Fosphenytoin
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Side Effects & Adverse Reactions
DOSES OF FOSPHENYTOIN SODIUM INJECTION 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 SODIUM INJECTION FOR PHENYTOIN SODIUM OR VICE VERSA. FOR EXAMPLE, IF A PATIENT IS RECEIVING 1,000 mg PE OF FOSPHENYTOIN SODIUM, THAT IS EQUIVALENT TO 1,000 mg OF PHENYTOIN SODIUM.
The following warnings are based on experience with fosphenytoin sodium injection or phenytoin.
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 have resulted in patients receiving the wrong dose of fosphenytoin. Fosphenytoin sodium injection is marketed in 2 mL vials containing a total of 100 mg PE and 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 injection 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 injection should always be expressed in milligrams of phenytoin equivalents (mg PE) (see DOSAGE AND ADMINISTRATION). Additionally, when ordering and storing fosphenytoin, consider displaying the total drug content (i.e., 100 mg PE/2 mL or 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 Care should be taken to ensure the appropriate volume of fosphenytoin is withdrawn from the vial when preparing the drug for administration. Attention to these details may prevent some fosphenytoin medication errors from occurring.
Because of the increased risk of adverse cardiovascular reactions associated with rapid administration, do not administer fosphenytoin sodium injection at a rate greater than 150 mg PE/min.
The dose of IV fosphenytoin sodium injection (15 to 20 mg PE/kg) that is used to treat status epilepticus is administered at a maximum rate of 150 mg PE/min. The typical fosphenytoin sodium injection infusion administered to a 50 kg patient would take between 5 and 7 minutes. Note that the delivery of an identical molar dose of phenytoin using parenteral phenytoin sodium or generic phenytoin sodium injection cannot be accomplished in less than 15 to 20 minutes because of the untoward cardiovascular effects that accompany the direct intravenous administration of phenytoin at rates greater than 50 mg/min.
If rapid phenytoin loading is a primary goal, IV administration of fosphenytoin sodium injection is preferred because the time to achieve therapeutic plasma phenytoin concentrations is greater following IM than that following IV administration (see DOSAGE AND ADMINISTRATION).
As non-emergency therapy, intravenous fosphenytoin should be administered more slowly. Because of the risks of cardiac and local toxicity associated with IV fosphenytoin, oral phenytoin should be used whenever possible.
Because adverse cardiovascular reactions have occurred during and after infusions, careful cardiac monitoring is needed during and after the administration of intravenous fosphenytoin. Reduction in rate of administration or discontinuation of dosing may be needed.
Adverse cardiovascular reactions include severe hypotension and cardiac arrhythmias. Cardiac arrhythmias have included bradycardia, heart block, QT interval prolongation, ventricular tachycardia, and ventricular fibrillation which have resulted in asystole, cardiac arrest, and death. Severe complications are most commonly encountered in critically ill patients, elderly patients, and patients with hypotension and severe myocardial insufficiency. However, cardiac events have also been reported in adults and children without underlying cardiac disease or comorbidities and at recommended doses and infusion rates.
Antiepileptic drugs 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.
Serious and sometimes fatal dermatologic reactions, including toxic epidermal necrolysis (TEN) and Stevens-Johnson syndrome (SJS), have been reported with phenytoin treatment. The onset of symptoms is usually within 28 days, but can occur later. Fosphenytoin should be discontinued at the first sign of a rash, unless the rash is clearly not drug-related. If signs or symptoms suggest SJS/TEN, use of this drug should not be resumed and alternative therapy should be considered. If a rash occurs, the patient should be evaluated for signs and symptoms of Drug Reaction with Eosinophilia and Systemic Symptoms (see DRESS/Multiorgan Hypersensitivity below).
Studies in patients of Chinese ancestry have found a strong association between the risk of developing SJS/TEN and the presence of HLA-B*1502, 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 other antiepileptic drugs associated with SJS/TEN, including phenytoin. Consideration should be given to avoiding fosphenytoin sodium injection as an alternative for carbamazepine patients positive for HLA-B*1502.
The use of HLA-B*1502 genotyping has important limitations and must never substitute for appropriate clinical vigilance and patient management. The role of other possible factors in the development of, and morbidity from, SJS/TEN, such as antiepileptic drug (AED) dose, compliance, concomitant medications, comorbidities, and the level of dermatologic monitoring have not been studied.
Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), also known as Multiorgan hypersensitivity, has been reported in patients taking antiepileptic drugs, including phenytoin and fosphenytoin. Some of these events have been fatal or life-threatening. 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, or myositis sometimes resembling an acute viral infection. Eosinophilia is often present. Because this disorder is variable in its expression, other organ systems not noted here may be involved. It is important to note that early manifestations of hypersensitivity, such as fever or lymphadenopathy, may be present even though rash is not evident. If such signs or symptoms are present, the patient should be evaluated immediately. Fosphenytoin sodium injection should be discontinued if an alternative etiology for the signs or symptoms cannot be established.
