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Identification
NameFosphenytoin
Accession NumberDB01320
TypeSmall Molecule
GroupsApproved
Description

Fosphenytoin is a water-soluble phenytoin prodrug used only in hospitals for the treatment of epileptic seizures. It works by slowing down impulses in the brain that cause seizures. Its main mechanism is to block frequency-dependent, use-dependent and voltage-dependent neuronal sodium channels, and therefore limit repetitive firing of action potentials.

Structure
Thumb
Synonyms
SynonymLanguageCode
(3-Phosphoryloxymethyl)phenytoinNot AvailableNot Available
CerebyxNot AvailableNot Available
FosfenitoinaSpanishINN
FosphenytoinNot AvailableNot Available
FosphenytoineFrenchINN
FosphenytoinumLatinINN
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
Cerebyxinjection, solution50 mg/mLintramuscular; intravenousPfizer Laboratories2013-10-28Not AvailableUs 0a2ef1ad1c84951dc1392a8bbe1f3cb241c91ed59e44ad8268635315440d978c
Cerebyxinjection, solution50 mg/mLintramuscular; intravenousPfizer Laboratories2013-10-28Not AvailableUs 0a2ef1ad1c84951dc1392a8bbe1f3cb241c91ed59e44ad8268635315440d978c
Cerebyxinjection, solution50 mg/mLintramuscular; intravenousPfizer Laboratories2013-10-28Not AvailableUs 0a2ef1ad1c84951dc1392a8bbe1f3cb241c91ed59e44ad8268635315440d978c
Cerebyxliquid75 mgintramuscularErfa Canada 2012 IncNot AvailableNot AvailableCanada 5f16b84899037e23705f146ff57e3794121879cb055f0954756d94bc690476b4
Generic Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
Fosphenytoin Sodiuminjection, solution50 mg/mLintramuscular; intravenousWest ward Pharmaceutical Corp2009-12-02Not AvailableUs 0a2ef1ad1c84951dc1392a8bbe1f3cb241c91ed59e44ad8268635315440d978c
Fosphenytoin Sodiuminjection, solution50 mg/mLintramuscular; intravascularWest ward Pharmaceutical Corp2009-12-02Not AvailableUs 0a2ef1ad1c84951dc1392a8bbe1f3cb241c91ed59e44ad8268635315440d978c
Fosphenytoin Sodiuminjection, solution50 mg/mLintramuscular; intravenousHospira, Inc.2007-08-06Not AvailableUs 0a2ef1ad1c84951dc1392a8bbe1f3cb241c91ed59e44ad8268635315440d978c
Fosphenytoin Sodiuminjection, solution50 mg/mLintramuscular; intravenousAmerican Regent, Inc.2010-07-30Not AvailableUs 0a2ef1ad1c84951dc1392a8bbe1f3cb241c91ed59e44ad8268635315440d978c
Fosphenytoin Sodiuminjection50 mg/mLintramuscular; intravenousWest Ward Pharmaceutical Corp.2007-08-06Not AvailableUs 0a2ef1ad1c84951dc1392a8bbe1f3cb241c91ed59e44ad8268635315440d978c
Fosphenytoin Sodiuminjection50 mg/mLintramuscular; intravenousWest Ward Pharmaceutical Corp.2007-08-06Not AvailableUs 0a2ef1ad1c84951dc1392a8bbe1f3cb241c91ed59e44ad8268635315440d978c
Fosphenytoin Sodiuminjection, solution50 mg/mLintramuscular; intravenousGenera Medix Inc.2007-08-06Not AvailableUs 0a2ef1ad1c84951dc1392a8bbe1f3cb241c91ed59e44ad8268635315440d978c
Fosphenytoin Sodiuminjection, solution50 mg/mLintramuscular; intravenousSun Pharma Global FZE2009-08-14Not AvailableUs 0a2ef1ad1c84951dc1392a8bbe1f3cb241c91ed59e44ad8268635315440d978c
Fosphenytoin Sodiuminjection, solution50 mg/mLintramuscular; intravenousSun Pharma Global FZE2009-08-14Not AvailableUs 0a2ef1ad1c84951dc1392a8bbe1f3cb241c91ed59e44ad8268635315440d978c
Fosphenytoininjection, solution50 mg/mLintramuscular; intravenousFresenius Kabi USA, LLC2009-12-14Not AvailableUs 0a2ef1ad1c84951dc1392a8bbe1f3cb241c91ed59e44ad8268635315440d978c
Fosphenytoininjection, solution50 mg/mLintramuscular; intravenousFresenius Kabi USA, LLC2009-12-14Not AvailableUs 0a2ef1ad1c84951dc1392a8bbe1f3cb241c91ed59e44ad8268635315440d978c
Fosphenytoin Sodiuminjection50 mg/mLintramuscular; intravenousAmneal Pharmaceuticals of New York, LLC2013-05-17Not AvailableUs 0a2ef1ad1c84951dc1392a8bbe1f3cb241c91ed59e44ad8268635315440d978c
Fosphenytoin Sodiuminjection50 mg/mLintramuscular; intravenousAmneal Pharmaceuticals of New York, LLC2013-05-17Not AvailableUs 0a2ef1ad1c84951dc1392a8bbe1f3cb241c91ed59e44ad8268635315440d978c
Over the Counter ProductsNot Available
International Brands
NameCompany
ProdilantinNot Available
Brand mixturesNot Available
Salts
Name/CASStructureProperties
Fosphenytoin sodium
Thumb
  • InChI Key: GQPXYJNXTAFDLT-UHFFFAOYSA-L
  • Monoisotopic Mass: 406.03066202
  • Average Mass: 406.2375
DBSALT000296
Categories
CAS number93390-81-9
WeightAverage: 362.2739
Monoisotopic: 362.066772734
Chemical FormulaC16H15N2O6P
InChI KeyXWLUWCNOOVRFPX-UHFFFAOYSA-N
InChI
InChI=1S/C16H15N2O6P/c19-14-16(12-7-3-1-4-8-12,13-9-5-2-6-10-13)17-15(20)18(14)11-24-25(21,22)23/h1-10H,11H2,(H,17,20)(H2,21,22,23)
IUPAC Name
[(2,5-dioxo-4,4-diphenylimidazolidin-1-yl)methoxy]phosphonic acid
SMILES
OP(O)(=O)OCN1C(=O)NC(C1=O)(C1=CC=CC=C1)C1=CC=CC=C1
Taxonomy
DescriptionThis compound belongs to the class of organic compounds known as phenylhydantoins. These are heterocyclic aromatic compounds containing an imiazolidinedione moiety substituted by a phenyl group.
KingdomOrganic compounds
Super ClassOrganoheterocyclic compounds
ClassAzolidines
Sub ClassImidazolidines
Direct ParentPhenylhydantoins
Alternative Parents
Substituents
  • 5-phenylhydantoin
  • Diphenylmethane
  • Phenylimidazolidine
  • Monoalkyl phosphate
  • Ureide
  • Benzenoid
  • Alkyl phosphate
  • Phosphoric acid ester
  • Organic phosphoric acid derivative
  • Organic phosphate
  • Monocyclic benzene moiety
  • Urea
  • Tertiary amine
  • Carboxamide group
  • Azacycle
  • Carboxylic acid derivative
  • Hydrocarbon derivative
  • Organooxygen compound
  • Organonitrogen compound
  • Carbonyl group
  • Amine
  • Aromatic heteromonocyclic compound
Molecular FrameworkAromatic heteromonocyclic compounds
External DescriptorsNot Available
Pharmacology
IndicationFor 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.
PharmacodynamicsFosphenytoin 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 actionFosphenytoin 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.
AbsorptionFosphenytoin is completely bioavailable following lM administration.
Volume of distribution
  • 4.3 to 10.8 L
Protein bindingExtensively bound (95% to 99%) to human plasma proteins, primarily albumin.
Metabolism

