(Invented) name Strength Pharmaceutical Form. Powder for

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1 ANNEX I LIST OF THE NAMES, PHARMACEUTICAL FORMS, STRENGTHS OF THE MEDICINAL PRODUCTS, ROUTES OF ADMINISTRATION, MARKETING AUTHORISATION HOLDERS IN THE MEMBER STATES 1

2 Member State EU/EEA Marketing Authorisation Holder (Invented) name Strength Pharmaceutical Form Route of administration Content (concentration ) Austria GlaxoSmithKline Pharma GmbH, Albert Schweitzer-Gasse 6, A-1140 Wien Fortum 0,5 g - Trockenstechampullen Fortum 1 g - Trockenstechampullen Fortum 2 g - Trockenstechampullen 500mg 1g 2g Powder for Powder for Powder for / Intravenous or intramuscular use Intravenous or intramuscular use Intravenous use Belgium Bulgaria GlaxoSmithKline s.a. / n.v. Rue du Tilleul Genval Belgium Glaxo Group Ltd. Glaxo Wellcome House, Berkeley avenue, Greenford, Middlesex UB6 0NN, England Glazidim 500mg Powder for Injection Glazidim 1g Powder for Infusion Glazidim 1g Powder for Injection Glazidim 2g Powder for Glazidim 2g Powder for Fortum 1g Powder for Injection For Intravenous or Intramuscular use For Intravenous or Intramuscular use For intravenous or intramuscular use 2

3 Member State EU/EEA Marketing Authorisation Holder (Invented) name Strength Pharmaceutical Form Route of administration Content (concentration ) Cyprus Glaxo Group Limited Berkeley Avenue Greenford Middlex UB6 0NN United Kingdom Fortum 1g Powder for Injection Vials contain 1g ceftazidime (as pentahydrate) Czech Republic Glaxo Group Ltd., Glaxo Welcome House, Berkeley avenue, Greenford, Middlesex UB6 0NN United Kingdom Denmark Estonia GlaxoSmithKline Pharma A/S Nykaer 68, 2605 Broendby Denmark Glaxo Wellcome Operations, Glaxo Wellcome House, Berkeley Avenue, Greenford, Middlesex, UB6 0NN United Kingdom Fortum 500mg 500mg Powder for Fortum 1g 1g Powder for Fortum 2g 2g Powder for Fortum 500mg Powder for Injection Fortum 1g Powder for Injection Fortum 2g Powder for Injection Fortum 1g Powder for / For intramuscular or intravenous use 1g 3

4 Member State EU/EEA Marketing Authorisation Holder (Invented) name Strength Pharmaceutical Form Route of administration Content (concentration ) Finland France Glaxo Operations UK Ltd, Glaxo Wellcome House, Berkeley Avenue, Greenford, Middlesex UB6 0NN England Glaxo Operations UK Ltd, Glaxo Wellcome House, Berkeley Avenue, Greenford, Middlesex UB6 0NN United Kingdom GlaxoSmithKline Oy, PB 24, Espoo GlaxoSmithKline Oy, PB 24, Espoo Finland GlaxoSmithKline Oy, PB 24, Espoo Finland Laboratoire GlaxoSmithKline 100, route de Versailles Marly-le-Roi Cedex France Glazidim 500mg Powder for Injection Glazidim 1g Powder for Glazidim 1g Powder for / Glazidim 2g Powder for / Glazidim 3g Powder for Fortum enfants et nourrisons Fortum enfants et nourrisons 250mg 500mg / Powder for Powder for For intramuscular or intravenous use For intramuscular or intravenous use For intramuscular or intravenous use For intramuscular or intravenous use For intramuscular or intravenous use For intravenous or intramuscular use For intravenous or intramuscular use Vials contain 500 mg ceftazidime (as pentahydrate) Vials contain 1 g ceftazidime (as pentahydrate) Vials contain 1 g ceftazidime (as pentahydrate) Vials contain 2 g ceftazidime (as pentahydrate) Vials contain 3 g ceftazidime (as pentahydrate) 295mg 591mg Fortumset 1g Powder for (IV) 1182mg 4

5 Member State EU/EEA Marketing Authorisation Holder (Invented) name Strength Pharmaceutical Form Route of administration Content (concentration ) Fortum 1g Powder for Injection Fortumset 2g Powder for (IV) Fortum 2g Powder for (IV) For intravenous or intramuscular use 1182mg 2364mg 2364mg Germany GlaxoSmithKline GmbH & Co. KG Theresienhöhe München Germany Fortum 500mg Powder for or For intravenous and intramuscular use Greece GlaxoSmithKline a.e.b.e, Leof. Kifissias 266, Halandri, Athens Greece Fortum 1g Powder for or Fortum 2g Powder for or Solvetan 1g Powder for Solvetan 2g Powder for For intravenous and intramuscular use For intramuscular or intravenous use Hungary GlaxoSmithKline Kft Bp, Csörsz u. 43. Fortum 500mg Powder for 5

6 Member State EU/EEA Marketing Authorisation Holder (Invented) name Strength Pharmaceutical Form Route of administration Content (concentration ) Iceland Ireland Hungary Fortum 1g Powder for Fortum 2g Powder for GlaxoSmithKline ehf. Fortum 1g Powder for Thverholt Reykjavík Iceland Fortum 2g Powder for GlaxoSmithKline (Ireland) Limited Stonemasons Way, Rathfarnham, Dublin 16 Ireland Italy GlaxoSmithKline S.p.A. - Via A. Fleming, Verona Italy Fortum 500mg Powder for Fortum 1g Powder for or, vial Fortum 1g Powder for, monovial Fortum 2g Powder for or, vial Fortum 2g Powder for, monovial Glazidim 250mg/ml Powder and solvent for For intravenous or intramuscular use For intravenous or intramuscular For intravenous or intramuscular or For For intravenous or intramuscular or For For intramuscular use Reconstituted solution contains 500mg ceftazidime Reconstituted solution contains 1g ceftazidime Reconstituted solution contains 1g ceftazidime Reconstituted solution contains 2g ceftazidime Reconstituted solution contains 2g ceftazidime 6

