeutic effect with higher
doses should be weighed against the possibility of a greater
incidence of adverse reactions.
G.I. Irritation: Patients who
experience G.I. irritation may benefit from administration
of the drug with food or by slowly building up the dose
from an initial low level.
HOW SUPPLIED
Depakote tablets are available as 125 mg tablets (salmon
pink-colored), 250 mg tablets (peach-colored), and 500
mg tablets (lavender-colored).
Storage: Store tablets and capsules
below 77°F (25°C).
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