Fosphenytoin and other hydantoins are contraindicated in patients who have experienced phenytoin hypersensitivity (see CONTRAINDICATIONS). Additionally, consider alternatives to structurally similar drugs such as carboxamides (e.g., carbamazepine), barbiturates, succinimides, and oxazolidinediones (e.g., trimethadione) in these same patients. Similarly, if there is a history of hypersensitivity reactions to these structurally similar drugs in the patient or immediate family members, consider alternatives to fosphenytoin sodium injection.
Cases of acute hepatotoxicity, including infrequent cases of acute hepatic failure, have been reported with phenytoin. These events may be part of the spectrum of DRESS or may occur in isolation. 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, fosphenytoin sodium injection should be immediately discontinued and not readministered.
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 symptoms and signs resembling 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 antiepileptic drugs.
Acute alcohol intake may increase plasma phenytoin concentrations while chronic alcohol use may decrease plasma concentrations.
Clinical
Risks to Mother. An increase in seizure frequency may occur during pregnancy because of altered phenytoin pharmacokinetics. Periodic measurement of plasma phenytoin concentrations may be valuable in the management of pregnant women as a guide to appropriate adjustment of dosage (see PRECAUTIONS , Laboratory Tests). However, postpartum restoration of the original dosage will probably be indicated.
Risks to the Fetus. If this drug is used during pregnancy, or if the patient becomes pregnant while taking the drug, the patient should be apprised of the potential harm to the fetus.
Prenatal exposure to phenytoin may increase the risks for congenital malformations and other adverse developmental outcomes. Increased frequencies of major malformations (such as orofacial clefts and cardiac defects), minor anomalies (dysmorphic facial features, nail and digit hypoplasia), growth abnormalities (including microcephaly), and mental deficiency have been reported among children born to epileptic women who took phenytoin alone or in combination with other antiepileptic drugs during pregnancy. There have also been several reported cases of malignancies, including neuroblastoma, in children whose mothers received phenytoin during pregnancy. The overall incidence of malformations for children of epileptic women treated with antiepileptic drugs (phenytoin and/or others) during pregnancy is about 10%, or two- to three-fold that in the general population. However, the relative contributions of antiepileptic drugs and other factors associated with epilepsy to this increased risk are uncertain and in most cases it has not been possible to attribute specific developmental abnormalities to particular antiepileptic drugs. Patients should consult with their physicians to weigh the risks and benefits of phenytoin during pregnancy.
Postpartum Period. A potentially life-threatening bleeding disorder related to decreased levels of vitamin K-dependent clotting factors may occur in newborns exposed to phenytoin in utero. This drug-induced condition can be prevented with vitamin K administration to the mother before delivery and to the neonate after birth.
Preclinical
Increased frequencies of malformations (brain, cardiovascular, digit, and skeletal anomalies), death, growth retardation, and functional impairment (chromodacryorrhea, hyperactivity, circling) were observed among the offspring of rats receiving fosphenytoin during pregnancy. Most of the adverse effects on embryo-fetal development occurred at doses of 33 mg PE/kg or higher (approximately 30% of the maximum human loading dose or higher on a mg/m2 basis), which produced peak maternal plasma phenytoin concentrations of approximately 20 mcg/mL or greater. Maternal toxicity was often associated with these doses and plasma concentrations, however, there is no evidence to suggest that the developmental effects were secondary to the maternal effects. The single occurrence of a rare brain malformation at a nonmaternotoxic dose of 17 mg PE/kg (approximately 10% of the maximum human loading dose on a mg/m2 basis) was also considered drug-induced. The developmental effects of fosphenytoin in rats were similar to those which have been reported following administration of phenytoin to pregnant rats. No effects on embryo-fetal development were observed when rabbits were given up to 33 mg PE/kg of fosphenytoin (approximately 50% of the maximum human loading dose on a mg/m2 basis) during pregnancy. Increased resorption and malformation rates have been reported following administration of phenytoin doses of 75 mg/kg or higher (approximately 120% of the maximum human loading dose or higher on a mg/m2 basis) to pregnant rabbits.
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 have resulted in patients receiving the wrong dose of fosphenytoin. Fosphenytoin sodium injection is marketed in 2 mL vials containing a total of 100 mg PE and 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 injection 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 injection should always be expressed in milligrams of phenytoin equivalents (mg PE) (see DOSAGE AND ADMINISTRATION). Additionally, when ordering and storing fosphenytoin, consider displaying the total drug content (i.e., 100 mg PE/2 mL or 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 is withdrawn from the vial when preparing the drug for administration. Attention to these details may prevent some fosphenytoin medication errors from occurring.
