London New Drugs Group APC/DTC Briefing

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1 London New Drugs Group APC/DTC Briefing Posaconazole for invasive fungal infections Contents Background 2 Dosing Information 3 Clinical evidence for treatment of infections 3 Clinical evidence for prophyactic use of posaconazole 5 Costing 9 Safety 10 Conclusion 10 Points for consideration 10 References 11 Produced for the London New Drugs Group Contact: Hina Radia Medicines Information Pharmacist London & South East Medicines Information Service Guy s Hospital London SE1 9RT Tel: hina.radia@gstt.nhs.uk Further copies of this document are available from URL product.aspx?id=9 Produced for use within the NHS. Not to be reproduced for commercial purposes Summary Posaconazole is licensed for the treatment of the following invasive fungal infections in patients who are intolerant of, or whose infection is refractory to other antifungal agents: invasive aspergillosis, fusariosis, chromoblastomycosis and mycetoma, coccidioidomycosis and oral candidiasis. Evidence for the use of posaconazole for the treatment of invasive fungal infections is limited to small uncontrolled descriptive analyses and one small controlled comparative study. Posaconazole is also licensed for the prophylaxis of invasive fungal infections in: patients receiving remission-induction chemotherapy for acute myelogenous leukaemia (AML) or myelodysplastic syndromes (MDS) expected to result in prolonged neutropenia and who are at high risk of developing invasive fungal infections, and, haematopoietic stem cell transplant (HSCT) recipients who are undergoing high-dose immunosuppressive therapy for graft-versus-host disease (GvHD) and who are at high risk of developing invasive fungal infections. Evidence for the prophylactic use of posaconazole is based on two large randomised controlled phase III studies. One phase III study investigating the prophylactic use of posaconazole in patients undergoing remission-induction chemotherapy showed that proven or probable invasive fungal infections occurred during the treatment phase in 7 (2%) patients on posaconazole and 25 (8%) patients in the fluconazole/ itraconazole group (absolute reduction -6%, 95% CI -9.7 to -2.5; p<0.0001), suggesting that 16 patients would need to be treated with posaconazole as compared to fluconazole or itraconazole in order to prevent one invasive fungal infection. Additionally, the estimated number needed to treat with posaconazole, as compared to fluconazole or itraconazole, to prevent one death was 14 patients. The second phase III study investigating the prophylactic use of posaconazole in allogeneic haematopoietic stem-cell transplant recipients with graft-versus-host disease (GVHD) showed that the incidence of invasive fungal infections was 5.3% for the posaconazole group and 9% in the fluconazole group (odds ratio for invasive fungal infection in the posaconazole group, 0.56; 95% CI 0.30 to 1.07). This suggests that 27 patients would need to be treated with posaconazole as compared to fluconazole in order to prevent one invasive fungal infection. The Scottish Medicines Consortium has advised that posaconazole is accepted for use within NHS Scotland for the treatment of adults with specific invasive fungal infections refractory to, or intolerant of, specified antifungal agents. For the prophylaxis of invasive fungal infections in immunocompromised patients, the Scottish Medicines Consortium has restricted the use of posaconazole to patients in whom there is a specific risk of aspergillus infection or where fluconazole or itraconazole are not tolerated. The British Committee for Standards in Haematology, in their guidelines on the management of fungal infection during therapy for haematological malignancies, state that prophylaxis of invasive fungal infections should be confined to high risk patients, and the drugs of choice are itraconazole which has clinically significant but manageable or avoidable interactions with other drugs and posaconazole which has not yet been shown to be superior in efficacy to itraconazole.

2 However, both are superior in efficacy to fluconazole. European provisional guidelines for the use of primary antifungal chemoprophylaxis (based on the European Conference on Infections in Leukaemia (ECIL) comprising of the European Blood and Marrow Transplantation Group, European Organisation for Treatment and Research of Cancer, and the European Leukaemia Net and Immunocompromised Host Society) state that provisional A1 recommendations should be implemented for the use of posaconazole 200mg three times a day during induction chemotherapy for AML/MDS and during intensive immunosuppressive therapy for acute and chronic GvHD following allogeneic haematopoietic stem cell transplantation. Published American guidelines state that for prophylaxis against invasive aspergillosis, posaconazole can be recommended in HSCT recipients with GVHD and in patients with acute myelogenous leukaemia or myelodysplastic syndrome who are at high risk for invasive aspergillosis (A1 recommendation). Adverse effect data from the two largest studies investigating prophylactic use of posaconazole showed the following effects occurred more frequently in the posaconazole group: bilirubinaemia (2-3%), liver function test abnormalities (1-3%), liver failure (< 1%), hepatitis (<1%), jaundice (<1%), diarrhoea (<1% to 3%), vomiting (4%), nausea (7%), atrial fibrillation (<1%), syncope (1%), decreased ejection fraction (<1%), QT or QTc prolongation (<1%), and Torsades de pointes (<1%). The cost of treating severe invasive fungal infections with posaconazole for one month is 3004, which is less than the cost of intravenous caspofungin ( 9264) or intravenous liposomal amphotericin ( 5415), but more expensive than the use of oral fluconazole ( 531), itraconazole ( 389) or voriconazole ( 2205). The cost of using posaconazole for 1 month for the prevention of fungal infections is 2003, which is more expensive than itraconazole ( 340) or fluconazole ( 531). Background Posaconazole is a triazole antifungal which inhibits ergosterol production by binding and inhibiting the lanosterol-14 alfa-demethylase which is present in most fungi except Pneumocystis and Pythium. Ergosterol depletion coupled with the accumulation of methylated sterol precursors results in the inhibition of fungal cell growth, fungal cell death, or both. Posaconazole has been shown in vitro to be active against the following microorganisms: Aspergillus species (Aspergillus fumigatus, A. flavus, A. terreus, A. nidulans, A. niger, A. ustus), Candida species (Candida albicans, C. glabrata, C. krusei, C. parapsilosis, C. tropicalis, C. dubliniensis, C. famata, C. inconspicua, C. lipolytica, C. norvegensis, C. pseudotropicalis), Coccidioides immitis, Fonsecaea pedrosoi, and species of Fusarium, Rhizomucor, Mucor, and Rhizopus.