Phenytoin
Phenytoin is a generic medication for the drug Dilantin infatabs:
Phenytoin medication comes in several different strengths; click on the strength you need to view prices from pharmacies competing to earn your business.
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Phenytoin 100 mg
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Phenytoin suspension 125mg/5mL
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Pharmacology
Pharmacokinetics
Following oral administration, phenytoin is slowly absorbed from the gastrointestinal tract. Absorption may be variable and sometimes incomplete. Dissolution is the rate-limiting step.
Phenytoin is slowly and erratically absorbed following i.m. administration due to precipitation of the drug at the injection site. Following absorption, the drug is rapidly distributed to all tissues. Peak serum drug concentrations are achieved between 3 and 12 hours after administration of an oral dose.
The plasma half-life in man after oral phenytoin administration averages 22 hours, with a range of 7 to 42 hours. Time to steady state is highly variable, ranging from 1 to 5 weeks. Therapeutic drug concentrations can be obtained in 1 to 2 hours when the drug is administered i.v. The clinically effective serum trough concentration is usually 40 to 80 µmol/L.
Phenytoin is greater than 90% protein bound. Free fraction may increase in patients with renal or hepatic failure and/or hypoalbuminemia. These patients are predisposed to toxicity, and free/unbound phenytoin levels may be helpful in their management. If free phenytoin levels are not readily available, the following equation can be used to correct for the presence of hypoalbuminemia in patients with creatinine clearance >0.17 mL/s:
| Cnorm = | Cobs | |
| (0.02)(Alb) + 0.1 | ||
| where Cnorm = | approximate phenytoin level adjusted for low albumin | |
| Cobs= | measured total phenytoin level | |
| Alb = | patient's albumin level (g/L). |
Phenytoin is metabolized by the hepatic microsomal isoenzyme CYP2C9 to an inactive metabolite 5-(p-hydroxyphenyl)-5-phenylhydantoin (HPPH), which undergoes enterohepatic circulation. Approximately 60 to 75% of the daily dose of the drug is excreted in the urine as the glucuronide. Other minor metabolites also appear in the urine. In therapeutic doses, approximately 1% is excreted unchanged in the urine; in toxic doses, up to 10% of the ingested drug may be excreted unchanged by the kidneys.
Phenytoin kinetics are nonlinear and saturable, resulting in highly variable concentrations with even minor dosage changes. The steady-state plasma concentration may double or triple from as little as a 10% increase in dose, possibly resulting in toxicity.
Indications
Phenytoin is used in the management of generalized tonic-clonic and simple or complex partial seizures, in the treatment and prevention of seizures during or following neurosurgery, and in the management of status epilepticus.
Phenytoin has also been used in the management of neuropathic pain and dermatologic conditions such as decubitous ulcers and epidermolysis bullosa.
Precautions
Drug Interactions
There are many drugs that may increase or decrease phenytoin levels or that phenytoin may affect. The most commonly occurring drug interactions are listed below.
When adding or deleting phenytoin from a patient's therapeutic regimen, pharmacotherapy must be monitored closely as dosage adjustment may be necessary. Serum level determinations of each drug are especially helpful when possible drug interactions are suspected.
Drugs that may increase phenytoin serum levels include: amiodarone, chloramphenicol, cimetidine, ciprofloxacin, erythromycin, fluconazole, fluoxetine, isoniazid, ketoconazole, methylphenidate, norfloxacin, omeprazole, phenylbutazone, salicylates, sulfonamides, trazodone, warfarin and acute alcohol ingestion.
Drugs that may decrease phenytoin levels include: carbamazepine, chronic alcohol abuse, diazoxide, rifampin and theophylline.
Drugs that may either increase or decrease phenytoin serum levels include: phenobarbital, valproic acid and sodium valproate. Similarly, the effect of phenytoin on phenobarbital, valproic acid and sodium valproate serum levels is unpredictable.
Drugs whose efficacy may be impaired by phenytoin include: corticosteroids, diazoxide, digitalis glycosides, doxycycline, estrogens, furosemide, itraconazole, levodopa, methadone, oral contraceptives, quinidine, theophylline, vitamin D and warfarin.
Phenytoin is an inducer of CYP1A2, 2C9, 2D6, 3A4 and 2B6, and may interact with drugs metabolized by these enzymes. For more information, see Cytochrome P450 Drug Interactions in the Clin-Info section.
Administration of phenytoin with sulcralfate, enteral feeds, antacids or calcium preparations should be separated by at least 3 hours to prevent a decrease in phenytoin absorption. Dosage adjustments may also be necessary.
