Phenytoin (Infatab: base; Cap/Inj: Na)

IndicationCapsule/Infatab: For the control of tonic-clonic and psychomotor (grand mal and temporal lobe) seizures and prevention and treatment of seizures occurring during or following neurosurgery.Phenytoin serum level determinations may be necessary for optimal dosage adjustments.Vial: For the control of the tonic-clonic (grand mal) type.For the control of status epilepticus, because of the required slow rate of administration of phenytoin, concomitant administration of an IV rapid onset anticonvulsant eg, diazepam or short-acting barbiturate will usually be necessary (see Dosage & Administration).Prevention and treatment of seizures occurring during or following neurosurgery and/or severe head injury.Phenytoin has also been used in the treatment of migraine, trigeminal neuralgia and schizophrenia. It has also been used in the treatment of cardiac arrhythmia, digitalis intoxication and post-event treatment of myocardial infarction.DosageSerum concentrations should be monitored in changing from the sodium salt to the free acid form. Dilantin capsule and parenteral are formulated with the sodium salt of phenytoin. The free acid form of phenytoin is used in Dilantin infatabs. Because there is approximately an 8% increase in drug content with the free acid form than the sodium salt, dosage adjustments and serum level monitoring may be necessary when switching from a product formulated with the free acid to a product formulated with the sodium salt and vice versa.Capsule: General: Dosage should be individualized to provide maximum benefit. In some cases where serum blood level determinations may be necessary for optimal dosage adjustments, the clinically effective serum level is usually 10-20 mcg/mL. With recommended dosage, a period of 7-10 days may be required to achieve steady-state blood levels with phenytoin and changes in dosage (increase or decrease) should not be carried out at intervals shorter than 7-10 days.Adults: Divided Daily Dosage: Patients who have received no previous treatment may be started on one 100-mg Dilantin (cap) 3 times daily and the dosage is then adjusted to suit individual requirements. For most adults, the satisfactory maintenance dosage will be 1 cap 3-4 times a day. An increase up to 2 caps 3 times a day may be made, if necessary.Once-A-Day Dosage: In adults, if seizure control is established with divided doses of three 100-mg Dilantin caps daily, once-a-day dosage with 300 mg of phenytoin sodium caps may be considered. Studies comparing divided doses of 300 mg with a single daily dose of this quantity indicated absorption, peak plasma levels, biologic half-life, difference between peak and minimum values, and urinary recovery were equivalent. Once-a-day dosage offers a convenience to the individual patient or to nursing personnel for institutionalized patients and is intended to be used only for patients requiring this amount of drug daily. A major problem in motivating noncompliant patients may also be lessened when the patient can take this drug once a day. However, patients should be cautioned not to miss a dose, inadvertently.Only phenytoin sodium capsules are recommended for once-a-day dosing. Inherent differences in dissolution characteristics and resultant absorption rates of phenytoin due to different manufacturing procedures and/or dosage forms preclude such recommendation for other phenytoin products. When a change in the dosage form or brand is prescribed, careful monitoring of phenytoin serum levels should be carried out.Infatab: Pediatric Dosage: 5 mg/kg/day in 2 or 3 equally divided doses, with subsequent dosage individualized to a maximum of 300 mg daily. A recommended daily maintenance dosage is usually 4-8 mg/kg. Children >6 years may require the minimum adult dose (300 mg/day).Parenteral: Parenteral phenytoin may be administered as a slow IV bolus or it may be administered via an IV infusion.Bolus Administration: A bolus of parenteral phenytoin should be injected slowly, not exceeding 50 mg/min in adults, into a large vein through a large-gauge needle or IV catheter. Each injection of IV phenytoin should be preceded by a saline flush and followed by an injection of sterile saline through the same needle or catheter to avoid local venous irritation due to the alkalinity of the solution.Infusion Administration: For infusion administration, the parenteral phenytoin should be diluted in 50-100 mL of normal saline with the final concentration of phenytoin in the solution not exceeding 10 mg/mL. Administration should commence immediately after the mixture has been prepared and must be completed within 1 hr (the infusion mixture should not be refrigerated). An in-line filter (0.22-0.5 microns) should be used. Each injection of IV phenytoin should be preceded by a saline flush and followed by an injection of sterile saline through the same needle or IV catheter to help reduce local venous irritation due to the alkalinity of the solution.Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.Both the undiluted form and the infusion mixture are suitable for use as long as they remain free of haziness and precipitate.The diluted infusion mixture (phenytoin plus normal saline) should not be refrigerated. If the undiluted parenteral phenytoin is refrigerated or frozen, a precipitate might form; this should dissolve again after the solution is allowed to stand at room temperature, in which case the product is still suitable for use. A faint yellow coloration may develop; however, this should have no effect on the potency of the solution.Dosage must not exceed 50 mg/min, IV in adults, and not to exceed 1-3 mg/kg/min in neonates. There is a relatively small margin between full therapeutic effect and minimally toxic doses of Dilantin.Because there is approximately an 8% increase in drug content with the free acid form over that of the sodium salt, dosage adjustments and serum level monitoring may be necessary when switching from a product formulated with the free acid to a product formulated with the sodium salt and vice versa.Status Epilepticus: IM administration should not be used in the treatment of status epilepticus because the attainment of peak serum levels may require up to 24 hrs. For the treatment of status epilepticus, IV administration of drug is necessary for rapid control of seizure. Because of the required slow rate of administration of phenytoin, the IV administration of a rapid onset anticonvulsant eg, diazepam or short-acting barbiturate will usually be necessary prior to the IV administration of phenytoin. In adults, a loading dose of 10-15 mg/kg should be administered slowly IV, at a rate not exceeding 50 mg/min (this will require approximately 20 min in a 70-kg patient). The loading dose should be followed by a maintenance dose of 100 mg orally or IV every 6-8 hrs.Absorption of phenytoin in neonates and children may be unreliable after oral administration. A loading dose of 15-20 mg/kg of phenytoin IV will usually produce serum concentrations of phenytoin within the generally accepted therapeutic range (10-20 mcg/mL). Dilantin should be injected slowly IV at a rate not exceeding 1-3 mg/kg/min.Continuous monitoring of the electrocardiogram and blood pressure is essential. The patient should be observed for signs of respiratory depression. Determination of phenytoin serum levels is advised when using phenytoin in the management of status epilepticus and in the subsequent establishment of maintenance dosage.If administration of parenteral phenytoin does not terminate seizures, the use of other anticonvulsants, IV barbiturates, general anesthesia, or other appropriate measures should be considered.Neurosurgery: Prophylactic Dosage: 100-200 mg (2-4 mL) IM at approximately 4-hr intervals during surgery and continued during the postoperative period. When IM administration is required for a patient previously stabilized orally, compensating dosage adjustments are necessary to maintain therapeutic serum levels. When IM administration is used, the drug should be given by deep IM injection. An IM dose 50% greater than the oral dose is necessary to maintain these levels. When the patient is returned to oral administration, the dose should be reduced by 50% of the original oral dose for 1 week to prevent excessive serum levels due to sustained release from intramuscular tissue sites.If the patient requires more than a week of IM phenytoin, alternative routes should be explored eg, gastric intubation. For time periods 40 mcg/mL, but a concentration as high as 50 mcg/mL has been reported without evidence of toxicity. As much as 25 times the therapeutic dose has been taken to result in a serum concentration >100 mcg/mL with complete recovery.Treatment: Treatment is nonspecific since there is no known antidote. The adequacy of the respiratory and circulatory systems should be carefully observed and appropriate supportive measures employed. Hemodialysis can be considered since phenytoin is not completely bound to plasma proteins. Total exchange transfusion has been used in the treatment of severe intoxication in children.In acute overdosage the possibility of other CNS depressants, including alcohol, should be borne in mind.ContraindicationPatients who are hypersensitive to phenytoin or other hydantoins.Vial: Because of its effect on ventricular automaticity, phenytoin is contraindicated in sinus bradycardia, sino-atrial block, 2nd and 3rd degree AV block and in patients with Adams-Stokes syndrome.WarningsAbrupt withdrawal of phenytoin in epileptic patients may precipitate status epilepticus. When, in the judgment of the clinician, the need for dosage reduction, discontinuation or substitution of alternative antiepileptic medication arises, this should be done gradually. However, in the event of an allergic or hypersensitivity reaction, rapid substitution of alternative therapy may be necessary. In this case, alternative therapy should be an antiepileptic drug not belonging to the hydantoin chemical class.