TRANSPARENCY COMMITTEE

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1 The legally binding text is the original French version TRANSPARENCY COMMITTEE Opinion 28 May 2014 MABELIO 500 mg, powder for concentrate for solution for infusion B/10 vials (CIP: ) Applicant: BASILEA MEDICAL LTD INN ATC Code (2013) ceftobiprole J01DI01 (Other cephalosporins) Reason for the request Inclusion List concerned Hospital use (French Public Health Code L ) Indications concerned MABELIO is indicated for the treatment of the following infections in adults: Hospital-acquired pneumonia (HAP), excluding ventilator-associated pneumonia (VAP); Community-acquired pneumonia (CAP). Consideration should be given to official guidelines on the appropriate use of antibacterial agents. " HAS - Medical, Economic and Public Health Assessment Division 1/28

2 Actual Benefit Improvement in Actual Benefit Therapeutic Use The actual benefit of MABELIO 500 mg is: - moderate in the indication "treatment in adults of hospital-acquired pneumonia, excluding ventilator-associated pneumonia" - insufficient in the indication "treatment in adults of community-acquired pneumonia" Based on the current data available, MABELIO does not provide an improvement in actual benefit (IAB V, non-existent) in relation to the treatments currently used for managing hospital-acquired pneumonia, excluding ventilator-associated pneumonia. Community-acquired pneumonia: not applicable In the treatment of hospital-acquired pneumonia, excluding ventilator-associated pneumonia, it is difficult at present to specify the therapeutic use of MABELIO due to insufficient documentation regarding its clinical efficacy. Based on the indication in the Marketing Authorisation, MABELIO would be earmarked more specifically for patients requiring intravenous treatment in the case of multidrug-resistant bacterial infections (methicillin-resistant Staphylococcus aureus, penicillin-resistant Streptococcus pneumoniae) sensitive to ceftobiprole and when there is no alternative treatment available or when other alternative treatments cannot be used. In the treatment of community-acquired pneumonia, ceftobiprole does not have a role in relation to existing alternative treatments that are easier to use and of a narrower spectrum, especially as there are missing data on efficacy in community-acquired methicillin-resistant Staphylococcus aureus pneumonia and regarding S. pneumoniae strains not susceptible to penicillin. HAS - Medical, Economic and Public Health Assessment Division 2/28

3 01 ADMINISTRATIVE AND REGULATORY INFORMATION Marketing Authorisation (procedure) Prescribing and dispensing conditions/special status 3 April 2014 (decentralised procedure) List I Medicine for hospital prescription ATC Classification 2013 J J01 J01D J01DI J01DI01 Antiinfectives for systemic use Antibacterials for systemic use Other beta-lactam antibacterials Other cephalosporins and penems ceftobiprole medocaril 02 BACKGROUND This is a review of the application for inclusion of the proprietary medicinal product MABELIO 500 mg, powder for concentrate for solution for infusion, on the list of medicinal products approved for hospital use. Ceftobiprole, the active substance in MABELIO, is a bactericidal antibiotic from the cephalosporin group. It is active against: - Gram-positive bacteria (Staphylococcus aureus including methicillin-resistant strains, Streptococcus spp, Streptococcus pneumoniae including penicillin- and ceftriaxone-resistant strains) - Extended-spectrum beta-lactamase non-secreting Gram-negative bacteria (Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, Haemophilus influenzae, Haemophilus parainfluenzae). MABELIO is not active against extended-spectrum beta-lactamase (ESBL)-producing Gram-negative bacteria. 03 THERAPEUTIC INDICATIONS MABELIO is indicated for the treatment of the following infections in adults: Hospital-acquired pneumonia (HAP), excluding ventilator-associated pneumonia (VAP); Community-acquired pneumonia (CAP). Consideration should be given to official guidelines on the appropriate use of antibacterial agents. " HAS - Medical, Economic and Public Health Assessment Division 3/28

4 04 DOSAGE "The recommended dose of MABELIO is 500 mg, administered as an intravenous infusion over 2 hours every 8 hours. For CAP, the transfer to a suitable oral antibiotic may be considered after at least 3 days of treatment with ceftobiprole medocaril sodium administered intravenously, depending on the patient's clinical response. Paediatric population The safety and efficacy of MABELIO in children from birth to 18 years of age have not been established. MABELIO is not recommended in children and adolescents aged below 18 years. Elderly population No dose adjustment is required in elderly patients except in cases of moderate to severe renal impairment. Renal impairment No dose adjustment is required in patients with mild renal impairment (i.e. creatinine clearance [CrCl] of 50 to 80 ml/min). In patients with moderate renal impairment (CrCl of 30 to < 50 ml/min), the recommended dose of MABELIO is 500 mg, administered every 12 hours in the form of a 2-hour intravenous infusion. In patients with severe renal impairment (CrCl of < 30 ml/min), the recommended dose of MABELIO is 250 mg, administered every 12 hours in the form of a 2-hour intravenous infusion. Given limited clinical data and expected increased exposure to MABELIO and its metabolite, MABELIO should be used with caution in patients with severe renal impairment. End-stage renal disease requiring dialysis Ceftobiprole medocaril sodium can be used in haemodialysis. The recommended dose for patients with end-stage renal disease, with or without intermittent haemodialysis, is 250 mg, administered once every 24 hours. Patients with a creatinine clearance > 150 ml/min At the start of treatment, the prescribing doctor should assess the renal function of the patient depending on the creatinine clearance expressed in ml/minute. In patients with a supranormal creatinine clearance (> 150 ml/min), according to pharmacokinetic/pharmacodynamic considerations, extending the duration of the infusion to 4 hours is recommended. Hepatic impairment There is no experience with hepatic impairment patients. However, as ceftobiprole undergoes minimal hepatic metabolism and is primarily eliminated via the kidneys, no dose adjustment is deemed necessary in patients with hepatic impairment. Method of administration MABELIO should be reconstituted then diluted before intravenous infusion administration over a period of 2 hours. Precipitation may occur when MABELIO is mixed with solutions containing calcium in the same intravenous administration line. Consequently, MABELIO and solutions containing calcium, except for lactated Ringer's solution for injectable preparations, should not be mixed or administered simultaneously in the same intravenous line. " HAS - Medical, Economic and Public Health Assessment Division 4/28

5 05 THERAPEUTIC NEED The therapeutic need in the treatment of community-acquired or hospital-acquired pneumonia is in antibiotic therapy, which is adapted to the identified or likely bacteria and to their level of resistance Hospital-acquired pneumonia Hospital-acquired pneumonia is a respiratory infection acquired after more than 48 hours of hospitalisation. Ventilator-associated pneumonia corresponds to "any pneumonia occurring in a patient whose breathing is assisted by a machine either invasively through an endotracheal tube or a tracheotomy or non-invasively through a facial mask or another procedure within 48 hours prior to the infection occurring". 1,2,3 Hospital-acquired pneumonia can be classified according to its time of onset in relation to the day of hospitalisation and depending on risk factors for multi-resistance: - early hospital-acquired pneumonia, occurring between the 48 th hour and the 5 th day of hospitalisation, caused by microorganisms of community-acquired origin: endogenous flora (S. pneumoniae, H. Influenzae, methicillin-susceptible Staphylococci, E. Coli); - late hospital-acquired pneumonia occurring beyond the 5 th day, caused by microorganisms of hospital-acquired origin: exogenous flora (Pseudomonas, Acinetobacter, methicillin-resistant Staphylococci, Klebsiella, Enterobacter, Serratia). Antibiotic therapy should be started as soon as the diagnosis is made without waiting for the microbiological results (with certain exceptions). In the event of hospital-acquired pneumonia documented microbiologically, antibiotic therapy is adapted to isolated infectious agents. Dual therapy may be justified to expand the spectrum and reduce the risk of resistant mutants emerging. It is recommended in the event of an infection due to Pseudomonas sp, due to enterobacteriaceae Enterobacter sp, Klebsiella sp, Serratia sp, or depending on the host (immunocompromised subject) and imperative when fosfomycin, fusidic acid, fluoroquinolones or rifampicin are used. In the event of hospital-acquired pneumonia not documented microbiologically, the choice of empirical antibiotic therapy depends essentially on the time to onset (early or late pneumonia), the existence of risk factors for multidrug-resistant pathogens and the existence of previous antibiotic therapy. It should also take account of the host (chronic respiratory failure, cystic fibrosis, immunosuppression, neutropenia), and environmental factors. The recognition of certain aetiological risk factors should allow for a better match of empirical antibiotic therapy: coma and S. aureus, immunosuppression, use of steroids and L. pneumophila, chronic obstructive pulmonary disease (COPD), assisted breathing > 8 d, prior broad-spectrum antibiotic therapy and P. aeruginosa, neurosurgery, cranial trauma, inhalation, prior broad-spectrum antibiotic therapy and A. baumannii, deterioration of consciousness and anaerobes. The main methods for management are summarised in Table 1 shown below. 1 SFAR [French Society of Anaesthesia and Intensive Care]. Pneumopathie acquise sous ventilation mécanique. Posted online on 03 March 2009 and amended on 14 January Available online: [URL]: 2 Raoof S, Baumann MH. An official multi-society statement: ventilator-associated events: the new definition. Chest 2014; 145: CTINILS [Technical Committee for Nosocomial Infections and Healthcare-Associated Infections] Définition des infections associées aux soins. May 2007 HAS - Medical, Economic and Public Health Assessment Division 5/28