(1) Administering posaconazole in divided doses increases its bioavailability; the relative bioavailability of posaconazole given at a single dose of 800mg increases by 98% when the total dose is given in 2 divided doses, and by 220% when the total dose is divided into four doses given 6 hours apart (2). Posaconazole is available as an oral suspension. Its absorption is also enhanced 2.6- fold to 4-fold by co-administration with food or nutritional supplements. (3) Posaconazole is licensed for use in the treatment of the following fungal infections in adults (1): Invasive aspergillosis in patients with disease that is refractory to amphotericin B or itraconazole or in patients who are intolerant of these medicinal products; Fusariosis in patients with disease that is refractory to amphotericin B or in patients who are intolerant of amphotericin B; Chromoblastomycosis and mycetoma in patients with disease that is refractory to itraconazole or in patients who are intolerant of itraconazole; Coccidioidomycosis in patients with disease that is refractory to amphotericin B, itraconazole or fluconazole or in patients who are intolerant of these medicinal products; Oropharyngeal candidiasis: as first-line therapy in patients who have severe disease or are immunocompromised, in whom response to topical therapy is expected to be poor. Refractoriness is defined as progression of infection or failure to improve after a minimum of 7 days of prior therapeutic doses of effective antifungal therapy.

3 Posaconazole is licensed for the prophylaxis of invasive fungal infections in the following patients (1): Patients receiving remission-induction chemotherapy for acute myelogenous leukaemia (AML) or myelodysplastic syndromes (MDS) expected to result in prolonged neutropenia and who are at high risk of developing invasive fungal infections; Haematopoietic stem cell transplant (HSCT) recipients who are undergoing high-dose immunosuppressive therapy for graft versus host disease and who are at high risk of developing invasive fungal infections. Patients with haematological malignancies often have a decreased integrity of host defence mechanisms placing them at high risk of life-threatening infections, including invasive fungal infections (IFIs). Although the incidence of IFIs vary among patients with haematological malignancies, the overall incidence of 10% is typically reported in patients with acute leukaemia, and 10-20% among allogeneic haematopoietic stem-cell transplant recipients (4). Dosing information Treatment of invasive fungal infections According to the SPC for posaconazole (Noxafil ), the dose of posaconazole for the treatment of refractory invasive fungal infections or for those who are intolerant to other antifungals is 400mg (10mL) twice a day. In patients who cannot tolerate a meal or a nutritional supplement, posaconazole should be administered at a dose of 200mg (5mL) four times a day. The duration of therapy is based on the severity of the underlying disease, recovery from immunosuppression, and clinical response. Treatment of oropharyngeal candidiasis Posaconazole should be initiated at a dose of 200mg (5mL) on day 1, then continued at a dose of 100mg (2.5mL) once daily for 13 days Prophylaxis in patients at a high risk of developing fungal infections According to the SPC for posaconazole (Noxafil ), the dose of posaconazole for the prophylaxis of invasive fungal infections is 200mg (5mL) three times a day. The duration of therapy is based on recovery from neutropenia or immunosuppression. For patients with acute myelogenous leukaemia or myelodysplastic syndromes, prophylaxis should start several days before the anticipated onset of neutropenia and continued for 7 days after the neutrophil count rises above 500 cells per mm 3. Clinical evidence for treatment of infections Invasive aspergillosis Invasive aspergillosis most frequently manifests as invasive pulmonary disease, accounting for 50 to 60% of all cases. Approximately 20% of invasive aspergillosis cases are disseminated, while 5% affect the skin, 5% affect the paranasal sinuses or 5% affect the central nervous system alone (5). There are no prospectively randomised controlled studies that have investigated the use of posaconazole for invasive aspergillosis. A salvage study published recently in Clinical Infectious Diseases investigated the safety and efficacy of posaconazole in patients with invasive aspergillosis and other mycoses who were refractory to or intolerant to conventional antifungal therapy (6). The study enrolled patients between January 1999 and April 2001, and an external control group study was conducted at the same time to provide a comparison group. In the posaconazole salvage therapy group, patients were included if they fulfilled the following criteria: a positive diagnosis of invasive aspergillosis in accordance with the European Organisation for Research and Treatment-Mycoses Study Group (EORTC-MSG) criteria if they were refractory to at least 7 days of antifungal therapy defined as failure to improve or as disease progression were intolerant of conventional therapy as defined by renal impairment (serum creatinine level greater than 2 times the upper limit of normal or at least double the baseline