PHENYTOIN
General Monograph,
Diphenylhydantoin
Anticonvulsant
Action And Clinical Pharmacology: Phenytoin is an anticonvulsant which elevates the seizure threshold in the motor cortex by limiting the post-tetanic potentiation (PTP) of synaptic transmission. It exerts this effect by preventing the excessive accumulation of intracellular sodium during tetanic stimulation by either reducing the passive influx of sodium or increasing the efficiency of the sodium pump. By limiting PTP, phenytoin prevents the spread of seizure activity to adjacent cortical areas.
Phenytoin also possesses antiarrhythmic activity similar to that of quinidine and procainamide. It increases the conduction velocity of the AV node and Purkinje fibres especially when conduction has been depressed by digitalis glycosides. Phenytoin decreases the automaticity of cardiac tissue by prolonging the effective refractory period. It also decreases the force of cardiac contraction. It may produce hypotension following i.v. administration.
Phenytoin has little hypnotic activity.
Pharmacokinetics: Following oral administration, phenytoin is slowly absorbed from the gastrointestinal tract. Absorption may be variable and sometimes incomplete. The drug 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.
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.
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 intravenously. The clinically effective serum trough concentration is usually 40 to 80 µmol/L.
Phenytoin is metabolized in the liver to an inactive metabolite 5-(p-hydroxyphenyl)-5-phenylhydantoin (HPPH). This metabolite 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 even with minor dosage changes. A small increase in dose may lead to a large increase in drug concentration as elimination becomes saturated.
Indications And Clinical Uses: Oral: Control of generalized tonic-clonic and complex partial seizures and in the treatment and prevention of seizures occurring during or following neurosurgery.
Parenteral: The treatment of status epilepticus and treatment and prevention of seizures occurring during or following neurosurgery.
Contra-Indications: 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, patients with Adams-Stokes syndrome.
Manufacturers’ Warnings In Clinical States: This drug must be administered slowly. I.V. administration should not exceed 50 mg/minute in adults. In neonates, the drug should be administered at a rate not exceeding 1 to 3 mg/kg/min. The response to phenytoin may be significantly altered by the concomitant use of other drugs (see Precautions, Drug Interactions).
Abrupt withdrawal of phenytoin in epileptic patients may precipitate seizures. When the need for dosage reduction, discontinuation, or substitution of other anticonvulsant medication arises, this should be done gradually. However, in the event of an allergic or hypersensitivity reaction, rapid initiation of alternative therapy may be necessary. In this case, alternative therapy should be an anticonvulsant drug not belonging to the hydantoin chemical class.
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.
Phenytoin should be used with caution in patients with hypotension and severe myocardial insufficiency.
Hypotension is associated with rapid i.v. administration.
The i.m. route is not recommended for the treatment of status epilepticus since absorption of the drug may be erratic.
There have been a number of reports suggesting a relationship between phenytoin and the development of lymphadenopathy (local or generalized) including benign lymph node hyperplasia, pseudolymphoma, lymphoma, and Hodgkin’s disease. Although a cause and effect relationship has not been established, the occurrence of lymphadenopathy indicates the need to differentiate such a condition from other types of lymph node pathology. Lymph node involvement may occur with or without symptoms and signs resembling serum sickness, e.g. fever, rash and liver involvement.
In all cases of lymphadenopathy, follow-up observation for an extended period is indicated and every effort should be made to achieve seizure control using alternative antiepileptic drugs.
Acute alcoholic intake may increase phenytoin serum levels while chronic use may decrease serum levels.
Pregnancy: The great majority of mothers on antiepileptic medication deliver normal infants. It is important to note that antiepileptic drugs 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 antiepileptic drugs, 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, alcohol, or trimethadione. However, these features are all interrelated and are frequently associated with intrauterine growth retardation from other causes.
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.
Precautions: The liver is the chief site of biotransformation of phenytoin; patients with impaired liver function, elderly patients, or those who are gravely ill may be particularly susceptible to toxicity.
A small percentage of individuals who have been treated with phenytoin have been shown to metabolize the drug slowly. Slow metabolism may be due to limited enzyme availability and lack of induction; it appears to be genetically determined.
Phenytoin should be discontinued if a skin rash appears (see Warnings). If the rash is exfoliative, purpuric, or bullous or if lupus erythematosus, Stevens-Johnson syndrome or toxic epidermal necrolysis is suspected, use of this drug should not be resumed and alternative therapy should be considered (see Adverse Effects). If the rash is of a milder type (measles-like or scarlatiniform), therapy may be resumed after the rash has completely disappeared. If the rash recurs upon reinstitution of therapy, further phenytoin therapy is contraindicated. Patients should be instructed to call their physician if skin rash develops.