Status Epilepticus Dosing RegimenBecause of the increased risk of adverse cardiovascular reactions associated with rapid administration, do not administer fosphenytoin sodium injection at a rate greater than 150 mg PE/min.
The dose of IV fosphenytoin sodium injection (15 to 20 mg PE/kg) that is used to treat status epilepticus is administered at a maximum rate of 150 mg PE/min. The typical fosphenytoin sodium injection infusion administered to a 50 kg patient would take between 5 and 7 minutes. Note that the delivery of an identical molar dose of phenytoin using parenteral phenytoin sodium or generic phenytoin sodium injection cannot be accomplished in less than 15 to 20 minutes because of the untoward cardiovascular effects that accompany the direct intravenous administration of phenytoin at rates greater than 50 mg/min.
If rapid phenytoin loading is a primary goal, IV administration of fosphenytoin sodium injection is preferred because the time to achieve therapeutic plasma phenytoin concentrations is greater following IM than that following IV administration (see DOSAGE AND ADMINISTRATION).
Cardiovascular Risk Associated with Rapid InfusionAs non-emergency therapy, intravenous fosphenytoin should be administered more slowly. Because of the risks of cardiac and local toxicity associated with IV fosphenytoin, oral phenytoin should be used whenever possible.
Because adverse cardiovascular reactions have occurred during and after infusions, careful cardiac monitoring is needed during and after the administration of intravenous fosphenytoin. Reduction in rate of administration or discontinuation of dosing may be needed.
Adverse cardiovascular reactions include severe hypotension and cardiac arrhythmias. Cardiac arrhythmias have included bradycardia, heart block, QT interval prolongation, ventricular tachycardia, and ventricular fibrillation which have resulted in asystole, cardiac arrest, and death. Severe complications are most commonly encountered in critically ill patients, elderly patients, and patients with hypotension and severe myocardial insufficiency. However, cardiac events have also been reported in adults and children without underlying cardiac disease or comorbidities and at recommended doses and infusion rates.
Withdrawal Precipitated Seizure, Status EpilepticusAntiepileptic drugs 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.
Serious Dermatologic ReactionsSerious and sometimes fatal dermatologic reactions, including toxic epidermal necrolysis (TEN) and Stevens-Johnson syndrome (SJS), have been reported with phenytoin treatment. The onset of symptoms is usually within 28 days, but can occur later. Fosphenytoin should be discontinued at the first sign of a rash, unless the rash is clearly not drug-related. If signs or symptoms suggest SJS/TEN, use of this drug should not be resumed and alternative therapy should be considered. If a rash occurs, the patient should be evaluated for signs and symptoms of Drug Reaction with Eosinophilia and Systemic Symptoms (see DRESS/Multiorgan Hypersensitivity below).
Studies in patients of Chinese ancestry have found a strong association between the risk of developing SJS/TEN and the presence of HLA-B*1502, 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 other antiepileptic drugs associated with SJS/TEN, including phenytoin. Consideration should be given to avoiding fosphenytoin sodium injection as an alternative for carbamazepine patients positive for HLA-B*1502.
The use of HLA-B*1502 genotyping has important limitations and must never substitute for appropriate clinical vigilance and patient management. The role of other possible factors in the development of, and morbidity from, SJS/TEN, such as antiepileptic drug (AED) dose, compliance, concomitant medications, comorbidities, and the level of dermatologic monitoring have not been studied.
Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/Multiorgan HypersensitivityDrug Reaction with Eosinophilia and Systemic Symptoms (DRESS), also known as Multiorgan hypersensitivity, has been reported in patients taking antiepileptic drugs, including phenytoin and fosphenytoin. Some of these events have been fatal or life-threatening. 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, or myositis sometimes resembling an acute viral infection. Eosinophilia is often present. Because this disorder is variable in its expression, other organ systems not noted here may be involved. It is important to note that early manifestations of hypersensitivity, such as fever or lymphadenopathy, may be present even though rash is not evident. If such signs or symptoms are present, the patient should be evaluated immediately. Fosphenytoin sodium injection should be discontinued if an alternative etiology for the signs or symptoms cannot be established.
HypersensitivityFosphenytoin and other hydantoins are contraindicated in patients who have experienced phenytoin hypersensitivity (see CONTRAINDICATIONS). Additionally, consider alternatives to structurally similar drugs such as carboxamides (e.g., carbamazepine), barbiturates, succinimides, and oxazolidinediones (e.g., trimethadione) in these same patients. Similarly, if there is a history of hypersensitivity reactions to these structurally similar drugs in the patient or immediate family members, consider alternatives to fosphenytoin sodium injection.
