Fosphenytoin (Page 8 of 8)
12.5 Pharmacogenomics
CYP2C9 activity is decreased in individuals with genetic variants such as the CYP2C9*2 and CYP2C9*3 alleles. Carriers of variant alleles, resulting in intermediate (e.g., *1/*3, *2/*2) or poor metabolism (e.g., *2/*3, *3/*3) have decreased clearance of phenytoin. Other decreased or nonfunctional CYP2C9*3 alleles may also result in decreased clearance of phenytoin (e.g., *5, *6, *8, *11).
The prevalence of the CYP2C9 poor metabolizer phenotype is approximately 2-3% in the White population, 0.5-4% in the Asian population, and <1% in the African American population. The CYP2C9 intermediate phenotype prevalence is approximately 35% in the White population, 24% in the African American population, and 15-36% in the Asian population [see Warnings and Precautions (5.4) and Use in Specific Populations (8.7)].
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenesis [see Warnings and Precautions (5.9)]
The carcinogenic potential of fosphenytoin has not been assessed. In carcinogenicity studies, phenytoin (active metabolite of fosphenytoin) was administered in the diet to mice (10, 25, or 45 mg/kg/day) and rats (25, 50, or 100 mg/kg/day) for 2 years. The incidences of hepatocellular tumors were increased in male and female mice at the highest dose. No increases in tumor incidence were observed in rats. The highest doses tested in these studies were associated with peak plasma phenytoin levels below human therapeutic concentrations.
In carcinogenicity studies reported in the literature, phenytoin was administered in the diet for 2 years at doses up to 600 ppm (approximately 160 mg/kg/day) to mice and up to 2,400 ppm (approximately 120 mg/kg/day) to rats. The incidences of hepatocellular tumors were increased in female mice at all but the lowest dose tested. No increases in tumor incidence were observed in rats.
Mutagenesis
An increase in structural chromosome aberrations were observed in cultured V79 Chinese hamster lung cells exposed to fosphenytoin in the presence of metabolic activation. No evidence of mutagenicity was observed in bacteria (Ames test) or Chinese hamster lung cells in vitro , and no evidence for clastogenic activity was observed in an in vivo mouse bone marrow micronucleus assay.
Impairment of Fertility
Fosphenytoin was administered to male and female rats during mating and continuing in females throughout gestation and lactation at doses of 50 mg PE/kg or higher. No effects on fertility were observed in males. In females, altered estrous cycles, delayed mating, prolonged gestation length, and developmental toxicity were observed at all doses, which were associated with maternal toxicity. The lowest dose tested is approximately 40% of the maximum human loading dose on a mg/m2 basis.
14 CLINICAL STUDIES
Infusion tolerance was evaluated in clinical studies. One double-blind study assessed infusion-site tolerance of equivalent loading doses (15 to 20 mg PE/kg) of fosphenytoin sodium infused at 150 mg PE/min or phenytoin infused at 50 mg/min. The study demonstrated better local tolerance (pain and burning at the infusion site), fewer disruptions of the infusion, and a shorter infusion period for fosphenytoin sodium-treated patients (Table 8).
| a Percent of patients | ||
| IV FosphenytoinSodiumN=90 | IV PhenytoinN=22 | |
| Local Intolerance | 9%a | 90% |
| Infusion Disrupted | 21% | 67% |
| Average Infusion Time | 13 min | 44 min |
Fosphenytoin sodium-treated patients, however, experienced more systemic sensory disturbances [see Warnings and Precautions (5.10)]. Infusion disruptions in fosphenytoin sodium-treated patients were primarily due to systemic burning, pruritus, and/or paresthesia while those in phenytoin-treated patients were primarily due to pain and burning at the infusion site (see Table 8). In a double-blind study investigating temporary substitution of fosphenytoin sodium injection for oral phenytoin, IM fosphenytoin sodium was as well-tolerated as IM placebo. IM fosphenytoin sodium injection resulted in a slight increase in transient, mild to moderate local itching (23% of fosphenytoin sodium-treated patients vs 11% of IM placebo-treated patients at any time during the study). This study also demonstrated that equimolar doses of IM fosphenytoin sodium injection may be substituted for oral phenytoin sodium with no dosage adjustments needed when initiating IM or returning to oral therapy. In contrast, switching between IM and oral phenytoin requires dosage adjustments because of slow and erratic phenytoin absorption from muscle.
16 HOW SUPPLIED/STORAGE AND HANDLING
16.1 How Supplied
Fosphenytoin Sodium Injection, USP is a clear, colorless to pale yellow solution supplied as follows:
| Product Code | Unit of Sale | Strength | Each |
| 400302 | NDC 63323-403-02Unit of 25 | 100 mg PE per 2 mL(50 mg PE per mL) | NDC 63323-403-012 mL fill in a 5 mL Single Dose Vial |
| 400310 | NDC 63323-403-10Unit of 10 | 500 mg PE per 10 mL(50 mg PE per mL) | NDC 63323-403-0410 mL Single Dose Vial |
The container closure is not made with natural rubber latex.
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 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.
16.2 Storage and Handling
Store under refrigeration at 2°C to 8°C (36°F 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.
