17th Expert Committee on the Selection and Use of Essential Medicines Geneva, March 2009

Transcription

1 17th Expert Committee on the Selection and Use of Essential Medicines Geneva, March 2009 APPLICATION FOR LISTING OF LIPOSOMAL AMPHOTERICIN B FOR THE TREATMENT OF INVASIVE FUNGAL INFECTIONS ON THE WHO MODEL LIST OF ESSENTIAL MEDICINES FOR CHILDREN NOVEMBER 2008 Liposomal amphotericin B fungal infections 1

2 TABLE OF CONTENTS 1. Summary statement of proposal for inclusion, change, or deletion Name of focal point in WHO submitting the application Name of the organisation(s) consulted and/or supporting the application International Nonproprietary Name (INN) Formulation proposed for inclusion International availability Category of listing requested Information supporting the public health relevance Epidemiological information on disease burden Assessment of current use Target population Treatment details Dosage regimen Treatment duration Reference to WHO and other clinical guidelines Need for special diagnostic or treatment facilities and skills Summary of comparative effectiveness Identification of clinical evidence Search strategy Systematic reviews identified Selection/exclusion of particular data Summary of available data Appraisal of quality Outcome measures Summary of results comparative trials Summary of results non-comparative studies Summary of results review studies Summary of available estimates of comparative effectiveness Summary of comparative evidence on safety Estimate of total patient exposure to date Description of adverse effects/reactions Identification of variation in safety due to health systems and patient factors Summary of comparative safety against comparators Summary of available data on comparative cost and cost-effectiveness Range of costs of the proposed medicine Comparative cost-effectiveness (presented as range of cost per routine outcome) Regulatory status Availability of pharmacopoeial standards Proposed text for the WHO Model Formulary...26 Attachment 1: Proposed text for the WHO Model Formulary...31 Attachment 2: Summary of Ellis et al (1998) trial...33 Liposomal amphotericin B fungal infections 2

3 WHO MODEL LIST OF ESSENTIAL MEDICINES FOR CHILDREN APPLICATION Liposomal amphotericin B for the treatment of invasive fungal infections in children 1. Summary statement of proposal for inclusion, change, or deletion Liposomal amphotericin B is proposed for inclusion on the WHO Model List of Essential Medicines for children for the treatment of invasive fungal infections.. 2. Name of focal point in WHO submitting the application 3. Name of the organisation(s) consulted and/or supporting the application None. 4. International Nonproprietary Name (INN) Amphotericin B 5. Formulation proposed for inclusion Sterile, non-pyrogenic lyophilized product for intravenous infusion. Each vial contains 50mg of amphotericin B, USP, intercalated into a liposomal membrane. It is available as single cartons and in packs of ten individual cartons. Each carton contains one pre-packaged disposable sterile 5-micron filter. 6. International availability Liposomal amphotericin B (AmBisome) is manufactured by Gilead and is available in Europe, Asia, South America, the United States, and Canada. 7. Category of listing requested Listing is requested as an individual drug. 8. Information supporting the public health relevance 8.1 Epidemiological information on disease burden Invasive fungal infections have been identified as a significant and increasing health problem (Zaoutis et al., 2006; Richardson 2005; Zaoutis et al., 2004; Hobson 2003; Dupont 2002; Singh 2001; Granier 2000). Infections due to Candida and Aspergillus species have increased (Hobson 2003; Zaoutis et al., 2006), as have those due to mycelial fungi other than Aspergillus and to nonalbicans species of Candida (Richardson 2005; Hobson 2003). While there is not a paediatric-specific assessment of fungal infections available, there are a number of country and infection-specific reports. Leibovitz (2002) reported that neonatal candidiasis is associated with morbidity of 25% and mortality of 25% to 54%. Pappas et al (2003) reported that Candida albicans was associated with mortality of 29% among children Liposomal amphotericin B fungal infections 3

4 (47% among adults). These highlight a significant degree of morbidity and mortality. While the impact does not always coincide with that observed in adults (Filioti et al., 2007), for example there is a lower mortality rate in neonates with invasive Candida infections compared to adults (Pappas et al., 2003), there remains considerable impact in terms of mortality, as well as on the health care system, given longer hospital stays and greater cost in children compared to adults (Filioti et al., 2007). Groll et al (1999) reported long-term survival (median follow-up of 5.68 years) of only 31% in paediatric cancer patients with invasive aspergillosis. Balwierz (2004) reported that mortality in immunosuppressed patients with fungal infections is in the range of 50% to 95%. Imwidthaya and Poungvarin (2000) reported mortality of 44% in children with cryptococcosis in developing countries. The young age of affected patients suggests that the morbidity and mortality associated with fungal infections has a greater potential to impact on productive years of life and on overall health care costs (Filioti et al., 2007), thus increasing the disease burden. Amphotericin B deoxycholate has been the drug of choice for treatment of fungal infections (Hay 1994; Patel 1998; Scarcella et al., 1998; Tollemar et al., 2001; Barrett et al., 2003; Ostrosky-Zeichner et al., 2003), however the use of amphotericin B has been limited by its toxicity, in particular nephrotoxicity, which has been estimated to occur in up to 80% of patients (Chan and Sorrell 2007). While some authors indicate that neonates may tolerate amphotericin B well (eg Leibovitz 2002), there remains considerable evidence of adverse effects with the use of amphotericin B in neonates and older children (Baley et al., 1984; Girois et al., 2005). Liposomal amphotericin B is a liposome-encapsulated formulation of amphotericin B. The use of liposomes alters the pharmacokinetic properties of the drug, which leads to changes in tissue distribution, antifungal activity and tolerability (Tollemar et al., 2001). One of the key advantages of liposomal amphotericin B compared to deoxycholate amphotericin B is the lower frequency of adverse events associated with liposomal amphotericin B. A review and meta-analysis of the frequency of adverse effects of the main systemic antifungal agents demonstrated that liposomal amphotericin B is the least nephrotoxic of the agents (14.6%) and amphotericin B deoxycholate is the most nephrotoxic (33.2%) (Girois et al, 2005). While the authors acknowledged that the lack of standard definitions of antifungal-related adverse events, heterogenous patient pools and different protocols raise questions about the validity of the results and make it difficult to draw direct comparisons, the available evidence indicates safety advantages for liposomal amphotericin B. The reduction in toxicity, in addition to reducing the number and severity of adverse events, also provides an opportunity to increase doses if required, resulting in an increased therapeutic index with the use of liposomal amphotericin B (Tollemar et al., 2001). Given the high disease burden associated with fungal infections and the safety advantages of liposomal amphotericin B compared to conventional amphotericin B, inclusion of liposomal amphotericin B for the treatment of invasive fungal infections on the WHO Model List for Children is sought. Liposomal amphotericin B fungal infections 4

