Divalproex Sodium

Brand Name: Depakote

Description

Divalproex Sodium (Depakote is an anticonvulsant used to control seizures and for treatment of acute mania associated with bipolar disorder. It may also be used to treat other conditions as determined by your doctor.

Pharmacology

Divalproex sodium is a stable co-ordination compound comprised of sodium valproate and 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).

Peak serum levels occur approximately 1 to 4 hours after a single oral dose. The therapeutic plasma concentration range is believed to be from 50 to 100 mcg/mL.

Indications and Usage

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 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 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

Contraindications

Divalproex sodium is contraindicated in patients with known hypersensitivity to the drug.

Patients with hepatic disease or significant dysfunction.

Warnings

Hepatic failure resulting in fatalities has occurred in patients receiving valproic acid. These incidents usually have occurred during the first six months of treatment. Serious or fatal hepatotoxicity may be preceded by non-specific symptoms such as loss of seizure control, malaise, weakness, lethargy, facial edema, anorexia and vomiting. In patients with epilepsy, a loss of seizure control may also occur. Patients should be monitored closely for appearance of these symptoms. Liver function tests should be performed prior to therapy and at frequent intervals thereafter, especially during the first six months. However, physicians should not rely totally on serum biochemistry since these tests may not be abnormal in all instances, but should also consider the results of careful interim medical history and physical examination.

Caution should be observed when administering divalproex sodium products to patients with a prior history of hepatic disease. Patients on multiple anticonvulsants, children, those with congenital metabolic disorders, those with severe seizure disorders accompanied by mental retardation, and those with organic brain disease may be at particular risk. Experience has indicated that children under the age of two years are at a considerably increased risk of developing fatal hepatotoxicity, especially those with the aforementioned conditions. When divalproex sodium is used in this patient group, it should be used with extreme caution and as a sole agent. The benefits of therapy should be weighed against the risks. Above this age group, experience in epilepsy has indicated that the incidence of fatal hepatotoxicity decreases considerably in progressively older patient groups.

The drug should be discontinued immediately in the presence of significant hepatic dysfunction, suspected or apparent. In some cases, hepatic dysfunction has progressed in spite of discontinuation of drug.

Usage in Pregnancy

According to recent reports in the medical literature, valproic acid may produce teratogenicity in the offspring of human females receiving the drug during pregnancy. The incidence of neural tube defects in the fetus may be increased in the mothers receiving valproic acid during the first trimester of pregnancy.

Multiple reports indicate an association between the use of antiepileptic drugs and an elevated incidence of birth defects in children born to epileptic women taking such medication during pregnancy. The incidence of congenital malformations in the general population is regarded to be approximately 2%, in children of treated epileptic women, this incidence may be increased 2 to 3-fold. The increase is largely due to specific defects, e.g., congenital malformations of the heart, cleft lip and/or palate and neural tube defects. Nevertheless, the great majority of mothers receiving anticonvulsant medications deliver normal infants.

Antiepileptic drugs should not be discontinued in patients to whom the drug is administered to prevent major seizures, because of the strong possibility of precipitating status epilepticus with attendant hypoxia and risks to both the mother and the unborn child. The risks of discontinuing drugs given for minor seizures prior to or during pregnancy should be weighed against the risk of congenital defects in the particular case and with the particular family history.

HEPATIC FAILURE, RESULTING IN THE DEATH OF A NEWBORN AND OF AN INFANT, HAVE BEEN REPORTED FOLLOWING THE USE OF VALPROATE DURING PREGNANCY.

IF YOU PLAN ON BECOMING PREGNANT, discuss with your doctor the benefits and risks of using this medicine during pregnancy. If you are or may be pregnant, check with your doctor for instructions on using this medicine during pregnancy.

Infant breast-feeding is not recommended for women taking this drug because valproic acid appears to be secreted in low concentrations in human milk.

Male Fertility: The effect of valproic acid on the development of the testes and on sperm production and fertility in humans is unknown. Long-term toxicity studies in rats and mice indicate a potential carcinogenic risk.

Precautions

Depakote may produce CNS depression, especially when combined with another CNS depressant such as alcohol.

Since divalproex sodium may interact with concurrently administered drugs which are capable of enzyme induction, periodic plasma concentration determinations of valproate and concomitant drugs are recommended during the early course of therapy.

Suicidal ideation may be a manifestation of certain psychiatric disorders, and may persist until significant remission of symptoms occurs. Close supervision of high risk patients should accompany initial drug therapy.