6 In all cases, initial antibiotic therapy should be re-assessed from the time the bacteriological results are obtained with, if possible, de-escalation of triple therapy towards dual therapy, or a broad-spectrum antibacterial towards a narrower spectrum one. The recommended duration of treatment is usually 7 days. In the presence of multilobe or necrotic disease, P. Aeruginosa, Acinetobacter sp, the duration of treatment is extended to 2 weeks. The initial combination of an aminoglycoside can usually be interrupted on the 3 rd day, in exceptional circumstances on the 5 th day of treatment. Table 1: EMPIRICAL ANTIBIOTIC THERAPY FOR HOSPITAL-ACQUIRED PNEUMONIA Early HAP Without prior antibiotic therapy With prior antibiotic therapy Monotherapy C3G or amoxicillin and clavulanic acid Dual therapy Suspected gram-negative bacilli [antipseudomonal beta-lactam 1 ] + [aminoglycoside or ciprofloxacin] Late HAP Not severe Severe - Suspected gram-negative bacilli [antipseudomonal beta-lactam 1 ] + [aminoglycoside or ciprofloxacin] -Suspected gram-positive cocci: glycopeptide/linezolid 3 Triple therapy [antipseudomonal beta-lactam 2 ] + [aminoglycoside or ciprofloxacin] + glycopeptide/linezolid 1 antipseudomonal beta-lactam: ceftazidime, cefepime, piperacillin/tazobactam 2 As well as the above-mentioned substances, imipenem and doripenem may be added 3 The quinupristin/dalfopristin combination could be an alternative 05.2 Community-acquired pneumonia Community-acquired pneumonia is an infection whose pathogen agent is acquired outside hospital. It is subdivided into four subgroups depending on epidemiological and clinical criteria: - outpatient, < 65 years, without co-morbidity; - outpatient, > 65 years and/or with co-morbidity; - patient who had to be hospitalised; - patient hospitalised in intensive care/critical care. The severity of pneumonia is also established on the basis of clinical and paraclinical data. The aetiology and management vary following the subgroup to which the patient is attached. The empirical character of the antibiotic therapy is the rule, in outpatients and in hospital. It should be started as soon as the diagnosis is made, ideally within 4 hours. The oral route is to be preferred when possible. The patient should have a systematic re-assessment after hours. The antibiotic therapy takes into account: - the bacteria most frequently involved and/or responsible for increased mortality: - S. pneumoniae, M. pneumoniae in outpatients - S. pneumoniae, L. pneumophila for severe CAP - reduced susceptibility of S. pneumoniae to penicillin (choice and dosages of β-lactam antibiotics), and especially resistance to macrolides; - the risk factors for the patient. In any event, Streptococcus pneumoniae should systematically and as a priority be taken into account because of the frequency and potential severity of the pneumococcal infection. It is only in cases of very serious forms of pneumonia hospitalised in critical care (bloody sputum, necrotising pneumonia, acute respiratory distress syndrome etc.) in a flu-like context that "heavy" antibiotic therapy active against methicillin-resistant S.aureus (MRSA) with antibiotics with anti-toxin activity may be proposed. HAS - Medical, Economic and Public Health Assessment Division 6/28

7 The recommended empirical antibiotic therapy depending on the clinical situations is the following (Tables 2.1,.2,.3,.4 and.5): 4 Table 2.1: Empirical antibiotic therapy for acute community-acquired pneumonia (ACAP) in outpatient adults, without any signs of severity Subject presumed healthy, without any signs of severity Suspected pneumococci (sudden onset) Doubt between "atypical" pneumococci and bacteria First choice Prioritise effective treatment against S. pneumoniae Amoxicillin Amoxicillin or pristinamycin or telithromycin 6 Failure at 48 h Macrolide or antipneumococcal fluoroquinolones (levofloxacin) 5 or pristinamycin or telithromycin 6 Hospitalisation if second failure Macrolide or antipneumococcal fluoroquinolones or pristinamycin or telithromycin 6 Hospitalisation if second failure Hospitalisation/diagnostic and therapeutic re-assessment** Suspicion of "atypical" bacteria 7 Macrolide Amoxicillin or antipneumococcal fluoroquinolones (levofloxacin)5 or pristinamycin or telithromycin 6 Subject with co-morbidity(ies) or elderly subjects (outside hospital) without any signs of severity [elderly subject in hospital see below] Amoxicillin/clavulanic acid or antipneumococcal fluoroquinolones (levofloxacin)5 or ceftriaxone* Hospitalisation if second failure Hospitalisation * IV, IM or SC, if oral route not possible ** Hospitalisation: pristinamycin and telithromycin being active against atypical pneumococci and bacteria, their failure should lead to diagnostic and therapeutic re-assessment 4 Mise au point: Antibiothérapie par voie générale dans les infections respiratoires basses de l adulte [Clarification : Systemic antibiotic therapy in lower respiratory tract infections in adults] AFSSAPS [French Healthcare Product Safety Agency] 14 June The antipneumococcal fluoroquinolones should not be prescribed if the patient has received fluoroquinolone antibiotics, whatever the indication, within the last 3 months. Using them with caution in hospital is recommended (risk of transmission of resistant strains) and in elderly subjects on corticotherapy via the general route of administration (increased risk of tendinopathy). Levofloxacin proved its clinical efficacy in severe CAP in critical care and legionella, and, as such, use of respiratory fluoroquinolone is to be preferred. Oral and intravenous moxifloxacin is restricted to the treatment of community-acquired pneumonia when no other antibiotic can be used. 6 In comparison with other antibiotics, telithromycin is associated with an increased risk of occurrence of serious adverse effects. It can be used if amoxicillin or pristinamycin cannot be prescribed. 7 Suspicion of atypical bacteria (Chlamydophila (ex Chlamydiae), Mycoplasma, Legionella) if young subject < 40 years, gradual onset, moderate fever, epidemiological context, associated extra-respiratory manifestations. HAS - Medical, Economic and Public Health Assessment Division 7/28