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 eg, 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 anticonvulsant drugs.Acute alcoholic intake may increase phenytoin serum levels while chronic alcoholic use may decrease serum levels.Vial: IV administration should not exceed 50 mg/min in adults. Drug should be administered to neonates at a rate not exceeding 1-3 mg/kg/min.Severe cardiotoxic reactions and fatalities have been reported with atrial and ventricular 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 usually occurs when phenytoin is administered by the IV route. The IM route is not recommended for the treatment of status epilepticus since serum levels of phenytoin in the therapeutic range cannot be readily achieved with doses and methods of administration ordinarily used.Cases of acute hepatotoxicity, including infrequent cases of acute hepatic failure, have been reported with phenytoin. These incidents have been associated with a hypersensitivity syndrome characterized by fever, skin eruptions, and lymphadenopathy, and usually occur within the first 2 months of treatment. Other common manifestations include jaundice, hepatomegaly, elevated serum transaminase levels, leukocytosis, and eosinophilia. The clinical course of acute phenytoin hepatotoxicity ranges from prompt recovery to fatal outcomes. In these patients with acute hepatotoxicity, phenytoin should be immediately discontinued and not re-administered.In view of isolated reports associating phenytoin with exacerbation of porphyria, caution should be exercised in using this medication in patients suffering from this disease.Use in pregnancy: A number of reports suggest an association between the use of anticonvulsant drugs by women with epilepsy and a higher incidence of birth defects in children born to these women. Data are more extensive with respect to phenytoin and phenobarbital, but these are also the most commonly prescribed anticonvulsant drugs. Less systematic or anecdotal reports suggest a possible similar association with the use of all known anticonvulsant drugs.The reports suggesting a higher incidence of birth defects in children of drug-treated epileptic women cannot be regarded as adequate to prove a definite cause and effect relationship. There are intrinsic methodologic problems in obtaining adequate data on drug teratogenicity in humans; genetic factors or the epileptic condition itself may be more important than drug therapy in leading to birth defects. The great majority of mothers on anticonvulsant medication deliver normal infants. It is important to note that anticonvulsant 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 hazards to the developing embryo or fetus. The prescribing physician will wish to weigh these considerations in treating and counseling epileptic women of childbearing potential.Do not use Dilantin while pregnant because it may cause teratogenicity.In addition to the reports of increased incidence of congenital malformation eg, cleft lip/palate and heart malformations in children of women receiving phenytoin and other anticonvulsant drugs, there have been reports of a 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 an appropriate adjustment of dosage. However, postpartum restoration of the original dosage will probably be indicated.Neonatal coagulation defects have been reported within the first 24 hrs 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 the neonate after birth.Drug interactionThere are many drugs which may increase or decrease phenytoin levels or which phenytoin may affect. Determinations of serum phenytoin concentrations are especially helpful when possible drug interactions are suspected. The most commonly occurring drug interactions are listed as follows:Drugs which may increase phenytoin serum levels include acute alcohol intake, dicumarol, disulfiram, methylphenidate, omeprazole, ticlopidine and viloxazine. The following drug classes are also included: Analgesic/anti-inflammatory agents (eg, azapropazone, phenylbutazone, salicylates); anesthetics (eg, halothane); antibacterial agents (eg, chloramphenicol, erythromycin, isoniazid, sulfonamides); anticonvulsants (eg, felbamate, succinimides); antifungal agents (eg, amphotericin B, fluconazole, ketoconazole, miconazole, itraconazole); benzodiazepines/psychotropic agents (eg, chlordiazepoxide, diazepam, trazodone); calcium-channel blockers/cardiovascular agents (eg, amiodarone, diltiazem, nifedipine); H2-antagonists; hormones (eg, estrogens); oral hypoglycemic agents (eg, tolbutamide); serotonin re-uptake