5 Evidence demonstrating the efficacy and safety of liposomal amphotericin B is provided in Sections 10 and Assessment of current use Liposomal amphotericin B is indicated for the treatment of patients with systemic fungal infections who are refractory to amphotericin B deoxycholate, and in patients where renal impairment or unacceptable toxicity precludes the use of amphotericin B deoxycholate. As such, liposomal amphotericin B is used primarily as second-line therapy. 8.3 Target population Children with invasive fungal infections, including infections due to Aspergillus species, Candida species and/or Cryptococcus species infections; cryptococcal meningitis and presumed fungal infections in neutropenic patients. 9. Treatment details 9.1 Dosage regimen The Product Information recommended initial dose for systemic fungal infections is 3 5 mg/kg/day, while the Product Information recommended dose for treatment of cryptococcal meningitis in HIV-infected patients is 6mg/kg/day. Liposomal amphotericin B is administered by intravenous infusion, over a period of approximately 120 minutes. Table summarises dosages recommended in treatment guidelines for different fungal infections. Table 9.1.1: Recommended dosages of liposomal amphotericin B and treatment duration for paediatric patients in available guidelines Guideline Dosage Treatment duration Systemic fungal infections (Richardson and Jones 2006) 1-5mg/kg/day not specified IDSA aspergillosis (Walsh 2008) 3-5mg/kg/day not specified IDSA histoplasmosis (Wheat et al., 2007) lipid preparations of amphotericin B not preferred as amphotericin B deoxycholate is usually well-tolerated IDSA candidiasis (Pappas et al., 3-5mg/kg/day not specified 2004) IDSA blastomycosis (Chapman et 3-5mg/kg/day initial therapy, al., 2008) a duration not specified CDC opportunistic infections in 3-5mg/kg/day based on clinical HIV-exposed and infected children (Mofenson et al., 2005) response, most patients treated for 2-4 weeks a Guidelines state that in general, children tolerate the deoxycholate formulation of amphotericin B better than adults and lipid formulations may not be needed A randomised trial comparing liposomal amphotericin doses of 1mg/kg/day and 4mg/kg/day in adult and paediatric patients with invasive aspergillosis (Ellis et al., 1998) found that the 1mg/kg/day dose is as effective as the 4mg/kg/day dose. The authors concluded that there are no advantages to the use of the higher and more expensive dose of liposomal amphotericin B. Liposomal amphotericin B fungal infections 5

6 Details of this trial are provided in Attachment 2. Prentice et al (1997) also found no difference between the 1mg/kg and 3mg/kg doses of liposomal amphotericin B. In contrast, in a review of antifungal treatment in paediatric patients (Zaoutis et al., 2005) the authors state that the preferred paediatric dose of liposomal amphotericin B is 5mg/kg/day, as most clinical data has been obtained with those dose and most clinicians prefer using the higher dose. 9.2 Treatment duration Treatment duration is based on clinical response. 9.3 Reference to WHO and other clinical guidelines Liposomal amphotericin B for the treatment of fungal infections in children is included in the following guidelines of the Infectious Diseases Society of America (IDSA): - Treatment of Aspergillosis: clinical practice guidelines of the Infectious Diseases Society of America. (Walsh et al., 2008) - Clinical Practice Guidelines for the Management of Patients with Histoplasmosis 2007 update (Wheat et al., 2007) - Guidelines for the Treatment of Candidiasis (Pappas et al., 2004) - Practice Guidelines for the Management of Cryptococcal Disease (Saag et al., 2000) - Clinical Practice Guidelines for the Management of Blastomycosis: 2008 update by the Infectious Diseases Society of America (Chapman et al., 2008) Other guidelines which recommend the use of liposomal amphotericin B in children include: - Therapeutic Guidelines in Systemic Fungal Infections (Richardson and Jones 2006) - Treating opportunistic infections among HIV-exposed and infected children: recommendations from CDC, the National Institutes of Health, and the Infectious Diseases Society of America (Mofenson et al., 2005) Table summarises the guideline recommendations. Table 9.3.1: Guideline recommendations for use of liposomal amphotericin B for treatment of fungal infections in children Guideline Recommendations Systemic fungal infections liposomal amphotericin B recommended for (Richardson and Jones treatment of serious fungal infections, eg Candida, 2006) Aspergillus and other filamentous fungi, and Cryptococcus species; patients who have developed side effects to amphotericin B deoxycholate; patients in whom amphotericin B deoxycholate is contraindicated because of renal impairment dosed at 1-5mg/kg/day IDSA aspergillosis liposomal amphotericin B 3-5mg/kg/day as alternative or salvage therapy in patients refractory to or Liposomal amphotericin B fungal infections 6

