Fosphenytoin Sodium - Fosphenytoin Sodium injection, Solution

(Fosphenytoin Sodium)

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Fosphenytoin Sodium - Fosphenytoin Sodium injection, Solution Prescribing Information

The rate of intravenous fosphenytoin sodium injection administration should not exceed 150 mg phenytoin sodium equivalents (PE) per minute in adults and 2 mg PE/kg/min (or 150 mg PE/min, whichever is slower) in pediatric patients because of the risk of severe hypotension and cardiac arrhythmias. Careful cardiac monitoring is needed during and after administering intravenous fosphenytoin sodium injection. Although the risk of cardiovascular toxicity increases with infusion rates above the recommended infusion rate, these events have also been reported at or below the recommended infusion rate. Reduction in rate of administration or discontinuation of dosing may be needed

[see Dosage and Administration (

2.3 Status Epilepticus

Because of the risk of hypotension and cardiac arrhythmias, the rate of administration for IV fosphenytoin sodium injection should be no greater than 150 mg PE/min in adults and 2 mg PE/kg/min (or 150 mg PE/min, whichever is slower) in pediatric patients [see Warnings and Precautions (5.2)]. 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
[see Dosage and Administration (2.4)]
.
If administration of fosphenytoin sodium injection does not terminate seizures, the use of other anticonvulsants and other appropriate measures should be considered.

Adult and Pediatric Status Epilepticus Dosing:

Table 1. Status Epilepticus Loading Dosages

Population	Dosage	Infusion rate
Adult	15 mg PE/kg to 20 mg PE/kg	100 mg PE/min to 150 mg PE/min, do not exceed a maximum rate of 150 mg PE/min
Pediatric (Birth to less than 17 years of age)	15 mg PE/kg to 20 mg PE/kg	2 mg PE/kg/min, or 150 mg PE/min, whichever is slower

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 sodium injection 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.

Intramuscular administration of fosphenytoin sodium injection should ordinarily not be used in pediatric patients. When IV access has been impossible, loading doses of fosphenytoin sodium injection have been given by the IM route.

2.4 Non-emergent Loading and Maintenance Dosing

Because of the risk of hypotension and cardiac arrhythmias, the rate of administration for IV fosphenytoin sodium injection should be no greater than 150 mg PE/min in adults. For loading doses in pediatric patients, the rate should not exceed 2 mg PE/kg/min (or 150 mg PE/min, whichever is slower). For maintenance doses in pediatric patients, the rate should not exceed 1 to 2 mg PE/kg/min (or 100 mg PE/min, whichever is slower). 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).
After the initial maintenance dose, subsequent maintenance doses should be individualized by monitoring serum phenytoin concentrations to achieve a target therapeutic concentration of phenytoin
[see Dosage and Administration (2.5)and Warnings and Precautions (5.17)].

Adult and Pediatric Non-emergent Loading and Maintenance Dosing:

Table 2. Non-emergent Loading Dosages

Population	Dosage	Infusion rate
Adult	10 mg PE/kg to 20 mg PE/kg	Not to exceed a maximum rate of 150 mg PE/min
Pediatric (Birth to less than 17 years of age)	10 mg PE/kg to 15 mg PE/kg	1 mg PE/kg/min to 2 mg PE/kg/min, or 150 mg PE/min, whichever is slower

Table 3. Maintenance Dosages

Population	Dosage	Infusion rate
Adult	Initial Maintenance Dosage: 4 mg PE/kg/day to 6 mg PE/kg/day in divided doses	Not to exceed a maximum rate of 150 mg PE/min
Pediatric (Birth to less than 17 years of age)	Initial Maintenance Dosage: 2 mg PE/kg to 4 mg PE/kg (dose given 12 hours after the loading dose)	1 mg PE/kg/min to 2 mg PE/kg/min, or 100 mg PE/min, whichever is slower
Pediatric (Birth to less than 17 years of age)	Maintenance Dosage after Initial Maintenance Dosage: 4 mg PE/kg/day to 8 mg PE/kg/day in divided doses (continued every 12 hours after initial maintenance dose)	1 mg PE/kg/min to 2 mg PE/kg/min, or 100 mg PE/min, whichever is slower

Because of the risks of cardiac and local toxicity associated with intravenous fosphenytoin sodium injection, oral phenytoin should be used whenever possible. Intramuscular administration of fosphenytoin sodium injection should ordinarily not be used in pediatric patients.