The importance of good dental hygiene should be stressed in order to minimize the development of gingival hyperplasia and its complications.
Hyperglycemia, resulting from the drug’s inhibitory effects on insulin release, has been reported. Phenytoin may also raise the serum glucose level in diabetic patients.
Osteomalacia has been associated with phenytoin therapy and is considered to be due to phenytoin’s interference with vitamin D metabolism.
Phenytoin is not indicated for seizures due to hypoglycemic or other metabolic causes.
Phenytoin is not effective for and may worsen absence (petit mal) seizures. If tonic-clonic (grand mal) and absence (petit mal) seizures are present, combined drug therapy is needed.
Each injection of i.v. phenytoin sodium should be followed by an injection of sterile saline through the same needle or i.v. catheter to avoid local venous irritation due to the alkalinity of the solution. Continuous infusion should be avoided.
Soft tissue irritation and inflammation has occurred at the site of injection with and without extravasation of i.v. phenytoin. Soft tissue irritation varying from slight tenderness to extensive necrosis and sloughing has been noted. s.c. or perivascular injection should be avoided.
Serum levels of phenytoin sustained above the 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 level determinations are recommended. Dose reduction of phenytoin therapy is indicated if plasma levels are excessive; if symptoms persist, termination is recommended (see Warnings).
Patients should be cautioned about the use of other drugs or alcoholic beverages without first seeking the physician’s advice.
Do not use capsules which are discolored.
Drug Interactions: There are many drugs which may increase or decrease phenytoin levels or which phenytoin may affect. The most commonly occurring drug interactions are listed below (see also Drug Interactions table in the Clin-Info section).
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 which may increase phenytoin serum levels include: amiodarone, chloramphenicol, cimetidine, disulfiram, erythromycin, fluconazole, fluoxetine, isoniazid, ketoconazole, methylphenidate, omeprazole, phenylbutazone, salicylates, sulfonamides, trazodone, warfarin and acute alcohol ingestion.
Drugs which may decrease phenytoin levels include: carbamazepine, chronic alcohol abuse, diazoxide, rifampin and theophylline.
Drugs which 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 is impaired by phenytoin include: corticosteroids, diazoxide, digitalis glycosides, doxycycline, estrogens, furosemide, levodopa, methadone, oral contraceptives, quinidine, theophylline, vitamin D and warfarin.
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.
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, alkaline phosphatase, and gamma glutamyl transpeptidase (GGT).
Pregnancy: See Warnings.
Lactation: If maternal levels are kept within therapeutic range, there is little risk of drug accumulation in the infant.
Adverse Reactions: 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 this drug 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/minute in adults, and 1 to 3 mg/kg/min in neonates. At this rate, toxicity should be minimized.
CNS: 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 neuroleptic drugs.
A predominantly sensory peripheral polyneuropathy has been observed in patients receiving long-term phenytoin therapy.
Connective Tissue: gingival hyperplasia, coarsening of the facial features, enlargement of the lips, systemic lupus erythematosus, hypertrichosis and Peyronie’s disease.
Dermatological: 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 Precautions).
Gastrointestinal: nausea, vomiting, and constipation.
Hematological: 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.
Symptoms And Treatment Of Overdose: Symptoms: The lethal dose in children is not known. The lethal dose in adults is estimated to be 2 to 5 g. The initial symptoms are nystagmus, ataxia and dysarthria. Other signs are tremor, hyperflexia, lethargy, slurred speech, nausea and vomiting. The patient may become comatose and hypotensive. Death is due to respiratory and circulatory depression.
There are marked variations among individuals with respect to phenytoin plasma levels where toxicity may occur. Nystagmus on lateral gaze usually appears at 80 µmol/L, ataxia at 119 µmol/L, dysarthria and lethargy appear when the plasma concentration is over 159 µmol/L, but as high a concentration as 198 µmol/L has been reported without evidence of toxicity. As much as 25 times the therapeutic dose has been taken resulting in a serum concentration of greater than 396 µmol/L with the achievement of complete recovery.
Treatment: The adequacy of the respiratory and circulatory systems should be carefully observed and appropriate supportive measures employed. Monitor ECG, serum levels and blood glucose. Empty stomach. Follow with activated charcoal and a cathartic. As phenytoin undergoes enterohepatic circulation and can form concretions which may remain in the gastrointestinal tract after initial stomach emptying, administration of activated charcoal should be repeated. Forced diuresis, hemodialysis, peritoneal dialysis, charcoal hemoperfusion, exchange transfusion and plasmapheresis are thought to be of no value.
In acute overdosage the possibility of other CNS depressants, including alcohol, should be borne in mind.
