Fosphenytoin

What is Fosphenytoin?

• Fosphenytoin (Cerebyx; Sesquient) is a prodrug of phenytoin and accordingly, its anticonvulsant effects are attributable to phenytoin.

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Fosphenytoin

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What are the uses of this medicine?

Fosphenytoin (Cerebyx; Sesquient) is used:

• for the treatment of generalized tonic-clonic status epilepticus.
• For prevention and treatment of seizures occurring during neurosurgery.
• control certain type of seizures in people who cannot take oral phenytoin.

Fosphenytoin sodium injection can also be substituted, as short-term use, for oral phenytoin.

How does this medicine work?

• The sodium salt form of fosphenytoin, a prodrug that is hydrolyzed to the anticonvulsant phenytoin upon parental administration.
• Phenytoin exerts its effect most likely through an enhancement of sodium efflux from neurons in the motor cortex.
• This leads to a suppression of excessive neuronal firing and spread of seizure activity.
• Other physiologic effects from actions of phenytoin include modulation of the voltage dependent calcium channels of neurons, inhibition of calcium flux across neuronal membranes and enhancement of sodium potassium atpase activity of neurons and glial cells.

Who Should Not Use this medicine ?

This medicine cannot be used in patients with:

• A history of hypersensitivity to fosphenytoin sodium injection or its inactive ingredients, or to phenytoin or other hydantoins.
• Sinus bradycardia, sino-atrial block, second and third degree A-V block, or Adams-Stokes syndrome.
• A history of prior acute hepatotoxicity attributable to fosphenytoin sodium injection or phenytoin.
• Coadministration with delavirdine.

What drug interactions can this medicine cause?

• Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.

Be sure to mention any of the following:

• albendazole (Albenza); amiodarone (Nexterone, Pacerone); anticoagulants ('blood thinners') such as warfarin (Coumadin, Jantoven); antifungal medications such as fluconazole (Diflucan), ketoconazole (Nizoral), itraconazole (Onmel, Sporanox, Tolsura), miconazole (Oravig), posaconazole (Noxafil), and voriconazole (Vfend); certain antivirals such as efavirenz (Sustiva, in Atripla), indinavir (Crixivan), lopinavir (in Kaletra), nelfinavir (Viracept), ritonavir (Norvir, in Kaletra), and saquinavir (Invirase); bleomycin; capecitabine (Xeloda); carboplatin; chloramphenicol; chlordiazepoxide (Librium, in Librax); cholesterol medications such as atorvastatin (Lipitor, in Caduet), fluvastatin (Lescol), and simvastatin (Zocor, in Vytorin); cisplatin; clozapine (Fazaclo, Versacloz); cyclosporine (Gengraf, Neoral, Sandimmune); diazepam (Valium); diazoxide (Proglycem); digoxin (Lanoxin); disopyramide (Norpace); disulfiram (Antabuse); doxorubicin (Doxil); doxycycline (Acticlate, Doryx, Monodox, Oracea, Vibramycin); fluorouracil; fluoxetine (Prozac, Sarafem, in Symbyax, others); fluvoxamine (Luvox); folic acid; fosamprenavir (Lexiva); furosemide (Lasix); H2 antagonists such as cimetidine (Tagamet), famotidine (Pepcid), nizatidine (Axid), and ranitidine (Zantac); hormonal contraceptives (birth control pills, patches, rings, or injections); hormone replacement therapy (HRT); irinotecan (Camptosar); isoniazid (Laniazid, in Rifamate, in Rifater); medications for mental illness and nausea; other medications for seizures such as carbamazepine (Carbatrol, Equetro, Tegretol, others), ethosuximide (Zarontin), felbamate (Felbatol), lamotrigine (Lamictal), methsuximide (Celontin), oxcarbazepine (Trilepta, Oxtellar XR), phenobarbital, topiramate (Topamax), and valproic acid (Depakene); methadone (Dolophine, Methadose); methotrexate (Otrexup, Rasuvo, Trexall, Xatmep); methylphenidate (Daytrana, Concerta, Metadate, Ritalin); mexiletine; nifedipine (Adalat, Procardia), nimodiwashpine (Nymalize), nisoldipine (Sular); omeprazole (Prilosec); oral steroids such as dexamethasone, methylprednisolone (Medrol), prednisolone, and prednisone (Rayos); paclitaxel (Abraxane, Taxol); paroxetine (Paxil, Pexeva); praziquantel (Biltricide); quetiapine (Seroquel); quinidine (in Nuedexta); reserpine; rifampin (Rifadin, Rimactane, in Rifamate, in Rifater); salicylate pain relievers such as aspirin, choline magnesium trisalicylate, choline salicylate, diflunisal, magnesium salicylate (Doan's, others), and salsalate; sertraline (Zoloft); sulfa antibiotics; teniposide; theophylline (Elixophyllin, Theo-24, Theochron); ticlopidine; tolbutamide; trazodone; verapamil (Calan, Verelan, in Tarka); vigabatrin (Sabril); and vitamin D.

