Fosphenytoin sodium

CLINICAL USE

Control of status epilepticus Seizures associated with neurosurgery or head injury when oral phenytoin is not possible

DOSE IN NORMAL RENAL FUNCTION

Status epilepticus: Treatment: 20 mg PE/kg (loading dose) —by

IV infusion

Maintenance: 4–5 mg PE/kg daily in —1–2 divided dosesProphylaxis or treatment of seizures: 10– 15 mg PE/kg by

IV infusion

; then convert to phenytoin or 4–5 mg PE/kg daily in 1–2 divided doses

PHARMACOKINETICS

  • Molecular weight                           :406.2
  • %Protein binding                           :95–99
  • %Excreted unchanged in urine     : 1–5
  • Volume of distribution (L/kg)       :4.3–10.8 litres
  • half-life – normal/ESRD (hrs)      :18.9 (IV), 41.2 (IM)/Unchanged

    DOSE IN RENAL IMPAIRMENT

    GFR (mL/MIN)

  • 20 to 50     : Reduce dose or rate by 10–25% and monitor carefully (except for status epilepticus)
  • 10 to 20     : Reduce dose or rate by 10–25% and monitor carefully (except for status epilepticus)
  • <10           : Reduce dose or rate by 10–25% and monitor carefully (except for status epilepticus)

    DOSE IN PATIENTS UNDERGOING RENAL REPLACEMENT THERAPIES

  • CAPD                :Unlikely to be dialysed. Dose as for GFR <10 mL/min
  • HD                     :Not dialysed. Dose as for GFR <10 mL/min
  • HDF/high flux   :Unlikely to be dialysed. Dose as for GFR <10 mL/min
  • CAV/VVHD      :Not dialysed. Dose as for GFR 10 to 20 mL/min

    IMPORTANT DRUG INTERACTIONS

    Potentially hazardous interactions with other drugs

  • Analgesics: enhanced effect with NSAIDs; metabolism of methadone accelerated
  • Anti-arrhythmics: increased concentration with amiodarone; concentration of disopyramide and mexiletine reduced
  • Antibacterials: level increased by clarithromycin, chloramphenicol, isoniazid, metronidazole, co-trimoxazole and trimethoprim (+ antifolate effect); concentration increased or decreased by ciprofloxacin; concentration of doxycycline and telithromycin reduced; concentration reduced by rifampicin
  • Anticoagulants: increased metabolism of coumarins (reduced effect but also reports of enhancement)
  • Antidepressants: MAOIs, SSRIs and tricyclics antagonise anticonvulsant effect, concentration increased by fluoxetine and fluvoxamine; reduced concentration of mianserin, mirtazepine, paroxetine and possibly tricyclics; concentration reduced by St John’s wort – avoid
  • Anti-epileptics: concentration of both drugs reduced with carbamazepine; concentration may also be increased by carbamazepine, ethosuximide, oxcarbazepine and topiramate; possibly reduced concentration of ethosuximide, active oxcarbazepine metabolite, primidone (but active metabolite increased), topiramate and valproate; reduced concentration of lamotrigine, tiagabine and zonisamide; primidone and valproate may alter concentration; concentration reduced by vigabatrin
  • Antifungals: reduced concentration of ketoconazole, itraconazole, posaconazole, voriconazole and possibly caspofungin – avoid with itraconazole, increase voriconazole dose and possibly caspofungin; levels increased by fluconazole, miconazole and voriconazole
  • Antimalarials: antagonise anticonvulsant effect; increased antifolate effect with pyrimethamine
  • Antipsychotics: antagonise anticonvulsant effect; aripiprazole concentration possibly reduced – increase aripiprazole dose; Fosphenytoin sodium.fOSPHeNYtOIN SODIUM 335metabolism of clozapine, quetiapine and sertindole increased
  • Calcium-channel blockers: levels increased by diltiazem; reduced concentration of diltiazem, felodipine, isradipine, nisoldipine and verapamil and possibly dihydropyridines, nicardipine and nifedipine
  • Ciclosporin: reduced ciclosporin levels Corticosteroids: metabolism accelerated (effect reduced)Cytotoxics: metabolism inhibited by fluorouracil; increased antifolate effect with methotrexate; reduced phenytoin absorption; reduced concentration of busulfan, etoposide and imatinib – avoid with imatinibDisulfiram: levels of phenytoin increased
  • Diuretics: concentration of eplerenone reduced – avoid concomitant use; increased risk of osteomalacia with carbonic anhydrase inhibitors; antagonises effect of furosemideOestrogens and progestogens: metabolism increased (reduced contraceptive effect)Sulfinpyrazone: concentration increased by sulfinpyrazone
  • Tacrolimus: reduced tacrolimus levels Theophylline: concentration of both drugs reduced
  • Ulcer-healing drugs: metabolism inhibited by cimetidine; absorption reduced by sucralfate; enhanced effect with esomeprazole and omeprazole

    ADMINISTRATION

    Reconstition

    –

    Route

    IV, IM

    Rate of Administration

    Status epilepticus : 100–150 mg PE/min Treatment and prophylaxis of seizures: 50–100 mg PE/min

    Comments

    Dilute further when using for

    IV infusion

    with sodium chloride 0.9% or glucose 5% to 1.5–25 mg PE/mL

    OTHER INFORMATION

    75 mg of fosphenytoin sodium is equivalent to 50 mg of phenytoin0.037 mmol of phosphate/mg of fosphenytoinDecreased protein binding in renal failure Monitor ECG, BP and respiratory function during infusionWhen substituting IV, IM use same dose and frequency as for oral phenytoin, administer at a rate of 50–100 mg PE/minMay increase blood glucose in diabetic patientsSome is dialysed out, as not all PE is protein-boundHalf-life of fosphenytoin to phenytoin is 15 minutes; more rapid in renal failure due to reduced protein binding.

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