Hepatic InjuryCases of acute hepatotoxicity, including infrequent cases of acute hepatic failure, have been reported with phenytoin. These events may be part of the spectrum of DRESS or may occur in isolation. 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, fosphenytoin sodium injection should be immediately discontinued and not readministered.
Hematopoietic SystemHematopoietic 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 symptoms and signs resembling 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 antiepileptic drugs.
Alcohol UseAcute alcohol intake may increase plasma phenytoin concentrations while chronic alcohol use may decrease plasma concentrations.
Usage in PregnancyClinical
Risks to Mother. An increase in seizure frequency may occur during pregnancy because of altered phenytoin pharmacokinetics. Periodic measurement of plasma phenytoin concentrations may be valuable in the management of pregnant women as a guide to appropriate adjustment of dosage (see PRECAUTIONS , Laboratory Tests). However, postpartum restoration of the original dosage will probably be indicated.
Risks to the Fetus. If this drug is used during pregnancy, or if the patient becomes pregnant while taking the drug, the patient should be apprised of the potential harm to the fetus.
Prenatal exposure to phenytoin may increase the risks for congenital malformations and other adverse developmental outcomes. Increased frequencies of major malformations (such as orofacial clefts and cardiac defects), minor anomalies (dysmorphic facial features, nail and digit hypoplasia), growth abnormalities (including microcephaly), and mental deficiency have been reported among children born to epileptic women who took phenytoin alone or in combination with other antiepileptic drugs during pregnancy. There have also been several reported cases of malignancies, including neuroblastoma, in children whose mothers received phenytoin during pregnancy. The overall incidence of malformations for children of epileptic women treated with antiepileptic drugs (phenytoin and/or others) during pregnancy is about 10%, or two- to three-fold that in the general population. However, the relative contributions of antiepileptic drugs and other factors associated with epilepsy to this increased risk are uncertain and in most cases it has not been possible to attribute specific developmental abnormalities to particular antiepileptic drugs. Patients should consult with their physicians to weigh the risks and benefits of phenytoin during pregnancy.
Postpartum Period. A potentially life-threatening bleeding disorder related to decreased levels of vitamin K-dependent clotting factors may occur in newborns exposed to phenytoin in utero. This drug-induced condition can be prevented with vitamin K administration to the mother before delivery and to the neonate after birth.
Preclinical
Increased frequencies of malformations (brain, cardiovascular, digit, and skeletal anomalies), death, growth retardation, and functional impairment (chromodacryorrhea, hyperactivity, circling) were observed among the offspring of rats receiving fosphenytoin during pregnancy. Most of the adverse effects on embryo-fetal development occurred at doses of 33 mg PE/kg or higher (approximately 30% of the maximum human loading dose or higher on a mg/m2 basis), which produced peak maternal plasma phenytoin concentrations of approximately 20 mcg/mL or greater. Maternal toxicity was often associated with these doses and plasma concentrations, however, there is no evidence to suggest that the developmental effects were secondary to the maternal effects. The single occurrence of a rare brain malformation at a nonmaternotoxic dose of 17 mg PE/kg (approximately 10% of the maximum human loading dose on a mg/m2 basis) was also considered drug-induced. The developmental effects of fosphenytoin in rats were similar to those which have been reported following administration of phenytoin to pregnant rats. No effects on embryo-fetal development were observed when rabbits were given up to 33 mg PE/kg of fosphenytoin (approximately 50% of the maximum human loading dose on a mg/m2 basis) during pregnancy. Increased resorption and malformation rates have been reported following administration of phenytoin doses of 75 mg/kg or higher (approximately 120% of the maximum human loading dose or higher on a mg/m2 basis) to pregnant rabbits.
Legal Issues
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FDA Safety Alerts
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Manufacturer Warnings
There is currently no manufacturer warning information available for this drug.
FDA Labeling Changes
There are currently no FDA labeling changes available for this drug.
Uses
Fosphenytoin sodium injection is indicated for the control of generalized tonic-clonic status epilepticus and prevention and treatment of seizures occurring during neurosurgery. Fosphenytoin sodium can also be substituted, short-term, for oral phenytoin. Fosphenytoin sodium should be used only when oral phenytoin administration is not possible. Fosphenytoin sodium must not be given orally.
History
There is currently no drug history available for this drug.
Other Information
Fosphenytoin Sodium Injection, USP is a prodrug intended for parenteral administration; its active metabolite is phenytoin. 1.5 mg of fosphenytoin sodium is equivalent to 1 mg phenytoin sodium, and is referred to as 1 mg phenytoin sodium equivalents (PE). The amount and concentration of fosphenytoin is always expressed in terms of mg PE.
