Voriconazole

Dogs: Loading dose 6mg/kg IV q12h x2 doses, then 4mg/kg IV q12h

Needs to be diluted to <5mg/mL prior to infusion (2-5mg/mL recommended)

Should be administered at rate of 2-3mg/kg/h (so the 4-6mg/kg dose goes in over 2h)

* Continue at 4mg/kg PO q12 or switch to fluconazole when transition to oral meds

* Oral and IV voriconazole doses are the same

Cats: Loading dose of 25mg (per cat NOT per kg), then 12.5mg per cat q72h beginning 72h after loading dose. This works out to approx 5mg/kg load and 2.5mg/kg maintenance dose based on cat size in the PK study. The mg/cat dosing is the practical dosing for cats.

* Therapeutic drug monitoring is recommended in cats because the PK still have not been completely worked out, and there may be a narrow therapeutic window. Target 1-3mcg/mL based on Vishkautsan 2016 paper. Possibly available at NCSU Clinical Pharmacology Laboratory?

Add 19mL sterile water to vial to reconstitute = 10mg/mL

Add entire contents to 100mL bag of 0.9% saline

Store refrigerated for up to 10 days

Manufacturer insert says the diluted product is good in the infusion bag for 24h in refrigerator once reconstituted and diluted.

Independent stability studies: (there are lots of them)

• Reconstitute with sterile water, dilute to 2mg/mL in 0.9% saline in infusion bag: at least 15d and maybe up to 32d in refrigerator depending of type of bag (PVC vs polyolefin)
• Reconstitute with sterile water, dilute to 2mg/mL in 0.9% saline in infusion bag: at least 8 days in fridge (2-8C) and at 25C (77F, so room temp)
• Reconstitute with sterile water, dilute to 2mg/mL in 5% dextrose in infusion bag: up to 6 days refrigerated or at 25C
• My opinion: at 2mg/mL in PVC bag I would feel good using out to 15 days, possibly up to 32d if I can get the German article & have it translated so I can read it. 

50mg tablets,   200mg tablets,   40mg/mL oral suspension,   200mg vials powder for IV suspension (see reconstitution above)

* One cat drooled so badly after the oral suspension was administered in the PK study that no drug was detected, the rest also had significant ptyalism after the oral suspension  –  go with tablets!

Triazole anti fungal drug, derivative of fluconazole. Higher oral bioavailability and better intrinsic activity against most fungal organisms than fluconazole or itraconazole. Superior side effect profile compared to both these drugs and amphotericin B. Considered drug of choice for Aspergillus in humans. Fungicidal (Aspergillus), fungistatic (other species? only reported in the Lemetayer paper) by inhibition of ergosterol resulting in cell wall disruption

In dogs: Completely absorbed from GI tract. Approx 51% protein bound. Peak plasma concentration achieved approx 3h post-administration. Half life approx 4.5h (single dose). Metabolized in liver, metabolites excreted in feces; approx 5% unchanged in urine.  Penetrates CNS effectively/reaches therapeutic concentrations in CNS.

In cats: More data is needed. Well absorbed from GI tract, very long (almost 72h) half life when given PO; shorter when given IV. See the Vishkautsan paper.

Adverse effects: liver toxicity (12mg/kg/d x 12 months; 24mg/kg/d x30d); KuKanich cites report of unknown toxicity when 10mg/kg IV administered to dogs, reference is no longer available. Cats dosed same as dogs: report of 3 cats with neuro signs ataxia progressing to paraplegia, visual abnormalities, mydriasis, absent PLR, decreased menace; arrhythmia and hyperkalemia also noted in 2 of the cats following administration (Quimby paper; PK data was later worked out and found cats need different dosing). Death in other case reports (when dosed as dogs). When dosed appropriately for cats (Vishkautsan paper): mydriasis (no visual abnormalities) and ptyalism. No cardiac or electrolyte abnormalities seen.

Lemetayer JD, et al. Pharmacokinetics and distribution of voriconazole in body fluids of dogs after repeated oral dosing. J VetPharmacol There. 2015 Oct;38(5):451-6.  PMID 25691353

Roffey SJ, et al. The disposition of voriconazole in mouse, rat, rabbit, guinea pig, dog, and human. Drug Metab Dispos. 2003 Jun;31(6):731-41.  PMID 12756205

Bentley RT, et al. Fungal Infections of the Central Nervous System in Small Animals: Clinical Features, Diagnosis, and Management. Vet Clin North Am Small Anim Pract. 2018 Jan;48(1):63-83.  PMID 18988704

Hoppe-Tichy T et al. [Stability of voriconazole in infusion bags]. Pharmazie. 2005 Jan;60(1):77-8.  PMID 15700785

Adams A, et al. Treatment of invasive fungal infections: Stability of voriconazole infusion solutions in PVC bags. Braz J Infect Dis. 2008 Oct; 12(5):400-4.  PMID 19219820

Nguyen KQ, et al. Stability and uniformity of extemporaneous preparations of voriconazole in two liquid suspension vehicles at two storage temperatures. Am J Vet Res. 2009 July;70(7):908-14.  PMID 19566477

Sahraoui L, et al. Stability of voriconazole injection in 0.9% sodium chloride and 5% dextrose injections. Am J Health Syst Pharm. 2006 Aug 1;63(15):1423-6.  PMID 16849707

Lat A, Thompson G. Update on the optimal use of voriconazole for invasive fungal infections. Infect Drug Resist. 2011;4:43-53.   PMID 21694908

KuKanich B. A review of selected systemic anti fungal drugs for use in dogs and cats. Jan 1, 2008. Published on dvm360.com   Link Here

Quimby JM, et al. Adverse neurologic events associated with voriconazole use in 3 cats. J Vet Intern Med. 2010 May-Jun;24(3):647-9.   PMID 20384957

Vishkautsan P, et al. Pharmacokinetics of voriconazole after intravenous and oral administration to healthy cats. Am J Vet Res. 2016 Sept;77(9):931-9.   PMID 27580104