If a patient's phenytoin (Dilantin) level improves to 17 mcg/mL after being held due to supratherapeutic levels, should it be restarted?

Management of Supratherapeutic Phenytoin Level After Improvement to 17 mcg/mL

Phenytoin should be restarted at a reduced dose when levels have improved to 17 mcg/mL after being held for supratherapeutic levels, as this value is within the therapeutic range but at the upper end.

Understanding Phenytoin Therapeutic Levels

Phenytoin (Dilantin) is an antiepileptic medication with a narrow therapeutic index. According to the FDA drug label:

• Therapeutic range: 10-20 mcg/mL 1
• Steady-state levels are achieved after 7-10 days (5-7 half-lives) of therapy 1
• Plasma half-life averages 22 hours but ranges from 7-42 hours 1
• Small dosage increases (even 10%) can produce substantial increases in serum levels when they are already in the upper range 1

Decision Algorithm for Restarting Phenytoin

1. Assess current level in relation to therapeutic range:

   • 17 mcg/mL is within therapeutic range (10-20 mcg/mL) but at the upper end
   • Risk of toxicity increases as levels approach 20 mcg/mL

2. Evaluate for signs of toxicity:

   • Common signs: nystagmus, ataxia, nausea, vomiting 2
   • Less recognized: vegetative depression, mood changes, sleep disturbances 2, 3
   • Cardiovascular effects (rare with oral dosing but possible with IV administration) 4

3. Restart decision:

   • Restart at a reduced dose (25-33% reduction from previous dose)
   • Monitor levels more frequently initially (within 5-7 days after restart)
   • Adjust dose based on subsequent levels and clinical response

Important Considerations

• Protein binding: Phenytoin is highly protein-bound, and free phenytoin levels may be altered in patients with different protein binding characteristics 1

• Metabolism: Phenytoin is metabolized by a saturable hepatic enzyme system, meaning small dose increases can cause disproportionate increases in serum levels 1

• Drug interactions: Many medications can alter phenytoin levels by affecting protein binding or metabolism 5

• Patient factors: Age, renal/hepatic function, and comorbidities may affect phenytoin metabolism and toxicity threshold 5

Monitoring Recommendations

• Obtain trough levels 5-7 days after restarting therapy 1
• Target the lower half of the therapeutic range (10-15 mcg/mL) if seizure control can be maintained
• Monitor for subtle signs of toxicity even within the therapeutic range
• Consider more frequent monitoring in patients with:
  • Hepatic or renal impairment
  • Multiple medications with potential interactions
  • Elderly patients (more susceptible to toxicity) 5

Pitfalls to Avoid

1. Unnecessary dose increases: Research shows that increasing doses in well-controlled patients with subtherapeutic levels does not improve seizure control but increases side effects 6

2. Missing subtle toxicity signs: Depression and other mood changes can be manifestations of phenytoin toxicity that are often overlooked 2, 3

3. Rapid dose adjustments: Due to phenytoin's non-linear pharmacokinetics, small changes in dose can lead to large changes in serum levels 1

4. Ignoring free phenytoin levels: In patients with hypoalbuminemia or other conditions affecting protein binding, total phenytoin levels may not accurately reflect the pharmacologically active free fraction 1