Powder for solution for infusion. Powder and solvent for solution for IM injection. Powder and solvent for solution for IV injection

Transcription

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) Belgium Belgium Belgium Denmark Denmark Denmark Finland Finland N.V. Roche S.A. Rue Dante Bruxelles Belgium N.V. Roche S.A. Rue Dante Bruxelles Belgium N.V. Roche S.A. Rue Dante Bruxelles Belgium Roche a/s Industriholmen 59, DK-2650 Hvidovre, Danmark Roche a/s Industriholmen 59, DK-2650 Hvidovre, Danmark Roche a/s Industriholmen 59, DK-2650 Hvidovre, Danmark Roche Oy Klovinpellontie 3 PL Espoo Finland Roche Oy Klovinpellontie 3 PL Espoo Finland Rocephine Rocephine Rocephine Rocephalin Rocephalin Rocephalin Rocephalin cum lidocain Rocephalin cum lidocain 500 mg 500 mg Powder for solution for infusion solution for IM injection solution for IV injection Concentrate for solution for infusion solution for injection solution for injection solution for injection solution for injection Intravenous use Intramuscular use Intravenous use Intravenous use Intramuscular or intravenous use Intramuscular or intravenous use Intramuscular use or intravenous use Intramuscular use or intravenous use 500 mg 500 mg 2

3 Member State EU/EEA Marketing authorisation holder (Invented) Name Strength Pharmaceutical form Route of administration Content (concentration) France France France France Germany Roche 52 Boulevard du Parc NEUILLY SUR SEINE cedex France Roche 52 Boulevard du Parc NEUILLY SUR SEINE cedex France Roche 52 Boulevard du Parc NEUILLY SUR SEINE cedex France Roche 52 Boulevard du Parc NEUILLY SUR SEINE cedex France Roche Pharma AG Emil-Barell-Str Grenzach-Wyhlen Germany Rocephine 1g/10 ml, powder and solvent for solution for injection (IV, SC) Rocephine 1 g/3.5 ml, powder and solvent for solution for injection (IM, SC) Rocephine 500 mg/2ml, powder and solvent for solution for injection (IM, SC) Rocephine 500 mg/5ml, powder and solvent for solution for injection (IV, SC) Rocephin zur Infusion /10 ml /3.5 ml 500 mg/2 ml 500 mg/5 ml solution for injection solution for injection solution for injection solution for injection Powder for solution for infusion Intravenous use or subcutaneous use Intramuscular use or subcutaneous use Intramuscular use or subcutaneous use Intravenous use or subcutaneous use Intravenous use 500 mg 500 mg 3

4 Member State EU/EEA Marketing authorisation holder (Invented) Name Strength Pharmaceutical form Route of administration Content (concentration) Germany Germany Greece Greece Greece Hungary Hungary Roche Pharma AG Emil-Barell-Str Grenzach-Wyhlen Germany Roche Pharma AG Emil-Barell-Str Grenzach-Wyhlen Germany Roche (Hellas) SA 4, Alamanas & Delfon Str., Maroussi 15125, Attiki Greece Roche (Hellas) SA 4, Alamanas & Delfon Str., Maroussi 15125, Attiki Greece Roche (Hellas) SA 4, Alamanas & Delfon Str., Maroussi 15125, Attiki Greece Roche (Hungary) Ltd. Edison utca 1 Budaörs H-2040 Hungary Roche (Hungary) Ltd. Edison utca 1 Budaörs H-2040 Hungary Rocephin i.v. 1g Rocephin 500 mg Rocephin Rocephin Rocephin Rocephin Rocephin 500 mg 500 mg solution for injection solution for injection Powder for solution for Infusion solution for Injection solution for Injection solution for injection solution for injection Intravenous use Intramuscular or intravenous use Intravenous use intravenous use Intramuscular use Intravenous use Intramuscular use 500 mg 1000 mg 500 mg 4

5 Member State EU/EEA Marketing authorisation holder (Invented) Name Strength Pharmaceutical form Route of administration Content (concentration) Hungary Roche (Hungary) Ltd. Edison utca 1 Budaörs H-2040 Hungary Rocephin 250 mg solution for injection Intramuscular use 250 mg Iceland Iceland Ireland Ireland Italy Italy Roche a/s Industriholmen 59, DK-2650 Hvidovre, Danmark Roche a/s Industriholmen 59, DK-2650 Hvidovre, Danmark Roche Products Limited, 6 Falcon Way, Shire Park, Welwyn Garden City, AL7 1TW, United Kingdom Roche Products Limited, 6 Falcon Way, Shire Park, Welwyn Garden City, AL7 1TW, United Kingdom Roche S.p.A. Piazza Durante Milano Italy Roche S.p.A. Piazza Durante Milano Italy Rocephalin Rocephalin Rocephin Rocephin Rocefin Rocefin Concentrate for solution for infusion solution for injection Powder for solution for injection or infusion solution for IM injection Powder for solution for infusion solution for injection Intravenous use Intramuscular or intravenous use Intramuscular or intravenous use Intramuscular use Intravenous use intravenous use 5

