Fosphenytoin

Fosphenytoin is a water-soluble phosphate ester prodrug of phenytoin, given intravenously or intramuscularly for status epilepticus and when oral phenytoin is not possible. It allows faster infusion, safer tissue tolerance and intramuscular use, but it is dosed in phenytoin sodium equivalents (PE), and confusing milligrams of drug with milligrams PE has caused serious errors.

Mechanism. After conversion to phenytoin it blocks voltage-gated sodium channels in a use-dependent way.

Pharmacokinetics. Phosphatases convert it with a half-life of 8 to 15 minutes, and conversion is complete within about 2 hours. Fosphenytoin 1.5 mg equals phenytoin sodium 1 mg, which equals 1 mg PE. Protein binding is 95 to 99%, and displaces phenytoin transiently, so free phenytoin peaks soon after infusion. Subsequent kinetics are those of phenytoin and are saturable.

Emergency use. Convulsive status epilepticus after a benzodiazepine has failed:

• Fosphenytoin intravenous loading 20 mg PE/kg (usual maximum 1500 mg PE) at up to 150 mg PE/min in adults. In children, up to 3 mg PE/kg/min, not over 150 mg PE/min. Give once. Continuous ECG and blood pressure monitoring is required.

• Maintenance 4 to 6 mg PE/kg daily intravenously or intramuscularly in two or three divided doses, starting 12 to 24 hours after the load. Switch to oral phenytoin at the same total daily dose in mg of phenytoin when feasible.

Alternative use. Non-emergency loading when oral phenytoin is not possible, for example after neurosurgery:

• Fosphenytoin 10 to 20 mg PE/kg intravenously at 100 to 150 mg PE/min, or intramuscularly in divided sites, followed by maintenance. Duration is days, until the oral route returns.

Kidney, liver, weight and age.

• Kidney and liver: free phenytoin rises because binding falls and conversion is faster. Use free level and give phosphate load caution in severe renal impairment, since each mg PE releases a small phosphate load (about 0.0037 mmol).

• Obesity: base the dose on ideal body weight.

• Older adults and those with cardiac disease: slow the rate, and monitor closely.

Contraindications. Sinus bradycardia, sinoatrial block, second or third degree atrioventricular block, Adams-Stokes syndrome, hypersensitivity to phenytoin or hydantoins, and delavirdine.

Serious adverse effects. Hypotension and arrhythmia with rapid infusion (boxed-warning-level risk), severe skin reactions, drug reaction with eosinophilia and systemic symptoms, hepatitis, blood dyscrasias and foetal hydantoin syndrome. Tissue injury is much less than with phenytoin.

Common adverse effects. Pruritus or burning, particularly in the groin, paraesthesia, nystagmus, dizziness, somnolence and ataxia. Slow the rate if sensory symptoms are troublesome.

Interactions. The same as for phenytoin: raised levels with isoniazid, fluconazole, metronidazole, amiodarone and co-trimoxazole; lowered levels with rifampicin; and induction that lowers warfarin, direct oral anticoagulants, hormonal contraceptives, dolutegravir, efavirenz, protease inhibitors, artemether-lumefantrine and praziquantel.

Common prescribing errors. Writing the dose in mg of fosphenytoin rather than mg PE. Measuring a phenytoin level less than 2 hours after an intravenous dose (4 hours after an intramuscular dose). Giving too fast.

Special groups.

• Pregnancy: teratogenic risk as with phenytoin. Use only when benefit clearly outweighs risk. Give folic acid 5 mg daily before conception.

• Breastfeeding: acceptable for short courses; monitor for drowsiness.

• Regional: availability varies and may be limited, so phenytoin is often the practical alternative, and rates for phenytoin must then be used.

Formulations. Injection 50 mg PE/mL (for example 500 mg PE in 10 mL). Store in a refrigerator at 2 to 8 degrees Celsius; it may be kept at room temperature for up to 48 hours.

Preparation. Dilute in 0.9% sodium chloride or 5% glucose to 1.5 to 25 mg PE/mL for intravenous infusion. The intramuscular route needs no dilution.

Monitoring.

• Continuous ECG, blood pressure and respiration during and for 10 to 20 minutes after infusion.

• Phenytoin level at least 2 hours after intravenous completion; target total 10 to 20 mg/L (free 1 to 2 mg/L). Also monitor albumin, liver function, full blood count and sodium.

Stopping. Convert to oral phenytoin or another antiseizure medicine. Stop for severe rash.

Referral and escalation. Seizures continuing after loading mean refractory status epilepticus and need anaesthetic-level care with neurology input.