) and Warnings and Precautions (

5.2 Cardiovascular Risk Associated with Rapid Infusion

Rapid intravenous administration of fosphenytoin sodium increases the risk of adverse cardiovascular reactions, including 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.

The rate of intravenous fosphenytoin sodium administration should not exceed 150 mg phenytoin sodium equivalents (PE) per minute in adults and 2 mg PE/kg/min (or 150 mg PE/min, whichever is slower) in pediatric patients

[see Dosage and Administration (2.3, 2.4)].

Although the risk of cardiovascular toxicity increases with infusion rates above the recommended infusion rate, these events have also been reported at or below the recommended infusion rate.

As non-emergency therapy, intravenous fosphenytoin sodium injection should be administered more slowly. Because of the risks of cardiac and local toxicity associated with IV fosphenytoin sodium injection, oral phenytoin should be used whenever possible.

Because adverse cardiovascular reactions have occurred during and after infusions, careful cardiac and respiratory monitoring is needed during and after the administration of intravenous fosphenytoin sodium. Reduction in rate of administration or discontinuation of dosing may be needed.

)].

Warnings and Precautions (

5.9 Hematopoietic Complications

Hematopoietic complications, some fatal, have occasionally been reported in association with administration of phenytoin (the active metabolite of fosphenytoin sodium injection). 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

[see Warnings and Precautions (5.5)]

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. Macrocytosis and megaloblastic anemia have occurred, these conditions usually respond to folic acid therapy. Pure red cell

aplasia

has also been reported with phenytoin.

) 4/2022

Fosphenytoin sodium injection is indicated for the treatment of generalized tonic-clonic status epilepticus and prevention and treatment of seizures occurring during neurosurgery. Fosphenytoin sodium injection can also be substituted, short-term, for oral phenytoin. Fosphenytoin sodium injection should be used only when oral phenytoin administration is not possible

[see

2.4 Non-emergent Loading and Maintenance Dosing

Because of the risk of hypotension and cardiac arrhythmias, the rate of administration for IV fosphenytoin sodium injection should be no greater than 150 mg PE/min in adults. For loading doses in pediatric patients, the rate should not exceed 2 mg PE/kg/min (or 150 mg PE/min, whichever is slower). For maintenance doses in pediatric patients, the rate should not exceed 1 to 2 mg PE/kg/min (or 100 mg PE/min, whichever is slower). 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).
After the initial maintenance dose, subsequent maintenance doses should be individualized by monitoring serum phenytoin concentrations to achieve a target therapeutic concentration of phenytoin
[see Dosage and Administration (2.5)and Warnings and Precautions (5.17)].

Adult and Pediatric Non-emergent Loading and Maintenance Dosing:

Table 2. Non-emergent Loading Dosages

Population	Dosage	Infusion rate
Adult	10 mg PE/kg to 20 mg PE/kg	Not to exceed a maximum rate of 150 mg PE/min
Pediatric (Birth to less than 17 years of age)	10 mg PE/kg to 15 mg PE/kg	1 mg PE/kg/min to 2 mg PE/kg/min, or 150 mg PE/min, whichever is slower

Table 3. Maintenance Dosages

Population	Dosage	Infusion rate
Adult	Initial Maintenance Dosage: 4 mg PE/kg/day to 6 mg PE/kg/day in divided doses	Not to exceed a maximum rate of 150 mg PE/min
Pediatric (Birth to less than 17 years of age)	Initial Maintenance Dosage: 2 mg PE/kg to 4 mg PE/kg (dose given 12 hours after the loading dose)	1 mg PE/kg/min to 2 mg PE/kg/min, or 100 mg PE/min, whichever is slower
Pediatric (Birth to less than 17 years of age)	Maintenance Dosage after Initial Maintenance Dosage: 4 mg PE/kg/day to 8 mg PE/kg/day in divided doses (continued every 12 hours after initial maintenance dose)	1 mg PE/kg/min to 2 mg PE/kg/min, or 100 mg PE/min, whichever is slower

and

5.2 Cardiovascular Risk Associated with Rapid Infusion

[see Dosage and Administration (2.3, 2.4)].

