Fosphenytoin
Encyclopedia
Fosphenytoin is a water-soluble phenytoin
prodrug
used only in hospitals for the treatment of epileptic seizure
s.
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.
or some other type of repeated seizures; vomiting, and/or the patient is unalert or not awake or both.
in Beersheba
reported that even though anticonvulsant
s 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.
Fosphenytoin was more successfully used to relieve pain refractory to opiate
s in a 37-year-old woman with neuroma
, according to Dr. Gary J. McCleane of the Rampark Pain Center in Lurgan
, Northern Ireland
. 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.
mole
) 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.
and more paresthesia
. Fosphenytoin can cause hyperphosphatemia
in end-stage renal failure
patients.
, weak acidity, and its being only sparingly soluble
in water. Simply putting patients on other drugs is not always an option; this was especially true before 1993, when the number of anticonvulsant
s available was much more limited. 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.
Phenytoin
Phenytoin sodium is a commonly used antiepileptic. Phenytoin acts to suppress the abnormal brain activity seen in seizure by reducing electrical conductance among brain cells by stabilizing the inactive state of voltage-gated sodium channels...
prodrug
Prodrug
A prodrug is a pharmacological substance administered in an inactive form. Once administered, the prodrug is metabolised in vivo into an active metabolite, a process termed bioactivation. The rationale behind the use of a prodrug is generally for absorption, distribution, metabolism, and...
used only in hospitals for the treatment of epileptic seizure
Seizure
An epileptic seizure, occasionally referred to as a fit, is defined as a transient symptom of "abnormal excessive or synchronous neuronal activity in the brain". The outward effect can be as dramatic as a wild thrashing movement or as mild as a brief loss of awareness...
s.
On 18 November 2004, Sicor (a subsidiary of Teva
Teva Pharmaceutical Industries
Teva Pharmaceutical Industries Ltd. , is an international pharmaceutical company headquartered in Petah Tikva, Israel. It specializes in generic and proprietary pharmaceuticals and active pharmaceutical ingredients...
) received a tentative approval letter from the United States Food and Drug Administration for a generic version of fosphenytoin.
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, such as endotracheal intubation, status epilepticusStatus epilepticus
Status epilepticus is a life-threatening condition in which the brain is in a state of persistent seizure. Definitions vary, but traditionally it is defined as one continuous unremitting seizure lasting longer than 5 minutes, or recurrent seizures without regaining consciousness between seizures...
or some other type of repeated seizures; vomiting, and/or the patient is unalert or not awake or both.
Unapproved/off-label/investigational
In April 2003, Applebaum and colleagues at the Ben-Gurion University of the NegevBen-Gurion University of the Negev
Ben-Gurion University of the Negev is a university in Beersheba, Israel, established in 1969. Ben-Gurion University of the Negev has a current enrollment of 17,400 students, and is one of Israel's fastest growing universities....
in Beersheba
Beersheba
Beersheba is the largest city in the Negev desert of southern Israel. Often referred to as the "Capital of the Negev", it is the seventh-largest city in Israel with a population of 194,300....
reported that even though anticonvulsant
Anticonvulsant
The anticonvulsants are a diverse group of pharmaceuticals used in the treatment of epileptic seizures. Anticonvulsants are also increasingly being used in the treatment of bipolar disorder, since many seem to act as mood stabilizers, and in the treatment of neuropathic pain. The goal of an...
s are often very effective in mania
Mania
Mania, the presence of which is a criterion for certain psychiatric diagnoses, is a state of abnormally elevated or irritable mood, arousal, and/ or energy levels. In a sense, it is the opposite of depression...
, and acute mania requires rapid treatment, fosphenytoin had no antimanic effect even 60 minutes after administration of doses used in status epilepticus.
Fosphenytoin was more successfully used to relieve pain refractory to opiate
Opiate
In medicine, the term opiate describes any of the narcotic opioid alkaloids found as natural products in the opium poppy plant.-Overview:Opiates are so named because they are constituents or derivatives of constituents found in opium, which is processed from the latex sap of the opium poppy,...
s in a 37-year-old woman with neuroma
Neuroma
A neuroma is a growth or tumor of nerve tissue. Just as the Latin word for swelling is now restricted to neoplasias, the equivalent Greek suffix -oma has shared in that fate. Thus, the typical modern usage of neuroma is for nerve tumors...
