Can a patient take Depakote (valproate) 500mg in the morning and 1000mg at night if they normally take 500mg three times a day?

Depakote Dosing Adjustment for Twice-Daily Administration

Yes, the patient can take Depakote 500mg in the morning and 1000mg at night to maintain the same total daily dose of 1500mg, though this creates unequal dosing intervals that may result in higher peak concentrations and lower trough concentrations compared to three-times-daily dosing. 1

FDA-Approved Dosing Guidance

• The FDA label explicitly states that if the total daily dose exceeds 250mg, it should be given in divided doses, but does not mandate equal division or specify that three times daily is required 1
• The label provides flexibility in dosing schedules as long as the total daily dose is maintained and tolerability is acceptable 1

Pharmacokinetic Considerations

• Valproate has an elimination half-life of 6-15 hours, which means twice-daily dosing can maintain therapeutic concentrations, though with greater fluctuation than three-times-daily dosing 2
• The proposed regimen (500mg AM, 1000mg PM) will create asymmetric peak and trough levels, with higher peaks occurring after the evening dose 3
• Increasing individual dose sizes raises peak serum levels and extends the duration of minimum effective concentrations, which may actually benefit seizure control 2

Practical Implementation Strategy

For the proposed twice-daily regimen:

• Administer 500mg in the morning (upon waking)
• Administer 1000mg in the evening (approximately 12 hours later) 1
• Monitor for dose-related adverse effects, particularly after the larger evening dose, as adverse effects (elevated liver enzymes, thrombocytopenia) are dose-related and increase at higher concentrations 1

Monitoring Requirements

• Therapeutic drug monitoring should account for timing of blood draws relative to the dosing schedule 3
• For the evening 1000mg dose, a trough level drawn 12 hours later (morning) will be approximately 18-25% higher than a true trough value 3
• The probability of thrombocytopenia increases significantly at total trough valproate concentrations above 110 μg/mL in females and 135 μg/mL in males 1

Critical Safety Considerations

• Watch for increased somnolence or sedation after the larger evening dose, particularly in elderly patients who may have decreased clearance 1
• GI irritation may be more pronounced with the 1000mg dose; taking with food can mitigate this 1
• The patient should be monitored for any increase in seizure frequency during the transition, though the total daily dose remains unchanged 1

Alternative Consideration

• If the facility can accommodate it, an alternative split would be 750mg twice daily, which would create more balanced peak and trough levels and potentially better tolerability 1
• However, if only 500mg tablets are available, the 500mg/1000mg split is acceptable and maintains the prescribed total daily dose 1