Fosphenytoin Sodium (Page 5 of 9)

6.2 Postmarketing Experience

The following adverse reactions have been identified during post-approval use of fosphenytoin. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Body as a Whole: Anaphylaxis, angioedema [see Warnings and Precautions (5.7)]

Laboratory Test Abnormality: Phenytoin or fosphenytoin sodium injection may decrease serum concentrations of T4. It may also produce lower than normal values for dexamethasone or metyrapone tests. Phenytoin may also cause increased serum levels of gamma glutamyl transpeptidase (GGT).

Nervous System Disorders: Dyskinesia

7 DRUG INTERACTIONS

Fosphenytoin is extensively bound to human plasma proteins. 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 sodium injection with other drugs that significantly bind to serum albumin. The most significant drug interactions following administration of fosphenytoin sodium injection 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 primarily metabolized by the hepatic cytochrome P450 enzyme CYP2C9 and to a lesser extent by 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. Monitoring of phenytoin serum levels is recommended when a drug interaction is suspected.

Phenytoin or fosphenytoin sodium injection is a potent inducer of hepatic drug-metabolizing enzymes.

7.1 Drugs that Affect Phenytoin or Fosphenytoin Sodium Injection

Table 6 includes commonly occurring drug interactions that affect phenytoin (the active metabolite of fosphenytoin sodium injection) concentrations. However, this list is not intended to be inclusive or comprehensive. Individual prescribing information from relevant drugs should be consulted.

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.

Table 6. Drugs That Affect Phenytoin Concentrations

Interacting Agent

Examples

Drugs that may increase phenytoin serum levels

Antiepileptic drugs

Ethosuximide, felbamate, oxcarbazepine, methsuximide, topiramate

Azoles

Fluconazole, ketoconazole, itraconazole, miconazole, voriconazole

Antineoplastic agents

Capecitabine, fluorouracil

Antidepressants

Fluoxetine, fluvoxamine, sertraline

Gastric acid reducing agents

H2 antagonists (cimetidine), omeprazole

Sulfonamides

Sulfamethizole, sulfaphenazole, sulfadiazine, sulfamethoxazole-trimethoprim

Other

Acute alcohol intake, amiodarone, chloramphenicol, chlordiazepoxide, disulfiram, estrogen, fluvastatin, isoniazid, methylphenidate, phenothiazines, salicylates, ticlopidine, tolbutamide, trazodone, warfarin

Drugs that may decrease phenytoin serum levels

Antineoplastic agents usually in combination

Bleomycin, carboplatin, cisplatin, doxorubicin, methotrexate

Antiviral agents

Fosamprenavir, nelfinavir, ritonavir

Antiepileptic drugs

Carbamazepine, vigabatrin

Other

Chronic alcohol abuse, diazepam, diazoxide, folic acid, reserpine, rifampin, St. John’s wort,a theophylline

Drugs that may either increase or decrease phenytoin serum levels

Antiepileptic drugs

Phenobarbital, valproate sodium, valproic acid

a The induction potency of St. John’s wort may vary widely based on preparation.

7.2 Drugs Affected by Phenytoin or Fosphenytoin Sodium Injection

Table 7 includes commonly occurring drug interactions affected by phenytoin (the active metabolite of fosphenytoin sodium injection). However, this list is not intended to be inclusive or comprehensive. Individual drug package inserts should be consulted. 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.

Table 7: Drugs Affected by Phenytoin

Interacting Agent

Examples

Drugs whose efficacy is impaired by phenytoin

Azoles

Fluconazole, ketoconazole, itraconazole, posaconazole, voriconazole

Antineoplastic agents

Irinotecan, paclitaxel, teniposide

Delavirdine

Phenytoin can substantially reduce the concentrations of delavirdine. This can lead to loss of virologic response and possible resistance [see Contraindications (4)].

Neuromuscular blocking agents

Cisatracurium, pancuronium, rocuronium and vecuronium: resistance to the neuromuscular blocking action of the nondepolarizing neuromuscular blocking agents has occurred in patients chronically administered phenytoin. Whether or not phenytoin has the same effect on other non-depolarizing agents is unknown.

Prevention or Management : Patients should be monitored closely for more rapid recovery from neuromuscular blockade than expected, and infusion rate requirements may be higher.

Warfarin

Increased and decreased PT/INR responses have been reported when phenytoin is coadministered with warfarin.

Other

Corticosteroids, doxycycline, estrogens, furosemide, oral contraceptives, paroxetine, quinidine, rifampin, sertraline, theophylline, and vitamin D

Drugs whose level is decreased by phenytoin

Antiepileptic drugsa

Carbamazepine, felbamate, lamotrigine, topiramate, oxcarbazepine

Antilipidemic agents

Atorvastatin, fluvastatin, simvastatin

Antiviral agents

Efavirenz, lopinavir/ritonavir, indinavir, nelfinavir, ritonavir, saquinavir Fosamprenavir: 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

Calcium channel blockers

Nifedipine, nimodipine, nisoldipine, verapamil

Other

Albendazole (decreases active metabolite), chlorpropamide, clozapine, cyclosporine, digoxin, disopyramide, folic acid, methadone, mexiletine, praziquantel, quetiapine

a The effect of phenytoin on phenobarbital, valproic acid and sodium valproate serum levels is unpredictable.

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