Fosphenytoin sodium

Originator

Cerebyx,Pfizer

Uses

Anti epileptic

Uses

PDE3 (phosphodiesterase 3) inhibitor

Uses

Fosphenytoin sodium is used in the treatment of epileptic seizures.

Manufacturing Process

By action of formaldehyde and hydrochloric acid on 5,5-diphenylhydantoin was prepared 3-hydroxymethyl-5,5-diphenyl-imidazolidine-2,4-dione which was converted by action PCl3 to 3-chloromethyl-5,5-diphenyl-imidazolidine-2,4- dione by action PCl3. Then the chlorine atom was substituted on P(O)(OBz)Ogroup by action of argentum salt of phosphoric acid dibenzyl ester. Removal of the protecting groups by hydrogenolysis gives the 2,4-imidazolidinedione, 5,5- diphenyl-3-((phosphonooxy)methyl)- (fosphenytoin).
In practice it is usually used as sodium salt.

brand name

Cerebyx (Parke-Davis).

Therapeutic Function

Antiepileptic, Anticonvulsant

Clinical Use

Control of status epilepticus
Seizures associated with neurosurgery or head injury when oral phenytoin is not possible

Drug interactions

Potentially hazardous interactions with other drugs Aminophylline and theophylline: concentration of both drugs reduced with aminophylline and theophylline. Analgesics: enhanced effect with NSAIDs; metabolism of methadone accelerated; possibly increases pethidine toxicity. Anthelmintics: concentration of albendazole and praziquantel reduced; concentration of fosphenytoin possibly increased by levamisole. Anti-arrhythmics: increased concentration with amiodarone; concentration of disopyramide and possibly dronedarone reduced - avoid with dronedarone. Antibacterials: level increased by clarithromycin, chloramphenicol, isoniazid, metronidazole, sulphonamides and trimethoprim (+ antifolate effect); concentration increased or decreased by ciprofloxacin; concentration of bedaquiline, doxycycline and telithromycin reduced - avoid with telithromycin; concentration reduced by rifamycins.
Anticoagulants: increased metabolism of coumarins (reduced effect but also reports of enhancement); possibly reduced apixaban, dabigatran, edoxaban and rivaroxaban concentration - avoid with dabigatran.
Antidepressants: antagonise anticonvulsant effect; concentration increased by fluoxetine and fluvoxamine and possibly sertraline; concentration of mianserin, mirtazapine and paroxetine and possibly tricyclics reduced; concentration reduced by St John’s wort - avoid.
Antiepileptics: concentration of both drugs reduced with carbamazepine, concentration may also be increased by carbamazepine, eslicarbazepine, ethosuximide, oxcarbazepine, stripentol and topiramate; concentration of ethosuximide, active oxcarbazepine metabolite, retigabine, rufinamide (concentration of phenytoin possibly increased), topiramate and valproate possibly reduced; concentration of eslicarbazepine, ethosuximide, lamotrigine, perampanel, tiagabine and zonisamide reduced; concentration of phenobarbital often
increased; phenobarbital and valproate may alter concentration; concentration reduced by vigabatrin.
Antifungals: concentration of ketoconazole, itraconazole, posaconazole, voriconazole and possibly isavuconazole and caspofungin reduced - avoid with isavuconazole and itraconazole, increase voriconazole dose and possibly caspofungin; levels increased by fluconazole, miconazole and voriconazole - consider reducing fosphenytoin dose.
Antimalarials: avoid with piperaquine with artenimol, mefloquine and pyrimethamine - antagonise anticonvulsant effect; increased antifolate effect with pyrimethamine.
Antipsychotics: antagonise anticonvulsant effect; possibly reduced aripiprazole concentration - increase aripiprazole dose; metabolism of clozapine, haloperidol, quetiapine and sertindole increased; concentration increased or decreased with chlorpromazine; possibly reduces lurasidone concentration - avoid.
Antivirals: possibly reduced concentration of abacavir, boceprevir, daclatasvir, darunavir, dasabuvir, dolutegravir, indinavir, lopinavir, ombitasvir, paritaprevir, ritonavir, saquinavir and simeprevir - avoid with boceprevir, daclatasvir, dasabuvir, ombitasvir, paritaprevir and simeprevir; rilpivirine reduced - avoid; concentration possibly increased by indinavir and ritonavir; concentration increased or decreased with zidovudine; avoid with elvitegravir,
etravirine and telaprevir.
Apremilast: concentration of apremilast reduced - avoid.
Calcium-channel blockers: levels increased by diltiazem; concentration of diltiazem, felodipine, isradipine, nimodipine and verapamil reduced; avoid with isradipine and nimodipine.
Cannabis extract: concentration possibly reduced by phenytoin - avoid.
Ciclosporin: reduced ciclosporin levels.
Cobicistat: concentration of cobicistat possibly reduced.
Corticosteroids: metabolism accelerated (effect reduced)
. Cytotoxics: metabolism possibly inhibited by
fluorouracil; increased antifolate effect with methotrexate; reduced fosphenytoin absorption; concentration of busulfan, cabozantinib, ceritinib, eribulin, etoposide and imatinib reduced - avoid with cabozantib, ceritinib and imatinib; concentration possibly reduced by bosutinib, cisplatin ibrutinib and idelalisib - avoid with ibrutinib and idelalisib; possibly reduced concentration of axitinib, increase axitinib dose; possibly reduced concentration of crizotinib - avoid; avoid with cabazitaxel, gefitinib, lapatinib, olaparib, panobinostat, vemurafenib and vismodegib; concentration of irinotecan and its active metabolite reduced.
Dexrazoxane: absorption of fosphenytoin possibly reduced.
Disulfiram: metabolism of fosphenytoin inhibited. Diuretics: concentration increased by acetazolamide; concentration of eplerenone reduced - avoid; increased risk of osteomalacia with carbonic anhydrses inhibitors; antagonises effect of furosemide.
Guanfacine: concentration of guanfacine possibly reduced - increase dose of guanfacine.
Hormone antagonists: possibly reduced concentration of abiraterone - avoid; metabolism of toremifene accelerated.
Ivacaftor: concentration of ivacaftor possibly reduced - avoid.
Muscle relaxants: long-term use of phenytoin reduces effects of non-depolarising muscle relaxants, but acute use may enhance effects.
Oestrogens and progestogens: metabolism increased (reduced contraceptive effect).
Orlistat: possibly increased risk of convulsions.
Sulfinpyrazone: concentration increased by sulfinpyrazone.
Ulcer-healing drugs: metabolism inhibited by cimetidine; absorption reduced by sucralfate;
enhanced effect with esomeprazole and omeprazole.
Ulipristal: contraceptive effect possibly reduced - avoid.

Metabolism

Fosphenytoin is rapidly and completely hydrolysed to phenytoin with a conversion half-life of about 15 minutes; one mmol of fosphenytoin yields one mmol of phenytoin. Phenytoin is hydroxylated in the liver to inactive metabolites chiefly 5-(4-hydroxyphenyl)-5- phenylhydantoin by an enzyme system which is saturable. Phenytoin undergoes enterohepatic recycling and is excreted in the urine, mainly as its hydroxylated metabolite, in either free or conjugated form.