Hepatic.

SubstrateEnzymesProduct
Fosphenytoin
Not Available
PhenytoinDetails
Route of eliminationPhenytoin 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.
Half lifeFosphenytoin has a half-life of approximately 15 minutes.
ClearanceNot Available
ToxicityNausea, 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.
Affected organisms
  • Humans and other mammals
Pathways
PathwayCategorySMPDB ID
Fosphenytoin (Antiarrhythmic) Metabolism PathwayDrug metabolismSMP00618
Fosphenytoin (Antiarrhythmic) Action PathwayDrug actionSMP00326
SNP Mediated EffectsNot Available
SNP Mediated Adverse Drug ReactionsNot Available
ADMET
Predicted ADMET features
PropertyValueProbability
Human Intestinal Absorption-0.5244
Blood Brain Barrier+0.9215
Caco-2 permeable-0.639
P-glycoprotein substrateSubstrate0.5
P-glycoprotein inhibitor INon-inhibitor0.7952
P-glycoprotein inhibitor IINon-inhibitor0.8466
Renal organic cation transporterNon-inhibitor0.8731
CYP450 2C9 substrateNon-substrate0.7094
CYP450 2D6 substrateNon-substrate0.9116
CYP450 3A4 substrateNon-substrate0.6873
CYP450 1A2 substrateNon-inhibitor0.8477
CYP450 2C9 substrateNon-inhibitor0.7802
CYP450 2D6 substrateNon-inhibitor0.8859
CYP450 2C19 substrateNon-inhibitor0.7169
CYP450 3A4 substrateNon-inhibitor0.7672
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.9083
Ames testNon AMES toxic0.614
CarcinogenicityNon-carcinogens0.7835
BiodegradationNot ready biodegradable0.9674
Rat acute toxicity2.4215 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.9578
hERG inhibition (predictor II)Non-inhibitor0.7299
Pharmacoeconomics
ManufacturersNot Available
Packagers
Dosage forms
FormRouteStrength
Injectionintramuscular; intravenous50 mg/mL
Injection, solutionintramuscular; intravascular50 mg/mL
Injection, solutionintramuscular; intravenous50 mg/mL
Liquidintramuscular75 mg
Prices
Unit descriptionCostUnit
Cerebyx 500 mg pe/10 ml vial8.63USD ml
Fosphenytoin 500 mg pe/10 ml0.61USD ml
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
PatentsNot Available
Properties
StateSolid
Experimental PropertiesNot Available
Predicted Properties
PropertyValueSource
Water Solubility0.145 mg/mLALOGPS
logP1.08ALOGPS
logP1.67ChemAxon
logS-3.4ALOGPS
pKa (Strongest Acidic)1.46ChemAxon
pKa (Strongest Basic)-9.7ChemAxon
Physiological Charge-2ChemAxon
Hydrogen Acceptor Count5ChemAxon
Hydrogen Donor Count3ChemAxon
Polar Surface Area116.17 Å2ChemAxon
Rotatable Bond Count5ChemAxon
Refractivity87.05 m3·mol-1ChemAxon
Polarizability33.23 Å3ChemAxon
Number of Rings3ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleYesChemAxon
Spectra
Mass Spec (NIST)Not Available
SpectraNot Available
References
Synthesis Reference

Volker Kirsch, “Process for the preparation of sodium fosphenytoin.” U.S. Patent US20050272706, issued December 08, 2005.