8 Table 2.2: Empirical antibiotic therapy of non-serious CAP, hospitalised (emergency or medical services), general situation First choice Failure at 48 h Arguments in favour of pneumococci (pneumococci strongly suspected or documented) Young subject, elderly subject Amoxicillin or subject with co-morbidity(ies) No arguments in favour of pneumococci First choice Re-assessment Failure of beta-lactam at 48 h Young subject Amoxicillin In combination with macrolide or substitution by antipneumococcal fluoroquinolones (levofloxacin)5 Elderly subject* Subject with co-morbidity(ies) or pristinamycin or telithromycin 6 Amoxicillin + clavulanic acid or cefotaxime or ceftriaxone or PO antipneumococcal fluoroquinolones (levofloxacin)5 Re-assessment In combination with macrolide or substitution by antipneumococcal fluoroquinolones (levofloxacin)5 Re-assessment including in hospital 3 Suspicion of atypical bacteria (Chlamydophila (ex Chlamydiae), Mycoplasma, Legionella) if young subject < 40 years, gradual onset, moderate fever, epidemiological context, associated extra-respiratory manifestations. 4 Presence of gram-positive cocci at the direct sputum cytology examination and/or positive pneumococcal antigenuria and negative Legionella antigenuria. Table 2.3: Empirical antibiotic therapy for serious CAP (intensive care unit or critical care unit) Young subject, elderly subject, subject with co-morbidity(ies) Risk factors for Pseudomonas: bronchiectasis, cystic fibrosis, history of COPD exacerbations caused by P. aeruginosa C3G (IV cefotaxime or IV ceftriaxone) + IV macrolide or antipneumococcal fluoroquinolones (levofloxacin) 5 Anti-Pseudomonas beta-lactam antibiotics: 8 - piperacillin/tazobactam - or cefepime - or carbapenem: 9 - imipenem/cilastatin - or meropenem - or doripenem + aminoglycoside (amikacin or tobramycin) for a maximum of 5 days + antibiotic active against intracellular bacteria: IV macrolide or IV antipneumococcal fluoroquinolones (levofloxacin) 5 8 Ceftazidime is not recommended due to insufficient intrinsic activity against S. pneumoniae. 9 Ertapenem is not recommended due to insufficient intrinsic activity against P. aeruginosa. HAS - Medical, Economic and Public Health Assessment Division 8/28

9 Table 2.4: Empirical antibiotic therapy for CAP, flu-like context outside critical care unit First choice Second choice No orientation Outpatient Amoxicillin/clavulanic acid pristinamycin or telithromycin 6 Hospitalisation Young subject Hospitalisation Elderly subject Co-morbidity(ies) Amoxicillin/clavulanic acid pristinamycin or telithromycin 6 Amoxicillin/clavulanic acid or C3G* (cefotaxime, ceftriaxone) antipneumococcal fluoroquinolones (levofloxacin) 5 In all cases if S. pneumoniae Amoxicillin** strongly suspected or documented 10 * C3G (3rd-generation cephalosporins): cefotaxime is to be preferred because of a better intrinsic activity against Staphylococcus ** If true allergy contraindicating beta-lactam antibiotics: Young subject: pristinamycin or telithromycin. Co-morbidity(ies), serious form, elderly subject: antipneumococcal fluoroquinolones Table 2.5: Empirical antibiotic therapy for pneumonia in critical care, flu-like context General case Very serious pneumonia Necrotising pneumonia, Strong presumption of PVL + MRSA First choice C3G* (cefotaxime) ± IV macrolide or antipneumococcal fluoroquinolones (levofloxacin) 5 C3G* (cefotaxime) + glycopeptide and clindamycin or rifampicin or C3G* (cefotaxime) + linezolid Second choice De-escalation depending on documentation when available * C3G (3rd-generation cephalosporins): ceftriaxone is not recommended because of an insufficient intrinsic activity against Staphylococcus PVL + MRSA Methicillin-resistant Staphylococcus aureus secreting the Panton Valentine toxin 05.3 Need for new medicines active against resistant bacteria For gram-positive aerobic cocci, there is a therapeutic need, particularly for treatment of vancomycin-resistant enterococci infections (VRE) and methicillin-resistant staphylococci (MRSA). Likewise, for gram-negative aerobic bacteria, the emergence of resistance (Enterobacteriaceae, Pseudomonas aeruginosa and Acinetobacter) is a serious problem. To date, for the treatment of MRSA infections, the therapeutic need is covered by a few complex antibiotics: glycopeptide (vancomycin, teicoplanin), synergistin (quinupristin-dalfopristin), oxazolidinones (linezolid), cyclic lipopeptide (daptomycin); vancomycin being the conventional treatment. In this regard, ceftobiprole (MABELIO), active at least in vitro against germs such as MRSA, is a new therapeutic option, in response to this identified therapeutic need. 10 Presence of gram-positive cocci at the direct sputum cytology examination and/or positive pneumococcal antigenuria and negative Legionella antigenuria. HAS - Medical, Economic and Public Health Assessment Division 9/28

10 06 CLINICALLY RELEVANT COMPARATORS 06.1 Hospital-acquired pneumonia, excluding ventilator-associated pneumonia The comparators of the same therapeutic category as ceftobiprole are 3 rd generation cephalosporins (ceftazidime) or 4th generation (cefepime) injectables recommended in the treatment of hospital-acquired pneumonia or ventilator-associated pneumonia. NAME (nonproprietary name) Company FORTUM (ceftazidime) and its generics GSK AXEPIM (cefepime) and its generics BMS Indication* Severe infections due to organisms susceptible to ceftazidime, including meningitis, particularly due to Pseudomonas, but excluding those due to Listeria monocytogenes. Community-acquired lower respiratory tract infections and severe pneumonia Reimbursement - Hospital use since National Health Insurance since Marketing since Hospital use since National Health Insurance since Marketing since 1988 Other comparators: antibiotics of the same therapeutic indication, the same spectrum of antimicrobial activity or neighbour spectrum, used systemically, recommended for the treatment of hospital-acquired pneumonia. Antibiotic (nonproprietary name) Aminopenicillin + beta-lactamase inhibitor Amoxicillin + clavulanic acid Piperacillin-Tazobactam Carbapenem Imipenem Doripenem Fluoroquinolones Ciprofloxacin Aminoglycosides Amikacin Gentamicin Netilmicin Tobramycin Synergistin Pristinamycin Glycopeptide Teicoplanin Vancomycin Oxazolidinone Linezolid Trade name (company) AUGMENTIN (GLAXOSMITHKLINE), CIBLOR (Pierre FABRE MEDICAMENT) TAZOCILLINE (PFIZER HOLDING France) TIENAM (MSD France) DORIBAX (JANSSEN CILAG) CIFLOX (BAYER SANTE) No brand drugs GENTALLINE (MSD France) NETROMICINE (MSD France) NEBCINE (EREMPHARMA) PYOSTACINE (SANOFI AVENTIS France) TARGOCID (SANOFI AVENTIS France) No brand drugs ZYVOXID (PFIZER HOLDING France) HAS - Medical, Economic and Public Health Assessment Division 10/28

11 06.2 Community-acquired pneumonia The comparators of the same therapeutic category as ceftobiprole are 3 rd generation cephalosporins (ceftriaxone, cefotaxime) or 4 th generation (cefepime) injectables recommended in the treatment of acute community-acquired pneumonia during hospitalisation. NAME (nonproprietary name) Company Indication* Reimbursement ROCEPHINE (ceftriaxone) and its generics ROCHE Lower respiratory tract infections, in severe forms, particularly in subjects at risk (elderly subjects, alcoholics, immunocompromised patients, smokers and those with respiratory failure etc.), in particular for bacterial pneumonia (pneumococci, presumed to be gram-negative bacilli). - National Health Insurance and hospital use since 1984 AXEPIM (cefepime) and its generics BMS CLAFORAN (cefotaxime) and its generics SANOFI FRANCE ZINFORO (ceftaroline) and its generics ASTRAZENECA Community-acquired lower respiratory tract infections and severe pneumonia Severe infections due to organisms susceptible to ceftaxime, particularly septicaemia, endocarditis and meningitis, excluding those due to Listeria monocytogenes. Community-acquired pneumonia (CAP) Complicated skin and soft tissue infections (cssti) - Hospital use since National Health Insurance since Marketing since Hospital use since Marketing since None (insufficient AB 11 ) - Hospital use since 2013 (substantial AB, 11 IAB IV) * these antibiotics have broader indications: the only ones mentioned are the indications including community-acquired pneumonia. Other comparators: antibiotics of the same therapeutic indication, the same spectrum of antimicrobial activity or neighbour spectrum, used systemically, recommended for the treatment of community-acquired pneumonia. 11 Transparency Committee Opinion of 9 January 2013: - the Committee considers that the actual benefit of ZINFORO in relation to the treatments that are already available is insufficient in the "treatment of acute community-acquired pneumonia" to justify reimbursement by National Health Insurance. - the Committee considers that the actual benefit of ZINFORO is substantial in the "treatment of complicated skin and soft tissue infections", subject to compliance with special warnings and precautions for use. The Committee considers that ZINFORO provides a minor improvement in actual benefit (IAB IV) in the management of "complicated skin and soft tissue infections" HAS - Medical, Economic and Public Health Assessment Division 11/28

