Fosphenytoin Sodium Injection: A Comprehensive Overview

Overview

Fosphenytoin sodium injection is prescribed for the treatment of status epilepticus (generalized tonic-clonic seizures) or grand mal seizures. The drug is also used to treat seizures (uncontrolled electrical activities in the brain cells) occurring during other neurosurgeries. The injection is also recommended for some duration in patients who cannot take oral Phenytoin. However, the Fosphenytoin injection should only be given as a replacement for oral dosage if oral Phenytoin administration is not possible. The drug is only given in hospital settings by professionals to treat status epilepticus.

The drug was approved by the United States Food and Drug Administration (USFDA) on August 5th, 1996, for the treatment of status epileptics or grand mal seizures.

Drug Group

Indications

Fosphenytoin sodium injection is recommended for treating status epilepticus, generalized tonic-clonic or grand mal seizures. It is also used to control seizures during neurosurgeries.

Dose Form and Strength:

The drug is available in a liquid or solution form for intravenous (IV) injection (in the veins) in a vial of 100 mL (milliliters) and 2 mL. Each vial of both strengths contains Sodium hydroxide or Hydrochloride acid, Tromethamine, and water for injection.

For Patients:

What Is Status Epilepticus?

Status epilepticus is a type of seizure that causes abnormal activity in the brain and affects both body and mind. Status epilepticus usually lasts more than five minutes, or a person may experience more than one seizure attack within five minutes without getting back to a normal conscious state within these episodes.

What Is Fosphenytoin Sodium Injection Used For?

Fosphenytoin sodium injection is used for the treatment of status epilepticus (grand mal seizures). The drug is usually given to those who cannot take the Phenytoin orally. Fosphenytoin sodium injection is an anticonvulsant drug that works by decreasing the brain’s abnormal activity.

How Should Fosphenytoin Sodium Injection Be Used?

The drug is available in a liquid or solution form to be given intravenously (IV or into the vein) or intramuscularly, or into the muscle by the healthcare provider in a hospital setting. The drug is injected slowly into the vein, and the drug dosage, duration, and length of treatment usually depend on the patient's response to the drug and their medical status.

What Precautions Should Be Followed Before Taking Fosphenytoin Sodium Injection?

• A person should inform the doctor about any allergic (hypersensitivity) reactions to the Fosphenytoin sodium injection drug, its ingredients, or any other drug.

• The doctor must be informed about all the prescription and non-prescription drugs that they are taking or planning to take, including herbal products, vitamins, and nutritional supplements. One must be careful about taking Delavirdine. This drug is not recommended for Fosphenytoin sodium injection. A doctor would probably stop the injection if one was taking Delavirdine. Also, the doctor might need to alter the drug dosage or monitor the patient for any side effects.

• If a person has any past or present medical history of liver disease, they must inform the doctor beforehand. Fosphenytoin injections are usually not recommended for patients having liver problems.

• One must inform the doctor if they are pregnant, planning to get pregnant, or breastfeeding. They must ask the doctor about effective ways of birth control while taking Fosphenytoin injections. This drug is known to cause harm to the fetus.

• The doctor must also be informed about any history of medical conditions, such as porphyria (abnormal behavior and stomach pain due to the build-up of some natural substance in the body), diabetes (high blood sugar), kidney disease, or blood-related diseases.

• Inform the doctor about any history of alcohol consumption in large amounts or an inherited risk factor causing serious skin reactions. The drug is likely to cause reactions in such cases; therefore, it is not recommended for these patients.

• A person should also ask the doctor about safe alcohol use if they are taking Fosphenytoin drug.

• If a person plans to undergo dental surgery, they must inform the doctor about taking Fosphenytoin injection.

• The drug causes gum damage; therefore, a person should take care of oral (mouth) health while taking this drug.

Drug Dosage and Administration (The Drug Is Given in Medical Settings)

NOTE: To avoid the need to perform molecular weight-based adjustments, the drug dose, concentration in solutions, and infusion rate of intravenous Fosphenytoin sodium injection are expressed as Phenytoin sodium equivalents (PE) when converting between Phenytoin and Fosphenytoin sodium doses. Fosphenytoin sodium injections should always be prescribed and dispensed in phenytoin sodium equivalent units (PE). Also, Fosphenytoin sodium injection has an important difference in administration from that for Phenytoin sodium (parenteral).

Drug Preparation:

• Before an intravenous infusion, Fosphenytoin sodium injection in 0.9 percent saline solution or five percent dextrose is diluted for injection to a concentration between 1.5 and 25 mg (milligrams) PE/mL (milliliters).