inhibitors (eg, fluoxetine).Drugs which may decrease phenytoin serum levels include antibacterial agents/fluoroquinolones (eg, ciprofloxacin and rifampin), chronic alcohol abuse, diazoxide, reserpine, sucralfate, theophylline and vigabatrin.Molindone HCl contains calcium ions which interfere with the absorption of phenytoin. Ingestion times of phenytoin and calcium preparations, including antacid preparations containing calcium, should be staggered to prevent absorption problems.Drugs which may either increase or decrease phenytoin serum levels include: Anticonvulsants (eg, carbamazepine, phenobarbital, sodium valproate, valproic acid); antineoplastic agents; benzodiazepines, phenothiazines, psychotropic agents (eg, chlordiazepoxide, diazepam).Similarly, the effect of phenytoin on carbamazepine, phenobarbital, valproic acid, and sodium valproate serum levels is unpredictable.Although not a true drug interaction, tricyclic antidepressants may precipitate seizures in susceptible and phenytoin dosage may need to be adjusted.Drugs whose blood levels and/or effects may be altered by phenytoin include clozapine, corticosteroids, coumarin anticoagulants, cyclosporine, diazoxide, furosemide, lamotrigine, paroxetine, theophylline and vitamin D.The following drug classes are also included: Antibacterial agents (eg, doxycycline, praziquantel, rifampin, tetracycline); antifungal agents; antineoplastic agents; calcium-channel blockers/cardiovascular agents (eg, digitoxin, nicardipine, nimodipine, quinidine, verapamil); hormones (eg, estrogens, oral contraceptives); neuromuscular-blocking agents (eg, alcuronium, pancuronium, vecuronium); opioid analgesics (eg, methadone); oral hypoglycemic agents (eg, chlorpropamide, glyburide, tolbutamide).Drug-Enteral Feeding/Nutritional Preparations Interaction: Literature reports suggest that patients who have received enteral feeding preparations and/or related nutritional supplements have lower than expected phenytoin plasma levels. It is therefore suggested that phenytoin not be administered concomitantly with an enteral feeding preparation.More frequent serum phenytoin level monitoring may be necessary in these patients.Drug/Laboratory Test Interactions: Phenytoin may cause decreased serum levels of protein-bound iodine (PBI). It may also produce lower than normal values for dexamethasone or metyrapone tests. Phenytoin may cause raised serum levels of glucose, alkaline phosphatase and -glutamyl transpeptidase (GGT).Phenytoin may affect blood calcium and blood sugar metabolism tests.PregnancyCategory D: There is positive evidence of human foetal risk, but the benefits from use in pregnant women may be acceptable despite the risk (e.g., if the drug is needed in a life-threatening situation or for a serious disease for which safer drugs cannot be used or are ineffective).StorageStore at room temperature not exceeding 25C. Protect from light.DescriptionEach capsule and vial contains phenytoin sodium. Each infatab contains phenytoin base.Phenytoin sodium, an anticonvulsant drug, is related to the barbiturates in chemical structure, but has a 5-membered ring. It is sodium 5,5-diphenyl-2,4-imidazolidinedione. Product in vivo performance is characterized by a slow rate of absorption with peak blood concentrations expected in 4-12 hrs.Dilantin ready-mixed sterile solution contains phenytoin sodium in a vehicle containing 40% propylene glycol and 10% alcohol in water for injection, adjusted to pH 12 with sodium hydroxide.MechanismPharmacology: Phenytoin is an anticonvulsant drug which can be useful in the treatment of epilepsy. The primary site of action appears to be the motor cortex where spread of seizure activity is inhibited. Possibly by promoting sodium efflux from neurons, phenytoin tends to stabilize the threshold against hyperexcitability caused by excessive stimulation or environmental changes capable of reducing membrane sodium gradient. This includes reduction of post-tetanic potentiation at synapses. Loss of post-tetanic potentiation prevents cortical seizure foci from detonating adjacent cortical areas. Phenytoin reduces the maximal activity of brainstem centers responsible for the tonic phase of tonic-clonic (grand mal) seizures.Pharmacokinetics: The plasma half-life in man after oral administration of phenytoin averages 22 hrs, with a range of 7-42 hrs. Steady-state therapeutic levels are achieved 7-10 days after initiation of therapy with recommended doses of 300 mg/day.When serum level determinations are necessary, they should be obtained at least 5-7 half-lives after treatment initiation, dosage change, or addition or subtraction of another drug to the regimen so that equilibrium or steady state will be achieved. Trough levels provide information about clinically effective serum level range, confirm patient compliance and are obtained just prior to the patient's next