12 Antibiotic (nonproprietary name) Aminopenicillin Amoxicillin Aminopenicillin + beta-lactamase inhibitor Amoxicillin + clavulanic acid Piperacillin-Tazobactam Carbapenem Imipenem Fluoroquinolones Moxifloxacin Levofloxacin Macrolides Erythromycin Spiramycin Josamycin Roxithromycin Clarithromycin Dirithromycin Ketolides Telithromycin Synergistin Pristinamycin Glycopeptide Teicoplanin Vancomycin Oxazolidinone Linezolid Trade name (company) Several presentations AUGMENTIN (GLAXOSMITHKLINE), CIBLOR (Pierre FABRE MEDICAMENT) TAZOCILLINE (PFIZER HOLDING France) TIENAM (MSD France) IZILOX (BAYER SANTE) TAVANIC (SANOFI AVENTIS France) Several presentations ROVAMYCINE (SANOFI AVENTIS France) JOSACINE (ASTELLAS PHARMA) CLARAMID (PFIZER HOLDING France), RULID (SANOFI AVENTIS France) NAXY (CEPHALON France), ZECLAR (ABBOTT FRANCE SA) DYNABAC (ALMIRALL SAS) KETEK (AVENTIS PHARMA SA) PYOSTACINE (SANOFI AVENTIS France) TARGOCID (SANOFI AVENTIS France) No brand drugs ZYVOXID (PFIZER HOLDING France) Conclusion The comparators mentioned are all clinically relevant because no antibiotic alone covers all the bacteria involved in the infections. In community-acquired pneumonia, the most relevant comparators are injectable cephalosporins (the same therapeutic category) recommended in the treatment of community-acquired pneumonia during hospitalisation (ceftriaxone, cefotaxime, cefepime). However, these antibiotics are not active against MRSA. In hospital-acquired pneumonia, the most relevant comparators are injectable cephalosporins (the same therapeutic category) recommended in the treatment of hospital-acquired pneumonia (ceftazidime, cefepime). In the two indications, given the activity of ceftobiprole in vitro against MRSA, the most relevant comparators in terms of this germ are glycopeptide-type antibiotics (vancomycin, teicoplanin) or oxazolidinones (linezolid). HAS - Medical, Economic and Public Health Assessment Division 12/28

13 07 INTERNATIONAL INFORMATION ON THE MEDICINAL PRODUCT MABELIO is not currently marketed in any country. 08 ANALYSIS OF AVAILABLE DATA 08.1 Efficacy In the indication "hospital-acquired pneumonia, excluding ventilatorassociated pneumonia" The evaluation of the efficacy of ceftobiprole (MABELIO) is based on non-inferiority versus ceftazidime + linezolid study in terms of the clinical cure rate during a follow-up visit in patients with hospital-acquired pneumonia (Study BAP248/307). This study was published. 12 Study design Double-blind, randomised, ceftazidime + linezolid-controlled phase III study. Therapeutic regimen IV ceftobiprole: 500 mg/8 h, 120 min. infusion Ceftazidime: 2 g/8 h, 120 min. infusion IV linezolid: 600 mg/12 h, 60 min. infusion The treatments were administered over 7 to 14 days. If the treatment exceeded 14 days, the patients had to interrupt the study. Inclusion and non-inclusion criteria: The patients included had to be aged at least 18 years and had to have hospital-acquired pneumonia and have an APACHE II (Acute Physiology Score and Chronic Health Evaluation II) score 8 and 25. The non-inclusion criteria included in particular any (co)-infection via ESBL-producing bacteria, Proteus vulgaris, non-fermenting bacteria resistant to ceftazidime or linezolid, the administration of systemic antibiotic therapy for more than 24 hours over the 48 hours preceding the inclusion or even the following lung conditions: - known bronchial obstruction or a history of post-obstructive pneumonia - primary lung cancer or any other unresectable malignant lung tumour - cystic fibrosis - pulmonary abscess - pleural effusion considered as the main reason for infection - active tuberculosis - pneumonia suspected as related to aspiration or atypical bacteria (Legionella spp., M. pneumoniae, or C. pneumoniae), or a virus or Pneumocystis jiroveci. Primary efficacy endpoint: Clinical cure rate at the follow-up visit (7 to 14 days after the end of treatment) in the clinically evaluable and intention to treat population. The clinical evaluation before and after the treatment included an examination of clinical signs associated with pneumonia (findings on auscultation, cough, sputum, fever or hypothermia). Statistical analysis - Intention to treat population (ITT): all patients randomised to one of the treatment groups, 12 Awad SS, Rodriguez AH, Chuang YC, et al. A phase 3 randomized double-blind comparison of ceftobiprole medocaril versus ceftazidime plus linezolid for the treatment of hospital-acquired pneumonia. Clin Infect Dis Apr 9. HAS - Medical, Economic and Public Health Assessment Division 13/28

14 - Microbiological intention to treat population (mitt): all patients randomised to one of the treatment groups and for whom the pathogen agent was determined from baseline, - Clinically evaluable population (CE): all patients randomised to one of the treatment groups and who received at least one dose of the studied treatment, but excluding patients considered "clinically non-evaluable" at the follow-up visit, - Microbiologically evaluable population (ME): all clinically evaluable patients randomised to one of the treatment groups for whom the pathogen agent was determined from baseline, but excluding patients considered "microbiologically non-evaluable" at the follow-up visit. - Safety analysis population: all patients who were randomised and received at least one dose of study treatment. Ceftobiprole was considered non-inferior to the comparator treatment if the lower limit of the 95% confidence interval of the difference between the clinical success rates of ceftobiprole and the comparator treatment was higher than -15% in the ITT and CE population. However, it should be noted that the EMA guidelines recommend a margin of non-inferiority of -12.5% in the evaluation of antibiotic therapies in hospital-acquired pneumonia and/or ventilator-associated pneumonia. 13 Results: A total of 781 patients were randomised (ITT population) according to a ratio of 1: 1, i.e. 391 patients in the ceftobiprole group and 390 patients in the ceftazidime in combination with linezolid group. The demographic and medical characteristics were comparable between the two treatment groups, apart from sex (71% men in the ceftobiprole group versus 62% in the ceftazidime-linezolid group). The mean age of the patients was 60.6 years. The percentage of subjects with an APACHE II score of between 8 and 19 was 88% on average in the two treatment groups and only 12% had a score of between 20 and 25. The mean duration of antibiotic therapy was comparable in the two groups of clinically evaluable patients (9.7 days in the ceftobiprole group vs 10 days in the ceftazidime+linezolid group, on average). The numbers in the CE population were as follows: - ceftobiprole group: n = ceftazidime + linezolid: n = 244 The main reasons for excluding patients in the CE population were: no follow-up visit and administration of an effective treatment in combination. Primary efficacy endpoint: The non-inferiority of ceftobiprole vs ceftazidime+linezolid was demonstrated in terms of the clinical cure rate at the follow-up visit, the lower limit of the confidence interval of the difference in clinical cure rates between the two treatment groups (difference: -2.0; 95% CI = [-10.0; 6.1]) being above the predefined non-inferiority threshold (-15%) (Table 3). 13 EMA/CHMP/351889/2013. Addendum to the guideline on the evaluation of medicinal products indicated for treatment of bacterial infections. 24 October EMA/CHMP/351889/2013 Available online: [URL]: HAS - Medical, Economic and Public Health Assessment Division 14/28