value) had severe infusion-related toxicity or other organ dysfunction or were considered to be at high risk of development of toxicity on the basis of underlying disease or concomitant use of nephrotoxic medications Patients received posaconazole 200mg four times daily with food or enteral feeding while in hospital, or 400mg twice daily as outpatients. The protocol specified that patients could be treated for up to 372 days or until the end of treatment of the invasive fungal infection, or when any of the discontinuation criteria were met. Cases of aspergillosis that were treated with posaconazole and those that were selected for the external control group were considered evaluable and were included in the modified intent-to-treat (MITT) subset if they fulfilled EORTC-MSG criteria for proven and probable invasive fungal infection and had demonstrated treatment refractory infections or developed intolerance to licensed antifungal therapy, as determined on the basis of pre-specified

4 criteria. In the external control group, most patients were selected from sites that had previously enrolled patients in the posaconazole study. Control patients were identified using hospital data records. The MITT subset was used for primary analysis for determination of efficacy based on a pre-specified data analysis plan. The primary efficacy endpoint was the global response rate at the end of treatment. One hundred and forty-one patients had invasive aspergillosis and were included in the ITT analysis, and 97 patients from the external controls fulfilled selection criteria for the external controls (ITT). The MITT subset consisted of 107 (76%) of 141 posaconazole ITT patients, and 86 (89%) of the 97 patients, and was used for primary analysis for the determination of efficacy. The following results were reported for the MITT patients: the median duration of posaconazole therapy in the MITT population was 56 days (range, 1 to 372 days); the median duration of treatment in the control group was 22 days (range, 3 to 360 days) Forty-five patients (42%) of the 107 MITT patients treated with posaconazole were blindly assessed as having a successful response compared with 22 of the 86 controls (26%) (OR by adjusted logistic regression model, 4.06; 95% CI 1.50 to 11.04, p=0.006 The rate of response to posaconazole among patients with pulmonary aspergillosis was 39% whereas for patients with extrapulmonary aspergillosis, the rate of response was 53%; the trend for control patients was similar A total of 47 patients (44%) in the posaconazole group reported treatment-related adverse effects, which included gastrointestinal events such as nausea, vomiting, anorexia, and abdominal pain, and hepatic events such as increased hepatic enzyme levels and rash; Other reported events were headache, fatigue, altered levels of concomitant drugs, dizziness, and increased serum creatinine levels The authors concluded that this study shows that posaconazole is active as salvage therapy for patients with invasive aspergillosis who were refractory to or intolerant of conventional antifungals such as amphotericin B and itraconazole. Fusariosis Fusarium species are among the leading fungal pathogens to cause invasive mould infection in patients with underlying haematological malignancy and in those who have undergone haematopoietic stem cell transplantation (HSCT). Mortality rates associated with fusariosis are over 70%. The primary antifungal therapy is amphotericin B or its lipid formulation, but this is of limited efficacy because of the potential for toxicity and poor activity against Fusarium organisms in vivo (7). There have been no controlled studies investigating the use of posaconazole for the treatment of invasive fusariosis. A retrospective analysis published in the Clinical Infectious Diseases journal evaluated the use of posaconazole as salvage treatment for invasive fusariosis in high-risk patients, particularly those with underlying haematological malignancies (7). The analysis involved 21 patients with proven or probable invasive fusariosis who were enrolled in 3 independent multi-centre, open-label clinical trials and who fulfilled the criteria of the European Organisation for Research and Treatment of Cancer/ National Institute of Allergy and Infectious Diseases Mycoses Study Group for probable or proven invasive fungal infection. All patients were considered intolerant of, or have fusariosis refractory to, conventional treatment with other antifungal therapy for 7 days (20 of the 21 patients had previously received treatment with amphotericin-b), i.e. categorising posaconazole as salvage treatment. Intolerance to conventional antifungal therapy was defined as severe infusion-related toxicity, nephrotoxicity, other organ dysfunction, or high risk of toxicity, as determined on the basis of underlying disease or concomitant medications. All patients received 800mg of posaconazole in 2 or 4 divided doses for up to 12 months. The primary efficacy endpoint was global response rate at the end of therapy; successful response was defined as resolution (complete response) or clinically meaningful improvement (partial response) of all symptoms, signs and radiographic or bronchoscopic abnormalities (failure), or persistent positive culture results or inability to determine response. Researchers reported that the overall success (complete or partial response) response to posaconazole was 48% (10 out of 21 patients responded), and those with disseminated infection (with or without pulmonary involvement) had a 30% response rate (3 out of 10 patients with disseminated infection). In terms of adverse effects, the researchers reported that the most common treatment-related adverse effects were nausea, vomiting, rash, confusion and asthenia (5% each), and all adverse events were mild to moderate in severity. The authors conclude that the results of this retrospective analysis suggests that posaconazole may be an appropriate alternative therapy to conventional amphotericin-b based regimens for the treatment of invasive fusariosis.

