phenytoin

Absorption: Absorbed slowly from the GI tract. Bioavailability differs among products; the Dilantin and Phenytek preparations are considered to be "extended" products. Other products are considered to be prompt release.

Distribution: Distributes into CSF and other body tissues and fluids. Enters breast milk; crosses the placenta, achieving similar maternal/fetal levels. Preferentially distributes into fatty tissue.

Protein Binding: Adults 90–95%; ↓ protein binding in neonates (up to 20% free fraction available), infants (up to 15% free), and patients with hyperbilirubinemia, hypoalbuminemia, severe renal dysfunction or uremia.

Metabolism/Excretion: Mostly metabolized by the liver via the CYP2C9 isoenzyme, and to a lesser extent by the CYP2C19 isoenzyme; the CYP2C9 isoenzyme exhibits genetic polymorphism (intermediate or poor metabolizers may have significantly ↑ phenytoin concentrations and an ↑ risk of adverse reactions); minimal amounts excreted in the urine.

Half-Life: 22 hr (range 7–42 hr).

Time/Action Profile ⬆ ⬇

(anticonvulsant effect)

ROUTE	ONSET	PEAK	DURATION
PO	2–24 hr (1 wk)*	1.5–3 hr	6–12 hr
PO-ER	2–24 hr (1 wk)	4–12 hr	12–36 hr
IV	0.5–1 hr (1 wk)	rapid	12–24 hr

*() = time required for onset of action without a loading dose.

Contraind./Precautions ⬆ ⬇

Contraindicated in:

Hypersensitivity;
Hypersensitivity to propylene glycol (phenytoin injection only);
History of hepatotoxicity related to phenytoin;
Alcohol intolerance (phenytoin injection and liquid only);
Sinus bradycardia, sinoatrial block, 2nd- or 3rd-degree heart block, or Stokes-Adams syndrome (phenytoin injection only);
OB: Pregnancy ( risk of congenital anomalies; risk of hemorrhage in newborn if used at term).

Use Cautiously in:

All patients (may ↑ risk of suicidal thoughts/behaviors);
Hepatic or renal disease (↑ risk of adverse reactions; dose reduction recommended for hepatic impairment);
Severe cardiac or respiratory disease (use of IV phenytoin may result in an ↑ risk of serious adverse reactions);
Cardiac disease (↑ risk of cardiac arrest or bradycardia);
CYP2C9 intermediate or poor metabolizers (↑ risk of phenytoin toxicity);
Lactation: Use while breastfeeding only if potential maternal benefit justifies potential harm to infant;
Pedi: Suspension contains sodium benzoate, a metabolite of benzyl alcohol that can cause potentially fatal gasping syndrome in neonates;
Geri: Use of IV phenytoin may result in an risk of serious adverse reactions in older adults.

Patients positive for human leukocyte antigen (HLA) allele, HLA-B*1502 allele or carriers of CYP2C9*3 variant (unless benefits clearly outweigh the risks) (↑ risk of serious skin reactions).

Adv. Reactions/Side Effects ⬆ ⬇

CV: hypotension (↑ with IV phenytoin), bradycardia, CARDIAC ARREST, tachycardia

Derm: hypertrichosis, rash, ACUTE GENERALIZED EXANTHEMATOUS PUSTULOSIS, DRUG REACTION WITH EOSINOPHILIA AND SYSTEMIC SYMPTOMS (DRESS), exfoliative dermatitis, pruritus, purple glove syndrome, STEVENS-JOHNSON SYNDROME (SJS), TOXIC EPIDERMAL NECROLYSIS (TEN)

EENT: diplopia, nystagmus

GI: gingival hyperplasia, nausea, constipation, drug-induced hepatitis, HEPATIC FAILURE, vomiting

Hemat: AGRANULOCYTOSIS, APLASTIC ANEMIA, leukopenia, lymphadenopathy, megaloblastic anemia, pure red cell aplasia, thrombocytopenia

MS: osteomalacia, osteoporosis

Neuro: ataxia, agitation, confusion, dizziness, drowsiness, dysarthria, dyskinesia, extrapyramidal syndrome, headache, insomnia, SUICIDAL THOUGHTS, vertigo, weakness.