6 Member State EU/EEA Marketing authorisation holder (Invented) Name Strength Pharmaceutical form Route of administration Content (concentration) Italy Italy Italy Latvia Luxembourg Luxembourg Luxembourg Malta Roche S.p.A. Piazza Durante Milano Italy Roche S.p.A. Piazza Durante Milano Italy Roche S.p.A. Piazza Durante Milano Italy Roche Latvija SIA 8b G.Astras Street, Riga, LV1082, Latvia N.V. Roche S.A. Rue Dante Bruxelles Belgium N.V. Roche S.A. Rue Dante Bruxelles Belgium N.V. Roche S.A. Rue Dante Bruxelles Belgium Roche Products Limited, 6 Falcon Way, Shire Park, Welwyn Garden City, AL7 1TW, United Kingdom Rocefin Rocefin Rocefin Rocephin pulveris injekciju šķīduma pagatavošanai Rocephine Rocephine Rocephine Rocephin 500 mg 250 mg solution for injection solution for injection solution for injection Powder for solution for injection Powder for solution for infusion solution for IV injection solution for IM injection Powder for solution for infusion Intramuscular use Intramuscular use Intramuscular use Intramuscular or intravenous use Intravenous use Intravenous use Intramuscular use Intravenous use 500 mg 250 mg 6

7 Member State EU/EEA Marketing authorisation holder (Invented) Name Strength Pharmaceutical form Route of administration Content (concentration) Malta Malta Netherlands Netherlands Netherlands Netherlands Netherlands Portugal Roche Products Limited, 6 Falcon Way, Shire Park, Welwyn Garden City, AL7 1TW, United Kingdom Roche Products Limited, 6 Falcon Way, Shire Park, Welwyn Garden City, AL7 1TW, United Kingdom Roche Nederland B.V. Beneluxlaan 2a, 3446 GR Woerden Netherlands Roche Nederland B.V. Beneluxlaan 2a, 3446 GR Woerden Netherlands Roche Nederland B.V. Beneluxlaan 2a, 3446 GR Woerden Netherlands Roche Nederland B.V. Beneluxlaan 2a, 3446 GR Woerden Netherlands Roche Nederland B.V. Beneluxlaan 2a, 3446 GR Woerden Netherlands Roche Farmacêutica Química, Lda., Estrada Nacional 249-1, Amadora, Portugal Rocephin Rocephin Rocephin 2 i.v. Rocephin 1 i.m. Rocephin 1 i.v. Rocephin 0,5 i.v. Rocephin 0,25 i.m. Rocephin 250 mg 500 mg 250 mg Powder for solution for injection Powder for solution for injection Powder for solution for infusion Powder for solution for injection Powder for solution for injection Powder for solution for injection Powder for solution for injection Powder for solution for infusion Intramuscular or intravenous use Intramuscular or intravenous use Intravenous use Intramuscular use Intravenous use Intravenous use Intramuscular use Intravenous use 250 mg 500 mg 250 mg 7

8 Member State EU/EEA Marketing authorisation holder (Invented) Name Strength Pharmaceutical form Route of administration Content (concentration) Portugal Portugal Portugal Portugal Romania Sweden Sweden Roche Farmacêutica Química, Lda., Estrada Nacional 249-1, Amadora, Portugal Roche Farmacêutica Química, Lda., Estrada Nacional 249-1, Amadora, Portugal Roche Farmacêutica Química, Lda., Estrada Nacional 249-1, Amadora, Portugal Roche Farmacêutica Química, Lda., Estrada Nacional 249-1, Amadora, Portugal Roche România SRL Piaţa Presei Libere, Nr. 3-5, Clădirea City Gate Turnul de Sud, Etajele 4A, 5 şi 6, Sector 1, Bucureşti, România Roche AB Box Stockholm Sweden Roche AB Box Stockholm Sweden Rocephin Rocephin Rocephin Rocephin Rocephin pulbere pentru soluţie perfuzabilă Rocephalin Rocephalin 1000 mg/10 ml 1000 mg/3,5 ml 500 mg/2 ml 250 mg/2 ml solution for injection solution for injection solution for injection solution for injection Powder for solution for infusion Powder for solution for infusion solution for injection intravenous use Intramuscular use Intramuscular use Intramuscular use Intravenous use Intravenous use Intramuscular or intravenous use 500 mg 250 mg 8

9 Member State EU/EEA Marketing authorisation holder (Invented) Name Strength Pharmaceutical form Route of administration Content (concentration) Sweden United Kingdom United Kingdom United Kingdom Roche AB Box Stockholm Sweden Roche Products Limited, 6 Falcon Way, Shire Park, Welwyn Garden City, AL7 1TW, United Kingdom Roche Products Limited, 6 Falcon Way, Shire Park, Welwyn Garden City, AL7 1TW, United Kingdom Roche Products Limited, 6 Falcon Way, Shire Park, Welwyn Garden City, AL7 1TW, United Kingdom Rocephalin Rocephin Rocephin Rocephin 250 mg solution for injection Powder for solution for injection/infusion Powder for solution for injection Powder for solution for injection Intramuscular use Intramuscular or intravenous use Intramuscular or intravenous use Intramuscular or intravenous use 250 mg 9

