P-RMS FINAL ASSESSMENT REPORT Procedure number AT/H/PSUR/0004/ November-2011

Transcription

1 P-RMS FINAL ASSESSMENT REPORT Procedure number AT/H/PSUR/0004/ November-2011 Active substance Sulbactam sodium Innovator name of product in the P-RMS Combactam <for MRP products also procedure number> national Pharmaceutical form(s)/strength powder for infusion, i.v. 1g MAH(s) Pfizer Corporation HBD and DLP / Nov 2010 PSUR period 01 December 2007 to 15 November 2010 P-RMS AT Assessor Dr. Susanne Wolf Contact point TIME TABLE Procedure Start Date 14-Feb-2011 Date of preliminary AR 26-Mar-2011 Deadline for comments to P-RMS 25-April-2011 Clockstop/ RFI / LoQ 29-April-2011 Procedure Restart Date 28-September-2011 Date of Draft Final AR 28-September-2011 Deadline for comments to P-RMS 13-October-2011 Date of Final AR 22-November-2011 Discussion at PhVWP DLP of the next PSUR submission November 2013 In addition to the innovator PSUR, the assessment report covers the following PSURs of additional products authorised in the P-RMS: MAHs / Contact MR procedure number (if applicable) Period covered by the PSUR The following PSURs of products not authorised in the P-RMS have been submitted in MSs as part of the worksharing procedure. MAHs / Contact Sandoz gpv.sandoz@sandoz.com Actavis pharmacovigilance@actavis.dk MR procedure number (if applicable) Period covered by the PSUR Hexal AG (national in DE) Sulbactam 1/16 FAR

2 INDICATIONS AUTHORISED IN THE P-RMS (INNOVATOR): Sulbactam is a penicillanic acid sulphone which acts as an inhibitor of most important β- lactamases that occur in penicillin-resistant organisms. Although sulbactam has minimal antibacterial activity when used alone, sulbactam can enhance the activity of penicillins and cephalosporins against many resistant strains of bacteria. Sulbactam is indicated for use in combination with a β-lactam antibiotic for infections in which β-lactamase producing pathogens are present or suspected. Extensive clinical experience with sulbactam administered in combination with penicillin G, ampicillin, mezlocillin, piperacillin, cefoperazone and cefotaxime supports the use of sulbactam/β-lactam antibiotic combinations in the following indications: upper and lower respiratory tract infections including sinusitis, otitis media, epiglottitis and bacterial pneumonias; urinary tract infections and pyelonephritis; intraabdominal infections including appendicular abscess, cholecystitis, peritonitis and pelvic infections; septicemias; skin and soft tissue and bone and joint infections; gonococcal infections; and posttraumatic and postoperative infections. Sulbactam administered prophylactically in combination with ampicillin and cefoperazone has also been shown to reduce the incidence of postoperative wound infections. WORLDWIDE MARKETING AUTHORISATION STATUS AND UPDATE OF REGULATORY ACTIONS TAKEN FOR SAFETY REASONS (MAH, AUTHORITIES) Has there been a change to the marketing authorisation status or have regulatory actions been taken for safety reasons? Yes No If yes, specify: SUMMARY OF PREVIOUS RELEVANT PhVWP/CHMP DISCUSSIONS *, IF ANY: * During the period under review CHANGES TO REFERENCE SAFETY INFORMATION Is the CCDS the reference document? Yes No If not, please indicate which document is used as reference document: Date of the last reference document : December 6, 2007 Which sections of the reference safety document have been changed during the period covered by the PSUR? Sulbactam 2/16 FAR

3 posology and method of administration (4.2) contraindications(4.3) special warnings and precautions for use(4.4) interaction with other medicinal products and other forms of interaction(4.5) pregnancy and lactation (4.6) effects on ability to drive and use machines(4.7) undesirable effects(4.8) overdose (4.9) Please specify the safety relevant changes: A statement on Clostridium Difficile Associated Diarrhea (CDAD) was added: Section 4.4: Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including sulbactam sodium, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile. C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibiotic use. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents. Assessor s comment: The inclusion of Clostridium difficile associated diarrhea (CDAD) in the RSI is endorsed since the current CSP already contains this warning. SERIOUS CASES AND ADRs Total number of serious cases, incl. fatalities 16 Number of fatal cases 4 SUSPECTED ADVERSE DRUG REACTIONS, overview TABLE OF ADVERSE DRUG REACTIONS (ADRs) Serious Non-serious Total * System Organ Class (SOC) Listed Unlisted Listed Unlisted Blood and lymphatic system disorders Cardiac disorders Congenital and familial and genetic disorders Ear and labyrinth disorders Endocrine disorders Eye disorders Gastrointestinal disorders General disorders and administration site conditions Hepatobiliary disorders Immune system disorders Sulbactam 3/16 FAR

