Preventing Phenytoin Intoxication: Safer Use of a Familiar Anticonvulsant
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Applied Evidence N EW R ESEARCH F INDINGS T HAT A RE C HANGING C LINICAL P RACTICE Preventing phenytoin intoxication: Safer use of a familiar anticonvulsant Thomas H. Glick, MD, Tom P.Workman, MD, and Slava V. Gaufberg, MD Cambridge Health Alliance, Cambridge, Mass; Harvard Medical School, Boston, Mass Practice recommendations ■ Safe practice for initiating or adjusting a maintenance dosage should include patient ■ To load phenytoin initially or to add a education and close follow-up (C). supplemental load, use this formula: for each µg/mL desired increase in the phenytoin serum level, increase the espite the introduction of new anticonvul- loading dose by 0.75 mg/kg (C). sant drugs, phenytoin is still a first-line medication for common types of epileptic ■ Measure the peak serum level shortly D seizures, particularly those caused by focal brain after loading—30 to 60 minutes or more lesions.1–4 Available in parenteral and oral form, after giving intravenous phenytoin, phenytoin (or its pro-drug, fosphenytoin) is widely 2 hours or more after intravenous used. An estimated 873,000 prescriptions for fosphenytoin, 4 hours or more after phenytoin were issued during office visits in 2001.5 intramuscular fosphenytoin, and 16–24 Phenytoin carries a special risk of dose-related hours after accelerated oral loading (C). toxicity, due to its saturation (zero-order) phar- ■ The daily maintenance dose (mg/kg/d) macokinetics: serum levels often rise much ordinarily needed to achieve a specified more than would ordinarily be expected after serum level or maintain it after loading is initiating or increasing a maintenance dose. calculated thus: (8 x target serum level) / This predicts a vulnerability to toxicity, but does not predict exactly when this will occur in the (6 + target serum level) (C). individual. The risk of toxicity can be minimized, however, by applying practical dosing and monitoring strategies based on the understanding of pheny- toin pharmacokinetics, and by educating From Department of Medicine, Cambridge Health Alliance, and patients appropriately. Department of Neurology, Harvard Medical School (T.H.G.); Department of Emergency Medicine, Cambridge Health Alliance, and Division of Emergency Medicine, Harvard Medical School ■ PATIENTS AT RISK: (T.P.W.); and Department of Emergency Medicine, Cambridge THE SCOPE OF THE PROBLEM Health Alliance, and Division of Emergency Medicine, Harvard Extrapolating from the more than 5000 hospitals Medical School (S.V.G.). Corresponding author: Thomas H. 6 Glick, MD, 1493 Cambridge St., Cambridge, MA 02139. in the US to our experience in an urban commu- E-mail: [email protected] nity hospital, we estimate there may be as many MARCH 2004 / VOL 53, NO 3 · The Journal of Family Practice 197 PREVENTING PHENYTOIN INTOXICATION as 25,000 cases of phenytoin intoxication pre- Phenytoin Loading Formula senting annually to emergency departments or resulting in hospitalization in the United States. For each increase of 1 point (1 µg/mL or mg/L) in the phenytoin serum level, increase the loading In 1 study, a tertiary hospital recorded phenytoin dose by 0.75 mg/kg. intoxication from all causes at a rate of 1 inpatient admission per month over a 10-year period.7 Another study at a major hospital found To load initially, or to add a supplemental load 143 instances of phenytoin levels >25 µg/mL in to increase an insufficient phenytoin level, the 1 year; 86% of 120 studied cases were toxic, rep- following formula based on a distribution constant resenting 33% of all adverse drug reactions for phenytoin indicates the amount of drug need- reported.8 Thus, evidence points to a substantial ed to raise the level by a specified amount.9 problem with patient safety nationwide. Use the loading formula. The peak serum Adverse drug events like phenytoin intoxica- level of phenytoin after intravenous loading is a tion increase morbidity, causing such injuries as function of the drug’s distribution in the body and falls due to ataxia and resulting in expenses of is independent of the pharmacokinetics of elimi- office or emergency department visits and hos- nation. Subsequent metabolism, which may be pitalization. While no prescription strategy, sys- affected by other drugs or impairments (eg, liver tem of monitoring, or “safety net” is likely to disease), will affect elimination of the loaded drug eliminate phenytoin mishaps, an informed and but not ordinarily the calculated loading dose. active approach to therapeutic management can Overloading phenytoin has been documented as a minimize instances of intoxication. cause of early toxicity.7 According to the formula above, a 60-kg patient with no detectable starting ■ ACTION POINTS AND