5 Chromoblastomycosis and mycetoma in patients with disease that is refractory to itraconazole or in patients who are intolerant of itraconazole There have been no controlled studies investigating the use of posaconazole in patients with chromoblastomycosis or mycetoma. Evidence for its use for these indications is limited to a description of its use in an open-label evaluation of 12 patients. Posaconazole was evaluated in 12 patients with eumycetoma (n=6) and chromoblastomycosis (n=6) refractory to existing antifungal therapies, or intolerant to standard therapies (8). Patients were considered to have refractory disease if their disease progressed or if they failed to improve clinically, despite extended or repetitive courses of antifungal therapy. In this open-label study, patients received posaconazole in doses of either 400mg twice daily or 200mg four times a day. The protocol defined treatment duration was a maximum of 12 months, and patients were monitored at week 1, 2, 4, and monthly thereafter; clinical response was evaluated at weeks 2 and 4, then monthly, then at the end of therapy. Treatment was considered a success if a patient experienced a total resolution (complete response) or improvement (partial response) in all attributable symptoms, signs and radiographic abnormalities. Safety and tolerability were evaluated throughout the study period and categorised according to the National Institute of Allergy and Infectious Diseases AIDS grading system. Prior antifungals used were ketoconazole and itraconazole for patients with eumycetoma, and terbinafine, itraconazole, and flucytosine for patients with chromoblastomycosis. According to the researchers, 5 patients (83%) in each group achieved clinical success, with 4 patients in each group showing a complete response and one patient in each group showing a partial response. Two patients showed stable disease following treatment with posaconazole; posaconazole was discontinued after the study period, but one of these patients received a second course of posaconazole following relapse, and received a second course of posaconazole with no effect. With respect to adverse effects, the researchers reported that posaconazole was generally welltolerated with 2 patients experiencing a headache and 2 patients showing raised bilirubin levels. The researchers conclude that posaconazole appears to be safe and well-tolerated when administered long term, and headache and gastrointestinal disorders such as nausea, diarrhoea, vomiting and abdominal pain are the most commonly reported treatment-emergent, treatment-related adverse events. Coccidioidomycosis There have been no controlled studies investigating the use of posaconazole in patients with coccidioidomycosis. A study published recently in Chest evaluated the use of posaconazole for 15 patients with coccidioidomycosis that was refractory to standard treatment (9). Patients were considered refractory if they had received an adequate duration of prior licensed antifungal therapy of at least 40 days at conventional doses or higher doses, and had failed to improve. The primary efficacy endpoint was of complete or partial response. The following results were reported: 11 patients achieved a response (4 patients showed complete responses and 7 patients showed a partial response) The condition of 11 patients were deemed to have improved after 1 month of therapy (compared to baseline) 5 patients achieved a durable response (i.e. response that was observed at 1 month, and which lasted to the end of the study period) Patients experienced some of the following side effects: diarrhoea (1), abdominal pain (2), nausea (2), headache (2), and hyperreflexia and alopecia. The researchers conclude that this study shows that posaconazole may be used for salvage therapy of chronic coccidioidomycosis refractory to prior therapy, but further larger, randomised controlled trials are needed. Scottish Medicines Consortium advice for use of posaconazole for the treatment of invasive fungal infections The Scottish Medicines Consortium has advised that posaconazole is accepted for use within NHS Scotland for the treatment of adults with specific invasive fungal infections refractory to or intolerant of specified antifungal agents (10). Clinical evidence for prophylactic use of posaconazole Posaconazole is licensed for prophylaxis in patients receiving remission-induction chemotherapy for acute myelogenous leukaemia (AML) or myelodysplastic syndromes (MDS) expected to result in prolonged neutropenia and who are at high risk of developing invasive fungal infections. Additionally, it is licensed for haematopoietic stem cell transplant (HSCT) recipients who are undergoing high-dose immunosuppressive therapy for graft versus host disease and who are at high risk of developing invasive fungal infections (1).

