Phenytoin

Phenytoin is indicated for the treatment of tonic-clonic (grand mal) and psychomotor (temporal lobe) seizures.

The precise mechanism by which phenytoin exerts its therapeutic effect has not been established but is thought to involve the voltage-dependent blockade of membrane sodium channels resulting in a reduction in sustained high-frequency neuronal discharges.

• Adult starting dose in patients who have received no previous treatment is 5 mL three times daily, with dose adjustments as necessary, up to 25 mL daily. • Pediatric starting dose is 5 mg/kg/day in two to three equally divided doses, with dosage adjustments as necessary, up to a maximum of 300 mg daily. Maintenance dosage is 4 to 8 mg/kg/day. • Serum blood level determinations may be necessary for optimal dosage adjustments—the clinically effective serum total concentration is 10 to 20 mcg/mL (unbound phenytoin concentration is 1 to 2 mcg/mL).

Phenytoin is contraindicated in patients with: • A history of hypersensitivity to phenytoin, its inactive ingredients, or other hydantoins. Reactions have included angioedema. • A history of prior acute hepatotoxicity attributable to phenytoin. • Coadministration with delavirdine because of the potential for loss of virologic response and possible resistance to delavirdine or to the class of non-nucleoside reverse transcriptase inhibitors. • Hypersensitivity to phenytoin, its ingredients, or other hydantoins. • A history of prior acute hepatotoxicity attributable to phenytoin. • Coadministration with delavirdine

• Withdrawal Precipitated Seizure: May precipitate status epilepticus. Dose reductions or discontinuation should be done gradually. • Suicidal Behavior and Ideation: Monitor patients for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior. • Serious Dermatologic Reactions: Discontinue phenytoin at the first sign of a rash, unless the rash is clearly not drug-related. If signs or symptoms suggest SJS/TEN, use of this drug should not be resumed and alternative therapy should be considered. • Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/Multiorgan Hypersensitivity: If signs or symptoms of hypersensitivity are present, evaluate the patient immediately. Discontinue if an alternative etiology cannot be established. • Cardiac Effects: Bradycardia and cardiac arrest have been reported.

The following serious adverse reactions are described elsewhere in the labeling: • Withdrawal Precipitated Seizure, Status Epilepticus • Suicidal Behavior and Ideation • Serious Dermatologic Reactions • Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/Multiorgan Hypersensitivity • Hypersensitivity • Cardiac Effects • Angioedema • Hepatic Injury • Hematopoietic Complications • Effects on Vitamin D and Bone • Exacerbation of Porphyria • Teratogenicity and Other Harm to the Newborn • Hyperglycemia The following adverse reactions associated with the use of phenytoin were identified in clinical studies or postmarketing reports. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Phenytoin is extensively bound to plasma proteins and is prone to competitive displacement. Phenytoin is primarily metabolized by the hepatic cytochrome P450 enzyme CYP2C9 and to a lesser extent by CYP2C19 and is particularly susceptible to inhibitory drug interactions because it is subject to saturable metabolism. Inhibition of metabolism may produce significant increases in circulating phenytoin concentrations and enhance the risk of drug toxicity. Monitoring of phenytoin serum levels is recommended when a drug interaction is suspected. Phenytoin is a potent inducer of hepatic drug-metabolizing enzymes. Multiple drug interactions because of extensive plasma protein binding, saturable metabolism and potent induction of hepatic enzymes.

Store at 20° to 25°C (68° to 77°F), see USP controlled room temperature. Do not freeze. Protect from light.