What are the guidelines for using Phenytoin (antiepileptic medication) in adults?

Phenytoin Guidelines for Adults

Phenytoin is an acceptable standard antiepileptic drug for convulsive epilepsy in adults, but should be used as monotherapy at the minimum effective dose, with important caveats regarding its narrow therapeutic index, significant adverse effects, and the availability of safer alternatives in specific populations. 1

Indications and Efficacy

Approved Seizure Types

• Generalized tonic-clonic seizures and partial seizures with or without secondary generalization are the primary indications 2
• Convulsive status epilepticus as second-line therapy after benzodiazepines fail 1
• Not recommended after a first unprovoked seizure 1

Comparative Positioning

• Phenytoin is one of four standard first-line antiepileptic drugs (carbamazepine, phenobarbital, phenytoin, valproic acid) for convulsive epilepsy 1
• Carbamazepine should be preferentially offered over phenytoin for partial onset seizures when available 1
• In patients with intellectual disability, valproic acid or carbamazepine are preferred over phenytoin due to lower risk of behavioral adverse effects 1

Dosing Protocols

Maintenance Therapy (Oral)

• Initial dose: 5 mg/kg/day in adults, divided into 2-3 doses 3
• Standard maintenance: 300 mg daily (one 100-mg capsule three times daily), adjustable to 300-400 mg daily 3
• Pediatric dosing: 4-8 mg/kg daily (maximum 300 mg/day); children >6 years may require adult dosing 3
• Once-daily dosing: Only extended phenytoin sodium capsules (Dilantin) at 300 mg can be given once daily after seizure control is established 3

Loading Dose Strategies

Oral Loading (clinic/hospital setting only):

• 1 gram divided into three doses (400 mg, 300 mg, 300 mg) at 2-hour intervals 3
• Contraindicated in patients with renal or liver disease 3
• Begin maintenance dosing 24 hours after loading with frequent serum level monitoring 3

IV Loading for Status Epilepticus:

• 18 mg/kg IV at maximum rate of 50 mg/min 1
• Requires cardiac monitoring, infusion pump, and filter 1
• Fosphenytoin alternative: 18 PE/kg IV at maximum rate of 150 PE/min with fewer cardiovascular complications 1, 4

Status Epilepticus Management Algorithm

Level A Recommendation

Administer an additional antiepileptic medication in patients with refractory status epilepticus who have failed benzodiazepines 1

Level B Recommendation

IV phenytoin, fosphenytoin, OR valproate may be administered as second-line agents 1

Comparative Efficacy Data

• Phenytoin shows only 56% success in terminating status epilepticus when used after diazepam 1
• Valproate demonstrated superior efficacy to phenytoin as second-line therapy: 79% vs 25% seizure control (NNT 1.9) 1
• Valproate has lower hypotension risk (0% vs 12%) compared to phenytoin 1

Therapeutic Drug Monitoring

Target Levels and Timing

• Therapeutic range: 10-20 mcg/mL total concentration 3, 5
• Steady-state achievement: 7-10 days; do not adjust dosing more frequently 3
• Monitor free (unbound) phenytoin in patients with hypoalbuminemia or renal failure 6

When to Monitor

• After 7-10 days of therapy initiation or dose change 3
• When switching between formulations (sodium salt vs free acid form represents ~8% content difference) 3
• With suspected toxicity or breakthrough seizures 7
• Avoid premature monitoring: 73.5% of phenytoin determinations in acute care are performed inappropriately (too soon after admission or dose change) 5

Critical Adverse Effects and Monitoring

Neurological Toxicity

• Phenytoin encephalopathy: cognitive impairment and cerebellar syndrome (nystagmus, ataxia, balance disturbances) 2
• Nystagmus is a dose-related adverse effect seen with both phenytoin and fosphenytoin 4
• Not recommended as first choice except as co-drug for status epilepticus due to adverse effect profile 2

Cardiovascular Complications

• Hypotension, bradyarrhythmias, cardiac arrest with IV administration 1
• Hypotension is rare with oral phenytoin but more common with IV formulation 4
• Fosphenytoin has fewer cardiovascular complications than IV phenytoin 4
• Extravasation injuries possible with IV phenytoin 1

High-Risk Populations Requiring Caution

• Patients with intellectual disability: susceptible to balance disturbances and cognitive dysfunction; consider replacing with carbamazepine or oxcarbazepine 2
• Patients with loss of locomotion, marked cognitive impairment, or cerebellar disease: long-term phenytoin not recommended 2
• Women of childbearing potential: use monotherapy at minimum effective dose; avoid valproic acid preferentially 1

Special Populations

Pregnancy and Breastfeeding

• Monotherapy at minimum effective dose is essential 1
• Folic acid supplementation should be routinely taken 1
• Standard breastfeeding recommendations remain appropriate for phenytoin 1
• Avoid polytherapy 1

Drug Interactions (High Clinical Impact)

• Rifampin and isoniazid: significantly decrease phenytoin levels, requiring dose increases and close monitoring 6, 8
• Valproic acid: displaces phenytoin from plasma proteins and inhibits metabolism (dual mechanism) 8
• Phenobarbital, carbamazepine: shorten phenytoin half-life through enzyme induction 2, 8
• Cimetidine, isoniazid, chloramphenicol, sulfonamides: inhibit phenytoin metabolism, increasing levels 8
• Phenytoin induces metabolism of carbamazepine, theophylline, methadone, corticosteroids, and cardiac antiarrhythmics 8

Discontinuation Guidelines

• Consider discontinuation after 2 seizure-free years 1
• Decision should involve consideration of clinical, social, and personal factors with patient and family involvement 1

Key Clinical Pitfalls

Formulation Switching

• Never assume bioequivalence between different phenytoin formulations 3
• Extended phenytoin sodium capsules are the ONLY formulation approved for once-daily dosing 3
• Switching between sodium salt and free acid forms requires dose adjustment and serum level monitoring 3

Nonlinear Pharmacokinetics

• Small dose increases can cause disproportionately large increases in plasma concentration due to saturable metabolism 2, 8
• This property makes phenytoin particularly prone to toxicity and necessitates careful dose titration 8

Protein Binding Considerations

• 90-95% protein bound under normal conditions 2
• Total phenytoin levels are misleading in hypoalbuminemia, renal failure, or with displacing drugs 6, 8
• Request free phenytoin levels in these situations 6