Intramuscular, Intravenous Tonic-clonic status epilepticus
Adult: 1.5 mg fosphenytoin is equivalent to 1 mg phenytoin Na, referred to as 1 mg phenytoin Na equivalents (PE). Doses are expressed as PE. IV benzodiazepine (e.g. diazepam or lorazepam) is given before administration: Loading: 15-20 mg/kg as a single dose by IV infusion at a rate of 100-150 mg/min. Maintenance: Initially, 4-5 mg/kg daily in 1-2 divided doses by IM inj or IV infusion at a rate of 50-100 mg/min; to be started at the next identified dosing interval. Subsequent doses are adjusted based on patient response and trough plasma-phenytoin levels. Child: For faster seizure control, IV diazepam or lorazepam may be given before administration. As PE: ≥5 years Loading: 15-20 mg/kg as a single dose by IV infusion at a rate of 2-3 mg/kg/min; max rate: 3 mg/kg/min or 150 mg/min (whichever is slower). Maintenance: Initially, 4-5 mg/kg daily in 1-4 divided doses by IV infusion at a rate of 1-2 mg/kg/min; max rate: 2 mg/kg/min or 100 mg/min (whichever is slower); to be started at the next identified dosing interval. Subsequent doses are adjusted based on patient response and trough plasma-phenytoin levels. Elderly: Lower loading dose and/or infusion rate, and lower or less frequent maintenance dose.
Intramuscular, Intravenous Seizures associated with head trauma, Seizures associated with neurosurgery
Adult: 1.5 mg fosphenytoin is equivalent to 1 mg phenytoin Na, referred to as 1 mg phenytoin Na equivalents (PE). Doses are expressed as PE. As treatment or prophylaxis: Loading: 10-15 mg/kg as a single dose by IM inj or IV infusion at a rate of 50-100 mg/min. Maintenance: Initially, 4-5 mg/kg daily in 1-2 divided doses by IM inj or IV infusion at a rate of 50-100 mg/min; to be started at the next identified dosing interval. Subsequent doses are adjusted based on patient response and trough plasma-phenytoin levels. Child: As PE: As treatment or prophylaxis: ≥5 years Loading: 10-15 mg/kg as a single dose by IV infusion at a rate of 1-2 mg/kg/min; max rate: 2 mg/kg/min or 100 mg/min (whichever is slower). Maintenance: Initially, 4-5 mg/kg daily in 1-4 divided doses by IV infusion at a rate of 1-2 mg/kg/min; max rate: 2 mg/kg/min or 100 mg/min (whichever is slower) to be started at the next identified dosing interval. Subsequent doses are adjusted based on patient response and trough plasma-phenytoin levels. Elderly: Lower loading dose and/or infusion rate, and lower or less frequent maintenance dose may be needed.
Special Patient Group
Pharmacogenomics:
Fosphenytoin is rapidly and completely metabolised to phenytoin by alkaline phosphatase (ALP) enzymes, forming a transient carbinolamine intermediate that spontaneously decomposes to phenytoin.
HLA-B is part of the class I human major histocompatibility complex (MHC) genes which encodes cell surface proteins that enables the immune system to distinguish self-proteins from foreign proteins. HLA-B*15:02-positive patients may have an increased risk of cutaneous adverse reactions in response to phenytoin therapy. Additionally, CYP2C9 is the enzyme responsible in metabolising phenytoin.
HLA-B*15:02
Patients with 1 or 2 copies of HLA-B*15:02 variant allele may have an increased risk of developing phenytoin-induced cutaneous adverse reactions such as Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). HLA-B*15:02 has the most prevalence in East Asian and Central/South Asian population ranging from 1%->20% and patients with ancestry from North China, Taiwan, Hong Kong, Thailand, Malaysia and parts of the Philippines and India have the highest risk of developing phenytoin-induced SJS/TEN that is associated with this allele. Conversely, HLA-B*15:02 is less prevalent in the European population (0-1%) and was not detected in several sub-Saharan African populations.
Genetic testing for HLA-B*15:02 may be considered for those ancestries that have a prevalence of this allele. Avoid the use of fosphenytoin in patients who are HLA-B*15:02-positive; although patients who have previously used fosphenytoin or phenytoin for >3 months without the development of cutaneous reactions may consider using fosphenytoin with caution.
