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GENERIC NAME: valproic acid, divalproex

BRAND NAME: Depakote, Depakote ER, Depakene

DRUG CLASS AND MECHANISM: Valproic acid (Depakene) is an anticonvulsant (anti-seizure medication) that is not chemically related to other anticonvulsants. Depakote is a form of valproic acid (divalproex) that is released and absorbed from the intestine more slowly than valproic acid. Depakote ER is an extended release form of divalproex that can be taken less frequently than Depakote. Valproic acid also is used for treating bipolar mania and migraine headaches.

Seizures are caused by abnormal stimulation of nerves in the brain by other nerves. Although the exact mechanism of action is not clear, it is believed that valproic acid prevents the stimulation of nerves by increasing the concentrations in the brain of the neurotransmitter, gamma-aminobutyric acid (GABA). (A neurotransmitter is a chemical that nerves use to communicate, that is, stimulate or inhibit other nerves.) Valproic acid is used for different types of seizures including absence seizures (petite mal seizures), generalized tonic-clonic seizures, complex partial seizures, and myoclonic seizures. Unlike some older anticonvulsants, e.g., phenobarbital; phenytoin (Dilantin), carbamazepine (Tegretol), sedation with valproic acid is minimal.

The mechanism whereby valproic acid prevents migraines is unclear but may be related to its effects on GABA.
The usefulness of valproic acid as an anticonvulsant was discovered in 1963, and it was approved by the FDA for seizures in 1978. In 1995, it was approved for use in bipolar depression (manic-depressive disorders) and, in 1996, for the prevention of migraine headaches.

PREPARATIONS: Depakote tablets: 125 mg (pink), 250 mg (peach) and 500 mg (pink). Depakote sprinkle capsules: 125 mg. Depakote ER tablets: 500 mg to be crushed or chewed. Depakene capsules: 250 mg. Depakene syrup: 250 mg/5 ml.

STORAGE: Tablets, capsules and syrup should be stored at room temperature,15-30°C (59-86°F).

PRESCRIBED FOR: Valproic acid is approved for the treatment of absence seizures, either simple or complex; complex partial seizures; myoclonic seizures; and tonic-clonic seizures. It also is used in the prevention of migraine headaches and the manic phase of bipolar depressive illness. Depakote ER is used for the prevention of migraine but has not been evaluated for seizures or the manic phase of bipolar depressive illness.

DOSING: Doses vary widely. Physicians often use blood concentrations to guide dosing. Food can delay the rate but not the extent of absorption of valproic acid. The full effects of valproic acid may not be seen until the drug has been taken for several days.

DRUG INTERACTIONS: Valproic acid can inhibit the ability of platelets to stick together and form a blood clot. Therefore, they 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 include warfarin (Coumadin), heparin or low- molecular weight heparin (Lovenox), NSAIDs (nonsteroidal anti-inflammatory drugs), e.g., ibuprofen (Motrin, Advil), naproxen (Naprosyn, Aleve), indomethacin (Indocin), nabumetone (Relafen), diclofenac (Voltaren, Cataflam, Arthrotec), ketorolac (Toradol) and aspirin.
Valproic acid depresses the activity of the brain. The following medications can increase the depression if used with divalproex: tricyclic antidepressants, e.g., amitriptyline (Elavil), imipramine (Tofranil), desipramine (Norpramin), doxepin (Sinequan)], haloperidol (Haldol), loxapine (Loxitane), maprotiline (Ludiomil), MAOIs (mono-amine oxidase inhibitors), i.e., isocarboxazid (Marplan), phenelzine (Nardil), tranylcypromine (Parnate), and procarbazine (Matulane), and phenothiazines, e.g., chlorpromazine (Thorazine), thioridazine (Mellaril), and trifluoperazine (Stelazine).

Isoniazid (INH) and felbamate (Felbatol) can reduce the normal metabolism (destruction) of valproic and result in elevated blood concentrations of valproic acid. Liver injury has been reported when isoniazid is used with valproic acid.

Rifampin (Rifadin; Rimactane), carbamazepine (Tegretol), phenytoin (Dilantin), and mefloquine (Lariam) can increase the metabolism of valproic acid, thereby reducing blood concentrations. Since this can result in loss of seizure control and seizures, adjustments in the dose of valproic acid may be necessary. Cholestyramine (Questran) can reduce the absorption of valproic acid from the intestine (and probably divalproex as well). Therefore, valproic acid should be taken at least 2 hours before or 6 hours after doses of cholestyramine.

Valproic acid can significantly decrease the metabolism of lamotrigine (Lamictal) and phenobarbital, thereby increasing their blood concentrations and possibly causing side effects. Therefore, the dose of lamotrigine or phenobarbital should be reduced when taken with divalproex.

Blood concentrations of zidovudine (Retrovir; AZT) and phenytoin (Dilantin) may be increased by valproic acid.

Valproic acid causes unpredictable effects on ethosuximide (Zarontin) blood concentrations. Concentrations may increase or decrease.

PREGNANCY: The use of valproic acid during pregnancy has been associated with fetal abnormalities. However, if valproic acid is being taking to prevent major seizures, it should not be withdrawn during pregnancy since seizures themselves are more dangerous to both the mother and the fetus than the medication.

NURSING MOTHERS: Valproic acid is excreted into breast milk and is not recommended for use during breast-feeding.

SIDE EFFECTS: The most serious side effect due to valproic acid is liver toxicity and failure. Liver toxicity is most common in the first 6 months of treatment. It also is more common in children, especially children less than 2 years old. Persons taking more than one type of anticonvulsant seem to be at higher risk. Symptoms of liver damage may include jaundice, malaise, weakness, tiredness, swelling in the face, loss of appetite, or vomiting.

The most common side effects with valproic acid therapy are nausea, vomiting and indigestion. Divalproex may have a lower incidence of these side effects than valproic acid. Taking valproic acid or divalproex with food can reduce these side effects. Other gastrointestinal side effects include abdominal pain, constipation or diarrhea. Both loss of appetite with weight loss and appetite stimulation with weight gain have been reported.

Valproic acid can inhibit the formation of blood clots by interfering with the clot-promoting effects of platelets. This can cause abnormal bleeding.

Although less common than with other anticonvulsants, drowsiness may occur with valproic acid. Tremors of all types may occur with valproic acid. Depression or agitation can occur and are most common in children. Other neurologic side effects include hallucinations, headache, double vision, spots before the eyes, dizziness, and loss of coordination.

Skin reactions include alopecia (loss of hair), skin rash, itching, sensitivity of the skin to sunlight (with severe sunburn), and, less commonly, even more severe skin reactions.

About 1 of every 5 women have menstrual disturbances while taking valproic acid. Other side effects affecting the endocrine system include breast enlargement and lactation (fluid leaking from the breasts). Valproic acid also can interfere with thyroid tests and make them inaccurate and can cause increases in blood sugar.

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