phenytoin (Rx)

Frequency Not Defined

Drowsiness

Fatigue

Ataxia

Irritability

Headache

Restlessness

Slurred speech

Nervousness

Nystagmus

Dizziness

Vertigo

Dysarthria

Paresthesia

Rash

Pruritus

Gingival hyperplasia (pediatric patients)

Ataxia

Paradoxical seizure

Drug withdrawal seizure

Diplopia

Psychosis (high dose)

Toxic amblyopia

Encephalopathy

AV conduction disorder

Ventricular fibrillation

Nausea

Vomiting

Constipation

Diarrhea

Megaloblastic (folate-deficiency) anemia

Hypocalcemia

Hepatotoxicity

Hypertrichosis

Lymphadenopathy

Purple glove syndrome

Rash

Allergic reactions in the form of rash or, rarely, more serious forms (drug reaction with eosinophilia and systemic symptoms, or DRESS) or anaphylaxis

Purpuric rash

Toxic epidermal necrolysis

Bullous dermatosis

Coarsening of facial features

Periarteritis nodosa

Immunoglobulin abnormalities

Altered taste sensation, including metallic taste

Peyronie disease

Postmarketing Reports

Cerebellar atrophy

Contraindications

Hypersensitivity

Sinus bradycardia

Sinoatrial block

Second and third degree A-V block

Adams-Stokes syndrome

Concurrent use with delavirdine

History of prior acute hepatotoxicity attributable to phenytoin

Cautions

Erratically absorbed when administered IM, so this route should be used as a last resort

ONLY extended-release capsules should be used for once-daily dosing regimens

Decreased bone mineral density reported with chronic use

Rapid intravenous administration increases the risk of adverse cardiovascular reactions, including severe hypotension and cardiac arrhythmias; in pediatric patients, administer the drug at a rate not exceeding 1 to 3 mg/kg/min or 50 mg per minute, whichever is slower; although risk of cardiovascular toxicity increases with infusion rates above recommended infusion rate, these events have also been reported at or below recommended infusion rate

May cause fetal harm when administered to a pregnant woman

If early signs of dose-related CNS toxicity develop, serum levels should be checked immediately DRESS typically, although not exclusively, presents with fever, rash, lymphadenopathy, and/or facial swelling, in association with other organ system involvement

Phenytoin induces hepatic metabolizing enzymes, which may enhance metabolism of vitamin D and decrease vitamin D levels, leading to vitamin D deficiency, hypocalcemia, and hypophosphatemia; consideration should be given to screening with bone-related laboratory and radiological tests as appropriate and initiating treatment plans according to established guidelines

Use caution in cardiovascular disease, hypoalbuminemia, hepatic impairment, hypothyroidism, or seizures; because fraction of unbound phenytoin is increased in patients with renal or hepatic disease, or in those with hypoalbuminemia, the monitoring of phenytoin serum levels should be based on the unbound fraction in those patients

Associated with exacerbation of porphyria; exercise caution when used in patients with this disease

Extensively bound to serum plasma proteins and is prone to competitive displacement

Acute alcoholic intake may increase phenytoin serum levels, while chronic alcoholic use may decrease serum levels

Metabolized by hepatic cytochrome P450 enzymes CYP2C9 and CYP2C19, and is particularly susceptible to inhibitory drug interactions because it is subject to saturable metabolism; if metabolism inhibited, may produce significant increases in circulating phenytoin concentrations and enhance the risk of drug toxicity

Risk of hypotension and arrhythmias with infusion rates that exceed 50 mg/min in adults and 1-3 mg/kg/min (or 50 mg/min, whichever is slower) for pediatric patients

Hematologic effects reported with use including agranulocytosis, leukopenia, pancytopenia, neutropenia, thrombocytopenia, and anemias

Phenytoin is a potent inducer of hepatic drug-metabolizing enzymes

Increased risk of suicidal thoughts or behavior reported

May render OCPs ineffective because of induction of hepatic metabolism

Risk of gingival hyperplasia

If rash occurs including toxic epiderma necrolysis (TEN) and Stevens-Johnson syndrome (SJS reported; onset of symptoms is usually within 28 days, but can occur later; phenytoin should be discontinued at first sign of a rash, unless rash is clearly not drug-related; if signs or symptoms suggest SJS/TEN, discontinue therapy permanently and consider alternative therapy; evaluate for signs and symptoms of DRESS, also known as multiorgan hypersensitivity

