Valproic Acid Dosing Frequency
Valproic acid should be dosed in divided doses (typically twice daily) when the total daily dose exceeds 250 mg, according to FDA labeling. 1
Standard Formulation Dosing
The FDA-approved labeling explicitly states: "If the total daily dose exceeds 250 mg, it should be given in divided doses." 1
For epilepsy management, valproic acid capsules are typically administered in divided doses throughout the day to maintain therapeutic levels and minimize side effects. 1
The standard immediate-release and delayed-release (enteric-coated) formulations require multiple daily doses (typically 2-3 times daily) to maintain stable plasma concentrations over 24 hours. 2, 3
Extended-Release Formulation Exception
Divalproex extended-release (ER) is specifically designed for once-daily dosing and maintains therapeutic valproic acid concentrations for 24 hours, unlike the standard enteric-coated formulation. 3, 4
When converting from standard divalproex to extended-release, an 8-20% dose increase is required due to lower bioavailability of the ER formulation. 5
Once-daily dosing with standard (non-ER) divalproex at high doses (≥2000 mg/day) produces dangerously high peak concentrations (Cmax >125 mg/L) and should be avoided. 3
Clinical Implications
Standard valproic acid formulations require divided dosing to avoid excessive peak-to-trough fluctuations that can cause both toxicity (at peaks) and breakthrough seizures (at troughs). 2, 3
The extended-release formulation achieves 4.4-6.2-fold less peak-trough fluctuation compared to once-daily standard divalproex, making it the only appropriate option for once-daily administration. 3
Twice-daily dosing is preferred over once-daily even with ER formulations, as it provides better "forgiveness" for missed doses and reduces the risk of breakthrough seizures. 2
Common Pitfall
Do not assume all valproic acid formulations can be dosed once daily—this is only appropriate for the extended-release formulation, and even then, twice-daily dosing may be safer for seizure control. 2, 3