15 Table 3: Clinical cure rate at the follow-up visit Treatment groups Difference [95% CI] BAP Study 248/307 Ceftobiprole n/n (%) Ceftazidime+linezolid CE population, n/n (%) 174/251 (69.3) 174/244 (71.3) -2.0 [-10.0; 6.1] ITT population, n/n (%) 195/391 (49.9) 206/390 (52.8) -2.9 [-10.0; 4.1] Subgroup analyses, planned in the protocol, were carried out using the primary efficacy endpoint (Table 4): A similar efficacy was observed between the two treatment groups, in the subgroup of patients with non-ventilator-associated hospital-acquired pneumonia, corresponding with the population defined by the Marketing Authorisation wording. The clinical cure rate was 77.8% in the ceftobiprole group versus 76.2% in the ceftazidime+linezolid group. However, the clinical cure rate was lower with ceftobiprole than with the ceftazidime+linezolid combination in the subgroup of patients with ventilator-associated hospital-acquired pneumonia (37.7% versus 55.9%). Table 4: Clinical cure rate at the follow-up visit in the CE population in patients with ventilator-associated hospital-acquired pneumonia or non-ventilator-associated hospital-acquired pneumonia Non-ventilator-associated hospital-acquired pneumonia Ventilator-associated hospital-acquired pneumonia Ceftobiprole n/n (%) Ceftazidime+linezolid n/n (%) Difference (%) [95% CI] 154/198 (77.8) 141/185 (76.2) 1.6 [-6.9; 10.0] 20/53 (37.7) 33/59 (55.9) [-36.4; -0.0] Secondary endpoint: In the ME population (n=332), the microbiological eradication percentage at the follow-up visit was 53.7% (87/162) in the ceftobiprole group vs 62.4% (106/170) in the ceftazidime+linezolid group (difference = -8.6; 95% CI = [-19.2; 1.9]). In the ME population of the subgroup of patients with non-ventilator-associated hospital-acquired pneumonia (population defined by the Marketing Authorisation wording) (n=236), the microbiological eradication percentage at the follow-up visit was 62.9% (73/116) in the ceftobiprole group vs 67.5% (81/120) in the ceftazidime+linezolid group (difference = -4.6; 95% CI = [-16.7; 7.6]). In the ME population of the subgroup of patients with ventilator-associated hospital-acquired pneumonia (n=96), the microbiological eradication percentage at the follow-up visit was 30.4% (14/46) in the ceftobiprole group vs 50.0% (25/50) in the ceftazidime+linezolid group (difference = -19.6; 95% CI = [-38.8; -0.4]). The numbers considered by identified strain are too low to allow any robust interpretation of the results in terms of clinical and microbiological success, in particular for MRSA, streptococci and Pseudomonas aeruginosa (Tables 5 and 6). HAS - Medical, Economic and Public Health Assessment Division 15/28

16 Table 5: Clinical cure rate and microbiological eradication percentage by major bacterial strain isolated at baseline / total ME study population Ceftobiprole N=162 n (%) Ceftazidime+ linezolid N=170 n (%) Gram-positive bacteria S. aureus Clinical cure rate MSSA MRSA S. pneumoniae Penicillin-resistant S. pneumoniae Gram-negative bacteria P. aeruginosa - with associated antipseudomonal treatment - without associated antipseudomonal treatment E. coli K. pneumoniae (58) 33 (59) (54) 20 (75) 27 17/27 13/ /11 7/11 3 1/3 1/ (63) 8/13 10/14 13 (48) 20 10/20 10/ /16 10/ (68) 49 (64) (69) 33 (67) 28 18/28 16/ /15 14/15 3 2/3 2/ (71) 9/14 14/20 19 (56) 14 8/14 8/ /23 16/23 HAS - Medical, Economic and Public Health Assessment Division 16/28

17 Table 6: Clinical cure rate and microbiological eradication percentage by major bacterial strain isolated at baseline / ME population (patients with ventilator-associated or non-ventilator-associated hospital-acquired pneumonia: non-vap HAP patients and VAP HAP patients) Non-VAP HAP patients VAP HAP patients Ceftobiprole N=116 n (%) Ceftazidime+ linezolid N=120 n (%) Ceftobiprole N=46 n (%) Ceftazidime+ linezolid N=50 n (%) Gram-positive bacteria S. aureus Clinical cure rate (72) 23 (59) (73) 31 (63) 25 9/25 10/ /28 18/28 MSSA 20 15/20 15/ (80) 21 (70) 17 5/17 5/ /19 12/19 MRSA 19 13/19 8/ /19 10/19 8 4/8 5/8 9 6/9 6/9 S. pneumoniae 7 7/ /14 4 0/4 1 1/1 Penicillin-resistant S. pneumoniae 1 1/1 3 2/3 2 0/2 0 - Gram-negative bacteria P. aeruginosa - with associated antipseudomonal treatment - without associated antipseudomonal treatment 16 12/16 5/6 7/10 9 (56) 20 14/20 5/6 9/14 11 (55) 11 5/11 3/7 2/4 4/ /14 5/8 5/6 8/14 E. coli 14 8/14 8/ /11 7/11 K. pneumoniae 12 11/12 10/ /19 15/ In the "community-acquired pneumonia" indication The evaluation of the efficacy of ceftobiprole (MABELIO) in this indication is based on a non-inferiority versus ceftriaxone ± linezolid study in terms of the clinical cure rate during a follow-up visit in patients with acute community-acquired pneumonia requiring hospitalisation (Study CAP-3001). This study was published. 14 Study design Double-blind, randomised, controlled, phase III study versus ceftriaxone with or without linezolid. 14 Nicholson SC, Welte T, File TM Jr, et al. A randomised, double-blind trial comparing ceftobiprole medocaril with ceftriaxone with or without linezolid for the treatment of patients with community-acquired pneumonia requiring hospitalisation. Int J Antimicrob Agents. 2012; 39: HAS - Medical, Economic and Public Health Assessment Division 17/28

18 Therapeutic regimen IV ceftobiprole: 500 mg/8 h, 120 min. infusion. IV ceftriaxone: 2 g/24 h, 30 min. infusion. IV linezolid: 600 mg/12 h, 60 min. infusion or IV placebo/12 h. Linezolid or the placebo was administered in patients for whom treatment for MRSA or ceftriaxone-resistant S. pneumoniae was considered necessary by the investigator, or when the incidence of MRSA was increased in the isolations of community-acquired pneumonia collected in the establishment or the region, or when the patients had specific risk factors (history of infection due to MRSA, positive MRSA culture). The treatment with linezolid or placebo had to be stopped after 48 hours if the MRSA was not isolated in the baseline cultures. Inclusion and non-inclusion criteria: The patients included had to be aged at least 18 years and had to have severe community-acquired pneumonia requiring hospitalisation and IV antibiotic therapy for at least 3 days (72 hours). The non-inclusion criteria included in particular any diagnosed or suspected extra-pulmonary infection (including meningitis, endocarditis, septic arthritis, osteomyelitis), the administration of systemic antibiotic therapy for more than 24 hours over 3 days preceding the inclusion (systemic antibiotic therapy for over 24 hours was permitted if the microbiologically identified bacteria in a patient were resistant to antibiotics previously administered) or even the following lung conditions: - known bronchial obstruction or a history of post-obstructive pneumonia - primary lung cancer or any other unresectable malignant lung tumour - cystic fibrosis - pulmonary abscess - pleural effusion considered as the main reason for infection - active tuberculosis - pneumonia suspected as related to aspiration or atypical bacteria (Legionella spp., M. pneumoniae, or C. pneumoniae), or a virus or Pneumocystis jiroveci. Primary efficacy endpoint: Clinical cure rate at the follow-up visit (7 to 14 days after the end of treatment) in the clinically evaluable and intention to treat population. Statistical analysis - Intention to treat population (ITT): all patients randomised to one of the treatment groups, - Microbiological intention to treat population (mitt): all patients randomised to one of the treatment groups and for whom the pathogen agent was determined from baseline, - Clinically evaluable population (CE): all patients randomised to one of the treatment groups and who received the study treatment for at least 48 hours, but excluding patients considered "clinically non-evaluable" at the follow-up visit, - Microbiologically evaluable population (ME): all clinically evaluable patients randomised to one of the treatment groups for whom the pathogen agent was determined from baseline, but excluding patients considered "microbiologically non-evaluable" at the follow-up visit. - Safety analysis population: all patients who were randomised and received at least one dose of study treatment. Ceftobiprole was considered non-inferior to the comparator treatment if the lower limit of the 95% confidence interval of the difference between the clinical success rates of ceftobiprole and the comparator treatment was lower than -10% in the ITT and CE population. The EMA 7 guidelines recommend a margin of non-inferiority of -10% in the evaluation of antibiotic therapies in community-acquired pneumonia. Results A total of 638 patients were randomised (ITT population) in a ratio of 1:1, i.e. 314 patients included in the ceftobiprole group and 324 patients included in the ceftazidime group with or without linezolid. HAS - Medical, Economic and Public Health Assessment Division 18/28

