Fosphenytoin

Fosphenytoin is an anticonvulsant medication used to prevent or control seizures in the short term or when other forms of phenytoin cannot be given.

• Fosphenytoin is available under the following different brand names: Cerebyx, Sesquient

Fosphenytoin is an anticonvulsant medication used to prevent or control seizures in the short term or when other forms of phenytoin cannot be given.

• Fosphenytoin is available under the following different brand names: Cerebyx, Sesquient

What Are Dosages of Fosphenytoin?

Adult and pediatric dosage

• Injectable solution
• Cerebyx, Sesquient, generic
  • 100mg PE/2mL
  • 500mg PE/10mL

Status Epilepticus

Adult dosage

Cerebyx, Sesquient, generic

• Loading dose: 15-20 mg PE/kg IV at a rate of 100-150 mg PE/min, not to exceed 150 mg PE/min 

Pediatric dosage

Cerebyx, generic

• Children between birth to 17 years: Loading dose: 15-20 mg PE/kg IV at a rate of 2 mg PE/kg/min (or 150 mg PE/min, whichever is slower) 
• Children above 17 years: Loading dose: 15-20 mg PE/kg IV at a rate of 100-150 mg PE/min, not to exceed 150 mg PE/min 

Nonemergent Seizures

Adult dosage

• Cerebyx, Sesquient, generic
• Loading dose: 10-20 mg PE/kg IV; not to exceed 150 mg PE/min
• Maintenance dose: 4-6 mg PE/kg/day IV in divided doses IV, not to exceed 150 mg PE/min

Pediatric dosage

• Children between birth to 17 years (Cerebyx, generic):
• Loading dose: 10-15 mg PE/kg IV; 1-2 PE/kg/min, or 150 mg PE/min, whichever is slower
• Maintenance dose
  • 2-4 mg PE/kg/day IV in every 12 hours divided doses initially, THEN
  • 4-8 mg PE/kg/day IV every 12 hours divided into doses
  • At a rate of 1-2 mg PE/kg/min (or 100 mg PE/min, whichever is slower)
• Children above 17 years (Cerebyx):
  • Loading dose: 10-15 mg PE/kg IV; not to exceed 150 mg PE/min
  • Maintenance dose: 4-6 mg PE/kg/day IV in divided doses, not to exceed 150 mg PE/min
• Children between 2 to 17 years (Sesquient):
• Below 2 years: Safety and efficacy not established
• Above 2 years
  • Loading dose: 10-15 mg PE/kg IV; not to exceed 0.4 mg PE/kg/min
  • 2-4 mg PE/kg IV in every 12 hours divided doses initially, THEN
  • 4-8 PE/kg/day IV every 12 hours divided into doses
  • Because the betadex sulfobutyl ether sodium ingredient in Sesquient does not exceed the administration rate in pediatric patients of 0.4 mg PE/kg/min

Dosage Considerations – Should be Given as Follows: 

• See “Dosages”

Common side effects of Fosphenytoin include:

• dizziness, 
• drowsiness;
• unusual or involuntary eye movements;
• headache,
• nausea,
• constipation,
• dry mouth,
• vomiting;
• itching,
• tremor,
• muscle weakness,
• ringing in ears,
• pain in hips or back,
• flushing (warmth, redness, or tingly feeling under the skin),
• low blood pressure,
• fast heart rate,
• spinning sensation,
• double vision,
• changes in taste, and
• problems with balance or muscle movement.

Serious side effects of Fosphenytoin include:

• very slow heartbeats, 
• shortness of breath,
• a light-headed feeling, like passing out,
• confusion, 
• unusual thoughts or behavior,
• pain, swelling, and purple discoloration where the medicine was injected that may spread to the hand or fingers,
• a tingling or burning sensation,
• sudden fever, chills, 
• sore throat, 
• weakness,
• easy bruising, 
• unusual bleeding, and
• low blood potassium--leg cramps, constipation, irregular heartbeats, fluttering in the chest, increased thirst or urination, numbness or tingling, muscle weakness, or limp feeling.