7 Member State EU/EEA Marketing Authorisation Holder (Invented) name Strength Pharmaceutical Form Route of administration Content (concentration ) Glazidim 500mg/1,5ml Powder and solvent for Glazidim 1g/3ml Powder and solvent for Glazidim 1g/10ml Powder and solvent for Glazidim 2g Powder for Glazidim 1g/100ml Powder and solvent for (Monovial) Glazidim 2g/100ml Powder and solvent for (Monovial) Glazidim 1g Powder for (Monovial) For intramuscular use For intramuscular use 7

8 Member State EU/EEA Marketing Authorisation Holder (Invented) name Strength Pharmaceutical Form Route of administration Content (concentration ) Glaxo Allen S.p.A Via Fleming, 2 Verona Italy Glazidim 2g Powder for (Monovial) Panzid 1g/3ml Powder and solvent for For intramuscular use Latvia Lithuania GlaxoSmithKline Latvia SIA Bruninieku 5, Riga, LV-1001, Latvia UAB GlaxoSmithKline Lietuva, A. Goštauto g. 40A, LT Vilnius, Lithuania Fortum 1 g powder for or 1g Powder for or Fortum 500mg Powder and solvent for Fortum 1g Powder and solvent for Fortum 2g Powder for or Fortum 3g Powder for or or intramuscular use Intravenous use or intramuscular use Intravenous use or intramuscular use Intravenous use Intravenous use 1 g ceftazidime (as ceftazidime pentahydrate) 8

9 Member State EU/EEA Marketing Authorisation Holder (Invented) name Strength Pharmaceutical Form Route of administration Content (concentration ) Luxembourg Malta Netherlands GlaxoSmithKline s.a. / n.v. Rue du Tilleul Genval Belgium Glaxo Operations UK Limited Glaxo Wellcome House Berkeley Avenue Greenford Middlesex UB6 0NN United Kingdom Glaxo Smith Kline B.V. Huis ter Heideweg LZ ZEIST THE NETHERLANDS Glazidim 500mg Powder for Glazidim 1g Powder for Glazidim 1g Powder for Glazidim 2g Powder for Glazidim 2g Powder for Fortum 1g per vial Powder for Fortum 500mg Powder for Fortum 1g Powder for Fortum 2g Powder for For Intravenous or Intramuscular use For Intravenous or Intramuscular use For intravenous or Intramuscular use For intravenous or intramuscular use For intravenous or intramuscular use 9

10 Member State EU/EEA Marketing Authorisation Holder (Invented) name Strength Pharmaceutical Form Route of administration Content (concentration ) Norway GlaxoSmithKline AS Forskningsveien 2A Fortum 500mg Powder for / Postboks 180 Vinderen Fortum 1g Powder for 0319 Oslo / Norway Fortum 2g Powder for / For intravenous or intramuscular use For intravenous or intramuscular use Poland Portugal GlaxoSmithKline Export Ltd 980 Great West Road Brentford, Middlesex, TW8 9GS United Kingdom Glaxo Wellcome Farmacêutica, Lda. Rua Dr. António Loureiro Borges, 3 Aquiparque Miraflores Algés Portugal Fortum 250mg Powder for Fortum 500mg Powder for Fortum 1g Powder for and Fortum 2g Powder solution for and Cefortam 500mg/1.5ml Powder and solvent for Cefortam 1g/3ml Powder and solvent for For intramuscular or intravenous use For intramuscular or intravenous use For intramuscular or intravenous use For intravenous or intramuscular use For intravenous or intramuscular use 10

11 Member State EU/EEA Marketing Authorisation Holder (Invented) name Strength Pharmaceutical Form Route of administration Content (concentration ) Romania Glaxo Wellcome UK Limited, Glaxo Wellcome House, Berkeley Avenue, Greenford, Middlesex, UB6 0NN United Kingdom Slovak Republic GlaxoSmithKline Slovakia sro., Galvaniho7/A, Bratislava, Slovakia. Slovenia Spain Cefortam 2g Powder for Fortum 500mg Powder for Fortum 1g Powder for Fortum 1g Powder for Fortum 1g Powder for Fortum 2g Powder for or Fortum 500mg Powder for Fortum 1g Powder for Fortum 2g Powder for Fortum 1g Powder for or GSK d.o.o., Ljubljana Knezov štradon 90 SI-1000 Ljubljana Slovenija Fortum Monovial 1g Powder for GlaxoSmithKline, S.A. P.T.M.- C/Severo Ochoa, Tres Cantos (Madrid) Spain Fortam IM/IV 500mg Powder for Fortam IV 1g Powder for Fortam 1g 1g Powder for For intravenous or intramuscular use For intravenous or intramuscular use For intravenous or intramuscular use For intravenous or intramuscular use For intravenous or intramuscular use For intravenous use/im For intravenous use/im 11

12 Member State EU/EEA Marketing Authorisation Holder (Invented) name Strength Pharmaceutical Form Route of administration Content (concentration ) Sweden GlaxoSmithKline AB Box Solna Sweden United Kingdom Glaxo Operations UK Ltd, Glaxo Wellcome House, Berkeley Avenue, Greenford Road, Middlesex, UB6 0NN United Kingdom Fortam IV 2g Powder for Fortum 250mg Powder for Fortum 500mg Powder for Fortum 1g Powder for Fortum 1g Powder for Fortum 1g Monovial Powder for Fortum 2g Monovial Powder for Fortum 2g Powder for / Fortum 250mg Powder for Fortum 500mg Powder for Fortum 1g Powder for Fortum 2g and 3g + Powder for 2g Monovial For intramuscular or intravenous use For intramuscular or intravenous use For intramuscular or intravenous use intravenous use and intramuscular use intravenous use and intramuscular use intravenous use and intramuscular use intravenous use and intramuscular use 250 mg ceftazidime (as pentahydrate ) 500 mg ceftazidime (as pentahydrate ) 1 g ceftazidime (as pentahydrate ) 1 g ceftazidime (as pentahydrate ) 1 g ceftazidime (as pentahydrate) 2 g ceftazidime (as pentahydrate) 2 g ceftazidime (as pentahydrate) 118mg per gram of ceftazidime 118mg per gram of ceftazidime 118mg per gram of ceftazidime 118mg per gram of ceftazidime 12

