Among 505 zonisamide-exposed subjects in the U.S. and European studies, 13 (2.6%) developed kidney stones, as compared to 2 patients out of 1,008 (0.2%) in Japanese studies. Stones are urate or calcium. They can develop slowly and may resolve spontaneously. They may be more likely in patients taking Zonegran for at least 6 months and those with a family history of nephrolithiasis.

In the same Japanese cohort, 17 patients were discontinued because of leukopenia or abnormal liver enzymes.

Oligohidrosis occurs rarely in children, typically presenting as decreased sweating and high fever.

Rash occurs in under 5% of patients. This reaction usually occurs within the first four months of therapy, and is especially likely in patients with a history of sulfa allergy (which is therefore a contraindication). The rash associated with zonisamide may take various forms, from small red spots or blotches on the surface of the skin to large blisters. It may be preceded or accompanied by itchiness. If severe, it may require treatment with an antihistamine or steroid.

In studies in which zonisamide was compared with a placebo, 2.2% of patients taking Zonegran stopped taking it or were hospitalized because of depression, versus 0.4% of those given the placebo. Similarly, 2.2% of the patients given zonisamide in these studies experienced psychosis or psychosis-related symptoms. None of the patients receiving a placebo had this experience.

On 2/23/2009, the US Food and Drug Administration issued a warning that the antiepileptic medication zonisamide (Zonegran) can cause metabolic acidosis in some patients. Metabolic acidosis is a condition of excess acidity (low pH) in the blood. The condition can manifest with a variety of symptoms, including chest pains, heart racing, rapid breathing, stomach upset, kidney stones, confusion and other symptoms. People who are already prone to have metabolic acidosis from kidney disease or drugs such as acetazolamide (Diamox), certain diabetes drugs or the ketogenic diet may be more prone to develop zonisamide-induced metabolic acidosis. Young people are also more likely to develop the condition. Metabolic acidosis is detected by measuring blood levels of bicarbonate (worrisome if less than 17 mEq/L), sometimes along with arterial blood gas measurement for levels of oxygen, carbon dioxide and acidity. Once diagnosed, the condition usually is treatable, most directly by stopping zonisamide. The FDA recommended that healthcare professionals measure serum bicarbonate before starting treatment and regularly thereafter.

On July 10, 2008, an advisory panel was convened by the Food and Drug Administration (FDA) to review data that the FDA had previously collected from drug studies showing an association between many of the antiepileptic drugs (AEDs) and suicidal ideation and behavior, which together are called suicidality. According to the FDA’s Alert, among the patients with epilepsy in these drug studies, 1 out of 1000 people taking the placebo (inactive substance) showed suicidality compared to approximately 3.5 out of 1000 people who took an AED. The FDA advisory panel voted to accept the FDA's data at its meeting on July 10. The FDA has provided the following information for patients, family members, and caregivers at www.fda.gov/cder/drug/InfoSheets/HCP/antiepilepticsHCP.htm.

• Taking antiepileptic medicines may increase the risk of having suicidal thoughts or actions;
• Do not make any changes to the medication regimen without first talking with the responsible healthcare professional;
• Pay close attention to any day-to-day changes in mood, behavior and actions. These changes can happen very quickly so it is important to be mindful of any sudden differences.
• Be aware of common warning signs that might be a signal for risk of suicide. Some of these are:
  • Talking or thinking about wanting to hurt yourself or end your life
  • Withdrawing from friends and family
  • Becoming depressed or having your depression get worse
  • Becoming preoccupied with death and dying
  • Giving away prized possessions

We again urge patients and families to contact their doctor before stopping an epilepsy medication because this may possibly lead to seizures and worsening of mood.

Reviewed July 2008 by Steven C. Schachter, MD, epilepsy.com Editorial Board.