Using voriconazole in patients

September 2002

Antifungal therapy is in a renaissance period after decades of research resulting in not only the first approval of an entirely new drug class (the echinocandins), but also synthesis of new chemical moieties of a familiar antifungal class, the azoles. Newer azoles being investigated are effective for treatment of disseminated fungal infections that are frequently eradicated only with amphotericin B. Voriconazole (Vfend, Pfizer) is a triazole antifungal that was recently approved for the treatment of invasive aspergillosis and the infrequently encountered Pseudallescheria boydii (Scedosporium apiospermum) and Fusarium spp. (including F. solani) in patients intolerant or refractory to other therapies.

The azoles inhibit fungal membrane synthesis by irreversible binding to cytochrome P450-dependent enzyme 14-a-sterol demethylase. This results in accumulation of ergosterol precursors in fungal cell membranes and inhibition of growth. Voriconazole is structurally similar to fluconazole (Diflucan, Pfizer) yet behaves in vivo more similarly to itraconazole due to it’s high lipophillicity. Voriconazole exhibits non-linear pharmacokinetics (metabolism becomes saturated), which increases the potential for drug interactions involving the hepatic metabolism of concomitant medications.

Antifungal activity

Fluconazole is ineffective in the treatment of Aspergillus spp. and has limited activity against Candida krusei and C. glabrata. Itraconazole (a systemic azole) has additional antifungal activity against invasive fungal infections including aspergillosis. Its use, however, is hindered by unpredictable bioavailability and extensive drug interactions. In contrast, voriconazole is fungicidal against all known pathogenic species of Aspergillus and is fungistatic against Candida spp. However, only a small amount of voriconazole is excreted unchanged in the urine making its use in the treatment of candidal urinary tract infections unlikely.

Table 1 lists in vitro MIC data of voriconazole, fluconazole and amphotericin B. Although the relationship between clinical outcome and in vitro MIC values remains to be elucidated for fungal infections, these values are useful for comparative and predictive purposes. In vitro MIC data reveal voriconazole activity against Aspergillus spp. comparable to itraconazole and amphotericin B.

Source: Sabo JA, Abdel-Rahman SM. Voriconazole: a new triazole antifungal.
Ann Pharmacother 2000;34:1032-43.

Efficacy

Clinical evidence from two global comparative aspergillosis trials with identical patient populations, treatments and assessments was presented to gain FDA approval. Immunocompromised males (n5392) with documented radiologic, mycologic, and clinical signs and symptoms consistent with invasive aspergillosis were enrolled. Over 80% of patients in each treatment group had pulmonary disease with immunosupression following bone marrow/peripheral stem cell transplant or another hematologic malignancy. Initially, 185 patients were randomized to therapy with conventional amphotericin B, 1-1.5 mg/kg/day for a median of 12 days. Intravenous voriconazole was administered to 196 patients with an optional switch to the oral formulation after at least seven days of intravenous therapy. Amphotericin B patients may have been switched to other licensed antifungal therapy (OLAT) including itraconazole or lipid amphotericin formulation at any point between days 2 and 12 of amphotericin B therapy. A blinded review committee assessed the certainty of infection at baseline and response after 12 weeks. Overall survival was assessed after 12 weeks from initial randomization. At the time of analysis, 133 patients in the amphotericin B and 144 patients in the voriconazole treatment groups were evaluated for success and survival.

Treatment success (complete or partial resolution of symptoms, signs and radiographic/bronchoscopic abnormalities) after 12 weeks for voriconazole and amphotericin B were 53% and 32%, respectively (P<0.0001). Survival rates at week 12 were 71% with voriconazole and 58% with amphotericin B (CI=2.1%, 24.2%, no P value was reported). Notably, visual disturbances (abnormal vision, photophobia or chromatopsia) were reported in 64 of 196 (32%) of voriconazole treated patients.

Significant differences in outcome attributable to therapy following randomization were demonstrated. Median duration of voriconazole treatment was 76 days vs. 12 days of conventional amphotericin B. The most common reasons for switching from amphotericin B to OLAT were failure to respond or drug intolerability. Patients continuing therapy with OLAT in either treatment group may have received a lipid formulation of the amphotericin B or oral itraconazole. Information regarding OLAT, including specific drugs used, adequacy of dosing and subsequent clinical response, is not available. These concerns should be addressed when these data are peer-reviewed for publication.