7 Guideline IDSA histoplasmosis IDSA candidiasis IDSA cryptococcal disease IDSA blastomycosis CDC opportunistic infections in HIV-exposed and infected children Recommendations intolerant of primary therapy amphotericin B deoxycholate; lipid preparations are not preferred 3-5mg/kg/day lipid formulations may be substituted for amphotericin B in patients whose renal function is impaired amphotericin B deoxycholate 0.7-1mg/kg/day or lipid amphotericin B 3-5mg/kg/day for 1-2 weeks amphotericin B lipid formulations have a role among children who are intolerant of amphotericin B, have disseminated candidal infection that is refractory to conventional amphotericin B, or are at high risk for nephrotoxicity because of pre-existing renal disease or use of other nephrotoxic drugs. For invasive candidiasis, liposomal amphotericin B 3-5mg/kg/day, most patients are treated for at least 2-4 weeks. For cryptococcal meningitis, liposomal amphotericin B at 4mg/kg/day; 2mg/kg/day has shown good effect and doses of 7.5mg/kg/day have been used for refractory cases. 9.4 Need for special diagnostic or treatment facilities and skills The diagnosis of fungal infections requires assessment of clinical criteria and microbiological criteria. Table provides the investigations required for the laboratory diagnosis of systemic fungal infection. Table 9.4.1: Investigations required for laboratory diagnosis of systemic fungal infection Infection Essential investigations Aspergillosis microscopy of sputum, BAL fluid (enhanced by Calcofluor white) and stained biopsy material culture of respiratory secretions and biopsy material twice weekly EIA for galactomannan (Platelia Aspergillus, Bio- Rad, FDA approval 2003) in high risk and intermediate risk patients (variable results between laboratories) detection of β-1,3-d-glucan PCR screening twice weekly on whole blood in high/intermediate risk hematology patients (if available locally) Candidiasis microscopy of body fluids (enhanced by Calcofluor white) and stained biopsy material culture of blood and other body fluids culture of respiratory secretions culture of biopsy material detection of precipitins by CIE ELISA for Candida-mannan (Bio-Rad) (variable results between laboratories) ELISA for Candida anti-mannan (limited value in immunocompromised patients) detection of β-1,3-d-glucan (Glucatel) PCR on whole blood (if available locally) Cryptococcus microscopy of CSF or other body fluids and secretions culture of CSF, blood, sputum, urine, and prostatic fluid detection of antigen in CSF, urine, and blood by latex agglutination Histoplasmosis microscopy of stained smears of peripheral blood, sputum, bronchial washings, and pus Liposomal amphotericin B fungal infections 7

8 Infection Essential investigations culture of blood, sputum, bone marrow, pus, and tissue detection of antibody by immunodiffusion and complement fixation detection of antigen by radioimmunoassay in blood, urine, CSF, and BAL Blastomycosis microscopy of pus, sputum, bronchial washings, and urine culture of pus, sputum, bronchial washings, and urine detection of antibody by immunodiffusion Source: Richardson and Jones 2006 Liposomal amphotericin B requires intravenous administration, delivered in a hospital setting. It also requires storage at <25C. 10. Summary of comparative effectiveness 10.1 Identification of clinical evidence Search strategy Medline, Embase and the Cochrane Library were searched for relevant trials assessing the use of liposomal amphotericin B for the treatment of fungal infections in a paediatric population. The search terms used, and number of articles returned, are provided in Table Table : Literature search results Search terms Medline Embase Cochrane Total 1) exp Antibiotics, Antifungal/ or exp Amphotericin B/ or exp Liposomes 2) (paediatric or pediatric or children).mp [mp=title, original title, abstract, name of substance word, subject heading word] 3) exp Antifungal Agents/ or exp Antibiotics, Antifungal/ 4) 2 and (1 or 3) ) liposomal amphotericin B.mp. [mp=title, original title, abstract, name of substance word, subject heading word] 6) 4 and Systematic reviews identified There were no systematic reviews identified comparing liposomal amphotericin B and amphotericin B deoxycholate in paediatric patients with fungal infections. There is one systematic review comparing lipid formulations of amphotericin B to amphotericin B deoxycholate for the treatment of systemic fungal infections (Robinson and Nahata 1999), however no paediatric-specific trials are identified. A second systematic review assessed the antifungal effectiveness and tolerability of amphotericin B formulations, comparing lipid-based formulations and amphotericin B deoxycholate (Barrett et al., 2003). Liposomal amphotericin B fungal infections 8

