Voriconazole

CLINICAL USE

Antifungal: Invasive aspergillosis Fluconazole-resistant serious invasive fungal infections Immunocompromised patients with progressive, possibly life-threatening infections

DOSE IN NORMAL RENAL FUNCTION

IV: 6 mg/kg 12 hourly for 24 hours, then 3–4 mg/kg 12 hourly Oral: <40 kg, 200 mg 12 hourly for 24 hours, then 100–150 mg twice daily >40 kg, 400 mg 12 hourly for 24 hours, then 200–300 mg twice daily

PHARMACOKINETICS

Molecular weight : 349.3

%Protein binding : 58

%Excreted unchanged in urine : <2

Volume of distribution (L/kg) : 4.6

half-life – normal/ESRD (hrs) : 6 (depends on dose)/ Unchanged

DOSE IN RENAL IMPAIRMENT

GFR (mL/MIN)

20 to 50 : Dose as in normal renal function

10 to 20 : Dose as in normal renal function

<10 : Dose as in normal renal function. See ‘Other Information’

DOSE IN PATIENTS UNDERGOING RENAL REPLACEMENT THERAPIES

CAPD : Probably dialysed. Dose as in normal renal function

HD : Dialysed. Dose as in normal renal function

HDF/high flux : Dialysed. Dose as in normal renal function

CAV/VVHD : Probably dialysed. Dose as in normal renal function

IMPORTANT DRUG INTERACTIONS

Potentially hazardous interactions with other drugs

Analgesics: methadone concentration increased

Antibacterials: concentration reduced by rifabutin; increase dose of voriconazole from 200 to 350 mg and from 100 to 200 mg (depends on patient’s weight), and increase IV dose to 5 mg/kg if used in combination – avoid concomitant use if possible; increased rifabutin levels – monitor for toxicity; avoid concomitant use with rifampicin

Anticoagulants: enhanced effect of coumarins

Antidepressants: avoid concomitant use with reboxetine Antidiabetics: possibly increased concentration of sulphonylureas

Anti-epileptics: concentration reduced by carbamazepine, barbiturates and primidone – avoid concomitant use; phenytoin reduces voriconazole concentration and voriconazole increases phenytoin concentration – double oral voriconazole dose and increase IV to 5 mg/ kg dose if using with phenytoin; avoid concomitant use if possible

Antimalarials: avoid concomitant use with artemether/lumefantrine

Antipsychotics: increased risk of ventricular arrhythmias with pimozide and sertindole – avoid concomitant use; possibly increased quetiapine levels – reduce dose of quetiapine

Antivirals: concentration reduced by efavirenz and ritonavir; also concentration of efavirenz increased – avoid concomitant use with ritonavir; with efavirenz reduce dose by 50% and increase dose of voriconazole to 400 mg twice daily; possibly increased saquinavir levels Benzodiazepines: may inhibit metabolism of midazolam

Ciclosporin: AUC increased – reduce ciclosporin dose by 50% and monitor closely

Ergot alkaloids: risk of ergotism – avoid concomitant use Lipid-lowering drugs: possibly increased risk of myopathy with atorvastatin or simvastatin . Sirolimus: increased sirolimus concentration – avoid concomitant use

Tacrolimus: AUC increased – reduce tacrolimus dose to a third and monitor closely

Ulcer-healing drugs: omeprazole concentration increased – reduce omeprazole dose by 50%

ADMINISTRATION

Reconstition

19 mL water for injection

Route

Oral, IV

Rate of Administration

1–2 hours (3 mg/kg/hour)

Comments

Not compatible with sodium bicarbonate or TPN solutions Dilute to a concentration of 2–5 mg/mL with sodium chloride 0.9%, Hartmann’s solution or glucose 5%

OTHER INFORMATION

Haemodialysis clearance is 121 mL/min Oral bioavailability is 96% Only use IV in renal patients if patient is unable to tolerate oral, as intravenous vehicle (SBECD) accumulates in renal failure. The vehicle is dialysed at a rate of 55 mL/min Take oral dose 1 hour before or an hour after meals Monitor renal function as can enhance nephrotoxicity of other drugs and concurrent conditions Rare reports of acute renal failure and discoid lupus erythematosus occurring Also reports of haematuria, nephritis and tubular necrosis In clinical trials, 30% of patients had visual problems, usually with higher doses .

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