Navigation

phenytoin (Dilantin, Dilantin 125, Phenytek)

 

Classes: Antidysrhythmics, Ib; Anticonvulsants, Hydantoins

Dosing and uses of Dilantin, Phenytek (phenytoin)

 

Adult dosage forms and strengths

capsule, immediate-release

  • 30mg
  • 100mg

capsule, extended-release

  • 100mg
  • 200mg
  • 300mg

tablet, chewable

  • 50mg

oral suspension

  • 125mg/5mL

injectable solution

  • 50mg/mL

 

Seizures

Status epilepticus

  • Load 10-15 mg/kg or 15-20 mg/kg at 25-50 mg/min, THEN
  • Maintenance: 100 mg IV/PO q6-8hr PRN
  • Administer IV slowly; not to exceed 50 mg/min

Anticonvulsant

  • Tablet
    • 100 mg PO TID
    • Maintenance: 300-400 mg/day; increase to 600 mg/day if necessary
    • May adjust dose no sooner than 7-10 day intervals when indicated
  • Suspension
    • 125 mg PO TID, initially
    • Increase to 625 mg/day if necessary
    • May adjust dose no sooner than 7-10 day intervals when indicated
  • Extended release
    • Loading dose: 1 g divided into 3 doses (400, 300, 300 mg) administered at 2 hr intervals; initiate dosage 24 hr after loading dose
    • Loading dose not for administration to patients with a history of renal or hepatic disease; reserve for patients who require rapid steady serum levels, when IV administration not desirable, and for patients in a clinic or hospital setting where phenytoin levels can be closely monitored
    • Treatment (naive): 100 mg PO TID initially
    • May adjust dose no sooner than 7-10 day intervals
  • Therapeutic range: 10-20 mcg/L (total) or 1-2 mcg/L free drug

 

Pediatric dosage forms and strengths

capsule, immediate-release

  • 30mg
  • 100mg

capsule, extended-release

  • 100mg
  • 200mg
  • 300mg

tablet

  • 50mg

oral suspension

  • 125mg/5mL

injectable solution

  • 50mg/mL

 

Status Epilepticus

15-20 mg/kg IV in single or divided dose; if necessary may administer additional dose of 5-10 mg/kg 10 min after loading dose

Maintenance: 4-8 mg/kg/day IV divided twice daily

 

Control of Tonic-Clonic and Complex Partial Seizures

Initial dosage

  • Neonates: 5 mg/kg/day in 2 divided doses
  • 6 months to 16 years: 5 mg/kg/day in 2-3 divided doses

Neonates (<28 days)

  • Initial: 5-8 mg/kg/day IV/PO divided q8-12hr

Age-based maintenance dose

  • 6 months-4 years: Usual range, 8-10 mg/kg/day IV/PO divided two to three times daily
  • 4-7 years: Usual range, 7.5-9 mg/kg/day IV/PO divided two to three times daily
  • 7-10 years: Usual range, 7-8 mg/kg/day IV/PO divided two to three times daily
  • 10-16 years: Usual range, 6-7 mg/kg/day IV/PO divided two to three times daily

 

Anticonvulsant (Nonemergent)

Children and adolescents

Immediate release

  • Tablet and suspension
  • 5 mg/kg/day PO in 2-3 divided doses, initially; may make dose adjustments no sooner than 7-10 day intervals
  • Maintenance: 4-8 mg/kg/day PO; not to exceed 300 mg/day; higher doses may be considered in infant and young children (range: 8-10 mg/kg/day in divided doses)

Extended release

  • 5 mg/kg/day PO, initially in 2-3 equally divided doses; may adjust dose no sooner than 7-10-day intervals
  • Maintenance: 4-8 mg/kg/day PO not to exceed 300 mg/day

 

Dosing Considerations

<6 years: Potential toxic dose, 20 mg/kg

Therapeutic range: 10-20 mcg/L (total) or 1-2 mcg/L free drug

ALWAYS administer IV slowly; not to exceed 1-3 mg/kg/min

 

Dilantin, Phenytek (phenytoin) adverse (side) effects

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

IV >50 mg/min

  • CNS depression
  • Cardiovascular collapse
  • Hypotension

Rare

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

 

Warnings

Black box warnings

Cardiovascular risk associated with rapid infusion rates

  • 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
  • Careful cardiac monitoring is needed during and after IV administration
  • These events have also been reported at or below 50 mg/min
  • Reduce infusion rate or discontinuation may be needed

 

Contraindications

Hypersensitivity

Sinus bradycardia

Sinoatrial block

Second and third degree A-V block

Adams-Stokes syndrome

Concurrent use with delavirdine

 

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

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

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

 

Pregnancy and lactation

Pregnancy category: d

Prenatal exposure to phenytoin may increase the risks for congenital malformation and other adverse development outcomes; risk of fetal hydantoin syndrome

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: Excreted in breast milk; not recommended

 

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.

 

Pharmacology of Dilantin, Phenytek (phenytoin)

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 (https://www.labcorp.com/)
  • Specialty Laboratories (https://www.specialtylabs.com)
  • Quest (https://www.questdiagnostics.com)

 

Administration

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