Dosing and uses of Cerebyx, ProEpanutin (fosphenytoin)
Adult dosage forms and strengths
injectable solution
- 100mg PE/2mL (2mL)
- 500mg PE/10mL (10mL)
Generalized Convulsive Status Epilepticus
15-20 mg PE/kg IV, infuse at 100-150 mg PE/min
Nonemergent Seizure
Load: 10-20 mg PE/kg IV/IM; infuse slowly over 30 min; not to exceed 150 mg PE/min)
Initial Maintenance: 4-6 mg PE/kg/day IV/IM in divided doses
Short-Term Substitution for PO Phenytoin
Can be substituted for PO phenytoin therapy at the same total daily dose; however, Dilantin capsules are 90% bioavailable PO while fosphenytoin is 100% bioavailable IM and IV
Plasma phenytoin concentrations my increase when fosphenytoin administered IM or IV
Administration
Maximum IV rate of 150 mg PE/min
Monitor: Phenytoin level 2 hr after IV, 4 hr after Im
All dosing in mg "phenytoin equivalents" (PE); 75 mg fosphenytoin equivalent to 50 mg phenytoin
Pediatric dosage forms and strengths
Safety and efficacy not established
Cerebyx, ProEpanutin (fosphenytoin) adverse (side) effects
>10%
IV
- Pruritis (40-50%)
- Dizziness (31%)
- Somnolence (20%)
- Ataxia (11%)
Im
- Nystagmus (15%)
1-10%
IV
- Tinnitus (6-10%)
- Deafness (2-5%)
Im
- Somnolence (6-10%)
- Bruising (7%)
- Pruritis (2-5%)
- Nausea (5%)
- Vomiting (3%)
- Weakness (4%)
<1%
Taste change (>1%)
Frequency not defined
Hypotension (esp with high rates of IV infusion)
Hypertension
Dysarthria
Fever
Increased reflex
Intracranial HTn
Hypesthesia
Sensory disturbances (burning, itching, paresthesia), withdrawal-precipitated seizures
Rash
Constipation
Hypokalemia
Cytopenias (can be fatal)
Hepatic injury
Myasthenia
Pneumonia
IV
- Hypotension, vasodilation, tachycardia
- Agitation, asthenia, headache, EPS, paresthesia, stupor, tremor
- Dry mouth, nausea, vomiting
- Pelvic and back pain
- Diplopia, nystagmus
- Body as a Whole: Allergic reactions in the form of rash and rarely more serious forms (DRESS) or anaphylaxis; coarsening of facial features, systemic lupus erythematosus, periarteritis nodosa, and immunoglobulin abnormalities
- Special Senses: Altered taste sensation including metallic taste
- Urogenital: Peyronie’s disease
Im
- Asthenia, ataxia, decreased reflex, dizziness, headache, paresthesia, tremor
- Nausea, vomiting
- Eccymosis
Warnings
Black box warnings
Cardiovascular risk associated with rapid infusion rates
- Risk of hypotension and arrhythmias with infusion rates that exceed 150 mg/minute of phenytoin sodium equivalents (PE)
- Careful cardiac monitoring is needed during and after administering IV administration; these events have also been reported at or below 150 mg PE/minute
- Recommended doses should not be changed when substituting fosphenytoin for phenytoin or vice versa; they are not equivalent on mg to mg basis
- Reduce infusion rate or discontinuation may be needed
Contraindications
Known hypersensitivity to hydantoins
Sinus bradycardia, sinoatrial block, 2nd or 3rd degree AV block, Adams-Stokes syndrome
Not indicated for absence seizures or seizures secondary to hypoglycemia or other metabolic disorder
Coadministration with delavirdine; potential for loss of virologic response and possible resistance to delavirdine or to the pharmacologic class of NNRTIs
Cautions
Do NOT give IM for status epilepticus initial dose
Renal, hepatic or other hypoalbuminemic disease: monitor unbound phenytoin concentration
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 possibility of increased seizure frequency, including status epilepticus; reduce dose gradually when necessary; in the event of allergic or hypersensitivity reaction, rapid substitution of alternative therapy, not belonging to hydantoin chemical class is necessary
Adverse cardiovascular reactions include severe hypotension and cardiac arrhythmias; because of risks of cardiac and local toxicity associated with IV fosphenytoin, oral phenytoin should be used whenever possible