A pooled analysis of treatment with voriconazole in 15 patients with invasive or disseminated Fusarium and 27 patients with S. apiospermum was considered when voriconazole was reviewed by the FDA. Based on success rates in these less commonly encountered infections, it was granted approval for treatment in patients intolerant or refractory to other antifungal therapies.

Dosing and safety

Vfend is supplied in 50-mg and 200-mg tablets and as a vial containing 200-mg lyophilized powder for reconstitution and IV infusion. Oral voriconazole therapy in adults >40 kg is initiated as a 400-mg loading dose every 12 hours for one day, followed by a 200-mg twice daily maintenance dose. Adults <40 kg should receive 50% of this dose. Voriconazole should be taken on an empty stomach (one hour before or one hour after a meal) to maximize absorption, and neither proton-pump inhibitors or histamine-2 receptor antagonists significantly alter absorption. If oral therapy is not tolerated, patients may receive an IV loading dose of 6 mg/kg every 12 hours for two doses followed by maintenance regimen of 4 mg/kg administered every 12 hours. However, oral therapy should ensue as early as possible to avoid accumulation of the IV exipient sulphobutylether-ß-cyclodextrin (SBECD), which is nephrotoxic.

The pharmacokinetics of oral voriconazole are not significantly altered in patients with renal insufficiency. However, accumulation of SBECD can occur in patients with creatinine clearance of <50 ml/min. It is recommended that patients with renal insufficiency receive only oral voriconazole.

Reported treatment-related adverse events during voriconazole therapy include elevated hepatic transaminases, rash and visual disturbances. Visual disturbances have been described as an increased sensitivity or altered perception of light, blurred vision, color changes or photophobia. They frequently occur within one hour of dosing, last for less than one hour and may be associated with higher plasma concentrations. The mechanism of this adverse effect is not known. Monitoring of visual function using a retinogram may be warranted if treatment continues beyond 28 days. Patients should not to drive at night while taking voriconazole and should avoid strong and direct sunlight. Postmarketing surveillance and clinician reporting of adverse drug reactions will be extremely important for describing the frequency of this side effect in clinical practice.

Source: Voriconazole Package Insert: 2002 Pfizer Inc.

Voriconazole is associated with an overall incidence of clinically significant transaminase abnormalities of 13%. Liver function tests and bilirubin should be evaluated at baseline and during therapy. Patients with severe hepatic cirrhosis or chronic hepatitis B or C have not been studied. Patients with mild to moderate hepatic cirrhosis can receive the standard loading dose but should receive 50 % of the recommended maintenance dose.

Voriconazole is both a substrate and an inhibitor of the cytochrome P450 enzyme system. Consequently, multiple drug interactions exist, and many are not yet adequately described in vivo. Signature drugs associated with QT prolongation (ie, pimozide and quinidine) should never be administered with voriconazole. Coadministration of sirolimus, rifampin, long-acting barbiturates, carbamazepine or the ergot alkaloids (ergotamine and dihydroergotamine) is contraindicated. HIV patients treated with non-nucleoside reverse transcriptase inhibitors (NNRTI) should be monitored for toxicity and efficacy of voriconazole. NNRTIs are both inducers and inhibitors of the cytochrome P450 enzyme system, and voriconazole can potentially inhibit the metabolism of NNRTIs. In vivo studies of voriconazole coadministration with indinavir did not significantly affect plasma levels of voriconazole, yet the potential for cytochrome P450 inhibition is significant with protease inhibitors. (See the Table 1, “Available voriconazole in vivo drug interaction data,” for additional drug contraindications and recommendations).

As with all newly approved FDA products, increased patient monitoring during maintenance therapy of voriconazole is recommended with strict adherence to the warnings and precautions specified in the package insert. Once additional postmarketing surveillance data is available regarding long-term ocular effects and increased experience in patients with hepatic dysfunction, voriconazole may have potential for expanding its indication for empiric use in febrile neutropenic patient populations, refractory mucosal candidiasis in AIDS patients and serious non-albicans Candida infections.