Misc: ANGIOEDEMA, fever

Interactions ⬆ ⬇

Drug-drug:

Acute ingestion of alcohol, amiodarone, benzodiazepines, capecitabine, chloramphenicol, chlordiazepoxide, cimetidine, disulfiram, estrogens, ethosuximide, felbamate, fluconazole, fluorouracil, fluoxetine, fluvastatin, fluvoxamine, halothane, isoniazid, itraconazole, ketoconazole, methylphenidate, miconazole, oxcarbazepine, omeprazole, phenothiazines, salicylates, sertraline, sulfonamides, trazodone, voriconazole, and warfarin may ↑ levels.
Chronic ingestion of alcohol, barbiturates, carbamazepine, diazepam, diazoxide, fosamprenavir, nelfinavir, rifampin, ritonavir, sucralfate, theophylline, and vigabatrin may ↓ levels.
May ↓ the effects of albendazole, amiodarone, apixaban, atorvastatin, benzodiazepines, carbamazepine, clozapine, cyclosporine, dabigatran, digoxin, edoxaban, efavirenz, estrogens, felbamate, fluvastatin, lacosamide, lamotrigine, lopinavir/ritonavir, methadone, mexiletine, nelfinavir, nifedipine, nimodipine, nisoldipine, oxcarbazepine, oral contraceptives, quetiapine, quinidine, rifampin, ritonavir, rivaroxaban, simvastatin, tacrolimus, theophylline, ticagrelor, topiramate, verapamil, and warfarin.
IV phenytoin and dopamine may cause additive hypotension.
Additive CNS depression with other CNS depressants, including alcohol, antihistamines, antidepressants, opioids, and sedative/hypnotics.
Antacids may ↓ absorption of orally administered phenytoin.
↑systemic clearance of methotrexate, which has been associated with a worse event free survival; phenytoin use is not recommended in children undergoing chemotherapy for acute lymphocytic leukemia.
May ↑ risk of hyperammonemia when used with valproate.

Drug-Natural Products:

St. John's wort may ↓ levels

Phenytoin may ↓ absorption of folic acid.
Concurrent administration of enteral tube feedings may ↓ phenytoin absorption.
Folic acid may ↓ levels

Route/Dosage ⬆ ⬇

IM administration is not recommended due to erratic absorption and pain on injection. Oral route should be used whenever possible.

Anticonvulsant

PO (Adults ): Loading dose of 15–20 mg/kg as extended capsules in 3 divided doses given every 2–4 hr; maintenance dose 5–6 mg/kg/day given in 1–3 divided doses; usual dosing range = 200–1200 mg/day.
PO (Children 10–16 yr): 6–7 mg/kg/day in 2–3 divided doses.
PO (Children 7–9 yr): 7–8 mg/kg/day in 2–3 divided doses.
PO (Children 4–6 yr): 7.5–9 mg/kg/day in 2–3 divided doses.
PO (Children 0.5–3 yr): 8–10 mg/kg/day in 2–3 divided doses.
PO (Neonates up to 6 mo): 5–8 mg/kg/day in 2 divided doses, may require every 8 hr dosing.
IV (Adults ): Status epilepticus loading dose: 15–20 mg/kg. Rate not to exceed 25–50 mg/min. Maintenance dose: same as PO dosing above.
IV (Children ): Status epilepticus loading dose: 15–20 mg/kg at 1–3 mg/kg/min. Maintenance dose: same as PO dosing above.

Antiarrhythmic

IV (Adults ): 50–100 mg every 10–15 min until arrhythmia is abolished, or a total of 15 mg/kg has been given, or toxicity occurs.
PO (Adults ): Loading dose: 250 mg 4 times daily for 1 day, then 250 mg twice daily for 2 days, then maintenance at 300–400 mg/day in divided doses 1–4 times/day.
IV (Children ): 1.25 mg/kg every 5 min, may repeat up to total loading dose of 15 mg/kg. Maintenance dose: 5–10 mg/kg/day in 2–3 divided doses IV or PO.