10 Annex II Scientific conclusions and grounds for the variation to the terms of the Marketing Authorisation 10

11 Scientific conclusions Overall summary of the scientific evaluation of Rocephin and associated names (see Annex I) Rocephin contains ceftriaxone, a cephalosporin antibacterial agent with in-vitro activity against a range of Gram-positive and Gram-negative bacteria. Rocephin inhibits bacterial enzymes necessary for cellwall synthesis (peptidoglycan synthesis) causing cell death. Rocephin is approved in 19 EU Member States with different nationally approved Summaries of Product Characteristics (SmPCs). Rocephin is administered parenterally either by intramuscular injection, intravenous injection or infusion. The medicinal product is available in vials as powder for solution for injection or infusion. Strengths available are 250 mg, 500 mg, 1g and 2g. Not all strengths are marketed in all EU Member States. Solvent vials contain either sterile water for injections or 1% lidocaine hydrochloride solution. Due to the divergent national decisions taken by Member States concerning the authorisation of Rocephin and associated names, the European Commission notified the EMA of an official referral under Article 30 of Directive 2001/83/EC in order to resolve divergences amongst the nationally authorised product informations for the above-mentioned products and thus to harmonise them across the EU. For the preparation of the harmonised product information, the MAH considered the current registered SmPCs of all EU Member States with an active registration, the published literature and the cumulative safety experience with Rocephin as reported in the company s drug safety database and reflected in the appropriate sections of the company s Core Data Sheet (CDS). The conclusions of the harmonisation of the different sections of the SmPC are summarised below. Section Therapeutic indications Bacterial Meningitis Taking into account the data from clinical studies and considerable clinical experience with ceftriaxone in the treatment of meningitis in adults and children the CHMP agreed with the harmonised indication of Bacterial meningitis. Lower Respiratory Tract Infections (LRTI) Current guidelines require indications to be specific where possible, as it was recognised that different clinical conditions summarised under LRTI have different etiology and therefore may require different treatment. For example, whether pneumonia was acquired in a hospital setting or not, provides additional clues to the pathogens involved and have led to definitions of hospital-acquired pneumonia (HAP) and community-acquired pneumonia (CAP). Community-acquired pneumonia (CAP) Ceftriaxone has been used as a comparator in several recently conducted clinical trials of newer antibacterial medicinal products including ceftaroline and ceftobiprole. The studies report similarly high success rates for both ceftriaxone and the comparator regimens. One paediatric study was also submitted by the MAH, which enrolled 48 patients aged 2 months to 5 years. Overall, the CHMP considered that ceftriaxone, used as a comparator agent in EU licensing trials, is an appropriate agent for the treatment of CAP in adults and children. Hospital-acquired pneumonia (HAP) 11

12 Overall, the CHMP considered that the evidence for the use of ceftriaxone in HAP was sufficient for accepting the harmonised indication taking into account that HAP is included in the indications LRTI or pneumonia, which are currently licensed in the majority of member states. Acute exacerbations of chronic bronchitis (AECB) Ceftriaxone has utility in cases of AECB, although the supporting study was small. Nevertheless, ceftriaxone has a place where intravenous treatment is needed. On balance, the CHMP considered that the indication Acute exacerbations of chronic obstructive pulmonary disease is approvable. Intra-abdominal infections (IAI) The CHMP noted that most of the clinical data stem from studies labeled complicated IAI (ciai), although these studies included a wide variety of conditions. However IAI was accepted as the indication for ceftriaxone as there are increasing discrepancies in the definition of ciai and a lack of acceptance of the term amongst many clinicians. In addition the draft addendum to the Note for guidance on evaluation of medicinal products indicated for treatment of bacterial infections (CPMP/EWP/558/95 rev 2) refers to IAI only. Therefore, the CHMP considered that the wording of the indication IAI acceptable. Urinary tract infections (UTI), including pyelonephritis The CHMP was of the opinion that overall, there is sufficient data from randomised controlled trials to support an indication in UTI (including pyelonephritis). It is not expected that a parenteral antibacterial agent would be prescribed or appropriate in truly uncomplicated UTIs (uuti). Therefore the CHMP limited the indication to complicated UTI (cuti), including pyelonephritis. Infections of bones and joints There is some evidence from clinical studies supporting the indication bone and joint infections. Therefore, in view of the available data and the fact that ceftriaxone has been approved by the majority of member states for bone and joint infections, the CHMP agreed with harmonised indication for: infections of bones and joints. Skin and soft tissue infections (SSTIs) In view of the available data, the antimicrobial activity of ceftriaxone in the indication of uncomplicated SSTI (ussti) is not considered to be appropriate for this agent. There is sufficient data to harmonise the indication for ceftriaxone in complicated SSTI (cssti), since the clinical data presented stem mostly from what was labelled as cssti. Therefore CHMP agreed with the wording proposed of complicated skin and soft tissue infections. Bacterial endocarditis The MAH s clinical trial data all stem from open, retrospective or observational uncontrolled studies enrolling small numbers of patients. The generally good tissue penetration, antibacterial activity, PK and PK/PD considerations provide scientific rationale for use of ceftriaxone in the treatment of bacterial endocarditis. Bacteraemia From the data presented for the various indications it appears that sufficient patients with bacteraemia were included in the clinical studies, which allow the conclusion that ceftriaxone can be used in the authorised indications when bacteraemia is present. It was noted that the proposal for the indication is aligned with the wording previously agreed on for similar antibiotics. Infections with impaired defence mechanisms 12