19 Patients demographic and medical characteristics were comparable in the different treatment groups: The mean age of the patients was 54.5 years (57% men) and around 18% of patients were aged over 75 years. The percentage of subjects with a PORT (FINE) classification 15 of I, II or III was 78% in the ceftobiprole group vs 77% in the ceftriaxone group, 21% vs 20% for those with a PORT classification of IV and 1% vs 2% for those with a classification of V. The percentage of patients with concomitant bacteriaemia was 3.0% versus 6.0%. The mean duration of antibiotic therapy was comparable in the two groups of patients with clinical cure (9.6 days on average). The numbers in the CE population were as follows: - ceftobiprole group: n = 231 (ceftobiprole + placebo n=23 (10%)) - ceftriaxone group: n = 238 (ceftriaxone + linezolid n=34 (14%)) The main reasons for non-inclusion of patients in the CE population were the non-confirmation of the diagnosis of community-acquired pneumonia during the central evaluation of chest x-rays carried out at baseline or isolation, at baseline, of a pathogen agent resistant to study treatments. Primary efficacy endpoint The non-inferiority of ceftobiprole vs ceftriaxone ± linezolid was demonstrated in terms of the clinical cure rate at the follow-up visit, the lower limit of the confidence interval of the difference in clinical cure rate between the two treatment groups (difference: -0.8; 95% CI = [-6.9; 5.3]) being above the predefined non-inferiority threshold (-10%) (Table 7). Table 7: Clinical cure rate at the follow-up visit Treatment groups Difference [95% CI] CAP-3001 Study Ceftobiprole n/n (%) Ceftriaxone +/- linezolid n/n (%) CE population, n/n (%) 200/231 (86.6) 208/238 (87.4) -0.8 [-6.9; 5.3] ITT population, n/n (%) 240/314 (76.4) 257/324 (79.3) -2.9 [-9.3; 3.6] NB.: The cure rate in patients who have been treated with linezolid in the ceftriaxone group was 73.5% (25/34) vs 82.6% (19/23) in patients who received the placebo in the ceftobiprole group. Secondary endpoint: In the ME population (n=144), the microbiological eradication percentage at the follow-up visit was 88.2% (60/68) in the ceftobiprole group vs 90.8% (69/76) in the ceftriaxone ± linezolid group (difference = -2.6; 95% CI = [-12.6; 7.5]). In terms of clinical and microbiological success by identified strain: the numbers considered by identified strain are quite low to allow any robust interpretation of the results to be made, in particular for MRSA, streptococci and Pseudomonas aeruginosa (Table 8). 15 Severity of pneumonia according to the Fine (PSI) score: Recommendations: Classes I-II: outpatient; class III: observation; classes IV-V: hospitalisation HAS - Medical, Economic and Public Health Assessment Division 19/28

20 Table 8: Clinical cure rate and microbiological eradication percentage by major bacterial strain isolated at baseline / ME population Ceftobiprole N=68 n (%) Ceftriaxone+/-linezolid N=76 n (%) Gram-positive bacteria S. aureus Clinical cure rate MSSA MRSA S. pneumoniae Penicillin-resistant S. pneumoniae Gram-negative bacteria P. aeruginosa E. coli K. pneumoniae H. influenzae H. parainfluenzae 7 7/7 7/7 6 6/6 6/6 1 1/1 1/ (93) 26 (93) 2 2/2 2/2 1 0/1 0/1 6 6/6 6/6 5 4/5 4/5 7 7/7 7/7 9 6/9 7/9 6 5/6 6/6 6 5/6 6/ (89) 33 (92) 3 3/3 3/3 2 2/2 2/2 1 0/1 0/1 7 7/7 7/ /14 13/14 7 6/7 6/7 HAS - Medical, Economic and Public Health Assessment Division 20/28

21 08.2 Safety/Adverse effects Study BAP248/307 The safety results were analysed in the ITT population, apart from 9 patients who had not received at least one dose of the treatment. - ceftobiprole group: n = ceftazidime+linezolid: n = 386 The adverse event rate was 77% (299/386 patients) in the ceftobiprole group versus 78% (300/386 patients) in the ceftazidime+linezolid group. The adverse event rate considered treatment-related was 25% (96/386) versus 25% (98/386). The most common adverse events related to treatment were: - gastrointestinal disorders (nausea, vomiting, diarrhoea) 7.0% versus 10.0%. - hyponatraemia (4.0% vs 3.0%), - hypokalaemia (2.0% vs 1.0%), - venous thrombosis (2.0% vs 1.0%), - skin rash (1.0% vs 2.0%), - oral candidiasis (2.0% vs 1.0%). The percentage of treatment discontinuations due to adverse events was higher in the ceftobiprole group (14%) than in the ceftazidime+linezolid group (10%). The percentage of treatment discontinuations due to adverse events considered treatment-related was comparable in the two treatment groups (4%). Serious adverse events were reported in 36% of patients in the ceftobiprole group and in 32% of patients in the ceftazidime+linezolid group. Serious adverse events that were treatment-related were reported in 4% versus 3%, the main ones being: hyponatraemia (1.0% vs 1.0%) and coma (1.0% vs 0.0%). Mortality rates were 23% in the ceftobiprole group and 22% in the ceftazidime+linezolid group. The mortality rate attributed to the treatment was comparable in both treatment groups (1%). In the patient subgroup "non-ventilator-associated hospital-acquired pneumonia", the safety results were comparable with the total study population in terms of AEs, serious AEs and treatment discontinuations due to AEs Study CAP-3001 The safety results were analysed in the ITT population, apart from 6 patients who had not received at least one dose of the treatment. - ceftobiprole group: n = ceftriaxone±linezolid: n = 322 The adverse event rate was 70% (217/310) in the ceftobiprole group versus 65% (208/322) in the ceftriaxone group. The adverse event rate considered treatment-related was higher in the ceftobiprole group (36%; 111/310) than in the ceftriaxone group (26%; 83/322). The most common adverse events related to treatment were: - nausea: 7.0% versus 2.0%, - vomiting: 5.0% vs 2.0%, - diarrhoea: 5.0% vs 5.0%, - venous thrombosis: 3.0% vs 2.0%, - skin rash: 2.0% vs <1.0%, - headaches: 3.0% vs 1.0%, HAS - Medical, Economic and Public Health Assessment Division 21/28

22 - dysgeusia: 2.0% vs <1.0%. The percentage of treatment discontinuations due to adverse events was 6% versus 4%. The percentage of treatment discontinuations due to adverse events considered treatment-related was 2% versus 1%. Serious adverse events were reported in 11% of patients in the ceftobiprole group versus 11% in the ceftriaxone group. There were very few serious adverse events considered related to treatment (1% in each group). The mortality rate was 3% in each treatment group. A death was attributed to the treatment in the ceftriaxone group due to "pneumonia" Summary of adverse effects (according to the SPC) The following adverse effects were reported during the treatment and follow-up at frequencies corresponding to: very common ( 1/10), common ( 1/100, <1/10), uncommon ( 1/1000, <1/100), rare ( 1/10,000, <1/1000), and frequency not known (cannot be estimated from the available data). Adverse effects reported in clinical trials and since marketing. System organ class Frequency Adverse events Infections Common Fungal infection (including vulvovaginal, oral and skin fungal infections) Blood and lymphatic system disorders Uncommon Clostridium difficile colitis** Uncommon Eosinophilia,*** leukopenia, anaemia, thrombocytosis, thrombocytopenia Frequency not known Agranulocytosis* Immune system disorders Common Uncommon Hypersensitivity (including urticaria, itchy rash and drug hypersensitivity) Anaphylaxis** Metabolism and nutrition disorders Common Uncommon Hyponatraemia Hypokalaemia Psychiatric disorders Uncommon Insomnia, agitation (including anxiety, panic attacks and nightmares) Nervous system disorders Respiratory, thoracic and mediastinal disorders Common Frequency not known Uncommon Dysgeusia, headache, dizziness, drowsiness*** Seizures*,** Dyspnoea, pharyngolaryngeal pain,*** asthma Gastrointestinal disorders Common Diarrhoea, nausea, vomiting, abdominal pain, dyspepsia Hepatobiliary disorders Common Elevated liver enzymes (including ASAT, ALAT, LDH and alkaline phosphatase) Skin and subcutaneous tissue disorders Common Rash (including macular, papular, maculopapular and generalised rash), pruritis. Musculoskeletal and Uncommon Muscle spasms*** connective tissue disorders Renal and Uncommon Renal impairment urinary disorders General disorders and Common Reactions at the infusion site administration site conditions Uncommon Peripheral oedema Investigations Uncommon Elevated serum triglycerides, elevation of serum creatinine, high blood sugar. Frequency not known Positive direct Coombs test * According to the cases reported post-marketing. As these reactions were cases reported spontaneously post-marketing, it is not possible to estimate their frequency reliably and this is therefore classified as unknown. ** see section 4.4 ***In the studies on cssti (complicated skin and soft tissue infections) only HAS - Medical, Economic and Public Health Assessment Division 22/28