Concurrent use of i.v. phenytoin with lidocaine or propranolol may produce additive cardiac depressant effects.
Although not a true drug interaction, tricyclic antidepressants may precipitate seizures in susceptible patients and phenytoin dosage may need to be adjusted.
Drug-Laboratory Test Interactions: Phenytoin may produce lower than normal values for dexamethasone or metyrapone tests. Phenytoin may cause increased serum levels of glucose and alkaline phosphatase. Like other inducers of hepatic microsomal enzymes, phenytoin administration will increase serum levels of gamma-glutamyl transferase (GGT).
Drug-Food Interactions: The presence of food may affect phenytoin absorption, but may also reduce its gastrointestinal side effects. Taking phenytoin with food on a consistent basis should minimize any food-associated fluctuations in bioavailability.
Phenytoin bioavailability can be significantly reduced in the presence of enteral nutrition products. Tube feeds should be held for 2 hours before and after phenytoin doses. See Dosage, Antiepileptic Dosage: Oral.
Lactation
If maternal levels are kept within therapeutic range, there is little risk of drug accumulation in the infant. Phenytoin is generally considered compatible with breast-feeding.
Children
AEDs, including phenytoin, may have adverse effects on behavior and cognition in children. Effects of phenytoin on behavior may include unsteadiness, involuntary movements, tiredness and alteration of emotional state. Effects of phenytoin on cognition may include deficits on neuropsychologic tests; impaired attention, problem-solving and visuomotor skills. Children treated with phenytoin and/or other antiepileptics should be closely monitored by clinicians, parents and teachers for changes in cognitive function, mood and behavior. If significant changes occur and another explanation is not obvious, the possibility that the antiepileptic is responsible should be considered. Dosage reduction or substitution of another AED may be necessary.
Pregnancy
See Warnings.
Supplied
Not currently available for CPhA monographs. Please consult individual product monographs.
Contraindications
Known hypersensitivity to hydantoin products. Because of its effect on ventricular automaticity, i.v. phenytoin is contraindicated in sinus bradycardia, sinoatrial block, second- and third-degree AV block without a functioning pacemaker, patients with Adams-Stokes syndrome.
Warnings
Occupational Hazards
Phenytoin may impair mental and/or physical abilities required for performance of hazardous tasks such as operating machinery or driving a motor vehicle.
Pregnancy
The majority of mothers on antiepileptic medication deliver normal infants. It is important to note that AEDs should not be discontinued in patients in whom the drug is administered to prevent major seizures because of the strong possibility of precipitating status epilepticus with attendant hypoxia and threat to life. In individual cases where the severity and frequency of the seizure disorder are such that the removal of medication does not pose a serious threat to the patient, discontinuation of the drug may be considered prior to and during pregnancy, although it cannot be said with any confidence that even minor seizures do not pose some hazard to the developing embryo or fetus. The prescribing physician should weigh these considerations in treating or counseling epileptic women of childbearing potential.
In addition to reports of increased incidence of congenital malformations, such as cleft lip/palate and heart malformations in children of women receiving phenytoin and other AEDs, there have been reports of fetal hydantoin syndrome. This consists of prenatal growth deficiency, microcephaly and mental deficiency in children born to mothers who have received phenytoin, barbiturates or alcohol. However, these features are all interrelated and are frequently associated with intrauterine growth retardation from other causes.
Phenytoin causes decreased folic acid levels, which may contribute to the risk of congenital malformations. Folic acid supplementation should begin several months prior to conception and continue for the first trimester of pregnancy, as for any woman who could become pregnant.
There have been isolated reports of malignancies, including neuroblastoma, in children whose mothers received phenytoin during pregnancy.
An increase in seizure frequency during pregnancy occurs in a high proportion of patients, because of altered phenytoin absorption or metabolism. Periodic measurement of serum phenytoin levels is particularly valuable in the management of a pregnant epileptic patient as a guide to appropriate dosage adjustment; however, restoration of the original dosage will probably be indicated postpartum.
Neonatal coagulation defects have been reported within the first 24 hours in babies born to epileptic mothers receiving phenobarbital and/or phenytoin. Vitamin K has been shown to prevent or correct this defect and has been recommended to be given to the mother before delivery and to the neonate after birth.
Adverse Effects
Gastrointestinal
nausea, vomiting, and constipation.
Central Nervous System
nystagmus, ataxia, slurred speech, decreased coordination and mental confusion. These are usually related to increased drug serum concentrations. Dizziness, insomnia, transient nervousness, motor twitching and headache have also been observed. There have also been rare reports of phenytoin induced dyskinesias, including chorea, dystonia and tremor, similar to those induced by phenothiazine and other antipsychotic drugs.