9 This review did not specifically identify or address paediatric patients, however two trials with paediatric patients were included (Prentice et al., 1997; Walsh et al., 1999). A meta-analysis of all lipid formulations versus amphotericin B deoxycholate showed that lipid-based formulations reduced the risk of all-cause mortality by 28% (OR=0.72; 95% CI: 0.54 to 0.97). There was no statistically significant difference between lipid-based formulations and amphotericin B deoxycholate in efficacy (OR=1.21; 95% CI: 0.98 to 1.49). The authors explain this inconsistency as likely due to the following: patients receiving lipid-based formulations would be less likely to experience changes in renal function and thus receive a greater dose which may explain their improved survival rate, while patients treated with amphotericin B deoxycholate may not receive an adequate dose and may also receive other medications that are nephrotoxic, thus compromising their outcomes. However these factors should also impact efficacy, ie a greater dose might be expected to lead to greater efficacy as well as preventing death. The final reason offered by the authors is the most probable, that the heterogeneity of the included trials and lack of efficacy standards may explain the inability to demonstrate improved efficacy with liposomal amphotericin B. A third systematic review compares lipid formulations of amphotericin B and amphotericin B deoxycholate in cancer patients with neutropenia (Johansen and Goetzsche 2004). The review identifies three trials comparing liposomal amphotericin B and amphotericin B deoxycholate and two of these trials include paediatric patients (Prentice et al., 1997; Walsh et al., 1999) and are presented in Section below. In contrast to the results presented by Barrett et al (2003), meta-analysis of three trials found no significant difference in mortality between liposomal amphotericin B and amphotericin B deoxycholate (RR=0.74; 95% CI: 0.52 to 1.07) although there was a trend toward greater efficacy for invasive fungal infection (RR=0.63; 95% CI: 0.39 to 1.01; p=0.053). There are two Cochrane reviews underway, one which will assess different antifungal agents or combinations of agents in children with proven, probable or suspected invasive fungal infections with respect to comparative effectiveness, toxicity and cost. The protocol for this review does not specify which antifungal agents are included. The second review aims to assess the effects of amphotericin B deoxycholate compared to liposomal amphotericin B on kidney function. No details of the patient population are provided for this review Selection/exclusion of particular data Randomised trials comparing liposomal amphotericin B and amphotericin B deoxycholate for the treatment of fungal infection in Liposomal amphotericin B fungal infections 9

10 paediatric patients were sought. Trials that included both adult and paediatric patients and identified the paediatric patients were included. Trials that included only adult patients were excluded. As the literature searches found only four comparative trials, an additional 19 non-comparative studies and case reports, and one open-label comparison against placebo, are included to provide a complete summary of available evidence. A number of review papers (13) assessing liposomal amphotericin B are available, although none provide separate results for paediatric patients. These reviews are briefly summarised in Section Table lists the included trials and studies. Table : Selected data Trial Design Comparative trials Prentice et al., 1997 randomised, open-label trial comparing liposomal amphotericin B and amphotericin B deoxycholate for the treatment of pyrexia of unknown origin in neutropenic patients. (published paper reports both trials together) Zoubeck et al., 1992 open-label trial comparing liposomal amphotericin B and amphotericin B deoxycholate in immunosuppressed children. Chisholm et al., 1999 comparative retrospective review of the use of liposomal amphotericin B in children with established renal impairment on treatment for febrile neutropenia compared to use of amphotericin B in children with normal renal function Walsh et al., 1999 randomised, double-blind, multicentre trial comparing liposomal amphotericin B and amphotericin B deoxycholate as empirical therapy in adult and paediatric patients with persistent fever and neutropenia Non-comparative studies including only paediatric patients Anak 2004 Avci et al., 2008 Allinson et al., 2008 Buckler et al., 2008 Cesaro et al., 2006 Dornbusch et al., 1995 Emminger et al., 1994 Juster-Reicher et al., 2000 Juster-Reicher et al., 2003 Lackner et al., 1992 Malani et al., 2005 multicentre, post-marketing surveillance study of the use of liposomal amphotericin B in patients with fungal infections, including 242 children and 43 infants. case report of two paediatric patients with invasive fungal infections treated with liposomal amphotericin B single centre observational cohort analysis of prophylactic use of liposomal amphotericin B in paediatric haemotopoietic stem cell recipients case report of the use of liposomal amphotericin B in paediatric patients with central venous catheter fungal infections case report of the use of high-dose liposomal amphotericin B in a paediatric allogeneic bone marrow transplant patient case report of five paediatric patients with invasive pulmonary aspergillosis treated with liposomal amphotericin B non-comparative study of the use of liposomal amphotericin B for the treatment of children with cancer and invasive fungal infection retrospective review of efficacy and safety of liposomal amphotericin B in neonatal patients with systemic candidiasis non-comparative study of the use of high-dose liposomal amphotericin B in neonates with systemic candidiasis case report describing two low birth-weight infants treated with liposomal amphotericin B retrospective review of the use of community-based amphotericin B treatment focusing on occurrence of adverse Liposomal amphotericin B fungal infections 10