US20050272706
General Reference
  1. Johnson J, Wrenn K: Inappropriate fosphenytoin use in the ED. Am J Emerg Med. 2001 Jul;19(4):293-4. Pubmed
  2. Applebaum J, Levine J, Belmaker RH: Intravenous fosphenytoin in acute mania. J Clin Psychiatry. 2003 Apr;64(4):408-9. Pubmed
  3. McCleane GJ: Intravenous infusion of fosphenytoin produces prolonged pain relief: a case report. J Pain. 2002 Apr;3(2):156-8. Pubmed
  4. Browne TR, Kugler AR, Eldon MA: Pharmacology and pharmacokinetics of fosphenytoin. Neurology. 1996 Jun;46(6 Suppl 1):S3-7. Pubmed 8649612
  5. Luszczki JJ: Third-generation antiepileptic drugs: mechanisms of action, pharmacokinetics and interactions. Pharmacol Rep. 2009 Mar-Apr;61(2):197-216. Pubmed
External Links
ATC CodesN03AB05
AHFS Codes
  • 28:12.12
PDB EntriesNot Available
FDA labelDownload (820 KB)
MSDSNot Available
Interactions
Drug Interactions
Drug
AcenocoumarolMay enhance the anticoagulant effect of Vitamin K Antagonists. Vitamin K Antagonists may increase the serum concentration of Fosphenytoin.
AcetaminophenFosphenytoin-Phenytoin may decrease the serum concentration of Acetaminophen. Specifically, serum concentrations of acetaminophen may be decreased (leading to decreased efficacy), but the formation of the toxic N-acetyl-p-benzoquinone imine (NAPQI) metabolite may be increased (leading to increased hepatotoxicity).
AcetazolamideMay enhance the adverse/toxic effect of Fosphenytoin-Phenytoin. Specifically, the risk for osteomalacia or rickets may be increased. Exceptions: Brinzolamide; Dorzolamide.
AfatinibP-glycoprotein/ABCB1 Inducers may decrease the serum concentration of Afatinib.
AlprazolamMay increase the serum concentration of Fosphenytoin. Short-term exposure to benzodiazepines may not present as much risk as chronic therapy. Exceptions: ALPRAZolam.
AminophyllineTheophylline Derivatives may decrease the serum concentration of Fosphenytoin. Fosphenytoin may decrease the serum concentration of Theophylline Derivatives.
AmiodaroneMay enhance the QTc-prolonging effect of Amiodarone. Amiodarone may increase the serum concentration of Fosphenytoin. Fosphenytoin may decrease the serum concentration of Amiodarone.
AmlodipineCalcium Channel Blockers may increase the serum concentration of Fosphenytoin.
AmrinoneMay increase the serum concentration of Fosphenytoin.
ApixabanCYP3A4 Inducers (Strong) may decrease the serum concentration of Apixaban.
ApremilastCYP3A4 Inducers (Strong) may decrease the serum concentration of Apremilast.
AripiprazoleCYP3A4 Inducers may decrease the serum concentration of ARIPiprazole.
ArtemetherCYP3A4 Inducers (Strong) may decrease serum concentrations of the active metabolite(s) of Artemether. Specifically, dihydroartemisinin concentrations may be reduced. CYP3A4 Inducers (Strong) may decrease the serum concentration of Artemether.
AtorvastatinMay decrease the serum concentration of HMG-CoA Reductase Inhibitors.
AxitinibCYP3A4 Inducers (Strong) may decrease the serum concentration of Axitinib.
bazedoxifeneFosphenytoin may decrease the serum concentration of Bazedoxifene. This may lead to loss of efficacy or, if bazedoxifene is combined with estrogen therapy, an increased risk of endometrial hyperplasia.
BedaquilineCYP3A4 Inducers (Strong) may decrease the serum concentration of Bedaquiline.
BepridilMay increase the serum concentration of Fosphenytoin.
BoceprevirFosphenytoin may decrease the serum concentration of Boceprevir.
BortezomibCYP3A4 Inducers (Strong) may decrease the serum concentration of Bortezomib.
BosutinibCYP3A4 Inducers (Strong) may decrease the serum concentration of Bosutinib.
Brentuximab vedotinCYP3A4 Inducers (Strong) may decrease the serum concentration of Brentuximab Vedotin. Specifically, concentrations of the active monomethyl auristatin E (MMAE) component may be decreased.
BromazepamMay increase the serum concentration of Fosphenytoin. Short-term exposure to benzodiazepines may not present as much risk as chronic therapy. Exceptions: ALPRAZolam.
BumetanideMay diminish the diuretic effect of Loop Diuretics.
BuprenorphineCNS Depressants may enhance the CNS depressant effect of Buprenorphine.
BusulfanMay decrease the serum concentration of Busulfan.
CabozantinibCYP3A4 Inducers (Strong) may decrease the serum concentration of Cabozantinib.
CamazepamMay increase the serum concentration of Fosphenytoin. Short-term exposure to benzodiazepines may not present as much risk as chronic therapy. Exceptions: ALPRAZolam.
CanagliflozinFosphenytoin may decrease the serum concentration of Canagliflozin.
CapecitabineCapecitabine may increase the serum concentration of Fosphenytoin.
CarbamazepineCarBAMazepine may decrease the serum concentration of Fosphenytoin. CarBAMazepine may increase the serum concentration of Fosphenytoin. Possibly by competitive inhibition at sites of metabolism. Fosphenytoin may decrease the serum concentration of CarBAMazepine.
CefazolinMay decrease the protein binding of Fosphenytoin.
ChlordiazepoxideMay increase the serum concentration of Fosphenytoin. Short-term exposure to benzodiazepines may not present as much risk as chronic therapy. Exceptions: ALPRAZolam.
ChlormezanoneMay increase the serum concentration of Fosphenytoin. Short-term exposure to benzodiazepines may not present as much risk as chronic therapy. Exceptions: ALPRAZolam.
CimetidineMay enhance the adverse/toxic effect of Fosphenytoin-Phenytoin. Cimetidine may increase the serum concentration of Fosphenytoin-Phenytoin.