13 The MAH s proposal Infections in patients with impaired defence mechanisms was not considered to be sufficiently supported by data. Therefore the revised indication Ceftriaxone may be used in the management of neutropenic patients with fever that is suspected to be due to a bacterial infection was proposed and considered acceptable by the CHMP. Acute otitis media (AOM) Overall, there is evidence from controlled clinical trials that ceftriaxone is effective in the treatment of AOM. Prophylaxis of perioperative infections There is evidence for the efficacy of ceftriaxone in the perioperative prophylaxis of infections in several types of surgery such as cardiac surgery, orthopaedic surgery, genitourinary surgery and transurethral resection of the prostate (TURP). Gonorrhoea, gonococcal arthritis, gonococcal eye infection Ceftriaxone was demonstrated to have good clinical efficacy in the treatment of gonorrhoea when used as a single dose treatment. The CHMP considered that there was insufficient data to justify the disease subsets of gonococcal arthritis and gonococcal eye infection as separate indications, and therefore these were deleted as specific indications in the SmPC. Syphilis including neurosyphilis Limited clinical data are available in support of the efficacy of ceftriaxone in the treatment of syphilis. Data in patients with neurosyphilis are even more limited. Considering the submitted data, the CHMP was of the view that ceftriaxone is useful in the treatment of syphilis. Lyme Borreliosis Ceftriaxone has been shown to be beneficial in both early (Stage II) and late (Stage III) disseminated Lyme borreliosis and is recommended in current clinical guidelines. Therefore the MAH s proposal to add Stage II and Stage III nomenclature to this indication was considered to be acceptable by the CHMP. Other indications The MAH s proposal to delete the indication for sinusitis, pharyngitis and prostatitis due to the scarcity of robust clinical trials in these conditions was agreed by the CHMP. Purpura fulminans was deleted as an indication as it was agreed that the condition is a manifestation of specific infections, all of which are already covered in the list of indications. Section Posology and method of administration Posology Dose recommendations have been listed in tabular format according to dosage schedules for each indication for: Adults and children over 12 years of age ( 50 kg), Neonates, infants and children 15 days to 12 years of age (< 50 kg) and Neonates 0-14 days. Rocephin can be administered by intravenous infusion over at least 30 minutes (preferred route) or by slow intravenous injection over 5 minutes, or by deep intramuscular injection. As agreed with the MAH, the CHMP was of the view that there is insufficient data to support the recommendation for subcutaneous administration of ceftriaxone. Based on the data presented, the same doses have been recommended for both populations - younger and older adults, provided renal and hepatic function are not relevantly impaired. 13

14 The MAH has provided studies indicating that the pharmacokinetics of ceftriaxoneare not significantly altered in patients with renal and hepatic impairment, both of which may complicate acute infections. However in cases of severe renal and hepatic impairment, close clinical monitoring for efficacy and safety has been recommended. Section 4.3 Contraindications There is a low incidence of cross allergy between penicillins and 2 nd or 3 rd generation cephalosporins. However, the use of ceftriaxone has been precluded if the patient has a history of a severe immediate hypersensitivity reaction to any other beta-lactam agent or any other cephalasporin. This section also states that ceftriaxone solutions containing lidocaine should never be administered intravenously. Section Special warnings and precautions for use The information on C. difficile and antibiotic- associated colitis was re-worded in line with previous Article 30 harmonisation procedures for beta- lactams and to include hypersensitivity reactions and interactions with calcium-containing products. Rocephin is contraindicated in premature and in fullterm neonates at risk of developing bilirubin encephalopathy or receiving calcium-containing intravenous infusions. In case a lidocaine solution is used as a solvent, ceftriaxone solutions must only be used for intramuscular injection. Adverse events such biliary lithiasis, biliary stasis and renal lithiasis have also been included with a cross reference to section 4.8 (undesirable effects). Section 4.5- Interaction with other medicinal products and other forms of interaction In order to comply with the Guideline on the Summary of product Characteristics, the statement mentioning incompatibilities with amsacrine, vancomycin, fluconazole & aminoglycosides (which is included in the EU CSP) has been moved to Section 6.2 (Incompatibilities). The statement on the lack of a disulfiram- like interaction with alcohol has been deleted as there is insufficient evidence to rule it out. At the request of the CHMP, information on drug-drug interactions (DDI) with anticoagulants was included, with a recommendation that the INR (international normalised ratio) is monitored frequently. Section 4.6 Fertility, pregnancy and lactation The pregnancy statements suggest that there is limited human experience, that animal studies do not indicate an embryotoxic or teratogenic effect, and that caution should be exercised if using during pregnancy. Amendments were made to the wording for the period of lactation, mentioning the fact that the risk of diarrhoea and fungus infection of the mucous membranes cannot be excluded and that breastfeeding might have to be discontinued due to these effects. The MAH has provided data to demonstrate that doses of up to 700 mg/kg of ceftriaxone had no significant effect on fertility or embryofoetal development and the studies conducted are considered adequate. On this basis, no further revisions were warranted. The amended wording was considered to be acceptable by the CHMP. Section Effects on ability to drive and use machines The MAH s proposed text was accepted with minor re-wording. 14

15 Section Undesirable effects Data to determine the frequency of Rocephin adverse drug reactions was derived from clinical trials. The MAH has reassigned adverse events that have not been observed in studies to the additional category, Not known, with an added explanatory footnote. The term convulsions has been added to the tabulated summary of adverse events in section 4.8 of the proposed SmPC following a cumulative review of the events related to convulsions during a Rocephin Periodic Safety Update Report (PSUR) work sharing procedure. The most frequently reported adverse reactions for Rocephin are eosinophilia, leucopenia, thrombocytopenia, diarrhoea, rash, and increased hepatic enzymes. Section 4.9 Overdose The MAH s proposed text that the symptoms of overdose - nausea, vomiting and diarrhoea cannot be reduced by haemodialysis or peritoneal dialysis and that there is no specific antidote was considered to be acceptable by the CHMP. It is stated that the treatment of overdose should be symptomatic. Section Pharmacokinetic properties Information on absorption, distribution, metabolism and elimination has been provided. Ceftriaxone distributes primarily into the extracellular space. Ceftriaxone is not metabolised systemically; but is converted to inactive metabolites by the gut flora. Ceftriaxone is eliminated unchanged renally (by glomerular filtration) and biliary secretion. The elimination half-life of total ceftriaxone in adults is about 8 hours. Total and renal plasma clearance (of total, i.e. free plus protein bound) ceftriaxone is dose dependent, while renal clearance of free ceftriaxone clearance is not. Special populations such as patients with renal and hepatic impairment and the paediatric population have also been included. The half-life increases in the elderly, and in older people aged over 75 years the average elimination half-life is usually two to three times that of young adults. However the changes are generally small and dose reduction is not required if renal and hepatic function is satisfactory. Section Preclinical safety data The MAH has proposed wording for section 5.3 of the SmPC, which reflects the relevant non clinical data with Rocephin that may be informative for safe clinical use. Taking into account the additional amendments to bring the wording is in line with the recommendations made in the Guideline on the Summary of Product Characteristics (2009), this section was considered to be acceptable by the CHMP. Package Leaflet (PL) The changes to the SmPC, when relevant for the user, have also been reflected in the PL and agreed by the CHMP. Readability testing has been performed at a national level. Grounds for the variation to the terms of the marketing authorisation(s) Based on the above, the CHMP considers the benefit/risk ratio of Rocephin and associated names to be favourable and the harmonised Product Information documents to be approvable. Whereas The committee considered the referral under Article 30 of Directive 2001/83/EC 15