17 PATIENT COUNSELING INFORMATION
Cardiovascular Risk Associated with Rapid Infusion
Inform patients that rapid intravenous administration of fosphenytoin sodium injection increases the risk of adverse cardiovascular reactions, including severe hypotension and cardiac arrhythmias. Cardiac arrhythmias have included bradycardia, heart block, ventricular tachycardia, and ventricular fibrillation which have resulted in asystole, cardiac arrest, and death. Patients should report cardiac signs or symptoms to their healthcare provider [see Warnings and Precautions (5.2)].
Withdrawal of Antiepileptic Drugs
Advise patients not to discontinue use of fosphenytoin sodium injection without consulting with their healthcare provider. Fosphenytoin sodium injection should normally be gradually withdrawn to reduce the potential for increased seizure frequency and status epilepticus [see Warnings and Precautions (5.3)].
Serious Dermatologic Reactions
Advise patients of the early signs and symptoms of severe cutaneous adverse reactions and to report any occurrence immediately to a physician [see Warnings and Precautions (5.4)].
Potential Signs of Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) and Other Systemic Reactions
Advise patients of the early toxic signs and symptoms of potential hematologic, dermatologic, hypersensitivity, or hepatic reactions. These symptoms may include, but are not limited to, fever, sore throat, rash, ulcers in the mouth, easy bruising, lymphadenopathy, facial swelling, and petechial or purpuric hemorrhage, and in the case of liver reactions, anorexia, nausea/vomiting, or jaundice. Advise the patient that, because these signs and symptoms may signal a serious reaction, that they must report any occurrence immediately to a physician. In addition, advise the patient that these signs and symptoms should be reported even if mild or when occurring after extended use [see Warnings and Precautions (5.4, 5.5, 5.6, 5.8, 5.9)].
Angioedema
Advise patients to discontinue fosphenytoin sodium injection and seek immediate medical care if they develop signs or symptoms of angioedema such as facial, perioral, or upper airway swelling [see Warnings and Precautions (5.7)].
Hyperglycemia
Advise patients that fosphenytoin sodium injection may cause an increase in blood glucose levels
[see Warnings and Precautions (5.16)].
Effects of Alcohol Use and Other Drugs and Over-the-Counter Drug Interactions
Caution patients against the use of other drugs or alcoholic beverages without first seeking their physician’s advice [see Drug Interactions (7.1, 7.2)].
Inform patients that certain over-the-counter medications (e.g., cimetidine and omeprazole), vitamins (e.g., folic acid), and herbal supplements (e.g., St. John’s wort) can alter their phenytoin levels.
Use in Pregnancy
Inform pregnant women and women of childbearing potential that use of fosphenytoin sodium injection during pregnancy can cause fetal harm, including an increased risk for cleft lip and/or cleft palate (oral clefts), cardiac defects, dysmorphic skull and facial features, nail and digit hypoplasia, growth abnormalities (including microcephaly), and cognitive deficits. When appropriate, counsel pregnant women and women of childbearing potential about alternative therapeutic options. Advise women of childbearing potential who are not planning a pregnancy to use effective contraception while using fosphenytoin sodium injection, keeping in mind that there is a potential for decreased hormonal contraceptive efficacy [see Drug Interactions (7.2)].
Instruct patients to notify their physician if they become pregnant or intend to become pregnant during therapy, and to notify their physician if they are breastfeeding or intend to breastfeed during therapy [see Use in Specific Populations (8.1, 8.2)].
Encourage patients to enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry if they become pregnant. This registry is collecting information about the safety of antiepileptic drugs during pregnancy [see Use in Specific Populations (8.1)].
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www.fresenius-kabi.com/us
451079L
PACKAGE LABEL — PRINCIPAL DISPLAY — Fosphenytoin 2 mL Single Dose Vial Label
NDC 63323-403-01
Fosphenytoin Sodium Injection, USP
100 mg PE per 2 mL (50 mg PE per mL)
(PE = phenytoin sodium equivalents)
PACKAGE LABEL — PRINCIPAL DISPLAY — Fosphenytoin 2 mL Single Dose Vial Tray Label
NDC 63323-403-02 Fosphenytoin Sodium Injection, USP
100 mg PE per 2 mL (50 mg PE per mL)
(PE = phenytoin sodium equivalents)
For intramuscular or intravenous use.
25 x 2 mL Single Dose Vials Rx only
PACKAGE LABEL – PRINCIPAL DISPLAY – Fosphenytoin 10 mL Single Dose Vial Label
Fosphenytoin Sodium Injection, USP
500 mg PE per 10 mL (50 mg PE per mL)
(PE = phenytoin sodium equivalents)
For intramuscular or intravenous use.
10 mL Single Dose Vial Rx only
PACKAGE LABEL – PRINCIPAL DISPLAY – Fosphenytoin 10 mL Single Dose Vial Tray Label
NDC 63323-403-10
Fosphenytoin Sodium Injection, USP
500 mg PE per 10 mL (50 mg PE per mL)
(PE = phenytoin sodium equivalents)
For intramuscular or intravenous use.
10 x 10 mL
Single Dose Vials Rx only
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| Labeler — Fresenius Kabi USA, LLC (608775388) |
| Establishment | |||
| Name | Address | ID/FEI | Operations |
| Fresenius Kabi USA, LLC | 840771732 | ANALYSIS (63323-403), MANUFACTURE (63323-403) | |
Revised: 01/2022 Fresenius Kabi USA, LLC
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