indication

For the control of generalized convulsive status epilepticus and prevention and treatment of seizures occurring during neurosurgery. It can also be substituted, short-term, for oral phenytoin.

pharmacology

Fosphenytoin is a water-soluble phenytoin prodrug used only in hospitals for the treatment of epileptic seizures. Following parenteral administration of fosphenytoin, fosphenytoin is converted to the anticonvulsant phenytoin by endogenous phosphatases. For every mmol of fosphenytoin administered, one mmol of phenytoin is produced. The pharmacological and toxicological effects of fosphenytoin include those of phenytoin.

mechanism of action

Fosphenytoin is a prodrug of phenytoin and accordingly, its anticonvulsant effects are attributable to phenytoin. Phenytoin acts on sodium channels on the neuronal cell membrane, limiting the spread of seizure activity and reducing seizure propagation. By promoting sodium efflux from neurons, phenytoin tends to stabilize the threshold against hyperexcitability caused by excessive stimulation or environmental changes capable of reducing membrane sodium gradient. This includes the reduction of post-tetanic potentiation at synapses. Loss of post-tetanic potentiation prevents cortical seizure foci from detonating adjacent cortical areas.

toxicity

Nausea, vomiting, lethargy, tachycardia, bradycardia, asystole, cardiac arrest, hypotension, syncope, hypocalcemia, metabolic acidosis, and death have been reported in cases of overdosage with fosphenytoin. The median lethal dose of fosphenytoin given intravenously in mice and rats was 156 mg PE/kg and approximately 250 mg PE/kg, or about 0.6 and 2 times, respectively, the maximum human loading dose on a mg/m2 basis. Signs of acute toxicity in animals included ataxia, labored breathing, ptosis, and hypoactivity.

biotransformation

Hepatic.

absorption

Fosphenytoin is completely bioavailable following lM administration.

half life

Fosphenytoin has a half-life of approximately 15 minutes.

route of elimination

Phenytoin derived from administration of Cerebyx is extensively metabolized in the liver and excreted in urine primarily as 5-(p-hydroxyphenyl)-5-phenylhydantoin and its glucuronide; little unchanged phenytoin (1%–5% of the Cerebyx dose) is recovered in urine.

drug interactions

Acenocoumarol: Increased hydantoin levels and risk of bleeding

Alprazolam: Fosphenytoin may increase the metabolism of alprazolam via CYP3A4.

Aminophylline: Decreased effect of both products

Amiodarone: Amiodarone may increase the effect of fosphenytoin.

Anisindione: Increased hydantoin levels and risk of bleeding

Aprepitant: The CYP3A4 inducer, fosphenytoin, may decrease the effect of aprepitant.

Atracurium: Phenytoin decreases the effect of muscle relaxant

Betamethasone: The enzyme inducer, fosphenytoin, may decrease the effect of the corticosteroid, betamethasone.

Bleomycin: The antineoplasic agent decreases the effect of hydantoin

Capecitabine: Capecitabine increases the effect of hydantoin

Carboplatin: The antineoplasic agent decreases the effect of hydantoin

Carmustine: The antineoplasic agent decreases the effect of hydantoin

Chloramphenicol: Increases phenytoin, modifies chloramphenicol

Chlordiazepoxide: Fosphenytoin may increase the metabolism of chlordiazepoxide via CYP3A4.

Chlorotrianisene: The enzyme inducer, fosphenytoin, decreases the effect of the hormone agent, chlorotrianisene.

Chlorpheniramine: The antihistamine increases the effect of hydantoin

Cimetidine: Cimetidine may increase the serum concentration of fosphenytoin by decreasing its metabolism. Consider alternate therapy or monitor for changes in the therapeutic and adverse effects of fosphenytoin if cimetidine is initiated, discontinued or dose changed.

Cisplatin: The antineoplasic agent decreases the effect of hydantoin

Clarithromycin: Clarithromycin may increase the therapeutic and adverse effects of fosphenytoin.

Clomifene: The enzyme inducer, fosphenytoin, decreases the effect of the hormone agent, clomifene.

Clorazepate: Fosphenytoin may increase the metabolism of clorazepate via CYP3A4.

Clozapine: Hydantoin decreases the effect of clozapine

Conjugated Estrogens: The enzyme inducer, fosphenytoin, decreases the effect of the hormone agent, conjugated estrogens.