11 Trial Melamed et al., 2000 Pasic et al., 1997 Ringden and Tollemar 1993 Ringden et al., 1997 Roman et al., 2008 Scarcella et al., 1998 Stuecklin-Utsch et al., 2002 Uhlenbrock et al., 2001 Weitkamp et al., 1997 Reviews Barrett et al., 2003 Design events case report of the use of liposomal amphotericin B to treat Candida endocarditis in a paediatric patient non-comparative study in which liposomal amphotericin B was administered to children who had undergone bone marrow transplant. non-comparative study of the use of liposomal amphotericin B for the treatment of invasive fungal infections in immunocompromised children retrospective review of children undergoing bone marrow transplantation receiving liposomal amphotericin B non-comparative study of the use of liposomal amphotericin B in paediatric allogeneic stem cell transplant patients non-comparative study of treatment of neonates with verified deep fungal infections with liposomal amphotericin B retrospective review of the use of liposomal amphotericin B in children with documented or suspected fungal infection, with a focus on occurrence of elevated serum lipase levels randomised, open-label comparison of prophylaxis with liposomal amphotericin B compared to no prophylaxis in children with chemotherapy-related neutropenia retrospective review of treatment of very low birth-weight infants with liposomal amphotericin B systematic review of effectiveness and safety of lipid amphotericin B formulations compared to amphotericin B deoxycholate. No paediatric-specific trials were identified. Chan and Sorrell 2007 review of antifungal agents, including lipid formulations of amphotericin B. No paediatric-specific studies are included. Includes guidelines for treatment of invasive fungal infections Chopra 2002 review of the use of liposomal amphotericin b in the treatment of fungal infections includes trials and studies which include paediatric patients (eg Prentice et al., 1997) however does not include any paediatriconly studies Dupont 2002 review of trials and studies using lipid formulations of amphotericin B Girois et al., 2005 review and meta-analysis of antifungal therapies including liposomal amphotericin B in the treatment of invasive fungal infections. No paediatric-specific analyses were conducted, however trials including paediatric patients were included. Hann and Prentice 2001 review of the use of lipid formulations of amphotericin B for the treatment of fungal infections; no paediatric-specific studies are reviewed, however studies including paediatric patients are included (eg Prentice et al., 1997). Also included is a review of cost-effectiveness studies. Hay 1994 review of the use of liposomal amphotericin B in the treatment of fungal infections; brief description of two paediatric studies (Zoubeck et al., 1992; Lackner et al., 1992) Johansen and Goetzsche systematic review of lipid-based formulations of amphotericin b 2004 versus amphotericin B deoxycholate in cancer patients with neutropenia Leibovitz 2002 review of treatment of neonatal candidiasis including description of three studies using liposomal amphotericin B Ringden 2002 review of trials and studies using liposomal amphotericin B, Robinson and Nahata 1999 including one paediatric study (Ringden et al., 1997) comparative review of trials and studies using amphotericin B deoxycholate and liposomal amphotericin B, with some cited Liposomal amphotericin B fungal infections 11

12 Trial Tollemar et al., 2001 Zaoutis et al., 2005 Design studies including paediatric patients provides comparative costs for amphotericin B deoxycholate and the lipid formulations retrospective review of the use of liposomal amphotericin B for fungal infections in immunocompromised adults and children (transplant recipients) as well as review of available studies comparing liposomal amphotericin B and amphotericin B deoxycholate description of the economic impact of liposomal amphotericin B therapy, ie summary of available health economic evidence review of antifungal treatment in paediatric patients, summarising efficacy and safety data 10.2 Summary of available data Appraisal of quality Table provides an assessment of trial quality of the included comparative paediatric trials, as well as the comparative adult and paediatric combined trials. The remaining studies, which consisted of 5 retrospective reviews, 6 case reports, 2 observational studies, 6 noncomparative prospective studies and one open-label comparison to placebo, were not randomised or blinded and thus assessment of trial quality as presented in Table cannot be completed. Table : Assessment of quality of trials presented in the application Trial Done Comments Prentice et al., 1997 randomisation central randomisation with each centre provided with a set of blinded numbered envelopes which required sequential opening. The arms were balanced per centre and per block of six patients blinding concealment of treatment allocation inclusion of all randomised participants in analysis (ITT) analysis for efficacy carried out on an ITT basis; analysis of safety based on all patients who received study medication description of withdrawals reasons for discontinuation of treatment are provided objective outcomes Zoubek et al., 1992 randomisation non-randomised blinding open-label trial concealment of treatment open-label trial allocation inclusion of all randomised NA participants in analysis (ITT) description of withdrawals no patients were withdrawn objective outcomes Walsh et al., 1999 (adult and paediatric patients) randomisation computerised randomisation assigned according to centre and risk stratum blinding double-blind concealment of treatment allocation study drug concentrations were adjusted so volume of solution in intravenous bag Liposomal amphotericin B fungal infections 12

13 Trial Done Comments was the same for both drugs; infusion bottles and tubing were opaque or covered in opaque wrapping inclusion of all randomised participants in analysis (ITT) description of withdrawals objective outcomes Chisholm et al., 1999 randomisation non-randomised (comparative retrospective review) blinding non-blinded concealment of treatment NA allocation inclusion of all randomised NA participants in analysis (ITT) description of withdrawals not reported objective outcomes NA=not applicable The Prentice et al (1997) trial is the only available randomised and blinded trial comparing liposomal amphotericin B and amphotericin B deoxycholate in paediatric patients (the paediatric trial is reported in combination with the adult trial). It appears that the Prentice et al (1997) trial is essentially accepted as providing sufficient confirmatory evidence for the use of liposomal amphotericin B in paediatric patients, given the lack of additional trials in the past decade. In addition, the range of infections, relatively small population sizes and severity of disease may limit the feasibility of large-scale randomised trials in this population. The Walsh et al (1999) trial is also randomised and blinded, however results for adult and paediatric patients are not separated. The remaining comparative trials were not randomised and not blinded. Consequently, the amount of high quality clinical trial evidence assessing the efficacy and safety of liposomal amphotericin B compared to amphotericin B deoxycholate in a paediatric population is minimal. However there is a considerable amount of non-randomised, non-comparative evidence assessing the use of liposomal amphotericin B in a paediatric population for a wide range of fungal infections. While this evidence may be subject to a number of sources of bias, and does not provide a comparison to amphotericin B deoxycholate, it does provide an indication of the safety and efficacy of liposomal amphotericin B in a number of situations. As such, a summary of this evidence is provided in Section to supplement the available comparative evidence Outcome measures Table provides the primary outcome measures used in the included comparative trials. Liposomal amphotericin B fungal infections 13

