Risk of vitamin B6 deficiency and associated seizures with carbidopa/levodopa or benserazide/levodopa

Levodopa, a metabolic precursor to dopamine, is the cornerstone replacement therapy for Parkinson’s disease, a neurodegenerative disorder characterised by the loss of dopamine-producing neurons. As levodopa is converted into dopamine via decarboxylation both centrally and peripherally, this limits the amount of levodopa available for delivery across the blood-brain barrier. To enhance its central bioavailability and reduce adverse effects, levodopa is typically co-administered with a peripheral decarboxylase inhibitor, such as carbidopa or benserazide, to prevent the peripheral conversion of levodopa to dopamine.

There are currently 14 products containing levodopa in combination with a peripheral decarboxylase inhibitor registered locally since 1990. Post-market cases of seizures, some with fatal outcomes, have been reported overseas and in published literature in patients using combination products containing levodopa and a peripheral decarboxylase inhibitor. To date, no cases have been reported locally.

Example of a case report published in the literature

One published overseas case report described a 78-year-old male patient with a six-year history of Parkinson’s disease who was taking carbidopa/levodopa and presented with new-onset myoclonus and focal to bilateral tonic-clonic seizures.¹ His Parkinson’s disease symptoms had worsened over the preceding five months despite dose escalation of carbidopa/ levodopa. Further evaluation showed an undetectable vitamin B6 level (<1 μg/dL), a critically low folate level (<2.2 ng/dL), and video electroencephalography findings consistent with moderate cerebral dysfunction and seizures with diffuse onset. Initially, the seizures did not respond to treatment with two concurrent anti-epileptic drugs (AED). They resolved only after intravenous vitamin B6 replacement together with the addition of the third AED and a five-day course of high-dose steroids. It was concluded that the patient’s epileptic events were secondary to depletion of vitamin B6 due to relatively high doses of carbidopa/levodopa.

Biological plausibility of levodopa and peripheral decarboxylase inhibitor in causing seizures

 As vitamin B6 is a cofactor required for the decarboxylation of levodopa to dopamine, the conversion process results in the depletion of vitamin B6 levels.^2,3 In addition, the peripheral decarboxylase inhibitors, carbidopa and benserazide, bind irreversibly to pyridoxal 5’-phosphate (PLP), the active form of vitamin B6, further reducing the availability of functional vitamin B6. PLP is essential for the synthesis of gamma-aminobutyric acid (GABA), the primary inhibitory neurotransmitter in the central nervous system. Reduced vitamin B6 and PLP levels may therefore lead to decreased GABA concentrations and contribute to an increased risk of seizures.

International regulatory actions

In March 2026, the US Food and Drug Administration (FDA) requested the addition of warnings on the risk of vitamin B6 deficiency and associated seizures to the prescribing information of all products containing carbidopa/levodopa.⁴ The US FDA identified 13 post-marketing cases and one case report in published literature, all with features consistent with seizures observed with vitamin B6-dependent epilepsy. These cases involved levodopa doses exceeding 1,000 mg daily, with higher doses (>1,500 mg levodopa) associated with a shorter time from treatment initiation to identification of vitamin B6 deficiency, suggesting a possible dose-related relationship. Nine patients treated with vitamin B6 supplementation had resolution of their seizures, although the majority had previously not responded to multiple AEDs. There were two fatalities, both with documented low vitamin B6 levels and poorly controlled seizures.

Local situation

HSA has not received any local adverse event reports of vitamin B6 deficiency or associated seizures arising from the use of products containing carbidopa/levodopa or benserazide/levodopa. The package inserts of levodopa-containing products registered locally will be updated to include additional warnings on the risk of reduced vitamin B6 levels and the relevant symptoms, as well as the consequent increased risk of seizures with carbidopa/levodopa or benserazide/levodopa treatment.

HSA’s advisory

Post-marketing   reports   indicate   that   seizures   associated with vitamin B6 deficiency were refractory to traditional AEDs and resolved after vitamin B6 administration. Healthcare professionals may consider evaluating vitamin B6 levels in patients before initiating and periodically during treatment with carbidopa/levodopa or benserazide/levodopa, and if symptoms suggestive of vitamin B6 deficiency develop. Such symptoms include depression, confusion, cheilosis, glossitis, dermatitis, anaemia, and/or neuropathy.  Higher doses of carbidopa/ levodopa or benserazide/levodopa may increase the risk of vitamin B6 deficiency and vitamin B6 supplementation may be considered where clinically appropriate.

References

1.  Case Rep Neurol. 2022; 14: 291−5

2.  Mov Disord. 2026; 41: 561−4

3.  Intractable Rare Dis Res. 2014; 3: 52−6

4.  https://www.fda.gov/drugs/drug-safety-communications/fda-requiring-warning-about-vitamin-b6-deficiency-and-associated-seizures-drug-products-containing ↗ (opens in new tab)