Fosphenytoin

Fosphenytoin, also known as fosphenytoin sodium, and sold under the brand name Cerebyx among others, is a water-soluble phenytoin prodrug that is administered intravenously to deliver phenytoin, potentially more safely than intravenous phenytoin. It is used in the acute treatment of convulsive status epilepticus.

Fosphenytoin
Clinical data
Trade namesCerebyx
AHFS/Drugs.comMonograph
MedlinePlusa604036
License data
Routes of
administration		Intravenous, intramuscular
ATC code
Legal status
Legal status
  • US: ℞-only
  • In general: ℞ (Prescription only)
Pharmacokinetic data
Bioavailability100% (IM)
Protein binding95–99%
MetabolismLiver
Elimination half-life15 minutes to convert to phenytoin
ExcretionKidney (as phenytoin)
Identifiers
IUPAC name
  • (2,5-Dioxo-4,4-diphenyl-imidazolidin-1-yl)methoxyphosphonic acid
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEMBL
CompTox Dashboard (EPA)
Chemical and physical data
FormulaC16H15N2O6P
Molar mass362.278 g·mol−1
3D model (JSmol)
SMILES
  • O=C3N(C(=O)C(c1ccccc1)(c2ccccc2)N3)COP(=O)(O)O
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) Y
  • Key:XWLUWCNOOVRFPX-UHFFFAOYSA-N Y
 NY (what is this?)  (verify)

Fosphenytoin was developed in 1996.[1] On 18 November 2004, Sicor (a subsidiary of Teva) received a tentative approval letter from the United States Food and Drug Administration for a generic version of fosphenytoin.[2]

Medical uses

Fosphenytoin is approved in the United States for the short-term (five days or fewer) treatment of epilepsy when more widely used means of phenytoin administration are not possible or are ill-advised,[3] such as endotracheal intubation, status epilepticus or some other type of repeated seizures; cluster seizure, vomiting, and/or the patient is unalert or not awake or both.[4]

Other

In 2003, it was reported that even though anticonvulsants are often very effective in mania, and acute mania requires rapid treatment, fosphenytoin had no antimanic effect.[5]

Metabolism

One millimole of phenytoin is produced for every millimole of fosphenytoin administered; the hydrolysis of fosphenytoin also yields phosphate and formaldehyde, the latter of which is subsequently metabolized to formate, which is in turn metabolized by a folate dependent mechanism.[3]

Side effects

Side effects are similar to intravenous phenytoin and include hypotension, cardiac arrhythmias, CNS adverse events (nystagmus, dizziness, sedation/somnolence, ataxia and stupor), and local dermatological reactions. Purple glove syndrome probably occurs with fosphenytoin but possibly at lower frequency than with intravenous phenytoin. Fosphenytoin can cause hyperphosphatemia in end-stage renal failure patients.[6]

History

Phenytoin, in both its acidic and sodium salt forms, is erratically bioavailable whether it is injected or taken orally due to its high melting point, weak acidity, and its being only sparingly soluble in water.[7] Simply putting patients on other drugs is not always an option; this was especially true before 1993, when the number of anticonvulsants available was much more limited.[8] One solution was to develop a prodrug that did not have these drawbacks.

Fosphenytoin was approved by the Food and Drug Administration (FDA) on August 5, 1996, for use in epilepsy.[9]

See also

References
  1. Pitkänen, Asla; Schwartzkroin, Philip A.; Moshé, Solomon L. (2005). Models of Seizures and Epilepsy. Burlington: Elsevier. p. 539. ISBN 9780080457024.
  2. "Fosphenytoin Sodium Approval History". Retrieved 20 October 2005.
  3. Parke-Davis (2001). "Cerebyx: Fosphenytoin Sodium Injection - Labeling Revision" (PDF). Cerebyx Approval History. Warner-Lambert Company. Archived from the original (PDF) on October 17, 2003. Retrieved 20 October 2005.
  4. Johnson J, Wrenn K (2001). "Inappropriate fosphenytoin use in the ED". American Journal of Emergency Medicine. 19 (4): 293–4. doi:10.1053/ajem.2001.24471. PMID 11447516. Fulltext options List of Library Holdings Worldwide
  5. Applebaum J, Levine J, Belmaker RH (2003). "Intravenous fosphenytoin in acute mania". Journal of Clinical Psychiatry. 64 (4): 408–9. doi:10.4088/JCP.v64n0408. PMID 12716241.
  6. McBryde KD, Wilcox J, Kher KK (2005). "Hyperphosphatemia due to fosphenytoin in a pediatric ESRD patient". Pediatric Nephrology (Berlin, Germany). 20 (8): 1182–5. doi:10.1007/s00467-005-1947-0. PMID 15965770. S2CID 6664220.
  7. Yamaoka Y, Roberts RD, Stella VJ (April 1983). "Low-melting phenytoin prodrugs as alternative oral delivery modes for phenytoin: a model for other high-melting sparingly water-soluble drugs". J Pharm Sci. 72 (4): 400–5. doi:10.1002/jps.2600720420. PMID 6864479.
  8. Anticonvulsants before 1993 Archived 2019-08-04 at the Wayback Machine Neuroland
  9. "Cerebyx Approval History". Retrieved 20 October 2005.
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