European Medicines Agency London, 4 December 2006 Product Name: POSACONAZOLE SP Procedure number: EMEA/H/C/611/II/01 authorised SCIENTIFIC DISCUSSION longer no product Medicinal 7 Westferry Circus, Canary Wharf, London, E14 4HB, UK Tel. (44-20) 74 18 84 00 Fax (44-20) 74 18 86 68 E-mail: [email protected] http://www.emea.europa.eu 1 Introduction Fungal infections are a major cause of morbidity and mortality in immunocompromised patients. Filamentous mould and yeast-like fungi are ubiquitous organisms found worldwide in many different media. The Candida species are the most common cause of fungal infections. However, epidemiologic shifts have begun to occur, most likely due to the prophylactic and empiric use of antifungal agents. Emerging fungal pathogens, such as Aspergillus, Fusarium, and Zygomycetes, are changing the clinical spectrum of fungal diagnoses. Pathogens General risk factors for invasive fungal infections are exposure to pathogens, an impaired immune system, and fungal spores. The presence of a colonised environment, partnered with a disruption in a physiologic barrier, potentiates the risk of an invasive fungal infection in an immunologically impaired host, such as a patient infected with HIV, someone taking chronic systemic steroids, or a transplant recipient. In addition, contaminated implanted devices (e.g., catheters, prostheses), external devices (e.g., contact lenses), and community reservoirs (e.g., hand lotion, pepper shakers) have all been implicated as sources of fungal outbreaks. Candida albicans continues to be the most frequent cause of invasive fungal infections in most patient populations. However, prophylaxis and the widespread use of antifungal agents as empiric therapy for neutropenic fever have led to a shift in the epidemiology of invasive Candida infections. Infections with species other than C. albicans (Candida glabrata, Candida parapsilosisauthorised, Candida tropicalis, Candida krusei, and Candida lusitaniae) are becoming more prevalent. Due to susceptibility variations between species, species identification and susceptibility testing have become important tools. The second most common fungal pathogen to cause invasive fungal disease is Aspergillus. Found worldwide, Aspergillus is able to thrive in almost every environment. The organism is found primarily in soil but is also commonly isolated from water, food,longer and air. The usual route of infection for invasive aspergillosis is via inhalation of conidia (asexual spores). As a result, the lung is the most common location of invasive infection. The sinuses, central nervous system, and skin are also areas that can become infected. Clinically, the most commonno species to cause infection are Aspergillus fumigatus, Aspergillus flavus, Aspergillus terreus, and Aspergillus niger. Despite the availability of antifungal agents to treat infections caused by Aspergillus, the morbidity and mortality of invasive aspergillosis remains high. Antifungal Therapy Diagnosing invasive fungal infections early, reliably, and definitively continues to be a major challenge to practitioners. product Systemic fungal infections lead to considerable morbidity and mortality in patients with suppressed immune systems, such as HIV, cancer and transplant patients. While the increasing size of such population groups has driven the need for effective treatments and prophylaxis, the advent of HAART and associated declining incidence among HIV patients has limited market growth. Posaconazole is a triazole antimycotic agent, currently indicated for a range of invasive fungal infections in adults, including invasive aspergillosis in patients with disease that is refractory to amphotericinMedicinal B or itraconazole or in patients who are intolerant of these medicinal products. The centralised licence was approved in October 2005. Up to now fluconazole is the only validated oral therapy in prophylaxis indication. Fluconazole is more reliably absorbed and probably less toxic overall. However, its poor activity on Aspergillus is a significant limitation of this therapeutic option. The proposed new indication for posaconazole assessed in this report is the prophylaxis of invasive fungal infections in high-risk patients. PosaconazoleSPl-H-611-II-01 2/23 2 Non Clinical aspects No new non clinical data have been submitted in support to the request of this extension of indication 3 Clinical aspects The 2 pivotal efficacy studies submitted are Study C/ I98-316 and Study P01899 Study C/I98-316 (study 316 in this report) was in patients with graft versus host disease following allogeneic stem-cell transplant, treated with high-dose immunosuppressive therapy, and study P01899 (study 1899 in this report) involved patients undergoing chemotherapy for acute leukemia