Fosphenytoin Sodium Injection, USP is marketed in 2 mL vials containing a total of 100 mg PE and 10 mL vials containing a total of 500 mg PE. The concentration of each vial is 50 mg PE/mL. Fosphenytoin Sodium Injection, USP, is supplied in vials as a ready-mixed solution in water for injection, and tromethamine (TRIS), buffer adjusted to pH 8.6 to 9.0 with either hydrochloric acid, or sodium hydroxide. Fosphenytoin Sodium Injection, USP, is a clear, colorless to pale yellow, sterile solution.
The chemical name of fosphenytoin is 5,5-diphenyl-3-[(phosphonooxy)methyl]-2,4- imidazolidinedione disodium salt. The molecular structure of fosphenytoin is:
M.W. 406.24
IMPORTANT NOTE: Throughout all fosphenytoin sodium injection product labeling, the amount and concentration of fosphenytoin are always expressed in terms of phenytoin sodium equivalents (PE). Fosphenytoin’s weight is expressed as phenytoin sodium equivalents to avoid the need to perform molecular weight-based adjustments when substituting fosphenytoin for phenytoin or vice versa.
Care should be taken to ensure that fosphenytoin sodium injection is always prescribed and dispensed in phenytoin sodium equivalents (PE) (see DOSAGE AND ADMINISTRATION).
Sources
Fosphenytoin Manufacturers
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Fresenius Kabi Usa, Llc
![Fosphenytoin (Fosphenytoin Sodium) Injection, Solution [Fresenius Kabi Usa, Llc]](/wp-content/themes/bootstrap/assets/img/loading2.gif)
Fosphenytoin | Fresenius Kabi Usa, Llc
The dose, concentration, and infusion rate of fosphenytoin sodium injection should always be expressed as phenytoin sodium equivalents (PE). There is no need to perform molecular weight-based adjustments when converting between fosphenytoin and phenytoin sodium doses. Fosphenytoin sodium injection should always be prescribed and dispensed in phenytoin sodium equivalent units (PE). 1.5 mg of fosphenytoin sodium is equivalent to 1 mg phenytoin sodium, and is referred to as 1 mg PE. The amount and concentration of fosphenytoin is always expressed in terms of mg of phenytoin sodium equivalents (mg PE).
Do not confuse the concentration of fosphenytoin sodium injection with the total amount of drug in the vial.
Caution must be used when administering fosphenytoin sodium injection due to the risk of dosing errors (see WARNINGS). Medication errors associated with fosphenytoin have resulted in patients receiving the wrong dose of fosphenytoin. Fosphenytoin sodium injection is marketed in 2 mL vials containing a total of 100 mg PE and 10 mL vials containing a total of 500 mg PE. Both vials contain a concentration of 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 injection since each of the vials 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 injection should always be expressed in milligrams of phenytoin equivalents (mg PE). Additionally, when ordering and storing fosphenytoin, consider displaying the total drug content (i.e., 100 mg PE/2 mL or 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 is withdrawn from the vial when preparing the dose for administration. Attention to these details may prevent some fosphenytoin medication errors from occurring.
Prior to IV infusion, dilute fosphenytoin sodium injection in 5% dextrose or 0.9% saline solution for injection to a concentration ranging from 1.5 to 25 mg PE/mL. The maximum concentration of fosphenytoin in any solution should be 25 mg PE/mL. When fosphenytoin is given as an intravenous infusion, fosphenytoin needs to be diluted and should only be administered at a rate not exceeding 150 mg PE/min.
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.
Status Epilepticus The loading dose of fosphenytoin sodium injection is 15 to 20 mg PE/kg administered at 100 to 150 mg PE/min. Because of the risk of hypotension, fosphenytoin should be administered no faster than 150 mg PE/min. Continuous monitoring of the electrocardiogram, blood pressure, and respiratory function is essential and the patient should be observed throughout the period where maximal serum phenytoin concentrations occur, approximately 10 to 20 minutes after the end of fosphenytoin sodium injection infusions. Because the full anti-epileptic effect of phenytoin, whether given as fosphenytoin sodium injection or parenteral phenytoin, is not immediate, other measures, including concomitant administration of an IV benzodiazepine, will usually be necessary for the control of status epilepticus. The loading dose should be followed by maintenance doses of either fosphenytoin sodium injection or phenytoin.If administration of fosphenytoin sodium injection does not terminate seizures, the use of other anticonvulsants and other appropriate measures should be considered.
Even though loading doses of fosphenytoin sodium injection have been given by the IM route for other indications when IV access is impossible, IM fosphenytoin should ordinarily not be used in the treatment of status epilepticus because therapeutic phenytoin concentrations may not be reached as quickly as with IV administration.
Nonemergent Loading and Maintenance DosingBecause of the risks of cardiac and local toxicity associated with intravenous fosphenytoin, oral phenytoin should be used whenever possible.