A predominantly sensory peripheral polyneuropathy has been observed in patients receiving long-term phenytoin therapy.
Connective Tissue: gingival hyperplasia, which is especially frequent in children, coarsening of the facial features, enlargement of the lips, systemic lupus erythematosus, hypertrichosis and Peyronie's disease.
Hematologic
thrombocytopenia, leukopenia, granulocytopenia, agranulocytosis, and pancytopenia with or without bone marrow suppression. Some reactions have been fatal. While macrocytosis and megaloblastic anemia have occurred, these conditions usually respond to folic acid therapy. Lymphadenopathy including benign lymph node hyperplasia, pseudolymphoma, lymphoma, and Hodgkin's disease have been reported (see Warnings).
Injection Site: Local irritation, inflammation, tenderness, necrosis, and sloughing have been reported with or without extravasation of i.v. phenytoin.
Other: Periarteritis nodosa, toxic hepatitis, liver damage, and immunoglobulin abnormalities may occur.
Dermatologic
scarlatiniform or morbilliform rashes sometimes accompanied by fever. Other more serious reactions which may be fatal have included bullous, exfoliative or purpuric dermatitis, lupus erythematosus, Stevens-Johnson syndrome and toxic epidermal necrolysis (see Warnings and Precautions).
Cardiovascular
Severe cardiotoxic reactions and fatalities have been reported with atrial and ventricular conduction depression and ventricular fibrillation. Severe complications are most commonly encountered in elderly or gravely ill patients.
The most notable signs of toxicity associated with the i.v. use of phenytoin are cardiovascular collapse and/or CNS depression. Hypotension does occur when the drug is administered rapidly by the i.v. route. The rate of administration is very important; it should not exceed 50 mg/min in adults, and 1 to 3 mg/kg/min in neonates. In geriatric patients with heart disease, it has been recommended that phenytoin be given at a rate of 50 mg over 2 to 3 minutes. At this rate, toxicity should be minimized.
Overdose
Symptoms
Symptoms may include nausea and vomiting, nystagmus and neurologic symptoms such as ataxia, tremor, hyperreflexia, slurred speech. Other neurologic symptoms may include hallucinations, opisthotonos (spastic state in which head, spine and heels are arched backward), choreoathetoid movements, and rarely seizures or coma. Seizures may occur in patients with or without pre-existing seizure disorder. Agitation and combativeness may alternate with periods of CNS depression. Respiratory depression occurs rarely, in severe cases.
Rapid i.v. injection may lead to hypotension, arrhythmias, seizures and cardiorespiratory arrest. These effects are generally not associated with oral overdose of phenytoin alone.
Death from phenytoin overdose is rare and usually associated with multiple drug ingestion or lack of adequate supportive care.
In overdose, phenytoin serum concentrations may not correlate well with clinical presentation. Therapeutic phenytoin levels range from 40 to 80 µmol/L. Mild to moderate neurologic toxicity is associated with levels of 80 to 160 µmol/L. At levels above 160 µmol/L, severe neurologic toxicity may occur. Patients with reduced protein binding may be at increased risk of toxicity due to higher free phenytoin levels.
Treatment
Respiratory and circulatory function should be carefully monitored and appropriate supportive measures employed. In addition, ECG, phenytoin serum levels and blood glucose should be monitored. Agitation and seizures may be managed with i.v. diazepam. Activated charcoal should be considered even if significant time has elapsed since ingestion. Studies have shown that multiple dose activated charcoal (MDAC) substantially increases phenytoin's rate of elimination, though it has not been demonstrated that this results in improved clinical outcomes. MDAC may be helpful even in cases of parenteral exposure. Forced diuresis, hemodialysis, peritoneal dialysis, charcoal hemoperfusion, exchange transfusion and plasmapheresis do not appear to enhance elimination significantly.
In acute overdose, the possibility of ingestion of other CNS depressants, including alcohol, should be considered.
Dosage
Dosage should be individualized to provide maximum benefit with minimum adverse effects. In many cases, serum concentration determinations will be necessary for optimal dosage adjustments; the clinically effective serum concentration is usually in the range of 40 to 80 µmol/L. Serum level determinations are especially helpful when toxicity, drug interactions or poor adherence to prescribed therapy is suspected. Dosage adjustments should not be made solely on the basis of serum levels, but should be based chiefly upon careful consideration of the patient's clinical response.
