No

Anticonvulsant, Hydantoin

Indicated for short-term parenteral administration when other means of phenytoin administration are unavailable, inappropriate or deemed less advantageous; the safety and effectiveness of fosphenytoin in this use has not been systematically evaluated for more than 5 days; may be used for the control of generalized convulsive status epilepticus and prevention and treatment of seizures occurring during neurosurgery

D

Clinical effects on the fetus: Crosses placenta with fetal serum concentrations equal to those of mother; eye, cardiac, cleft palate, and skeletal malformations have been noted; fetal hydantoin syndrome associated with maternal ingestion of 100-800 mg/kg during 1st trimester

Breast-feeding/lactation: Distributes into breast milk

Hypersensitivity to phenytoin or fosphenytoin; occurrence of any rash while on treatment; the drug should not be resumed if rash is exfoliative, purpuric, or bullous; not recommended for use in children <4 years of age

Use with caution in patients with severe cardiovascular, hepatic, renal disease or diabetes mellitus; avoid abrupt discontinuation; dosing should be slowly reduced to avoid precipitation of seizures; increased toxicity with nephrotic syndrome patient; may increase frequency of petit mal seizures; use with caution in patients with porphyria, fever, or hypothyroidism

Percentage unknown: Pain on injection, sensory paresthesia (long-term treatment), nephrotic syndrome

>10%:

Central nervous system: Dizziness (31%), somnolence (21%), ataxia (11%)

Dermatologic: Pruritus (48.9%)

Ocular: Nystagmus (44%)

1% to 10%:

Cardiovascular: Hypotension (7.7%), vasodilation (>1%), tachycardia (2.2%)

Central nervous system: Stupor (7.7%), incoordination (4.4%), paresthesia (4.4%), choreathetosis (4.4%), tremor (3.3%), agitation (3.3%)

Gastrointestinal: Nausea (>5%), vomiting (2%)

Ocular: Blurred vision (2%), diplopia (3.3%)

<1%: Rash, exfoliative dermatitis, erythema multiforme, acne, diabetes insipidus, lymphadenopathy, neutropenia, thrombocytopenia, anemia (megaloblastic)

Signs and symptoms of toxicity include unsteady gait, tremors, hyperglycemia, chorea (extrapyramidal), gingival hyperplasia, gynecomastia, myoglobinuria, nephrotic syndrome, slurred speech, mydriasis, myoclonus, confusion, encephalopathy, hyperthermia, drowsiness, nausea, hypothermia, fever, hypotension, respiratory depression, leukopenia; neutropenia; agranulocytosis; granulocytopenia; hyper-reflexia, coma, systemic lupus erythematosus (SLE), ophthalmoplegia

Treatment is supportive for hypotension; treat with I.V. fluids and place patient in Trendelenburg position; seizures may be controlled with lorazepam or diazepam 5-10 mg (0.25-0.4 mg/kg in children); intravenous albumin (25 g every 6 hours has been used to increase bound fraction of drug). Multiple dosing of activated charcoal may be effective; peritoneal dialysis, diuresis, hemodialysis, hemoperfusion, and plasmapheresis is of little value

No drug interaction noted with diazepam

Refrigerated vials are stable for 2 years; at room temperature, stable for 3 months; I.V. solutions are stable for one day when refrigerated

Diphosphate ester salt of phenytoin which acts as a water soluble prodrug of phenytoin; after administration, plasma esterases convert fosphenytoin to phosphate, formaldehyde and phenytoin as the active moiety; phenytoin works by stabilizing neuronal membranes and decreasing seizure activity by increasing efflux or decreasing influx of sodium ions across cell membranes in the motor cortex during generation of nerve impulses

Fosphenytoin is a prodrug of phenytoin and its anticonvulsant effects are attributable to phenytoin

Conversion to phenytoin: Following I.V. administration conversion half-life is 15 minutes; following I.M. administration peak phenytoin levels are reached in 3 hours

The dose, concentration in solutions, and infusion rates for fosphenytoin are expressed as phenytoin sodium equivalents; fosphenytoin should always be prescribed and dispensed in phenytoin sodium equivalents

Nonemergent loading and maintenance dosing: I.V. or I.M.: Adults:

Loading dose: Phenytoin equivalent: 10-20 mg/kg I.V. or I.M. (maximum I.V. rate: 150 mg/minute)

Initial daily maintenance dose: Phenytoin equivalent: 4-6 mg/kg/day I.V. or I.M.