CinolazepamMay increase the serum concentration of Fosphenytoin. Short-term exposure to benzodiazepines may not present as much risk as chronic therapy. Exceptions: ALPRAZolam.
ClarithromycinCYP3A4 Inducers (Strong) may increase serum concentrations of the active metabolite(s) of Clarithromycin. Clarithromycin may increase the serum concentration of CYP3A4 Inducers (Strong). CYP3A4 Inducers (Strong) may decrease the serum concentration of Clarithromycin.
ClobazamMay increase the serum concentration of Fosphenytoin. Short-term exposure to benzodiazepines may not present as much risk as chronic therapy. Exceptions: ALPRAZolam.
ClonazepamMay increase the serum concentration of Fosphenytoin. Short-term exposure to benzodiazepines may not present as much risk as chronic therapy. Exceptions: ALPRAZolam.
ClotiazepamMay increase the serum concentration of Fosphenytoin. Short-term exposure to benzodiazepines may not present as much risk as chronic therapy. Exceptions: ALPRAZolam.
CloxazolamMay increase the serum concentration of Fosphenytoin. Short-term exposure to benzodiazepines may not present as much risk as chronic therapy. Exceptions: ALPRAZolam.
ClozapineCYP3A4 Inducers (Strong) may decrease the serum concentration of CloZAPine.
CrizotinibCYP3A4 Inducers (Strong) may decrease the serum concentration of Crizotinib.
Dabigatran etexilateP-glycoprotein/ABCB1 Inducers may decrease the serum concentration of Dabigatran Etexilate.
DabrafenibMay decrease the serum concentration of CYP2C9 Substrates.
DarunavirMay decrease the serum concentration of Darunavir.
DasatinibCYP3A4 Inducers (Strong) may decrease the serum concentration of Dasatinib.
DeferasiroxFosphenytoin may decrease the serum concentration of Deferasirox.
DelavirdineDelavirdine may increase the serum concentration of Fosphenytoin. Fosphenytoin may decrease the serum concentration of Delavirdine.
DesogestrelMay diminish the therapeutic effect of Contraceptives (Estrogens). Contraceptive failure is possible.
DexmethylphenidateMay increase the serum concentration of Fosphenytoin.
DiazoxideDiazoxide may decrease the serum concentration of Fosphenytoin. Total phenytoin concentrations may be affected more than free phenytoin concentrations.
DiclofenamideMay enhance the adverse/toxic effect of Fosphenytoin-Phenytoin. Specifically, the risk for osteomalacia or rickets may be increased. Exceptions: Brinzolamide; Dorzolamide.
DiltiazemCalcium Channel Blockers may increase the serum concentration of Fosphenytoin.
DisopyramideDisopyramide may enhance the QTc-prolonging effect of Fosphenytoin. Fosphenytoin may decrease the serum concentration of Disopyramide.
DisulfiramDisulfiram may increase the serum concentration of Fosphenytoin.
DolutegravirFosphenytoin-Phenytoin may decrease the serum concentration of Dolutegravir.
DoxycyclineMay decrease the serum concentration of Doxycycline.
DoxylamineMay enhance the CNS depressant effect of CNS Depressants.
DronabinolCYP3A4 Inducers (Strong) may decrease the serum concentration of Dronabinol.
DronedaroneCYP3A4 Inducers (Strong) may decrease the serum concentration of Dronedarone.
DroperidolMay enhance the CNS depressant effect of CNS Depressants.
DrospirenoneMay diminish the therapeutic effect of Contraceptives (Progestins). Contraceptive failure is possible.
EfavirenzMay increase the serum concentration of Fosphenytoin. Fosphenytoin may decrease the serum concentration of Efavirenz.
EliglustatCYP3A4 Inducers (Strong) may decrease the serum concentration of Eliglustat.
EnzalutamideCYP2C8 Inducers (Strong) may decrease the serum concentration of Enzalutamide.
ErlotinibCYP3A4 Inducers (Strong) may decrease the serum concentration of Erlotinib.
EstazolamBenzodiazepines may increase the serum concentration of Fosphenytoin. Short-term exposure to benzodiazepines may not present as much risk as chronic therapy.
Ethacrynic acidMay diminish the diuretic effect of Loop Diuretics.
EthanolAlcohol (Ethyl) may enhance the CNS depressant effect of Fosphenytoin. Alcohol (Ethyl) may decrease the serum concentration of Fosphenytoin. This may be particularly applicable with chronic, heavy alcohol consumption. Alcohol (Ethyl) may increase the serum concentration of Fosphenytoin. This may be particularly applicable with acute, heavy alcohol consumption.
Ethinyl EstradiolMay diminish the therapeutic effect of Contraceptives (Estrogens). Contraceptive failure is possible.
EthosuximideEthosuximide may enhance the CNS depressant effect of Fosphenytoin. Ethosuximide may increase the serum concentration of Fosphenytoin. Fosphenytoin may decrease the serum concentration of Ethosuximide.
EthoxzolamideMay enhance the adverse/toxic effect of Fosphenytoin-Phenytoin. Specifically, the risk for osteomalacia or rickets may be increased. Exceptions: Brinzolamide; Dorzolamide.
EthynodiolMay diminish the therapeutic effect of Contraceptives (Estrogens). Contraceptive failure is possible.
EtonogestrelMay diminish the therapeutic effect of Contraceptives (Progestins). Contraceptive failure is possible.
EtoposideMay decrease the serum concentration of Etoposide.
EtravirineFosphenytoin may decrease the serum concentration of Etravirine.
EverolimusCYP3A4 Inducers (Strong) may decrease the serum concentration of Everolimus.
ExemestaneCYP3A4 Inducers (Strong) may decrease the serum concentration of Exemestane.
FelbamateFelbamate may increase the serum concentration of Fosphenytoin. Fosphenytoin may decrease the serum concentration of Felbamate.
