Fosphenytoin

Fosphenytoin

Systematic (IUPAC) name
(2,5-dioxo-4,4-diphenyl-imidazolidin-1-yl)methoxyphosphonic acid
Clinical data
Trade names	Cerebyx
AHFS/Drugs.com	monograph
MedlinePlus	a604036
Pregnancy cat.	D(US)
Legal status	℞ Prescription only
Routes	Intravenous, intramuscular
Pharmacokinetic data
Bioavailability	100% (IM)
Protein binding	95 to 99%
Metabolism	Hepatic
Half-life	15 minutes to convert to phenytoin
Excretion	Renal (as phenytoin)
Identifiers
CAS number	93390-81-9 Y
ATC code	N03AB05
PubChem	CID 56339
DrugBank	APRD00241
ChemSpider	50839 Y
UNII	B4SF212641 Y
KEGG	D07993 Y
ChEMBL	CHEMBL919 N
Chemical data
Formula	C16H15N2O6P
Mol. mass	362.274 g/mol
SMILES	eMolecules & PubChem
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
N(what is this?)  (verify)

Fosphenytoin (Cerebyx, Parke-Davis; Prodilantin, Pfizer Holding France^[1]) is a water-soluble phenytoin prodrug used only in hospitals for the treatment of epileptic seizures.

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]

Uses

Approved

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; vomiting, and/or the patient is unalert or not awake or both.^[4]

Unapproved/off-label/investigational

In April 2003, Applebaum and colleagues at the Ben-Gurion University of the Negev in Beersheba reported that even though anticonvulsants are often very effective in mania, and acute mania requires rapid treatment, fosphenytoin had no antimanic effect even 60 minutes after administration of doses used in status epilepticus.^[5]

Fosphenytoin was more successfully used to relieve pain refractory to opiates in a 37-year-old woman with neuroma, according to Dr. Gary J. McCleane of the Rampark Pain Center in Lurgan, Northern Ireland.^[6] She was given 1,500 phenytoin equivalent units of fosphenytoin over a 24 hour period, producing pain relief that last three to fourteen weeks after each infusion, allowing her to use less opiates.^[6]

Metabolism

One mmol (millimole) of phenytoin is produced for every mmol 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 phenytoin, except that fosphenytoin causes less hypotension and more paresthesia.^[7] Fosphenytoin can cause hyperphosphatemia in end-stage renal failure patients.^[8]

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.^[9] 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.^[10] 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.^[11]

References

1. ^ "PRODILANTIN 75 mg/ml sol inj IM et p perf IV". VIDAL, l'information de référence sur les produits de santé. http://www.vidal.fr/Medicament/prodilantin-13783.htm. Retrieved 23 October 2005. 
2. ^ "Fosphenytoin Sodium Approval History". http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Search.Label_ApprovalHistory#apphist. Retrieved 20 October 2005. 
3. ^ ^{a b} Parke-Davis (2001). "Cerebyx: Fosphenytoin Sodium Injection - Labeling Revision" (PDF). Cerebyx Approval History. Warner-Lambert Company. http://www.fda.gov/cder/foi/label/2001/20450s4s5lbl.pdf. Retrieved 20 October 2005. ^{[dead link]}
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" (PDF). Journal Clinical Psychiatry 64 (4): 408–9. doi:10.4088/JCP.v64n0408. PMID 12716241. http://www.psychiatrist.com/privatepdf/2003/v64n04/v64n0408.pdf. 
6. ^ ^{a b} McCleane GJ (2002). "Intravenous infusion of fosphenytoin produces prolonged pain relief: a case report". The Journal of Pain 3 (2): 156–8. doi:10.1054/jpai.2002.123004. PMID 14622802.  List of Library Holdings Worldwide
7. ^ Browne TR. (1997). "Fosphenytoin (Cerebyx)". Clinical Neuropharmacology 20 (1): 1–12. doi:10.1097/00002826-199702000-00001. PMID 9037568.  List of Library Holdings Worldwide
8. ^ McBryde KD, Wilcox J, Kher KK (2005). "Hyperphosphatemia due to fosphenytoin in a pediatric ESRD patient" (PDF). Pediatric Nephrology (Berlin, Germany) 20 (8): 1182–5. doi:10.1007/s00467-005-1947-0. PMID 15965770. 
9. ^ 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. 
10. ^ Anticonvulsants before 1993 Neuroland
11. ^ "Cerebyx Approval History". http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Search.Label_ApprovalHistory. Retrieved 20 October 2005. 

See also

• hydantoin
• ethotoin
• mephenytoin
• phenytoin