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FDA Approves Noxafil(R) (Posaconazole) for Prevention of Invasive Fungal Infections

Only Antifungal Agent Approved for Prevention of Aspergillus Infections

KENILWORTH, NJ -- September 18, 2006 -- Schering-Plough Corporation today reported that the U.S. Food and Drug Administration (FDA) has approved Noxafil(R) (posaconazole) Oral Suspension for prophylaxis (prevention) of invasive Aspergillus and Candida infections in patients 13 years of age and older who are at high risk of developing these infections due to being severely immunocompromised, such as hematopoietic stem cell transplant (HSCT) recipients with graft-versus-host disease (GVHD) or those with hematologic malignancies with prolonged neutropenia from chemotherapy.

Noxafil is the first and only antifungal agent approved by FDA for the prevention of invasive fungal infections (IFIs) caused by Aspergillus species.

Invasive fungal infections most often occur in people who are immunocompromised or immunosuppressed, and are increasingly caused by moulds such as Aspergillus. IFIs are a leading cause of death in these high-risk populations. Patients undergoing hematopoietic stem cell transplant or chemotherapy for hematological malignancies such as acute myelogenous leukemia (AML) or myelodysplastic syndromes (MDS) who develop IFIs have a high mortality rate of 60-90%.(1)

The Noxafil approval is based on results of two head-to-head randomized clinical studies, the largest prophylaxis studies conducted to date in these high-risk patient populations. A total of more than 1,200 patients were enrolled in these studies, which demonstrated substantially fewer breakthrough Aspergillus infections in these patients. In high-risk neutropenic patients, prophylaxis with Noxafil was associated with decreased all cause mortality versus the comparator drugs.

"Noxafil can help prevent patients from developing life-threatening invasive fungal infections while being treated for serious conditions, such as acute leukemia or graft-versus-host disease," said John Perfect, MD, Professor, Department of Medicine, Division of Infectious Diseases, and Director, Duke University Mycology Research Unit. "With this FDA approval, Noxafil offers physicians an important new therapeutic option for preventing invasive fungal infections in patients at high risk," he said.

"We are very pleased with today's FDA action and what it means for critically ill patients who are at high-risk for acquiring these fungal infections," said Robert J. Spiegel, MD, chief medical officer and senior vice president, Schering-Plough Research Institute. "The approval of Noxafil, a product discovered and developed by Schering-Plough, reinforces our ongoing commitment to improving treatment options for patients facing life-threatening diseases."

Noxafil Prophylaxis Studies
Two large, randomized, controlled head-to-head clinical studies were conducted using Noxafil as prophylaxis for the prevention of IFIs among patients at high risk because of severely compromised immune systems.

An open-label study compared Noxafil Oral Suspension 200 mg three times daily (n=304) to pooled standard azole therapies (fluconazole oral suspension 400 mg once daily or itraconazole oral solution 200 mg twice daily) (n=298) as prophylaxis against IFIs in neutropenic patients who were receiving cytotoxic chemotherapy for AML or MDS. The study assessed all patients while on therapy plus 7 days and at 100 days post-randomization. Efficacy of prophylaxis was evaluated using a composite endpoint of proven/probable IFIs, death or treatment with systemic antifungal therapy. Patients may have met more than one of these criteria. In this study, Noxafil demonstrated:

-- A reduction in treatment failure (as defined by breakthrough IFIs, death and use of systemic antifungal therapy) vs. the comparator group (pooled fluconazole/itraconazole) (27% vs. 42%) [95% CI -22.9% to -7.8%].

-- A reduction in proven and probable IFIs vs. fluconazole/itraconazole (2% vs. 8%).

-- A reduction in breakthrough Aspergillus infections vs. fluconazole/itraconazole (1% vs. 7%). Aspergillosis was the most common breakthrough infection seen in the study.

-- Decreased all cause mortality at 100 days post-randomization in favor of Noxafil compared to fluconazole or itraconazole (14% vs. 21%).

-- Comparable safety and tolerability to fluconazole.

A double-blind study compared Noxafil Oral Suspension 200 mg three times daily (n=301) to fluconazole capsules 400 mg once daily (n=299) as prophylaxis against IFIs in allogeneic hematopoietic stem cell transplant (HSCT) recipients with graft-versus-host disease (GVHD). The study assessed all patients while on therapy plus 7 days and at 16 weeks post-randomization. Efficacy of prophylaxis was evaluated using a composite endpoint of proven/probable IFIs, death or treatment with systemic antifungal therapy. Patients may have met more than one of these criteria. In this study, Noxafil demonstrated:

-- A reduction in proven/probable IFIs at 16 weeks compared to fluconazole (5% vs. 9%).

-- A reduction in breakthrough Aspergillus infections at 16 weeks compared to fluconazole (2% vs. 7%).

-- Decreased IFI-related mortality at 16 weeks in favor of Noxafil compared to fluconazole (3% vs. 5%).

-- Comparable safety and tolerability to fluconazole.

Noxafil Safety Information
Clinical studies have demonstrated that Noxafil Oral Suspension is generally safe and well tolerated. The most common treatment-related serious adverse events (1% each) in the combined prophylaxis studies were bilirubinemia, increased hepatic enzymes, hepatocellular damage, nausea and vomiting. In clinical trials, there were infrequent cases of hepatic reactions (e.g., mild to moderate elevations in ALT, AST, alkaline phosphatase, total bilirubin, and/or clinical hepatitis).

LFTs should be monitored at the start of and during the course of therapy. Co-administration with the CYP3A4 substrates terfenadine, astemizole, cisapride, pimozide, halofantrine or quinidine is contraindicated since this may result in increased plasma concentrations of these medicinal products, leading to QTc prolongation and rare occurrences of torsades de pointes. Co- administration with ergot alkaloids is also contraindicated.

Dose reduction and more frequent clinical monitoring of cyclosporine, tacrolimus and sirolimus should be performed when Noxafil therapy is initiated. The safety and effectiveness of Noxafil in patients below the age of 13 years old have not been established.

About Noxafil
Noxafil is a novel triazole antifungal agent discovered and developed by Schering-Plough Research Institute. Schering-Plough has filed a new drug application for Noxafil prophylaxis with the European Medicines Agency (EMEA), and this application is currently under review. Noxafil is approved in the European Union (EU) and Australia for the treatment of certain IFIs in adult patients with disease that is refractory to or in patients who are intolerant of certain commonly used antifungal agents.

In the United States, a new drug application for Noxafil for treatment of certain refractory IFIs received an approvable letter from FDA in June 2005 and is pending review of additional data. Schering-Plough also is seeking U.S. and EU marketing approval of Noxafil for the treatment of oropharyngeal candidiasis (OPC). These applications are currently under regulatory review. OPC is a fungal infection of the mouth and throat caused by the yeast Candida and is often referred to informally as thrush.

Schering-Plough is a global science-based health care company with leading prescription, consumer and animal health products. Through internal research and collaborations with partners, Schering-Plough discovers, develops, manufactures and markets advanced drug therapies to meet important medical needs. Schering-Plough's vision is to earn the trust of the physicians, patients and customers served by its more than 32,000 people around the world. The company is based in Kenilworth, N.J.

REFERENCE:
1. Hagen EA, Stern H, Porter D, et al. High rate of invasive fungal infections following nonmyeloablative allogeneic transplantation. Clin Infect Dis. 2003;36:9-15.


SOURCE: Schering-Plough Corporation

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