Pharmacology Update
Posaconazole Oral Suspension (Noxafil®)
By William T. Elliott, MD, FACP, and James Chan, PhD, PharmD, Dr. Elliott is Chair, Formulary Committee, Northern California Kaiser Permanente; Assistant Clinical Professor of Medicine, University of California, San Francisco; Dr. Chan is Pharmacy Quality and Outcomes Manager, Kaiser Permanente, Oakland, CA. Drs. Chan and Elliott report no financial relationships to this field of study.
The FDA has approved a new antifungal agent for the prevention of Aspergillus and Candida infections in at-risk individuals. Posaconazole is an oral triazole, broad spectrum, antifungal chemically similar to itraconazole. It is marketed by the Schering Corporation as Noxafil®.
Indications
Posaconazole is indicated for prophylaxis of invasive Aspergillus and Candida infection in patients (13 years or older) who are at high risk of developing these infections. These include severely immunocompromised patients such as hematopoietic stem cell transplant (HSCT) recipients with graft-versus-host disease (GVHD) or those with hematologic malignancies with prolonged neutropenia from chemotherapy.1
Dosage
The recommended dose is 200 mg (5 mL) three times a day with a full meal or with a liquid nutritional supplement for those who cannot eat a full meal. The duration of therapy is based on recovery from neutropenia or immunosuppression.1
Posaconazole as Noxafil is available as a 4-ounce suspension with each mL containing 40 mg of posaconazole.
Potential Advantages
Posaconazole is the most active among the triazoles against Candida species and filamentous fungi (eg, Aspergillus species, Zygomycetes) including isolates resistant to other triazoles.2,3 Clinical efficacy has been demonstrated in patients who are refractory or resistant to other antifungals.4,5 It may be less susceptible than fluconazole or voriconazole to mutations of CYP51, the target enzyme for antifungal activity.4 In vitro data suggest synergy with caspofungin against Aspergillus species.4 Posaconazole is not metabolized significantly by the cytochrome P450 enzyme system and does not inhibit these isoenzymes except for CYP3A4.4,5
Potential Disadvantages
Patients with severe diarrhea or vomiting should be monitored for breakthrough fungal infection.1 Coadministration of posaconazole and rifabutin, phenytoin, ergot derivatives, quinidine, and cimetidine should be avoided. Liver functions should be monitored at the start, and during the course of therapy. The dose of midazolam, cyclosporine, tacrolimus, and sirolimus should be reduced and patients monitored if posaconazole is initiated.1 Common adverse events associated with posaconazole are similar to those of fluconazole or itraconazole. Common adverse events include nausea (9%), vomiting (6%), abdominal pain (5%), headache, diarrhea, rash, and elevation of ALT or AST (each 3%). Serious adverse events include nephrotoxicity, adrenal insufficiency and prolongation of QTc.4 Resistant isolates of Candida species have been reported.1 Posaconazole is not available in a parenteral form.
Comments
Posaconazole is a new triazole antifungal agent that is highly active against a broad spectrum of fungi. Posaconazole (200 mg three times a day) is at least as effective as fluconazole (400 mg once daily) or itraconazole (200 mg twice daily) for the prophylaxis of invasive fungal infections in patients who are receiving chemotherapy for acute myelogenous leukemia or myelodysplastic syndrome or those with HSCT with GVHD.1 In one study (n = 602), treatment failure (breakthrough invasive fungal infection, death, or systemic antifungal therapy) was 27% for posaconazole and 42% for fluconazole/itraconazole. All cause mortality at 100 days was in favor of posaconazole, 14% vs 21%. In a second study (n = 600) proven or probable invasive fungal infection was 5% for posaconazole and 9% for fluconazole. All-cause mortality was 19% and 20% respectively.1 Posaconazole has shown effectiveness in patients who are intolerant of other agents or whose fungal infections are refractory to other antifungals as well as in salvage therapy and CNS infections.2,4 Posaconazole is generally well tolerated. The adverse reaction profile appears similar in those treated for less than 6 months or those treated for longer than 6 months.4 The cost of posaconazole suspension is $480 for 4 ounces.
Clinical Implications
Invasive mold infections, particularly Candida species and Aspergillus species are the major cause of morbidity and mortality in immunocompromised patients such as hematopoietic stem cell transplant recipients.6 Prophylaxis in high-risk individuals has been recommended and antifungal options include azoles, amphotericin, and caspofungin.7 Posaconazole provides an option with good in vitro antifungal activity including isolates resistant to other agents.
References
1. Noxafil Product Information. Schering Corporation. September 2006.
2. Torres HA, et al. Posaconazole: a broad-spectrum triazole antifungal. Lancet Infect Dis. 2005;5:775-785.
3. Sabatelli F, et al. In vitro activities of posaconazole, fluconazole, itraconazole, voriconazole, and amphotericin B against a large collection of clinically important molds and yeasts. Antimicrob Agents Chemother. 2006;50:2009-2015.
4. Keating GM. Posaconazole. Drugs. 2005;65:1553-1567.
5. Groll AH, Walsh TJ. Posaconazole: clinical pharmacology and potential for management of fungal infections. Expert Rev Anti Infect Ther. 2005;3:467-487.
6. Bhatti Z, et al. Review of epidemiology, diagnosis, and treatment of invasive mould infections in allogeneic hematopoietic stem cell transplant recipients. Mycopathologia. 2006;162:1-15.
7. Raman T, Marik PE. Fungal infections in bone marrow transplant recipients. Expert Opin Pharmacother. 2006;7:307-315.
The FDA has approved a new antifungal agent for the prevention of Aspergillus and Candida infections in at-risk individuals. Posaconazole is an oral triazole, broad spectrum, antifungal chemically similar to itraconazole.You have reached your article limit for the month. Subscribe now to access this article plus other member-only content.
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