OBJECT DRUGS

• Valproic Acid (Depakene, etc.)

PRECIPITANT DRUGS

• Topiramate (Topamax, etc.)

Comment:

Valproic acid often causes an asymptomatic increase in blood ammonia, but occasionally can cause severe hyperammonemic encephalopathy. There are many case reports suggesting that concurrent administration of topiramate and valproic acid increases the risk of encephalopathy. A study also found cognitive dysfunction in some patients when topiramate was added to valproic acid therapy. Most of the symptoms are behavioral or neurologic, but severe cases can be life-threatening. The mechanism for the interaction is not clear, but may involve additive effects on blood ammonia as well as other pharmacodynamic effects. Some evidence suggests that concurrent use of phenobarbital increases the risk of encephalopathy due to valproic acid plus topiramate. Valproic acid and topiramate do not appear to have significant pharmacokinetic interactions with each other.

Class 3: Assess Risk & Take Action if Necessary

• Consider Alternative: In patients receiving valproic acid, consider using an alternative to topiramate, especially if the patient has other factors that may predispose to encephalopathy which may include concurrent phenobarbital therapy, pre-existing chronic encephalopathy, and febrile states.
• Monitor: If the combination is used, it is imperative that the patient and/or caregivers are alert for evidence of encephalopathy, such as confusion, memory impairment, drowsiness, lethargy, slow speech, irritability, sleep disturbances, motor impairment, increased seizure frequency, and hypothermia. Diagnosis may be problematic if the patient displays symptoms that mimic the disorder for which he or she has received the valproate. Prompt discontinuation of the valproic acid is usually followed by resolution of the symptoms, sometimes within the first day or two.