• Tell your doctor what herbal products you are taking, especially St. John's wort.

Is this medicine FDA approved?

• Fosphenytoin was approved for use in the United States in 1996.

How should this medicine be used?

Recommended dosage: For Status Epilepticus:

• Adult loading dose is 15 to 20 mg PE/kg at a rate of 100 to 150 mg PE/min.
• Pediatric loading dose is 15 to 20 mg PE/kg at a rate of 2 mg PE/kg/min (or 150 mg PE/min, whichever is slower).

For Non-emergent Loading and Maintenance Dosing:

• Adult loading dose is 10 to 20 mg PE/kg given IV or IM; initial maintenance dose is 4 to 6 mg PE/kg/day in divided doses.
• Pediatric loading dose is 10 to 15 mg PE/kg at a rate of 1 to 2 mg PE/kg/min (or 150 mg PE/min, whichever is slower)
• Initial maintenance dose is 2 to 4 mg PE/kg every 12 hours at a rate of 1 to 2 mg PE/kg/min (or 100 mg PE/min, whichever is slower).

Administration:

• Fosphenytoin injection comes as a solution to be injected intravenously or intramuscularly by a doctor or nurse in a medical facility.
• When fosphenytoin is injected intravenously, it is usually injected slowly.
• How often you receive fosphenytoin injection and the length of your treatment depends on how your body responds to the medication.
• Your doctor will tell you how often you will receive fosphenytoin injection.

What are the dosage forms and brand names of this medicine?

This medicine is available in fallowing doasage form:

• As Injection: 50 mg phenytoin sodium equivalents.

This medicine is available in fallowing brand namesː

• Cerebyx; Sesquient

What side effects can this medication cause?

The most common side effects of this medicine include: In Adults:

• pruritus, nystagmus, dizziness, somnolence, and ataxia

In Pediatrics:

• vomiting, nystagmus, and ataxia

Fosphenytoin injection may cause serious side effects, including:

• Cardiovascular Risk Associated with Rapid Infusion
• Withdrawal Precipitated Seizure, Status Epilepticus
• Serious Dermatologic Reactions
• Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)
• Hypersensitivity
• Angioedema
• Hepatic Injury
• Hematopoietic Complications
• Sensory Disturbances
• Local Toxicity (Including Purple Glove Syndrome)
• Exacerbation of Porphyria
• Teratogenicity and Other Harm to the Newborn
• Hyperglycemia

What special precautions should I follow?

• Do not confuse the amount of drug to be given in Phenytoin Sodium Equivalents (PE) with the concentration of the drug in the vial. Ensure the appropriate volume is withdrawn from the vial when preparing for administration.
• Rapid intravenous administration of fosphenytoin sodium injection increases the risk of adverse cardiovascular reactions, including severe hypotension and cardiac arrhythmias. Cardiac arrhythmias have included bradycardia, heart block, ventricular tachycardia, and ventricular fibrillation which have resulted in asystole, cardiac arrest, and death. Patients should report cardiac signs or symptoms to their healthcare provider.
• Patients should not discontinue use of fosphenytoin sodium injection without consulting with their healthcare provider. Fosphenytoin sodium injection should normally be gradually withdrawn to reduce the potential for increased seizure frequency and status epilepticus.
• Advise patients of the early signs and symptoms of severe cutaneous adverse reactions and to report any occurrence immediately to a physician.
• Advise patients of the early toxic signs and symptoms of potential hematologic, dermatologic, hypersensitivity, or hepatic reactions. These symptoms may include, but are not limited to, fever, sore throat, rash, ulcers in the mouth, easy bruising, lymphadenopathy, facial swelling, and petechial or purpuric hemorrhage, and in the case of liver reactions, anorexia, nausea/vomiting, or jaundice. Advise the patient that, because these signs and symptoms may signal a serious reaction, that they must report any occurrence immediately to a physician. In addition, advise the patient that these signs and symptoms should be reported even if mild or when occurring after extended use.
• Patients need to discontinue fosphenytoin sodium injection and seek immediate medical care if they develop signs or symptoms of angioedema such as facial, perioral, or upper airway swelling.
• Fosphenytoin sodium injection may cause an increase in blood glucose levels.
• Caution patients against the use of other drugs or alcoholic beverages without first seeking their physician's advice.
• Hematopoietic complications, some fatal, have occasionally been reported in association with administration of phenytoin (the active metabolite of fosphenytoin sodium injection). In all cases of lymphadenopathy, follow-up observation for an extended period is indicated and every effort should be made to achieve seizure control using alternative antiepileptic drugs.
• Severe burning, itching, and/or paresthesia were reported. The occurrence and intensity of the discomfort can be lessened by slowing or temporarily stopping the infusion.
• Edema, discoloration, and pain distal to the site of injection (described as “purple glove syndrome”) have also been reported following peripheral intravenous fosphenytoin sodium injection.
• The phosphate load provided by fosphenytoin sodium injection (0.0037 mmol phosphate/mg PE fosphenytoin sodium injection) should be considered when treating patients who require phosphate restriction, such as those with severe renal impairment.
• Fosphenytoin sodium not specifically associated with cases of drug induced liver injury, fosphenytoin is converted to phenytoin which is a well known cause of acute idiosyncratic drug induced liver disease.
• Caution should be exercised in using fosphenytoin sodium injection in patients suffering from Porphyria.
• Fosphenytoin sodium injection may cause fetal harm when administered to a pregnant woman. A potentially life-threatening bleeding disorder related to decreased levels of vitamin K-dependent clotting factors may occur in newborns exposed to phenytoin.
• It is not known whether fosphenytoin is secreted in human milk.

