In this episode I’ll discuss the drug phenytoin.
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Indications
Common indications for the use of phenytoin are:
Control of generalized tonic-clonic and complex partial (psychomotor, temporal lobe) seizures
Prevention and treatment of seizures occurring during or following neurosurgery
Prevention of early (within 1 week) post-traumatic seizures following traumatic brain injury
Initial dose
The initial dose of phenytoin is a loading dose of 15-20 mg/kg, followed by a maintenance dose of 5-6mg/kg/day.
How can I tell if the phenytoin concentration is therapeutic?
To determine if a patient has a therapeutic phenytoin level, I look at 4 things in the following order:
– Are seizures controlled?
– Are side effects present?
– Is the drug at steady-state?
– What is the phenytoin level?
As with all drugs, it is important to treat the patient and not the number. For most patients the therapeutic range of phenytoin is 10-20 mcg/mL. However if seizures are controlled at 9 mcg/mL or side effects are present at 12 mcg/mL, a patient specific therapeutic range should be considered.
Phenytoin is highly protein bound. In the setting of hypoalbuminemia, either a corrected phenytoin level should be estimated or a free phenytoin level should be checked.
Formulas for adjusting the measured phenytoin level for hypoalbuminemia are population-based and may not be accurate in any given patient. A large number of conditions including burns, sepsis, uremia, liver disease (and many more!) can alter the serum binding of phenytoin.
My preference is always to measure the free phenytoin if the patient has hypoalbuminemia because this is a patient-specific result.
The average half-life of phenytoin in adults is about 24 hours, so any level taken within the first 5 days of initiation or dose change should not be considered a steady-state level.
I’ll check a level 2-3 days after initiation to make sure phenytoin metabolism is not significantly abnormal, and again 5 days after initiation or any dose change to assess the steady-state concentration. After that, I’ll monitor the phenytoin level weekly while the patient is still in the hospital.
Monitoring & dose adjustments
I remember my pharmacokinetics class being split into two parts:
– Phenytoin kinetics
– All other drugs
The body’s capacity to metabolize phenytoin is fixed and saturable. This is referred to as zero-order or Michaelis-Menten kinetics.
The mnemonic “Peas & WHEATS” has been used to remember all the drugs that have saturable metabolism:
Phenytoin, Phenylbutazone
Warfarin
Heparin
Ethanol
Acetaminophen
Theophylline, Tolbutamide
Salicylates
What makes phenytoin unique from these other medications is that the saturation point can overlap with the normal therapeutic dose range. A small change in dose can result in a massive change in plasma concentration if the saturation point is unknowingly exceeded. Even the 8% increase in bioavailability between the phenytoin base (oral suspension and chewable tablets) compared to phenytoin sodium (oral capsules and IV formulation) could be enough to surpass the saturation point and cause toxicity.
Adjustments to the maintenance dose of phenytoin should be made in small increments. A fantastic guideline for maintenance dose adjustment is used by the University of Michigan Medical School:
A rough guide to making an adjustment to the daily dose that should increase a serum level without leading to supratherapeutic / toxic levels is:
If the phenytoin concentration is < 7 mcg/mL, the dose may be increased by 100 mg/day.
If the phenytoin concentration is 7-12 mcg/mL, the dose may be increased by 50 mg/day.
If the phenytoin concentration is >12 mcg/mL, the dose may be increased by 30 mg/day.
If the phenytoin concentration is >16 mcg/mL, any change may result in a significant increase in serum level and should be done very carefully.
If the phenytoin level is subtherapeutic, and seizures are not controlled, it is best to re-load the patient to quickly obtain a therapeutic level rather than make a large change to the daily dose. The University of Michigan Medical School also gives a nice rule of thumb for re-loading a patient with phenytoin to achieve a therapeutic level:
loading dose = (goal total phenytoin level – current total phenytoin level) x weight in kilograms
Toxicity
Cardiac toxicity may occur with phenytoin administration, even at normal infusion rates. Because of this the FDA has added a warning to the prescribing information for phenytoin that suggests cardiac monitoring occur during and after IV phenytoin administration.
At supratherapeutic levels, phenytoin can be extremely toxic. The expected toxicities according to the plasma level are:
20 and 30 mcg/mL – Nystagmus
30 and 40 mcg/mL – Ataxia, slurred speech, nausea, and vomiting
40 and 50 mcg/mL – Lethargy and confusion
> 50 mcg/mL – Coma and seizures
The treatment of chronic phenytoin toxicity involves supportive care. Multiple dose activated charcoal may help enhance elimination. Lidocaine use should be avoided as the two drugs are both Vaughan Williams Class IB antiarrhythmic agents.