The loading dose of fosphenytoin sodium injection is 10 to 20 mg PE/kg given IV or IM. The rate of administration for IV fosphenytoin sodium injection should be no greater than 150 mg PE/min. Continuous monitoring of the electrocardiogram, blood pressure, and respiratory function is essential and the patient should be observed throughout the period where maximal serum phenytoin concentrations occur (approximately 20 minutes after the end of fosphenytoin sodium injection infusion).
The initial daily maintenance dose of fosphenytoin sodium injection is 4 to 6 mg PE/kg/day in divided doses.
IM or IV Substitution for Oral Phenytoin TherapyWhen treatment with oral phenytoin is not possible, fosphenytoin sodium injection can be substituted for oral phenytoin at the same total daily dose. Phenytoin sodium capsules are approximately 90% bioavailable by the oral route. Phenytoin, supplied as fosphenytoin sodium injection, is 100% bioavailable by both the IM and IV routes. For this reason, plasma phenytoin concentrations may increase modestly when IM or IV fosphenytoin sodium injection is substituted for oral phenytoin sodium therapy. The rate of administration for IV fosphenytoin sodium injection should be no greater than 150 mg PE/min. In controlled trials, IM fosphenytoin sodium injection was administered as a single daily dose utilizing either 1 or 2 injection sites. Some patients may require more frequent dosing.
Dosing in Special PopulationsPatients with Renal or Hepatic Disease: 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 (see CLINICAL PHARMACOLOGY, Special Populations). Unbound phenytoin concentrations may be more useful in these patient populations. After IV fosphenytoin sodium injection administration 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 (see PRECAUTIONS).
Elderly Patients: Age does not have a significant impact on the pharmacokinetics of fosphenytoin following fosphenytoin sodium injection administration. Phenytoin clearance is decreased slightly in elderly patients and lower or less frequent dosing may be required.
Pediatric: The safety and efficacy of fosphenytoin sodium injection in pediatric patients have not been established.
Status Epilepticus The loading dose of fosphenytoin sodium injection is 15 to 20 mg PE/kg administered at 100 to 150 mg PE/min. Because of the risk of hypotension, fosphenytoin should be administered no faster than 150 mg PE/min. Continuous monitoring of the electrocardiogram, blood pressure, and respiratory function is essential and the patient should be observed throughout the period where maximal serum phenytoin concentrations occur, approximately 10 to 20 minutes after the end of fosphenytoin sodium injection infusions. Because the full anti-epileptic effect of phenytoin, whether given as fosphenytoin sodium injection or parenteral phenytoin, is not immediate, other measures, including concomitant administration of an IV benzodiazepine, will usually be necessary for the control of status epilepticus. The loading dose should be followed by maintenance doses of either fosphenytoin sodium injection or phenytoin.If administration of fosphenytoin sodium injection does not terminate seizures, the use of other anticonvulsants and other appropriate measures should be considered.
Even though loading doses of fosphenytoin sodium injection have been given by the IM route for other indications when IV access is impossible, IM fosphenytoin should ordinarily not be used in the treatment of status epilepticus because therapeutic phenytoin concentrations may not be reached as quickly as with IV administration.
Nonemergent Loading and Maintenance DosingBecause of the risks of cardiac and local toxicity associated with intravenous fosphenytoin, oral phenytoin should be used whenever possible.
The loading dose of fosphenytoin sodium injection is 10 to 20 mg PE/kg given IV or IM. The rate of administration for IV fosphenytoin sodium injection should be no greater than 150 mg PE/min. Continuous monitoring of the electrocardiogram, blood pressure, and respiratory function is essential and the patient should be observed throughout the period where maximal serum phenytoin concentrations occur (approximately 20 minutes after the end of fosphenytoin sodium injection infusion).
The initial daily maintenance dose of fosphenytoin sodium injection is 4 to 6 mg PE/kg/day in divided doses.
IM or IV Substitution for Oral Phenytoin TherapyWhen treatment with oral phenytoin is not possible, fosphenytoin sodium injection can be substituted for oral phenytoin at the same total daily dose. Phenytoin sodium capsules are approximately 90% bioavailable by the oral route. Phenytoin, supplied as fosphenytoin sodium injection, is 100% bioavailable by both the IM and IV routes. For this reason, plasma phenytoin concentrations may increase modestly when IM or IV fosphenytoin sodium injection is substituted for oral phenytoin sodium therapy. The rate of administration for IV fosphenytoin sodium injection should be no greater than 150 mg PE/min. In controlled trials, IM fosphenytoin sodium injection was administered as a single daily dose utilizing either 1 or 2 injection sites. Some patients may require more frequent dosing.
Dosing in Special PopulationsPatients with Renal or Hepatic Disease: 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 (see CLINICAL PHARMACOLOGY, Special Populations). Unbound phenytoin concentrations may be more useful in these patient populations. After IV fosphenytoin sodium injection administration 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 (see PRECAUTIONS).