• The maximum dose of Fosphenytoin sodium injection in any preparation should be only 25 mg PE/mL.

• The injection should only be administered in diluted form intravenously at a rate of 150 mg PE/minute.

NOTE: Parenteral drugs should be checked before administering for discoloration and particulate matter whenever the container and solution permit. Also, single-dose vials of unused products should be discarded after opening.

Adult Dose for Status Epilepticus:

• The recommended adult loading drug dosage is 15 to 20 mg (milligrams) PE/mL to be infused at a rate of 100 to 150 mg PE/minute.

• The drug infusion rate while administering should not be exceeded beyond 150 mg PE/mL because Fosphenytoin sodium injection has a risk of causing hypotension.

• The patient should be continuously monitored for blood pressure, electrocardiogram (ECG), and respiratory functions. Also, the patient should be observed for at least 10 to 20 minutes (during maximum Phenytoin serum concentration) after the infusion of Fosphenytoin injection.

• The drug does not show immediate antiepileptic effects after taking parenteral Phenytoin or injecting Fosphenytoin; therefore, intravenous (IV) benzodiazepines are often given concomitantly to control seizures or status epilepticus.

Maintenance Dose:

The loading dosage should be followed by the maintenance dose of Phenytoin (orally or parenteral), or Fosphenytoin sodium injection. The daily maintenance dose of Fosphenytoin injection is 2 to 6 mg PE/kg/day (Phenytoin sodium equivalents per kilogram daily).

NOTE: Intramuscular (IM) Fosphenytoin sodium injection should not be given for treating status epilepticus. This is because intravenous (IV) administration may not achieve the desired concentration. The intramuscular route should only be preferred if IV dosage is not possible or the drug needs to be given IM for various other indications.

Pediatric Dose for Status Epilepticus:

• The recommended pediatric loading drug dosage is 15 to 20 mg (milligrams) PE/mL to be infused at 2 mg PE/kg/mL or 150 mg PE/minute (whichever is slower).

What Are the Side Effects of Fosphenytoin Sodium Injection?

Common Side Effects

• Burning, itching, tingling sensation.

• Dizziness.

• Confusion.

• Agitation.

• Weakness.

• Abnormal body movements.

• Slurred speech.

• Need for coordination.

• Involuntary (uncontrollable) eye movements.

• Constipation.

• Dry mouth (xerostomia).

• Headache.

• Vision defects.

• Changes in the sense of taste.

• Hearing difficulty or tinnitus (ringing of the ears).

Serious Side Effects

• Rash.

• Hives.

• Pain, swelling, and discoloration at the injection site.

• Blisters.

• Nausea.

• Vomiting.

• Hoarseness.

• Excessive tiredness.

• Swollen gland.

• Swallowing or breathing difficulties.

• Loss of appetite.

• Bruising or bleeding unusually.

• Swelling of hands, arms, lower legs, and ankles.

• Pain in the abdomen (upper right side).

• Red or purple spots on the skin.

• Yellowish discoloration of skin or eyes.

• Sore throat, mouth ulcers, facial swelling, fever, bruising, or rash.

Missed Dose

Note: The drug is given in hospital settings as the doctor instructs.

Overdose

In cases of drug overdose from Fosphenytoin sodium injection, the poison control department should be contacted.

Medical health services should be contacted immediately if the person collapses, seizures, or has trouble breathing.

Overdose Symptoms:

• Fatigue.

• Nausea.

• Vomiting.

• Need for coordination.

• Fainting.

• Slurred or slow speech.

• Uncontrolled eye movement.

• Irregular heartbeat.

• Uncontrolled body movements or shaking.

Drug Storage and Disposal

The hospital authorities store and discard the drug in a medical setting. The drug is stored in the hospital in refrigeration at two to eight degrees Celsius (36 to 46 degrees Fahrenheit). The vials of the drug should be stored at room temperature for up to 48 hours. Unused product vials that develop particulate matter should not be used. Also, after opening, any unused product should be discarded as vials of the drug are for single use only.

For Doctors:

Clinical Pharmacology

Mechanism of Action

Fosphenytoin is a Phenytoin prodrug. Therefore, its anticonvulsant effects are attributable to Phenytoin. The cellular mechanisms of Phenytoin are responsible for its anticonvulsant actions, including modulation of voltage-dependent sodium channels of neurons, modulation of voltage-dependent calcium channels of neurons, inhibition of calcium flux across neuronal membranes, and enhancement of the sodium-potassium ATPase activity of neurons and glial cells.

