How should phenytoin (Dilantin) serum levels be drawn for therapeutic drug monitoring?

How to Draw Phenytoin (Dilantin) Levels

Yes, phenytoin levels should be drawn at steady state (7-10 days after starting therapy or dose changes), with timing based on whether you're checking trough levels (immediately before next dose) or peak levels (4-12 hours post-dose for extended-release formulations). 1

Timing of Blood Draws

Steady-State Considerations

• Wait 7-10 days before drawing levels after initiating therapy or changing doses, as this is the time required to reach steady-state blood levels 1
• Do not perform dosage adjustments at intervals shorter than 7-10 days 1
• Drawing levels too early is a common error—73.5% of phenytoin determinations in one study were deemed inappropriate, primarily because they were done too soon after admission or therapy changes 2

Specific Timing for Sample Collection

• Trough levels (most common): Draw immediately before the next scheduled dose
• Peak levels: Draw 4-12 hours after dose for extended-release formulations 1
  • Peak levels help identify the threshold for dose-related side effects
  • Extended-release formulations have slower absorption compared to immediate-release (1.5-3 hours to peak) 1

Special Populations Requiring Modified Monitoring

When to Measure Free (Unbound) Phenytoin Instead of Total

Measure free phenytoin levels in patients with:

• Hypoalbuminemia (albumin <3.5 g/dL) 1
• Renal disease 1
• Hepatic disease 1
• Pregnancy 1
• Elderly patients 1
• Critically ill patients 3

Why this matters: Total phenytoin measurements can be misleading in these populations because the fraction of unbound (active) drug increases. Studies show 50% of patients have free phenytoin fractions outside the expected 8-12% range, and 30% demonstrate discrepancy between therapeutic status when comparing free versus total levels 4. In critically ill patients, 57.1% had supratherapeutic unbound phenytoin despite total levels appearing therapeutic 3.

Alternative: Adjusted Phenytoin Calculation

If direct free phenytoin measurement is unavailable:

• Use the Sheiner-Tozer equation to calculate adjusted phenytoin based on albumin levels 5
• Albumin measurements up to 7 days prior to phenytoin measurement can be used 5
• Caveat: Adjusted phenytoin tends to underestimate free phenytoin more often than overestimate, particularly at low albumin concentrations 5
• Free phenytoin measurement remains the gold standard when available 5, 4

Therapeutic Ranges

Standard Ranges

• Total phenytoin: 10-20 mcg/mL 1
• Free (unbound) phenytoin: 1-2 mcg/mL 1

Clinical Correlation with Toxicity

• Nystagmus on lateral gaze: appears at 20 mcg/mL
• Ataxia: appears at 30 mcg/mL
• Dysarthria and lethargy: appear above 40 mcg/mL 1

Common Pitfalls to Avoid

1. Drawing levels too early: Most inappropriate determinations occur because samples are drawn before steady state is reached 2

2. Relying on total levels in high-risk populations: In patients with hypoalbuminemia, renal/hepatic disease, or critical illness, total levels grossly misrepresent therapeutic status 4, 3

3. Not accounting for CYP2C9 polymorphisms: Intermediate or poor metabolizers (*1/*3, *2/*2, *3/*3 genotypes) may have elevated levels at standard doses and require immediate level checking if CNS toxicity develops 1

4. Ignoring pregnancy-related changes: Phenytoin clearance increases during pregnancy; monitor unbound fraction and adjust doses accordingly, with postpartum restoration of original dosing 1