Although the risk of cardiovascular toxicity increases with infusion rates above the recommended infusion rate, these events have also been reported at or below the recommended infusion rate.

]

The dose, concentration, and infusion rate of fosphenytoin sodium injection should always be expressed as phenytoin sodium equivalents (PE)
(
2.1 Important Administration Instructions to Avoid Dosing Errors

Use caution when administering fosphenytoin sodium injection because of the risk of dosing errors
[see Warnings and Precautions (5.1)].

Phenytoin Sodium Equivalents (PE)

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). The amount and concentration of fosphenytoin is always expressed in terms of mg of phenytoin sodium equivalents (mg PE).

Concentration of 50 mg PE/mL

Do not confuse the concentration of fosphenytoin sodium injection with the total amount of drug in the vial.

Errors, including fatal overdoses, 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 (2 mL vial) or 500 mg PE (10 mL vial). Ensure the appropriate volume of fosphenytoin sodium injection is withdrawn from the vial when preparing the dose for administration. Attention to these details may prevent some fosphenytoin sodium injection medication errors from occurring.
)

For Status Epilepticus:

Adult loading dose is 15 to 20 mg PE/kg at a rate of 100 to 150 mg PE/min (

2.3 Status Epilepticus

Because of the risk of hypotension and cardiac arrhythmias, the rate of administration for IV fosphenytoin sodium injection should be no greater than 150 mg PE/min in adults and 2 mg PE/kg/min (or 150 mg PE/min, whichever is slower) in pediatric patients [see Warnings and Precautions (5.2)]. 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
[see Dosage and Administration (2.4)]
.
If administration of fosphenytoin sodium injection does not terminate seizures, the use of other anticonvulsants and other appropriate measures should be considered.

Adult and Pediatric Status Epilepticus Dosing:

Table 1. Status Epilepticus Loading Dosages

Population	Dosage	Infusion rate
Adult	15 mg PE/kg to 20 mg PE/kg	100 mg PE/min to 150 mg PE/min, do not exceed a maximum rate of 150 mg PE/min
Pediatric (Birth to less than 17 years of age)	15 mg PE/kg to 20 mg PE/kg	2 mg PE/kg/min, or 150 mg PE/min, whichever is slower

)

Pediatric loading dose is 15 to 20 mg PE/kg at a rate of 2 mg PE/kg/min (or 150 mg PE/min, whichever is slower) (

2.3 Status Epilepticus

Because of the risk of hypotension and cardiac arrhythmias, the rate of administration for IV fosphenytoin sodium injection should be no greater than 150 mg PE/min in adults and 2 mg PE/kg/min (or 150 mg PE/min, whichever is slower) in pediatric patients [see Warnings and Precautions (5.2)]. 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
[see Dosage and Administration (2.4)]
.
If administration of fosphenytoin sodium injection does not terminate seizures, the use of other anticonvulsants and other appropriate measures should be considered.

Adult and Pediatric Status Epilepticus Dosing:

Table 1. Status Epilepticus Loading Dosages

Population	Dosage	Infusion rate
Adult	15 mg PE/kg to 20 mg PE/kg	100 mg PE/min to 150 mg PE/min, do not exceed a maximum rate of 150 mg PE/min
Pediatric (Birth to less than 17 years of age)	15 mg PE/kg to 20 mg PE/kg	2 mg PE/kg/min, or 150 mg PE/min, whichever is slower

)

For Non-emergent Loading and Maintenance Dosing:

Adult loading dose is 10 to 20 mg PE/kg given IV or IM; initial maintenance dose is 4 to 6 mg PE/kg/day in divided doses (

