What to do if Voriconazole (antifungal medication) induces a seizure?

Management of Voriconazole-Induced Seizure

If voriconazole induces a seizure, immediately discontinue the drug and switch to an alternative antifungal agent, specifically liposomal amphotericin B (L-AmB) at 3-5 mg/kg IV daily for invasive aspergillosis or other serious fungal infections. 1

Immediate Actions

Discontinue Voriconazole

• Stop voriconazole immediately upon clinical suspicion of drug-induced neurotoxicity, as the prognosis is promising when discontinued promptly. 2
• Voriconazole-associated neurologic adverse events include seizures, encephalopathy, visual hallucinations, and posterior reversible encephalopathy syndrome (PRES), which can occur even at therapeutic drug levels. 2, 3
• Do not wait for confirmatory testing—clinical suspicion warrants immediate cessation. 2

Seizure Management

• Initiate standard anticonvulsant therapy as clinically indicated for acute seizure control. 1
• Be aware that if anticonvulsants are required long-term, there are significant drug interactions between anticonvulsants and triazole antifungals (particularly enzyme-inducing anticonvulsants like phenytoin, carbamazepine, and phenobarbital, which dramatically reduce voriconazole levels). 1

Alternative Antifungal Selection

Primary Alternative: Liposomal Amphotericin B

• Switch to liposomal amphotericin B (L-AmB) 3-5 mg/kg IV daily, which is the recommended alternative when voriconazole is contraindicated or not tolerated. 1
• L-AmB is particularly appropriate for CNS aspergillosis, where voriconazole would typically be first-line but is now contraindicated due to the seizure. 1
• L-AmB has no significant drug interactions with anticonvulsants, unlike azoles. 1

Secondary Alternatives

• Isavuconazole may be considered as an alternative azole if the seizure was definitively voriconazole-specific toxicity rather than a class effect, though caution is warranted and therapeutic drug monitoring is essential. 1
• Echinocandins (caspofungin 70 mg loading, then 50 mg daily; or micafungin 100 mg daily) can be used for invasive aspergillosis in salvage therapy settings when both azoles and polyenes are contraindicated, though they are not recommended as primary monotherapy. 1

Diagnostic Evaluation

Assess for Alternative Causes

• Obtain brain imaging (MRI preferred) to evaluate for PRES, cerebral aspergillosis, or other structural lesions that may have contributed to seizure. 2
• PRES on MRI shows characteristic posterior white matter changes on T2/FLAIR sequences with restricted diffusion. 2
• Check serum electrolytes, glucose, calcium, and magnesium to exclude metabolic causes. 2

Therapeutic Drug Monitoring

• If voriconazole levels were not previously monitored, obtain a trough level retrospectively if possible to document supratherapeutic concentrations (>5.5 mcg/mL associated with increased neurotoxicity). 1, 4
• High voriconazole levels are associated with neurologic adverse effects including seizures, hallucinations, and encephalopathy. 4, 3

Ongoing Antifungal Management

Treatment Duration

• Continue alternative antifungal therapy for a minimum of 6-12 weeks for invasive aspergillosis, depending on degree and duration of immunosuppression, site of disease, and evidence of clinical improvement. 1
• For CNS aspergillosis specifically, treatment duration is typically longer and should continue until radiographic resolution. 1

Monitoring for Treatment Response

• Perform serial clinical evaluations and repeat CT imaging at individualized intervals based on acuity and rapidity of disease evolution. 1
• Pulmonary infiltrate volume may increase during the first 7-10 days of therapy, especially with granulocyte recovery, which does not necessarily indicate treatment failure. 1
• Serial serum galactomannan assays can be used for therapeutic monitoring, with progressive increases indicating poor prognosis. 1

Adjunctive Measures

• Reduce immunosuppression when feasible, as this is critical for favorable outcomes in invasive aspergillosis. 1
• Consider surgical resection of infected tissue if feasible, particularly for CNS lesions or pulmonary lesions in proximity to great vessels. 1

Critical Pitfalls to Avoid

• Do not rechallenge with voriconazole after a seizure, as neurotoxicity can recur and may be more severe. 2, 3
• Do not use echinocandins as primary monotherapy for invasive aspergillosis—they are only appropriate when both azoles and polyenes are absolutely contraindicated. 1
• Do not overlook drug interactions if anticonvulsants are required—enzyme-inducing anticonvulsants will significantly reduce levels of any subsequent azole therapy. 1
• Do not assume therapeutic voriconazole levels exclude neurotoxicity—PRES and seizures can occur even with levels in the therapeutic range. 2