From the FDA Drug Label
Hyperammonemia has been reported in association with valproate therapy and may be present despite normal liver function tests. Concomitant administration of topiramate and valproic acid has been associated with hyperammonemia with or without encephalopathy in patients who have tolerated either drug alone
The medications associated with hyperammonemia (elevated ammonia levels) are:
- Valproic acid: associated with hyperammonemia, which may be present despite normal liver function tests 1
- Topiramate: when used concomitantly with valproic acid, associated with hyperammonemia with or without encephalopathy 1
From the Research
Valproic acid is the most strongly associated medication with hyperammonemia, particularly at higher doses or in combination with other anticonvulsants, as evidenced by the most recent study in 2023 2.
Medications Associated with Hyperammonemia
Several medications can cause hyperammonemia, a condition characterized by elevated blood ammonia levels that can lead to neurological symptoms.
- Valproic acid, a common antiepileptic drug, is strongly associated with hyperammonemia, particularly at higher doses or in combination with other anticonvulsants.
- Other anticonvulsants like carbamazepine, phenytoin, and phenobarbital can also increase ammonia levels.
- Chemotherapeutic agents including 5-fluorouracil, asparaginase, and cytarabine may cause hyperammonemia as a side effect.
- Certain antibiotics such as ribavirin and sulfadiazine have been implicated as well.
- Diuretics like acetazolamide can contribute to hyperammonemia by altering acid-base balance.
- Among psychiatric medications, risperidone and haloperidol have been reported to cause this condition.
Risk Factors and Mechanisms
These drugs typically cause hyperammonemia by either inhibiting enzymes in the urea cycle, increasing ammonia production, or interfering with ammonia elimination.
- The use of topiramate and phenobarbital in combination with valproic acid has been identified as a risk factor for hyperammonemia 2.
- A dose-dependent association between valproate and hyperammonemia has been found, with higher doses increasing the risk of hyperammonemia 3.
- Hyperammonemia can lead to an increase in the glutamine level in the brain, which produces astrocyte swelling and cerebral edema 4.
Monitoring and Treatment
Patients taking these medications should be monitored for symptoms like confusion, lethargy, vomiting, and seizures, especially those with underlying liver disease or urea cycle disorders who are at higher risk.