Chapter 15: Phenytoin and Fosphenytoin

OVERVIEW OF PHENYTOIN

Phenytoin (5,5-diphenylimidazolidine-2,4-dione, referred to as diphenylhydantoin) is an anticonvulsant medication that was first discovered in 1908 by Heinrich Biltz at the University of Kiel in Germany. In the 1920s, Arthur Dox, a chemist in Parke-Davis, compounded diphenylhydantoin in search of a hypnotic agent. Because the drug was not a hypnotic, he shelved it as “inactive.” It was not until November 1936 that Tracy Putnam discovered the anticonvulsant activity of diphenylhydantoin, and in June 1938, Parke, Davis, and Company marketed sodium diphenylhydantoin (Dilantin^®). In the 1970s, the generic name of Dilantin^® was shortened to phenytoin.¹ Today, it is FDA-approved for the management of generalized tonic clonic (grand mal) seizures, complex partial seizures, and for the prevention of seizures after head trauma and neurosurgery.² Phenytoin also has multiple unlabeled indications including the management of trigeminal neuralgia, syndrome of inappropriate antidiuretic hormone (SIADH), torsade de pointes, and arrhythmias (as a Class IB antiarrhythmic). Topical phenytoin has also been used to heal multiple acute and chronic wounds.³ As an anticonvulsant, phenytoin works by increasing the efflux and decreasing the influx of sodium ions in cell membranes of the motor cortex during the generation of nerve impulses.²

DOSING

Phenytoin is available in multiple dosage forms including an injectable formulation, extended-release capsule, oral suspension, and chewable tablet (Table 15-1).² Intramuscular (IM) administration of phenytoin is not recommended due to its erratic absorption and pain on injection. If IM administration is required, fosphenytoin is preferred. Intravenously (IV), phenytoin may be administered by IV push or IV piggyback using a 0.22 micron filter. The filter is used to remove crystals and minimize the incidence of phlebitis. The maximum rate of administration is 50 mg/min in adults and 0.5–1 mg/kg/min in neonates due to the risk of hypotension, as noted in a boxed warning in the drug package insert. In elderly or patients with preexisting cardiovascular conditions, phenytoin may be administered more slowly at 20 mg/minute.⁴ It must be noted that the oral suspension and chewable tablets contain 8 percent more phenytoin than the other formulations (92 mg of phenytoin base is equivalent to 100 mg of phenytoin sodium). Therefore, when patients are being switched from one dosage formulation to another, dosage adjustments and closer serum monitoring are recommended.^2,4 The recommended dose for adult patients in status epilepticus is 15–20 mg/kg. For maintenance doses, adults may be loaded at 15–20 mg/kg. Due to the rate-limited gastrointestinal (GI) absorption of phenytoin, no more than 400 mg should be administered at a time. Hence, in order to ensure complete absorption and a decrease in GI side effects, a 1,000 mg loading dose may be administered in three divided doses at 400 mg, 300 mg, and 300 mg every two hours. A target level is achieved within 6–10 hours. The maintenance dose is 300 mg/day or 5–6 mg/kg/day in ...