23 08.3 Summary & discussion In the indication "hospital-acquired pneumonia, excluding ventilator-associated pneumonia": In a double-blind, randomised study (Studies BAP248/307, n=781) conducted in patients with hospital-acquired pneumonia, with or without mechanical ventilation, ceftobiprole (500 mg/8 hours, for on average 10 days) was non-inferior (delta threshold = 15%) to IV ceftazidime (2 g/8 h) in combination with IV linezolid (600 mg/12 h). In the clinically evaluable population (patients who received treatment for at least 48 h and evaluable at the follow-up visit 7 to 14 days after stopping the treatment), the clinical cure rates (primary endpoint) were, in patients treated with ceftobiprole versus those treated with ceftazidime+linezolid, 69.3% vs 71.3% (difference = -2.0, 95% CI = [-10.0; 6.1]). In the intention to treat population, these cure rates were 49.9% versus 52.8% (difference = -2.9, 95% CI = [-10.0; 4.1]). Moreover, the Marketing Authorisation only considers patients with hospital-acquired pneumonia, excluding ventilator-associated pneumonia. Indeed, a subgroup analysis showed a difference in response between patients with non-ventilator-associated hospital-acquired pneumonia and those with ventilator-associated hospital-acquired pneumonia: - For patients with non-ventilator-associated pneumonia, a similar efficacy was observed between both treatment groups (77.8% versus 76.2%, difference = 1.6, 95% CI [-6.9; 10.0]). - In contrast, in patients with ventilator-associated pneumonia, the clinical cure rate was lower with ceftobiprole than with the ceftazidime+linezolid combination (37.7% versus 55.9%, difference = 18.2, 95% CI [-36.4; -0.0]). Moreover, attention must be drawn to the limited number of infections caused by multidrug-resistant bacteria (MRSA, penicillin-resistant S. pneumoniae) and the absence of evaluation (non-inclusion criteria) in patients with prognostic factors of severity, such as septic shock, associated respiratory distress, an underlying precarious host (immunosuppression, cystic fibrosis etc.). Ceftobiprole has not demonstrated its efficacy against Pseudomonas aeruginosa and is not active against ESBL enterobacteriaceae. In the "community-acquired pneumonia" indication: In a double-blind, randomised study (Studies CAP-3001, n=638) conducted in hospitalised patients, ceftobiprole (500 mg/8 hours, for on average 10 days) was non-inferior (delta threshold = 10%) to IV ceftriaxone (2 g/day) whether combined or not combined with IV linezolid (600 mg/12 h). In the clinically evaluable population (patients who received treatment for at least 48 h and evaluable at the follow-up visit 7 to 14 days after stopping the treatment), the clinical cure rates (primary endpoint) were, in patients treated with ceftobiprole versus those treated with ceftriaxone+/-linezolid, 86.6% vs 87.4% (difference = -0.8, 95% CI = [-6.9; 5.3]). In the intention to treat population, these cure rates were 76.4% versus 79.3% (difference = -2.9, 95% CI = [-9.3; 3.6]). However, the clinical relevance of these results is questionable and their transferability to (severe) community-acquired pneumonia due to penicillin-resistant S. pneumoniae is very limited. In fact: On the one hand, in terms of organisms identified at baseline The clinical efficacy of ceftobiprole has not been established in community-acquired pneumonia due to penicillin-resistant S. pneumoniae, very few of whichhave been included in the trials (2 cases treated with ceftobiprole and 3 cases treated with ceftriaxone +/- linezolid), or in the case of community-acquired pneumonia due to methicillin-resistant staphylococci (1 MRSA included in the group treated with ceftobiprole and none in the ceftriaxone +/- linezolid group), but with organisms "susceptible" to ceftobiprole in vitro. On the other hand, in terms of the population studied HAS - Medical, Economic and Public Health Assessment Division 23/28

24 Not very serious community-acquired pneumonia (PORT class I, II or III) 16 was mostly evaluated (78% of patients in the ceftobiprole group vs 77% in the ceftriaxone group). Community-acquired pneumonia PORT class IV represented 21% of patients in the ceftobiprole group vs 20% of patients in the ceftriaxone group. Finally, few patients with severe community-acquired pneumonia (PORT class V and/or requiring assisted breathing or intensive care) were included in the trials (1% vs 2%), such as immunocompromised patients, with severe sepsis ± septic shock, carriers of serious underlying lung disease. Safety: In Study BAP248/307, the incidence of adverse events was of the same magnitude (around 77%) in the different treatment groups, the same was true of the adverse events considered treatment-related (25%). The most commonly observed adverse events occurring in at least 3% of patients treated with ceftobiprole (versus comparator) were gastrointestinal disorders (nausea, vomiting, diarrhoea) (7.0% vs. 10.0%) and hyponatraemia (4.0% vs 3.0%). In Study CAP-3001, the incidence of adverse events was higher in the ceftobiprole group (70% vs 65%), the same was true of the adverse events considered treatment-related (36% vs 26%). The most commonly observed adverse events occurring in at least 3% of patients treated with ceftobiprole (versus comparator) were nausea (7.0% vs 2.0%), vomiting (5.0% vs 2.0%), diarrhoea (5.0% vs 5.0%), venous thrombosis (3.0% vs 2.0%), headache (3.0% vs 1.0%). As is the case for the other antibiotics in the beta-lactam group, hypersensitivity reactions and colitis associated with antibacterials (Clostridium difficile colitis), serious but not very common, were observed during the clinical trials (see SPC: special warnings and precautions for use) Planned studies MABELIO has a risk management plan as part of the obtaining of the Marketing Authorisation. Identified or potential major risks and missing information relating to safety to be provided in the PSURs: Identified risks - Increase in the concentration of hepatic enzymes - Hyponatraemia - Anaphylactic reactions - Hypersensitivity reactions - Pseudomembranous colitis / Clostridium difficile colitis - Reactions at the injection site - Local fungal infections - Seizures - Renal toxicity (including assessment of potential interactions with nephrotoxic medicinal products) - Precipitation of infusion solutions when mixed with solutions containing calcium Potential risks - Emergence of ceftobiprole-resistant bacteria - Off-label use in adults and children - Haemolytic anaemia / Coombs test - Interactions with certain analytical techniques (measure of glucose level in the urine and serum creatinine) - Interactions with medicinal products transported via certain transporters (OATP1B1 and OATP1B3) - Interactions with medicinal products metabolised by P450 cytochromes Missing information on safety 16 Severity of pneumonia according to the Fine (PSI) score: Recommendations: Classes I-II: outpatient; class III: observation; classes IV- V: hospitalisation HAS - Medical, Economic and Public Health Assessment Division 24/28