13 ANNEX II SCIENTIFIC CONCLUSIONS AND GROUNDS FOR AMENDMENT OF THE SUMMARY OF PRODUCT CHARACTERISTICS, LABELLING AND PACKAGE LEAFLET PRESENTED BY THE EUROPEAN MEDICINES AGENCY 13

14 SCIENTIFIC CONCLUSIONS Overall summary of the scientific evaluation of Fortum and associated names (see Annex I) Due to the divergent national decisions taken by Member States concerning the authorisation of Fortum and its associated names (ceftazidime), a referral under Article 30 of Directive 2001/83/EC, as amended was triggered in order to harmonise its divergent SPCs across the EU. Fortum contains ceftazidime, a third-generation cephalosporin antibacterial agent with in-vitro activity against some Gram-positive and many Gram-negative bacteria, including P. aeruginosa. Fortum inhibits bacterial enzymes necessary for cell-wall synthesis (peptidoglycan synthesis) causing cell death. Ceftazidime has been in clinical use since it was first registered in 1983 and has an established place in clinical practice. It is now widely prescribed worldwide. Fortum is approved in all 27 EU member states, as well as in Norway and Iceland. The CHMP convened a drafting group in February and September Section Therapeutic Indications The CHMP noted the divergences in Sections 4.and referred to the current guidelines (EC guideline on the SPC, October 2005 and CPMP/EWP/558/95 rev 1 - Note for Guidance on Evaluation of Medicinal Products Indicated for Treatment of Bacterial Infections, 2004). According to these guidelines, an indication may be granted if the clinical data support a favourable benefit-risk ratio and reflect the range of type and severity of infections that are commonly encountered. Indications have to be infection (site) specific. The CHMP expressed considerable doubts regarding the appropriateness of ceftazidime in the empirical treatment of a number of infections, based on the antibacterial activity of ceftazidime and clinical data, as this data is frequently (and in some indications almost exclusively) derived from open and/ or uncontrolled trials. An appropriate warning was therefore inserted in Section 4.4 to highlight the limitations of the studies, rather than restricting the indications. 1. Lower Respiratory Tract Infections (LRTI) The CHMP regarded the terms respiratory tract infection (RTI) and lower respiratory tract infections (LRTI) as non-specific and their precise meaning as open to interpretation. Bacterial LRTIs may include such infections as pneumonia, acute bronchitis, acute exacerbations of chronic obstructive pulmonary disease, pleural empyema, lung abscess, and pulmonary infection associated with cystic fibrosis. Current guidelines require indications to be more specific as the different clinical entities summarized under LRTI have different aetiology and may therefore require different treatments. The CHMP therefore split the indication into community acquired pneumonia (CAP) and hospital acquired pneumonia (HAP), in line with current guidelines. Regarding CAP, the CHMP noted the submitted studies, including a range of non comparative studies performed in patients with RTIs including acute chronic bronchitis, LRTIs (including pneumonia) and acute exacerbation of chronic bronchitis (AECB). The supporting studies were considered to be of limited use and insufficiently described. The studies addressing CAP were usually small, and from the data provided, the study population could not be appropriately characterized. Comparative studies generally seem to indicate better point estimates of clinical efficacy for the comparator regimes compared to ceftazidime and the in vitro activity of ceftazidime would suggest it may not be a first line treatment choice in CAP. In summary, the CHMP considered that the data provided did not support an indication for use in CAP and expressed particular concern regarding the activity of ceftazidime against S. pneumoniae and the optimal dose regimen for ceftazidime when this is the primary pathogen in CAP. In conclusion, the CHMP did not agree to the indication in communityacquired pneumonia. Regarding HAP, the CHMP noted that the submitted studies including a range of non comparative studies conducted involving patients with RTIs including acute chronic bronchitis, LRTIs (including pneumonia) and acute exacerbation of chronic bronchitis (AECB). Several studies were presented that include patients with HAP only while others included under HAP were performed in patients with ventilator associated pneumonias (VAP). The CHMP considered that the studies presented provide 14