16 The committee considered the identified divergences for the Rocephin and associated names regarding with respect to the therapeutic indications, posology and method of administration sections, as well as the remaining sections of the SmPC. The committee reviewed the data submitted by the MAH from the existing clinical studies, published literature and the cumulative safety experience with Rocephin as reported on the company s drug safety database justifying the proposed harmonisation of the Product Information. The committee agreed the harmonisation of the summary of product characteristic, labelling and package leaflet proposed by the marketing authorisation holders. the CHMP has recommended the variation to the terms of the marketing authorisations for which the summary of product characteristics, labelling and package leaflet are set out in Annex III for Rocephin and associated names (see Annex I). 16

17 Annex III Summary of product characteristics, labelling and package leaflet Note: This Summary of Product Characteristics, labelling and package leaflet is the outcome of the referral procedure to which this Commission decision relates. The product information may be subsequently updated by the Member State competent authorities, in liaison with the Reference Member State, as appropriate, in accordance with the procedures laid down in Chapter 4 of Title III of Directive 2001/83/EC. 17

18 SUMMARY OF PRODUCT CHARACTERISTICS, LABELLING AND PACKAGE LEAFLET 18

19 SUMMARY OF PRODUCT CHARACTERISTICS 19

20 1. NAME OF THE MEDICINAL PRODUCT Rocephin and associated names (see Annex I) Powder for Solution for Infusion Rocephin and associated names (see Annex I) Powder for Solution for Injection or Infusion Rocephin and associated names (see Annex I) Powder for Solution for Injection or Infusion Rocephin and associated names (see Annex I) Powder and Solvent for Solution for Injection Rocephin and associated names (see Annex I) 500 mg Powder and Solvent for Solution for Injection Rocephin and associated names (see Annex I) 250 mg Powder and Solvent for Solution for Injection Rocephin and associated names (see Annex I) 250 mg Powder for Solution for Injection [See Annex I - To be completed nationally] 2. QUALITATIVE AND QUANTITATIVE COMPOSITION 3. PHARMACEUTICAL FORM powder for solution for infusion Powder for solution for infusion Powder for Solution for injection or infusion powder for solution for injection or infusion Powder for solution for injection or infusion 250 mg, 500 mg, powder and solvent for solution for injection solution for injection 250 mg powder for solution for injection Powder for solution for injection 4. CLINICAL PARTICULARS 4.1 Therapeutic indications Rocephin is indicated for the treatment of the following infections in adults and children including term neonates (from birth): Bacterial Meningitis Community acquired pneumonia Hospital acquired pneumonia Acute otitis media Intra-abdominal infections Complicated urinary tract infections (including pyelonephritis) Infections of bones and joints Complicated skin and soft tissue infections Gonorrhoea Syphilis Bacterial endocarditis 20

21 Rocephin may be used: For treatment of acute exacerbations of chronic obstructive pulmonary disease in adults For treatment of disseminated Lyme borreliosis (early (stage II) and late (stage III)) in adults and children including neonates from 15 days of age For Pre-operative prophylaxis of surgical site infections In the management of neutropenic patients with fever that is suspected to be due to a bacterial infection In the treatment of patients with bacteraemia that occurs in association with, or is suspected to be associated with, any of the infections listed above Rocephin should be co-administered with other antibacterial agents whenever the possible range of causative bacteria would not fall within its spectrum (see section 4.4). Consideration should be given to official guidelines on the appropriate use of antibacterial agents. 4.2 Posology and method of administration Posology The dose depends on the severity, susceptibility, site and type of infection and on the age and hepato-renal function of the patient. The doses recommended in the tables below are the generally recommended doses in these indications. In particularly severe cases, doses at the higher end of the recommended range should be considered. Adults and children over 12 years of age ( 50 kg) Ceftriaxone Treatment Indications Dosage* frequency** 1- Once daily Community acquired pneumonia Acute exacerbations of chronic obstructive pulmonary disease Intra-abdominal infections Complicated urinary tract infections (including pyelonephritis) Once daily Hospital acquired pneumonia Complicated skin and soft tissue infections Infections of bones and joints 2-4 g Once daily Management of neutropenic patients with fever that is suspected to be due to a bacterial infection Bacterial endocarditis Bacterial meningitis * In documented bacteraemia, the higher end of the recommended dose range should be considered. ** Twice daily (12 hourly) administration may be considered where doses greater than daily are administered. Indications for adults and children over 12 years of age ( 50 kg) that require specific dosage schedules: 21