14 Table : Outcome measures used in the comparative trials Trial/study Outcomes Prentice et al., 1997 Primary outcome: safety, as measured by the number and severity of reported adverse reactions and blood chemistry and haematology laboratory assessments Zoubek et al., 1992 Primary outcome: rise in serum creatinine level; occurrence of fever and chills; death Walsh et al., 1999 Primary outcome: success of treatment, defined as composite of five criteria: survival for seven days after initiation of study drug; resolution of fever during the period of neutropenia; successful treatment of any baseline fungal infection if present; the absence of breakthrough fungal infections during drug administration or within seven days after treatment completion; absence of premature discontinuation of study drug due to toxicity or lack of efficacy. Chisholm et al., 1999 Primary outcome: nephrotoxicity measured by serum creatinine levels and serum potassium levels Summary of results comparative trials Table provides the baseline demographic characteristics of paediatric patients in the Prentice et al (1997) trial. Table : Baseline demographic characteristics of paediatric patients in the Prentice et al (1997) trial Characteristic c-amb (n=63) L-AMB 1 (n=70) L-AMB 3 (n=71) Age (median years) ANC < / ANC / ANC > / Temp 38 C Acute lymphoblastic leukaemia Acute myeloblastic leukaemia Lymphoma Others c-amb=conventional amphotericin B deoxycholate; L-AMB 1=liposomal amphotericin B 1mg/kg/day; L-AMB 3=liposomal amphotericin B 3mg/kg/day In the Prentice et al (1997) trial the primary outcome measure was safety, as measured by the number and severity of adverse events, blood chemistry and haematology assessment. These results are provided in Section 11.2 (Description of adverse events/reactions) below. Table provides the number and percentage of patients responding to treatment in the Prentice et al (1997) paediatric trial. Table : Responders in the Prentice et al (1997) paediatric trial Outcome c-amb L-AMB 1 L-AMB 3 p value Responders n (% of patients) 31 (51%) 45 (64%) 45 (63%) 0.22 c-amb=conventional amphotericin B deoxycholate; L-AMB 1=liposomal amphotericin B 1mg/kg/day; L-AMB 3=liposomal amphotericin B 3mg/kg/day Liposomal amphotericin B fungal infections 14

15 While a greater proportion of patients treated with liposomal amphotericin B responded to treatment compared to those treated with amphotericin B deoxycholate, there was no statistically significant difference between the treatment groups. The Prentice et al (1997) paper reported that for adult and paediatric patients combined, liposomal amphotericin B 3mg/kg/day was statistically significantly more efficacious than amphotericin B deoxycholate (64% responders compared to 49%; p=0.03). There were no statistically significant differences observed between the 1mg/kg and 3mg/kg doses of liposomal amphotericin B. Table provides the baseline demographic characteristics of patients in the Walsh et al (1999) trial Table : Baseline demographic characteristics of patients in the Walsh et al (1999) trial Characteristic L-AMB (n=343) c-amb (n=344) Age mean years (range) 41 (2-79) 42 (2-80) Age group n (%) (11%) 37 (11%) (78%) 258 (75%) (11%) 49 (14%) Primary diagnosis n (%) Acute leukaemia 168 (49%) 165 (48%) Chronic leukaemia 23 (7%) 15 (4%) Lymphoma 64 (19%) 65 (19%) Myeloma 10 (3%) 13 (4%) Myelodysplasia 5 (1%) 8 (2%) Solid tumour 59 (17%) 56 (6%) Other 14 (4%) 22 (6%) c-amb=conventional amphotericin B deoxycholate; L-AMB=liposomal amphotericin B Table provides the results of the Walsh et al (1999) trial. Table : Results of the Walsh et al (1999) trial L-AMB (n=343) c-amb (n=344) Success rate Success rate Outcome Number (95% CI) Number (95% CI) Overall success % (45-56) % (44-55) Fever resolved during neutropenic % (53-63) % (53-63) period No breakthrough fungal infection % (86-93) % (85-92) Baseline fungal infection cured a % (48-98) % (39-94) Survived 7 days after drug initiation % (89-95) % (86-93 Study drug not prematurely discontinued due to toxicity or lack of efficacy % (82-89) % (77-85) c-amb=conventional amphotericin B deoxycholate; L-AMB=liposomal amphotericin B a 11 patients in each group had baseline fungal infections The Walsh paper reports that when sub-groups, including children only, were analysed for differences in efficacy, the results were consistent with the overall results of the trial which demonstrated no Liposomal amphotericin B fungal infections 15

16 differences between liposomal amphotericin B and amphotericin B deoxycholate. For all patients there was a trend toward improved survival for patients treated with liposomal amphotericin B as 25 patients died compared to 36 receiving amphotericin B deoxycholate (p=0.18). Fungal infections were reported as the primary or contributing cause of death in 4 patients receiving liposomal amphotericin B and 11 receiving amphotericin B deoxycholate (p=0.11). The Zoubek et al (1992) and Chisholm et al (1999) trials assessed only adverse events, results are provided in Section Summary of results non-comparative studies Table provides a summary of results of the non-comparative studies addressing the use of liposomal amphotericin B in paediatric patients. Table : Results of non-comparative studies Study Design Results Anak 2004 multicentre, post-marketing surveillance study of the use of liposomal amphotericin B in patients with fungal infections, including 242 children and 43 infants. Avci et al., 2008 Allinson et al., 2008 Buckler et al., 2008 Cesaro et al., 2006 Dornbusch et al., 1995 case report of two paediatric patients with invasive fungal infections treated with liposomal amphotericin B single centre observational cohort analysis of prophylactic use of liposomal amphotericin B in paediatric haemotopoietic stem cell recipients case report of the use of liposomal amphotericin B in paediatric patients with central venous catheter fungal infections case report of the use of high-dose liposomal amphotericin B in a paediatric allogeneic bone marrow transplant patient case report of five paediatric patients with invasive pulmonary aspergillosis treated with liposomal amphotericin B infants and children tolerated liposomal amphotericin B for greater duration than adults 1 patient recovered from fungal infection but died of massive pulmonary haemorrhage 1 patient received 42 days of liposomal amphotericin B treatment and recovered following 180 days 8 patients (73%) were alive and six had achieved a complete response and one a near complete and ongoing response to antifungal therapy one patient discontinued prophylaxis due to adverse events successful eradication of 4 of 6 cases of infection patient received cumulative dose of mg of liposomal amphotericin B over 21 months no discontinuation of treatment was required due to adverse events and liposomal amphotericin B was welltolerated patient died from septic shock one allergic reaction to liposomal amphotericin B; reversible renal potassium loss in all patients 3 of 5 patients died Liposomal amphotericin B fungal infections 16