Hyperammonemia with or without lethargy or coma has been reported and may be present in the absence of abnormal liver function tests; if elevation occurs the divalproex sodium should be discontinued.

There have been reports of thrombocytopenia and inhibition of platelet aggregation. Platelet counts and bleeding time determination are recommended before instituting therapy and at periodic intervals. It is recommended that patients be monitored for platelet count prior to planned surgery. Clinical evidence of hemorrhage, bruising or a disorder of hemostasis/coagulation is an indication for reduction of dosage or withdrawal of therapy pending investigation.

Interference with Cognitive or Motor Performance: Since divalproex sodium products may produce CNS depression, especially when combined with another CNS depressant (e.g., alcohol), patients should be advised not to engage in hazardous activities, such as driving an automobile or operating dangerous machinery, until it is known that they do not become drowsy from the drug.

Drug Interactions

BEFORE USING THIS MEDICINE: INFORM YOUR DOCTOR OR PHARMACIST of all prescription and over-the-counter medicine that you are taking. This includes medicines used to treat seizures, anxiety, infections, and medicines containing aspirin or salicylates. Inform your doctor of any other medical conditions including liver conditions, allergies, pregnancy, or breast-feeding.

Divalproex sodium will add to the effects of alcohol and other depressants.

Caution is recommended when valproic acid is administered with drugs affecting coagulation, e.g., ASA and warfarin.

Adverse Reactions

CHECK WITH YOUR DOCTOR AS SOON AS POSSIBLE if you experience diarrhea, abdominal cramps, bruising, change in weight, tremor, changes in mood or behavior, change in menstrual period, swelling of the face, loss of appetite, vomiting, or extreme tiredness. If you notice other effects not listed above, contact your doctor, nurse, or pharmacist.

Other less serious side effects, that may go away during treatment, include nausea, indigestion, drowsiness, or hair loss. If they continue or are bothersome, check with your doctor.

Mania: The incidence of treatment-emergent events has been ascertained based on combined data from two placebo-controlled clinical trials of divalproex sodium in the treatment of manic episodes associated with bipolar disorder. The adverse events were usually mild or moderate in intensity, but sometimes were serious enough to interrupt treatment. In clinical trials, the rates of premature termination due to intolerance were not statistically different between placebo, divalproex sodium, and lithium carbonate. A total of 4%, 8%, and 11% of patients discontinued therapy due to intolerance in the placebo, divalproex sodium, and lithium carbonate groups, respectively.

Overdose

Symptoms of overdose may include deep sleep, irregular heartbeat, and loss of consciousness.

In acute overdosage the possibility of other CNS depressants, including alcohol, should be borne in mind.

Treatment

If you or someone you know may have used more than the recommended dose of this medicine, contact your local poison control center or emergency room immediately.

Treatment should be symptomatic and supportive. Naloxone has been reported to reverse the CNS depressant effects of valproic acid overdose. Because naloxone could theoretically also reverse the antiepileptic effects of valproic acid it should be used with caution.

Dosage

Do not exceed the recommended dosage.

Do not stop taking this medicine without first checking with your doctor. Keep all doctor and laboratory appointments while you are taking this medicine.

Follow the directions for using this medicine provided by your doctor.
Swallow whole. Do not break, crush, or chew before swallowing.
This medicine may be taken with food if it upsets your stomach.
Store this medicine at room temperature, away from heat and light.
If you miss a dose of this medicine, and it is within 6 hours of the missed dose, take it as soon as possible. Take the remaining doses of the day at evenly spaced intervals. If you miss a dose of this medicine and you are taking 1 dose daily, take the missed dose if you remember the same day. Skip the missed dose if you do not remember until the next day. DO NOT take 2 doses at once.

Additional Information: Do not share this medicine with others for whom it was not prescribed. Do not use this medicine for other health conditions. Keep this medicine out of the reach of children.

IF YOU WILL BE USING THIS MEDICINE FOR AN EXTENDED PERIOD OF TIME, be sure to obtain necessary refills before your supply runs out.

For 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.

For Epilepsy:
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 to 15 mg/kg/day. The dosage should be increased by 5 to 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 to 100mcg/ml). No recommendation regarding the safety of valproate for use at doses above 60 mg/kg/day can be made.

Conversion to Monotherapy: Patients should initiate therapy at 10 to 15 mg/kg/day. The dosage should be increased by 5 to 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.

For Migraines:
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.

How Supplied

Depakote tablets are supplied in three dosage strengths containing divalproex sodium equivalent to 125 mg, 250 mg or 500 mg of valproic acid.