Availability ⬆ ⬇

(Generic available)

Capsules: 30 mg; 100 mg; 200 mg; 300 mg
Chewable tablets: 50 mg
Oral suspension: 30 mg/5 mL; 100 mg/4 mL; 125 mg/5 mL
Solution for injection: 50 mg/mL

Assessment ⬆ ⬇

Assess mental status (orientation, mood, behavior) before and periodically during therapy. Monitor closely for notable changes in behavior that could indicate the emergence or worsening of suicidal thoughts or behavior or depression.
Assess oral hygiene. Vigorous cleaning beginning within 10 days of initiation of phenytoin therapy may help control gingival hyperplasia.
- Assess patient for phenytoin hypersensitivity syndrome (fever, skin rash, lymphadenopathy, angioedema). Rash usually occurs within the first 2 wk of therapy. Hypersensitivity syndrome usually occurs at 3–8 wk but may occur up to 12 wk after initiation of therapy. May lead to renal failure, rhabdomyolysis, or hepatic necrosis; may be fatal.
- Observe patient for development of rash. Discontinue phenytoin at the first sign of skin reactions. Serious adverse reactions such as exfoliative, purpuric, or bullous rashes or the development of lupus erythematosus, SJS, or TEN preclude further use of phenytoin or fosphenytoin. SJS and TEN are significantly more common in patients with a particular HLA allele, HLA-B*1502 (occurs almost exclusively in patients with Asian ancestry, including Han Chinese, Filipinos, Malaysians, South Asian Indians, and Thais). Avoid using phenytoin or fosphenytoin as alternatives to carbamazepine for patients who test positive. If less serious skin eruptions (measles-like or scarlatiniform) occur, phenytoin may be resumed after complete clearing of the rash. If rash reappears, further use of fosphenytoin or phenytoin should be avoided.
Monitor for signs and symptoms of DRESS (fever, rash, lymphadenopathy, and/or facial swelling), associated with involvement of other organ systems (hepatitis, nephritis, hematologic abnormalities, myocarditis, myositis) during therapy. May resemble an acute viral infection. Eosinophilia is often present. Discontinue therapy if signs occur.
Seizures: Assess location, duration, frequency, and characteristics of seizure activity. EEG may be monitored periodically during therapy.
- Monitor BP, ECG, and respiratory function continuously during administration of IV phenytoin and throughout period when peak serum phenytoin levels occur (15–30 min after administration).
Arrhythmias: Monitor ECG continuously during treatment of arrhythmias.

Lab Test Considerations:

Monitor CBC, serum calcium, albumin, and hepatic function tests prior to and monthly for the first several mo, then periodically during therapy.
- May cause ↑ serum alkaline phosphatase, GGT, and glucose levels.
- Monitor serum folate concentrations periodically during prolonged therapy.

Toxicity and Overdose:

Monitor serum phenytoin levels routinely. Therapeutic blood levels are 10–20 mcg/mL (8–15 mcg/mL in neonates) in patients with normal serum albumin and renal function. In patients with altered protein binding (neonates, patients with renal failure, hypoalbuminemia, acute trauma), free phenytoin serum concentrations should be monitored. Therapeutic serum free phenytoin levels are 1–2 mcg/mL.
- Progressive signs and symptoms of phenytoin toxicity include nystagmus, ataxia, confusion, nausea, slurred speech, and dizziness.

Implementation ⬆ ⬇

Implement seizure precautions.
- When transferring from phenytoin to another anticonvulsant, dose adjustments are made gradually over several wk.
- When substituting fosphenytoin for oral phenytoin therapy, the same total daily dose may be given as a single dose. Unlike parenteral phenytoin, fosphenytoin may be given safely by the IM route.
PO: Administer with or immediately after meals to minimize GI irritation. Shake liquid preparations well before pouring. Use a calibrated measuring device for accurate dose. Chewable tablets must be crushed or chewed well before swallowing. Capsules may be opened and mixed with food or fluids for patients with difficulty swallowing. To prevent direct contact of alkaline drug with mucosa, have patient swallow a liquid first, follow with mixture of medication, then follow with a full glass of water or milk or with food.
- If patient is receiving enteral tube feedings, 2 hr should elapse between feeding and phenytoin administration. If phenytoin is administered via nasogastric tube, flush tube with 2–4 oz water before and after administration.
- Do not interchange chewable phenytoin tablets with phenytoin sodium capsules; they are not bioequivalent.
- Capsules labeled "extended" may be used for once-a-day dose; those labeled "prompt" may result in toxic serum levels if used for once-a-day dose.