If dosage adjustment is required, phenytoin's nonlinear pharmacokinetics must be taken into consideration. Maintenance doses should generally only be increased in small increments, often by no more than 10% of the total daily dose. Some experts suggest that, in adults, if the steady-state serum level is less than 28 µmol/L, the dose should be increased by 100 mg/day. If the concentration is between 28 and 48 µmol/L, the dose can be increased by 50 mg/day. If the concentration is greater than 48 µmol/L, the dose should be increased by 30 mg/day or less. The time required to reach steady-state after each dosage adjustment may be prolonged (e.g., several weeks), and must be taken into account in order to avoid premature and unnecessary modifications which might result in toxicity or loss of seizure control (see Pharmacokinetics).
Both phenytoin acid and its sodium salt may be administered orally. Phenytoin sodium may also be administered i.v. Phenytoin sodium 100 mg is approximately equivalent to phenytoin acid 92 mg. This should be taken into consideration when a patient is switched from one form to the other.
Antiepileptic Dosage: Oral: In most adults, phenytoin may be administered in a once-daily dose using the extended-release capsules. The suspension and chewable tablets are not recommended for once-daily dosing. When using the suspension, it is important to shake the suspension well before measuring and to measure the dose accurately using a calibrated measuring device. Otherwise, clinically significant variations in dose may occur.
The suspension may be administered through a nasogastric tube. If this is necessary, the suspension should be diluted (e.g., 2- to 3-fold) with a compatible diluent (e.g., sterile water) prior to administration, and the tube should be flushed with at least 20 mL of diluent before and after administration. Enteral feeds should be stopped 2 hours before and resumed 2 hours after phenytoin doses, to minimize reduction of phenytoin bioavailability.
Adults: The usual starting dose of phenytoin is 5 mg/kg/day. The dose should be adjusted, if necessary, as described above.
Some clinicians have advocated the use of oral loading doses in adults who require rapid attainment of steady-state levels and where i.v. administration is not desirable or feasible. Approximately 18 mg/kg is administered in divided doses over 4 hours. For example, a 1 g dose would be divided into 3 doses (400 mg, 300 mg, 300 mg) which would be administered every 2 hours. Normal maintenance dose is then instituted 24 hours after completion of the loading dose. This should generally only be performed in a clinic or hospital setting where the patient can be closely monitored for adverse effects, and should be used in patients with normal renal and hepatic function.
Children: Initially, 5 mg/kg/day in 2 or 3 equally divided doses with subsequent dosage individualization. The usual maintenance dose varies from 4 to 8 mg/kg/day.
Parenteral: Whenever parenteral administration of phenytoin is necessary, the use of the prodrug fosphenytoin should be considered. For specific information on fosphenytoin, please consult the product monograph.
I.M. injection of phenytoin is not recommended (see Warnings).
Parenteral phenytoin should be injected slowly and directly into a large vein through a large-gauge needle or i.v. catheter or administered as an intermittent infusion. The patency of the vein and position of the venous catheter must be ascertained prior to injection, since extravasation of phenytoin can cause serious tissue damage (see Precautions and Adverse Effects). Each injection should be followed by an injection of sterile saline through the same needle or catheter to avoid local venous irritation due to the alkalinity of phenytoin solution. If given as an intermittent infusion, phenytoin should be administered under close observation immediately after preparation. Many clinicians recommend the use of a 0.22 µm in-line filter during infusion. Phenytoin is not compatible with solutions containing dextrose.
Do not exceed an injection rate of 50 mg/min in adults or 1 to 3 mg/kg/min (maximum 50 mg/min) in children. In geriatric patients, or patients with cardiovascular disease, a maximum rate of 25 mg/min has been advocated by some experts (see Warnings and Overdose). Many clinicians recommend continuous monitoring of ECG and blood pressure during injection. The patient should be observed for signs of respiratory depression.
Adults: When rapid attainment of therapeutic serum concentrations is desired, an i.v. loading dose may be administered. The usual dose is 15 to 20 mg/kg i.v. given at a rate of 25 to 50 mg/min (see above).
Generalized Convulsive Status Epilepticus (GCSE): Adults: 15 to 20 mg/kg administered at a rate of 25 to 50 mg/min. If seizures are not controlled, additional doses of 5 to 10 mg/kg (max 30 mg/kg) may be given.
Children: Children in GCSE not currently on phenytoin should receive 20 mg/kg i.v. initially, administered at a rate of 1 mg/kg/min (children <50 kg) or 50 mg/min (children ≥50 kg). If the seizure continues, additional 5 mg/kg doses may be given. A maximum of 30 mg/kg (up to 1000 mg) can be given in total.
Children in GCSE already on phenytoin may receive an initial booster dose of 5 mg/kg, pending serum level determinations.