I.M. or I.V. substitution for oral phenytoin therapy: May be substituted for oral phenytoin sodium at the same total daily dose, however, Dilantin® capsules are ~90% bioavailable by the oral route; phenytoin, supplied as fosphenytoin, is 100% bioavailable by both the I.M. and I.V. routes; for this reason, plasma phenytoin concentrations may increase when I.M. or I.V. fosphenytoin is substituted for oral phenytoin sodium therapy; in clinical trials I.M. fosphenytoin was administered as a single daily dose utilizing either 1 or 2 injection sites; some patients may require more frequent dosing

Dosing adjustments in renal/hepatic impairment: Phenytoin clearance may be substantially reduced in cirrhosis and plasma level monitoring with dose adjustment advisable; free phenytoin levels should be monitored closely in patients with renal or hepatic disease or in those with hypoalbuminemia; furthermore, fosphenytoin clearance to phenytoin may be increased without a similar increase in phenytoin in these patients leading to increase frequency and severity of adverse events

Blood pressure, vital signs (with I.V. use), plasma level monitoring, CBC, liver function tests

Therapeutic: 10-20 mg/mL (SI: 40-79 mmol/L); toxicity is measured clinically, and some patients require levels outside the suggested therapeutic range

Toxic: 30-50 mg/mL (SI: 120-200 mmol/L)

Lethal: >100 mg/mL (SI: >400 mmol/L)

Manifestations of toxicity:

Nystagmus: 20 mg/mL (SI: 79 mmol/L)

Ataxia: 30 mg/mL (SI: 118.9 mmol/L)

Decreased mental status: 40 mg/mL (SI: 159 mmol/L)

Coma: 50 mg/mL (SI: 200 mmol/L)

Peak serum phenytoin level after a 375 mg I.M. fosphenytoin dose in healthy males: 5.7 mg/mL

Peak serum fosphenytoin levels and phenytoin levels after a 1.2 g infusion (I.V.) in healthy subjects over 30 minutes were 129 mg/mL and 17.2 mg/mL respectively

Increases glucose, alkaline phosphatase (S); decreases thyroxine (S), calcium (S); serum sodium increases in overdose setting

May cause dizziness, drowsiness, or visual hallucinations

May cause neutropenia; use caution with clozapine and carbamazepine

No information available to require special precautions

No effects or complications reported

Patients may not be in a position to evaluate their response. If conscious or alert, advise patient to report signs or symptoms of palpitations, racing or falling heartbeat, difficulty breathing, acute faintness, or CNS disturbances (eg, somnolence, ataxia), and visual disturbances. Pregnancy precautions: Inform prescriber if you are pregnant.

I.V. injections should be followed by normal saline flushes through the same needle or I.V. catheter to avoid local irritation of the vein; must be diluted to concentrations <6 mg/mL, in normal saline, for I.V. infusion

Injection, as sodium: 150 mg [equivalent to phenytoin sodium 100 mg] in 2 mL vials; 750 mg [equivalent to phenytoin sodium 500 mg] in 10 mL vials

Bebin M and Bleck TP, "New Anticonvulsant Drugs. Focus on Flunarizine, Fosphenytoin, Midazolam, and Stiripentol," Drugs, 1994, 48(2):153-71.

Boucher BA, "Fosphenytoin: A Novel Phenytoin Prodrug," Pharmacotherapy, 1996, 16(5):777-91.

Boucher BA, Feler CA, Dean JC, et al, "The Safety, Tolerability, and Pharmacokinetics of Fosphenytoin After Intramuscular and Intravenous Administration in Neurosurgery Patients," Pharmacotherapy, 1996, 16(4):638-45.

Fischer JH, Cwik MS, Luer MS, et al, "Stability of Fosphenytoin Sodium With Intravenous Solutions in Glass Bottles, Polyvinyl Chloride Bags, and Polypropylene Syringes," Ann Pharmacother, 1997, 31(5):553-9.

Jamerson BD, Dukes GE, Brouwer KL, et al, "Venous Irritation Related to Intravenous Administration of Phenytoin Versus Fosphenytoin," Pharmacotherapy, 1994, 14(1):47-52.

Leppik IE, Boucher R, Wilder BJ, et al, "Phenytoin Prodrug: Preclinical and Clinical Studies," Epilepsia, 1989, 30(Suppl 2):S22-6.

Pellock JM, "Fosphenytoin Use in Children," Neurology, 1996, 46(6 Suppl 1):S14-6.

Wilder BJ, Campbell K, Ramsay RE, et al, "Safety and Tolerance of Multiple Doses of Intramuscular Fosphenytoin Substituted for Oral Phenytoin in Epilepsy or Neurosurgery," Arch Neurol, 1996, 53(8):764-8.