15 evidence for the effectiveness in the treatment of patients with HAP, although the success rates were variable. Regarding VAP, the CHMP considered the data to be insufficient to support an indication. The CHMP also considered that data in the paediatric population are very sparse but noted the two studies presented by the MAH. The considerations for CAP and HAP are largely the same for adults and for children and data on effectiveness can be extrapolated from adult studies. Clinical experience in children with ceftazidime outside controlled clinical trials was taken into account and the CHMP therefore considered that the indication granted in the adult population should be extended to the paediatric population. The CHMP consequently adopted the following indication: Nosocomial pneumonia 2. Acute infections in cystic fibrosis The CHMP noted that P. aeruginosa and Burkholderia cepacia are the most commonly isolated organisms in CF and that ceftazidime has in-vitro activity against both. Both are however frequently resistant to many antibacterial agents, including ceftazidime, particularly in the CF population. Most studies presented were small and uncontrolled and included patients with P. aeruginosa infection only. Clinical success rates ranged from 75 to 100% while bacterial eradication ranged from about 20 to 80%. Despite its limitations, the CHMP still considered that the data supports the clinical efficacy of ceftazidime in bronchopulmonary infections in patients with cystic fibrosis. Safety of treatment is of particular concern in patients with cystic fibrosis and the comparatively good tolerability and low risk of hepatotoxicity were taken into account in assessing the benefit-risk ratio of ceftazidime in this population. The CHMP consequently adopted the following indication: Broncho-pulmonary infections in cystic fibrosis 3. Febrile Neutropenia The CHMP noted the clinical studies presented by the MAH, which included patients with a variety of different underlying diseases and causes for neutropenia, different degrees of severity of neutropenia or granulocytopenia and different types of infections. Despite the limitations of the data, the CHMP considered that there is a reasonable amount of data available on ceftazidime either as monotherapy or in combination with other antibacterial agents. Recent systematic reviews and meta-analysis of the available literature suggest that initial monotherapy with a broad spectrum beta- lactam is as effective while at the same time results in less side effects than treatment with a broad spectrum beta- lactam plus aminoglycoside. The CHMP adopted the following indication: Ceftazidime may be used in the management of neutropenic patients with fever that is suspected to be due to a bacterial infection. 4. Skin and Soft Tissue Infections The CHMP noted the studies submitted in support of the skin and soft tissue infections (SSTI) indication. The increased resistance of Gram negative and particularly Gram positive bacteria makes the treatment of complicated SSTIs (csstis) more complex. The pharmacokinetic data presented suggests that ceftazidime has good tissue penetration and is present in sufficient concentration in skin tissue/ blisters to make it suitable for the treatment of SSTI. The additional clinical studies presented by the MAH did not contribute any new data compared to the initial responses. While the bacteriological data from the submitted studies were limited, the CHMP considered that they did provide some support for the efficacy of ceftazidime in infections with Gram negatives and particularly P. aeruginosa. However, concerns regarding Gram positives and in particular S. aureus remain. Based on in vitro data, the CHMP considered that ceftazidime is not appropriate for empirical treatment of cssti, however there is some evidence for efficacy of ceftazidime in moderate to severe and complicated SSTI, although the available supporting data are of limited quality and that combination with an antibacterial agent with better activity against Gram-positive bacteria (e.g. glycopeptides) may be necessary. Although no studies were presented supporting the use of ceftazidime in children or neonates in SSTI, the CHMP was of the opinion that the considerations for cssti are the same for adults and children. In conclusion, the CHMP restricted the indication to 15

16 complicated SSTIs, which better reflects the data from the studies and adopted the following indication: Complicated skin and soft tissue infections 5. Bone and Joint Infections The CHMP considered the data provided in support of the indication to be very limited but acknowledged the overall lack of good quality clinical studies in the treatment of bone and joint infections. There is no consensus regarding the most appropriate antibiotic regimen as the mostly uncontrolled studies do not allow differentiating between different agents. The animal models presented were only of limited use and there were no in vitro data in Gram positive species, however the pharmacokinetic properties of ceftazidime suggest reasonable bone penetration; its antibacterial spectrum makes it a potentially useful agent for osteomyelitis treatment in case of a Gram negative infection. Regarding paediatric patients, the CHMP considered that despite the lack of studies supporting use in children or neonates in bone and joint infections, the considerations are the same for adults as for paediatric patients. In conclusion, the CHMP adopted the following harmonised indication: Bone and joint infections 6. Ear infections (including chronic suppurative otitis media and malignant external otitis) The CHMP noted the studies submitted to support this indication but considered that very little clinical data were presented. The CHMP discussed the indication in chronic suppurative otitis and malignant otitis externa as two separate indications. Regarding chronic suppurative otitis media (CSOM), the CHMP considered that efficacy is expected in view of the anti-bacterial activity of ceftazidime and the tissue penetration. PK data were presented to support relevant tissue penetration for middle ear infections. In summary, the CHMP concluded that although the clinical studies provide very limited support, ceftazidime may be considered useful in the treatment of CSOM where systemic antibiotic treatment has become necessary and if the results of a culture and sensitivity test are known before treatment is commenced. Regarding malignant otitis externa (MOE), the CHMP considered that the antibacterial activities of ceftazidime, together with its PK properties, suggest efficacy. The CHMP therefore considered the indication to be justified, despite the lack of good clinical studies, based on the very high prevalence of Pseudomonas as a causative agent, the antipseudomonas activity and the suitable PK of ceftazidime, with some supporting evidence from clinical studies. The longstanding clinical experience with ceftazidime and its comparatively good safety profile were also taken into account. In conclusion, the CHMP adopted the following indications: Chronic suppurative otitis media and Malignant otitis externa 7. Gastrointestinal, Biliary and Abdominal Infections The CHMP noted that clinical data in support of this indication was sparse. The only randomised study presented shows efficacy of ceftazidime in combination with clindamycin in patients with peritonitis after bowel perforation, i.e. complicated intra-abdominal infections. Bacteroides and E. coli were the most commonly expected organisms, confirming the need for an antibacterial regimen with appropriate anaerobic cover in many cases. Regarding PK/PD, the CHMP acknowledged that the antibacterial activity of ceftazidime does cover a significant proportion of expected pathogens, but there are also relevant gaps, particularly anaerobes and of more controversial importance, Enterococci. PK data demonstrate adequate penetration of ceftazidime into peritoneal fluid, reaching around 60% of plasma levels in most studies. PK/PD data combined with Monte Carlo simulations suggest that ceftazidime, when combined with anaerobic cover, may be suitable for complicated intra-abdominal infections. The CHMP was of the opinion that there is some evidence that ceftazidime may be useful in complicated intra-abdominal infections (ciais), provided the dose is sufficiently high. Based on the data provided, the CHMP agreed on an indication in ciai, linked to a statement that ceftazidime should be co-administered with another antibacterial agent whenever the possible range of causative bacteria does not fall within its spectrum of activity. The CHMP noted that no data were provided for the use in children but was of the view that the considerations for intra-abdominal infections are the 16