2.4 Non-emergent Loading and Maintenance Dosing

Because of the risk of hypotension and cardiac arrhythmias, the rate of administration for IV fosphenytoin sodium injection should be no greater than 150 mg PE/min in adults. For loading doses in pediatric patients, the rate should not exceed 2 mg PE/kg/min (or 150 mg PE/min, whichever is slower). For maintenance doses in pediatric patients, the rate should not exceed 1 to 2 mg PE/kg/min (or 100 mg PE/min, whichever is slower). 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).
After the initial maintenance dose, subsequent maintenance doses should be individualized by monitoring serum phenytoin concentrations to achieve a target therapeutic concentration of phenytoin
[see Dosage and Administration (2.5)and Warnings and Precautions (5.17)].

Adult and Pediatric Non-emergent Loading and Maintenance Dosing:

Table 2. Non-emergent Loading Dosages

Population	Dosage	Infusion rate
Adult	10 mg PE/kg to 20 mg PE/kg	Not to exceed a maximum rate of 150 mg PE/min
Pediatric (Birth to less than 17 years of age)	10 mg PE/kg to 15 mg PE/kg	1 mg PE/kg/min to 2 mg PE/kg/min, or 150 mg PE/min, whichever is slower

Table 3. Maintenance Dosages

Population	Dosage	Infusion rate
Adult	Initial Maintenance Dosage: 4 mg PE/kg/day to 6 mg PE/kg/day in divided doses	Not to exceed a maximum rate of 150 mg PE/min
Pediatric (Birth to less than 17 years of age)	Initial Maintenance Dosage: 2 mg PE/kg to 4 mg PE/kg (dose given 12 hours after the loading dose)	1 mg PE/kg/min to 2 mg PE/kg/min, or 100 mg PE/min, whichever is slower
Pediatric (Birth to less than 17 years of age)	Maintenance Dosage after Initial Maintenance Dosage: 4 mg PE/kg/day to 8 mg PE/kg/day in divided doses (continued every 12 hours after initial maintenance dose)	1 mg PE/kg/min to 2 mg PE/kg/min, or 100 mg PE/min, whichever is slower

)

Pediatric loading dose is 10 to 15 mg PE/kg at a rate of 1 to 2 mg PE/kg/min (or 150 mg PE/min, whichever is slower); initial maintenance dose is 2 to 4 mg PE/kg every 12 hours at a rate of 1 to 2 mg PE/kg/min (or 100 mg PE/min, whichever is slower) (

2.4 Non-emergent Loading and Maintenance Dosing

Because of the risk of hypotension and cardiac arrhythmias, the rate of administration for IV fosphenytoin sodium injection should be no greater than 150 mg PE/min in adults. For loading doses in pediatric patients, the rate should not exceed 2 mg PE/kg/min (or 150 mg PE/min, whichever is slower). For maintenance doses in pediatric patients, the rate should not exceed 1 to 2 mg PE/kg/min (or 100 mg PE/min, whichever is slower). 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).
After the initial maintenance dose, subsequent maintenance doses should be individualized by monitoring serum phenytoin concentrations to achieve a target therapeutic concentration of phenytoin
[see Dosage and Administration (2.5)and Warnings and Precautions (5.17)].

Adult and Pediatric Non-emergent Loading and Maintenance Dosing:

Table 2. Non-emergent Loading Dosages

Population	Dosage	Infusion rate
Adult	10 mg PE/kg to 20 mg PE/kg	Not to exceed a maximum rate of 150 mg PE/min
Pediatric (Birth to less than 17 years of age)	10 mg PE/kg to 15 mg PE/kg	1 mg PE/kg/min to 2 mg PE/kg/min, or 150 mg PE/min, whichever is slower