Cortisone acetate: The enzyme inducer, fosphenytoin, may decrease the effect of the corticosteroid, cortisone acetate.

Cyclosporine: The hydantoin decreases the effect of cyclosporine

Delavirdine: The anticonvulsant, fosphenytoin, decreases the effect of delavirdine.

Dexamethasone: The enzyme inducer, fosphenytoin, may decrease the effect of the corticosteroid, dexamethasone.

Diazepam: Fosphenytoin may increase the metabolism of diazepam via CYP3A4.

Diazoxide: Diazoxide decreases the hydantoin effect

Dicumarol: Increased hydantoin levels and risk of bleeding

Diethylstilbestrol: The enzyme inducer, fosphenytoin, may decrease the therapeutic effect of diethylstilbestrol.

Disopyramide: The hydantoin decreases the effect of disopyramide

Disulfiram: Disulfiram may increase the effect of fosphenytoin.

Dopamine: Risk of severe hypotension

Doxacurium chloride: Phenytoin decreases the effect of muscle relaxant

Doxycycline: The anticonvulsant, fosphenytoin, decreases the effect of doxycycline.

Dyphylline: Decreased effect of both products

Estradiol: The enzyme inducer, fosphenytoin, decreases the effect of the hormone agent, estradiol.

Estriol: The enzyme inducer, fosphenytoin, decreases the effect of the hormone agent, estriol.

Estrone: The enzyme inducer, fosphenytoin, decreases the effect of the hormone agent, estrone.

Estropipate: The enzyme inducer, fosphenytoin, decreases the effect of the hormone agent, estropipate.

Ethinyl Estradiol: This product may cause a slight decrease of contraceptive effect

Felbamate: Increased phenytoin levels and decreased felbamate levels

Felodipine: The hydantoin decreases the effect of felodipine

Fluconazole: Fluconazole may increase the effect of hydantoin.

Fludrocortisone: The enzyme inducer, fosphenytoin, may decrease the effect of the corticosteroid, fludrocortisone.

Fluorouracil: Fluorouracil increases the effect of hydantoin

Fluoxetine: Fluoxetine increases the effect of phenytoin

Flurazepam: Fosphenytoin may increase the metabolism of flurazepam via CYP3A4.

Fluvoxamine: Fluvoxamine may increase the therapeutic and adverse effects of fosphenytoin.

Folic Acid: Folic acid decreases the levels of hydantoin

Furosemide: The hydantoin decreases the effect of furosemide

Gabapentin: Gabapentin may increase the effect of fosphenytoin.

Gefitinib: The CYP3A4 inducer, fosphenytoin, may decrease the serum concentration and therapeutic effects of gefitinib.

Hydrocortisone: The enzyme inducer, fosphenytoin, may decrease the effect of the corticosteroid, hydrocortisone.

Imatinib: The hydantoin decreases the levels of imatinib

Irinotecan: The hydantoin decreases the effect of irinotecan

Isoniazid: Isoniazid may increase the effect of phenytoin in 20% of patients.

Itraconazole: Phenytoin decreases the effect of itraconazole

Lamotrigine: Phenytoin may reduce levels of lamotrigine

Levodopa: The hydantoin decreases the effect of levodopa

Levonorgestrel: Phenytoin decreases the contraceptive effect

Lopinavir: Levels of both drugs are affected

Mebendazole: The hydantoin decreases the efficiency of mebendazole

Medroxyprogesterone: The enzyme inducer, fosphenytoin, may decrease the effect of the hormone, medroxyprogesterone.

Megestrol: The enzyme inducer, fosphenytoin, may decrease the effect of the hormone, megestrol.

Mestranol: This product may cause a slight decrease of contraceptive effect

Methadone: The hydantoin decreases the effect of methadone

Methotrexate: The antineoplasic agent decreases the effect of hydantoin

Methoxsalen: The hydantoin decreases the effect of psoralene

Methylprednisolone: The enzyme inducer, fosphenytoin, may decrease the effect of the corticosteroid, methylprednisolone.

Metocurine: Phenytoin decreases the effect of muscle relaxant

Metyrapone: The combination renders the test invalid

Mexiletine: The hydantoin decreases the effect of mexiletine

Midazolam: Fosphenytoin may increase the metabolism of midazolam via CYP3A4.