SAFETY level and an (arbitrary) target serum level of 15 TIPS IN PHENYTOIN THERAPY µg/mL should need only 675 mg of phenytoin, and Safe therapy with phenytoin depends on observ- not the 1000 mg often administered. ing particular courses of action at 4 stages: This loading formula is also applicable to 1. Loading supplementary (“booster”) loading to reach a 2. Institution of a maintenance regimen higher serum level quickly, either because the 3. Adjustment of the regimen initial loading dose did not achieve the intended 4. Monitoring, follow-up, and patient education. level or because that level was inadequate to control seizures. In this context, simply increas- Loading ing the existing or planned daily maintenance Loading is indicated when the risk of seizures is dose raises the level too slowly. In addition, so great that adequate serum levels of the drug the increased maintenance dosage may be must be reached rapidly. Such situations would inappropriate if the cause of the low level is non- include status epilepticus; repeated new seizures compliance. A higher maintenance dose, under (excluding most withdrawal seizures, for exam- conditions of complete or improved compliance, ple); breakthrough seizures with a low anticon- probably will lead to toxicity. vulsant level; and a first seizure with a high like- Measure serum levels. A sound preventive lihood of repeating, as with a demonstrated focal approach10 is to measure the peak serum level brain lesion. Depending on the degree of urgency, shortly after loading11,12—one-half hour to 1 hour loading can be accomplished with intravenous or more after giving intravenous phenytoin, 2 phenytoin (at an infusion rate of no more than 50 hours or more after intravenous fosphenytoin, 4 mg/min), with intravenous or intramuscular fos- hours or more after intramuscular fosphenytoin, phenytoin, or with oral phenytoin. and 16 to 24 hours after accelerated oral loading. 198 MARCH 2004/ VOL 53, NO 3 · The Journal of Family Practice PREVENTING PHENYTOIN INTOXICATION While measuring a post-load serum level is not AppliTABLE 1 established as a standard of care, the rationale Preventing phenytoin is that a relatively high serum level forewarns of intoxication at loading increased risk of early intoxication because of a (independent of high starting point for maintenance therapy, and pharmacokinetics of elimination) a low level indicates greater vulnerability to seizures (Table 1). Toxicity risk Preventive action Complications Avoid excessive infusion rate Initial maintenance dosing of intravenous (maximum, 50 mg/min); monitor A useful maintenance dose formula yields the infusion blood pressure and ECG; assure good IV placement dose ordinarily needed to achieve a specified serum level or maintain it after loading:9 Overload Calculate dose by formula, best estimate of prior level Loading formula: to increase Initial maintenance dosing the phenytoin serum level by point (1 µg/mL or mg/L), the The daily maintenance dose in mg/kg/d= loading dose should be (8 x target serum level) 0.75 mg/kg. (6 + target serum level) Check post-load level: • Intravenous phenytoin: 1/2 hr to 1 hr or more For a target maintenance level of 15 µg/mL in a 60-kg adult, the dose would be 5.71 mg/kg/d • Intravenous fosphenytoin: 2 hr or more x 60 kg = 343 mg/d (which can guide selection • Intramuscular fosphenytoin: of a practical, starting dosage regimen, such as 4 hr or more 300 or 350 mg/d, or 5–6 mg/kg/d, as is often • Oral phenytoin: 16–24 hr recommended).13 This formula is more accurate than guessing at 5 mg/kg vs 6 mg/kg; increas- ingly, such formulas will be incorporated into cause or exacerbate toxicity. Consider obtaining a computerized dosing protocols, thus putting the free phenytoin level, commonly available by spe- advised dose only a click or 2 away. cific requisition, if clinical toxicity is suspected Even calculated dosages should be subject to despite total levels that do not suggest toxicity. modification by individual patient factors, Consultation or careful review of all potential including age, reliability, health status (such as metabolic interactions helps to ensure proper liver function), and potential medication inter- management in such cases. actions. Computerized protocols will help, but Adjusting dosage and the maintenance the uncertainty of individual responses14 simply level. Here is a practical guide16 for incremen- means that close symptomatic or serum moni- tally increasing the phenytoin maintenance toring must be implemented, while not overre- regimen (at steady state) for an adult: acting to isolated variations (Table 2).15 • serum level <7 µg/mL, increase daily mainte- Important caveat. Phenytoin is typically 90% nance dose by 100 mg protein-bound in the serum. Active free phenytoin • serum level of 7–11 µg/mL, increase by 50 mg