Fosphenytoin

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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
category

US:

Legal status

(Prescription only)

Routes of
administration

D (Evidence of risk)

Intravenous, intramuscular
Pharmacokinetic data

Bioavailability

100% (IM)

Protein binding

95 to 99%

Metabolism

Hepatic

Biological half-life

15 minutes to convert to phenytoin

Excretion

Renal (as phenytoin)

Identifiers
CAS Registry Number

93390-81-9

ATC code

N03AB05

PubChem

CID: 56339

IUPHAR/BPS

7190

DrugBank

DB01320

ChemSpider

50839

UNII

B4SF212641

KEGG

D07993

ChEMBL

CHEMBL919

Chemical data
Formula

C16H15N2O6P

Molecular mass

362.274 g/mol

SMILES
[show]

InChI

[show]

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Fosphenytoin (fosphenytoin sodium injection, previously

Cerebyx, Parke-Davis; Prodilantin, Pfizer Holding France[1]) is a
water-soluble phenytoin prodrug that is administered intravenously
to deliver phenytoin, potentially more safely than intravenous
phenytoin. It is most commonly used in the acute treatment
convulsive status epilepticus.
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]

1 Uses

Contents [hide]

D
D
D
D
D
D
D

1.1 Approved
1.2 Unapproved/off-label/investigational
2 Metabolism
3 Side effects
4 History
5 References
6 See also

Uses[edit]

Approved[edit]
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 illadvised,[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[edit]

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[edit]

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[edit]

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.[7]

History[edit]

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.[8] 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.[9] 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.[10]
Severe low blood pressure and irregular heartbeat have
been reported in patients taking Cerebyx. The risk may be
increased if it is given faster than recommended. Contact
your doctor right away if you develop an irregular
heartbeat or symptoms of low blood pressure (eg, fainting,
severe or persistent dizziness or light-headedness).

Cerebyx is used for:

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Treating certain types of severe seizures (eg, status
epilepticus). It is also used to prevent and treat
seizures that may occur during or after brain or
nervous system surgery. It may also be used for

other conditions as determined by your doctor.

Cerebyx is an anticonvulsant. It works in the brain
to block the spread of seizure activity.
&
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Do NOT use Cerebyx if:

you are allergic to any ingredient in Cerebyx or to

other hydantoins (eg, phenytoin)
you have certain types of heart problems (eg, very
slow heartbeat, certain types of heart block,
Adams-Stokes syndrome)
you are taking delavirdine
Contact your doctor or health care provider right
away if any of these apply to you.

Slideshow: 12 Things You Need to Know

About Lyrica

Before using Cerebyx:

&
&

Some medical conditions may interact with

Cerebyx. Tell your doctor or pharmacist if you have
any medical conditions, especially if any of the
following apply to you:
if you are pregnant, planning to become pregnant,
or are breast-feeding
if you are taking any prescription or
nonprescription medicine, herbal preparation, or

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&

&

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dietary supplement
if you have allergies to medicines, foods, or other
substances
if you or a family member have had an allergic
reaction to a barbiturate (eg, phenobarbital),
carbamazepine, an oxazolidinedione (eg,
trimethadione), oxcarbazepine, or a succinimide
(eg, ethosuximide, methsuximide)
if you have heart problems (eg, heart block), low
blood pressure, the blood disease porphyria, liver
or kidney disease, low blood albumin levels,
diabetes, bone marrow problems, or a history of
lymph gland problems
if you are in very poor health
if you drink alcohol or have a history of alcohol
abuse
if you have been tested and know whether or not
you have a gene type called HLA-B*1502
if you have a history of mental or mood problems
(eg, depression), or suicidal thoughts or attempts
Some MEDICINES MAY INTERACT with Cerebyx. Tell
your health care provider if you are taking any
other medicines, especially any of the following:
Many other prescription and nonprescription
medicines (eg, used for allergic reactions, asthma
or other breathing problems, blood thinning,
diabetes, infections, inflammation, aches and
pains, attention deficit hyperactivity disorder,
alcoholism, cancer, erectile dysfunction, high blood
pressure, indigestion, irregular heartbeat or other
heart problems, hepatitis C, high blood iron levels,
high cholesterol, HIV, birth control, hormone
replacement, immune system suppression, low
blood sugar, mental or mood problems, narcotic
addiction, pain, seizures, stomach or bowel
problems, trouble sleeping), multivitamin products,
and herbal or dietary supplements (eg, herbal teas,

coenzyme Q10, garlic, ginseng, ginkgo, St. John's

wort) may interact with Cerebyx. Ask your doctor
or pharmacist if you are unsure if any of your
medicines might interact with Cerebyx
This may not be a complete list of all interactions
that may occur. Ask your health care provider if
Cerebyx may interact with other medicines that
you take. Check with your health care provider
before you start, stop, or change the dose of any
medicine.
CEREBYX is indicated for the control of generalized tonic-clonic
status epilepticus and prevention and treatment of seizures
occurring during neurosurgery. CEREBYX can also be substituted,
short-term, for oral phenytoin. CEREBYX should be used only
when oral phenytoin administration is not possible. CEREBYX
must not be given orally.
The dose, concentration, and infusion rate of CEREBYX
should always be expressed as phenytoin sodium equivalents
(PE). There is no need to perform molecular weight-based
adjustments when converting between fosphenytoin and
phenytoin sodium doses. CEREBYX should always be
prescribed and dispensed in phenytoin sodium equivalent
units (PE). 1.5 mg of fosphenytoin sodium is equivalent to 1 mg
phenytoin sodium, and is referred to as 1 mg PE. The amount and
concentration of fosphenytoin is always expressed in terms of mg
of phenytoin sodium equivalents (mg PE).
Do not confuse the concentration of CEREBYX with the total
amount of drug in the vial.
Caution must be used when administering CEREBYX due to the
risk of dosing errors (see WARNINGS). Medication errors
associated with CEREBYX have resulted in patients receiving the
wrong dose of fosphenytoin. CEREBYX is marketed in 2 mL vials
containing a total of 100 mg PE and 10 mL vials containing a total
of 500 mg PE. Both vials contain a concentration of 50 mg PE/mL.
Errors have occurred when the concentration of the vial (50 mg
PE/mL) was misinterpreted to mean that the total content of the
vial was 50 mg PE. These errors have resulted in two- or ten-fold
overdoses of CEREBYX since each of the vials actually contains a
total of 100 mg PE or 500 mg PE. In some cases, ten-fold