Rare side effects of Fosphenytoin include:

• none 

If your medical doctor is using this medicine to treat your pain, your doctor or pharmacist may already be aware of any possible drug interactions and may be monitoring you for them. Do not start, stop, or change the dosage of any medicine before checking with your doctor, health care provider, or pharmacist first

• Fosphenytoin has severe interactions with at least 27 drugs.
• Fosphenytoin has serious interactions with at least 154 other drugs.
• Fosphenytoin has moderate interactions with at least 325 other drugs.
• Fosphenytoin has minor interactions with at least 115 other drugs. 

This information does not contain all possible interactions or adverse effects. Visit the RxList Drug Interaction Checker for any drug interactions. Therefore, before using this product, tell your doctor or pharmacist about all the products you use. Keep a list of all your medications with you and share this information with your doctor and pharmacist. Check with your health care professional or doctor for additional medical advice, or if you have health questions or concerns.

Contraindications

• Hypersensitivity to or its inactive ingredients, or to phenytoin or other hydantoins
• Sinus bradycardia, sinoatrial block, 2nd or 3rd degree AV block, Adams-Stokes syndrome
• Prior history of acute hepatotoxicity attributable to fosphenytoin or phenytoin
• Coadministration with delavirdine

Effects of drug abuse

• None

Short-Term Effects

• See “What Are Side Effects Associated with Using Fosphenytoin?”

Long-Term Effects

• See “What Are Side Effects Associated with Using Fosphenytoin?”

Cautions

• Do NOT give IM for status epilepticus initial dose
• Renal, hepatic, or other hypoalbuminemia diseases: monitor unbound phenytoin concentration
• Do not abruptly discontinue antiepileptic drugs because of the possibility of increased seizure frequency, including status epilepticus; in the event of an allergic or hypersensitivity reaction, the rapid substitution of alternative therapy may be necessary
• Associated with exacerbation of porphyria; exercise caution when fosphenytoin is used in patients with this disease
• Hyperglycemia, resulting from phenytoin’s inhibitory effect on insulin release, reported; phenytoin may also raise serum glucose concentrations in diabetic patients
• Do not discontinue antiepileptic drugs abruptly because of the possibility of increased seizure frequency, including status epilepticus; reduce the dose gradually when necessary; in the event of allergic or hypersensitivity reaction, the rapid substitution of alternative therapy, not belonging to the hydantoin chemical class is necessary
• Cases of acute hepatotoxicity, including infrequent cases of acute hepatic failure, are reported with phenytoin; discontinue and do not readminister if acute hepatotoxicity occurs
• Hematopoietic complications (eg, thrombocytopenia, leukopenia, granulocytopenia, agranulocytosis, pancytopenia with or without bone marrow suppression), some fatal, have occasionally been reported; in cases of lymphadenopathy, follow-up observation for an extended period is indicated
• Consider phosphate load (0.0037 mmol phosphate/mg PE fosphenytoin) when treating patients who require phosphate restriction, such as those with severe renal impairment
• Safety/efficacy not evaluated for administration more than 5 days
• Consider alternatives to structurally similar drugs such as carboxamides (eg, carbamazepine), barbiturates, succinimides, and oxazolidinediones (eg, trimethadione) in patients who experienced phenytoin hypersensitivity
• Angioedema reported with phenytoin and fosphenytoin; discontinue immediately if symptoms of angioedema (eg, facial, perioral, or upper airway swelling) occur
• Severe burning, itching, and/or paresthesia were reported; IV fosphenytoin at doses of 20 mg PE/kg at 150 mg PE/min are expected to experience the discomfort of some degree; occurrence and intensity of discomfort can be lessened by slowing or temporarily stopping the infusion
• Local toxicity (Purple Glove Syndrome) that includes edema, discoloration, and pain distal to the site of injection has been reported following peripheral IV injection; may or may not be associated with extravasation; this syndrome may not develop for several days after injection
• It May cause fetal harm when administered to pregnant females
• Hyperglycemia, resulting from the inhibitory effect of phenytoin on insulin release, has been reported; phenytoin may also raise serum glucose concentrations in diabetic patients
• Serum levels of phenytoin (the active metabolite of fosphenytoin) sustained above the therapeutic range may produce confusional states referred to as “delirium,” “psychosis,” or “encephalopathy,” or rarely, irreversible cerebellar dysfunction and/or cerebellar atrophy; at the first sign of acute toxicity, check serum levels immediately; reduce dose if serum levels are excessive; discontinue therapy if symptoms persist