17 same for adults as for paediatric patients. In conclusion, the CHMP adopted the following harmonised indication: Complicated intra-abdominal infections 8. Bacterial Meningitis The CHMP considered that the PK data presented support the claim that ceftazidime has PK properties that make it a suitable candidate for the treatment of acute bacterial meningitis in adults and children. In clinical practice, ceftazidime is used particularly in hospital acquired meningitis, where Gram negative bacteria are the suspected or confirmed cause. E. coli, P. aeruginosa and Enterobacter are frequently isolated species. It is also used in meningitis after penetrating head injury. Apart from the expected range of bacteria, CSF penetration is the most important factor determining the suitability of an antibacterial agent for the treatment of meningitis. Guidelines recommend the use of ceftazidime in meningitis in specific scenarios such as after trauma or neurosurgery, in patients with indwelling devices or caused by specific pathogens. The CHMP considered that the evidence submitted together with the clinical experience gained over more than two decades provide sufficient support for this indication. The data does however not support empirical treatment of non-traumatic community acquired meningitis and ceftazidime is generally not considered appropriate in staphylococcal meningitis. The CHMP adopted the following indications for both adults and paediatric patients: Bacterial meningitis 9. Urinary tract infections The CHMP noted the data submitted in support of this indication. The type and the severity of the infections in the studies varied and the majority included patients with complicated UTI (cuti). Bacterial resistance to antibacterial agents is more prevalent in complicated UTI than in uncomplicated UTI and cuti are amongst the most common nosocomial infections with the majority of patients have indwelling catheters. Where empirical therapy is necessary, the antibacterial spectrum of the antibacterial agent should include the most relevant pathogens. As an intravenous broad spectrum antibacterial agent, ceftazidime is not generally appropriate for use in mild to moderate uncomplicated UTI as its role would be expected to be in moderate and severe cuti and possibly severe uncomplicated UTI. In conclusion, the CHMP qualified the indication and adopted the following indication for adult and paediatric patients: Complicated urinary tract infections 10. Transurethral Surgery (TURP) The CHMP noted that according to literature data, the rate of postoperative infection after TURP is around 6% with a significantly higher rate of postoperative bacteriuria. The spectrum of bacteria encountered in complicated and nosocomial UTIs must be covered and the PK of the antibacterial agent must allow effective site concentrations. The CHMP was of the opinion that ceftazidime fulfils these criteria in the context of TURP. The most relevant study indicated that ceftazidime significantly reduced the combined endpoint of postoperative bacteriuria/clinical infection in the peri-operative prophylaxis of TURP. However, the CHMP considered that defining the situations in which peri-operative prophylaxis is administered should be left to national guidelines. In conclusion, the CHMP adopted the following harmonised indication: Ceftazidime may be used in the peri-operative prophylaxis of urinary tract infections for patients undergoing trans-urethal resection of the prostrate (TURP) 11. Infection in Dialysis Patients The CHMP noted the data submitted by the MAH in support of this indication. Abdominal infections in patients on chronic ambulatory peritoneal dialysis (CAPD) are frequently introduced through catheter manipulation and consequently predominantly Gram positive infections are expected. Due to recurrent infections and frequent hospital contacts of the population, resistant organisms are frequently encountered. All studies presented exclusively include peritonitis in patients on CAPD and confirm Gram positive species as the predominant cause of peritoneal infections. However, the CHMP noted 17

18 that no studies using ceftazidime as single treatment agent were presented. In conclusion, the CHMP was of the opinion that the presented data provided evidence only for the usefulness of ceftazidime in peritonitis associated with CAPD and therefore adopted the following harmonised indication: Peritonitis associated with dialysis in patients on CAPD 12. Septicaemia, bacteraemia The CHMP noted the available data from studies in adult patients, most of whom had a variety of underlying infections. The antibacterial spectrum of ceftazidime is very limited against Gram-positive pathogens and therefore it is not an agent suitable for monotherapy in bacteraemia unless the pathogen has already been cultured and at least provisionally identified. Even if the pathogen is of a species normally susceptible to ceftazidime the increasing risk of encountering ceftazidime-hydrolysing betalactamases, with or without impermeability mechanisms of resistance, poses a risk for use before results of susceptibility testing are available. Therefore, the CHMP considered the submitted data to be inadequate to support the unqualified use of ceftazidime but that the use of ceftazidime in bacteraemia with certain restrictions would be acceptable. In line with the position of the CHMP drafting group, the CHMP was of the opinion that despite the limited available evidence regarding the treatment of bacteraemia, there is longstanding clinical experience with this agent and therefore adopted the following harmonised indication: Treatment of patients with bacteraemia that occurs in association with, or is suspected to be associated with, any of the infections listed above. Section 4.2 Posology and method of administration The CHMP listed the posology separately for each indication, revised the terminology used in the table of posologies and revised the dosages based on the available data. For intermittent administration, the following dosages were adopted: For broncho-pulmonary infections in cystic fibrosis: 100 to 150 mg/kg/day every 8 hours. For febrile neutropenia, nosocomial pneumonia and bacterial meningitis: 2g every 8 hours. For bone and joint infections, complicated skin and soft tissue infections, complicated intraabdominal infections and peritonitis associated with dialysis in patients on CAPD: 1-2 g every 8 hours. For complicated urinary tract infections: 1-2 g every 8 or 12 hours. For peri-operative prophylaxis for transuretheral resection of prostate (TURP): 1 g at induction of anaesthesia with a second dose at catheter removal. For chronic suppurative otitis media and malignant otitis externa: 1 g to 2 g every 8 hours. For continuous, the following dosages were adopted: For broncho-pulmonary infections in cystic fibrosis, febrile neutropenia, nosocomial pneumonia, bacterial meningitis, bone and joint infections, complicated skin, soft tissue infections, complicated intra-abdominal infections and peritonitis associated with dialysis in patients on CAPD: a loading dose of 2 g followed by a continuous of 4 to 6 g every 24 hours. Section Contraindications The CHMP discussed a number of contraindications, including hypersensitivity to excipients and cephalosporin antibiotics and hypersensitivity reactions to all beta-lactam antibiotics. The CHMP also considered the cross reactivity between different types of beta lactam antibiotics. In conclusion, the CHMP adopted a harmonised wording for Section 4.3. Section Special warnings and precautions for use The CHMP noted and agreed with the majority of the MAH proposals, although some of these were re-worded. In particular, the paragraph on allergy to beta-lactam agents was re-worded to align it with the contraindication in section 4.3. In conclusion, the CHMP adopted a harmonised text for Section

