Preventing phenytoin intoxication: Safer use of a familiar anticonvulsant
Monitoring for “dose-related” (concentration related) toxicity
After starting or adjusting a phenytoin regi-men, a common practice—but an inadequate one from a preventive point of view—is to order a serum drug level 2 or more weeks hence, to determine the steady-state level. If toxicity is to occur, however, it will happen before a steady state is reached, which is normally expected in 5 to 7 half-lives (or in 5–14 days at a typical phenytoin “half-life” of 24–48 hours).
Phenytoin toxicity may occur earlier than this because of its zero-order, saturation kinetics, which progressively increases the time required for 50% elimination as the level rises. Arrangements should be made to monitor the patient for toxic symptoms and consider a serum level several days (eg, 3–7 days) after dosage adjustment. Even if this level is not excessively elevated, a rise from a post-load level portends heightened risk of toxicity.
Follow-up management: educate patients
Patient safety during therapy depends not only on adhering to rational pharmacologic principles, but also on patient education and active safeguards. A patient’s awareness of toxic symptoms functions as an early-warning system. Inform patients not only about “allergic” side effects, but about incipient, dose-related side effects, including drowsiness and impaired balance, and drug-drug and drug-disease interactions. Follow-up cannot follow a cookbook approach, and slowly developing symptoms, such as drowsiness, may be minimized by the patient.
As they are developed, computer-based protocols can facilitate dosing orders and can prompt patient education, provision of handouts, and appropriate follow-up appointments or other monitoring contacts.
Follow-up intervals depend upon the condition of the patient, including the ability to recognize and report symptoms. Ideally, a weekly phone call or other contact—initiated by the patient, family, other caregivers, or clinician—should be made until the patient appears to be well controlled with an acceptable serum level and without side effects. Subsequently, patient and caregiver attention to monitoring symptoms and potential interactions remains the best, practicable safeguard against clinical toxicity.14
Our 140-bed, urban community teaching hospital logs 30,000 emergency visits each year. We retrospectively documented an average of 5 cases of inadvertent, symptomatic phenytoin intoxication per year in our emergency department over a 4-year period. The range of phenytoin levels was 22.2–59.4 μg/mL (therapeutic range 10–20 μg/mL), and the median was 39 μg/mL.
Of the 15 patients seen in the first 3 years, 12 were admitted to the hospital, generating an average charge of $4119. During the fourth year, we implemented a didactic and case-based program to educate house officers and attending physicians about phenytoin pharmacokinetics, the risks of dose-related toxicity, and ways to prevent it.
Over the subsequent 3 years (without any major change in overall patterns of drug choice), prospective surveillance revealed only 1 to 2 cases of phenytoin intoxication per year, 2 of which occurred in difficult-to-control patients with repeated emergency visits.
Acknowledgments
The authors thank Blaise F.D. Bourgeois, MD, for providing pharmacologic background information.
- Bupropion • Zyban
- Carbamazepine • Atretol, Depitol, Epitol, Tegretol
- Gabapentin • Neurontin
- Lamotrigine • Lamictal
- Nortriptyline • Aventyl, Pamelor
- Oxcarbazepine • Trileptal
- Phenytoin • Dilantin, Phenytek
- Tiagabine • Gabitril
- Topiramate • Topamax
- Valproic acid • Depakene, Depakote
- Vigabatrin • Sabril (available only in Canada)
Corresponding author
Thomas H. Glick, MD, 1493 Cambridge St., Cambridge, MA 02139. E-mail: thomas_glick@hms.harvard.edu