Patients with decreased CYP2C9 function

• A small percentage of treated individuals have been shown to metabolize phenytoin slowly; slow metabolism may be caused by limited enzyme availability and lack of induction
• Patients who are intermediate or poor metabolizers of CYP2C9 substrates (eg, *1/*3, *2/*2, *3/*3) may exhibit increased phenytoin serum concentrations compared to patients who are normal metabolizers (eg, *1/*1); patients who are known to be intermediate or poor metabolizers may ultimately require lower doses to maintain similar steady-state concentrations compared to normal metabolizers
• In patients who are known to be carriers of the decreased function CYP2C9*2 or *3 alleles (intermediate and poor metabolizers), consider starting at the low end of the dosage range and monitor serum concentrations to maintain total phenytoin concentrations of 10 to 20 mcg/mL; if early signs of dose-related central nervous system (CNS) toxicity develop, serum concentrations should be checked immediately

Cardiovascular risk associated with rapid infusion

• Rapid IV administration increases the risk of adverse cardiovascular reactions, including severe hypotension and cardiac arrhythmias (eg, bradycardia, heart block, QT prolongation, ventricular tachycardia, ventricular fibrillation); use oral phenytoin whenever possible
• Carefully monitor cardiac and respiratory function and after IV administration; consider reducing rate or discontinuing dose

Severe cutaneous reactions

• Can cause severe cutaneous adverse reactions (SCARs), which may be fatal
• Reported reactions include toxic epidermal necrolysis (TEN), Stevens-Johnson syndrome (SJS), acute generalized exanthematous pustulosis (AGEP), and Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)
• Onset is usually within 28 days but can occur later
• Discontinue at the first sign of a rash, unless the rash is not drug-related
• If signs or symptoms suggest a severe cutaneous adverse reaction, do not resume drug; consider alternant therapy
• Studies in patients of Chinese ancestry have found a strong association between the risk of developing SJS/TEN and the presence of HLA-B*1502, an inherited allelic variant of the HLA B gene in patients taking carbamazepine
• Limited evidence suggests that HLA-B*1502 or CYP2C9*3 may also be a risk factor for the development of SJS/TEN in patients taking other antiepileptic drugs

DRESS

• DRESS, also known as multiorgan hypersensitivity, reported in patients taking antiepileptic drugs, including phenytoin and fosphenytoin
• Some of these events have been fatal or life-threatening
• DRESS typically, although not exclusively, presents with fever, rash, lymphadenopathy, and/or facial swelling, in association with other organ system involvement (eg, hepatitis, nephritis, hematological abnormalities, myocarditis, or myositis sometimes resembling an acute viral infection); eosinophilia is often present
• Early manifestations of hypersensitivity (eg, fever or lymphadenopathy) may be present even though rash is not evident
• If such signs or symptoms are present, evaluate patient immediately; discontinue drug if unable to confirm other etiology for the rash

Dosing errors

• Do not confuse the amount of drug to be given in PE with a concentration of drug in the vial
• Medication errors associated with fosphenytoin have resulted in the wrong dose being administered