Local toxicity (purple glove syndrome) that includes edema, discoloration, and pain distal to the site of injection has been reported following peripheral IV injection; may or may not be associated with extravasation; this syndrome may not develop for several days after injection

IV infusion not recommended by many due to poor solubility and risk of crystal formation; others state it is doable with right solvent and concentration

Good for automatic and reentrant arrhythmias, not PSVT's

Phenytoin was listed by the FDA as one of the drugs to monitor after having identified potential signs of serious risks or new safety information in the agency's Adverse Event Reporting System (AERS) database during the last 3 months of 2011

Drug interactions resulting in decreased effectiveness of nondepolarizing neuromuscular blocking agents have been reported

The FDA has not suggested that clinicians stop prescribing any drugs on the watch list or that patients stop taking them; it has, however, advised that patients with questions about watch-list drugs discuss them with their clinician

Antiepileptic drugs should not be abruptly discontinued because of the possibility of increased seizure frequency, including status epilepticus

Hyperglycemia, resulting from drug's inhibitory effect on insulin release reported; phenytoin may also raise serum glucose level in patients diabetes mellitus; use caution

Not indicated for seizures resulting from hypoglycemia or other metabolic causes; appropriate diagnostic procedures should be performed as indicated

Not effective for absence seizures; if tonic-clonic and absence seizures present, combined drug therapy needed

Sustained serum levels of phenytoin above optimal range may produce confusional states referred to as "delirium", "psychosis", or "encephalopathy", or rarely irreversible cerebellar dysfunction; accordingly, at the first sign of acute toxicity, plasma levels are recommended; dose reduction of phenytoin therapy is indicated if plasma levels are excessive; termination recommended if symptoms persist

The lethal dose in pediatric patients is not known; in adults, the lethal dose is estimated to be 2- 5 g; initial symptoms include nystagmus, ataxia, and dysarthria; other signs are tremor, hyperreflexia, lethargy, slurred speech, blurred vision, nausea, and vomiting; death is due to respiratory and circulatory depression

Phenytoin may decrease serum concentrations of thyroid hormone (T4 and T3), sometimes with an accompanying increase in thyroid-stimulating hormone (TSH), but usually in absence of clinical hypothyroidism

Cases of bradycardia and cardiac arrest reported, both at recommended phenytoin doses and levels, and in association with phenytoin toxicity; most reports of cardiac arrest occurred in patients with underlying cardiac disease

Mechanism of Action

Promotes Na+ efflux or decreases Na+ influx from membranes in motor cortex neurons; stabilizes neuronal membrane

Slows conduction velocity

Absorption

Bioavailability: May vary between different manufacturers; dependent on formulation

Onset: 1 week (PO); 2-24 hr (PO with loading dose); 0.5-1 hr (IV)

Peak plasma time: 1.5-3 hr (immediate-release); 4-12 hr (extended-release)

Distribution

Protein bound: 95% (adults); 85% (infants); 80% (neonates)

Vd: 0.6-0.7 L/kg (adults); 0.7 L/kg (children); 0.7-0.8 L/kg (infants); 0.8-0.9 L/kg (full-term neonate); 1-1.2 L/kg (premature neonate)

Metabolism

Metabolized by hepatic P450 enzyme CYP2C9

Metabolites: Inactive

Enzymes induced: CYP3A4

Elimination

Half-life: 22 hr (PO); 10-15 hr (IV)

Excretion: Urine

Pharmacogenomics

IV Incompatibilities

IV Compatibilities

IV Preparation

Load IV in 250 mL NS; monitor BP

Further dilution of IV infusion solution is controversial, and no consensus exists as to optimal concentration and length of stability

Stability is concentration and pH dependent

Based on limited clinical consensus, NS and LR are recommended diluents; dilutions of 1-10 mg/mL have been used and should be administered ASAP after preparation

IV/IM Administration

Administer slowly; no more than 50 mg/min in adults and no more than 1-3 mg/kg/min in pediatric patients

IM: Although approved for IM use, IM administration is not recommended, due to erratic absorption and pain on injection; fosphenytoin may be considered

IV: IV infusion not recommended

Storage

Store intact vials at room temperature; protect from freezing

If refrigerated, ppt forms, but dissolves on standing at room temp; OK for use