FelodipineCalcium Channel Blockers may increase the serum concentration of Fosphenytoin.
FentanylCYP3A4 Inducers (Strong) may decrease the serum concentration of FentaNYL.
FloxuridineFloxuridine may increase the serum concentration of Fosphenytoin.
FluconazoleFluconazole may increase the serum concentration of Fosphenytoin.
FludiazepamMay increase the serum concentration of Fosphenytoin. Short-term exposure to benzodiazepines may not present as much risk as chronic therapy. Exceptions: ALPRAZolam.
FlunarizineMay increase the serum concentration of Fosphenytoin.
FlunitrazepamMay increase the serum concentration of Fosphenytoin. Short-term exposure to benzodiazepines may not present as much risk as chronic therapy. Exceptions: ALPRAZolam.
FluoxetineMay enhance the QTc-prolonging effect of FLUoxetine. FLUoxetine may increase the serum concentration of Fosphenytoin.
FluvastatinMay decrease the serum concentration of HMG-CoA Reductase Inhibitors.
FluvoxamineFluvoxaMINE may increase the serum concentration of Fosphenytoin.
Folic AcidFolic Acid may decrease the serum concentration of Fosphenytoin.
FosamprenavirFosamprenavir may decrease the serum concentration of Fosphenytoin. Fosphenytoin may increase the serum concentration of Fosamprenavir.
FurosemideMay diminish the diuretic effect of Loop Diuretics.
GabapentinMay increase the serum concentration of Fosphenytoin.
GefitinibCYP3A4 Inducers (Strong) may decrease the serum concentration of Gefitinib.
GuanfacineCYP3A4 Inducers (Strong) may decrease the serum concentration of GuanFACINE.
HalazepamMay increase the serum concentration of Fosphenytoin. Short-term exposure to benzodiazepines may not present as much risk as chronic therapy. Exceptions: ALPRAZolam.
HalothaneMay increase the serum concentration of Fosphenytoin.
HydrocodoneCNS Depressants may enhance the CNS depressant effect of Hydrocodone.
HydroxyzineMay enhance the CNS depressant effect of CNS Depressants.
ImatinibCYP3A4 Inducers (Strong) may decrease the serum concentration of Imatinib.
IrinotecanCYP3A4 Inducers (Strong) may decrease serum concentrations of the active metabolite(s) of Irinotecan. Specifically, serum concentrations of SN-38 may be reduced. CYP3A4 Inducers (Strong) may decrease the serum concentration of Irinotecan.
IsoniazidIsoniazid may increase the serum concentration of Fosphenytoin.
IsradipineCalcium Channel Blockers may increase the serum concentration of Fosphenytoin.
ItraconazoleCYP3A4 Inducers (Strong) may decrease the serum concentration of Itraconazole.
IvacaftorCYP3A4 Inducers (Strong) may decrease the serum concentration of Ivacaftor.
IxabepiloneCYP3A4 Inducers (Strong) may decrease the serum concentration of Ixabepilone.
KetazolamMay increase the serum concentration of Fosphenytoin. Short-term exposure to benzodiazepines may not present as much risk as chronic therapy. Exceptions: ALPRAZolam.
LacosamideFosphenytoin may decrease the serum concentration of Lacosamide.
LamotrigineMay decrease the serum concentration of LamoTRIgine.
LapatinibCYP3A4 Inducers (Strong) may decrease the serum concentration of Lapatinib.
LedipasvirP-glycoprotein/ABCB1 Inducers may decrease the serum concentration of Ledipasvir.
LercanidipineMay increase the serum concentration of Fosphenytoin.
LevonorgestrelMay diminish the therapeutic effect of Contraceptives (Progestins). Contraceptive failure is possible.
LevothyroxineMay decrease the serum concentration of Thyroid Products. Phenytoin may also displace thyroid hormones from protein binding sites.
LinagliptinCYP3A4 Inducers (Strong) may decrease the serum concentration of Linagliptin.
LiothyronineMay decrease the serum concentration of Thyroid Products. Phenytoin may also displace thyroid hormones from protein binding sites.
LiotrixMay decrease the serum concentration of Thyroid Products. Phenytoin may also displace thyroid hormones from protein binding sites.
LithiumFosphenytoin may enhance the adverse/toxic effect of Lithium.
LopinavirFosphenytoin may decrease the serum concentration of Lopinavir. Lopinavir may decrease the serum concentration of Fosphenytoin.
LorazepamBenzodiazepines may increase the serum concentration of Fosphenytoin. Short-term exposure to benzodiazepines may not present as much risk as chronic therapy.
LovastatinMay decrease the serum concentration of HMG-CoA Reductase Inhibitors.
LULICONAZOLEMay increase the serum concentration of CYP2C19 Substrates.
LumefantrineCYP3A4 Inducers (Strong) may decrease the serum concentration of Lumefantrine.
LurasidoneCYP3A4 Inducers (Strong) may decrease the serum concentration of Lurasidone.
MACITENTANCYP3A4 Inducers (Strong) may decrease the serum concentration of Macitentan.
Magnesium SulfateMay increase the serum concentration of Fosphenytoin.
MaravirocCYP3A4 Inducers (Strong) may decrease the serum concentration of Maraviroc.
MebendazoleMay decrease the serum concentration of Mebendazole.
Medroxyprogesterone AcetateMay diminish the therapeutic effect of Contraceptives (Progestins). Contraceptive failure is possible.
MefloquineMefloquine may diminish the therapeutic effect of Anticonvulsants. Mefloquine may decrease the serum concentration of Anticonvulsants.
MestranolMay diminish the therapeutic effect of Contraceptives (Estrogens). Contraceptive failure is possible.
MethadoneMay decrease the serum concentration of Methadone.
MethotrexateMay decrease the serum concentration of Fosphenytoin-Phenytoin. Fosphenytoin-Phenytoin may increase the serum concentration of Methotrexate. Specifically, fosphenytoin-phenytoin may displace methotrexate from serum proteins, increasing the concentration of free, unbound drug.
