Fosphenytoin Sodium 50 mg/mL Injection

WARNINGS DOSES OF FOSPHENYTOIN ARE ALWAYS EXPRESSED IN TERMS OF MILLIGRAMS OF PHENYTOIN SODIUM EQUIVALENTS (mg PE). 1 mg PE IS EQUIVALENT TO 1 mg PHENYTOIN SODIUM. DO NOT, THEREFORE, MAKE ANY ADJUSTMENT IN THE RECOMMENDED DOSES WHEN SUBSTITUTING FOSPHENYTOIN FOR PHENYTOIN SODIUM OR VICE VERSA.

FOR EXAMPLE, IF A PATIENT IS RECEIVING 1000 mg PE OF FOSPHENYTOIN, THAT IS EQUIVALENT TO 1000 mg OF PHENYTOIN SODIUM. The following warnings are based on experience with fosphenytoin or phenytoin. Dosing Errors Do not confuse the amount of drug to be given in PE with the concentration of the drug in the vial.

Medication errors associated with fosphenytoin have resulted in patients receiving the wrong dose of fosphenytoin. Fosphenytoin is marketed in 2 mL vials containing a total of 100 mg PE and 10 mL vials containing a total of 500 mg PE. The concentration of each vial is 50 mg PE/mL.

Errors 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 since each vial actually contains a total of 100 mg PE or 500 mg PE. In some cases, ten-fold overdoses were associated with fatal outcomes.

To help minimize confusion, the prescribed dose of fosphenytoin should always be expressed in milligrams of phenytoin equivalents (mg PE) (see DOSAGE AND ADMINISTRATION ). Additionally, when ordering and storing fosphenytoin, consider displaying the total drug content (i.e., 100 mg PE/2 mL or 500 mg PE/10 mL) instead of concentration in computer systems, pre-printed orders, and automated dispensing cabinet databases to help ensure that total drug content can be clearly identified. Care should be taken to ensure the appropriate volume of fosphenytoin is withdrawn from the vial when preparing the drug for administration .

Attention to these details may prevent some fosphenytoin medication errors from occurring. Status Epilepticus Dosing Regimen Because of the increased risk of adverse cardiovascular reactions associated with rapid administration, do not administer fosphenytoin at a rate greater than 150 mg PE/min. The dose of IV fosphenytoin (15 to 20 mg PE/kg) that is used to treat status epilepticus is administered at a maximum rate of 150 mg PE/min.

The typical fosphenytoin infusion administered to a 50 kg patient would take between 5 and 7 minutes. Note that the delivery of an identical molar dose of phenytoin using parenteral phenytoin sodium or generic phenytoin sodium injection cannot be accomplished in less than 15 to 20 minutes because of the untoward cardiovascular effects that accompany the direct intravenous administration of phenytoin at rates greater than 50 mg/min. If rapid phenytoin loading is a primary goal, IV administration of fosphenytoin is preferred because the time to achieve therapeutic plasma phenytoin concentrations is greater following IM than that following IV administration (see DOSAGE AND ADMINISTRATION ).

Cardiovascular Risk Associated with Rapid Infusion As non-emergency therapy, intravenous fosphenytoin should be administered more slowly. Because of the risks of cardiac and local toxicity associated with IV fosphenytoin, oral phenytoin should be used whenever possible. Because adverse cardiovascular reactions have occurred during and after infusions, careful cardiac monitoring is needed during and after the administration of intravenous fosphenytoin.

Reduction in rate of administration or discontinuation of dosing may be needed. Adverse cardiovascular reactions include 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. Howe…

ADVERSE REACTIONS The more important adverse clinical events caused by the IV use of fosphenytoin or phenytoin are cardiovascular collapse and/or central nervous system depression. Hypotension can occur when either drug is administered rapidly by the IV route. The rate of administration is very important; for fosphenytoin, it should not exceed 150 mg PE/min.

The adverse clinical events most commonly observed with the use of fosphenytoin in clinical trials were nystagmus, dizziness, pruritus, paresthesia, headache, somnolence, and ataxia. With two exceptions, these events are commonly associated with the administration of IV phenytoin. Paresthesia and pruritus, however, were seen much more often following fosphenytoin administration and occurred more often with IV fosphenytoin administration than with IM fosphenytoin administration.

These events were dose and rate related; most alert patients (41 of 64; 64%) administered doses of ≥15 mg PE/kg at 150 mg PE/min experienced discomfort of some degree. These sensations, generally described as itching, burning, or tingling, were usually not at the infusion site. The location of the discomfort varied with the groin mentioned most frequently as a site of involvement.

