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, exfoliative, or purpuric dermatitis

Coarsening of facial features

Periarteritis nodosa

Immunoglobulin abnormalities

Altered taste sensation, including metallic taste

Peyronie disease

IV >50 mg/min

• CNS depression
• Cardiovascular collapse
• Hypotension

Rare

• Dyskinesia
• Ophthalmoplegia
• Nephrotoxicity
• Stevens-Johnson syndrome
• Lupus erythematosus
• Rickets
• Osteomalacia

Postmarketing Reports

Cerebellar atrophy

Angioedema

Generalized exanthematous pustulosis

Urticaria

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

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

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

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

Angioedema reported with phenytoin and fosphenytoin; discontinue immediately if symptoms of angioedema (eg, facial, perioral, or upper airway swelling) occur

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

Patients with decreased CYP2C9 function

• Patients who are intermediate or poor metabolizers of CYP2C9 substrates (eg, *1/*3, *2/*2, *3/*3) may exhibit increased phenytoin serum concentrations compared to patients who are normal metabolizers (eg, *1/*1); patients who are known to be intermediate or poor metabolizers may ultimately require lower doses to maintain similar steady-state concentrations compared to normal metabolizers
• In patients who are known to be carriers of the decreased function CYP2C9*2 or *3 alleles (intermediate and poor metabolizers), consider starting at the low end of the dosage range and monitor serum concentrations to maintain total phenytoin concentrations of 10 to 20 mcg/mL; if early signs of dose-related central nervous system (CNS) toxicity develop, serum concentrations should be checked immediately

Severe cutaneous reactions

• Can cause severe cutaneous adverse reactions (SCARs), which may be fatal
• Reported reactions include toxic epidermal necrolysis (TEN), Stevens-Johnson syndrome (SJS), acute generalized exanthematous pustulosis (AGEP), and Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)
• Onset is usually within 28 days, but can occur later
• Discontinue at the first sign of a rash, unless the rash is clearly not drug-related
• If signs or symptoms suggest a severe cutaneous adverse reaction, do not resume drug; consider alternant therapy
• Studies in patients of Chinese ancestry have found a strong association between risk of developing SJS/TEN and the presence of HLA-B*1502, an inherited allelic variant of the HLA B gene in patients taking carbamazepine
• Limited evidence suggests that HLA-B*1502 or CYP2C9*3 may also be a risk factor for the development of SJS/TEN in patients taking other antiepileptic drugs

• DRESS

  • DRESS, also known as multiorgan hypersensitivity, reported in patients taking antiepileptic drugs, including phenytoin and fosphenytoin
  • Some of these events have been fatal or life-threatening
  • DRESS typically, although not exclusively, presents with fever, rash, lymphadenopathy, and/or facial swelling, in association with other organ system involvement (eg, hepatitis, nephritis, hematological abnormalities, myocarditis, or myositis sometimes resembling an acute viral infection); eosinophilia is often present
  • Early manifestations of hypersensitivity (eg, fever or lymphadenopathy) may be present even though rash is not evident
  • If such signs or symptoms are present, evaluate patient immediately; discontinue drug if unable to confirm other etiology for the rash

Pregnancy: Pregnancy exposure registry that monitors pregnancy outcomes in women exposed to antiepileptic drugs (AEDs), such as phenytoin, during pregnancy is available; pregnant patients taking should enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry by calling the toll free number 1-888-233-2334; it must be done by patients themselves; Information on the registry can also be found at the website http://www.aedpregnancyregistry.org/

An increased incidence of major malformations (such as orofacial clefts and cardiac defects) and abnormalities characteristic of fetal hydantoin syndrome (dysmorphic skull and facial features, nail and digit hypoplasia, growth abnormalities [including microcephaly], and cognitive deficits) reported among children born to epileptic women who took phenytoin alone or in combination with other antiepileptic drugs during pregnancy

An increase in seizure frequency may occur during pregnancy; periodic measurement of plasma phenytoin concentrations may be valuable to make appropriate dosage adjustments; postpartum restoration of original dosage will probably be indicated

Consider vitamin K supplementation for 1 month before birth

Lactation: Phenytoin is secreted in human milk; developmental and health benefits of breastfeeding should be considered along with mother’s clinical need for therapy and any potential adverse effects on breastfed infant from phenytoin or from underlying maternal condition

Pregnancy Categories

A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA: Information not available.

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

HLA variants

• Patients with HLA-B*1502 with are more likely to have a severe dermatologic reaction (eg, toxic epidermal necrolysis, Stevens-Johnson syndrome) when taking phenytoin
• This allele occurs almost exclusively in patients with ancestry across broad areas of Asia, including Han Chinese, Filipinos, Malaysians, South Asian Indians, and Thais

Epoxide genotypes

• Maternal epoxide (EPHX1) genotypes 113*H and 139*R are associated with risk of fetal hydantoin syndrome among pregnant women taking phenytoin
• Increased levels of the reactive epoxide metabolites by either inhibiting the detoxification of these metabolites by epoxide hydrolase or by increasing conversion to epoxide metabolites by inducing CYP3A4, 2C9, or 2C19

Genetic testing laboratories (for HLA variants)

• Kashi Clinical Laboratories (www.kashilab.com)
• LabCorp (http://www.labcorp.com/)
• Specialty Laboratories (http://www.specialtylabs.com)
• Quest (http://www.questdiagnostics.com)

IV Incompatibilities

Solution

• D5/NS
• D5W
• LR
• 1/2NS
• NS(?)

Additive

• Amikacin
• Bretylium
• Dobutamine
• Hydroxyzine
• Insulin (regular)
• Levorphanol, lidocaine, lincomycin
• Meperidine, metaraminol, morphine sulfate
• Nitroglycerin, norepinephrine
• Pentobarbital, procaine
• Streptomycin

Syringe

• Hydromorphone
• Sufentanil

Y-site

• Ampho B cholesteryl sulfate, ciprofloxacin, clarithromycin, diltiazem, enalaprilat, fenoldopam, fentanyl, gatifloxacin, heparin, heparin/hydrocortisone, hydromorphone, linezolid, methadone, morphine sulfate, KCl, propofol, sufentanil, theophylline, vitamins B/C

IV Compatibilities

Additive

• Verapamil

Y-site

• Esmolol
• Famotidine
• Fluconazole
• Foscarnet
• Tacrolimus

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