Table 3. Maintenance Dosages

Population	Dosage	Infusion rate
Adult	Initial Maintenance Dosage: 4 mg PE/kg/day to 6 mg PE/kg/day in divided doses	Not to exceed a maximum rate of 150 mg PE/min
Pediatric (Birth to less than 17 years of age)	Initial Maintenance Dosage: 2 mg PE/kg to 4 mg PE/kg (dose given 12 hours after the loading dose)	1 mg PE/kg/min to 2 mg PE/kg/min, or 100 mg PE/min, whichever is slower
Pediatric (Birth to less than 17 years of age)	Maintenance Dosage after Initial Maintenance Dosage: 4 mg PE/kg/day to 8 mg PE/kg/day in divided doses (continued every 12 hours after initial maintenance dose)	1 mg PE/kg/min to 2 mg PE/kg/min, or 100 mg PE/min, whichever is slower

)

Intramuscular Administration:

Fosphenytoin sodium injection should ordinarily not be given intramuscularly (

2.3 Status Epilepticus

Because of the risk of hypotension and cardiac arrhythmias, the rate of administration for IV fosphenytoin sodium injection should be no greater than 150 mg PE/min in adults and 2 mg PE/kg/min (or 150 mg PE/min, whichever is slower) in pediatric patients [see Warnings and Precautions (5.2)]. 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
[see Dosage and Administration (2.4)]
.
If administration of fosphenytoin sodium injection does not terminate seizures, the use of other anticonvulsants and other appropriate measures should be considered.

Adult and Pediatric Status Epilepticus Dosing:

Table 1. Status Epilepticus Loading Dosages

Population	Dosage	Infusion rate
Adult	15 mg PE/kg to 20 mg PE/kg	100 mg PE/min to 150 mg PE/min, do not exceed a maximum rate of 150 mg PE/min
Pediatric (Birth to less than 17 years of age)	15 mg PE/kg to 20 mg PE/kg	2 mg PE/kg/min, or 150 mg PE/min, whichever is slower

2.4 Non-emergent Loading and Maintenance Dosing

Because of the risk of hypotension and cardiac arrhythmias, the rate of administration for IV fosphenytoin sodium injection should be no greater than 150 mg PE/min in adults. For loading doses in pediatric patients, the rate should not exceed 2 mg PE/kg/min (or 150 mg PE/min, whichever is slower). For maintenance doses in pediatric patients, the rate should not exceed 1 to 2 mg PE/kg/min (or 100 mg PE/min, whichever is slower). 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).
After the initial maintenance dose, subsequent maintenance doses should be individualized by monitoring serum phenytoin concentrations to achieve a target therapeutic concentration of phenytoin
[see Dosage and Administration (2.5)and Warnings and Precautions (5.17)].

Adult and Pediatric Non-emergent Loading and Maintenance Dosing:

Table 2. Non-emergent Loading Dosages

Population	Dosage	Infusion rate
Adult	10 mg PE/kg to 20 mg PE/kg	Not to exceed a maximum rate of 150 mg PE/min
Pediatric (Birth to less than 17 years of age)	10 mg PE/kg to 15 mg PE/kg	1 mg PE/kg/min to 2 mg PE/kg/min, or 150 mg PE/min, whichever is slower

Table 3. Maintenance Dosages

Population	Dosage	Infusion rate
Adult	Initial Maintenance Dosage: 4 mg PE/kg/day to 6 mg PE/kg/day in divided doses	Not to exceed a maximum rate of 150 mg PE/min
Pediatric (Birth to less than 17 years of age)	Initial Maintenance Dosage: 2 mg PE/kg to 4 mg PE/kg (dose given 12 hours after the loading dose)	1 mg PE/kg/min to 2 mg PE/kg/min, or 100 mg PE/min, whichever is slower
Pediatric (Birth to less than 17 years of age)	Maintenance Dosage after Initial Maintenance Dosage: 4 mg PE/kg/day to 8 mg PE/kg/day in divided doses (continued every 12 hours after initial maintenance dose)	1 mg PE/kg/min to 2 mg PE/kg/min, or 100 mg PE/min, whichever is slower

)

•

Pregnancy:

Phenytoin (the active metabolite of fosphenytoin sodium injection) prenatal exposure may increase risks for congenital malformations and other adverse developmental outcomes (

5.15 Teratogenicity and Other Harm to the Newborn

Fosphenytoin sodium may cause fetal harm when administered to a pregnant woman. Prenatal exposure to phenytoin (the active metabolite of fosphenytoin sodium) may increase the risks for congenital malformations and other adverse developmental outcomes

[see Use in Specific Populations (8.1)]

.