, according to Dr. Gary J. McCleane of the Rampark Pain Center in Lurgan
Lurgan
Lurgan is a town in County Armagh, Northern Ireland. The town is near the southern shore of Lough Neagh and in the north-eastern corner of the county. Part of the Craigavon Borough Council area, Lurgan is about 18 miles south-west of Belfast and is linked to the city by both the M1 motorway...
, Northern Ireland
Northern Ireland
Northern Ireland is one of the four countries of the United Kingdom. Situated in the north-east of the island of Ireland, it shares a border with the Republic of Ireland to the south and west...
. 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.
Metabolism
One mmol (milliMilli
Milli is a prefix in the metric system denoting a factor of one thousandth . Adopted in 1795, the prefix comes from the Latin mille, meaning one thousand ....
mole
Mole (unit)
The mole is a unit of measurement used in chemistry to express amounts of a chemical substance, defined as an amount of a substance that contains as many elementary entities as there are atoms in 12 grams of pure carbon-12 , the isotope of carbon with atomic weight 12. This corresponds to a value...
) of phenytoin is produced for every mmol of fosphenytoin administered; the hydrolysis
Hydrolysis
Hydrolysis is a chemical reaction during which molecules of water are split into hydrogen cations and hydroxide anions in the process of a chemical mechanism. It is the type of reaction that is used to break down certain polymers, especially those made by condensation polymerization...
of fosphenytoin also yields phosphate
Phosphate
A phosphate, an inorganic chemical, is a salt of phosphoric acid. In organic chemistry, a phosphate, or organophosphate, is an ester of phosphoric acid. Organic phosphates are important in biochemistry and biogeochemistry or ecology. Inorganic phosphates are mined to obtain phosphorus for use in...
and formaldehyde
Formaldehyde
Formaldehyde is an organic compound with the formula CH2O. It is the simplest aldehyde, hence its systematic name methanal.Formaldehyde is a colorless gas with a characteristic pungent odor. It is an important precursor to many other chemical compounds, especially for polymers...
, the latter of which is subsequently metabolized to formate
Formate
Formate or methanoate is the ion CHOO− or HCOO− . It is the simplest carboxylate anion. It is produced in large amounts in the hepatic mitochondria of embryonic cells and in cancer cells by the folate cycle Formate or methanoate is the ion CHOO− or HCOO− (formic acid minus one hydrogen ion). It...
, which is in turn metabolized by a folate dependent mechanism.
Side effects
Side effects are similar to phenytoin, except that fosphenytoin causes less hypotensionHypotension
In physiology and medicine, hypotension is abnormally low blood pressure, especially in the arteries of the systemic circulation. It is best understood as a physiologic state, rather than a disease. It is often associated with shock, though not necessarily indicative of it. Hypotension is the...
and more paresthesia
Paresthesia
Paresthesia , spelled "paraesthesia" in British English, is a sensation of tingling, burning, pricking, or numbness of a person's skin with no apparent long-term physical effect. It is more generally known as the feeling of "pins and needles" or of a limb "falling asleep"...
. Fosphenytoin can cause hyperphosphatemia
Hyperphosphatemia
Hyperphosphatemia is an electrolyte disturbance in which there is an abnormally elevated level of phosphate in the blood. Often, calcium levels are lowered due to precipitation of phosphate with the calcium in tissues.-Signs and symptoms:...
in end-stage renal failure
Renal failure
Renal failure or kidney failure describes a medical condition in which the kidneys fail to adequately filter toxins and waste products from the blood...
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 pointMelting point
The melting point of a solid 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 depends on pressure and is usually specified at standard atmospheric pressure...
, weak acidity, and its being only sparingly soluble
Solubility
Solubility is the property of a solid, liquid, or gaseous chemical substance called solute to dissolve in a solid, liquid, or gaseous solvent to form a homogeneous solution of the solute in the solvent. The solubility of a substance fundamentally depends on the used solvent as well as on...
in water. Simply putting patients on other drugs is not always an option; this was especially true before 1993, when the number of anticonvulsant
Anticonvulsant
The anticonvulsants are a diverse group of pharmaceuticals used in the treatment of epileptic seizures. Anticonvulsants are also increasingly being used in the treatment of bipolar disorder, since many seem to act as mood stabilizers, and in the treatment of neuropathic pain. The goal of an...
s available was much more limited. One solution was to develop a prodrug that did not have these drawbacks.
Fosphenytoin was approved by the Food and Drug Administration
Food and Drug Administration
The Food and Drug Administration is an agency of the United States Department of Health and Human Services, one of the United States federal executive departments...
(FDA) on August 5, 1996 for use in epilepsy.