CHAPTER 19 PHENYTOIN AND FOSPHENYTOIN Michael E. Winter

Phenytoin, a hydantoin-derivative anticonvulsant, is indicated for the treatment of tonic-clonic and complex partial seizures and for seizure prophylaxis following neurosurgery. Phenytoin also exhibits antiarrhythmic properties similar to those of lidocaine but is seldom if ever used as an antiarrhythmic.

USUAL DOSAGE RANGE IN ABSENCE OF CLEARANCE- ALTERING FACTORS Loading dose1-7 When a rapid therapeutic concentration is desired, a loading dose is recommended (Table 19-1). Because of the slow absorption characteristics of phenytoin, the loading dose is often administered by the intravenous (IV) route. The maximum IV infusion rate of phenytoin sodium injection is 0.5 mg/kg/min for neonates, 1 mg/kg/min for children and adolescents, and for adults, the maximum infusion rate is 50 mg/min. Fosphenytoin, administered as phenytoin equivalents (PE), has a maximum administration rate of 1.5 mg PE/kg/min for neonates, 3 mg PE/kg/min for children and adolescents, and for adults the maximum infusion rate is 150 mg PE/min. For children, adolescents, and adults, oral loading doses are usually given in 5 mg/kg increments every 2 hr until the total dose has been administered (Table 19-1). The usual adult dose is 1,000 mg (~15 mg/kg multiplied by 70 kg), given in three doses: 400-, 300-, and 300-mg doses, each separated by 2 hr.

TABLE 19-1. LOADING DOSES Age Loading Dose Neonates and infants (<1 yr) 15–20 mg/kg Children (1–<12 yr) 15–18 mg/kg Adolescents (≥12 yr), adults, and geriatrics 15–18 mg/kg

Maintenance dose1-3,8,9 In infants, children, and adolescents, the total daily dose (Table 19-2) is usually divided into equal doses and given at evenly spaced intervals of 6, 8, or 12 hr. In adults, the usual initial daily dose is 300 mg given once a day at bedtime (for the once-daily schedule, phenytoin sodium extended must be used).

TABLE 19-2. MAINTENANCE DOSES Age Maintenance Dosage

Neonates (<4 wk) 3–5 mg/kg/daya Infants (4 wk–<1 yr) 4–8 mg/kg/daya Children (1–<12 yr) 4–10 mg/kg/daya Adolescents (12–<18 yr) 4–8 mg/kg/daya Adults and geriatrics (≥18 yr) 4–7 mg/kg/day aUsually given in divided doses.

333 334 CLINICAL PHARMACOKINETICS

DOSAGE FORM AVAILABILITY1-3,10-16 Phenytoin is available in the acid or sodium salt form and as the phosphate ester prodrug (fosphenytoin) of phenytoin. The sodium salt has a salt fraction (S) of ~92% phenytoin (S = 0.92) and 8% sodium. Phenytoin sodium is available both IV and as a capsule. Phenytoin as the acid form is available as a suspension or chewable tablet (S = 1). Fosphenytoin is available only as an injectable dosage form that can be administered either IV or intramuscularly (IM). Fosphenytoin is labeled as milligrams of phenytoin equivalents (PE) of phenytoin sodium injection; therefore, the S factor for fosphenytoin PE to calculate the milligrams of acid phenytoin is 0.92. Phenytoin sodium injection contains propylene glycol, a cardiac depressant. The maximum recommended infusion rate is 50 mg/min for adults and 0.5 mg/kg/min for neonates and 1 mg/kg/min for older children is primarily due to this cardiac depressant. Patients receiving phenytoin sodium injection should be monitored for bradycardia, hypotension, and, if electrocardiogram is available, widened PR, QRS, or QT intervals as indications of myocardial depression. In most instances, the actual infusion rate is about ½ to ¼ of the usually recommended maximum. If phenytoin sodium injection is diluted prior to infusion, normal saline should be used as other IV diluents result in rapid precipitation. Fosphenytoin does not contain propylene glycol and, therefore, can be administered more rapidly (maximum recommended infusion rate for adults is 150 mg/min). However, bradycardia and hypotension can still occur and transient pruritus is relatively common. Therefore, cardiovascular monitoring is required and infusion rates of less than 150 mg/min should be considered. Fosphenytoin, although requiring refrigeration for storage, is more soluble than phenytoin for injection and when reconstituted can be prepared in either dextrose or saline solution. Even though fosphenytoin is probably a better parenteral product, with fewer side effects, some institutions may limit its use because it is somewhat more expensive. Daily doses of phenytoin injectable (fosphenytoin and IV sodium phenytoin) and oral acid phenytoin (chew tabs and suspension) should be divided. Phenytoin sodium extended may be dosed once daily; but in children, even if the extended product is used, the daily doses are often divided. In addition, to minimize phenytoin concentration fluctuations and potential gastrointestinal (GI) disturbances, single daily doses of phenytoin sodium extended greater than 6 mg/kg/day also may need to be divided. The suspension form requires complete dispersion and accurate volume delivery to ensure accurate dose administration. The suspension should be shaken vigorously prior to administration (1–2 min if the container has not been used for some time). IM administration of phenytoin sodium injection is not recommended. Although absorption following IM administration is probably complete, it is erratic due to precipitation at the injection site. Absorption of IM fosphenytoin appears to be complete with peak phenytoin concentrations occurring ~30 minutes after injection. However, the IV route is still preferred for fosphenytoin and phenytoin sodium injection when rapid achievement of phenytoin concentration is the goal (e.g., acute seizures or status epilepticus). Table 19-3 gives the available dosage forms.

GENERAL PHARMACOKINETIC INFORMATION

Absorption1,2,5,8,17-30 Although all dosage forms of phenytoin, including generic products, are assumed to have a bioavailability of 100%, phenytoin has capacity-limited metabolism; as a result, bioavailability studies are difficult to interpret. Unless the capacity-limited metabolism is carefully considered in the bioavailability analysis, drug products with the same fraction absorbed but having different rates of absorption can appear to have different bioavailabilities. In addition, because phenytoin is a weak acid with limited water solubility, its absorption is slow and peak concentrations are delayed for several hours following oral administration.