MethotrimeprazineCNS Depressants may enhance the CNS depressant effect of Methotrimeprazine. Methotrimeprazine may enhance the CNS depressant effect of CNS Depressants.
MethylphenidateMethylphenidate may increase the serum concentration of Fosphenytoin.
MethylprednisoloneCYP3A4 Inducers (Strong) may decrease the serum concentration of MethylPREDNISolone.
MetyraponeMay decrease the serum concentration of Metyrapone. The oral metyrapone test would thus be unreliable unless the metapyrone dosage was substantially increased (e.g., 750 mg every 2 hours).
MetyrosineCNS Depressants may enhance the sedative effect of Metyrosine.
MexiletineMay decrease the serum concentration of Mexiletine.
MianserinMay diminish the therapeutic effect of Fosphenytoin. Fosphenytoin may decrease the serum concentration of Mianserin.
MiconazoleMiconazole (Oral) may increase the serum concentration of Fosphenytoin.
MifepristoneCYP3A4 Inducers (Strong) may decrease the serum concentration of Mifepristone.
NabiloneMay enhance the CNS depressant effect of CNS Depressants.
NelfinavirMay decrease the serum concentration of Nelfinavir. Nelfinavir may decrease the serum concentration of Fosphenytoin.
NicardipineMay increase the serum concentration of Fosphenytoin.
NifedipineCYP3A4 Inducers (Strong) may decrease the serum concentration of NIFEdipine.
NilotinibCYP3A4 Inducers (Strong) may decrease the serum concentration of Nilotinib.
NimodipineCalcium Channel Blockers may increase the serum concentration of Fosphenytoin.
NisoldipineMay increase the serum concentration of Fosphenytoin.
NitrazepamBenzodiazepines may increase the serum concentration of Fosphenytoin. Short-term exposure to benzodiazepines may not present as much risk as chronic therapy.
NitrendipineMay increase the serum concentration of Fosphenytoin.
NorelgestrominMay diminish the therapeutic effect of Contraceptives (Estrogens). Contraceptive failure is possible.
NorethindroneMay diminish the therapeutic effect of Contraceptives (Progestins). Contraceptive failure is possible.
NorgestimateMay diminish the therapeutic effect of Contraceptives (Progestins). Contraceptive failure is possible.
OmeprazoleMay decrease the serum concentration of Omeprazole. Omeprazole may increase the serum concentration of Fosphenytoin.
OrlistatOrlistat may decrease the serum concentration of Anticonvulsants. Exceptions: Fosphenytoin; PENTobarbital; Thiopental.
OrphenadrineCNS Depressants may enhance the CNS depressant effect of Orphenadrine.
OxazepamBenzodiazepines may increase the serum concentration of Fosphenytoin. Short-term exposure to benzodiazepines may not present as much risk as chronic therapy.
OxcarbazepineFosphenytoin-Phenytoin may decrease serum concentrations of the active metabolite(s) of OXcarbazepine. Specifically, concentrations of the major active 10-monohydroxy metabolite may be reduced. OXcarbazepine may increase the serum concentration of Fosphenytoin-Phenytoin.
PanobinostatCYP3A4 Inducers (Strong) may decrease the serum concentration of Panobinostat.
PazopanibCYP3A4 Inducers (Strong) may decrease the serum concentration of PAZOPanib.
PerampanelFosphenytoin may decrease the serum concentration of Perampanel.
PerhexilineMay increase the serum concentration of Fosphenytoin.
PethidineMay decrease the serum concentration of Meperidine.
PhenobarbitalMay enhance the CNS depressant effect of PHENobarbital. Fosphenytoin may increase the serum concentration of PHENobarbital. PHENobarbital may decrease the serum concentration of Fosphenytoin.
PonatinibCYP3A4 Inducers (Strong) may decrease the serum concentration of PONATinib.
PosaconazoleMay decrease the serum concentration of Antifungal Agents (Azole Derivatives, Systemic). Antifungal Agents (Azole Derivatives, Systemic) may increase the serum concentration of Fosphenytoin. Applicable Isavuconazonium considerations are addressed in separate monographs.
PramipexoleCNS Depressants may enhance the sedative effect of Pramipexole.
PravastatinMay decrease the serum concentration of HMG-CoA Reductase Inhibitors.
PraziquantelCYP3A4 Inducers (Strong) may decrease the serum concentration of Praziquantel.
PrednisoneCYP3A4 Inducers (Strong) may decrease the serum concentration of PredniSONE.
PrenylamineMay increase the serum concentration of Fosphenytoin.
PrimidoneMay increase the metabolism of Primidone. The ratio of primidone:phenobarbital is thus changed.
PyridoxinePyridoxine may increase the metabolism of Fosphenytoin. This is most apparent in high pyridoxine doses (e.g., 80 mg to 200 mg daily)
QuazepamMay increase the serum concentration of Fosphenytoin. Short-term exposure to benzodiazepines may not present as much risk as chronic therapy. Exceptions: ALPRAZolam.
QuetiapineCYP3A4 Inducers (Strong) may decrease the serum concentration of QUEtiapine.
QuinidineMay enhance the QTc-prolonging effect of QuiNIDine. Fosphenytoin may decrease the serum concentration of QuiNIDine.
QuinineMay decrease the serum concentration of QuiNINE.
RanolazineCYP3A4 Inducers (Strong) may decrease the serum concentration of Ranolazine.
RegorafenibCYP3A4 Inducers (Strong) may decrease the serum concentration of Regorafenib.
RifampicinRifampin may decrease the serum concentration of Fosphenytoin.
RilpivirineFosphenytoin may decrease the serum concentration of Rilpivirine.
RisedronateMay increase the serum concentration of Fosphenytoin.