Patients administered fosphenytoin at doses of 20 mg PE/kg at 150 mg PE/min are expected to experience discomfort of some degree; occurrence and intensity of discomfort can be lessened by slowing or temporarily stopping the infusion
Plasma concentrations of phenytoin sustained above optimal range may produce confusional states referred to as “delirium,” “psychosis,” or “encephalopathy,” or rarely, irreversible cerebellar dysfunction and/or cerebellar atrophy; at first sign of acute toxicity, determination of plasma phenytoin concentrations recommended fosphenytoin dose reduction indicated if phenytoin concentrations excessive; if symptoms persist, discontinue therapy
Cases of acute hepatotoxicity, including infrequent cases of acute hepatic failure, reported with phenytoin; discontinue and do not readminister if acute hypatotoxicity occurs
Hematopoietic complications, some fatal, have occasionally been reported in association with administration of phenytoin; these have included thrombocytopenia, leukopenia, granulocytopenia, agranulocytosis, and pancytopenia with or without bone marrow suppression; 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 > 5 days
Phenytoin has potential to lower serum folate levels
Discontinue at first sign of rash, unless rash is clearly not drug-related; if signs or symptoms suggest SJS/TEN, use of this drug should not be resumed and alternative therapy considered; serious and sometimes fatal dermatologic reactions, including toxic epidermal necrolysis (TEN) and Stevens-Johnson syndrome (SJS), reported with phenytoin treatment
If rash occurs, evaluate for signs and symptoms of Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), also known as multiorgan hypersensitivity
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
Pregnancy and lactation
Pregnancy category: d
Lactation: Excretion in milk unknown; not recommended
Pregnancy categories
A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.
B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.
C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.
D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.
X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.
NA: Information not available.
Pharmacology of Cerebyx, ProEpanutin (fosphenytoin)
Mechanism of action
Converted to phenytoin after injection; stabilizes neuronal membranes and decrease seizure activity by increasing efflux or decreasin influx of sodium ions across cell membranes in the motor cortex during generation of nerve impulses
Pharmacokinetics
Half-Life: 15 min (phenytoin)
Peak Plasma Time: 15 min (IM); 3 hr (phenytoin)
Therapeutic phenytoin level: 10-20 mcg/mL
Bioavailability: ~100% IV/Im
Protein Bound: 95-99%; 70-88% (phenytoin)
Vd: 4.3-10.8 L
Metabolism: Liver
Metabolite: PhenytoinExcretion: urine (metabolites)
Excretion: Urine
Pharmacogenomics
Patients with HLA-B*1502 with are more likely to have a severe dermatologic reaction (eg, TEN, Stevens-Johnson syndrome) when taking phenytoin
This allele occurs almost exclusively in patients with ancestry across broad areas of Asia, including Han Chinese, Filipinos, Malaysians, South Asian Indians, and Thais
Maternal epoxide (EPHX1) genotypes 113*H and 139*R are associated with risk of fetal hydantoin syndrome among pregnant women taking phenytoin
Increased levels of the reactive epoxide metabolites by either inhibiting the detoxification of these metabolites by epoxide hydrolase or by increasing conversion to epoxide metabolites by inducing CYP3A4, 2C9, or 2C19
Genetic testing laboratories
- The following companies provide genetic testing for HLA variants
- Kashi Clinical Laboratories (www.kashilab.com)
- LabCorp (https://www.labcorp.com/)
- Specialty Laboratories (https://www.specialtylabs.com)
- Quest (https://www.questdialgnotics.com)
Administration
IV Incompatibilities
Y-site: fenoldopam, midazolam
IV Preparation
Dilute in D5W or NS to 1.5-25 mg PE/mL
IV Administration
Infused at NMT 150 mg/min
