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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 hypoglycemic 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 judgment 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 (polymorphism).
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 hyperbilirubinemia. 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 meta-analysis of randomized placebo-controlled trials of anti-epileptic drugs has also shown a small increased risk of suicidal ideation and behavior. The mechanism of this risk is not known, and the available data do not exclude the possibility of an increased risk for phenytoin.
Cardiac Effects: Cases of bradycardia and asystole/cardiac arrest have been reported, most commonly in association with phenytoin toxicity (see Overdosage), but also at recommended phenytoin doses and levels.
Hypersensitivity Syndrome/Drug Reaction with Eosinophilia and Systemic Symptoms: Hypersensitivity syndrome (HSS) or drug reaction with eosinophilia and systemic symptoms (DRESS) has been reported in patients taking anticonvulsant drugs, including phenytoin. Some of these events have been fatal or life threatening.
HSS/DRESS typically, although not exclusively, presents with fever, rash, and/or lymphadenopathy in association with other organ system involvement, such as hepatitis, nephritis, hematological 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, severe cutaneous adverse reactions (SCARS) such as acute generalized exanthematous pustulosis (AGEP) (see Dermatologic System under Adverse Reactions), exfoliative dermatitis, Stevens-Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN), and DRESS, 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 (see Hypersensitivity Syndrome/Drug Reaction with Eosinophilia and Systemic Symptoms as previously mentioned), 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 may be higher in black patients.
Studies in patients of Chinese ancestry have found a strong association between the risk of developing SJS/TEN and the presence of human leukocyte antigen HLA-B*1502, an inherited allelic variant of the HLA-B gene, in patients using another carbamazepine. Limited evidence suggests that HLA-B*1502 may be a risk factor for the development of SJS/TEN in patients of Asian ancestry taking drugs associated with SJS/TEN, including phenytoin. Consideration should be given to avoiding use of drugs associated with SJS/TEN, including phenytoin, in HLA-B* 1502-positive patients when alternative therapies are otherwise equally available.
Literature reports suggest that the combination of phenytoin, cranial irradiation and the gradual reduction of corticosteroids may be associated with the development of erythema multiforme, and/or SJS, and/or TEN.
Angioedema: Angioedema has been reported in patients treated with phenytoin. Phenytoin should be discontinued immediately if symptoms of angioedema, such as facial, perioral, or upper airway swelling occur (see Immunologic under Adverse Reactions).
Hematopoietic System: Hematopoietic complications, some fatal, have occasionally been reported in association with administration 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 signs and symptoms resembling HSS/DRESS (see Hypersensitivity Syndrome/Drug Reaction with Eosinophilia and Systemic Symptoms as previously mentioned.). 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 Effect: 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, determination of serum drug levels is recommended. Dose reduction of phenytoin therapy is indicated if serum levels are excessive; if symptoms persist, termination of phenytoin therapy is recommended.
Metabolic Effect: 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.
Hyperglycemia, resulting from the drug's inhibitory effects on insulin release, has been reported. Phenytoin may also 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.
Information for the Patient: Patients 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 also 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.
Hepatic Injury: The liver is the chief site of biotransformation of phenytoin.
Toxic hepatitis and liver damage have been reported and may, in rare cases, be fatal.
Cases of acute hepatotoxicity, including infrequent cases of acute hepatic failure, have been reported with phenytoin. These incidents usually occur within the first 2 months of treatment and may be associated with HSS/DRESS (see Hypersensitivity Syndrome/Drug Reaction with Eosinophilia and Systemic Symptoms as previously mentioned). 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.
Women of Childbearing Potential: Phenytoin may cause fetal harm when administered to a pregnant woman. Prenatal exposure to phenytoin may increase the risks for congenital malformations and other adverse development outcomes (see Use in Pregnancy & lactation).