19 Section Interaction with other medicinal products and other forms of interaction The CHMP noted that studies conducted on probenecid and furosemide, which did not show any interactions with ceftazidime and stated this in the text. Further interactions were discussed and revised. In conclusion, the CHMP adopted a harmonised wording for Section 4.5. Section 4.6 Fertility, pregnancy and lactation The CHMP noted the limited human experience but that animal studies do not indicate an embryotoxic or teratogenic effect. The CHMP concluded that caution should be exercised if using during pregnancy but that ceftazidime should not be excluded from use by women who are breastfeeding. In conclusion, the CHMP adopted a harmonised wording for Section 4.6. Section Effects on ability to drive and use machines The CHMP noted that no studies have been undertaken by the MAH to investigate the effects of ceftazidime on the ability to drive or use machines and therefore stated this. In conclusion, the CHMP adopted a harmonised wording for Section 4.7. Section Undesirable effects Within each frequency grouping, undesirable effects were presented in order of decreasing seriousness and a number of adverse events were revised. In conclusion, the CHMP adopted a harmonised wording for Section 4.8. Section Overdose The CHMP included detailed information on symptoms gained from experience in overdose in patients with renal failure as present in some national SPCs. In conclusion, the CHMP adopted a harmonised wording for Section 4.9. Section Pharmacodynamic properties The final table of species was revised and brought in line with the indications adopted by only including species relevant to the listed indications. In conclusion, the CHMP adopted a harmonised wording and a revised microbiological susceptibility table for Section 5.1. Section Pharmacokinetics The CHMP revised this section to include comprehensive information, including basic PK data and information on PK in special populations. In conclusion, the CHMP adopted a harmonised wording for Section 5.2. Section Preclinical Safety data The CHMP considered that although the non-clinical studies conducted in support of the original marketing authorisation application were acceptable at that time, they are not a conventional battery by today s standards and therefore removed the word conventional. In conclusion, the CHMP adopted a harmonised wording for Section 5.3. Grounds for amendment of the summary of product characteristics, labelling and package leaflet Whereas the scope of the referral was the harmonisation of the summary of products characteristics, labelling and package leaflet the summary of products characteristic, labelling and package leaflet proposed by the marketing authorisation holders have been assessed based on the documentation submitted and the scientific discussion within the Committee 19

20 the CHMP has recommended the amendment of the marketing authorisations for which the summary of product characteristics, labelling and package leaflet are set out in Annex III for Fortum and associated names (see Annex I). 20

21 ANNEX III SUMMARY OF PRODUCT CHARACTERISTICS, LABELLING AND PACKAGE LEAFLET Note: This SPC, labelling and package leaflet is the version valid at the time of Commission decision. After the Commission decision the Member State competent authorities, in liaison with the reference Member State, will update the product information as required. Therefore, this SPC, labelling and package leaflet may not necessarily represent the current text. 21

22 SUMMARY OF PRODUCT CHARACTERISTICS 22

23 1. NAME OF THE MEDICINAL PRODUCT Fortum and associated names (see Annex I) 250 mg powder for Fortum and associated names (see Annex I) 500 mg powder for Fortum and associated names (see Annex I) 1 g powder for Fortum and associated names (see Annex I) 1 g powder for or Fortum and associated names (see Annex I) 2 g powder for or Fortum and associated names (see Annex I) 3 g powder for or Fortum and associated names (see Annex I) 1 g powder for Fortum and associated names (see Annex I) 2 g powder for [See Annex 1 to be completed nationally] 2. QUALITATIVE AND QUANTITATIVE COMPOSITION 3. PHARMACEUTICAL FORM 250 mg, 500 mg, 1 g powder for Powder for 1 g, 2 g, 3 g powder for or Powder for or 1 g, 2 g powder for (Monovial presentation) Powder for 4. CLINICAL PARTICULARS 4.1 Therapeutic indications Fortum is indicated for the treatment of the infections listed below in adults and children including neonates (from birth). Nosocomial pneumonia Broncho-pulmonary infections in cystic fibrosis Bacterial meningitis Chronic suppurative otitis media Malignant otitis externa Complicated urinary tract infections Complicated skin and soft tissue infections Complicated intra-abdominal infections Bone and joint infections Peritonitis associated with dialysis in patients on CAPD. Treatment of patients with bacteraemia that occurs in association with, or is suspected to be associated with, any of the infections listed above. Ceftazidime may be used in the management of neutropenic patients with fever that is suspected to be due to a bacterial infection. 23

24 Ceftazidime may be used in the peri-operative prophylaxis of urinary tract infections for patients undergoing trans-urethral resection of the prostate (TURP). The selection of ceftazidime should take into account its antibacterial spectrum, which is mainly restricted to aerobic Gram negative bacteria (see sections 4.4 and 5.1). Ceftazidime should be co-administered with other antibacterial agents whenever the possible range of causative bacteria would not fall within its spectrum of activity. Consideration should be given to official guidelines on the appropriate use of antibacterial agents. 4.2 Posology and method of administration Posology Table 1: Adults and children 40 kg Intermittent Administration Infection Dose to be administered Broncho-pulmonary infections in cystic fibrosis Febrile neutropenia Nosocomial pneumonia Bacterial meningitis Bacteraemia* Bone and joint infections Complicated skin and soft tissue infections Complicated intra-abdominal infections Peritonitis associated with dialysis in patients on CAPD Complicated urinary tract infections Peri-operative prophylaxis for transuretheral resection of prostate (TURP) Chronic suppurative otitis media Malignant otitis externa Continuous Infusion Infection Febrile neutropenia Nosocomial pneumonia Broncho-pulmonary infections in cystic fibrosis Bacterial meningitis Bacteraemia* Bone and joint infections Complicated skin and soft tissue infections Complicated intra-abdominal infections Peritonitis associated with dialysis in patients on CAPD 100 to 150 mg/kg/day every 8 h, maximum 9 g per day 1 2 g every 8 h 1-2 g every 8 h 1-2 g every 8 h or 12 h 1 g at induction of anaesthesia, and a second dose at catheter removal 1 g to 2 g every 8h Dose to be administered Loading dose of 2 g followed by a continuous of 4 to 6 g every 24 h 1 1 In adults with normal renal function 9 g/day has been used without adverse effects. * When associated with, or suspected to be associated with, any of the infections listed in section