Increased frequencies of major malformations (such as orofacial clefts and cardiac defects), and abnormalities characteristic of fetal hydantoin syndrome, including dysmorphic skull and facial features, nail and digit hypoplasia, growth abnormalities (including microcephaly), and cognitive deficits, have been reported among children born to epileptic women who took phenytoin alone or in combination with other antiepileptic drugs during pregnancy. There have been several reported cases of malignancies, including neuroblastoma.

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.

8.1 Pregnancy

Pregnancy Exposure Registry

There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to antiepileptic drugs (AEDs), such as fosphenytoin sodium, during pregnancy. Physicians are advised to recommend that pregnant patients taking fosphenytoin sodium enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry. This can be done by calling the toll-free number 1-888-233-2334, and must be done by patients themselves. Information on the registry can also be found at the website http://www.aedpregnancyregistry.org/.

Risk Summary

In humans, prenatal exposure to phenytoin (the active metabolite of fosphenytoin sodium) may increase the risks for congenital malformations and other adverse developmental outcomes. Prenatal phenytoin exposure is associated with an increased incidence of major malformations, including orofacial clefts and cardiac defects. In addition, the fetal hydantoin syndrome, a pattern of abnormalities including dysmorphic skull and facial features, nail and digit hypoplasia, growth abnormalities (including microcephaly), and cognitive deficits has been reported among children born to epileptic women who took phenytoin alone or in combination with other antiepileptic drugs during pregnancy

[see Data]

. There have been several reported cases of malignancies, including neuroblastoma, in children whose mothers received phenytoin during pregnancy.

Administration of phenytoin to pregnant animals resulted in an increased incidence of fetal malformations and other manifestations of developmental toxicity (including embryofetal death, growth impairment, and behavioral abnormalities) in multiple species at clinically relevant doses

[see Data].

In the U.S. general population, the estimated background risk of major birth defects and of miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. The background risk of major birth defects and miscarriage for the indicated population is unknown.

Clinical Considerations

Disease-associated maternal risk

An increase in seizure frequency may occur during pregnancy because of altered phenytoin pharmacokinetics. Periodic measurement of serum phenytoin concentrations may be valuable in the management of pregnant women as a guide to appropriate adjustment of dosage

[see Dosage and Administration (2.5, 2.9)]

. However, postpartum restoration of the original dosage will probably be indicated.

Fetal/Neonatal adverse reactions

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.

Data

Human Data

Meta-analyses using data from published observational studies and registries have estimated an approximately 2.4-fold increased risk for any major malformation in children with prenatal phenytoin exposure compared to controls. An increased risk of heart defects, facial clefts, and digital hypoplasia has been reported. The fetal hydantoin syndrome is a pattern of congenital anomalies including craniofacial anomalies, nail and digital hypoplasia, prenatal-onset growth deficiency, and neurodevelopmental deficiencies.

Animal Data

Administration of phenytoin to pregnant rats, rabbits, and mice during organogenesis resulted in embryofetal death, fetal malformations, and decreased fetal growth. Malformations (including craniofacial, cardiovascular, neural, limb, and digit abnormalities) were observed in rats, rabbits, and mice at doses as low as 100, 75, and 12.5 mg/kg, respectively.

)

•

Renal and/or Hepatic Impairment or Hypoalbuminemia:

Monitor unbound phenytoin concentrations in these patients (

8.6 Renal and/or Hepatic Impairment, or Hypoalbuminemia

The liver is the site of biotransformation. Patients with impaired liver function, elderly patients, or those who are gravely ill may show early toxicity.

Because the fraction of unbound phenytoin (the active metabolite of fosphenytoin sodium) is increased in patients with renal or hepatic disease, or in those with hypoalbuminemia, the monitoring of phenytoin serum levels should be based on the unbound fraction in those patients.

After IV 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.

)

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