6 The recently published British Committee for Standards in Haematology guidelines on the management of invasive fungal infections (IFIs) during therapy for haematological malignancies have made the following recommendations for the use of prophylactic antifungals (taken directly)(18): Prophylaxis of IFI should be confined to high risk patients. The drugs of choice are itraconazole which has clinically significant but manageable or avoidable interactions with other drugs and posaconazole which has not yet been shown to be superior in efficacy to itraconazole (evidence level: grade A, level Ia ). Both are superior in efficacy to fluconazole. There are no data to justify the use of voriconazole for prophylaxis. Secondary prophylaxis may be effective for patients who have had a prior proven IFI (grade C, level IV). It is not possible to recommend an exact duration of prophylaxis for all patients because of the multifactorial nature of severe immunosuppression. In patients treated for acute leukaemia with chemotherapy, prophylaxis should continue until the neutrophil count exceeds 0.5x10 9 /L; in stem-cell transplant patients prophylaxis should continue if patients remain at high risk of IFI (grade B, level III). The European guidelines for the primary antifungal prophylaxis in leukaemia patients discussed the use of posaconazole but at the time of publication, the phase III studies discussed below had not been fully published. Therefore, the guidelines stated that provisional A1 recommendations would be implemented for the use of posaconazole 200mg three times a day during induction chemotherapy for AML/ MDS and during intensive immunosuppressive therapy for acute and chronic GvHD following allogeneic haematopoietic stem cell transplantation (11). Following this, a discussion at the annual meeting of the European Congress of Clinical Microbiology and Infectious Diseases concluded that for allogeneic HSCT, the guidelines proposing A1 recommendations for posaconazole 200mg tds and fluconazole 200mg od, and the B1 recommendation for itraconazole 200mg bd are maintained. The Infectious Diseases Society of America (IDSA) have recently published their guidelines on the management of aspergillosis infections (17). The guidelines state that for prophylaxis against invasive aspergillosis, antifungal prophylaxis with posaconazole can be recommended in HSCT recipients with GVHD who are at high risk for invasive aspergillosis and in patients with acute myelogenous leukaemia or myelodysplastic syndrome who are at high risk for invasive aspergillosis (A1 recommendation i.e. Good evidence to support a recommendation for use and the evidence comes from at least 1 properly randomised, controlled trial). The guidelines also state that itraconazole may be effective, but tolerability limits its use (B1 recommendation i.e. Moderate evidence to support a recommendation for use, and the evidence comes from at least 1 properly randomised, controlled trial). A systematic review and meta-analysis of antifungal prophylaxis in cancer patients after chemotherapy or HSCT has evaluated the effect of antifungal prophylaxis on all-cause mortality as a primary outcome, together with adverse events observed (12). The review included data from 64 randomised trials which met inclusion criteria, comparing a systemic antifungal drug with placebo, no intervention, or other antifungal agents for the prophylaxis of fungal infections in afebrile patients. The primary outcome was all-cause mortality by the end of follow-up, as defined in each study, and 30-day mortality after the end of treatment. For the main outcome, a modifiedintention-to-treat analysis was performed, for which all known events in both the numerator and denominator were included, even if they were excluded in the trial s original analysis. Study regimens included fluconazole in 37 trials, itraconazole in 18 trials, ketoconazole in 12 trials, amphotericin B in 9 trials, posaconazole in 2 trials, and one trial each for voriconazole and caspofungin. Thirty-five trials included a majority (>70%) of patients with haematological malignancies consisting of acute leukaemia or lymphoma, chronic myelocytic leukaemia in blast crisis, high-risk myelodysplastic syndrome, and multiple myeloma. Fifteen studies included patients who underwent bone marrow transplantation. Fourteen trials included a mixed population of patients with solid tumours or haematological malignancies and those who had undergone HSCT. Prophylaxis was initiated either at the start of chemotherapy (42 trials) or when the patient became neutropenic (13 trials). The following results were reported for all-cause mortality, as reported in 31 trials comparing systemic antifungals with placebo, no treatment or non-systemic antifungals: Antifungal prophylaxis decreased the risk for mortality significantly at the end of follow-up (RR 0.84; 95% CI 0.74 to 0.95), with no significant heterogeneity (p=0.46, I 2 =0.7%). The corresponding number of patients needed to treat to prevent 1 death at the end of follow up was 43 (26 to 138 patients, with a control group mortality rate of 15%). Early death, occurring up to 30 days after the end of treatment was also significantly lower with prophylaxis (28 trials, RR 0.79; 0.68 to 0.92). An analysis of secondary outcome measures showed that antifungal prophylaxis resulted in a statistically significant reduction in the risk

7 of fungal-related death (RR 0.55; 0.41 to 0.71) and documented invasive fungal infections (RR 0.50; 0.41 to 0.61) The following results were presented for trials that compared two systemic antifungal agents: 19 trials compared the efficacy of systemic antifungals in both arms, of which 12 compared the study drug with fluconazole With respect to posaconazole, the researchers reported data from the two trials published in the New England Journal of Medicine as highlighted below. They state that the use of posaconazole compared with fluconazole or itraconazole resulted in a reduction in allcause mortality of borderline statistical significance (RR 0.77, 0.59 to 1.01) When posaconazole was compared with fluconazole alone, there was a significant reduction in all-cause mortality (RR 0.74, 0.56 to 0.98) Posaconazole prophylaxis resulted in significant reduction of fungal-related mortality (RR 0.25, 0.11 to 0.57), and in documented probable invasive fungal infections (0.47, 0.30 to 0.74) Posaconazole prophylaxis produced a significant reduction in invasive Aspergillus infections (RR 0.22, 0.11 to 0.42) Overall, the researchers reported that in trials comparing systemic antifungal prophylaxis with placebo, no treatment, or non-systemic antifungals after chemotherapy, prophylaxis reduced all-cause mortality statistically significantly, by 16% (5% to 26%) at the end of follow-up and by 21% (8% to 32%) at 30- days after treatment. Additionally, they state that the major deterrents to the use of posaconazole are cost and selection pressure, which might favour the emergence of resistant strains. Furthermore, posaconazole may not be suitable for prophylaxis in patients who cannot eat regular meals, for whom, its bioavailability is low. There have been two fully published randomised controlled trials that have evaluated the prophylactic use of posaconazole. One randomised Phase III study compared the efficacy and safety of