4 Infections and infestations Injury poisoning and procedural complications Investigations Metabolism and nutrition disorders Musculoskeletal and connective tissue disorders Neoplasms benign, malignant and unspecified Nervous system disorders Pregnancy, puerperium and perinatal conditions Psychiatric disorders Renal and urinary disorders Reproductive system and breast disorders Respiratory thoracic and mediastinal disorders Social circumstances Skin and subcutaneous tissue disorders Surgical and medical procedure Vascular disorders Total *MAH: For some adverse events the column does not equal the number of listed and unlisted columns because the listedness was not completed or not determined per current business practices for those adverse events at the time of PSUR table generation. TABLE OF SELECTED* SERIOUS UNLISTED ADRs : Serious unlisted ADRs (MedDRA PT in agreed SOC order) Number of serious unlisted ADRs Sepsis 3 Renal failure (acute) 3 Stevens-Johnson syndrome 1 Toxic epidermal necrolysis 3 * Selection is within the discretion of the P-RMS VALUABLE INFORMATION FROM PSURs FOR OTHER PRODUCTS AUTHORISED IN THE P-RMS Do any of the PSURs for other products authorised in the P-RMS contain information not addressed in the PSUR for the originator product(s)? Yes No There are no other products authorised in AT. If yes, specify in table below: Sulbactam 4/16 FAR

5 TABLE OF SELECTED* SERIOUS UNLISTED ADRs IN OTHER PSURs AUTHORISED IN THE P-RMS Serious unlisted ADRs (MedDRA PT in agreed SOC order) Number of serious unlisted ADRs * Selection is within the discretion of the P-RMS Other information: OVERALL ASSESSOR COMMENTS ON CASE REPORTS (INCL. LITERATURE CASES) A total of 17 cases from health care professionals and any other medically confirmed cases (containing 30 events) fulfilled criteria for inclusion in this 3-year safety update report. Safety topics reviewed by the MAH: The event Stevens-Johnson syndrome (SJS) was identified for review in this PSUR in reply to the FAR for the previous PSUR and also based on the conclusions of continued monitoring of the last two sulbactam PSURs (01 May 2000 through 30 April 2005; 01 May 2005 through 30 November 2007). Cases reporting Toxic epidermal necrolysis are also discussed in this section. A total of 3 cases, from the German Documentation Centre of Severe Skin Reactions reporting SJS and TEN, were received during the reporting period. Two of these cases ( and ) had a fatal outcome and in the third case ( ) the event was not recovered at the time of reporting. These 3 patients were notable for the presence of severe underlying conditions and for the use of multiple suspect medications. Medical review of these 3 cases does not support a clear and definitive role of sulbactam in the occurrence of these skin reactions. Table 9 below shows the details of these 3 cases and the project experts assessements: Sulbactam 5/16 FAR

6 The previous 4 cases of SJS and TEN presented similar aspects of those received during the current period: patients with extensive comorbidities and treatment with multiple suspect medications (A020608, M , A128209, A203227). Upon review, it could not be clearly determined to what extent sulbactam treatment might have contributed to the reported events, but a possible association could not be entirely excluded. No changes to the CDS are warranted based on the review of all these cases; the MAH will continue to monitor cases reporting SJS and TEN. Assessor`s comment: Cumulatively, the MAH has received 7 cases of SJS and TEN however one set of cases was found to be a potential duplicate. A total of 3 cases reporting SJS and TEN, were received during the reporting period. Two of these cases had a fatal outcome and in the third case the event was not recovered at the time of reporting. The previous 4 cases of SJS and TEN presented similar aspects of those received during the current period. Although multiple suspect medications and extensive comorbidities could have contributed to the reported events, a possible association with sulbactam in these cases cannot be ruled out. As sulbactam is used with betalactam antibiotics, which are known for causing SJS and TEN, these adverse events should be included in section 4.8 of the proposed CSP. Death Four cases with a fatal outcome were received during the reporting period. Two fatalities involved patients diagnosed with SJS and TEN and have been described in Safety Topic Review. The other two cases are discussed here below: Case , involved a 98-year-old male patient with a history of Parkinson's disease and suspected epilepsy who started to receive IV sulbactam 1.5g/day in combination with piperacillin 12g/day, for fever and leukocytosis of unclear etiology. On this therapy, he developed sepsis and acute renal failure (ARF) with an increase of creatinine and C- reactive protein. The adverse events were life-threatening. The patient did not smoke, drink alcohol, had no pacemaker and no allergies. He died on an unknown date. No information was provided whether an autopsy was performed or not. The hospital physician assessed a possible causal relationship between the events and therapy with sulbactam and piperacillin. Sepsis, especially septic shock, is one of the main causes of ARF. Very old people, like this patient, are at risk for sepsis; however, the limited information provided in this report does not allow a complete assessment of the potential role of sulbactam in these events. Case DE-WYE-G reported limited information about a 61-year old male patient on lorazepam who developed sepsis and subsequently died for rhabdomyolysis, red urine and ARF which were reported to be possibly related to all recently administered suspect medications (range therapy from 1- to 8 days): fondaparinux sodium, acetylsalicylic acid, lansoprazole, carbamazepine, simvastatin, metoprolol, ramipril, zopiclone, melperone, clonidine, torasemide, norepinephrine, sulbactam, piperacillin, flunitrazepam, furosemide, cilastatin sodium/imipenem, insulin, acetylcysteine and potassium chloride. This patient had a significant medical history of Acute myocardial infarction, Coronary artery disease, Diabetes mellitus, Epilepsy, Polyneuropathy, Respiratory failure ventilation-requiring. Summary No modification to the reference safety document is necessary based on this review. Assessor`s comment: The first case involved a very old patient with some concomitant diseases but important information is missing (e.g. co-medication, etiology for fever and leucocytosis). In the second case there is also very limited information (e.g. no indication, no concomitant diseases) about the patient but there are lots of co-medications which are possibly related to the events causing the patients` death. No new safety concerns were identified from these cases. Sulbactam 6/16 FAR

