Healthcare Industry News:  myelodysplastic syndromes 

Biopharmaceuticals Regulatory

 News Release - November 9, 2006

Noxafil(R) (Posaconazole) Oral Suspension Approved in European Union for Prevention of Invasive Fungal Infections

Treatment of Oropharyngeal Candidiasis (OPC) Also Approved

KENILWORTH, N.J., Nov. 9 (HSMN NewsFeed) -- Schering-Plough Corporation (NYSE: SGP ) today announced that the European Commission has granted marketing approval to NOXAFILŽ (posaconazole) Oral Suspension for prophylaxis (prevention) of invasive fungal infections (IFIs) in the following patients at high risk of developing these infections: patients receiving remission-induction chemotherapy for acute myelogenous leukemia (AML) or myelodysplastic syndromes (MDS) expected to result in prolonged neutropenia and hematopoietic stem cell transplant (HSCT) recipients who are undergoing high-dose immunosuppressive therapy for graft versus host disease (GVHD).

Invasive fungal infections most often occur in people who are immunocompromised or immunosuppressed, and are a leading cause of death in these high-risk populations. Patients undergoing hematopoietic stem cell transplant or chemotherapy for hematological malignancies such as AML or MDS who develop IFIs have a high mortality rate ranging from 50-90 percent.(1)

"The approval of NOXAFIL for prophylaxis of invasive fungal infections in high-risk patients has the potential to change medical practice in this area," said Oliver Cornely, M.D., University of Cologne, Germany, and lead investigator of one of the pivotal clinical studies supporting the approval. "In patients with a compromised immune system, invasive fungal infections are very serious and can be difficult to treat once they've become established, so preventing these infections in the first place is critically important for these seriously ill patients."

The European Commission also approved NOXAFIL for oropharyngeal candidiasis (OPC) as first-line therapy in patients who have severe disease or are immunocompromised, in whom response to topical therapy is expected to be poor. OPC is a fungal infection of the mouth and throat.

The Commission approval of the prophylaxis and OPC indications for NOXAFIL results in Marketing Authorization with unified labeling that is valid in the current European Union (EU) 25 member states as well as in Iceland and Norway. NOXAFIL was previously approved in the 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.

"We are very pleased with the Commission's decision and the new therapeutic options it now brings for patients with these serious fungal infections," said Robert J. Spiegel, M.D., chief medical officer and senior vice president, Schering-Plough Research Institute. "With this approval, NOXAFIL is now approved in the European Union for both prophylaxis and treatment indications, broadening its utility to physicians as an important antifungal agent."

NOXAFIL Prophylaxis in High-Risk Patients

The EU approval of NOXAFIL for prophylaxis is based primarily on the results of two head-to-head randomized clinical studies, the largest prophylaxis studies to date conducted in these high-risk patient populations. A total of more than 1,200 patients were enrolled in these studies. In both prophylaxis studies, aspergillosis was the most common breakthrough infection. There were fewer breakthrough Aspergillus infections in patients receiving NOXAFIL prophylaxis when compared to control patients on standard azole therapy (fluconazole or itraconazole).

An open-label, evaluator-blinded study compared NOXAFIL Oral Suspension 200 mg three times daily (n=304) to 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 patients during the while-on-prophylaxis time period (randomization to last dose of study drug plus 7 days) and at 100 days post-randomization. The primary efficacy endpoint was the incidence of proven/probable IFIs as determined by an independent, blinded external expert panel during the while-on-prophylaxis time period. In this study, NOXAFIL demonstrated:

-- A reduction in proven and probable IFIs vs. fluconazole/itraconazole [7/304 (2 percent) vs. 25/298 (8 percent), p=0.0009].

-- A significant decrease in all cause mortality vs. fluconazole/itraconazole [49/304 (16 percent) vs. 67/298 (22 percent), p=0.048]. Based on Kaplan-Meier estimates, the survival time during the first 100 days after randomization was significantly higher for NOXAFIL; this survival benefit was demonstrated when the analysis considered all causes of death (p=0.0354) as well as IFI-related deaths (p=0.0209).