Mirtazapine: The hydantoins may reduce mirtazapine plasma concentrations and pharmacological effects

Mivacurium: Phenytoin decreases the effect of muscle relaxant

Nisoldipine: Phenytoin decreases the efficiency of nisoldipine

Norethindrone: This product may cause a slight decrease of contraceptive effect

Omeprazole: Omeprazole increases the effect of hydantoin

Oxcarbazepine: Oxcarbazepine increases the effect of hydantoin

Oxtriphylline: Decreased effect of both products

Oxyphenbutazone: The NSAID, oxphenbutazone, may increase the hydantoin effect of fosphenytoin.

Pancuronium: Phenytoin decreases the effect of muscle relaxant

Paramethasone: The enzyme inducer, fosphenytoin, may decrease the effect of the corticosteroid, paramethasone.

Phenylbutazone: The NSAID, phenylbutazone, may increase the hydantoin effect of fosphenytoin.

Posaconazole: Modifications of drug levels for both agents

Prednisolone: The enzyme inducer, fosphenytoin, may decrease the effect of the corticosteroid, prednisolone.

Prednisone: The enzyme inducer, fosphenytoin, may decrease the effect of the corticosteroid, prednisone.

Quetiapine: Phenytoin decreases the effect of quetiapine

Quinestrol: The enzyme inducer, fosphenytoin, decreases the effect of the hormone agent, quinestrol.

Quinidine: The anticonvulsant, fosphenytoin, decreases the effect of quinidine.

Quinupristin: This combination presents an increased risk of toxicity

Rifampin: Rifampin may decrease the effect of fosphenytoin.

Sertraline: Sertraline increases the effect of hydantoin

Sirolimus: The hydantoin decreases sirolimus levels

Sucralfate: Sucralfate decreases the effect of hydantoin

Sulfadiazine: The sulfonamide increases the effect of hydantoin

Sulfamethizole: The sulfonamide increases the effect of hydantoin

Tacrolimus: The hydantoin decreases the effect of tacrolimus

Telithromycin: Fosphenytoin may decrease the plasma concentration of Telithromycin. Consider alternate therapy.

Temsirolimus: Fosphenytoin may increase the metabolism of Temsirolimus decreasing its efficacy. Concomitant therapy should be avoided.

Theophylline: Decreased effect of both products

Thiotepa: Possible increase in thiotepa levels

Ticlopidine: Ticlopidine may decrease the metabolism and clearance of Fosphenytoin. Consider alternate therapy or monitor for adverse/toxic effects of Fosphenytoin if Ticlopidine is initiated, discontinued or dose changed.

Tolbutamide: Tolbutamide, a strong CYP2C9 inhibitor, may decrease the metabolism and clearance of Fosphenytoin. Consider alternate therapy or monitor for changes in Fosphenytoin therapeutic and adverse effects if Tolbutamide is initiated, discontinued or dose changed.

Topiramate: Increased phenytoin/decreased topiramate

Tramadol: Fosphenytoin may decrease the effect of Tramadol by increasing Tramadol metabolism and clearance.

Trazodone: The CYP3A4 inducer, Fosphenytoin, may decrease Trazodone efficacy by increasing Trazodone metabolism and clearance. Monitor for changes in Trazodone efficacy/toxicity if Fosphenytoin is initiated, discontinued or dose changed.

Tretinoin: The strong CYP2C8 inducer, Fosphenytoin, may increase the metabolism and clearance of oral Tretinoin. Consider alternate therapy to avoid failure of Tretinoin therapy or monitor for changes in Tretinoin effectiveness and adverse/toxic effects if Fosphenytoin is initiated, discontinued or dose changed.

Triamcinolone: The enzyme inducer, fosphenytoin, may decrease the effect of the corticosteroid, triamcinolone.

Triazolam: Fosphenytoin may increase the metabolism of triazolam via CYP3A4.

Trimethoprim: Trimethoprim increases the effect of hydantoin

Trioxsalen: The hydantoin decreases the effect of psoralene

Triprolidine: The CNS depressants, Triprolidine and Fosphenytoin, may increase adverse/toxic effects due to additivity. Monitor for increased CNS depressant effects during concomitant therapy.

Tubocurarine: Phenytoin decreases the effect of muscle relaxant

Vecuronium: Phenytoin decreases the effect of muscle relaxant

Vigabatrin: Vigabatrin decreases the effect of hydantoin

Vinblastine: The antineoplasic agent decreases the effect of hydantoin

Voriconazole: The hydantoin decreases the effect of voriconazole

Warfarin: Increased hydantoin levels and risk of bleeding