22 Acute otitis media A single intramuscular dose of Rocephin 1- can be given. Limited data suggest that in cases where the patient is severely ill or previous therapy has failed, Rocephin may be effective when given as an intramuscular dose of 1- daily for 3 days. Pre-operative prophylaxis of surgical site infections as a single pre-operative dose. Gonorrhoea 500 mg as a single intramuscular dose. Syphilis The generally recommended doses are 500 mg- once daily increased to once daily for neurosyphilis for days. The dose recommendations in syphilis, including neurosyphilis, are based on limited data. National or local guidance should be taken into consideration. Disseminated Lyme borreliosis (early [Stage II] and late [Stage III]) once daily for days. The recommended treatment durations vary and national or local guidelines should be taken into consideration. Paediatric population Neonates, infants and children 15 days to 12 years of age (< 50 kg) For children with bodyweight of 50 kg or more, the usual adult dosage should be given. Ceftriaxone Treatment Indications dosage* frequency** mg/kg Once daily Intra-abdominal infections Complicated urinary tract infections (including pyelonephritis) Community acquired pneumonia Hospital acquired pneumonia mg/kg (Max 4 g) Once daily Complicated skin and soft tissue infections Infections of bones and joints Management of neutropenic patients with fever that is suspected to be due to a bacterial infection mg/kg Once daily Bacterial meningitis (max 4 g) 100 mg/kg (max 4 g) Once daily Bacterial endocarditis * In documented bacteraemia, the higher end of the recommended dose range should be considered. ** Twice daily (12 hourly) administration may be considered where doses greater than daily are administered. Indications for neonates, infants and children 15 days to 12 years (< 50 kg) that require specific dosage schedules: Acute otitis media For initial treatment of acute otitis media, a single intramuscular dose of Rocephin 50 mg/kg can be given. Limited data suggest that in cases where the child is severely ill or initial therapy has failed, Rocephin may be effective when given as an intramuscular dose of 50 mg/kg daily for 3 days. Pre-operative prophylaxis of surgical site infections mg/kg as a single pre-operative dose. 22

23 Syphilis The generally recommended doses are mg/kg (max 4 g) once daily for days. The dose recommendations in syphilis, including neurosyphilis, are based on very limited data. National or local guidance should be taken into consideration. Disseminated Lyme borreliosis (early [Stage II] and late [Stage III]) mg/kg once daily for days. The recommended treatment durations vary and national or local guidelines should be taken into consideration. Neonates 0-14 days Rocephin is contraindicated in premature neonates up to a postmenstrual age of 41 weeks (gestational age + chronological age). Ceftriaxone Treatment Indications dosage* frequency mg/kg Once daily Intra-abdominal infections Complicated skin and soft tissue infections Complicated urinary tract infections (including pyelonephritis) Community acquired pneumonia Hospital acquired pneumonia Infections of bones and joints Management of neutropenic patients with fever that is suspected to be due to a bacterial infection 50 mg/kg Once daily Bacterial meningitis Bacterial endocarditis * In documented bacteraemia, the higher end of the recommended dose range should be considered. A maximum daily dose of 50 mg/kg should not be exceeded. Indications for neonates 0-14 days that require specific dosage schedules: Acute otitis media For initial treatment of acute otitis media, a single intramuscular dose of Rocephin 50 mg/kg can be given. Pre-operative prophylaxis of surgical site infections mg/kg as a single pre-operative dose. Syphilis The generally recommended dose is 50 mg/kg once daily for days. The dose recommendations in syphilis, including neurosyphilis, are based on very limited data. National or local guidance should be taken into consideration. Duration of therapy The duration of therapy varies according to the course of the disease. As with antibiotic therapy in general, administration of ceftriaxone should be continued for hours after the patient has become afebrile or evidence of bacterial eradication has been achieved. Older people The dosages recommended for adults require no modification in older people provided that renal and hepatic function is satisfactory. 23

24 Patients with hepatic impairment Available data do not indicate the need for dose adjustment in mild or moderate liver function impairment provided renal function is not impaired. There are no study data in patients with severe hepatic impairment (see section 5.2). Patients with renal impairment In patients with impaired renal function, there is no need to reduce the dosage of ceftriaxone provided hepatic function is not impaired. Only in cases of preterminal renal failure (creatinine clearance < 10 ml/min) should the ceftriaxone dosage not exceed daily. In patients undergoing dialysis no additional supplementary dosing is required following the dialysis. Ceftriaxone is not removed by peritoneal- or haemodialysis. Close clinical monitoring for safety and efficacy is advised. Patients with severe hepatic and renal impairment In patients with both severe renal and hepatic dysfunction, close clinical monitoring for safety and efficacy is advised. Method of administration Rocephin can be administered by intravenous infusion over at least 30 minutes (preferred route) or by slow intravenous injection over 5 minutes, or by deep intramuscular injection. Intravenous intermittent injection should be given over 5 minutes preferably in larger veins. Intravenous doses of 50 mg/kg or more in infants and children up to 12 years of age should be given by infusion. In neonates, intravenous doses should be given over 60 minutes to reduce the potential risk of bilirubin encephalopathy (see section 4.3 and 4.4). Intramuscular injections should be injected well within the bulk of a relatively large muscle and not more than should be injected at one site. Intramuscular administration should be considered when the intravenous route is not possible or less appropriate for the patient. For doses greater than intravenous administration should be used. If lidocaine is used as a solvent, the resulting solution should never be administered intravenously (see section 4.3). The information in the Summary of Product Characteristics of lidocaine should be considered. Ceftriaxone is contraindicated in neonates ( 28 days) if they require (or are expected to require) treatment with calcium-containing intravenous solutions, including continuous calcium-containing infusions such as parenteral nutrition, because of the risk of precipitation of ceftriaxone-calcium (see section 4.3). Diluents containing calcium, (e.g. Ringer s solution or Hartmann s solution), should not be used to reconstitute ceftriaxone vials or to further dilute a reconstituted vial for intravenous administration because a precipitate can form. Precipitation of ceftriaxone-calcium can also occur when ceftriaxone is mixed with calcium-containing solutions in the same intravenous administration line. Therefore, ceftriaxone and calcium-containing solutions must not be mixed or administered simultaneously (see sections 4.3, 4.4 and 6.2). For pre-operative prophylaxis of surgical site infections, ceftriaxone should be administered minutes prior to surgery. For instructions on reconstitution of the medicinal product before administration, see section Contraindications 24