25 Table 2: Children < 40 kg Infants and toddlers> 2 months and children < 40 kg Intermittent Administration Continuous Infusion Infection Complicated urinary tract infections Chronic suppurative otitis media Malignant otitis externa Neutropenic children Broncho-pulmonary infections in cystic fibrosis Bacterial meningitis Bacteraemia* Bone and joint infections Complicated skin and soft tissue infections Complicated intra-abdominal infections Peritonitis associated with dialysis in patients on CAPD Usual dose mg/kg/day in three divided doses, maximum 6 g/day 150 mg/kg/day in three divided doses, maximum 6 g/day mg/kg/day in three divided doses, maximum 6 g/day Neonates and infants 2 months Intermittent Administration Febrile neutropenia Nosocomial pneumonia Broncho-pulmonary infections in cystic fibrosis Bacterial meningitis Bacteraemia* Bone and joint infections Complicated skin and soft tissue infections Complicated intra-abdominal infections Peritonitis associated with dialysis in patients on CAPD Infection Loading dose of mg/kg followed by a continuous mg/kg/day, maximum 6 g/day Usual dose Most infections mg/kg/day in two divided doses 1 1 In neonates and infants 2 months, the serum half life of ceftazidime can be three to four times that in adults. * Where associated with, or suspected to be associated with, any of the infections listed in section 4.1. Paediatric population The safety and efficacy of Fortum administered as continuous to neonates and infants 2 months has not been established. Elderly 25

26 In view of the age related reduced clearance of ceftazidime in elderly patients, the daily dose should not normally exceed 3 g in those over 80 years of age. Hepatic impairment Available data do not indicate the need for dose adjustment in mild or moderate liver function impairment. There are no study data in patients with severe hepatic impairment (see also section 5.2). Close clinical monitoring for safety and efficacy is advised. Renal impairment Ceftazidime is excreted unchanged by the kidneys. Therefore, in patients with impaired renal function, the dosage should be reduced (see also section 4.4). An initial loading dose of 1 g should be given. Maintenance doses should be based on creatinine clearance: Table 3: Recommended maintenance doses of Fortum in renal impairment intermittent Adults and children 40 kg Creatinine clearance (ml/min) <5 Approx. serum creatinine µmol/l (mg/dl) ( ) ( ) ( ) >500 (>5.6) Recommended unit dose of Fortum (g) Frequency of dosing (hourly) In patients with severe infections the unit dose should be increased by 50% or the dosing frequency increased. In children the creatinine clearance should be adjusted for body surface area or lean body mass. Children < 40 kg Creatinine clearance (ml/min)** <5 Approx. serum creatinine* µmol/l (mg/dl) ( ) ( ) ( ) >500 Recommended individual dose mg/kg body weight Frequency of dosing (hourly) (>5.6) * The serum creatinine values are guideline values that may not indicate exactly the same degree of reduction for all patients with reduced renal function. ** Estimated based on body surface area, or measured. Close clinical monitoring for safety and efficacy is advised. 26

27 Table 4: Recommended maintenance doses of Fortum in renal impairment continuous Adults and children 40 kg Creatinine clearance (ml/min) Approx. serum creatinine µmol/l (mg/dl) ( ) ( ) >350 (>4.0) Frequency of dosing (hourly) Loading dose of 2 g followed by 1 g to 3 g /24 hours Loading dose of 2 g followed by 1 g/24 hours Not evaluated Caution is advised in dose selection. Close clinical monitoring for safety and efficacy is advised. Children < 40 kg The safety and effectiveness of Fortum administered as continuous in renally impaired children < 40 kg has not been established. Close clinical monitoring for safety and efficacy is advised. If continuous is used in children with renal impairment, the creatinine clearance should be adjusted for body surface area or lean body mass. Haemodialysis The serum half-life during haemodialysis ranges from 3 to 5 h. Following each haemodialysis period, the maintenance dose of ceftazidime recommended in the below table should be repeated. Peritoneal dialysis Ceftazidime may be used in peritoneal dialysis and continuous ambulatory peritoneal dialysis (CAPD). In addition to intravenous use, ceftazidime can be incorporated into the dialysis fluid (usually 125 to 250 mg for 2 litres of dialysis solution). For patients in renal failure on continuous arterio-venous haemodialysis or high-flux haemofiltration in intensive therapy units: 1 g daily either as a single dose or in divided doses. For low-flux haemofiltration, follow the dose recommended under renal impairment. For patients on veno-venous haemofiltration and veno-venous haemodialysis, follow the dosage recommendations in the tables below. 27

