UMEM Educational Pearls

Phenytoin can be a complex medication.  There are different levels than can be ordered, adjustments based on albumin, various pharmacokinetic equations, and multiple formulations.  Below are the simplified answers to some of the most common questions (see in-depth section for explanations):

Which phenytoin level (free or total) do I order?

Total Phenytoin Level.

 

What do I do after the level results?

Undetectable Level: Load patient with 20 mg/kg of total body weight (max dose 1,500 mg).

Subtherapeutic Level (<10 mcg/mL): Calculate an approximate loading dose using this equation….Phenytoin Dose (mg)=(15-measured total level)*(0.7*patient weight).

Therapeutic Level (10-20 mcg/mL): Add an additional agent.

Supratherapetutic/Toxic Level (>20 mcg/mL): Contact Poison Center (1-800-222-1222).

 

What formulation do I order for loading?

IV: Use fosphenytoin.

PO: Any formulation will work.  Give as a single loading dose or, if concerned for GI upset, give in 2-3 divided doses separated by 2 hours.

 

 

***Disclaimer: These answers are simplified for the initial management of most patients in the ED. More complex answers may be required in some situations.***

Additional Information

Which phenytoin level (free or total) do I order?

Total Phenytoin Level

Free and total phenytoin levels are available at most institutions. Free levels are more predictive of efficacy and toxicity; however, free levels are tested only at certain times at most institutions which can lead to a delay in results. Total phenytoin levels are a good approximation of therapeutic levels and are easier to perform pharmacokinetic caculations.

 

What do I do after the level results?

Undetectable Level: Load patient with 20 mg/kg of total body weight (max dose 1,500 mg)

For phenytoin naive or noncompliant patients that present with an undetectable level, the guideline recommended loading dose is phenytoing 20 mg/kg.

 

Subtherapeutic Level (<10 mcg/mL): Calculate an approximate loading dose using this equation….Phenytoin Dose (mg)=(15-measured total level)*(0.7*patient weight)

Phenytoin has many complex equations related to the pharmacokinetics of the medication.  There are adjustments for albumin, approximations of free/total levels, estimations of loading doses, etc.  A simple PK equation that can be applied to most medications is concentration=(dose*salt factor)/(volume of distribution).  For application to clinical cases with phenytoin this equation can be manipulated to yield the dose=(desired concentration-measured concentration)*(population Vd*patient weight).

 

For the equation given to you above, this equation has modified.  The equation was manipulated to solve for dose.  The salt correction factor was removed.  For phenytoin the salt correction factor is 0.92, thus removing it does not significantly affect the results.  There are also two variables of the equation that are prepopulated.  Therapeutic levels of phosphenytoin are 10-20 mcg/mL.  A simplified desired concentration is to aim for the middle concentration of 15 mcg/mL.  The population Vd is a range; however, we use 0.7 L/kg for ease of caculations.

 

Therapeutic Level (10-20 mcg/mL): Add an additional agent

There is no therapeutic benefit to giving additional phenytoin in these patients.  Phenytoin has complex pharmacokinetics and giving patient additional phenytoin will likely lead to phenytoin toxicity.

 

Supratherapetutic/Toxic Level (>20 mcg/mL): Contact Poison Center (1-800-222-1222)

Experts in toxicology are available 24/7 to assist in the managment of patients with phenytoin toxicity.

 

What formulation do I order for loading?

IV: Use fosphenytoin

For initial IV loading, fosphenytoin (a prodrug of phenytoin) is preferred.  Compared to phenytoin, fosphenytoin can be administer faster, has less side effects, and does not require a filter for administration; making fosphenytoin the preferred product.  Fosphenytoin is doses in phenytoin equivalents (PE) to prevent confusion with dosing.

 

PO: Any formulation will work.  Give as a single loading dose or, if concerned for GI upset, give in divided doses separated by 2 hours.

Any oral formulation of phenytoin (immediate release, extended release, oral solution) is appropriate for oral loading of phenytoin. There is evidence supporting a single oral loading dose of phenytoin can be tolerated; however, due to historical guidance of limiting the oral dose to <400 mg and separating doses by 2 hours due to concern for absorption and potential for GI upset some providers may find a single dose controversial. An alternative method is to divide the total phenytoin dose into 2-3 doses and administer separated by 2 hours for each dose.

References

1. Abernethy DR, Greenblatt DJ. Phenytoin disposition in obesity. Determination of loading dose. Arch Neurol. 1985;42(5):468-71.

2. Anderson GD, Pak C, Doane KW, et al. Revised Winter-Tozer equation for normalized phenytoin concentrations in trauma and elderly patients with hypoalbuminemia. Ann Pharmacother. 1997;31(3):279-84.

3, Glauser T, Shinnar S, Gloss D, et al. Evidence-Based Guideline: Treatment of Convulsive Status Epilepticus in Children and Adults: Report of the Guideline Committee of the American Epilepsy Society. Epilepsy Curr. 2016;16(1):48–61. doi:10.5698/1535-7597-16.1.48

4. Kane SP, Bress AP, Tesoro EP. Characterization of unbound phenytoin concentrations in neurointensive care unit patients using a revised Winter-Tozer equation. Ann Pharmacother. 2013;47(5):628-36.

5. Osborn HH, Zisfein J, Sparano R. Single-dose oral phenytoin loading. Ann Emerg Med. 1987;16(4):407-12.

6. Ratanakorn D, Kaojarern S, Phuapradit P, Mokkhavesa C. Single oral loading dose of phenytoin: a pharmacokinetics study. J Neurol Sci. 1997;147(1):89-92.

7. Soriano VV, Tesoro EP, Kane SP. Characterization of Free Phenytoin Concentrations in End-Stage Renal Disease Using the Winter-Tozer Equation. Ann Pharmacother. 2017 May 1.

8. Winter MG, Tozer TN. Chapter 25. Phenytoin. In: Evans WE, Schentag JJ, Jusko WJ. Applied pharmacokinetics: principles of therapeutic drug monitoring. 3rd ed. Vancouver, WA: Applied Therapeutics, 1992:1-44.