-- A reduction in proven and probable Aspergillus infections vs. fluconazole/itraconazole [2/304 (1 percent) vs. 20/298 (7 percent)].

-- A safety and tolerability profile comparable 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 primary efficacy endpoint, regardless of discontinuation of drug, was the incidence of proven/probable IFIs during the primary time period (112 days post-baseline), as determined by an independent, blinded external expert panel. The study also assessed patients during the while-on-prophylaxis time period (first dose to last dose of study drug plus 7 days). In this study, NOXAFIL demonstrated:

-- A reduction in proven/probable IFIs during the primary time period (112 days post-baseline) compared to fluconazole [16/301 (5 percent) vs. 27/299 (9 percent)].

-- Overall mortality similar to fluconazole (25 percent vs. 28 percent); however, the number of IFI-related deaths was significantly lower for NOXAFIL (4/301) compared to fluconazole (12/299) (p=0.0413).

-- A reduction in breakthrough Aspergillus infections during the primary time period (112 days post-baseline) compared to fluconazole [7/301 (2 percent) vs. 21/299 (7 percent)].

-- A safety and tolerability profile comparable to fluconazole.

NOXAFIL for OPC The EU approval of NOXAFIL for the treatment of OPC is based primarily on the results of a randomized, evaluator-blinded, controlled clinical study conducted in HIV-infected patients with azole-susceptible oropharyngeal candidiasis. The primary efficacy endpoint was the clinical success rate (defined as cure or improvement) after 14 days of treatment. This study compared NOXAFIL Oral Suspension (n=169) to fluconazole oral suspension (n=160), both given as 100 mg twice daily for one day followed by 100 mg once daily for 13 days.

In this study, NOXAFIL was shown to be non-inferior to fluconazole for clinical success rates at day 14 [155/169 (91.7 percent) vs. 148/160 (92.5 percent)] and at 4 weeks after the end of treatment [98/143 (68.5 percent) vs. 84/136 (61.8 percent)].

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 percent 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). Liver function tests (LFTs) should be monitored at the start of and during the course of therapy.

In clinical studies of patients with oropharyngeal candidiasis (OPC), including those with refractory OPC, adverse events were reported more frequently in the pool of patients with refractory oropharyngeal candidiasis. The most commonly reported serious adverse events included fever (13 percent) and neutropenia (10 percent).

NOXAFIL has been shown to interact with several medications, including drugs that suppress the immune system, and these reactions may be serious. The product label should be consulted when other drugs are prescribed with NOXAFIL.

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.

Serious and rare fatal toxicity from cyclosporine has occurred when taken in combination with NOXAFIL and therefore reduction of the dose of drugs like cyclosporine, tacrolimus or sirolimus and frequent monitoring of drug levels of these medications is necessary when taking them in combination with NOXAFIL. The safety and effectiveness of NOXAFIL for prophylaxis in patients below the age of 13 years old have not been established. In the EU, NOXAFIL is recommended for use in patients 18 years of age and older.

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., and its Web site is www.schering-plough.com.

SCHERING-PLOUGH DISCLOSURE NOTICE: The information in this press release includes certain "forward-looking statements" within the meaning of the Securities Litigation Reform Act of 1995, including statements related to NOXAFIL, its potential and the company's strategy. Forward-looking statements relate to expectations or forecasts of future events. Schering-Plough does not assume the obligation to update any forward-looking statement. Many factors could cause actual results to differ materially from Schering-Plough's forward-looking statements, including market forces, economic factors, product availability, patent and other intellectual property protection, current and future branded, generic or over-the-counter competition, the regulatory process, and any developments following regulatory approval, among other uncertainties. For further details about these and other factors that may impact the forward-looking statements, see Schering-Plough's Securities and Exchange Commission filings, including Item 1A. Risk Factors in the Company's second quarter 2006 10-Q.

Reference:

(1) Bow EJ, Laverdiere M, Lussier N, et al. Antifungal Prophylaxis for Severely Neutropenic Chemotherapy Recipients. Cancer 2002;94:3230-46.


Source: Schering-Plough

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