Pharmacodynamics

Fosphenytoin is a water-soluble Phenytoin prodrug prescribed for treating status epilepticus. After parenteral administration of Fosphenytoin sodium injection, the drug gets converted to Phenytoin anticonvulsant by endogenous phosphatases. Each dose of 1.5 milligrams (mg) of Fosphenytoin sodium is equivalent to 1.0 mg of Phenytoin sodium (PE equivalents).

Pharmacokinetics

Absorption:

After IV administration, the drug reaches its maximum concentration at the end of the dose administration. After intramuscular (IM) infusion, the drug reaches its peak concentration within 30 minutes, showing complete bioavailability.

Distribution:

The volume of distribution of Fosphenytoin sodium is 4.3 and 10.8 liters. It extensively bounds to 95 to 99 percent of human plasma proteins (albumin).

Metabolism:

The metabolites of Fosphenytoin get extensively metabolized into the liver. Fosphenytoin gets converted to phenytoin within 15 minutes (conversion half-life). The former gets metabolized into Phenytoin, Phosphatase, Formaldehyde (converted to formate), and phosphate.

Excretion:

Phenytoin derived from Fosphenytoin infusion gets excreted in the urine mainly as 5-(p-hydroxyphenyl)-5-phenylhydantoin and its glucuronide. There is little unchanged one to five percent of unchanged Phenytoin from the administered dose, and essentially, no Fosphenytoin is recovered in urine.

Ingredients

Active Ingredients: Fosphenytoin sodium.

Inactive Ingredients: Sodium hydroxide or Hydrochloride acid, Tromethamine, and water for injection

Contraindications for Fosphenytoin Sodium Injection

• The drug is contraindicated in patients having a history of hypersensitivity reaction to Phenytoin, Fosphenytoin sodium injection, or any of its ingredients. The drug can cause angioedema. Hence, it should be avoided.

• The drug is also contraindicated because of its effects, such as sino-atrial block, sinus bradycardia, Adams-Stokes syndrome, second and third-degree A-V block, and parenteral Fosphenytoin sodium injection or Phenytoin on ventricular automaticity.

• Coadministration of Fosphenytoin sodium injection with Delavirdine because of the expected potential for loss of virologic response and possible resistance to Delavirdine or the class of non-nucleoside reverse transcriptase inhibitors.

• A history of acute liver problems or hepatotoxicity associated with Fosphenytoin sodium injection or Phenytoin.

Warnings and Precautions for Fosphenytoin Sodium Injection

• Cardiovascular Depression: After intravenous administration at high doses and high rates of administration, hypotension may occur. Following the administration of Phenytoin, severe cardiovascular reactions and fatalities have been reported, including atrial and ventricular conduction depression and ventricular fibrillation. Various complications are also encountered in elderly or gravely ill patients. Therefore, doctors should do careful cardiac monitoring while administering intravenous (IV) loading doses of Fosphenytoin sodium injection. Also, a reduction in the infusion rate or discontinuation of dosing may be needed. Therefore, Fosphenytoin sodium injection should be used with great caution in patients with hypotension and severe myocardial insufficiency.

• Withdrawal Precipitated Seizure or Status Epilepticus: Antiepileptic drugs should not be discontinued abruptly because of the risk of increased seizure frequency. Therefore, if a doctor wants to reduce the drug dosage, discontinue, or substitute any alternative antiepileptic medication, they should do it gradually. However, in cases of an allergic or hypersensitivity reaction, the doctor needs to rapidly substitute an alternative therapy if necessary.

• Rash: Fosphenytoin sodium injection should be discontinued by the doctor if a skin rash appears. In case of exfoliating, purpuric, or bullous rash, lupus erythematosus, toxic epidermal necrolysis, or Stevens-Johnson syndrome is suspected, the drug should not be used, and an alternative therapy should be opted for. If it is a milder rash, such as measles-like or scarlatiniform, therapy can be resumed after the rash disappears completely. In cases of recurrence of rash upon reinstitution of therapy, Fosphenytoin sodium injection or Phenytoin drug administration is contraindicated.

• Alcohol Use: Acute alcohol intake may increase plasma Phenytoin concentrations, while chronic alcohol use may decrease plasma concentrations of the drug.