17 Study Design Results Emminger et al., 1994 Juster- Reicher et al., 2000 Juster- Reicher et al., 2003 Lackner et al., 1992 Malani et al., 2005 Melamed et al., 2000 Pasic et al., 1997 Ringden and Tollemar 1993 Ringden et al., 1997 non-comparative study of the use of liposomal amphotericin B for the treatment of children with cancer and invasive fungal infection retrospective review of efficacy and safety of liposomal amphotericin B in neonatal patients with systemic candidiasis non-comparative study of the use of high-dose liposomal amphotericin B in neonates with systemic candidiasis case report describing two low birthweight infants treated with liposomal amphotericin B retrospective review of the use of community-based amphotericin B treatment focusing on occurrence of adverse events study included adult and paediatric patients, with 14% of patients younger than 13 years case report of the use of liposomal amphotericin b to treat Candida endocarditis in a paediatric patient non-comparative study in which liposomal amphotericin B was administered to children who had undergone bone marrow transplant. non-comparative study of the use of liposomal amphotericin B for the treatment of invasive fungal infections in 61 immunocompromised children retrospective review of children undergoing bone marrow transplantation receiving liposomal amphotericin B no acute adverse reactions or organ function abnormalities in 402 administrations of liposomal amphotericin b to 16 children fungal eradication achieved in92% of episodes 83% of infants considered clinically cured no major adverse events recorded 2 infants (8%) died due to systemic candidiasis fungal eradication achieved in 39 of 41 (95%) episodes fungal eradication more rapid in patients treated early with high doses overall mortality 5% (2 of 37 patients) although mortality related to candidiasis in only 1 patient liposomal amphotericin b given for 41 courses (36%) lowest rate of nephrotoxicity associated with liposomal amphotericin B (13 of 41 courses, 32%) but not statistically significant different from that with amphotericin B deoxycholate (12 of 31 courses, 39% (p=0.17) complete disappearance of interatrial septal and superior vena cava vegetations after 14 days of liposomal amphotericin B treatment; no adverse events occurred 1 patient had a clinical reaction to treatment; one had a significant increase in creatinine level while on concomitant nephrotoxic therapy; 4 patients developed mild hypokalaemia which resolved with potassium supplementation no significant renal or hepatic toxicity observed no acute toxic side effects observed slight increases in serum creatinine in 3 cases of 8 cases of proven infection 67 were clinically cured of 8 cases of presumed infection 6 were clinically cured overall cure rate of 86% in 31 children with suspected invasive fungal infection fever cured in 21 (68%); in 14 verified or suspected cases treated for 5 days or more, clinical cure rate was 86% renal toxicity in 22 cases, increase in alkaline phosphatases in 24 cases Liposomal amphotericin B fungal infections 17

18 Study Design Results Roman et al., 2008 Scarcella et al., 1998 Stuecklin- Utsch et al., 2002 Uhlenbrock et al., 2001 Weitkamp et al., 1997 non-comparative study of the use of liposomal amphotericin B in paediatric allogeneic stem cell transplant patients open-label treatment of 40 neonates with verified deep fungal infections with liposomal amphotericin B retrospective review of the use of liposomal amphotericin B in children with documented or suspected fungal infection, with a focus on occurrence of elevated serum lipase levels randomised, open-label comparison of prophylaxis with liposomal amphotericin B compared to no prophylaxis in children with chemotherapy-related neutropenia retrospective review of treatment of very low birth-weight infants with liposomal amphotericin B liposomal amphotericin B was welltolerated and incidence of invasive mold infections following prophylaxis was 0% treatment was effective in 72.2% of patients 5 of 31 patients (16%) showed elevated serum levels of lipase no difference between liposomal amphotericin prophylaxis and no prophylaxis in occurrence of invasive fungal infections at one year liposomal amphotericin B discontinued in 19% of patients in prophylaxis arm due to infusionrelated adverse events significant increase in serum creatinine for liposomal amphotericintreated patients however elevation was reversible hypokalaemia observed in 30% of patients before liposomal amphotericin B treatment and 15% after; maximum creatinine levels decreased during treatment liposomal amphotericin B showed no nephrotoxicity all patients treated with liposomal amphotericin B eradicated fungi and recovered clinically Given the nature of the studies (case reports, retrospective reviews) and lack of comparison, no conclusions regarding the efficacy and safety of liposomal amphotericin B relative to amphotericin B deoxycholate can be drawn. However, the available evidence does suggest that across studies with considerable differences in design, patient populations, treatment courses and outcomes assessed, there is a low occurrence of adverse events associated with prophylaxis or treatment with liposomal amphotericin B as well as successful eradication of fungi or prevention of infection Summary of results review studies Table provides a summary of results reported by review studies addressing the use of liposomal amphotericin B in fungal infections. Liposomal amphotericin B fungal infections 18

