FOSPHENYTOIN SODIUM- fosphenytoin injection

Country: United States

Language: English

Source: NLM (National Library of Medicine)

Active ingredient:

FOSPHENYTOIN SODIUM (UNII: 7VLR55452Z) (PHENYTOIN - UNII:6158TKW0C5)

Available from:

Amneal Pharmaceuticals LLC

INN (International Name):

FOSPHENYTOIN SODIUM

Composition:

PHENYTOIN SODIUM 50 mg in 1 mL

Administration route:

INTRAMUSCULAR

Prescription type:

PRESCRIPTION DRUG

Therapeutic indications:

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 Dosage and Administration (2.4)  and Warnings and Precautions (5.2)] . Fosphenytoin sodium injection is contraindicated in patients with: - A history of hypersensitivity to fosphenytoin sodium injection or its inactive ingredients or to phenytoin or other hydantoins [see Warnings and Precautions (5.6)] . Reactions have included angioedema. - Sinus bradycardia, sino-atrial block, second and third degree A-V block or Adams-Stokes syndrome because of the effect of parenteral phenytoin or fosphenytoin sodium injection on ventricular automaticity. - A history of prior acute hepatotoxicity attributable to fosphenytoin sodium or phenytoin [see Warnings and Precautions (5.8)] . - Co-administration with delavirdine because of the potential for loss of virologic response and possible resistance to delavirdine or to the class of non-nucleoside reverse transcriptase inhibitors. 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. 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 mg/kg, 75 mg/kg and 12.5 mg/kg, respectively. Risk Summary It is not known whether fosphenytoin is secreted in human milk. Following administration of phenytoin (the active metabolite of fosphenytoin sodium), phenytoin is secreted in human milk. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for fosphenytoin sodium and any potential adverse effects on the breastfed infant from fosphenytoin sodium or from the underlying maternal condition. Fosphenytoin sodium is indicated for the treatment of generalized tonic-clonic status epilepticus and prevention and treatment of seizures occurring during neurosurgery in all pediatric age groups [see Indications and Usage (1)  and Dosage and Administration (2.3, 2.4)] . Because rapid intravenous administration of fosphenytoin sodium increases the risk of adverse cardiovascular reactions, the rate of administration should not exceed 2 mg PE/kg/min (or 150 mg PE/min, whichever is slower) in pediatric patients [see Dosage and Administration (2.3, 2.4)  and Warnings and Precautions (5.2)] . No systematic studies in geriatric patients have been conducted. Phenytoin clearance tends to decrease with increasing age [see Clinical Pharmacology (12.3)] . Lower or less frequent dosing may be required [see Clinical Pharmacology (12.3)  and Dosage and Administration (2.8)] . 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 intravenous 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. Patients who are intermediate or poor metabolizers of CYP2C9 substrates (e.g., *1/*3, *2/*2, *3/*3) may exhibit increased phenytoin serum concentrations compared to patients who are normal metabolizers (e.g., *1/*1). Thus, patients who are known to be intermediate or poor metabolizers may ultimately require lower doses to maintain similar steady-state concentrations compared to normal metabolizers. In patients who are known to be carriers of the decreased function CYP2C9*2 or *3 alleles (intermediate and poor metabolizers), consider starting at the low end of the dosage range and monitor serum concentrations to maintain total phenytoin concentrations of 10 mcg/mL to 20 mcg/mL. If early signs of dose-related central nervous system (CNS) toxicity develop, serum concentrations should be checked immediately [see Clinical Pharmacology (12.5)] .

Product summary:

Fosphenytoin sodium injection, USP is a clear, colorless to pale yellow, sterile solution supplied as follows: mg phenytoin sodium, USP equivalents (PE) per vial Volume per vial (mL) Package Configuration (Carton) NDC (Vial) 500 mg PE/10 mL vial 10 mL per vial Package contains 10 vials of NDC 70121-1390-7 NDC 70121-1390-1 100 mg PE/2 mL vial 2 mL per vial Package contains 25 vials of NDC 70121-1381-5 NDC 70121-1381-1 Both sizes of vials contain Tromethamine, USP (TRIS), Hydrochloric Acid, NF or Sodium Hydroxide, NF and Water for Injection, USP. Fosphenytoin sodium injection, USP should always be prescribed in phenytoin sodium equivalents (PE) [see Dosage and Administration (2.1)  and Warnings and Precautions (5.1)] . 1.5 mg of fosphenytoin sodium, USP 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 (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. Store under refrigeration at 2° to 8°C (36° to 46°F). The product should not be stored at room temperature for more than 48 hours. Vials that develop particulate matter should not be used. Injection vials are single-dose only. After opening, any unused product should be discarded.

Authorization status:

Abbreviated New Drug Application

Summary of Product characteristics

FOSPHENYTOIN SODIUM- FOSPHENYTOIN INJECTION
AMNEAL PHARMACEUTICALS LLC
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HIGHLIGHTS OF PRESCRIBING INFORMATION
THESE HIGHLIGHTS DO NOT INCLUDE ALL THE INFORMATION NEEDED TO USE
FOSPHENYTOIN SODIUM
INJECTION SAFELY AND EFFECTIVELY. SEE FULL PRESCRIBING INFORMATION FOR
FOSPHENYTOIN
SODIUM INJECTION.
FOSPHENYTOIN SODIUM INJECTION, FOR INTRAVENOUS OR INTRAMUSCULAR USE
INITIAL U.S. APPROVAL: 1996
WARNING: CARDIOVASCULAR RISK ASSOCIATED WITH RAPID INFUSION RATES
_SEE FULL PRESCRIBING INFORMATION FOR COMPLETE BOXED WARNING._
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 BECAUSE OF
THE RISK OF
SEVERE HYPOTENSION AND CARDIAC ARRHYTHMIAS.
CAREFUL CARDIAC MONITORING IS NEEDED DURING AND AFTER ADMINISTERING
INTRAVENOUS
FOSPHENYTOIN SODIUM.
REDUCTION IN RATE OF ADMINISTRATION OR DISCONTINUATION OF DOSING MAY
BE NEEDED
(2.3, 2.4, 5.2).
RECENT MAJOR CHANGES
Warnings and Precautions (5.9) 4/2022
INDICATIONS AND USAGE
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, as short-term use, for oral phenytoin.
Fosphenytoin sodium injection should be
used only when oral phenytoin administration is not possible. (1)
DOSAGE AND ADMINISTRATION
THE DOSE, CONCENTRATION AND INFUSION RATE OF FOSPHENYTOIN SODIUM
INJECTION SHOULD
ALWAYS BE EXPRESSED AS PHENYTOIN SODIUM EQUIVALENTS (PE). (2.1)
FOR STATUS EPILEPTICUS:
Adult loading dose is 15 mg to 20 mg PE/kg at a rate of 100 mg to 150
mg PE/min. (2.3)
Pediatric loading dose is 15 mg to 20 mg PE/kg at a rate of 2 mg
PE/kg/min (or 150 mg PE/min,
whichever is slower). (2.3)
FOR NON-EMERGENT LOADING AND MAINTENANCE DOSING:
Adult loading dose is 10 mg to 20 mg PE/kg given intravenous or
intramuscular; initial maintenance
dose is 4 mg to 6