RitonavirMay decrease the serum concentration of Ritonavir. Ritonavir may decrease the serum concentration of Fosphenytoin.
RivaroxabanCYP3A4 Inducers (Strong) may decrease the serum concentration of Rivaroxaban.
RoflumilastCYP3A4 Inducers (Strong) may decrease the serum concentration of Roflumilast.
RomidepsinCYP3A4 Inducers (Strong) may decrease the serum concentration of RomiDEPsin.
RopiniroleCNS Depressants may enhance the sedative effect of ROPINIRole.
RotigotineCNS Depressants may enhance the sedative effect of Rotigotine.
RufinamideFosphenytoin may decrease the serum concentration of Rufinamide. Rufinamide may increase the serum concentration of Fosphenytoin.
SaxagliptinCYP3A4 Inducers may decrease the serum concentration of Saxagliptin.
SertralineMay decrease the serum concentration of Sertraline. Sertraline may increase the serum concentration of Fosphenytoin.
SimeprevirCYP3A4 Inducers (Strong) may decrease the serum concentration of Simeprevir.
SimvastatinMay decrease the serum concentration of HMG-CoA Reductase Inhibitors.
SirolimusMay decrease the serum concentration of Sirolimus.
SofosbuvirP-glycoprotein/ABCB1 Inducers may decrease the serum concentration of Sofosbuvir.
SorafenibCYP3A4 Inducers (Strong) may decrease the serum concentration of SORAfenib.
SulfamethoxazoleMay decrease the serum concentration of Trimethoprim. Trimethoprim may increase the serum concentration of Fosphenytoin.
SunitinibCYP3A4 Inducers (Strong) may decrease the serum concentration of SUNItinib.
SuvorexantCYP3A4 Inducers (Strong) may decrease the serum concentration of Suvorexant.
TadalafilCYP3A4 Inducers (Strong) may decrease the serum concentration of Tadalafil.
TapentadolMay enhance the CNS depressant effect of CNS Depressants.
TelaprevirFosphenytoin may decrease the serum concentration of Telaprevir. Telaprevir may increase the serum concentration of Fosphenytoin.
TemazepamBenzodiazepines may increase the serum concentration of Fosphenytoin. Short-term exposure to benzodiazepines may not present as much risk as chronic therapy.
TemsirolimusFosphenytoin may decrease the serum concentration of Temsirolimus. Concentrations of the active metabolite, sirolimus, are also likely to be decreased (and maybe to an even greater degree).
TeniposideMay decrease the serum concentration of Teniposide.
ThalidomideCNS Depressants may enhance the CNS depressant effect of Thalidomide.
TheophyllineTheophylline Derivatives may decrease the serum concentration of Fosphenytoin. Fosphenytoin may decrease the serum concentration of Theophylline Derivatives.
TicagrelorCYP3A4 Inducers (Strong) may decrease serum concentrations of the active metabolite(s) of Ticagrelor. CYP3A4 Inducers (Strong) may decrease the serum concentration of Ticagrelor.
TiclopidineTiclopidine may increase the serum concentration of Fosphenytoin.
TipranavirMay decrease the serum concentration of Tipranavir. Tipranavir may decrease the serum concentration of Fosphenytoin.
TofacitinibCYP3A4 Inducers (Strong) may decrease the serum concentration of Tofacitinib.
TofisopamMay increase the serum concentration of Fosphenytoin. Short-term exposure to benzodiazepines may not present as much risk as chronic therapy. Exceptions: ALPRAZolam.
TolvaptanCYP3A4 Inducers (Strong) may decrease the serum concentration of Tolvaptan.
TopiramateMay decrease the serum concentration of Topiramate. Topiramate may increase the serum concentration of Fosphenytoin.
TopotecanFosphenytoin-Phenytoin may decrease the serum concentration of Topotecan.
ToremifeneCYP3A4 Inducers (Strong) may decrease the serum concentration of Toremifene.
TrabectedinCYP3A4 Inducers (Strong) may decrease the serum concentration of Trabectedin.
TrazodoneFosphenytoin may decrease the serum concentration of TraZODone. TraZODone may increase the serum concentration of Fosphenytoin.
TreprostinilCYP2C8 Inducers (Strong) may decrease the serum concentration of Treprostinil.
TriazolamMay increase the serum concentration of Fosphenytoin. Short-term exposure to benzodiazepines may not present as much risk as chronic therapy. Exceptions: ALPRAZolam.
TrimethoprimMay decrease the serum concentration of Trimethoprim. Trimethoprim may increase the serum concentration of Fosphenytoin.
UlipristalCYP3A4 Inducers (Strong) may decrease the serum concentration of Ulipristal.
VandetanibCYP3A4 Inducers (Strong) may decrease the serum concentration of Vandetanib.
VemurafenibCYP3A4 Inducers (Strong) may decrease the serum concentration of Vemurafenib.
VerapamilMay increase the serum concentration of Fosphenytoin.
VigabatrinVigabatrin may decrease the serum concentration of Fosphenytoin.
VilazodoneCYP3A4 Inducers (Strong) may decrease the serum concentration of Vilazodone.
VincristineMay decrease the serum concentration of VinCRIStine. VinCRIStine may decrease the serum concentration of Fosphenytoin.
VorapaxarCYP3A4 Inducers (Strong) may decrease the serum concentration of Vorapaxar.
VoriconazoleMay decrease the serum concentration of Antifungal Agents (Azole Derivatives, Systemic). Antifungal Agents (Azole Derivatives, Systemic) may increase the serum concentration of Fosphenytoin. Applicable Isavuconazonium considerations are addressed in separate monographs.
ZolpidemCNS Depressants may enhance the CNS depressant effect of Zolpidem.
ZonisamideMay decrease the serum concentration of Zonisamide.
Food Interactions
  • Avoid alcohol.
  • Do not take calcium, aluminum, magnesium or Iron supplements within 2 hours of taking this medication.
  • Take with food.

