Pyridoxine for Levetiracetam-

Induced Agitation
Medication Use Evaluation

Emily Harvath, PharmD

PGY1 Pharmacy Resident | IU Health AAHC
Objectives
Understand existing literature regarding pyridoxine use for
levetiracetam-induced agitation
Discuss current pyridoxine dosing practices at Riley Hospital for
Children
Analyze future directions for pyridoxine dosing regimens at Riley
Hospital for Children

2
Background

3
 Background

Benefits of levetiracetam

• Bioavailability
• Few drug interactions

Most common levetiracetam side effects

• Aggression
• Decreased appetite
• Irritability
4
Keppra. Package insert. UCB, Inc; 2020.
 Levetiracetam Systematic Review

Behavioral side Levetiracetam

3 randomized effects discontinuation
controlled trials
62/203 (30.5%) 2/102 (2%)

5
Halma et al. Seizure. 2014;23(9):685-691.
 Pyridoxine
Used to mitigate levetiracetam-induced agitation

Proposed • Active form of pyridoxine acts as cofactor

Mechanism for neurotransmitter metabolism

Safety • Toxicity only at doses > 1000 mg/day

• Minimal literature to support efficacy

Efficacy
• Recommended dose unknown
6
Jiao et al. Pediatr Neurol. 1997 Jul;17(1):54-7.
 Marino et al
Study Design
• Randomized, case-control trial
• Levetiracetam vs Levetiracetam + Pyridoxine
Population
• 50 patients with epilepsy, ages 7-16
Results
• Levetiracetam discontinuation
• 76% monotherapy vs 8% with pyridoxine (p<0.001)
• Average pyridoxine dose: 7 mg/kg/day 7
Marino et al. Ann Pharmacother. 2018 Jul;52(7):645-649
 Mahmoud et al
Study Design
• Randomized interventional study
• Pyridoxine homeopathic (“placebo”) vs pyridoxine treatment
Population
• 105 patients with epilepsy taking levetiracetam, ages 1-17
Results
• Relative reduction in behavioral symptoms with pyridoxine
• Average pyridoxine dose: 197.2 mg/day
• Majority required 15 mg/kg/day 8
Mahmoud et al. Pediatr Neurol. 2021 Jun;119:15-21.
 Mahmoud et al
Behavioral Score
Developed by
authors
Not validated
Subjective behavior
interpretation

9
Mahmoud et al. Pediatr Neurol. 2021 Jun;119:15-21.
 Mahmoud et al Dosing Strategy

Placebo Treatment

Start:
0.5 mg/kg/day
10 mg/kg/day

<50% score improvement

Increase to 15 mg/kg/day
(max: 200mg) 10
Mahmoud et al. Pediatr Neurol. 2021 Jun;119:15-21.
Medication Use Evaluation

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Medication Use Evaluation (MUE)
Retrospective chart review from September 1, 2021 through
September 30, 2022
Objective: describe current pyridoxine dosing patterns when used
for levetiracetam-induced behavioral side effects
Results analyzed using descriptive statistics

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MUE Population

Inclusion Criteria Exclusion Criteria

Age ≤ 18 Primary deficiency in

Coadministration of pyridoxine vitamin B6
and levetiracetam Pyridoxine indication for seizure
Admitted to Riley Hospital for treatment
Children

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Results

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Patient Inclusion
All pyridoxine + levetiracetam
coadministrations (N = 154)

Excluded encounters:
Seizure indication (N=2)
B6 Deficiency (N=0)

152 encounters included, composed

of 107 unique patients 15
Baseline Characteristics
Variable Result
Gender
Male 61/107 (57%)
Female 46/107 (43%)
Average Age (years) 8.8 ± 5.6
Average Weight (kg) 36 ± 26.3
Race
White 84/107 (78.5%)
African American 19/107 (17.8%)
On Pyridoxine Prior to Admission 81.6% of admissions
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Dosing Results

Medication Average Dose (mg/kg/day)

Levetiracetam
Admission 40.7 ± 17.4
Discharge 42.3 ± 17.0
Pyridoxine
Admission 1.9 ± 1.4
Discharge 1.9 ± 1.5

Pyridoxine dose increase in 2 patients

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Dosing Results

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Dosing Formulations
Levetiracetam and Pyridoxine Dosage Forms
250 mg
Small Tablet 25 mg

500 mg
Medium Tablet 50 mg

750 mg
Large Tablet
100 mg

Solution

0 20 40 60 80 100 120

Number of Admissions
19
Levetiracetam Pyridoxine
Levetiracetam Discontinuation

Levetiracetam
discontinued
9 patients

Persistent Medically
Unknown
agitation unnecessary
1 patient
5 patients 3 patients
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Summary
Average pyridoxine dose for this indication ranges from 6-
15 mg/kg/day in published literature
Average pyridoxine dose at Riley Hospital for Children is
1.9 mg/kg/day
Pyridoxine most commonly prescribed in tablet form (73.6%)
Levetiracetam discontinuation rate at Riley is similar to published
literature
8.4% at Riley
8% in Marino et al (levetiracetam + pyridoxine group)
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Recommendations
Continue current dosing practices
Consider increasing patient’s dose if symptoms fail to respond
Reasonable to round up calculated dose to next 25 mg increment

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Pyridoxine for Levetiracetam-
Induced Agitation
Medication Use Evaluation

Emily Harvath, PharmD

PGY1 Pharmacy Resident | IU Health AAHC