Fosphenytoin (Page 8 of 8)

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 90 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 5).

TABLE 5. Infusion Tolerance of Equivalent Loading Doses of IV Fosphenytoin Sodium and IV Phenytoin

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 5). 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 mLSingle 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, (TRIS), hydrochloric acid, or sodium hydroxide, and water for injection.

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 (5.17)].

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)].

The brand names mentioned in this document are the trademarks of their respective owners.

Fresenius Kabi Logo

www.fresenius-kabi.com/us

451079K

Revised: October 2019

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)

2 mL Single Dose Vial Rx only

PACKAGE LABEL -- PRINCIPAL DISPLAY -- Fosphenytoin 2 mL Single Dose Vial Label
(click image for full-size original)

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 2 mL Single Dose Vial Tray Label
(click image for full-size original)

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 Label
(click image for full-size original)

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

PACKAGE LABEL – PRINCIPAL DISPLAY – Fosphenytoin 10 mL Single Dose Vial Tray Label
(click image for full-size original)
FOSPHENYTOIN fosphenytoin sodium injection, solution
Product Information
Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:63323-403
Route of Administration INTRAMUSCULAR, INTRAVENOUS DEA Schedule
Active Ingredient/Active Moiety
Ingredient Name Basis of Strength Strength
FOSPHENYTOIN SODIUM (PHENYTOIN) PHENYTOIN SODIUM 50 mg in 1 mL
Inactive Ingredients
Ingredient Name Strength
TROMETHAMINE
HYDROCHLORIC ACID
SODIUM HYDROXIDE
Packaging
# Item Code Package Description Multilevel Packaging
1 NDC:63323-403-02 25 VIAL in 1 TRAY contains a VIAL (63323-403-01)
1 NDC:63323-403-01 2 mL in 1 VIAL This package is contained within the TRAY (63323-403-02)
2 NDC:63323-403-10 10 VIAL in 1 TRAY contains a VIAL (63323-403-04)
2 NDC:63323-403-04 10 mL in 1 VIAL This package is contained within the TRAY (63323-403-10)
Marketing Information
Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
ANDA ANDA078052 12/14/2009
Labeler — Fresenius Kabi USA, LLC (608775388)
Establishment
Name Address ID/FEI Operations
Fresenius Kabi USA, LLC 840771732 MANUFACTURE (63323-403)

Revised: 01/2020 Fresenius Kabi USA, LLC

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