Intravenous Candidaemia, Deep tissue candida infections, Invasive aspergillosis, Scedosporiosis and fusariosis
Adult: 6 mg/kg 12 hrly for the 1st 24 hr. Maintenance: 4 mg/kg 12 hrly; (3-4 mg/kg 12 hrly for candidaemia in non-neutropenic patients or for deep tissue Candida infections, or patients intolerant of high doses). Max duration: 6 mth. Max infusion rate: 3 mg/kg/hr over 1-2 hr. May switch to oral therapy once patient is able to tolerate oral admin. Child: 2-14 yr <50 kg: 9 mg/kg 12 hrly for the 1st 24 hr, then 8 mg/kg 12 hrly. Max infusion rate: 3 mg/kg/hr. May switch to oral therapy once patient is able to tolerate oral admin.
Oral Candidaemia, Deep tissue candida infections, Invasive aspergillosis, Scedosporiosis and fusariosis
Adult: ≥40 kg: 400 mg (10 mL) 12 hrly for the 1st 24 hr, followed by 200 mg (5 mL) 12 hrly, may increase to 300 mg 12 hrly or reduce by decrements of 50 mg if necessary. <40 kg: 200 mg (5 mL) 12 hrly for the 1st 24 hr, followed by 100 mg (2.5 mL) 12 hrly, may increase to 150 mg 12 hrly or reduce by decrements of 50 mg if necessary. For oesophageal candidiasis: Treatment should be given for at least 14 days and continued for 7 days after symptoms resolved. Child: 2-14 yr <50 kg: 9 mg/kg (Max: 350 mg) 12 hrly.
Special Patient Group
Pharmacogenomics:
Voriconazole is influenced by hepatic enzyme saturation and genetic polymorphisms of CYP2C19. It affects variability on pharmacokinetics, adverse effects, and clinical efficacy. Available studies suggest that approx 15-20% of Asian, 3-5% Caucasians and Blacks are poor metabolizers of CYP2C19.
Monitor for voriconazole serum concentration.
Ultrarapid metabolisers (2 increased function alleles e.g. *17/*17):
Reduced plasma concentration of voriconazole including treatment failure have been reported.. Choose an alternative agent e.g. isavuconazole, liposomal amphotericin B, and posaconazole that is not dependent on CYP2C19 metabolism as primary therapy in lieu of voriconazole.
Rapid metabolisers (carrier of 1 normal function allele and 1 increased function allele e.g. *1/*17):
Choose an alternative agent e.g. isavuconazole, liposomal amphotericin B, and posaconazole that is not dependent on CYP2C19 metabolism as primary therapy in lieu of voriconazole.
Normal metaboliser (2 normal function alleles e.g. *1/*1):
Follow standard therapy, no dose adjustment needed.
Intermediate metabolisers (one normal function allele and one no/increased function allele e.g. *1/*2, *2/*17):
Follow standard therapy, no dose adjustment needed.
Poor metabolisers (two no function alleles e.g. *2/*2, *2/*3, *3/*3):
Increased serum concentration and increased risk of drug toxicity (e.g. QTc prolongation) of voriconazole and choose an alternative agent e.g. isavuconazole, liposomal amphotericin B, and posaconazole that is not dependent on CYP2C19 metabolism as primary therapy in lieu of voriconazole. May administer a lower dose of voriconazole than the standard dose in case that it is considered to be most appropriate treatment. Monitor therapy with therapeutic drug monitoring.
Renal Impairment
Intravenous:
CrCl
Dosage
<50
Use oral voriconazole when possible.
Hepatic Impairment
Mild to moderate (Child-Pugh category A and B): Standard loading dose but maintenance doses should be reduced by 50%.
Administration
Should be taken on an empty stomach. Take at least 1 hr before or after meals.
Reconstitution
Oral:
Add 46 mL of water to the bottle containing 45 g of voriconazole to provide a susp containing 40 mg/mL. Shake vigorously for about 1 min. Intravenous:
Add 19 mL of sterile water for inj to prepare a soln containing 10 mg/mL. Shake the vial until the powder is dissolved. The required volume is then further diluted w/ a suitable IV infusion soln prior to admin.
Incompatibility
Intravenous:
Tigecycline, Na bicarbonate 4.2% infusion. Do not infuse into the same line or cannula concomitantly w/ other drug infusions. Do not infuse concomitantly w/ concentrated electrolytes or any blood products even in separate line or cannula.
Patients w/ potentially proarrhythmic conditions, risk for acute pancreatitis. Correct electrolyte disturbances e.g. hypokalaemia, hypomagnesaemia and hypocalcaemia prior to treatment. CYP2C19 ultrarapid, intermediate and poor metabolisers. Hepatic and renal impairment. Pregnancy and lactation.
May impair ability to drive or operate machinery. Avoid intense or prolonged exposure to direct sunlight.
Monitoring Parameters
Monitor hepatic (prior and during treatment) and renal (during treatment) function, serum electrolytes, visual and pancreatic function.
Overdosage
Symptom: Photophobia. Management: May remove via haemodialysis.
Drug Interactions
Increased prothrombin time w/ oral anticoagulants. May increase plasma concentrations of ciclosporin and tacrolimus, long-acting opiates (e.g. oxycodone, methadone), NSAIDs (e.g. ibuprofen, diclofenac), omeprazole, short-acting opiates (e.g. alfentanil, fentanyl). Decreased voriconazole plasma concentration and increased phenytoin plasma concentrations when used concomitantly. May increase plasma concentration w/ oral contraceptives. Potentially Fatal: May increase risk of QT prolongation or torsades de pointes w/ astemizole, cisapride, pimozide, quinidine and terfenadine. May increase risk of ergotism w/ ergot alkaloids (e.g. ergotamine and dihydroergotamine). May significantly increase plasma concentrations of sirolimus. Decreased plasma concentrations w/ rifampicin, carbamazepine, long-acting barbiturates (e.g. phenobarbital, mephobarbital), efavirenz (≥400 mg once daily), ritonavir (≥400 mg bid). Concomitant use may significantly increase rifabutin and decrease voriconazole plasma concentration.
Food Interaction
Decreased voriconazole levels w/ St John's wort. Food may decrease voriconazole absorption.
Action
Description: Voriconazole is a triazole antifungal agent which inhibits cytochrome P450-dependent enzymes thereby inhibiting ergosterol synthesis in fungal cell membranes. It has a broad spectrum of activity against all Candida species (including strains resistant to fluconazole), Aspergillus spp., Scedosporium spp., and Fusarium spp. Pharmacokinetics: Absorption: Rapidly and almost completely absorbed from the GI tract. Food decreases absorption. Bioavailability: 96%. Time to peak plasma concentration: Approx 1-2 hr. Distribution: Diffuses in CSF. Plasma protein binding: Approx 58%. Metabolism: Saturable metabolism. Metabolised by CYP2C19 isoenzyme to the major metabolite (inactive N-oxide), and also by CYP2C9 and CYP3A4 isoenzymes. Excretion: Via urine (approx 80%).
Chemical Structure
Voriconazole Source: National Center for Biotechnology Information. PubChem Database. Voriconazole, CID=71616, https://pubchem.ncbi.nlm.nih.gov/compound/Voriconazole (accessed on Jan. 24, 2020)
Storage
Intravenous:
Unreconstituted vials: Store between 15- 30°C. Reconstituted concentrate: Store between 2-8°C, stable for up to 24 hr. Oral:
Tablet: Store between 15-30°C. Powd for oral susp: Store between 2-8°C. Reconstituted oral susp: Store between 15-30°C (do not refrigerate or freeze), stable for up to 14 days.
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