25 Hypersensitivity to ceftriaxone, to any other cephalosporin or to any of the excipients listed in section 6.1. History of severe hypersensitivity (e.g. anaphylactic reaction) to any other type of beta-lactam antibacterial agent (penicillins, monobactams and carbapenems). Ceftriaxone is contraindicated in: Premature neonates up to a postmenstrual age of 41 weeks (gestational age + chronological age)* Full-term neonates (up to 28 days of age): - with hyperbilirubinaemia, jaundice, or who are hypoalbuminaemic or acidotic because these are conditions in which bilirubin binding is likely to be impaired* - if they require (or are expected to require) intravenous calcium treatment, or calcium-containing infusions due to the risk of precipitation of a ceftriaxone-calcium salt (see sections 4.4, 4.8 and 6.2). * In vitro studies have shown that ceftriaxone can displace bilirubin from its serum albumin binding sites leading to a possible risk of bilirubin encephalopathy in these patients. Contraindications to lidocaine must be excluded before intramuscular injection of ceftriaxone when lidocaine solution is used as a solvent (see section 4.4). See information in the Summary of Product Characteristics of lidocaine, especially contraindications. Ceftriaxone solutions containing lidocaine should never be administered intravenously. 4.4 Special warnings and precautions for use Hypersensitivity reactions As with all beta-lactam antibacterial agents, serious and occasionally fatal hypersensitivity reactions have been reported (see section 4.8). In case of severe hypersensitivity reactions, treatment with ceftriaxone must be discontinued immediately and adequate emergency measures must be initiated. Before beginning treatment, it should be established whether the patient has a history of severe hypersensitivity reactions to ceftriaxone, to other cephalosporins or to any other type of beta-lactam agent. Caution should be used if ceftriaxone is given to patients with a history of non-severe hypersensitivity to other beta-lactam agents. Severe cutaneous adverse reactions (Stevens Johnson syndrome or Lyell s syndrome/toxic epidermal necrolysis) have been reported; however, the frequency of these events is not known (see section 4.8). Interaction with calcium containing products Cases of fatal reactions with calcium-ceftriaxone precipitates in lungs and kidneys in premature and fullterm neonates aged less than 1 month have been described. At least one of them had received ceftriaxone and calcium at different times and through different intravenous lines. In the available scientific data, there are no reports of confirmed intravascular precipitations in patients, other than neonates, treated with ceftriaxone and calcium-containing solutions or any other calcium-containing products. In vitro studies demonstrated that neonates have an increased risk of precipitation of ceftriaxone-calcium compared to other age groups. In patients of any age ceftriaxone must not be mixed or administered simultaneously with any calciumcontaining intravenous solutions, even via different infusion lines or at different infusion sites. However, in patients older than 28 days of age ceftriaxone and calcium-containing solutions may be administered sequentially one after another if infusion lines at different sites are used or if the infusion lines are replaced or thoroughly flushed between infusions with physiological salt-solution to avoid precipitation. In patients requiring continuous infusion with calcium-containing total parenteral nutrition (TPN) solutions, healthcare professionals may wish to consider the use of alternative antibacterial treatments which do not carry a similar risk of precipitation. If the use of ceftriaxone is considered necessary in patients requiring continuous nutrition, TPN solutions and ceftriaxone can be administered simultaneously, albeit via different infusion lines at different sites. Alternatively, infusion of TPN solution could be 25

26 stopped for the period of ceftriaxone infusion and the infusion lines flushed between solutions (see sections 4.3, 4.8, 5.2 and 6.2). Paediatric population Safety and effectiveness of Rocephin in neonates, infants and children have been established for the dosages described under Posology and Method of Administration (see section 4.2). Studies have shown that ceftriaxone, like some other cephalosporins, can displace bilirubin from serum albumin. Rocephin is contraindicated in premature and full-term neonates at risk of developing bilirubin encephalopathy (see section 4.3). Immune mediated haemolytic anaemia An immune mediated haemolytic anaemia has been observed in patients receiving cephalosporin class antibacterials including Rocephin (see section 4.8). Severe cases of haemolytic anaemia, including fatalities, have been reported during Rocephin treatment in both adults and children. If a patient develops anaemia while on ceftriaxone, the diagnosis of a cephalosporin-associated anaemia should be considered and ceftriaxone discontinued until the aetiology is determined. Long term treatment During prolonged treatment complete blood count should be performed at regular intervals. Colitis/Overgrowth of non-susceptible microorganisms Antibacterial agent-associated colitis and pseudo-membranous colitis have been reported with nearly all antibacterial agents, including ceftriaxone, and may range in severity from mild to life-threatening. Therefore, it is important to consider this diagnosis in patients who present with diarrhoea during or subsequent to the administration of ceftriaxone (see section 4.8). Discontinuation of therapy with ceftriaxone and the administration of specific treatment for Clostridium difficile should be considered. Medicinal products that inhibit peristalsis should not be given. Superinfections with non-susceptible micro-organisms may occur as with other antibacterial agents. Severe renal and hepatic insufficiency In severe renal and hepatic insufficiency, close clinical monitoring for safety and efficacy is advised (see section 4.2). Interference with serological testing Interference with Coombs tests may occur, as Rocephin may lead to false-positive test results. Rocephin can also lead to false-positive test results for galactosaemia (see section 4.8). Non-enzymatic methods for the glucose determination in urine may give false-positive results. Urine glucose determination during therapy with Rocephin should be done enzymatically (see section 4.8). Sodium Each gram of Rocephin contains 3.6 mmol sodium. This should be taken into consideration in patients on a controlled sodium diet. Antibacterial spectrum 26