Dosage And Administration: Phenytoin and its sodium salt are administered orally, often in combination with phenobarbital or other anticonvulsant agents; however, monotherapy is preferred. In most adults, phenytoin may be administered as a once daily dose. Suspensions and chewable tablets are not generally recommended for once-a-day dosing. The sodium salt of phenytoin may be administered by direct i.v. injection for the initial treatment of status epilepticus and for prophylaxis of seizures in neurosurgery.
Serum concentrations should be monitored when switching a patient from the sodium salt to the free acid form.
Phenytoin sodium 100 mg is approximately equivalent to phenytoin acid 92 mg. This difference in phenytoin content should be considered when the dosage form is changed.
Oral: Individualize dosage to provide maximum benefit. In some cases, serum blood concentration determinations may be necessary for optimal dosage adjustments – the clinically effective serum concentration is usually in the range of 40 to 80 µmol/L. Serum blood level determinations are especially helpful when possible drug interactions or poor adherence to prescribed therapy are suspected. With recommended dosage, a period of 7 to 10 days may be required to achieve therapeutic blood concentrations and changes in dosage (increase or decrease) should generally not be carried out at intervals shorter than 7 to 10 days. A small increase in dose can result in a disproportionate increase in serum concentration and possible toxicity.
Adults: Patients who have received no previous treatment may be started on 100 mg of phenytoin 3 times daily. For most adults a satisfactory maintenance dose will be 300 to 400 mg daily; however, maintenance doses of up to 600 mg may be required. Clinical studies with phenytoin have indicated that both single and divided dosage schedules demonstrate similar rates of absorption and equilibrium concentrations in adults. This means that a patient stabilized with 100 mg doses 3 times daily by mouth may respond to the more convenient single daily dose of 300 mg. There has been no reported evidence of increased drug toxicity when single daily doses of 300 mg have been administered to patients previously receiving the same quantity in divided doses.
Children: Initially, 5 mg/kg/day in 2 or 3 equally divided doses with subsequent dosage individualized to a maximum of 300 mg daily. The usual maintenance dose varies between 4 and 8 mg/kg. Children over 6 years old may require the minimum adult dose (300 mg/day).
Parenteral: Do not exceed a rate of 50 mg/minute, i.v. in adults and 1 to 3 mg/kg/min in neonates. Because of the unpredictable differences in absorption of phenytoin when given i.m., the i.v. route is preferred.
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 (minibag or piggyback). Each injection should be followed by an injection of sterile saline through the same needle or catheter to avoid local venous irritation due to alkalinity of the solution.
Continuous monitoring of the ECG and blood pressure is essential when administered by direct injection. The patient should be observed for signs of respiratory depression. Determination of phenytoin plasma levels is advised when using phenytoin in the management of status epilepticus and in the subsequent establishment of maintenance dosage.
Status Epilepticus: In adults, a loading dose of 10 to 15 mg/kg should be administered slowly i.v. at a rate not exceeding 50 mg/minute (this will require approximately 20 minutes in a 70 kg patient). The loading dose should be followed by maintenance doses of 100 mg orally or i.v. every 6 to 8 hours.
Children: Recent work in neonates and children has shown that absorption of phenytoin is unreliable after oral administration, but a loading dose of 15 to 20 mg/kg i.v. will usually produce plasma concentrations of phenytoin within the generally accepted therapeutic range (40 to 80 µmol/L). The drug should be injected slowly i.v. at a rate not exceeding 1 to 3 mg/kg/min.
Other measures, including concomitant administration of an i.v. benzodiazepine such as diazepam, or an i.v. short-acting barbiturate, will usually be necessary for rapid control of seizures because of the required slow rate of administration of phenytoin.
If administration of parenteral phenytoin does not terminate seizures, the use of other anticonvulsants, i.v. barbiturates, general anesthesia, and other appropriate measures should be considered.
I.M. administration should not be used in the treatment of status epilepticus because the attainment of peak plasma levels may require up to 24 hours.
Neurosurgery: Prophylactic dosage: 100 to 200 mg i.m. at approximately 4 hour intervals during surgery and continued during the postoperative period.
When i.m. administration is required for a patient previously stabilized orally, compensating dosage adjustments are necessary to maintain therapeutic plasma levels. An i.m. dose 50% greater than the oral dose is necessary to maintain these levels. When returned to oral administration, the dose should be reduced by 50% of the original oral dose for 1 week to prevent excessive plasma levels due to sustained release from i.m. tissue sites.
If the patient requires more than a week of i.m. phenytoin, alternative routes should be explored, such as gastric intubation. For time periods less than 1 week, the patient shifted back from i.m. administration should receive one half the original oral dose for the same period of time the patient received i.m. phenytoin. Monitoring plasma levels will help prevent a fall into the subtherapeutic range.
PHENYTOIN General Monograph, Diphenylhydantoin Anticonvulsant
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