The paresthesia and pruritus were transient events that occurred within several minutes of the start of infusion and generally resolved within 10 minutes after completion of fosphenytoin infusion. Some patients experienced symptoms for hours. These events did not increase in severity with repeated administration.

Concurrent adverse events or clinical laboratory change suggesting an allergic process were not seen (see PRECAUTIONS, Sensory Disturbances ). Approximately 2% of the 859 individuals who received fosphenytoin in premarketing clinical trials discontinued treatment because of an adverse event. The adverse events most commonly associated with withdrawal were pruritus (0.5%), hypotension (0.3%), and bradycardia (0.2%).

Dose and Rate Dependency of Adverse Events Following IV Fosphenytoin : The incidence of adverse events tended to increase as both dose and infusion rate increased. In particular, at doses of ≥15 mg PE/kg and rates ≥150 mg PE/min, transient pruritus, tinnitus, nystagmus, somnolence, and ataxia occurred 2 to 3 times more often than at lower doses or rates. 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 therapy. The prescriber should be aware that these figures cannot be used to predict the frequency of adverse events in the course of usual medical practice where patient characteristics and other factors may differ from those prevailing during clinical studies.

Similarly, the cited frequencies cannot be directly compared with figures obtained from other clinical investigations involving different treatments, uses or investigators. An inspection of these frequencies, however, does provide the prescribing physician with one basis to estimate the relative contribution of drug and nondrug factors to the adverse event incidences in the population studied. Incidence in Controlled Clinical Trials - IV Administration To Patients With Epilepsy or Neurosurgical Patients : Table 2 lists treatment-emergent adverse events that occurred in at least 2% of patients treated with IV fosphenytoin at the maximum dose and rate in a randomized, double-blind, controlled clinical trial where the rates for phenytoin and fosphenytoin administration would have resulted in equivalent systemic exposure to phenytoin.

TABLE 2. Treatment-Emergent Adverse Event Incidence Following IV Administration at the Maximum Dose and Rate to Patients with Epilepsy or…

Drug Interactions No drugs are known to interfere with the conversion of fosphenytoin to phenytoin. Conversion could be affected by alterations in the level of phosphatase activity, but given the abundance and wide distribution of phosphatases in the body it is unlikely that drugs would affect this activity enough to affect conversion of fosphenytoin to phenytoin. Drugs highly bound to albumin could increase the unbound fraction of fosphenytoin.

Although, it is unknown whether this could result in clinically significant effects, caution is advised when administering fosphenytoin with other drugs that significantly bind to serum albumin. The pharmacokinetics and protein binding of fosphenytoin, phenytoin, and diazepam were not altered when diazepam and fosphenytoin were concurrently administered in single submaximal doses. The most significant drug interactions following administration of fosphenytoin are expected to occur with drugs that interact with phenytoin.

Phenytoin is extensively bound to serum plasma proteins and is prone to competitive displacement. Phenytoin is metabolized by hepatic cytochrome P450 enzymes CYP2C9 and CYP2C19 and is particularly susceptible to inhibitory drug interactions because it is subject to saturable metabolism. Inhibition of metabolism may produce significant increases in circulating phenytoin concentrations and enhance the risk of drug toxicity.

Phenytoin is a potent inducer of hepatic drug-metabolizing enzymes. The most commonly occurring drug interactions are listed below: Note: The list is not intended to be inclusive or comprehensive. Individual drug package inserts should be consulted.

Drugs that affect phenytoin concentrations: Drugs that may increase plasma phenytoin concentrations include: acute alcohol intake, amiodarone, anti-epileptic agents (ethosuximide, felbamate, oxcarbazepine, methsuximide, topiramate), azoles (fluconazole, ketoconazole, itraconazole, miconazole, voriconazole), capecitabine, chloramphenicol, chlordiazepoxide, disulfiram, estrogens, fluorouracil, fluoxetine, fluvastatin, fluvoxamine, H 2 -antagonists (e.g. cimetidine), halothane, isoniazid, methylphenidate, omeprazole, phenothiazines, salicylates, sertraline, succinimides, sulfonamides (e.g., sulfamethizole, sulfaphenazole, sulfadiazine, sulfamethoxazole-trimethoprim), tacrolimus, ticlopidine, tolbutamide, trazodone and warfarin.

Drugs that may decrease plasma phenytoin concentrations include: anticancer drugs usually in combination (e.g., bleomycin, carboplatin, cisplatin, doxorubicin, methotrexate), carbamazepine, chronic alcohol abuse, diazepam, diazoxide, folic acid, 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 unpredictable. 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), ato…