Home' The Source : Fourth Quarter 2016 Contents fosamprenavir, nelfinavir, reserpine, rifampin, ritonavir, St. John’s
Wort, theophylline and vigabatrin.
• Drugs that may either increase or decrease plasma phenytoin
concentrations include: phenobarbital, valproic acid and sodium
valproate. Similarly, the effects of phenytoin on phenobarbital,
valproic acid and sodium plasma valproate concentrations are
• The addition or withdrawal of these agents in patients on phenytoin
therapy may require an adjustment of the phenytoin dose to achieve
optimal clinical outcome.
Drugs affected by phenytoin:
• Drugs that should not be coadministered with phenytoin:
Delavirdine (see CONTRAINDICATIONS).
• Drugs whose efficacy is impaired by phenytoin include: azoles
(fluconazole, ketoconazole, itraconazole, voriconazole,
posaconazole), corticosteroids, doxycycline, estrogens, furosemide,
irinotecan, oral contraceptives, paclitaxel, paroxetine, quinidine,
rifampin, sertraline, teniposide, theophylline and vitamin D.
• Increased and decreased PT/INR responses have been reported when
phenytoin is coadministered with warfarin.
• Phenytoin decreases plasma concentrations of active metabolites of
albendazole, certain HIV antivirals (efavirenz, lopinavir/ritonavir,
indinavir, nelfinavir, ritonavir, saquinavir), anti-epileptic agents
(carbamazepine, felbamate, lamotrigine, topiramate, oxcarbazepine,
quetiapine), atorvastatin, chlorpropamide, clozapine, cyclosporine,
digoxin, fluvastatin, folic acid, methadone, mexiletine, nifedipine,
nimodipine, nisoldipine, praziquantel, simvastatin and verapamil.
• Phenytoin when given with fosamprenavir alone may decrease the
concentration of amprenavir, the active metabolite. Phenytoin when
given with the combination of fosamprenavir and ritonavir may
increase the concentration of amprenavir.
• Resistance to the neuromuscular blocking action of the
nondepolarizing neuromuscular blocking agents pancuronium,
vecuronium, rocuronium and cisatracurium has occurred in patients
chronically administered phenytoin. Whether or not phenytoin has
the same effect on other non-depolarizing agents is unknown.
Patients should be monitored closely for more rapid recovery from
neuromuscular blockade than expected, and infusion rate
requirements may be higher.
• The addition or withdrawal of phenytoin during concomitant therapy
with these agents may require adjustment of the dose of these agents
to achieve optimal clinical outcome.
Monitoring of plasma phenytoin concentrations may be helpful when
possible drug interactions are suspected (see Laboratory Tests).
Drug/Laboratory Test Interactions
Phenytoin may decrease serum concentrations of T4. It may also
produce artifactually low results in dexamethasone or metyrapone tests.
Phenytoin may also cause increased serum concentrations of glucose,
alkaline phosphatase, and gamma glutamyl transpeptidase (GGT). Care
should be taken when using immunoanalytical methods to measure
plasma concentrations following fosphenytoin administration (see
Carcinogenesis, Mutagenesis, Impairment of Fertility
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.
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
Pregnancy - Category D: (see WARNINGS)
Use in Nursing Mothers
It is not known whether fosphenytoin is excreted in human milk.
Following administration of phenytoin sodium, phenytoin appears to be
excreted in low concentrations in human milk. Therefore, breast-
feeding is not recommended for women receiving fosphenytoin.
Safety and effectiveness of fosphenytoin in pediatric patients has not
No systematic studies in geriatric patients have been conducted.
Phenytoin clearance tends to decrease with increasing age (see
CLINICAL PHARMACOLOGY, Special Populations).
Incidence in Controlled Clinical Trials
All adverse events were recorded during the trials by the clinical
investigators using terminology of their own choosing. Similar types of
events were grouped into standardized categories using modified
COSTART dictionary terminology. These categories are used in the
tables and listings below with the frequencies representing the
proportion of individuals exposed to fosphenytoin or comparative
TABLE 2. Treatment-Emergent Adverse Event Incidence Following IV
Administration at the Maximum Dose and Rate to Patients with
Epilepsy or Neurosurgical Patients
(Events in at Least 2% of Fosphenytoin-Treated Patients)
BODY AS A WHOLE
Incidence in Controlled Trials - IM Administration To Patients With
Epilepsy: Table 3 lists treatment-emergent adverse events that occurred
in at least 2% of fosphenytoin-treated patients in a double-blind,
randomized, controlled clinical trial of adult epilepsy patients receiving
either IM fosphenytoin substituted for oral phenytoin sodium or
continuing oral phenytoin sodium. Both treatments were administered
for 5 days.
TABLE 3. Treatment-Emergent Adverse Event Incidence
Following Substitution of IM Fosphenytoin for Oral Phenytoin
Sodium in Patients With Epilepsy
(Events in at Least 2% of Fosphenytoin-Treated Patients)
BODY AS A WHOLE
SKIN AND APPENDAGES
To report SUSPECTED ADVERSE REACTIONS, contact Amneal
Biosciences at 1-855-266-3251 or FDA at 1-800 -FDA-1088 or
DOSAGE AND ADMINISTRATION
The dose, concentration, and infusion rate of intravenous
fosphenytoin 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 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
Do not confuse the concentration of fosphenytoin with the total
amount of drug in the vial.
Prior to intravenous infusion, dilute fosphenytoin 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
Intramuscular or Intravenous Substitution for Oral Phenytoin
When treatment with oral phenytoin is not possible, fosphenytoin can
be substituted for oral phenytoin at the same total daily phenytoin
sodium equivalents (PE) dose.
Phenytoin sodium capsules are approximately 90% bioavailable by the
oral route. Phenytoin, supplied as fosphenytoin, is 100% bioavailable
by both the intramuscular and intravenous routes. For this reason,
plasma phenytoin concentrations may increase modestly when
intramuscular or intravenous fosphenytoin is substituted for oral
phenytoin sodium therapy.
The rate of administration for intravenous fosphenytoin should be no
greater than 150 mg PE/min.
In controlled trials, intramuscular fosphenytoin was administered as a
single daily dose utilizing either 1 or 2 injection sites. Some patients
may require more frequent dosing.
Dosing in Special Populations
Patients 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
intravenous fosphenytoin 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
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 in pediatric patients
have not been established.
Fosphenytoin Sodium Injection, USP is supplied as follows:
10 mL per vial [NDC 70121-1390-1] — Each 10 mL vial contains
Fosphenytoin Sodium, USP 750 mg equivalent to 500 mg of phenytoin
sodium, USP: (Packages of 10 - NDC 70121-1390-7).
2 mL per vial [NDC 70121-1381-1] — Each 2 mL vial contains
Fosphenytoin Sodium, USP 150 mg equivalent to 100 mg of phenytoin
sodium, USP: (Packages of 25 - NDC 70121-1381-5).
Both sizes of vials contain Tromethamine, USP (TRIS), Hydrochloric
Acid, NF, or Sodium Hydroxide, NF, and Water for Injection, USP.
Fosphenytoin sodium should always be prescribed in phenytoin
1.5 mg of fosphenytoin sodium is equivalent to 1 mg phenytoin sodium,
and is referred to as 1 mg PE.
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.
For single-use only. After opening, any unused product should be
Brands listed are the trademarks of their respective owners.
Made in India
Amneal Pharmaceuticals Pvt. Ltd., Parenteral Unit
Ahmedabad, Gujarat 382213, INDIA
Bridgewater, NJ 08807
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