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overdoses were associated with fatal outcomes. To help minimize

confusion, the prescribed dose of CEREBYX should always be
expressed in milligrams of phenytoin equivalents (mg PE).
Additionally, when ordering and storing CEREBYX, consider
displaying the total drug content (i.e., 100 mg PE/ 2 mL or 500 mg
PE/ 10 mL) instead of concentration in computer systems, preprinted orders, and automated dispensing cabinet databases to
help ensure that total drug content can be clearly identified. Care
should be taken to ensure the appropriate volume of CEREBYX is
withdrawn from the vial when preparing the dose for
administration. Attention to these details may prevent some
CEREBYX medication errors from occurring.
Prior to IV infusion, dilute CEREBYX in 5% dextrose or 0.9% saline
solution for injection to a concentration ranging from 1.5 to 25 mg
PE/mL. The maximum concentration of CEREBYX in any solution
should be 25 mg PE/mL. When CEREBYX is given as an
intravenous infusion, CEREBYX needs to be diluted and should
only be administered at a rate not exceeding 150 mg PE/min.
Parenteral drug products should be inspected visually for
particulate matter and discoloration prior to administration,
whenever solution and container permit.
Status Epilepticus
The loading dose of CEREBYX is 15 to 20 mg PE/kg administered
at 100 to 150 mg PE/min.
Because of the risk of hypotension, CEREBYX should be
administered no faster than 150 mg PE/min. Continuous
monitoring of the electrocardiogram, blood pressure, and
respiratory function is essential and the patient should be observed
throughout the period where maximal serum phenytoin
concentrations occur, approximately 10 to 20 minutes after the end
of CEREBYX infusions.
Because the full antiepileptic effect of phenytoin, whether given as
CEREBYX or parenteral phenytoin, is not immediate, other
measures, including concomitant administration of an IV
benzodiazepine, will usually be necessary for the control of status
epilepticus.
The loading dose should be followed by maintenance doses of
either CEREBYX or phenytoin.
If administration of CEREBYX does not terminate seizures, the use
of other anticonvulsants and other appropriate measures should be
considered. Even though loading doses of CEREBYX have been
given by the IM route for other indications when IV access is
impossible, IM CEREBYX should ordinarily not be used in the

treatment of status epilepticus because therapeutic phenytoin

concentrations may not be reached as quickly as with IV
administration.
Nonemergent Loading And Maintenance Dosing
Because of the risks of cardiac and local toxicity associated with
intravenous CEREBYX, oral phenytoin should be used whenever
possible.
The loading dose of CEREBYX is 10 20 mg PE/kg given IV or
IM. The rate of administration for IV CEREBYX should be no
greater than 150 mg PE/min. Continuous monitoring of the
electrocardiogram, blood pressure, and respiratory function is
essential and the patient should be observed throughout the period
where maximal serum phenytoin concentrations occur
(approximately 20 minutes after the end of CEREBYX infusion).
The initial daily maintenance dose of CEREBYX is 4 6 mg
PE/kg/day in divided doses.
IM Or IV Substitution For Oral Phenytoin Therapy
When treatment with oral phenytoin is not possible, CEREBYX can
be substituted for oral phenytoin at the same total daily dose.
Dilantin capsules are approximately 90% bioavailable by the oral
route. Phenytoin, supplied as CEREBYX, is 100% bioavailable by
both the IM and IV routes. For this reason, plasma phenytoin
concentrations may increase modestly when IM or IV CEREBYX is
substituted for oral phenytoin sodium therapy. The rate of
administration for IV CEREBYX should be no greater than 150 mg
PE/min. In controlled trials, IM CEREBYX was administered as a
single daily dose utilizing either 1 or 2 injection sites. Some
patients may require more frequent dosing.
Dosing In Special Populations
Patients with Renal or Hepatic Disease
Due to an increased fraction of unbound phenytoin in patients with
renal or hepatic disease, or in those with hypoalbuminemia, the
interpretation of total phenytoin plasma concentrations should be
made with caution (see CLINICAL PHARMACOLOGY: Special
Populations). Unbound phenytoin concentrations may be more
useful in these patient populations. After IV CEREBYX
administration to patients with renal and/or hepatic disease, or in
those with hypoalbuminemia, fosphenytoin clearance to phenytoin
may be increased without a similar increase in phenytoin
clearance. This has the potential to increase the frequency and
severity of adverse events (see PRECAUTIONS).
Elderly Patients
Age does not have a significant impact on the pharmacokinetics of

fosphenytoin following CEREBYX administration. Phenytoin

clearance is decreased slightly in elderly patients and lower or less
frequent dosing may be required.
Pediatric
The safety and efficacy of CEREBYX in pediatric patients have not
been established.