posaconazole with that of fluconazole or itraconazole for the prevention of invasive fungal infections in patients with neutropenia who were undergoing remission-induction chemotherapy for acute myelogenous leukaemia or the myelodysplastic syndrome (13). The trial involved 602 patients aged 13 years and older who were randomised to receive either fluconazole 400mg od (n=240) or itraconazole 200mg bd (n=58), or posaconazole 200mg tds (n=304). Patients were eligible if they had, or were anticipated to have, neutropenia with an absolute neutrophil count of 500cells/m 3 or less, for 7 days or more, resulting from remission-induction chemotherapy for newly diagnosed, or the first relapse of, acute myelogenous leukaemia or the myelodysplastic syndrome. Exclusion criteria were: An invasive fungal infection within the previous 30 days Clinically significant hepatic or renal impairment An abnormal QTc interval A baseline ECOG performance score of more than 2 Prophylaxis was administered with each chemotherapy cycle, starting either 24hours after the last anthracycline dose or, in patients not receiving an anthracycline based regimen, on the first day of chemotherapy. Prophylaxis was continued until recovery from neutropenia and complete remission, until the occurrence of an invasive fungal infection, or for up to 12 weeks from randomisation, whichever came first. Patients were evaluated for the presence of an invasive fungal infection at the beginning and the end of prophylaxis, 30 days after the last dose of the study drug had been administered and 100 days after randomisation. The primary efficacy endpoint was the incidence of proven or probable invasive fungal infection during the treatment phase, and was assessed using intention-to-treat principles. The trial was powered to show: Non-inferiority of posaconazole compared with fluconazole or itraconazole if the upper bound of the 95% CI for the difference between the incidence of proven or probable fungal infection for posaconazole and that for fluconazole or itraconazole was less than 4% Superiority of posaconazole if the upper bound of the same 95% CI would be negative Safety was assessed from randomisation until 30 days after the last dose of the study drug had been administered. The following results were reported: Proven or probable invasive fungal infections occurred during the treatment phase in 7 (2%) patients on posaconazole and 25 (8%) patients in the fluconazole/itraconazole group (absolute reduction -6%, 95% CI -9.7 to -2.5; p<0.0001). This suggests that 16 patients would need to be treated with posaconazole as compared to fluconazole or itraconazole in order to prevent one invasive fungal infection. Overall, the estimated number needed to treat with posaconazole, as compared to fluconazole or itraconazole, to prevent one death was 14 patients. During the 100-day period post randomisation, 14 patients (5%) in the posaconazole group had a proven or possible fungal infection compared to 33 patients (11%) in the itraconazole/fluconazole group (p=0.003)

8 The mean time (+/-SD) to invasive fungal infection was 41 +/- 26 days in the posaconazole group and 25 +/- 26 days in the fluconazole/itraconazole group (p=0.003) 81 patients (27%) on posaconazole received an empirical antifungal agent during the treatment phase, compared to 112 patients (38%) in the fluconazole/itraconazole group (p=0.004) Of the 116 deaths that occurred during the study, 21 were considered to be related to fungal infections: 5 occurred in the posaconazole group and 16 in the fluconazole/ itraconazole group (p=0.01) Serious adverse events possibly or probably related to treatment was reported by 19 patients (6%) in the posaconazole group and 6 patients (2%) in the fluconazole/itraconazole group (p = 0.01) The authors concluded that prophylaxis with posaconazole was superior to prophylaxis with fluconazole or itraconazole in the prevention of proven or probable invasive fungal infection and resulted in lower mortality from any cause and longer survival free from proven or probable invasive fungal infection, and posaconazole prophylaxis may be a useful addition to the standard of care for patients with acute myelogenous leukaemia or myelodysplastic syndromes who are undergoing remission-induction chemotherapy. Another fully published phase III study compared the efficacy and safety of posaconazole with that of fluconazole for the prevention of invasive fungal infections in allogeneic haematopoietic stem-cell transplant recipients with graft-versus-host disease (GVHD) who were receiving immunosuppressive therapy (14). The primary endpoint was the incidence of proven or probable invasive fungal infections from randomisation to day 112 of the fixed treatment period of the study failure of prophylaxis was defined as the development of an invasive fungal infection during the fixed treatment period. Patients over 13 years were eligible if they had undergone haematopoietic stem-cell transplantation and if they had either acute GVHD grade II to IV or chronic extensive GVHD or if they were being treated with intensive immunosuppressive therapy. Patients were randomised to receive either posaconazole 200mg tds with placebo od (n=301), or fluconazole 400mg od with placebo tds (n=299). Safety and tolerability was assessed based on paired electrocardiographic and lab evaluations and evaluations for changes in clinical signs and symptoms. Patients were monitored for the 112 days of the treatment period, and additionally followed up for another 8 weeks. Posaconazole was considered to be non-inferior to fluconazole, with respect to the primary efficacy endpoint, on the basis of evaluations of all patients if the upper limit of the 95% CI for the adjusted odds ratio did not exceed a maximum value corresponding to a relative difference of 15 percentage points from the observed incidence rates in the fluconazole group. The following results were presented: The incidence of invasive fungal infections was 5.3% for the posaconazole group and 9% in the fluconazole group (odds ratio for invasive fungal infection in the posaconazole group, 0.56; 95% CI 0.30 to 1.07) Ruling out a 15% relative difference between the 2 groups resulted in an odds ratio of 1.16; since the upper limit of the CI was 1.07, which is less than 1.16, the non-inferiority of posaconazole was established. The frequency of serious adverse events in the posaconazole group was 13% vs. 10% in the fluconazole group The authors concluded that posaconazole was as effective as fluconazole in preventing all invasive fungal infections, and that it should be considered an option for prophylaxis in patients with severe GVHD. Although this was not the primary endpoint, posaconazole was shown to be superior in preventing invasive aspergillosis in a high-risk population of patients who had undergone HSCT and in reducing the rate of death attributable to invasive fungal infections. Scottish Medicines Consortium advice for use of posaconazole for the prophylaxis of invasive fungal infections The Scottish Medicines Consortium has accepted posaconazole for restricted use for the prophylaxis of invasive fungal infections in immunocompromised patients. It is restricted to patients in whom there is a specific risk of aspergillus infection or where fluconazole or itraconazole are not tolerated (15).

