What antiepileptic medications (AEDs) can cause pancytopenia?

Antiepileptic Drugs That Cause Pancytopenia

Carbamazepine and valproic acid are the primary antiepileptic drugs associated with pancytopenia and other serious blood dyscrasias, with carbamazepine carrying a ninefold increased risk of aplastic anemia. 1

Primary Offending Agents

Carbamazepine

• Carbamazepine is the most frequently implicated AED in serious blood dyscrasias, including pancytopenia, aplastic anemia, agranulocytosis, and thrombocytopenia 2, 1
• The FDA drug label explicitly warns that carbamazepine can cause significant bone marrow depression and requires baseline and periodic monitoring of complete blood counts 3
• Discontinuation should be considered if any evidence of significant bone marrow depression develops 3
• Patients should be monitored closely if they exhibit low or decreased white blood cell or platelet counts during treatment 3

Valproic Acid

• Valproic acid is the second most commonly associated AED with aplastic anemia and pancytopenia 2, 1
• The drug carries specific risks for thrombocytopenia and requires regular hematologic monitoring 4
• In one case series, 17 of 21 cases of serious blood dyscrasia occurred in patients taking carbamazepine, phenobarbital, phenytoin, or valproate, with 7 patients taking two or more drugs 2

Phenytoin and Phenobarbital

• Both phenytoin and phenobarbital are associated with blood dyscrasias, though less frequently documented than carbamazepine and valproate 2, 1
• These older aromatic anticonvulsants can cause immune-mediated thrombocytopenia and cross-reactivity reactions 5

Newer Generation AEDs

Levetiracetam

• While generally considered safer, levetiracetam has rare case reports of causing severe pancytopenia 6
• In one documented case, severe anemia, leukopenia, and thrombocytopenia developed within 2 days of initiating levetiracetam, requiring 2 weeks for cell counts to normalize after discontinuation 6
• The intrinsic pathogenesis remains unknown, but the temporal relationship suggests causality 6

Clinical Risk Assessment

Overall Incidence

• The overall rate of serious blood dyscrasias with AEDs is 3-4 per 100,000 prescriptions 2
• Age increases risk: patients under 60 years have a rate of 2.0 per 100,000 prescriptions compared to 4.0 per 100,000 for those 60 or older 2
• Specific dyscrasia rates per 100,000 prescriptions: neutropenia (1.2), thrombocytopenia (0.9), and hemolytic anemia (0.4) 2

Duration of Exposure

• Blood dyscrasias can occur at any point during treatment, with documented cases ranging from 17 days to 6.8 years of AED use 1
• The heterogeneous presentation (ages 1-92 years, variable exposure duration) makes prediction difficult 1

Monitoring Recommendations

Baseline and periodic complete blood counts are mandatory for patients on carbamazepine, valproic acid, phenytoin, and phenobarbital 3, 2

Key Monitoring Points:

• Obtain baseline CBC before initiating therapy with high-risk AEDs 3
• Monitor CBC periodically during treatment, with increased frequency if any abnormalities develop 3
• Immediately discontinue the AED if significant bone marrow depression is detected 3
• Recovery typically occurs after discontinuation, with 20 of 21 patients in one cohort recovering from serious blood dyscrasias 2

Safer Alternatives When Pancytopenia Risk Is a Concern

When blood dyscrasia risk must be minimized, consider lamotrigine, gabapentin, topiramate, or zonisamide as alternatives 5, 7

• These newer agents have lower documented rates of hematologic toxicity 5, 7
• Levetiracetam, despite rare case reports, generally has a more favorable hematologic safety profile than older agents 7
• Avoid polytherapy with multiple aromatic anticonvulsants (carbamazepine, phenytoin, phenobarbital) due to cross-reactivity and additive risk 5