Elderly Patients: Age does not have a significant impact on the pharmacokinetics of fosphenytoin following fosphenytoin sodium injection administration. Phenytoin clearance is decreased slightly in elderly patients and lower or less frequent dosing may be required.
Pediatric: The safety and efficacy of fosphenytoin sodium injection in pediatric patients have not been established.
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Fresenius Kabi Usa, Llc
Fosphenytoin | Fresenius Kabi Usa, Llc
The dose, concentration, and infusion rate of fosphenytoin sodium injection should always be expressed as phenytoin sodium equivalents (PE). There is no need to perform molecular weight-based adjustments when converting between fosphenytoin and phenytoin sodium doses. Fosphenytoin sodium injection should always be prescribed and dispensed in phenytoin sodium equivalent units (PE). 1.5 mg of fosphenytoin sodium is equivalent to 1 mg phenytoin sodium, and is referred to as 1 mg PE. The amount and concentration of fosphenytoin is always expressed in terms of mg of phenytoin sodium equivalents (mg PE).
Do not confuse the concentration of fosphenytoin sodium injection with the total amount of drug in the vial.
Caution must be used when administering fosphenytoin sodium injection due to the risk of dosing errors (see WARNINGS). Medication errors associated with fosphenytoin have resulted in patients receiving the wrong dose of fosphenytoin. Fosphenytoin sodium injection is marketed in 2 mL vials containing a total of 100 mg PE. Each vial contains a concentration of 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 injection since each of the vials actually contains a total of 100 mg PE. In some cases, ten-fold overdoses were associated with fatal outcomes. To help minimize confusion, the prescribed dose of fosphenytoin sodium injection should always be expressed in milligrams of phenytoin equivalents (mg PE). Additionally, when ordering and storing fosphenytoin, consider displaying the total drug content (i.e., 100 mg PE/2 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 is withdrawn from the vial when preparing the dose for administration. Attention to these details may prevent some fosphenytoin medication errors from occurring.
Prior to IV infusion, dilute fosphenytoin sodium injection in 5% dextrose or 0.9% saline solution for injection to a concentration ranging from 1.5 to 25 mg PE/mL. The maximum concentration of fosphenytoin in any solution should be 25 mg PE/mL. When fosphenytoin is given as an intravenous infusion, fosphenytoin needs to be diluted and should only be administered at a rate not exceeding 150 mg PE/min.
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.
Status Epilepticus The loading dose of fosphenytoin sodium injection is 15 to 20 mg PE/kg administered at 100 to 150 mg PE/min. Because of the risk of hypotension, fosphenytoin should be administered no faster than 150 mg PE/min. Continuous monitoring of the electrocardiogram, blood pressure, and respiratory function is essential and the patient should be observed throughout the period where maximal serum phenytoin concentrations occur, approximately 10 to 20 minutes after the end of fosphenytoin sodium injection infusions. Because the full antiepileptic effect of phenytoin, whether given as fosphenytoin sodium injection or parenteral phenytoin, is not immediate, other measures, including concomitant administration of an IV benzodiazepine, will usually be necessary for the control of status epilepticus. The loading dose should be followed by maintenance doses of either fosphenytoin sodium injection or phenytoin.If administration of fosphenytoin sodium injection does not terminate seizures, the use of other anticonvulsants and other appropriate measures should be considered.
Even though loading doses of fosphenytoin sodium injection have been given by the IM route for other indications when IV access is impossible, IM fosphenytoin should ordinarily not be used in the treatment of status epilepticus because therapeutic phenytoin concentrations may not be reached as quickly as with IV administration.
Nonemergent Loading and Maintenance DosingBecause of the risks of cardiac and local toxicity associated with intravenous fosphenytoin, oral phenytoin should be used whenever possible.
The loading dose of fosphenytoin sodium injection is 10 to 20 mg PE/kg given IV or IM. The rate of administration for IV fosphenytoin sodium injection should be no greater than 150 mg PE/min. Continuous monitoring of the electrocardiogram, blood pressure, and respiratory function is essential and the patient should be observed throughout the period where maximal serum phenytoin concentrations occur (approximately 20 minutes after the end of fosphenytoin sodium injection infusion).
The initial daily maintenance dose of fosphenytoin sodium injection is 4 to 6 mg PE/kg/day in divided doses.
