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Phenytoin sodium equivalents (PE): Doses of fosphenytoin sodium (Aurantin) are always expressed in terms of milligrams of phenytoin sodium equivalents (mg PE). 1 mg PE is equivalent to 1 mg phenytoin sodium. Do not, therefore, make any adjustment in the recommended doses when substituting fosphenytoin for phenytoin sodium or vice versa. For example, if a patient is receiving 1000 mg PE of fosphenytoin sodium (Aurantin), that is equivalent to 1000 mg of phenytoin sodium.
Dosing Errors: Do not confuse the amount of drug to be given in PE with the concentration of the drug in the vial.
Medication errors associated with fosphenytoin sodium (Aurantin) have resulted in patients receiving the wrong dose of fosphenytoin sodium (Aurantin). Fosphenytoin sodium (Aurantin) is marketed in 10 mL vials containing a total of 500 mg PE. The concentration of each vial is 50 mg PE/mL. Errors have occurred when the concentration of the vial (50 mg PE/mL) was misinterpreted to mean that the total content of the vial was 50 mg PE. These errors have resulted in two- or ten-fold overdoses of fosphenytoin sodium (Aurantin) since each vial actually contains a total of 100 mg PE or 500 mg PE. In some cases, ten-fold overdoses were associated with fatal outcomes. To help minimize confusion, the prescribed dose of fosphenytoin sodium (Aurantin) should always be expressed in milligrams of phenytoin equivalents (mg PE). Additionally, when ordering and storing fosphenytoin sodium (Aurantin), consider displaying the total drug content (i.e., 500 mg PE/10 mL) instead of concentration in computer systems, pre-printed orders, and automated dispensing cabinet databases to help ensure that total drug content can be clearly identified. Care should be taken to ensure the appropriate volume of fosphenytoin sodium (Aurantin) is withdrawn from the vial when preparing the drug for administration. Attention to these details may prevent some fosphenytoin medication errors from occurring.
Maximum Infusion Rate: Because of the increased risk of adverse cardiovascular reactions associated with rapid administration, do not administer fosphenytoin sodium (Aurantin) at a rate greater than 150 mg PE/min (see Dosage & Administration).
The following warnings are based on experience with fosphenytoin or phenytoin.
General: Phenytoin and, consequently, fosphenytoin sodium (Aurantin) are not effective for the treatment of 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.
Antiepileptic drugs (AEDs) 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 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.
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 alcohol intake may increase plasma phenytoin concentrations, while chronic alcohol use may decrease plasma phenytoin concentrations.
The phosphate load provided by fosphenytoin sodium (Aurantin) (0.0037 mmol phosphate/mg PE fosphenytoin) should be considered when treating patients who require phosphate restriction, such as those with severe renal impairment.
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. After IV administration of fosphenytoin sodium (Aurantin) to patients with renal and/or hepatic disease, or in those with hypoalbuminemia, fosphenytoin clearance to phenytoin may be increased without a similar increase in phenytoin clearance. This has the potential to increase the frequency and severity of adverse events.
Phenytoin has the potential to lower serum folate levels.
Suicide: Some AEDs have been associated with an increased risk of suicidal ideation and/or behavior. Based on a meta-analysis of 11 different AEDs, which did not include fosphenytoin/phenytoin, class labeling for all AEDs was instituted by a number of regulatory authorities. The relationship between fosphenytoin/phenytoin and an increased risk of suicidal ideation and/or behavior is unknown. All patients treated with AEDs should be routinely evaluated for depression, anxiety, and suicidality.
Cardiovascular Effect: Hypotension may occur, especially after IV administration at high doses and high rates of administration. Following administration of fosphenytoin or phenytoin, severe cardiovascular reactions have been reported, including atrial and ventricular conduction depression and ventricular fibrillation. In some cases, cardiac arrhythmias have resulted in asystole/cardiac arrest and death. Severe cardiac complications are most commonly encountered in elderly or gravely ill patients. Cardiac adverse events have also been reported in adults and children without underlying cardiac disease or comorbidities and at recommended doses and infusion rates. Therefore, careful cardiac (including respiratory) monitoring is needed when administering IV loading doses of fosphenytoin sodium (Aurantin). Reduction in rate of administration or discontinuation of dosing may be needed.
Fosphenytoin sodium (Aurantin) should be used with caution in patients with hypotension and severe myocardial insufficiency.
Local Toxicity (Including Purple Glove Syndrome): Edema, discoloration, and pain distal to the site of injection (described as "purple glove syndrome") have also been reported following peripheral IV fosphenytoin sodium (Aurantin) injection. This may or may not be associated with extravasation. The syndrome may not develop for several days after injection.
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 anticonvulsants, including phenytoin and fosphenytoin. 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 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. Fosphenytoin sodium (Aurantin) 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, fosphenytoin or other anticonvulsants), 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), exfoliative dermatitis, Stevens-Johnson Syndrome (SJS), 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 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 fosphenytoin sodium (Aurantin) 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-B*1502 (HLA-B), an inherited allelic variant of the HLA B gene, in patients using 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 and fosphenytoin. Fosphenytoin sodium (Aurantin) should be discontinued immediately if symptoms of angioedema, such as facial, perioral, or upper airway swelling occur.
Hepatic Injury: The liver is the chief site of biotransformation of phenytoin.
Toxic hepatitis and liver damage have been reported with phenytoin 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 under Precautions). 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 patients with acute hepatotoxicity, fosphenytoin sodium (Aurantin) 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 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 that have suggested 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 under Precautions). 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 AEDs.
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, serum drug level determination of phenytoin is recommended (see Laboratory Tests under Dosage & Administration). Fosphenytoin sodium (Aurantin) dose reduction is indicated if phenytoin concentrations are excessive; if symptoms persist, administration of fosphenytoin sodium (Aurantin) should be discontinued.
Metabolic Effect: Phenytoin has been infrequently associated with the exacerbation of porphyria. Caution should be exercised when fosphenytoin sodium (Aurantin) is used in patients with this disease.
Hyperglycemia, resulting from phenytoin's inhibitory effect on insulin release, has been reported. Phenytoin may also raise serum glucose concentrations in diabetic 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 Pregnancy & Lactation).
Patient Information: 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.
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.