19 Table : Summary of review studies Review Description/Results Barrett et al., 7 trials were included, no paediatric-specific analyses conducted; metaanalyses showed that lipid-based formulations significantly reduced risk of all cause mortality by 28% compared to amphotericin B deoxycholate, although there was no significant difference in efficacy; liposomal amphotericin B significantly reduced risk of doubling serum creatinine by 58% Chan and brief description of different antifungal agents, no paediatric-specific use Sorrell 2007 Chopra 2002 Dupont 2002 Girois et al., 2005 Hann and Prentice 2001 Hay 1994 Johansen and Goetzsche 2004 Leibovitz 2002 Ringden 2002 Robinson and Nahata 1999 Tollemar et al., 2001 Zaoutis et al., 2005 described prophylaxis of fungal infections found incidence of proven or probable invasive pulmonary aspergillosis to be 19%, with no mortality; liposomal amphotericin B was most effective fungal agent for treating rarer fungal species and could be used at doses of up to 12mg/kg with few side effects. No paediatric-specific assessment. review of efficacy and safety of lipid formulations of amphotericin B; no paediatric-specific review provided. liposomal amphotericin B was the least nephrotoxic of the lipid-based formulations of amphotericin B and amphotericin B deoxycholate the most nephrotoxic (see Section 11.2) review of trials of lipid-based formulations of amphotericin B, no specific paediatric assessment. Provides description of two abstracts assessing costeffectiveness of liposomal amphotericin B (see Section 12.2) review of the use of liposomal amphotericin B in the treatment of fungal infections; brief description of two paediatric studies (Zoubeck et al., 1992; Lackner et al., 1992) meta-analysis of 12 trials showed that lipid-based amphotericin B formulations were not more effective than amphotericin B deoxycholate for mortality, but decreased fungal infection, nephrotoxicity and number of dropouts. Metaanalysis of 3 trials showed no difference in mortality between liposomal amphotericin B and amphotericin B deoxycholate and greater efficacy for invasive fungal infections. No paediatric-specific analyses were conducted. three uncontrolled studies of liposomal amphotericin B in neonates with candidiasis demonstrated that the drug was effective and safe; there is some evidence supporting us eof high-dose (5-7mg/kg/day) treatment in very low birth weight infants as well as first line therapy. report on experience with liposomal amphotericin B in transplant recipients at a Swedish hospital; liposomal amphotericin B showed significant reduction in fungal colonisation and invasive Candida infections compared to placebo in a double-blind study in bone marrow transplantations, and eradication of fungal infections in 86% of 14 children undergoing bone marrow transplantation. Based on 1995 costs, the average cost of therapy based on 9 studies was $12,992. reviews 4 trials comparing liposomal amphotericin B and amphotericin B deoxycholate, only one (Prentice et al., 1997) includes paediatric patients; provides a monthly cost comparison of treatment for a 30kg child (see Section 12.2) found a good safety profile, improved rate of curing mycological proven infections and reduced mortality in fungal infections with liposomal amphotericin B in transplant recipients at a Swedish hospital, In two placebocontrolled prophylactic trials found liposomal amphotericin B was effective for preventing fungal colonization and invasive fungal infections. provide a description of available health economic evidence (see Section 12.2 for studies described) review of antifungal therapy for children; describes Anak Provides dosing table which recommends dose of 5mg/kg/day of liposomal amphotericin B. Liposomal amphotericin B fungal infections 19

20 10.3 Summary of available estimates of comparative effectiveness The one randomised trial comparing liposomal amphotericin B and amphotericin B deoxycholate in paediatric patients (Prentice et al., 1997) demonstrated similar efficacy between the two treatments, with a slightly greater proportion of responders observed with liposomal amphotericin B, however no statistically significant differences were observed for paediatric subjects. The Prentice et al (1997) trial (which focused on adverse events, see Section 10.4 below) is cited throughout the literature as evidence of the efficacy and safety of liposomal amphotericin B. The Walsh et al (1999) trial which included both adult and paediatric patients also reported no significant differences in efficacy between liposomal amphotericin B and amphotericin B deoxycholate. The two remaining comparative trials (Zoubek et al., 1992 and Chisholm et al., 1999) did not address efficacy. A review of the conventional and lipid formulations of amphotericin B (Robinson and Nahata 1999) stated that the only demonstrated advantage of the lipid formulations of amphotericin B is that larger doses can be given over longer periods with relatively lower toxicity than conventional amphotericin B. A meta-analysis of three trials comparing liposomal amphotericin B and amphotericin B deoxycholate (Johansen and Goetzsche 2004) found no significant difference in mortality between liposomal amphotericin B and amphotericin B deoxycholate although there was a trend toward greater efficacy for invasive fungal infection. Two of the trials in this metaanalysis included paediatric patients (Prentice et al., 1997; Walsh et al., 1999). These results contrast to those presented by Barrett et al (2003) who reported a meta-analysis examining all lipid formulations versus amphotericin B deoxycholate. This analysis showed that lipid-based formulations reduced the risk of all-cause mortality by 28%, however there was no statistically significant difference between lipid-based formulations and amphotericin B deoxycholate in efficacy. This apparent inconsistency in results is likely due to trial heterogeneity within the analyses. The available non-comparative studies provide some evidence of the efficacy of liposomal amphotericin B in preventing or curing fungal infections, however the design of these trials (case reports, retrospective reviews) does not allow firm conclusions to be drawn and provides no comparative evidence. Overall, the available comparative evidence indicates similar efficacy for liposomal amphotericin B and amphotericin B deoxycholate. 11. Summary of comparative evidence on safety 11.1 Estimate of total patient exposure to date There is no published estimate of total paediatric patient exposure to date available Description of adverse effects/reactions Liposomal amphotericin B fungal infections 20