IM or IV Substitution For Oral Phenytoin TherapyWhen treatment with oral phenytoin is not possible, fosphenytoin sodium injection can be substituted for oral phenytoin at the same total daily dose. Phenytoin sodium capsules are approximately 90% bioavailable by the oral route. Phenytoin, supplied as fosphenytoin sodium injection, is 100% bioavailable by both the IM and IV routes. For this reason, plasma phenytoin concentrations may increase modestly when IM or IV fosphenytoin sodium injection is substituted for oral phenytoin sodium therapy. The rate of administration for IV fosphenytoin sodium injection should be no greater than 150 mg PE/min. In controlled trials, IM fosphenytoin sodium injection was administered as a single daily dose utilizing either 1 or 2 injection sites. Some patients may require more frequent dosing.
Dosing in Special PopulationsPatients with Renal or Hepatic Disease: 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 (see CLINICAL PHARMACOLOGY, Special Populations). Unbound phenytoin concentrations may be more useful in these patient populations. After IV fosphenytoin sodium injection administration 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 (see PRECAUTIONS).
Elderly Patients: Age does not have a significant impact on the pharmacokinetics of fosphenytoin following fosphenytoin sodium injection administration. Phenytoin clearance is decreased slightly in elderly patients and lower or less frequent dosing may be required.
Pediatric: The safety and efficacy of fosphenytoin sodium injection in pediatric patients has not been established.
Status Epilepticus The loading dose of fosphenytoin sodium injection is 15 to 20 mg PE/kg administered at 100 to 150 mg PE/min. Because of the risk of hypotension, fosphenytoin should be administered no faster than 150 mg PE/min. Continuous monitoring of the electrocardiogram, blood pressure, and respiratory function is essential and the patient should be observed throughout the period where maximal serum phenytoin concentrations occur, approximately 10 to 20 minutes after the end of fosphenytoin sodium injection infusions. Because the full antiepileptic effect of phenytoin, whether given as fosphenytoin sodium injection or parenteral phenytoin, is not immediate, other measures, including concomitant administration of an IV benzodiazepine, will usually be necessary for the control of status epilepticus. The loading dose should be followed by maintenance doses of either fosphenytoin sodium injection or phenytoin.If administration of fosphenytoin sodium injection does not terminate seizures, the use of other anticonvulsants and other appropriate measures should be considered.
Even though loading doses of fosphenytoin sodium injection have been given by the IM route for other indications when IV access is impossible, IM fosphenytoin should ordinarily not be used in the treatment of status epilepticus because therapeutic phenytoin concentrations may not be reached as quickly as with IV administration.
Nonemergent Loading and Maintenance DosingBecause of the risks of cardiac and local toxicity associated with intravenous fosphenytoin, oral phenytoin should be used whenever possible.
The loading dose of fosphenytoin sodium injection is 10 to 20 mg PE/kg given IV or IM. The rate of administration for IV fosphenytoin sodium injection should be no greater than 150 mg PE/min. Continuous monitoring of the electrocardiogram, blood pressure, and respiratory function is essential and the patient should be observed throughout the period where maximal serum phenytoin concentrations occur (approximately 20 minutes after the end of fosphenytoin sodium injection infusion).
The initial daily maintenance dose of fosphenytoin sodium injection is 4 to 6 mg PE/kg/day in divided doses.
IM or IV Substitution For Oral Phenytoin TherapyWhen treatment with oral phenytoin is not possible, fosphenytoin sodium injection can be substituted for oral phenytoin at the same total daily dose. Phenytoin sodium capsules are approximately 90% bioavailable by the oral route. Phenytoin, supplied as fosphenytoin sodium injection, is 100% bioavailable by both the IM and IV routes. For this reason, plasma phenytoin concentrations may increase modestly when IM or IV fosphenytoin sodium injection is substituted for oral phenytoin sodium therapy. The rate of administration for IV fosphenytoin sodium injection should be no greater than 150 mg PE/min. In controlled trials, IM fosphenytoin sodium injection was administered as a single daily dose utilizing either 1 or 2 injection sites. Some patients may require more frequent dosing.
Dosing in Special PopulationsPatients with Renal or Hepatic Disease: 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 (see CLINICAL PHARMACOLOGY, Special Populations). Unbound phenytoin concentrations may be more useful in these patient populations. After IV fosphenytoin sodium injection administration 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 (see PRECAUTIONS).
Elderly Patients: Age does not have a significant impact on the pharmacokinetics of fosphenytoin following fosphenytoin sodium injection administration. Phenytoin clearance is decreased slightly in elderly patients and lower or less frequent dosing may be required.
Pediatric: The safety and efficacy of fosphenytoin sodium injection in pediatric patients has not been established.
![Fosphenytoin (Fosphenytoin Sodium) Injection, Solution [Fresenius Kabi Usa, Llc]](http://dailymed.nlm.nih.gov/dailymed/image.cfm?setid=a9f7e7fd-7ca2-47ac-8856-999e110e2b9a&name=fosphenytoin-sodium-injection-usp-figure-4-np400302-vial.jpg)
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