scheduled dose. Peak levels indicate an individual's threshold for emergence of dose-related side effects and are obtained at the time of expected peak concentration. For Dilantin capsule, peak serum levels occur 4-12 hrs after administration.Optimum control without clinical signs of toxicity occurs more often with serum levels between 10 and 20 mcg/mL, although some mild cases of tonic-clonic (grand mal) epilepsy may be controlled with lower serum levels of phenytoin. In most patients maintained at a steady dosage, stable phenytoin serum levels are achieved. There may be wide interpatient variability in phenytoin serum levels with equivalent dosages. Patients with unusually low levels may be noncompliant or hypermetabolizers of phenytoin. Unusually high levels result from liver disease, congenital enzyme deficiency or drug interactions which result in metabolic interference. The patient with large variations in phenytoin plasma levels, despite standard doses, presents a difficult clinical problem. Serum level determinations in such patients may be particularly helpful.Most of the drug is excreted in the bile as inactive metabolites which are then reabsorbed from the intestinal tract and excreted in the urine. Urinary excretion of phenytoin and its metabolites occurs partly with glomerular filtration but more importantly, by tubular secretion. Because phenytoin is hydroxylated in the liver by an enzyme system which is saturable, small incremental doses may produce very substantial increases in serum levels, when these are in the upper range. The steady-state level may be disproportionately increased, with resultant intoxication, from an increase in dosage of 10%.Vial: The pharmacokinetic characteristics of phenytoin are markedly influenced by its limited aqueous solubility and by dose-dependent elimination. Its inactivation by the hepatic microsomal enzyme system is susceptible to alteration by other drugs. After absorption, phenytoin distributes freely throughout the body and quickly reaches it maximum volume of distribution. In serum, phenytoin binds rapidly and reversibly to proteins. About 90% of phenytoin in plasma is bound to albumin; the fraction is less in neonates, in patients with hypoalbuminemia and in patients with uremia. After IV administration, phenytoin is distributed to tissues rapidly. Free phenytoin distributes into all transcellular fluids. The concentration of phenytoin in CSF, bile, saliva, semen, gastrointestinal fluid and breast milk is the same as the level of free phenytoin in the blood. The plasma half-life of phenytoin in man averages 22 hrs with a range of 7-42 hrs. Half-life increases with increasing dosage of phenytoin, a phenomenon which results from the saturable metabolism of phenytoin. Another factor influencing the half-life of phenytoin is concomitant medication. Less than 5% of phenytoin is excreted unchanged in the urine and only a very small amount is excreted unchanged in the feces. The remainder is metabolized primarily by hepatic hydroxylation. Metabolism is relatively slow and is not substantially altered by changes in hepatic blood flow. The major metabolite, the parahydroxyphenyl derivative, is inactive. It accounts for 60-70% of a single dose of the drug and a somewhat smaller fraction during chronic medication. Other metabolites include the dihydroxy catechol and its 3-methoxy derivative and the dihydrodiol. The metabolites are excreted in the bile, reabsorbed from the gut and excreted in urine. The enzyme system that metabolizes phenytoin becomes saturated by concentrations of the drug in the therapeutic range; hence the half-life for elimination is dose-dependent and unexpected toxicity can occur.Optimum control without clinical signs of toxicity occurs most often with serum levels between 10 and 20 mcg/mL.A fall in serum levels may occur when patients are changed from oral to IM administration. The drop is caused by slower absorption, as compared to oral administration, due to the poor water solubility of phenytoin. IV administration is the preferred route for producing rapid therapeutic serum levels.On those occasions when IM administration may be required ie, postoperatively, in comatose patients, a sufficient dose must be administered IM to maintain the serum level within the therapeutic range. Where oral dosage is resumed following IM usage, the oral dosage should be adjusted to compensate for the slow, continuing IM absorption to avoid toxic symptoms. To avoid drug accumulation due to absorption from the muscle depots, it is recommended that for the 1st week back on oral phenytoin, the oral dose be reduced to of the original dose (1/3 of the IM dose).ClassAnticonvulsantsClassificationN03AB02 - phenytoin ; Belongs to the class of hydantoin derivatives antiepileptics.PackingCap 100 mg x 100's. Infatab 50 mg x 1000's. Inj (vial) 50 mg/mL x 5 mL.