valproic acid

Valproic acid and its derivative, divalproex, are oraldrugsthat are used for the treatment of convulsions,migrainesand bipolar disorder. The active ingredient in both products is valproic acid. Divalproex is converted to valproic acid in the stomach. Scientists do not know the mechanism of action of valproic acid. The most popular theory is that valproic acid exerts its effects by increasing the concentration of gamma-aminobutyric acid (GABA) in the brain. GABA is a neurotransmitter, a chemical that nerves use to communicate with one another. The FDA approved valproic acid in February, 1978 and divalproex in March 1983.

Depakote, Depakote ER, Depakote Sprinkle, Depakene, Depacon, Stavzor

GENERIC AVAILABLE: Yes

Yes

The most common side effects with valproic acid therapy are:

• drowsiness,
• 头晕,
• nausea,
• vomiting,
• indigestion,
• diarrhea,
• weight lossand
• tremors.

Divalproex may have a lower incidence of stomach upset, and taking valproic acid or divalproex with food can reduce the stomach upset. Valproic acid also causes skin reactions such asalopecia(loss of hair),rash,itchingand sensitivity to sunlight.

The most serious side effects due to valproic acid areliverinjury,pancreatitisand abnormal bleeding. Liver injury is most common in the first 6 months of treatment. It also is more common in children, especially children less than two years old. Persons taking more than one type of anticonvulsant seem to be at higher risk. Symptoms of liver damage includejaundice, malaise,weakness, swelling in the face,loss of appetiteandvomiting. Pancreatitis due to valproic acid can occur early in treatment or after several years of use. Symptoms of pancreatitis are unexplainedweight loss,nausea, vomiting and severeabdominal pain. Valproic acid inhibits the formation ofblood clotsby interfering with the clot-promoting effects of platelets. This can cause abnormal bleeding.

Antiepileptic medications have been associated with an increased risk ofsuicidalthinking and behavior. Anyone considering the use of antiepileptic drugs must balance this risk ofsuicidewith the clinical need for the antiepileptic drug. Patients who begin antiepileptic therapy should be closely observed for clinical worsening,suicidal thoughtsor unusual changes in behavior.

Forseizures, therapy is initiated at 10-15 mg/kg/day and increased by 5-10 mg/kg/day every week to achieve the desired response. Response usually is seen when the blood concentration of valproic acid is 50-100 mcg/mL.

For acutemaniadue tobipolar disorder, treatment is started at 750 mg per day of delayed-release tablets in divided doses. The dose should be increased rapidly to achieve the desired effect. The maximum dose is 60 mg/kg/day.

The recommended dose forpreventionofmigrainesis 250 mg twice daily of delayed-release tablets. The maximum recommended dose is 1000 mg/day. When using extended release tablets, the recommended dose is 500-1000 mg given once daily.

Valproic acid has numerous suspected or proven drug interactions. Valproic acid can reduce the number of platelets or inhibit the ability of platelets to stick together and form ablood clot. Therefore, it may exaggerate the effects of other medications which inhibit the stickiness of platelets or inhibit other steps in the clotting of blood. This can lead to abnormal bleeding due to the inability of blood to clot. Such medications includewarfarin(Coumadin),heparinor low-molecular weight heparin (Lovenox), clopidogrel (Plavix),ticlopidine(Ticlid), and nonsteroidal antiinflammatory drugs (NSAIDs) such asibuprofen(Motrin,Advil),naproxen(Naprosyn,Aleve),indomethacin(Indocin),nabumetone(Relafen),diclofenac(Voltaren,Cataflam,Arthrotec),ketorolac(Toradol) andaspirin.

Aspirin andfelbamate(Felbatol) can reduce the elimination of valproic acid and result in elevated blood concentrations of valproic acid and toxicity due to the valproic acid.

Rifampin (Rifadin,Rimactane),carbamazepine(Tegretol),phenytoin(Dilantin) can increase the elimination of valproic acid, thereby reducing blood concentrations. Since this can result in loss ofseizurecontrol andseizures, adjustments in the dose of valproic acid may be necessary if these medications are begun.

Cholestyramine(Questran) can reduce the absorption of valproic acid from the intestine and reduce its effectiveness. Therefore, valproic acid should be taken at least 2 hours before or 6 hours after doses of cholestyramine.

Valproic acid can significantly decrease the elimination oflamotrigine(Lamictal),ethosuximide(Zarontin),diazepam(Valium),zidovudine(AZT) and phenobarbital, thereby increasing their concentrations in blood and leading to toxicity. Valproic acid also increases the blood levels of warfarin and phenytoin by displacing them from blood proteins that they bind to. Since increased blood concentrations of these drugs may lead to an increase in side effects, the dose of warfarin and phenytoin may need to be altered when they are taken with valproic acid.

The use of valproic acid duringpregnancyhas been associated with fetal abnormalities such asspina bifida, cardiovascular abnormalities, andneural tube defects. The risk of spina bifida in the offspring of mothers taking valproic acid during pregnancy is 1%-2%. Valproic acid also may cause reduced clotting in the mother and baby. Because of the risk of harm to thenewborn, valproic acid should only be used bypregnantwomen when its benefits outweigh the risks.

The concentration of valproic acid inbreast milkof women taking valproic acid is 1-10%. Although the effect on thenursinginfant, is not certain, nursing mothers probably should notbreastfeedingif they are taking valproic acid.

What preparations of valproic acid are available?

• Delayed release tablets: 125, 250 and 500 mg.
• Extended release tablets: 250 and 500 mg.
• Sprinkle capsules: 125 mg.
• Capsules: 250 mg.
• Syrup: 250 mg/5 ml.
• Injection: 100 mg/5 ml.

How should I keep valproic acid stored?

Valproic acid should be stored at room temperature, 15 C - 30 C (59 F - 86 F).