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General: Phenytoin is not effective for absence (petit mal) seizures. If tonic-clonic (grand mal) and absence (petit mal) seizures are present, combined drug therapy is needed. Phenytoin is not indicated for seizures due to hypoglycemia or other metabolic causes. Appropriate diagnostic procedures should be performed as indicated. Phenytoin should not be abruptly discontinued because of the possibility of increased seizure frequency, including status epilepticus. When, in the judgement of the clinician, the need for dosage reduction, discontinuation, or substitution of alternative anti-epileptic 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 anticonvulsant drug not belonging to the hydantoin chemical class.
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.
Acute alcoholic intake may increase Phenytoin serum levels, while chronic alcoholic use may decrease serum levels.
Due to an increased fraction of unbound Phenytoin in patients with renal or hepatic disease, or in those with hypoalbuminemia, the interpretation of total phenytoin plasma concentrations should be made with caution. Unbound concentration of Phenytoin may be elevated in patients with hyperalbuminemia. Unbound Phenytoin concentrations may be more useful in these patient populations.
Suicide: Suicidal ideation and behavior have been reported in patients treated with anti-epileptic agents in several indications. A small increased risk of suicidal ideation and behavior. The mechanism of the risk is not known and the available data do not exclude the possibility of an increased risk for Phenytoin.
Hypersensitivity Syndrome/Drug Reaction with Eosinophilia and Systemic Symptoms: Hypersensitivity syndrome (HSS) or drug reaction with eosinophilia and systemic symptoms (DRESS) has been occurred in patients taking anticonvulsant drugs, including Phenytoin. Some of these events have been fatal or life threatening.
Hypersensitivity syndrome (HSS) or drug reaction with eosinophilia and Systemic Symptoms (DRESS) typically, although not exclusively, present fever, rash, and/or lymphadenopathy in association with other organ system involvement, such as hepatitis, nephritis, haematological abnormalities, myocarditis, myositis or pneumonitis. Initial symptoms may resemble an acute viral infection. Other common manifestations include arthralgias, jaundice, hepatomegaly, leukocytosis, and eosinophilia. The interval between the first drug exposure and symptoms is usually 2 to 4 weeks, but has been reported in individuals receiving anticonvulsants for 3 or more months. If such signs and symptoms occur, the patient should be evaluated immediately. Phenytoin should be discontinued if an alternative etiology for the signs and symptoms cannot be established.
Patients at higher risk for developing HSS/DRESS include black patients, patients who have experienced this syndrome in the past (with Phenytoin or other anticonvulsant drugs), patients who have a family history of this syndrome and immunosuppressed patients. The syndrome is more severe in previously sensitized individuals.
Serious Dermatologic Reactions: Phenytoin can cause rare, serious skin adverse events, such as exfoliative dermatitis, Stevens-Johnson Syndrome (SJS) and toxic epidermal necrolysis (TEN), which can be fatal. Although serious skin reactions may occur without warning, patients should be alert for the occurrence of rash and other symptoms of HSS/DRESS, and should seek medical advice from their physician immediately when observing any indicative signs or symptoms. The physician should advise the patient to discontinue treatment if the rash appears.
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 medication is contraindicated. The risk of serious skin reactions and other hypersensitivity reactions to Phenytoin, literature report suggests that may be higher in black patients. The literature suggests that the combination of Phenytoin, cranial irradiation, and a gradual decrease in corticosteroids can lead to the development of erythema multiform, and/or SJS, and/or TEN.
Hepatic Injury: The liver is the chief site of biotransformation of Phenytoin.
Toxic hepatitis and liver damage may occurred rarely, can be fatal.
Cases of acute hepatotoxicity, including infrequent cases of acute hepatic failure, have been occurred with Phenytoin. These incidents usually occur within the first 2 months of treatment and may be associated with HSS/DRESS. Patients with impaired liver function, elderly patients, or those who are gravely ill may show early signs of toxicity.
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.
The risk of hepatotoxicity and other hypersensitivity reactions to Phenytoin may be higher in black patients.
Hematopoietic System: Hematopoietic complications, some fatal, have occasionally been occurred in association with administrations of Phenytoin. These have included thrombocytopenia, leukopenia, granulocytopenia, agranulocytosis and pancytopenia with or without bone marrow suppression.
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 HSS/DRESS. 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.
While macrocytosis and megaloblastic anemia have occurred, these conditions usually respond to Folic Acid therapy. If Folic Acid is added to Phenytoin therapy, a decrease in seizure control may occur.
Central Nervous System: 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 and/or cerebellar atrophy. Accordingly, at the first sign of acute toxicity, serum drug level determinations are recommended. Dose reduction of Phenytoin therapy is indicated if serum levels are excessive; if symptoms persist, termination of therapy with Phenytoin is recommended.
Metabolic Effect: Phenytoin can caused exacerbation of porphyria, caution should be exercised in using this medication in patients suffering from this disease.
Hyperglycemia, resulting from the drug's inhibitory effect on insulin release, has been reported. Phenytoin also may raise serum glucose levels in diabetic patients.
Musculoskeletal Effect: Phenytoin and other anticonvulsants that have been shown to induce the CYP450 enzyme are thought to affect bone mineral metabolism indirectly by increasing the metabolism of Vitamin D3. This may lead to Vitamin D deficiency and heightened risk of osteomalacia, bone fractures, osteoporosis, hypocalcemia, and hypophosphatemia in chronically treated epileptic patients.
Women of Childbearing Potential: Phenytoin may cause fetal harm when administered to a pregnant women. Prenatal exposure to Phenytoin may increase the risks for congenital malformations and other adverse development outcomes.
Fertility: In animal studies, Phenytoin had no direct effect on fertility.
Information for the Patient: Patient taking Phenytoin should be advised of the importance of adhering strictly to the prescribed dosage regimen and of informing their physician of any clinical condition in which it is not possible to take the drug orally as prescribed, e.g., surgery, etc.
Patients should be cautioned on the use of other drugs or alcoholic beverages without first seeking their physician's advice.
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.
Effects on Ability to Drive and Use Machines: Patients should be advised not to drive a car or operate potentially dangerous machinery until it is known that this medication does not affect their ability to engage in these activities.
Use in Pregnancy: Phenytoin crosses the placenta in humans.
There is 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. There are also a possible similar association with the use of all known anticonvulsant drugs.
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 hazard to the developing embryo or fetus. The prescribing physician will wish to weigh these considerations in treating or counseling epileptic women of child-bearing potential.
In addition there is also increased incidence of congenital malformations, such as cleft lip/palate and heart malformations in children of women receiving Phenytoin and other anticonvulsant drugs, there have been occurred of a fetal hydantoin syndrome. This consists of pre-natal dysmorphic facial features, nail and digit hypoplasia, growth deficiency (including 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.
Phenytoin should only be used in women of childbearing potential and pregnant women if the potential benefit outweighs the risk. When appropriate, counsel pregnant women and women of childbearing potential about alternative therapeutic options.
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 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.
Women of childbearing potential who are not planning a pregnancy should be advised regarding the use of effective contraception during treatment. Phenytoin may result in a failure of the therapeutic effect of hormonal contraceptives.
Phenytoin is teratogenic in rats, mice and rabbits.
Use in Lactation: Breast-feeding is not recommended for women taking this drug because phenytoin appears to be secreted in low concentrations in human milk. Phenytoin concentration in breast milk is approximately one-third of the corresponding maternal plasma concentration.