Conclusion
Phenytoin is a complex medication to use safely. If you are not already familiar with phenyotin, you can expand your understanding beyond this podcast by reading an excellent review article found in Pharmacotherapy here.
Do you have your own preference for dosing phenytoin? Post it in the comment section below!
If you like this post, check out my book – A Pharmacist’s Guide to Inpatient Medical Emergencies: How to respond to code blue, rapid response calls, and other medical emergencies.
Hi Joe – Great podcast! Three questions: 1) Can you comment on the correlation between total vs free phenytoin level and how to best titrate the dosages based on free phenytoin level? 2) How fast do you infuse your loading dose? My experience is that hemodynamic compromise occurs even at a slower than recommended infusion rate… 3) Can you comment on when to use fospheny vs phenytoin? Thank you!
Great questions!
1. Since the ratio is 10:1 between total and free phenytoin levels, just divide the cut-offs by 10 and adjust accordingly.
2. I give the loading dose at about 20-25 mg/minute if possible.
3. Our fosphenytoin supply has been very spotty, so we don’t bother with it. If supply was steady and cost not appreciably different, I’d give all IV doses as fosphenytoin.
Thanks for such a great podcast! I just have a question on phenytoin load. After loading a patient on phenytoin, would you suggest doing a random level the next day to make sure it’s within therapeutic range? I know you had mentioned it’s important to treat the patient and not the number, but I’m thinking if you check the level the next day, you may be able to prevent another seizure from happening if the level is subtherapeutic. I know most references suggest doing a level 2-4 hours after a IV load but if the load was given overnight and you notice a level not drawn the next day, given the half-life of 24 hours for phenytoin, you would assume the level would still be in therapeutic range the next day right?
Sure, if you need to ensure therapeutic levels immediately, you can check a level at 2 hours after the dose and if you don’t get around to it until the next morning that should be OK too.
This may be a “duh” question but when increasing the dose by 50mg/day. Does this mean you increase all the doses or do you increase the total 24 hour dose?
I like to keep the total daily dose increases to 50mg/day.
If levels are not therapeutic you can always re-load the patient – this is safer than a large daily dose increase.
How long after neuro surgery should dilantin be administered if no seizure activity present after confirmation by a 24 hour eeg? How often should blood test be given during administration of the drug to ascertain safe levels?
also should the patient be given a medalert wrist band to notify medical peronel that she is taking it?
If the phenytoin level is supratherapeutic (level adjusted for albumin of 3 and hemodialysis patient) is it best to hold a few doses or lower maintenance dose ?
If I had a patient like that I would consider how high the levels were and whether the patient was having side effects before deciding whether to hold a few doses or to lower the maintenance dose.
Hi Pharmacy Joe,
How would you recommend adjusting supratherapeutic phenytoin levels?
I either hold a few doses or lower the maintenance dose, depending on what is going on with the patient (how high is the level, are they having side effects, etc…).
With a patient with a free level of 2.3 and level of 19.1 on Dilantin 200 mg in am and at hs along with Depakote ER 250mg in am and HS, how would you approach the elevated free level? Patient weighs 130 lbs and is 72 year female old showing symptoms of dizziness, headache and slight ataxia. Would it be correct to reduce the Dilantin level to 300mg a day? Thank you.
Hi Marion!
If I had a patient like that I would look to reduce the phenytoin dose exactly as you described.
I was wondering if you could shed light on what weight is recommended to be used when dosing phenytoin? (IBW? actual?) In another popular pharmacist-led website they state IBW is to be used but cannot give an explanation as to why. Just curious what weight other hospitals or pharmacists are utilizing. Thanks pharmacy joe! 🙂
Hi Elyse!
Because of the larger Vd of phenytoin in obese patients, they will need a higher loading dose but will have a longer half-life.
I like the protocol used in this article for loading doses in obese patients:
17 mg/kg for obese patients (BMI of 31–40 kg/m2), or 18 mg/kg for morbidly obese patients (BMI exceeding 40 kg/m2), with a cap at 2g for any individual dose.
For maintenance dosing I would be inclined to use IBW or adjusted body weight and adjust from there.
Hi
A patient taking phenytoin 100mg BID has serum level of 5mg/l. Even then has one attack per week. Physician increase the dose to 200mg BID. How much percent increase in the serum phenytoin level will be there??
Please explain
If I had a patient like this I would still follow the University of Michigan Medical School guidelines as listed above. I don’t believe the percent increase can be accurately predicted.