9 Cost The basic NHS price for a 105mL bottle of posaconazole 40mg/mL (Noxafil ) is (16). For the treatment of invasive fungal infections, the comparative approximate cost of using various licensed antifungals for the treatment of one patient for one month is: Drug Regimen Cost for one month 16* Posaconazole 400mg twice daily 3004 or 200mg four times a day Intravenous caspofungin 70mg on day 1, followed by 50mg daily, or 70mg daily for patients over 80kg 9264 (assuming patient <80kg) Conventional intravenous amphotericin B Intravenous liposomal amphotericin (AmBisome ) in patients intolerant to conventional amphotericin, Voriconazole oral suspension Fluconazole oral suspension Itraconazole oral liquid 250micrograms/kg daily, increasing over 2-4 days to 1.5mg/kg daily for severe infections 1mg/kg to 3mg/kg once daily (upto a maximum of 5mg/ kg as stated in BNF 54, although this is not a licensed dose) 400mg every 12 hours for 2 doses then 200mg twice daily, increased if necessary to 300mg twice daily 400mg on day 1, followed by 200 to 400mg daily 200mg twice daily (assuming an average weight of 70 kg, and using the maximum dose) 5,415 for 1mg/kg dose, to 10,829 for 3mg/kg dose, and 18,951 for a 5mg/kg unlicensed dose (assuming an average weight of 70kg) 2205 for 400mg every 12 hours for 2 doses then 200mg twice daily 531 (assuming maximum dose of 400mg daily) According to a budget impact statement by the SMC, in Scotland only 6 patients in 2006 rising to 7 in 2010 are estimated to be eligible for posaconazole oral solution for use as salvage therapy in the treatment of invasive aspergillosis (10). For the prophylaxis of fungal infections in high risk patients, the comparative approximate cost of using various licensed antifungals for one month is: Drug Regimen Cost for one month 16* Posaconazole oral 200mg three times daily, suspension starting several days before 2003 the anticipated onset of neutropenia and continue for 7 days after the neutrophil count rises above 500 cells per mm 3 Itraconazole oral liquid Fluconazole oral suspension Intravenous liposomal amphotericin (AmBisome) in patient intolerant to conventional amphotericin (unlicensed) 5mg/kg in 2 divided doses, starting before commencement of chemotherapy and ontinued until neutrophil count recovers above 1000 cells per mm 3 400mg daily, starting several days before the anticipated onset of neutropenia, and continued for 7 days after neutrophil count rises above 1000 cells per mm 3 At Guy s and St. Thomas Hospital NHS Foundation Trust, 3mg/kg three times a week, or 10mg/kg once weekly (unlicensed) (19) 340 (assuming an average weight of 70kg) 531 4,641 (for a dose of 3mg/ kg, assuming an average weight of 70kg) or 6,188 (for a dose of 10mg/ kg once weekly) The Scottish Medicines Consortium, in their advice for the prophylactic use of posaconazole, suggest that based upon around 600 AML/MDS and 60 GVHD patients being eligible and requiring prophylactic antifungals, and based on a 20% market share for posaconazole, the total direct posaconazole drug cost is estimated at around 320,000 (15). Offsetting this from the reduction in the use of fluconazole and itraconazole, the net direct drug cost is estimated at around 250,000 (based on cost information obtained from the evadis database February 2007). The comparative cost per patient for the use of oral posaconazole, fluconazole or itraconazole for the treatment of oropharyngeal candidiasis is: Drug Regimen Cost 16* Posaconazole 200mg stat then 100mg daily for 13 days Itraconazole 100mg daily for 15 days (or 200mg per day for AIDS or neutropenic patients) to Fluconazole mg daily for 14 days, depending on the severity of the infection (based on the use of the maximum dose of fluconazole i.e. 100mg od) *Cost calculated using prices from the British National Formulary September 2007; no. 54

10 Safety Safety data from the two largest studies have been described below. A comprehensive list of adverse effects experienced in the whole population of healthy volunteers and patients, is available in the SPC for posaconazole (Noxafil ) (1). According to data presented in the study investigating prophylactic use of posaconazole in patients with neutropenia, serious adverse events reported more frequently in the posaconazole group compared to itraconazole or fluconazole, and possibly or probably related to treatment were bilirubinaemia, liver function test abnormalities, liver failure, hepatitis, jaundice, diarrhoea, atrial fibrillation, syncope, decreased ejection fraction, QT or QTc prolongation, and Torsades de pointes (13). However, a statistical analysis was not conducted to determine the difference in incidence between treatment with posaconazole and either itraconazole or fluconazole. Conclusion Evidence for the use of posaconazole for the treatment of invasive fungal infections is limited to small uncontrolled descriptive analyses and one small controlled comparative study. Prophylactic use of posaconazole in patients undergoing HSCT or in patients with severe GVHD has shown a statistically significantly better efficacy than fluconazole, but has only been investigated in two phase III trials. It is costly, and