IV Administration:

IV: Slight yellow color will not alter solution potency. If refrigerated, may form precipitate, which dissolves after warming to room temperature. Discard solution that is not clear.
- To prevent precipitation and minimize local venous irritation, follow infusion with 0.9% NaCl through the same needle or catheter. Avoid extravasation; phenytoin is caustic to tissues; may lead to purple glove syndrome. Monitor infusion site closely.
Administer undiluted.
Rate: Administer at a rate not to exceed 50 mg over 1 min in adults or 1–3 mg/kg/min in neonates. Rapid administration may result in severe hypotension, cardiovascular collapse, or CNS depression.
Intermittent Infusion: Diluent: Administer by mixing with no more than 50 mL of 0.9% NaCl.Concentration: 1–10 mg/mL. Administer immediately following admixture. Use tubing with a 0.45- to 0.22-micron in-line filter.
Rate: Complete infusion within 1 hr at a rate not to exceed 50 mg/min. In patients who may develop hypotension, patients with cardiovascular disease, or geriatric patients maximum rate of 25 mg/min [may be as low as 5–10 mg/min]. Maximum rate in neonates is 1–3 mg/kg/min. Monitor cardiac function and BP throughout infusion.
Do not admix with other solutions or medications, especially dextrose, because precipitation will occur.

Patient/Family Teaching ⬆ ⬇

Instruct patient to take phenytoin as directed, at the same time each day. If a dose is missed from a once-a-day schedule, take as soon as possible and return to regular dosing schedule. If taking several doses a day, take missed dose as soon as possible within 4 hr of next scheduled dose; do not double doses. Consult health care professional if doses are missed for 2 consecutive days. Abrupt withdrawal may lead to status epilepticus. Advise patient to read Medication Guide before starting therapy and with each Rx refill in case of changes.
May cause drowsiness or dizziness. Caution patient to avoid driving or other activities requiring alertness until response to medication is known. Do not resume driving until health care professional gives clearance based on control of seizure disorder.
Caution patient to avoid alcohol and CNS depressants. Advise patient to notify health care professional of all Rx or OTC medications, vitamins, or herbal products being taken and to consult with health care professional before taking other medications and alcohol.
Instruct patient on importance of maintaining good dental hygiene and seeing dentist frequently for teeth cleaning to prevent tenderness, bleeding, and gingival hyperplasia. Starting oral hygiene program within 10 days of starting phenytoin therapy may minimize growth rate and severity of gingival enlargement. Patients under 23 yr of age and those taking doses >500 mg/day are at increased risk for gingival hyperplasia.
Advise patient that brands of phenytoin may not be equivalent. Check with health care professional if brand or dose form is changed.
Advise diabetic patients to monitor blood glucose carefully and to notify health care professional of significant changes.
Instruct patient to notify health care professional of medication regimen prior to treatment or surgery.
Advise patient not to take phenytoin within 2–3 hr of antacids.
Advise patient to carry identification describing disease process and medication regimen at all times.
Instruct patients that behavioral changes, skin rash, facial or perioral, swelling, shortness of breath, fever, sore throat, mouth ulcers, easy bruising, petechiae, unusual bleeding, abdominal pain, chills, pale stools, dark urine, jaundice, severe nausea or vomiting, drowsiness, slurred speech, unsteady gait, swollen glands, or persistent headache should be reported to health care professional immediately. Advise patient and family to notify health care professional if thoughts about suicide or dying, attempts to commit suicide; new or worse depression; new or worse anxiety; feeling very agitated or restless; panic attacks; trouble sleeping; new or worse irritability; acting aggressive; being angry or violent; acting on dangerous impulses; an extreme increase in activity and talking; other unusual changes in behavior or mood occur.
Rep: May cause fetal harm. Advise female patients to use an additional nonhormonal method of contraception during therapy and until next menstrual period. Instruct patient to notify health care professional if pregnancy is planned or suspected. Encourage patients who become pregnant to enroll in the North American Antiepileptic Drug Pregnancy Registry that monitors pregnancy outcomes in women exposed to antiepileptic drugs, such as phenytoin, during pregnancy by calling 1-888-233-2334 or on the web at www.aedpregnancyregistry.org. Enrollment must be done by patients themselves. Monitor serum phenytoin concentrations periodically during pregnancy to determine need for dose adjustments. May cause depletion of vitamin K–dependent clotting factors in newborns. Administer vitamin K to mother before delivery and to neonate after birth to prevent bleeding related to decreased levels of vitamin K–dependent clotting factors which may occur in newborns exposed to phenytoin in utero.
Emphasize the importance of routine exams to monitor progress. Patient should have routine physical exams, especially monitoring skin and lymph nodes, and EEG testing.

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Pronunciation ⬇

Classifications ⬆ ⬇

Indications ⬆ ⬇

Action ⬆ ⬇

Pharmacokinetics ⬆ ⬇