or myelodysplastic syndromes. Study 316 Design The study 316 was a multi-centre, randomised, double-blind, double dummy, parallel-group, active comparator-controlled study. The objective of the study was to evaluate the safety and efficacy of posaconazoleauthorised oral suspension vs Fluconazole in the Prophylaxis of Invasive Fungal Infections in High-Risk Recipients of Allogeneic Progenitor Cell Transplantation With Graft-Versus-Host Disease (GVHD). The patients included had Grade 2 to 4 acute graft-versus-host disease (GVHD) or extensive chronic GVHD, with intensive immunosuppressive therapy for at least 2 weeks after enrolment. This study was first designed as a two stages study (firstlonger for equivalence then for superiority if equivalence is demonstrated. Further to a specific amendment after the interim analysis of the data obtained the equivalence was changed to a non-inferiority demonstration. no The posaconazole dose was 600 mg daily (200 mg or 5 mL of 40 mg/ml suspension, administered three times daily), taken orally with food. The comparator was fluconazole only, 400 mg daily (100 mg capsules, 4 capsules), taken orally once daily at the same time, preferably in the morning. As a capsule was being compared against a suspension, a double-dummy design was used to enable blinding. The duration of therapy was product16 weeks, or until an (Invasive Fungal Infection) IFI was suspected or diagnosed. The use of empiric systemic antifungal therapy was prohibited by the study protocol except for the use of one short (<5 days) empiric course, and one short (<5 days) course during a period of study drug interruption (either due to an inability to take oral medication or due to an AE). Primary Endpoint IncidenceMedicinal rate of DRC-adjudicated proven or probable1 IFI within the time period from randomisation to 16 weeks after the start of treatment or 112 days from randomization if study drug was never taken. The IFI status of the subject was determined by the Data Review Committee (DRC) based on the European Organization for Research and Treatment of Cancer Mycoses study group (EORTC-MSG) criteria. 1 proven, probable and possible IFI definitions; see: Clinical Infectious Diseases, 2002, 34: p7-14 PosaconazoleSPl-H-611-II-01 3/23 Secondary Endpoint The clinical outcome was treatment success versus failure where a clinical failure was defined as the presence of a proven or probable IFI or more than 5 consecutive days of empiric treatment with an antifungal other than POS within 16 weeks of start of treatment. The secondary efficacy parameters were also to be summarized by treatment group (Incidence rate of DRC adjudicated proven, probable, or possible IFI according to the EORTC-MSG criteria, Time to first diagnosis of IFI, Incidence rate of IFI during the follow-up period, Incidence of fungal-related mortality during the study period, All cause mortality during the study period, Performance status (ECOG score) by visit and by treatment group, Grading of GVHD and steroids requirements, Use of empiric systemic antifungal therapy, Incidence of a fungal colonization, Incidence rate of mucocutaneous or superficial fungal infections, Incidence of proven or probable IFI within the time period from randomization to the end of treatment, defined as the time of the last dose of study drug plus 7 days). Study 1899 Design The study 1899 was an open label with evaluator blinding multi-centre, randomised, parallel-group, active comparator-controlled study. authorised The objective of the study was to evaluate the safety and efficacy of posaconazole oral suspension (POS) compared with fluconazole (FLU) or itraconazole (ITZ) in the prevention of invasive fungal infections (IFI) in subjects with prolonged neutropenia due to remission-induction chemotherapy for acute myelogenous leukemia or myelodysplastic syndromes. longer This study was designed to show statistical equivalence (non-inferiority) or superiority between POS and the standard azole (FLU/ITZ) reference arm. no The duration of therapy was until complete remission of neutropenia, or until other protocol-specified endpoints were reached, for up to a maximum of 12 weeks. All subjects had routine evaluations for the presence of fungal infection at baseline and during the study, this included screening questions, physical examination, Aspergillus antigen testing, and fungal blood cultures/ PCR every 2 weeks, with other investigations as clinically necessary. At any time during the study, if a subject productdeveloped a fever, or any other sign or symptom of infection, a complete evaluation was performed. Primary endpoint As primary endpoint was defined the incidence of proven or probable IFI from randomization to the end of the Oral Treatment Phase, defined as the period