Targets

1. Sodium channel protein type 5 subunit alpha

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: inhibitor

Components

Name UniProt ID Details
Sodium channel protein type 5 subunit alpha Q14524 Details

References:

  1. Swadron SP, Rudis MI, Azimian K, Beringer P, Fort D, Orlinsky M: A comparison of phenytoin-loading techniques in the emergency department. Acad Emerg Med. 2004 Mar;11(3):244-52. Pubmed
  2. Mantegazza M, Curia G, Biagini G, Ragsdale DS, Avoli M: Voltage-gated sodium channels as therapeutic targets in epilepsy and other neurological disorders. Lancet Neurol. 2010 Apr;9(4):413-24. Pubmed
  3. Lenkowski PW, Ko SH, Anderson JD, Brown ML, Patel MK: Block of human NaV1.5 sodium channels by novel alpha-hydroxyphenylamide analogues of phenytoin. Eur J Pharm Sci. 2004 Apr;21(5):635-44. Pubmed
  4. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. Pubmed

Enzymes

1. Cytochrome P450 2C8

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate inducer

Components

Name UniProt ID Details
Cytochrome P450 2C8 P10632 Details

References:

  1. Kim KA, Park JY: Inhibitory effect of glyburide on human cytochrome p450 isoforms in human liver microsomes. Drug Metab Dispos. 2003 Sep;31(9):1090-2. Pubmed

2. Cytochrome P450 2C19

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate inducer

Components

Name UniProt ID Details
Cytochrome P450 2C19 P33261 Details

References:

  1. Anderson GD: Pharmacokinetic, pharmacodynamic, and pharmacogenetic targeted therapy of antiepileptic drugs. Ther Drug Monit. 2008 Apr;30(2):173-80. Pubmed
  2. Hennessy S, Leonard CE, Freeman CP, Metlay JP, Chu X, Strom BL, Bilker WB: CYP2C9, CYP2C19, and ABCB1 genotype and hospitalization for phenytoin toxicity. J Clin Pharmacol. 2009 Dec;49(12):1483-7. Epub 2009 Jul 17. Pubmed
  3. Klotz U: The role of pharmacogenetics in the metabolism of antiepileptic drugs: pharmacokinetic and therapeutic implications. Clin Pharmacokinet. 2007;46(4):271-9. Pubmed

3. Cytochrome P450 2B6

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: inducer

Components

Name UniProt ID Details
Cytochrome P450 2B6 P20813 Details

References:

  1. Wang H, Faucette S, Moore R, Sueyoshi T, Negishi M, LeCluyse E: Human constitutive androstane receptor mediates induction of CYP2B6 gene expression by phenytoin. J Biol Chem. 2004 Jul 9;279(28):29295-301. Epub 2004 Apr 28. Pubmed
  2. Faucette SR, Wang H, Hamilton GA, Jolley SL, Gilbert D, Lindley C, Yan B, Negishi M, LeCluyse EL: Regulation of CYP2B6 in primary human hepatocytes by prototypical inducers. Drug Metab Dispos. 2004 Mar;32(3):348-58. Pubmed

4. Cytochrome P450 2C9

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate inducer

Components

Name UniProt ID Details
Cytochrome P450 2C9 P11712 Details

References:

  1. Sahi J, Shord SS, Lindley C, Ferguson S, LeCluyse EL: Regulation of cytochrome P450 2C9 expression in primary cultures of human hepatocytes. J Biochem Mol Toxicol. 2009 Jan-Feb;23(1):43-58. Pubmed
  2. Zhou SF, Zhou ZW, Yang LP, Cai JP: Substrates, inducers, inhibitors and structure-activity relationships of human Cytochrome P450 2C9 and implications in drug development. Curr Med Chem. 2009;16(27):3480-675. Epub 2009 Sep 1. Pubmed
  3. Goldstein JA: Clinical relevance of genetic polymorphisms in the human CYP2C subfamily. Br J Clin Pharmacol. 2001 Oct;52(4):349-55. Pubmed
  4. Klotz U: The role of pharmacogenetics in the metabolism of antiepileptic drugs: pharmacokinetic and therapeutic implications. Clin Pharmacokinet. 2007;46(4):271-9. Pubmed

5. Cytochrome P450 3A4

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: inducer

Components

Name UniProt ID Details
Cytochrome P450 3A4 P08684 Details

References:

  1. Zhou SF: Drugs behave as substrates, inhibitors and inducers of human cytochrome P450 3A4. Curr Drug Metab. 2008 May;9(4):310-22. Pubmed

Carriers

1. Serum albumin

Kind: protein

Organism: Human

Pharmacological action: no

Actions: other/unknown

Components

Name UniProt ID Details
Serum albumin P02768 Details

References:

  1. Walker MC, Patsalos PN: Clinical pharmacokinetics of new antiepileptic drugs. Pharmacol Ther. 1995;67(3):351-84. Pubmed

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Drug created on June 30, 2007 11:18 / Updated on September 16, 2013 17:14