thus consideration of local factors e.g. local epidemiology of fungal infections need to be accounted for during the selection of the most appropriate antifungal for prophylaxis. Posaconazole may be considered in patients with hepatic GVHD as it is less hepatotoxic compared to itraconazole or voriconazole. According to data presented in the study investigating prophylactic use of posaconazole in patients with severe GVHD, serious adverse events reported more frequently in the posaconazole group compared to the fluconazole group were: liver function test abnormalities, bilirubinaemia, vomiting and nausea. Abnormal hepatic function was reported more frequently in the fluconazole treated patients compared to posaconazole (14). A statistical analysis was not presented to determine the significance in difference of the incidence rates. Points for consideration Use of posaconazole for the treatment of invasive fungal infections is limited to small descriptive analyses. There have been no head-to-head comparisons with other antifungals, and therefore, it may be considered reasonable to reserve its use for those who are intolerant to, or have an infection that is refractory to treatment with other antifungals. Patients with a recent fungal infection were excluded from the trials for the prophylactic use of posaconazole. It appears that posaconazole may be considered first line in patients who may not be able to tolerate fluconazole or in whom fluconazole is contra-indicated. Is it suitable or effective in patients in whom fluconazole may already have been initiated, but cannot be continued? Oral fluconazole and itraconazole are not usually considered first line for the treatment of severe invasive fungal infections. Therefore cost comparisons for posaconazole should be with intravenous liposomal amphotericin or caspofungin, or intravenous fluconazole? Posaconazole is only available as a formulation for oral administration, and thus rendering it unsuitable for those patients who are not able to tolerate oral administration. Posaconazole absorption is enhanced by co-administration with food or nutritional supplements, and thus more suitable for patients who are able to eat or tolerate nutritional supplements.

11 References 1. Noxafil SPC (posaconazole) 40 mg/ml oral suspension; Date of revision: 30 October Keating G M. Posaconazole. Drugs 2005; 65 (11): Torres H A et al. Posaconazole: a broadspectrum triazole antifungal. The Lancet Infectious Diseases 2005; 5: Maertens J. Evaluating prophylaxis of invasive fungal infections in patients with haematological malignancies. European Journal of Haematology 2007; 78: Maschmeyer G et al. Invasive aspergillosis. Epidemiology, diagnosis and management in immunocompromised patients. Drugs 2007; 67 (11): Walsh T J et al. Treatment of invasive aspergillosis with posaconazole in patients who are refractory to or intolerant of conventional therapy: an externally controlled trial. Clinical Infectious Diseases 2007; 44: Read I I et al. Posaconazole as salvage treatment for invasive fusariosis in patients with underlying haematologic malignancy and other conditions. Clin Infect Dis May 15;42 (10): Negroni R et al. Posaconazole treatment of refractory eumycetoma and chromoblastomycosis. Rev Inst Med trop S. Paulo 2005; 47 (6): Stevens D A. Posaconazole therapy for chronic refractory coccidioidomycosis. Chest 2007; 132: Scottish Medicines Consortium. Posaconazole 40mg/ml oral suspension for treatment of specific invasive fungal infections; 5 May Maertens J A et al. European guidelines for the primary antifungal prophylaxis in leukaemia. European Journal of Cancer Supplements 2007; 5 (2): Robenshtok E et al. Antifungal prophylaxis in cancer patients after chemotherapy or haematopoietic stem-cell transplantation: systematic review and meta-analysis. Journal of Clinical Oncology 2007; published early online on 1 October Cornely O A et al. Posaconazole vs. fluconazole or itraconazole prophylaxis in patients with neutropenia. NEJM 2007: 356: Ullmann A J et al. Posaconazole or fluconazole for prophylaxis in severe graft-versus-host disease. NEJM 2007; 356: Scottish Medicines Consortium. Posaconazole 40mg/ml oral suspension for prophylaxis of invasive fungal infections in immunocompromised patients; 4 May British Medical Association and Royal Pharmaceutical Society of Great Britain. British National Formulary 54, September Walsh T J et al. Treatment of aspergillosis: Clinical practice guidelines of the Infectious Diseases Society of America. Clinical Infectious Diseases 2008; 46: British Committee for Standards in Haematology. Guidelines on the management of invasive fungal infection during therapy for haematological malignancy. Published online on the British Committee for Standards in Haematology website on 13 March Personal correspondence - Jacky Turner, Principal pharmacist for oncology and haematology at Guy s Hospital NHS Foundation Trust The document reflects the views of LNDG and may not reflect those of the reviewers Please direct any comments to Hina Radia, London & South East Medicines Information Service, Guy s Hospital, Great Maze Pond, London SE1 9RT Tel: , Fax: , hina.radia@gstt.nhs.uk