28 Table 5: Continuous veno-venous haemofiltration dose guidelines Residual renal function (creatinine clearance ml/min) Maintenance dose (mg) for an ultrafiltration rate (ml/min) of 1 : Maintenance dose to be administered every 12 h. Table 6: Continuous veno-venous haemodialysis dose guidelines Residual renal function (creatinine clearance in ml/min) Maintenance dose (mg) for a dialysate in flow rate of 1 : 1.0 litre/h 2.0 litre/h Ultrafiltration rate (litre/h) Ultrafiltration rate (litres/h) Maintenance dose to be administered every 12 h. Method of administration Fortum should be administered by intravenous or, or by deep intramuscular. Recommended intramuscular sites are the upper outer quadrant of the gluteus maximus or lateral part of the thigh. Fortum solutions may be given directly into the vein or introduced into the tubing of a giving set if the patient is receiving parenteral fluids. The standard recommended route of administration is by intravenous intermittent or intravenous continuous. Intramuscular administration should only be considered when the intravenous route is not possible or less appropriate for the patient. The dose depends on the severity, susceptibility, site and type of infection and on the age and renal function of the patient. 4.3 Contraindications Hypersensitivity to ceftazidime, to any other cephalosporin or to any of the excipients. History of severe hypersensitivity (e.g. anaphylactic reaction) to any other type of beta-lactam antibacterial agent (penicillins, monobactams and carbapenems). 4.4 Special warnings and precautions for use As with all beta-lactam antibacterial agents, serious and occasionally fatal hypersensitivity reactions have been reported. In case of severe hypersensitivity reactions, treatment with ceftazidime must be discontinued immediately and adequate emergency measures must be initiated. 28

29 Before beginning treatment, it should be established whether the patient has a history of severe hypersensitivity reactions to ceftazidime, to other cephalosporins or to any other type of beta-lactam agent. Caution should be used if ceftazidime is given to patients with a history of non-severe hypersensitivity to other beta-lactam agents. Ceftazidime has a limited spectrum of antibacterial activity. It is not suitable for use as a single agent for the treatment of some types of infections unless the pathogen is already documented and known to be susceptible or there is a very high suspicion that the most likely pathogen(s) would be suitable for treatment with ceftazidime. This particularly applies when considering the treatment of patients with bacteraemia and when treating bacterial meningitis, skin and soft tissue infections and bone and joint infections. In addition, ceftazidime is susceptible to hydrolysis by several of the extended spectrum beta lactamases (ESBLs). Therefore information on the prevalence of ESBL producing organisms should be taken into account when selecting ceftazidime for treatment. 1. Antibacterial agent-associated colitis and pseudo-membranous colitis have been reported with nearly all anti-bacterial agents, including ceftazidime, and may range in severity from mild to lifethreatening. Therefore, it is important to consider this diagnosis in patients who present with diarrhoea during or subsequent to the administration of ceftazidime (see section 4.8). Discontinuation of therapy with ceftazidime and the administration of specific treatment for Clostridium difficile should be considered. Medicinal products that inhibit peristalsis should not be given. Concurrent treatment with high doses of cephalosporins and nephrotoxic medicinal products such as aminoglycosides or potent diuretics (e.g. furosemide) may adversely affect renal function. Ceftazidime is eliminated via the kidneys, therefore the dose should be reduced according to the degree of renal impairment. Patients with renal impairment should be closely monitored for both safety and efficacy. Neurological sequelae have occasionally been reported when the dose has not been reduced in patients with renal impairment (see sections 4.2 and 4.8). Prolonged use may result in the overgrowth of non-susceptible organisms (e.g. Enterococci, fungi) which may require interruption of treatment or other appropriate measures. Repeated evaluation of the patient's condition is essential. Ceftazidime does not interfere with enzyme-based tests for glycosuria, but slight interference (falsepositive) may occur with copper reduction methods (Benedict's, Fehling's, Clinitest). Ceftazidime does not interfere in the alkaline picrate assay for creatinine. The development of a positive Coombs test associated with the use of ceftazidime in about 5% of patients may interfere with the cross-matching of blood. Important information about one of the ingredients of Fortum: 250 mg powder for Fortum 250 mg contains 13 mg of sodium per vial. 500 mg powder for Fortum 500 mg contains 26 mg of sodium per vial. 1 g powder for or, 1 g powder for Fortum 1 g contains 52 mg of sodium per vial. 2 g powder for or, 2 g powder for Fortum 2 g contains 104 mg of sodium per vial. 29

30 3 g powder for or Fortum 3 g contains 156 mg of sodium per vial. This should be considered for patients who are on a controlled sodium diet. 4.5 Interaction with other medicinal products and other forms of interaction Interaction studies have only been conducted with probenecid and furosemide. Concurrent use of high doses with nephrotoxic medicinal products may adversely affect renal function (see section 4.4). Chloramphenicol is antagonistic in vitro with ceftazidime and other cephalosporins. The clinical relevance of this finding is unknown, but if concurrent administration of ceftazidime with chloramphenicol is proposed, the possibility of antagonism should be considered. 4.6 Fertility, pregnancy and lactation Pregnancy There are limited amounts of data from the use of ceftazidime in pregnant women. Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy, embryonal/foetal development, parturition or postnatal development (see section 5.3). Fortum should be prescribed to pregnant women only if the benefit outweighs the risk. Breast-feeding Ceftazidime is excreted in human milk in small quantities but at therapeutic doses of ceftazidime no effects on the breast-fed infant are anticipated. Ceftazidime can be used during breast-feeding. Fertility No data are available. 4.7 Effects on ability to drive and use machines No studies on the effects on the ability to drive and use machines have been performed. However, undesirable effects may occur (e.g. dizziness), which may influence the ability to drive and use machines (see section 4.8). 4.8 Undesirable effects The most common adverse reactions are eosinophilia, thrombocytosis, phlebitis or thrombophlebitis with intravenous administration, diarrhoea, transient increases in hepatic enzymes, maculopapular or urticarcial rash, pain and/or inflammation following intramuscular and positive Coomb s test. Data from sponsored and un-sponsored clinical trials have been used to determine the frequency of common and uncommon undesirable effects. The frequencies assigned to all other undesirable effects were mainly determined using post-marketing data and refer to a reporting rate rather than a true frequency. Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness. The following convention has been used for the classification of frequency: Very common (1/10) Common (1/100 to <1/10) Uncommon (1/1,000 to <1/100) 30