27 Ceftriaxone has a limited spectrum of antibacterial activity and may not be suitable for use as a single agent for the treatment of some types of infections unless the pathogen has already been confirmed (see section 4.2). In polymicrobial infections, where suspected pathogens include organisms resistant to ceftriaxone, administration of an additional antibiotic should be considered. Use of lidocaine In case a lidocaine solution is used as a solvent, ceftriaxone solutions must only be used for intramuscular injection. Contraindications to lidocaine, warnings and other relevant information as detailed in the Summary of Product Characteristics of lidocaine must be considered before use (see section 4.3). The lidocaine solution should never be administered intravenously. Biliary lithiasis When shadows are observed on sonograms, consideration should be given to the possibility of precipitates of calcium ceftriaxone. Shadows, which have been mistaken for gallstones, have been detected on sonograms of the gallbladder and have been observed more frequently at ceftriaxone doses of per day and above. Caution should be particularly considered in the paediatric population. Such precipitates disappear after discontinuation of ceftriaxone therapy. Rarely precipitates of calcium ceftriaxone have been associated with symptoms. In symptomatic cases, conservative nonsurgical management is recommended and discontinuation of ceftriaxone treatment should be considered by the physician based on specific benefit risk assessment (see section 4.8). Biliary stasis Cases of pancreatitis, possibly of biliary obstruction aetiology, have been reported in patients treated with Rocephin (see section 4.8). Most patients presented with risk factors for biliary stasis and biliary sludge e.g. preceding major therapy, severe illness and total parenteral nutrition. A trigger or cofactor of Rocephin-related biliary precipitation cannot be ruled out. Renal lithiasis Cases of renal lithiasis have been reported, which is reversible upon discontinuation of ceftriaxone (see section 4.8). In symptomatic cases, sonography should be performed. Use in patients with history of renal lithiasis or with hypercalciuria should be considered by the physician based on specific benefit risk assessment. 4.5 Interaction with other medicinal products and other forms of interaction Calcium-containing diluents, such as Ringer s solution or Hartmann s solution, should not be used to reconstitute Rocephin vials or to further dilute a reconstituted vial for intravenous administration because a precipitate can form. Precipitation of ceftriaxone-calcium can also occur when ceftriaxone is mixed with calcium-containing solutions in the same intravenous administration line. Ceftriaxone must not be administered simultaneously with calcium-containing intravenous solutions, including continuous calcium-containing infusions such as parenteral nutrition via a Y-site. However, in patients other than neonates, ceftriaxone and calcium-containing solutions may be administered sequentially of one another if the infusion lines are thoroughly flushed between infusions with a compatible fluid. In vitro studies using adult and neonatal plasma from umbilical cord blood demonstrated that neonates have an increased risk of precipitation of ceftriaxone-calcium (see sections 4.2, 4.3, 4.4, 4.8 and 6.2). Concomitant use with oral anticoagulants may increase the anti-vitamin K effect and the risk of bleeding. It is recommended that the International Normalised Ratio (INR) is monitored frequently and the posology of the anti-vitamin K drug adjusted accordingly, both during and after treatment with ceftriaxone (see section 4.8). 27

28 There is conflicting evidence regarding a potential increase in renal toxicity of aminoglycosides when used with cephalosporins. The recommended monitoring of aminoglycoside levels (and renal function) in clinical practice should be closely adhered to in such cases. In an in-vitro study antagonistic effects have been observed with the combination of chloramphenicol and ceftriaxone. The clinical relevance of this finding is unknown. There have been no reports of an interaction between ceftriaxone and oral calcium-containing products or interaction between intramuscular ceftriaxone and calcium-containing products (intravenous or oral). In patients treated with ceftriaxone, the Coombs' test may lead to false-positive test results. Ceftriaxone, like other antibiotics, may result in false-positive tests for galactosaemia. Likewise, non-enzymatic methods for glucose determination in urine may yield false-positive results. For this reason, glucose level determination in urine during therapy with ceftriaxone should be carried out enzymatically. No impairment of renal function has been observed after concurrent administration of large doses of ceftriaxone and potent diuretics (e.g. furosemide). Simultaneous administration of probenecid does not reduce the elimination of ceftriaxone. 4.6 Fertility, pregnancy and lactation Pregnancy Ceftriaxone crosses the placental barrier. There are limited amounts of data from the use of ceftriaxone in pregnant women. Animal studies do not indicate direct or indirect harmful effects with respect to embryonal/foetal, perinatal and postnatal development (see section 5.3). Ceftriaxone should only be administered during pregnancy and in particular in the first trimester of pregnancy if the benefit outweighs the risk. Breastfeeding Ceftriaxone is excreted into human milk in low concentrations but at therapeutic doses of ceftriaxone no effects on the breastfed infants are anticipated. However, a risk of diarrhoea and fungal infection of the mucous membranes cannot be excluded. The possibility of sensitisation should be taken into account. A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from ceftriaxone therapy, taking into account the benefit of breast feeding for the child and the benefit of therapy for the woman. Fertility Reproductive studies have shown no evidence of adverse effects on male or female fertility. 4.7 Effects on ability to drive and use machines During treatment with ceftriaxone, undesirable effects may occur (e.g. dizziness), which may influence the ability to drive and use machines (see section 4.8). Patients should be cautious when driving or operating machinery. 4.8 Undesirable effects 28