Drug interaction overview

• CYP2C9 and CYP2C19 substrate; potent inducer of hepatic drug-metabolizing enzymes
• Extensively bound to human plasma proteins
• The addition or withdrawal of these agents in patients on phenytoin therapy may require a dosage adjustment of the phenytoin to achieve the optimal clinical outcome
• Drugs that may increase phenytoin concentration
  • Antiepileptic drugs (ie, ethosuximide, felbamate, oxcarbazepine, methsuximide, topiramate)
  • Azoles (ie, fluconazole, ketoconazole, itraconazole, miconazole, voriconazole)
  • Antineoplastic agents (eg, capecitabine, fluorouracil)
  • Antidepressants (ie, fluoxetine, fluvoxamine, sertraline)
  • Gastric acid-reducing agents (eg, H2 antagonists, omeprazole)
  • Sulfonamides (eg, sulfamethizole, sulfaphenazole, sulfadiazine, sulfamethoxazole/trimethoprim)
  • Acute alcohol intake, amiodarone, chloramphenicol, chlordiazepoxide, disulfiram, estrogen, fluvastatin, isoniazid, methylphenidate, phenothiazines, salicylates, ticlopidine, tolbutamide, trazodone, warfarin
  • Drugs highly bound to albumin could increase the unbound fraction of fosphenytoin
• Drugs that may decrease phenytoin serum levels
  • Antineoplastic agents, usually in combination (eg, bleomycin, carboplatin, cisplatin, methotrexate
  • Antiviral agents (eg, fosamprenavir, nelfinavir, ritonavir)
  • Antiepileptic drugs (eg, carbamazepine, vigabatrin)
  • Chronic alcohol abuse, diazepam, diazoxide, folic acid, reserpine, rifampin, St. John wort, theophylline
  • Drugs that may either increase or decrease phenytoin serum levels H5
    • Antiepileptic drugs (eg, phenobarbital, valproate sodium, valproic acid)
• Drugs that decrease efficacy by phenytoin
  • Azoles (eg, fluconazole, ketoconazole, itraconazole, posaconazole, voriconazole)
  • Antineoplastic agents (eg, irinotecan, paclitaxel, teniposide)
  • Increased and decreased PT/INR responses have been reported when phenytoin is coadministered with warfarin
  • Coadministration with NNRTIs may cause loss of virologic response and possible resistance to NNRTIs (eg, delavirdine)
  • Cisatracurium, pancuronium, rocuronium, and vecuronium: resistance to the neuromuscular blocking action of the nondepolarizing neuromuscular blocking agents has occurred in patients chronically administered phenytoin; closely monitor for more rapid recovery from neuromuscular blockade than expected, and infusion rate requirements may be higher
  • Others: Corticosteroids, doxycycline, estrogens, furosemide, oral contraceptives, paroxetine, quinidine, rifampin, sertraline, theophylline, and vitamin D
• Drugs whose level is decreased by phenytoin
  • Antiepileptic drugs (eg, carbamazepine, felbamate, lamotrigine, topiramate, oxcarbazepine)
  • Antilipidemic agents (eg, atorvastatin, fluvastatin, simvastatin)
  • Antiviral agents (eg, efavirenz, lopinavir/ritonavir, indinavir, nelfinavir, ritonavir, saquinavir)
  • Fosamprenavir: Phenytoin is coadministered with fosamprenavir alone may decrease the concentration of amprenavir (active metabolite); when phenytoin is coadministered with the combination of fosamprenavir and ritonavir may increase the concentration of amprenavir
  • Calcium channel blockers (eg, nifedipine, nimodipine, nisoldipine, verapamil)
  • Others: Albendazole (decreases active metabolite), chlorpropamide, clozapine, cyclosporine, digoxin, disopyramide, folic acid, methadone, mexiletine, praziquantel, quetiapine
• Drug/laboratory test interactions
  • Exercise caution when using immunoanalytical methods to measure serum phenytoin concentrations following administration

Pregnancy and Lactation

• Exposure to phenytoin may increase the risks of congenital malformations and other adverse developmental outcomes
• Prenatal phenytoin exposure is associated with an increased incidence of major malformations, including orofacial clefts and cardiac defects
• In addition, fetal hydantoin syndrome, a pattern of abnormalities including dysmorphic skull and facial features, nail and digit hypoplasia, growth abnormalities (including microcephaly), and cognitive deficits has been reported among children born to epileptic women who took phenytoin alone or in combination with other antiepileptic drugs during pregnancy
• There have been several reported cases of malignancies, including neuroblastoma, in children whose mothers received phenytoin during pregnancy

Pregnancy exposure registry

• Monitors pregnancy outcomes in women exposed to antiepileptic drugs during pregnancy
• Advised pregnant females to enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry by calling the toll free number 1-888-233-2334, and must be done by patients themselves
• Information on the registry can also be found at http://www.aedpregnancyregistry.org/

Clinical considerations

• An increase in seizure frequency may occur during pregnancy because of altered phenytoin pharmacokinetics
• Consider periodic measurement of serum phenytoin concentrations to provide the appropriate dosage adjustment; postpartum restoration of the original dosage may be necessary
• A potentially life-threatening bleeding disorder related to decreased levels of vitamin K-dependent clotting factors may occur in newborns exposed to phenytoin in utero; may be prevented with vitamin K administration to the mother before delivery and to the neonate after birth

Lactation

• It is not known whether fosphenytoin is secreted in human milk
• Following administration of phenytoin, phenytoin is secreted in human milk