Fosphenytoin, also known as fosphenytoin

sodium Sodium is a chemical element with the symbol Na (from Latin ''natrium'') and atomic number 11. It is a soft, silvery-white, highly reactive metal. Sodium is an alkali metal, being in group 1 of the periodic table. Its only stable ...

, and sold under the brand name Cerebyx among others, is a water-soluble

phenytoin Phenytoin (PHT), sold under the brand name Dilantin among others, is an anti-seizure medication. It is useful for the prevention of tonic-clonic seizures (also known as grand mal seizures) and focal seizures, but not absence seizures. The in ...

prodrug A prodrug is a medication or compound that, after intake, is metabolized (i.e., converted within the body) into a pharmacologically active drug. Instead of administering a drug directly, a corresponding prodrug can be used to improve how the dru ...

that is administered intravenously to deliver phenytoin, potentially more safely than intravenous

. It is used in the acute treatment of convulsive

status epilepticus Status epilepticus (SE), or status seizure, is a single seizure lasting more than 5 minutes or 2 or more seizures within a 5-minute period without the person returning to normal between them. Previous definitions used a 30-minute time limit. The s ...

. Fosphenytoin was developed in 1996. On 18 November 2004, Sicor (a subsidiary of Teva) received a tentative approval letter from the

United States Food and Drug Administration The United States Food and Drug Administration (FDA or US FDA) is a federal agency of the Department of Health and Human Services. The FDA is responsible for protecting and promoting public health through the control and supervision of food s ...

for a generic version of fosphenytoin.

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, such as

endotracheal intubation Tracheal intubation, usually simply referred to as intubation, is the placement of a flexible plastic tube into the trachea (windpipe) to maintain an open airway or to serve as a conduit through which to administer certain drugs. It is frequentl ...

or some other type of repeated seizures; cluster seizure, vomiting, and/or the patient is unalert or not awake or both.Fulltext optionsList of Library Holdings Worldwide
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Other

In 2003, it was reported that even though

anticonvulsant Anticonvulsants (also known as antiepileptic drugs or recently as antiseizure drugs) are a diverse group of pharmacological agents used in the treatment of epileptic seizures. Anticonvulsants are also increasingly being used in the treatment of ...

s are often very effective in

mania Mania, also known as manic syndrome, is a mental and behavioral disorder defined as a state of abnormally elevated arousal, affect, and energy level, or "a state of heightened overall activation with enhanced affective expression together wi ...

, and acute mania requires rapid treatment, fosphenytoin had no antimanic effect.

Metabolism

One milli mole of phenytoin is produced for every millimole of fosphenytoin administered; the

hydrolysis Hydrolysis (; ) is any chemical reaction in which a molecule of water breaks one or more chemical bonds. The term is used broadly for substitution, elimination, and solvation reactions in which water is the nucleophile. Biological hydrolysi ...

of fosphenytoin also yields

phosphate In chemistry, a phosphate is an anion, salt, functional group or ester derived from a phosphoric acid. It most commonly means orthophosphate, a derivative of orthophosphoric acid . The phosphate or orthophosphate ion is derived from phosph ...

and

formaldehyde Formaldehyde ( , ) ( systematic name methanal) is a naturally occurring organic compound with the formula and structure . The pure compound is a pungent, colourless gas that polymerises spontaneously into paraformaldehyde (refer to section ...

, the latter of which is subsequently metabolized to

formate Formate (IUPAC name: methanoate) is the conjugate base of formic acid. Formate is an anion () or its derivatives such as ester of formic acid. The salts and esters are generally colorless.Werner Reutemann and Heinz Kieczka "Formic Acid" in ''Ull ...

, which is in turn metabolized by a folate dependent mechanism.

Side effects

Side effects are similar to intravenous phenytoin and include hypotension, cardiac arrhythmias, CNS adverse events (

nystagmus Nystagmus is a condition of involuntary (or voluntary, in some cases) eye movement. Infants can be born with it but more commonly acquire it in infancy or later in life. In many cases it may result in reduced or limited vision. Due to the invol ...

, dizziness, sedation/somnolence,

ataxia Ataxia is a neurological sign consisting of lack of voluntary coordination of muscle movements that can include gait abnormality, speech changes, and abnormalities in eye movements. Ataxia is a clinical manifestation indicating dysfunction of ...

and

stupor Stupor is the lack of critical mental function and a level of consciousness, in which an affected person is almost entirely unresponsive and responds only to intense stimuli such as pain. The word derives from the Latin '' stupor'' ("numbness, inse ...

), and local dermatological reactions.

Purple glove syndrome Purple glove syndrome (PGS) is a poorly understood skin disease in which the extremities become swollen, discoloured and painful. PGS is potentially serious, and may require amputation. PGS is most common among elderly patients and those receivin ...

probably occurs with fosphenytoin but possibly at lower frequency than with intravenous phenytoin. Fosphenytoin can cause

hyperphosphatemia Hyperphosphatemia is an electrolyte disorder in which there is an elevated level of phosphate in the blood. Most people have no symptoms while others develop calcium deposits in the soft tissue. Often there is also low calcium levels which can ...

in end-stage

renal failure Kidney failure, also known as end-stage kidney disease, is a medical condition in which the kidneys can no longer adequately filter waste products from the blood, functioning at less than 15% of normal levels. Kidney failure is classified as eit ...

patients.

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 The melting point (or, rarely, liquefaction point) of a substance is the temperature at which it changes state from solid to liquid. At the melting point the solid and liquid phase exist in equilibrium. The melting point of a substance depen ...

, weak

acidity In computer science, ACID ( atomicity, consistency, isolation, durability) is a set of properties of database transactions intended to guarantee data validity despite errors, power failures, and other mishaps. In the context of databases, a ...

, and its being only sparingly

soluble In chemistry, solubility is the ability of a substance, the solute, to form a solution with another substance, the solvent. Insolubility is the opposite property, the inability of the solute to form such a solution. The extent of the solubi ...

in water. Simply putting patients on other drugs is not always an option; this was especially true before 1993, when the number of

s available was much more limited.Anticonvulsants before 1993
Neuroland One solution was to develop a prodrug that did not have these drawbacks. Fosphenytoin was approved by the

Food and Drug Administration The United States Food and Drug Administration (FDA or US FDA) is a federal agency of the Department of Health and Human Services. The FDA is responsible for protecting and promoting public health through the control and supervision of food ...

(FDA) on August 5, 1996, for use in epilepsy.

References

External links

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