CYP2C9
CYP2C9 polymorphism may be associated with phenytoin pharmacokinetic variability. Genetic testing for CYP2C9 may be considered before initiating therapy.
CYP2C9 Phenotype
Activity Score
CPIC Recommendations
Normal metabolisers, Intermediate metabolisers
≥1.5
No dosage adjustments needed.
Intermediate metabolisers
1.0
Usual loading dose followed by at least 25% reduction in the recommended starting maintenance dose.
Poor metabolisers
≤0.5
Usual loading dose then consider at least 50% reduction in the starting maintenance dose.
Renal Impairment
Seizures associated with neurosurgery and/or head trauma:
Lower loading dose and/or infusion rate, and lower or less frequent maintenance dose may be needed.
Hepatic Impairment
Seizures associated with neurosurgery and/or head trauma:
Lower loading dose and/or infusion rate, and lower or less frequent maintenance dose may be needed.
Reconstitution
Dilute with dextrose 5% or NaCl 0.9% solution to produce a concentration between 1.5-25 mg PE/mL.
Contraindications
Sinus bradycardia, sino-atrial block, 2nd- or 3rd-degree AV block, Stokes-Adams syndrome; history of acute hepatotoxicity associated with fosphenytoin or phenytoin; acute intermittent porphyria. Concomitant use with delavirdine.
Special Precautions
Patients with hypotension, severe myocardial insufficiency, acute cerebrovascular event, hyperbilirubinaemia, hypoalbuminaemia, hypothyroidism, phosphate restriction, diabetes mellitus. Critically ill and debilitated patients. Patients of Asian ancestry. Patients who are positive for HLA-B*15:02 allele; CYP2C9 poor metabolisers or intermediate metabolisers with CYP2C9 activity score of 1. Not indicated for the treatment of absence seizures and seizures associated with hypoglycaemia or other metabolic causes. Avoid abrupt withdrawal. Renal and hepatic impairment. Children and elderly. Pregnancy and lactation.
Adverse Reactions
Significant: Suicidal ideation and behaviour, confusional states (e.g. delirium, psychosis or encephalopathy) or rarely, irreversible cerebellar dysfunction and/or atrophy; oedema, discolouration and pain at the inj site), skin necrosis and limb ischaemia; lymphadenopathy (local or generalised) including benign lymph node hyperplasia, pseudolymphoma, lymphoma and Hodgkin’s disease; angioedema; transient itching, burning and/or paraesthesia in the groin during or post-infusion. Cardiac disorders: CV collapse (IV). Ear and labyrinth disorders: Tinnitus, vertigo. Eye disorders: Blurred vision, visual impairment. Gastrointestinal disorders: Dysgeusia, dry mouth, nausea, vomiting. General disorders and administration site conditions: Ataxia, asthenia. Metabolism and nutrition disorders: Hyperglycaemia. Musculoskeletal and connective tissue disorders: Chills. Nervous system disorders: Dizziness, headache, nystagmus, tremor, abnormal coordination; CNS depression (IV). Psychiatric disorders: Somnolence, euphoric mood, stupor, dysarthria. Skin and subcutaneous tissue disorders: Pruritus, ecchymosis. Vascular disorders: Hypotension, vasodilation. Potentially Fatal: Severe CV reactions (e.g. atrial and ventricular conduction depression, hypotension, ventricular fibrillation, asystole) associated with rapid infusion, hypersensitivity syndrome or drug reaction with eosinophilia and systemic symptoms (DRESS), severe cutaneous adverse reactions (e.g. acute generalised exanthematous pustulosis, exfoliative dermatitis, Stevens-Johnson syndrome, toxic epidermal necrolysis), toxic hepatitis, acute hepatoxicity, haematopoietic complications (e.g. thrombocytopenia, leucopenia, granulocytopenia, agranulocytosis, pancytopenia).
IM/IV/Parenteral: Z (Congenital malformations, foetal hydantoin syndrome and haemorrhage have been reported. Use only when benefits outweigh risks. If used, monitor drug levels and adjust dose accordingly.)
