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.
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.
