FDA Drug Safety Communication: Drug Products Containing Carbidopa/Levo

FDA conducted a safety review and identified 14 cases of seizures linked to vitamin B6 deficiency in patients using drug products containing carbidopa/levodopa. The 14 cases included postmarketing reports submitted to FDA[1] (13 reports) or found in the medical literature (1 report), so there are likely additional cases about which we are unaware. All of the reviewed cases involved levodopa doses exceeding 1,000 mg daily, with higher doses (>1,500 mg levodopa) associated with shorter duration from treatment initiation to identification of vitamin B6 deficiency. The seizure cases were split among oral formulations and an enteral suspension, with latency periods ranging from 23 to 132 months. The seizures have typically presented as focal onset seizures with secondary generalization, consistent with seizures observed with vitamin B6-dependent epilepsy, and progression to status epilepticus was observed in some cases, indicating an urgent need for rapid identification and treatment.

In these cases of reported seizures, there was additional clinical evidence supportive of vitamin B6 deficiency, including elevated homocysteine levels in four cases, microcytic or normocytic anemia in three cases, and neuropsychiatric symptoms in four cases. Of the 9 patients treated with vitamin B6 supplementation, all 9 had resolution of their seizures, despite the majority of these patients previously demonstrating a lack of response to multiple antiseizure medications. Two fatalities occurred, both with documented low vitamin B6 levels and poorly controlled seizures.

The review found no cases of vitamin B6-associated seizures associated with carbidopa/levodopa/entacapone products or with the injectable carbidopa/levodopa product, which may reflect lower usage patterns, more recent approval dates, and/or different dosing and administration requirements. However, biological plausibility suggests there may be a similar risk across all drug products containing carbidopa/levodopa, as vitamin B6 deficiency was also observed in the clinical trials that supported the original approval of the injectable carbidopa/levodopa product. Based on the available data, FDA concluded there is reasonable evidence of a causal association between drug products containing carbidopa/levodopa and vitamin B6 deficiency-associated seizures.

[1] The cases were reported to the FDA Adverse Event Reporting System (FAERS) database.

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