• Hepatic Injury: Acute hepatotoxicity, including rare cases of acute hepatic failure, has also been reported with Phenytoin. These cases have been associated with an allergic or hypersensitivity syndrome characterized by skin eruptions, fever, and lymphadenopathy, usually occurring within the first two months of treatment. Other common manifestations include hepatomegaly, jaundice, elevated serum transaminase levels, eosinophilia, and leukocytosis. Also, acute phenytoin hepatotoxicity can lead to recovery or fatal outcomes. Therefore, in patients with acute hepatotoxicity, the injection should be immediately discontinued and not readministered.

• Hemopoietic System: Hemopoietic complications may be fatal and have occasionally been reported in association with infusion of Phenytoin. These complications may include granulocytopenia, thrombocytopenia, agranulocytosis, leukopenia, and pancytopenia with or without bone marrow suppression. Various research reports have also suggested a relationship between Phenytoin and the occurrence of lymphadenopathy (local or generalized), including pseudolymphoma, benign lymph node hyperplasia, Hodgkin’s disease, and lymphoma. Although this association's actual cause and effects have not been established, lymphadenopathy indicates the need to rule out such a condition from other types of lymph node pathology. Therefore, a doctor must advise the patient that regular follow-up observation is needed for an extended period, and the doctor should make every effort to achieve seizure control using alternative antiepileptic drugs.

Drug Interactions

No drugs are known to affect the conversion of Fosphenytoin to phenytoin. It could be affected by changes in the level of phosphatase activity. However, because of the abundance and wide distribution of phosphatases in the body, the drugs cannot affect this activity enough to affect the conversion of Fosphenytoin to Phenytoin.

Some of the drug interactions are as follows:

• Acute alcohol intake.

• Amiodarone.

• Chloramphenicol.

• Chlordiazepoxide.

• Cimetidine.

• Diazepam.

• Dicumarol.

• Disulfiram.

• Estrogens.

• Ethosuximide.

• Fluoxetine.

• H2 -antagonists.

• Halothane.

• Isoniazid.

• Methylphenidate.

• Phenothiazines.

• Phenylbutazone.

• Salicylates.

• Succinimides.

• Sulfonamides.

• Tolbutamide.

• Trazodone.

• Carbamazepine.

• Chronic alcohol abuse.

• Reserpine.

• Phenobarbital.

• Valproic acid.

• Sodium valproate.

• Phenobarbital.

• Valproic acid.

• Anticoagulants.

• Corticosteroids.

• Coumarin.

• Digitoxin.

• Doxycycline.

• Estrogens.

• Furosemide.

• Oral contraceptives.

• Rifampin.

• Quinidine.

• Theophylline.

• Vitamin D.

Uses in Specific Populations

Pregnancy

Human exposure to the active metabolite (phenytoin) of Fosphenytoin sodium injection can increase the risks of congenital malformations. Also, prenatal exposure to the drug increases the incidence of major malformations, such as cardiac defects and orofacial clefts. Furthermore, there is an increased risk of fetal hydantoin syndrome characterized by dysmorphic skulls, growth abnormalities (including microcephaly), hypoplasia of digits and nails, facial features, and cognitive deficits.

Additionally, some malignancies, such as neuroblastoma, have been reported in children born to mothers who have received Phenytoin during pregnancy. Also, bleeding disorders related to reduced levels of vitamin K-dependent clotting factors can occur in infants exposed to Phenytoin in the gestation phase and can be life-threatening.

This fatal event can be prevented by administering vitamin K to the mother before delivery and to the neonate after birth. An event of increased seizure frequency may occur during pregnancy due to changes in phenytoin pharmacokinetics. Therefore, doctors should note that regular measurement of serum phenytoin concentrations should be advised when managing pregnant women for proper dose adjustment.

Breastfeeding

There is no specific data available regarding using Fosphenytoin during breastfeeding. The drug gets metabolized in the body to phenytoin, and very low levels of the drug's metabolite are found in breast milk. Therefore, the amount of drug the infant ingests is small, and no adverse effects are reported in breastfed infants except for rare idiosyncratic reactions.

Also, the use of drugs during breastfeeding has not shown any effects on infant growth or development. If the pregnant woman needs Fosphenytoin, discontinuing breastfeeding is not needed. However, combining Fosphenytoin with other anticonvulsants may result in sedation in infants, or discontinuation of the drug may cause withdrawals.

Pediatric Use

The drug safety in the pediatric population has yet to be established.

Geriatric Use

The drug clearance rate tends to decrease with increasing age. Therefore, elderly people may require low drug dosages.