HOSPITAL OF THE UNIVERSITY OF PENNSYLVANIA

Guidelines for Use of Voriconazole (Vfend)

The Antibiotic Subcommittee of the Pharmacy & Therapeutics Committee and the Antibiotic Management Program have reviewed and discussed all of the clinical, pharmacokinetic, drug interaction and safety data relating to the new second generation triazole antifungal, voriconazole.   One major randomized, multicenter, comparative trial has found that voriconazole is superior to amphotericin B and other licensed antifungal therapy for the primary treatment of pulmonary aspergillus.  This trial also demonstrated favorable results in the treatment of disseminated aspergillus, but the number of patients was much smaller. 1 Another noncomparative trial showed favorable results for voriconazole in the treatment of all aspergillus infections as primary or salvage therapy.2   Lastly, voriconazole has been shown to be effective in the treatment of infections due to Fusarium spp. and Scedosporium apiospermum. In addition to the clinical data, there are several issues regarding use of voriconazole in patients with renal impairment and in populations of patients likely to be on other medications that interact with this agent.3 Due to a lack of data supporting this indication, voriconazole is only recommended in the management of febrile neutropenia in specific clinical settings.4 After reviewing all of this data, the following recommendations are made for the safe and appropriate use of voriconazole.

Oral voriconazole is approximately 96% bioavailable.  For this reason, it is recommended that oral voriconazole be used whenever possible.

Indications for using voriconazole:

1.  Primary treatment of pulmonary aspergillus

2.  Primary treatment of amphotericin B and fluconazole resistant fungal infections (including Fusarium spp. and Scedosporium

     apiospermum - asexual form of Pseudoallescheria boydii )

3.  Treatment of invasive fungal infections in patients who are intolerant of, or refractory to, other antifungal therapy

4.  Empirical therapy of neutropenic fever in patients receiving concomitant nephrotoxins (cyclosporin, tacrolimus).

5.  Prophylaxis in high risk patients undergoing mini MUD transplants, mini allogeneic BMTs, allogeneic BMTs, or patients with

     severe graft versus host disease (GVHD).

Intolerance to conventional amphotericin B (CAB) is defined as:

1.   Renal Insufficiency:

§        If baseline SCr < 1.2 mg% on CAB, switch to oral voriconazole when SCr increases to > 2.5 mg%

§        If baseline SCr > 1.2 mg% on CAB, switch to oral voriconazole when SCr doubles or

§        If estimated CrCl < 30 ml/min on CAB, switch to oral voriconazole

      BMT and SOT with baseline SCr > 2.5 mg% or estimated CrCl < 30 ml/min may receive oral voriconazole without a trial

      of CAB.

      In all other patients with baseline SCr > 2.5 mg% and estimated CrCl < 30 ml/min, a trial of CAB should be attempted.

      If there is a 20% increase in SCr on CAB, the patient may be switched to oral voriconazole.  (Note that the day to day

     variation of the laboratory assay for serum creatinine can be as much as 10%)

      Patients with ESRD on chronic PD or HD will receive CAB.

2.  Infusion-related toxicity secondary to CAB:

§        anaphylactoid reaction, including hypoxia and hypotension

§        rigors that are refractory to 3 days of Meperidine or the patient is unable to receive Meperidine

3.  Severe electrolyte abnormalities secondary to CAB:

§        hypokalemia, hypomagnesemia, hypophosphatemia refractory to supplementation

 

 

 

 

Voriconazole Dosing:

 

Intravenous

Oral

Patients > 40 kg

Patients < 40 kg

Loading Dose

6 mg/kg q12h x 2 doses

400 mg q12h x 2 doses

200 mg q12h x 2 doses

Maintenance Dose

4 mg/kg q12h

200 mg q12h

100 mg q12h

§         Patients receiving voriconazole 4 mg/kg IV q12h should be switched to 200 mg PO q12h when tolerating oral medications.

§         Patients receiving voriconazole 200 mg PO q12h may be increased to 300 mg q12h if response to therapy is inadequate

Renal Insufficiency and Voriconazole Use

The intravenous preparation of voriconazole is solubilized in sulfobutylether-β-cyclodextrin (SBECD).  SBECD is cleared by the kidney (clearance approximates GFR).  Therefore, it will accumulate in patients with renal insufficiency.  There is very limited animal toxicology data regarding the accumulation of SBECD in the bloodstream.  There is also very limited data regarding safety of accumulation of SBECD in patients with renal insufficiency or in patients receiving any form of dialysis (HD, CVVH(D), PD).  Therefore, use of intravenous voriconazole is NOT RECOMMENDED for:

§        patients with CrCL < 50 ml/min

§        patients receiving any form of dialysis (HD, CVVH(D), PD)

These patients should be treated with oral voriconazole. If oral dosing is not possible, another antifungal agent should be considered.

Hepatic Insufficiency and Voriconazole Use

Voriconazole has been studied in patients with mild to moderate hepatic impairment (Child-Pugh Class A and B).  In these patients, it is recommended to give the standard loading dose followed by half the normal maintenance dose.  Voriconazole was not studied in patients with severe hepatic impairment (Child-Pugh Class C).

Drug Interactions and Voriconazole Use

1.  The following agents are CONTRAINDICATED with voriconazole:

      terfenadine                      pimozide                rifampin                  long-acting barbiturates

      astemizole                        quinidine              rifabutin                 ergot alkaloids

      cisapride                          sirolimus                carbamazepine    

2.  Phenytoin induces the hepatic clearance of voriconazole.  It is recommended to increase the voriconazole dose to 5 mg/kg IV q12h

     or double the oral maintenance dose (400 mg po BID) and monitor phenytoin plasma levels.

3.  Voriconazole inhibits the metabolism of the following agents and the following dose reductions are recommended.

      Drug                                Recommendation

       tacrolimus                       reduce tacrolimus dose to one-third and monitor drug levels

       cyclosporine                  reduce cyclosporine dose to one half and monitor drug levels

       omeprazole*                   reduce omeprazole dose to one half and monitor drug levels

       *lansoprazole is a substrate of cytochrome-P450 isoenzymes 3A4 and 2C19, however, no in vitro or clinical data is available

       regarding dose adjustment

4.  The following agents may require dose reductions when used concomitantly with voriconazole because of the potential for

     interaction:

      statins                            benzodiazepines                                vinca alkaloidsŦ                       HIV Protease Inhibitors (other than indinavir)

      sulfonylureasŦ                warfarin*                              calcium channel blockers                              

     † In vitro data suggest a clinical interaction

     Ŧ Interaction suggested by pharmacokinetics of these drugs, but they have not been studied

     * This interaction has been clinically studied

References:

1.  Herbrecht R, Denning DW, Patterson TF, et.al.  Voriconazole versus amphotericin b for primary treatment of invasive aspergillosis. New England Journal of  Medicine  2002;347(6): 408-15.

2.  Denning DW, Ribaud P, Milpied N, et.al.  Efficacy and safety of voriconazole in the treatment of acute invasive aspergillosis.  Clinical Infectious Diseases  2002;34: 563-71.

3.  Voriconazole package insert, 2002 and Voriconazole FDA Docket

4.  Walsh TJ, Pappas P, Winston DJ, et.al. Voriconazole compared with liposomal amphotericin b for empirical antifungal therapy in patients with neutropenia and persistent fever.  New England Journal of Medicine.  2002;34(6): 225-34.