What side effects necessitate discontinuation of Zonegran (zonisamide)?

Discontinuation of Zonegran (Zonisamide) for Serious Side Effects

Discontinue Zonegran immediately if you develop serious skin reactions (rash, Stevens-Johnson syndrome, toxic epidermal necrolysis), signs of blood disorders (fever, sore throat, easy bruising), kidney problems (sudden back pain, blood in urine), decreased sweating with fever (especially in children), or signs of hypersensitivity reactions. 1

Serious Reactions Requiring Immediate Discontinuation

Life-Threatening Skin Reactions

• Stop zonisamide immediately if any unexplained rash develops 1
• Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) have caused fatalities, with 7 deaths reported in the first 11 years of Japanese marketing 1
• The reporting rate in Japan was 46 cases per million patient-years, with 85-90% of rashes occurring within the first 2-16 weeks of treatment 1
• Any signs of hypersensitivity reactions warrant immediate discontinuation, as zonisamide is a sulfonamide and can cause fatal reactions including fulminant hepatic necrosis 1

Hematologic Emergencies

• Discontinue immediately if signs of blood disorders appear: fever, sore throat, oral ulcers, or easy bruising 1
• Aplastic anemia and agranulocytosis have been confirmed in post-marketing surveillance, though rare 1
• These blood dyscrasias can be fatal and may occur with any sulfonamide exposure 1

Oligohidrosis and Hyperthermia (Especially Pediatric Patients)

• Stop zonisamide if decreased sweating occurs, particularly with fever or after heat exposure 1
• This can progress to heat stroke requiring hospitalization 1
• The US reporting rate was approximately 12 cases per 10,000 patient-years in the first year of marketing, though this likely underestimates true incidence 1
• Parents should contact physicians immediately if a child is not sweating as usual 1

Renal Complications

• Discontinue if acute renal failure develops or if there is a clinically significant sustained increase in creatinine/BUN 1
• Stop immediately if signs of kidney stones appear: sudden back pain, abdominal pain, or blood in urine 1
• Kidney stones occurred in 4% of patients during development (34 per 1000 patient-years), with analyzed stones composed of calcium or urate salts 1

Serious Reactions Requiring Careful Evaluation

Psychiatric and Behavioral Symptoms

• Psychotic episodes occurred in 14 of 74 patients (18.9%) in one retrospective study, with most occurring within a few years of starting zonisamide 2
• Discontinue if severe psychiatric adverse effects develop, though the decision should weigh seizure control against psychiatric symptoms 3
• One study found only 4.3% discontinued due to severe psychiatric effects (major depressive disorder) in patients with pre-existing mental disorders 3
• Suicidal ideation, mania, and psychosis have been reported and require immediate physician contact 3

Metabolic Acidosis

• Monitor for signs of metabolic acidosis, which can increase the risk of kidney stone formation 1
• While not always requiring discontinuation, severe or symptomatic metabolic acidosis may warrant stopping the medication 1

Common Side Effects NOT Requiring Discontinuation

The following are common but typically do not necessitate stopping zonisamide unless severe:

• Somnolence, anorexia, dizziness, and ataxia (most common, dose-related) 1
• Transient myalgias, arthralgias, and flu-like symptoms after first infusions 1
• Difficulty with memory and concentration 1
• Nausea and vomiting 1

Clinical Monitoring Recommendations

• Observe patients frequently if rash develops and medication is continued 1
• Monitor renal function, as zonisamide causes an 8% mean increase in serum creatinine and BUN 1
• Increase fluid intake to reduce kidney stone risk, particularly in patients with predisposing factors 1
• The drug should not be used in patients with renal failure (eGFR <50 mL/min) 1

Important Caveats

• In controlled trials, 12% of patients discontinued zonisamide due to adverse reactions versus 6% on placebo 1
• The most common reasons for discontinuation overall were somnolence, fatigue, ataxia (6%), anorexia (3%), and difficulty concentrating (2%) 1
• Never restart zonisamide if serious hypersensitivity reactions, severe skin reactions, or blood dyscrasias occurred, as sulfonamide reactions may recur regardless of route of administration 1