Measure serum levels. A sound preventive approach10 is to measure the peak serum level shortly after loading11,12—one-half hour to 1 hour or more after giving intravenous phenytoin, 2 hours or more after intravenous fosphenytoin, 4 hours or more after intramuscular fosphenytoin, and 16 to 24 hours after accelerated oral loading. While measuring a post-load serum level is not established as a standard of care, the rationale is that a relatively high serum level forewarns of increased risk of early intoxication because of a high starting point for maintenance therapy, and a low level indicates greater vulnerability to seizures (Table 1).
TABLE 1
Preventing phenytoin intoxication at loading (independent of pharmacokinetics of elimination)
| Toxicity risk | Preventive action |
|---|---|
| Complications of intravenous infusion | Avoid excessive infusion rate (maximum, 50 mg/min); monitor blood pressure and ECG; assure good IV placement |
| Overload | Calculate dose by formula, best estimate of prior level |
| Loading formula: to increase the phenytoin serum level by point (1 μg/mL or mg/L), the loading dose should be 0.75 mg/kg. | |
Check post-load level:
|
Initial maintenance dosing
A useful maintenance dose formula yields the dose ordinarily needed to achieve a specified serum level or maintain it after loading:9
For a target maintenance level of 15 μg/mL in a 60-kg adult, the dose would be 5.71 mg/kg/d x 60 kg = 343 mg/d (which can guide selection of a practical, starting dosage regimen, such as 300 or 350 mg/d, or 5–6 mg/kg/d, as is often recommended).13 This formula is more accurate than guessing at 5 mg/kg vs 6 mg/kg; increasingly, such formulas will be incorporated into computerized dosing protocols, thus putting the advised dose only a click or 2 away.
Even calculated dosages should be subject to modification by individual patient factors, including age, reliability, health status (such as liver function), and potential medication interactions. Computerized protocols will help, but the uncertainty of individual responses14 simply means that close symptomatic or serum monitoring must be implemented, while not overreacting to isolated variations (Table 2).15
Important caveat. Phenytoin is typically 90% protein-bound in the serum. Active free phenytoin may be higher than expected if serum albumin is decreased or if bound phenytoin is displaced by other drugs (eg, valproate). Thus, toxicity may be present despite non-elevated total levels of phenytoin, and successive increases in the dosage may cause or exacerbate toxicity. Consider obtaining a free phenytoin level, commonly available by specific requisition, if clinical toxicity is suspected despite total levels that do not suggest toxicity. Consultation or careful review of all potential metabolic interactions helps to ensure proper management in such cases.
Adjusting dosage and the maintenance
level. Here is a practical guide16 for incrementally increasing the phenytoin maintenance regimen (at steady state) for an adult:
- serum level <7 μg/mL, increase daily maintenance dose by 100 mg
- serum level of 7–11 μg/mL, increase by 50 mg
- serum level 12 μg/mL, increase by only 30 mg.
This guide reflects the fundamental principle of phenytoin’s pharmacokinetics: as the serum level approaches, enters, and increases through the therapeutic range, metabolic elimination does not rise proportionately, as it would in the more usual, first-order pharmacokinetics. In zero-order, saturation kinetics, an absolute amount of drug is eliminated per unit of time (as in the case of ethanol). The higher the phenytoin level, the more likely a seemingly reasonable increment in daily dosage, such as 100 mg (as from 300 mg to 400 mg per day) will turn out to be a prescription for toxicity (Table 3).
TABLE 2
Preventing phenytoin intoxication at initial maintenance dosing
| Toxicity risk | Preventive action |
|---|---|
| Excessive dose, causing rising level to toxicity | Dose by maintenance-dose formula, adjusting for individual patient factors (eg, liver function). The best safety net is following closely.Maintenance Dose Formula: dose (mg/kg/d) = (8 x target serum level)/(6 + target level). |
| Incipient side effects going unrecognized | Patient education on early side effects (eg, drowsiness, grogginess, imbalance, vague, dizziness) and need to report promptly; follow-up monitoring by provider for symptoms and serum level. |
TABLE 3
Preventing phenytoin intoxication at dosage adjustment
| Toxicity risk | Preventive action |
|---|---|
| Mistaken change in maintenance dosage, leading to toxicity (eg, dosage is appropriate, but patient has been noncompliant) | Determine whether need for change is urgent; if so, give supplemental load to achieve target, by loading dose formula. |
| Do not increase maintenance dose for acute response but only for sustained response if prior maintenance dosage shown to be inadequate. | |
Maintenance dose adjustment guideline:
| |
| Increasing maintenance dose by too large an increment at one time (eg, 100 mg/d with a level of 14 μg/mL) | Focus on the patient, not the serum level in isolation. Only if clinically indicated, increase the maintenance dose according to guideline based on current serum level. Close follow-up, monitoring, and patient education as above. |
| Unnecessary increase in dose in patient who has long been optimally controlled with a “low” level (eg, 9 μg/mL, therapeutic range 10–20 μg/mL) | Use “therapeutic range” as a general guide, but individualize dose according to each patient’s seizure control, any particular risks (eg, driving, job safety), and any side effects. |