Patient Counseling Information
This drug may cause dizziness and drowsiness if affected, do not drive or operate machinery. Women of childbearing potential must use proven birth control methods during therapy. Consider using other reliable contraceptive methods recommended by the doctor as hormonal contraceptives may be ineffective.
Monitoring Parameters
Pregnancy test may be considered in women of childbearing potential to rule out pregnancy before initiating treatment. Monitor ECG, blood pressure, heart rate, and respiratory function during and approx 30 minutes post-infusion; vital signs, CBC, LFT, plasma phenytoin concentrations; signs of suicidal ideation and behaviours.
Increased plasma levels with amiodarone, azole antifungals (e.g. fluconazole), capecitabine, chloramphenicol, disulfiram, estrogens, felbamate, fluorouracil, fluoxetine, fluvoxamine, H2-antagonists (e.g. cimetidine), halothane, isoniazid, methylphenidate, omeprazole, oxcarbazepine, salicylates, sertraline, succinimides (e.g. ethosuximide), sulfonamides (e.g. sulfamethizole), tacrolimus, ticlopidine, tolbutamide, topiramate, trazodone. Decreased plasma levels with antineoplastic drugs (e.g. bleomycin, carboplatin, doxorubicin), diazoxide, folic acid, fosamprenavir, nelfinavir, reserpine, rifampicin, ritonavir, theophylline, vigabatrin. Altered (increased or decreased) plasma levels with carbamazepine, chlordiazepoxide, ciprofloxacin, diazepam, phenobarbital, phenothiazines, valproic acid, Na valproate. May impair the efficacy of corticosteroids, doxycycline, furosemide, fluvastatin, irinotecan, oral contraceptives, glibenclamide, paclitaxel, paroxetine, quinidine, rifampicin, teniposide, theophylline, vitamin D. Increased and decreased prothrombin time or INR responses with warfarin. May decrease plasma levels of active metabolites of albendazole, certain HIV antivirals (e.g. efavirenz), atorvastatin, chlorpropamide, clozapine, ciclosporin, digoxin, methadone, mexiletine, nifedipine, nimodipine, nisoldipine, praziquantel, simvastatin, verapamil. May decrease serum levels of amprenavir (active metabolite of fosamprenavir) when given with fosamprenavir alone. May increase amprenavir concentration when given with fosamprenavir and ritonavir combination. May cause resistance to the neuromuscular blocking action of the non-depolarising neuromuscular blocking agents (e.g. pancuronium). Potentially Fatal: May cause loss of virologic response and possible resistance to delavirdine or the class of non-nucleoside reverse transcriptase inhibitors.
Food Interaction
Plasma phenytoin level may be increased with acute alcohol intake while chronic alcohol intake may decrease plasma phenytoin level. Decreased plasma levels with St John's wort.
Lab Interference
May decrease serum concentrations of T4. May produce low results in dexamethasone or metyrapone tests. May cause increased serum concentrations of glucose, alkaline phosphatase and γ-glutamyl transpeptidase (GGT). Additionally, may affect blood Ca and sugar metabolism tests and may decrease serum folate levels.
Action
Description: Fosphenytoin, a diphosphate ester salt of phenytoin, acts as a water-soluble prodrug of phenytoin. After administration, fosphenytoin is converted to phosphate, formaldehyde and phenytoin (as the active moiety) by the plasma esterases. Phenytoin stabilises neuronal membranes and decreases seizure activity by increasing efflux or decreasing influx of Na ions across cell membranes in the motor cortex during the generation of nerve impulses. Pharmacokinetics: Absorption: Bioavailability: 100% (IM). Time to peak plasma concentration: At the end of IV infusion; approx 30 minutes (IM). Distribution: Volume of distribution: 4.3-10.8 L (increases with dose and rate of administration). Plasma protein-binding: 95-99% (mainly to albumin). Metabolism: Rapidly and completely hydrolysed to phenytoin; phenytoin is metabolised into phosphate and formaldehyde. Excretion: Elimination half-life: Approx 15 minutes (IV); approx 30 minutes (IM).
Chemical Structure
Fosphenytoin Source: National Center for Biotechnology Information. PubChem Database. Fosphenytoin, CID=56339, https://pubchem.ncbi.nlm.nih.gov/compound/Fosphenytoin (accessed on Jan. 21, 2020)
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