What to do in case of emergency/overdose?

Symptoms of overdose may include:

• Nausea, vomiting, lethargy, tachycardia, bradycardia, asystole, cardiac arrest, hypotension, syncope, hypocalcemia, metabolic acidosis, and death
• Initial symptoms of acute phenytoin toxicity are nystagmus, ataxia, and dysarthria.
• Other signs include tremor, hyperreflexia, lethargy, slurred speech, nausea, vomiting, coma, and hypotension.

• Formate and phosphate are metabolites of fosphenytoin sodium injection and therefore may contribute to signs of toxicity following overdosage.
• Signs of formate toxicity are similar to those of methanol toxicity and are associated with severe anion-gap metabolic acidosis.
• Large amounts of phosphate, delivered rapidly, could potentially cause hypocalcemia with paresthesia, muscle spasms, and seizures.

Management of overdosage:

• In case of overdose, call the poison control helpline of your country. In the United States, call 1-800-222-1222.

• Overdose related information is also available online at poisonhelp.org/help.
• In the event that the victim has collapsed, had a seizure, has trouble breathing, or can't be awakened, immediately call emergency services. In the United States, call 911.
• Treatment is nonspecific since there is no known antidote to fosphenytoin sodium injection or phenytoin overdosage.
• The adequacy of the respiratory and circulatory systems should be carefully observed, and appropriate supportive measures employed.
• Hemodialysis can be considered since phenytoin is not completely bound to plasma proteins.
• Total exchange transfusion has been used in the treatment of severe intoxication in children.
• In acute overdosage the possibility of other CNS depressants, including alcohol, should be borne in mind.

Can this medicine be used in pregnancy?

• Fosphenytoin sodium injection may cause fetal harm when administered to a pregnant woman.
• Prenatal exposure to phenytoin (the active metabolite of fosphenytoin sodium injection) may increase the risks for congenital malformations and other adverse developmental outcomes.
• A potentially life-threatening bleeding disorder related to decreased levels of vitamin K-dependent clotting factors may occur in newborns exposed to phenytoin.
• This drug-induced condition can be prevented with vitamin K administration to the mother before delivery and to the neonate after birth.

Can this medicine be used in children?

• Fosphenytoin sodium injection is indicated for the treatment of generalized tonic-clonic status epilepticus and prevention and treatment of seizures occurring during neurosurgery in all pediatric age groups.

What are the active and inactive ingredients in this medicine?

Active ingredient:

• FOSPHENYTOIN SODIUM

Inactive ingredients:

• TROMETHAMINE
• HYDROCHLORIC ACID
• SODIUM HYDROXIDE
• WATER

Who manufactures and distributes this medicine?

• Fresenius Kabi USA, LLC

What should I know about storage and disposal of this medication?

• Store under refrigeration at 2°C to 8°C (36°F to 46°F).
• The product should not be stored at room temperature for more than 48 hours.
• Vials that develop particulate matter should not be used.
• Injection vials are single-dose only.
• After opening, any unused product should be discarded.

See also

• hydantoin
• ethotoin
• mephenytoin
• phenytoin

• Dailymed label info on Fosphenytoin
• FDA Fosphenytoin

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