25 - Patients who are pregnant or breastfeeding - Paediatric patients - Patients with end-stage renal or hepatic disease - Patients with HIV, or neutropenia, immunosuppression or even myelosuppression Moreover, a non-interventional post-authorisation safety study is being implemented with the aim of characterising more accurately the safety profile of ceftobiprole in patients with severe renal impairment or end-stage nephropathy, hepatic impairment or immunocompromised patients (HIV patients, immunocompromised, or with neutropenia / myelosuppression at baseline). Finally, a paediatric study will be implemented in accordance with the paediatric investigation approved by the EMA. 09 THERAPEUTIC USE The drug treatment of these infections lies in antibiotic therapy, which is adapted to the identified or likely bacteria and to their level of resistance (see section 05). MABELIO (ceftobiprole) is indicated in the "treatment of hospital-acquired pneumonia, excluding ventilator-associated pneumonia and in the treatment of community-acquired pneumonia". This is a hospital prescription medicinal product targeting severe infections requiring hospitalisation and intravenous antibiotic therapy. In the treatment of hospital-acquired pneumonia, excluding ventilator-associated pneumonia, it is difficult at present to specify the therapeutic use of MABELIO due to insufficient documentation regarding its clinical efficacy. Based on the indications in the Marketing Authorisation, MABELIO would be earmarked more specifically for patients requiring intravenous treatment in the case of multidrug-resistant bacterial infections (methicillin-resistant Staphylococcus aureus, penicillin-resistant Streptococcus pneumoniae) susceptible to ceftobiprole and when there is no alternative treatment available or when other alternative treatments cannot be used. In the treatment of community-acquired pneumonia, ceftobiprole does not have a role in relation to existing alternative treatments that are easier to use and of a narrower spectrum, especially as there are missing data on efficacy in community-acquired methicillin-resistant Staphylococcus aureus pneumonia and regarding S. pneumoniae strains not susceptible to penicillin. HAS - Medical, Economic and Public Health Assessment Division 25/28

26 010 TRANSPARENCY COMMITTEE CONCLUSIONS In view of all the above information, and following the debate and vote, the Committee s opinion is as follows: Actual benefit Hospital-acquired pneumonia, excluding ventilator-associated pneumonia The disorders addressed by this proprietary medicinal product are either immediately life-threatening to the patient or life-threatening after complications. This medicinal product is intended as curative therapy. The efficacy/adverse effects ratio for this medicinal product is modest. There are treatment alternatives, including treatments for multidrug-resistant organisms. This is a treatment which must be earmarked for patients requiring intravenous treatment in the case of multidrug-resistant bacterial infections (methicillin-resistant Staphylococcus aureus, penicillin-resistant Streptococcus pneumoniae) susceptible to ceftobiprole and when there is no alternative treatment available or when other alternative treatments cannot be used. Public health benefit: The impact of these infections on public health, excluding ventilator-associated pneumonia, is low. Providing new antibiotic substances is a public health need which is part of the national alert plan on antibiotics whose objective is to fight against the development of resistance to antibiotics and against the growing number of situations of therapeutic impasse encountered (with a stated objective of a 25% reduction in the consumption of antibiotics in 5 years to result from the implementation of a strategy of a fair use of antibiotics). Given available data (non-inferiority, ceftazidime + linezolid-controlled trial), ceftobiprole would not be expected to have any additional impact on the reduction in mortality and morbidity compared with treatments in current use. Ceftobiprole is not expected to have any impact on the quality of life of the patients treated. No impact on the organisation of care is expected. In contrast, as the clinical cure rates and microbiological eradication percentages are not optimal, a negative impact cannot be ruled out because of the resistance phenomena that might develop. The transferability of data to current practice cannot be guaranteed completely because of the non-inclusion in the trial of patients with a severe prognosis. Ceftobiprole only provides a partial response to the identified public health need, but its use may be advantageous in cases of hospital infections due to MRSA. Its use will therefore have to be limited to this type of situation so as not to promote the development of resistance. Consequently, it is not expected that MABELIO will benefit public health in this indication. Consequently, the Committee considers that the actual benefit of MABELIO 500 mg is moderate in the "treatment in adults of hospital-acquired pneumonia, excluding ventilator-associated pneumonia". The Committee recommends inclusion on the list of medicines approved for hospital use in this indication and at the dosages in the Marketing Authorisation. Community-acquired pneumonia The disorders addressed by this proprietary medicinal product are either immediately life-threatening to the patient or life-threatening after complications. This medicinal product is intended as curative therapy. The efficacy/adverse effects ratio for this medicinal product has not been clearly established. There are treatment alternatives, including treatments for multidrug-resistant organisms. HAS - Medical, Economic and Public Health Assessment Division 26/28

27 Ceftobiprole does not have a role in this indication in relation to existing alternative treatments that are easier to use and of a narrower spectrum, especially as there are missing data on efficacy in community-acquired methicillin-resistant Staphylococcus aureus pneumonia and regarding S. pneumoniae strains not susceptible to penicillin. Public health benefit: The impact of these infections on public health, in patients requiring hospitalisation and intravenous management, is low. Providing new antibiotic subtances is a public health need which is part of the national alert plan on antibiotics whose objective is to fight against the development of resistance to antibiotics and against the growing number of situations of therapeutic impasse encountered (with a stated objective of a 25% reduction in the consumption of antibiotics in 5 years to result from the implementation of a strategy of a fair use of antibiotics). Given available data (non-inferiority ceftriaxone+/-linezolid-controlled trial), ceftobiprole would not be expected to have any additional impact on the reduction in mortality and morbidity compared with treatments in current use. Ceftobiprole is not expected to have any impact on the quality of life of the patients treated. Ceftobiprole is not expected to have any impact on the organisation of care. A negative impact on the quality of life of patients treated, as well as on the organisation of care (treatment with MABELIO requiring hospitalisation with 3 intravenous infusions per day and being more constricting than ceftriazone, for example) is expected. However, in the absence of data, this impact cannot be quantified. The transferability of experimental data is not assured, especially considering the very low number of patients with pneumopathy due to resistant germs (1 case of MRSA and 2 cases of penicillin-resistant S. pneumoniae) or severe forms included in the study and also the long-term risk of resistance selection because of MABELIO's very broad spectrum of activity (there are alternatives with a narrower spectrum). MABELIO therefore does not provide a response to the identified public health need. Consequently, it is not expected that MABELIO will benefit public health in this indication. Consequently, the Committee considers that the actual benefit of MABELIO 500 mg in comparison with the treatments that are already available is insufficient in the "treatment in adults of community-acquired pneumonia" to justify reimbursement by National Health Insurance Improvement in actual benefit (IAB) Hospital-acquired pneumonia, excluding ventilator-associated pneumonia Based on the current data available, MABELIO does not provide an improvement in actual benefit (IAB V, non-existent) in relation to the treatments currently used for managing hospital-acquired pneumonia, excluding ventilator-associated pneumonia. Community-acquired pneumonia Not applicable HAS - Medical, Economic and Public Health Assessment Division 27/28

28 010.3 Target population In the indication "hospital-acquired pneumonia, excluding ventilator-associated pneumonia" MABELIO is a hospital prescription medicinal product targeting severe infections requiring parenteral treatment lasting 7 to 14 days as part of a treatment for hospital-acquired pneumonia. If the frequency of non-intubation-associated pneumonia (and consequently non-ventilator-associated) in the first 48 hours (66.8% according to the latest ECDC report 17 on the survey of hospital-acquired infections) is applied to the prevalence of HAP in France (0.9% according to the latest report on the survey of hospital-acquired infections), the prevalence of non-vap HAP may be estimated at around 0.6% in France. Finally, if this prevalence is applied to all hospital stays identified for 2011 in the PMS I[Information System Medicalisation Programme]--MCO 18 (Médecine/Chirurgie/Obstétrique) [Medicine/Surgery/Obstetrics] database, excluding stays of less than 48 hours, i.e. 2,729,858 stays, the number of cases of hospital-acquired pneumonia may be estimated at around 16,000 patients. We do not therefore have any epidemiological data specifying the incidence of severe forms or those due to multidrug-resistant organisms, requiring IV empirical antibiotic therapy targeting gram-positive and gram-negative bacteria in this patient subpopulation. In practice, the number of patients likely to receive MABELIO will probably be very limited as the percentage of patients eligible particularly for this treatment is fairly low: patients requiring intravenous treatment, in cases of multidrug-resistant bacteria infections susceptible to ceftobiprole and when there is no alternative treatment available or when other alternative treatments cannot be used. In the community-acquired pneumonia indication Not applicable 011 TRANSPARENCY COMMITTEE RECOMMENDATIONS Packaging Appropriate for the prescribing conditions as regards indication, dosage and treatment duration. 17 European Centre for Disease Prevention and Control. Surveillance report: Point prevalence survey of healthcareassociated infections and antimicrobial use in European acute care hospitals Stockholm: ECDC; 2013, 217p HAS - Medical, Economic and Public Health Assessment Division 28/28