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 a blood 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 include warfarin (Coumadin), heparin or low-molecular weight heparin (Lovenox), clopidogrel (Plavix), ticlopidine (Ticlid), and nonsteroidal antiinflammatory drugs (NSAIDs) such as ibuprofen (Motrin, Advil), naproxen (Naprosyn, Aleve), indomethacin (Indocin), nabumetone (Relafen), diclofenac (Voltaren, Cataflam, Arthrotec), ketorolac (Toradol) and aspirin.

Aspirin and felbamate (Felbatol) can reduce the elimination of valproic acid and result in elevated blood concentrations of 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 of seizure control and seizures, 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. 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 of lamotrigine (Lamictal), ethosuximide (Zarontin), diazepam (Valium), zidovudine (AZT) and phenobarbital, thereby increasing their concentrations in blood. 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 most common side effects with Valproic acid therapy are drowsiness, dizziness, nausea, vomiting, indigestion, diarrhea, weight loss and 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 as alopecia (loss of hair), rash, itching and sensitivity to sunlight.

The most serious side effects due to Valproic acid are liver injury, pancreatitis and 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 include jaundice, malaise, weakness, swelling in the face, loss of appetite and vomiting. Pancreatitis due to Valproic acid can occur early in treatment or after several years of use. Symptoms of pancreatitis are unexplained weight loss, nausea, vomiting and severe abdominal pain. Valproic acid inhibits the formation of blood clots by interfering with the clot-promoting effects of platelets. This can cause abnormal bleeding.

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

The use of Valproic acid during pregnancy has been associated with fetal abnormalities such as spina bifida, cardiovascular abnormalities, and neural 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 the newborn, Valproic acid should only be used by pregnant women when its benefits outweigh the risks.