7 OVERALL ASSESSOR COMMENTS ON MAH SPONSORED STUDIES Newly analyzed company-sponsored studies: No non-clinical studies and clinical studies containing important safety information were analyzed during the reporting period. Targeted new safety studies MAH: Worth of note, the previous sulbactam PSUR reported as targeted safety study the trial A of which, the primary objective was to evaluate the overall safety of cefoperazone/sulbactam (SulperazonTM) in the treatment of patients with bacterial infections in adults. This study was conducted in Indonesia and a final study report is not available at this time. The MAH will provide with the final safety conclusions in the upcoming cefoperazone/sulbactam PSUR with data lock-point January Assessor`s comment: This is acknowledged, however the MAH should provide a short safety conclusion of this trial (A : Post marketing surveillance on the efficacy, safety and tolerability of cefoperazone/sulbactam (sulperazone)1:1 ratio in the treatment of bacterial systemic infection in adults). No non-clinical or clinical targeted safety studies (i.e., studies designed to examine specific safety concerns) were planned or conducted during this reporting period. Published safety studies Review of the literature search from Medline, Embase, and Derwent Drug File for the current reporting period and review of a retrospective literature search of the articles covering nonclinical/toxicology information from the IBD (16 November 1987) did not identified relevant published study containing important new safety findings. OVERALL ASSESSOR COMMENTS ON STUDIES FROM THE LITERATURE Describe and comment on literature studies of relevance to safety of the product(s). OVERALL ASSESSOR COMMENTS ON NEW INFORMATION REGARDING Special populations: Use in the Elderly Nine serious cases (including 17events) involved elderly patients. There were 3 female and 6 male patients with a mean age of 83-year-old. The indications reported in the majority of the cases were Unknown and Pneumonia (2). Two cases had a fatal outcome and have been respectively described in Safety Topic Review section (case , SJS and TEN) and Death section ( , Sespis and ARF). The remaining 7 cases, had outcome recovered/recovering (5) and unknown (2). The MedDRA SOCs containing the greatest number of events was Blood and lymphatic system disorders (5). The most commonly reported adverse events (2 occurrences each) were Sepsis and Thrombocytopenia which are both unlisted in the CDS. All 7 cases involved the use of sulbactam in combination with piperacillin, and 5 were assessed as possibly related to the reported events, despite the underlying severe patients conditions. Pregnancy/lactation: No cases of sulbactam used in pregnancy and lactation were reported during this period. Drug interaction: No cases of a possible drug interaction with sulbactam were reported during this period. Sulbactam 7/16 FAR

8 Overdose: No cases of overdose were reported for sulbactam during this reporting period. Abuse or misuse: No cases of abuse, misuse and drug dependence were reported for sulbactam during this reporting period. Medication errors: No cases of prescription and medication errors were reported for sulbactam during this reporting period. Long-term treatment: To identify long-term adverse effects of sulbactam, the MAH conducted a search to identify cases that described a duration of 20 days between the start of sulbactam therapy and event occurrence. A duration of 20 days was selected based on the fact that sulbactam, as a betalactamase inhibitor, is used only in combination with a beta-lactam antibiotic, and for most indications administration of a beta-lactam for more than 20 days would be considered a longer than typical treatment. There was one case that met this criterion during the current reporting period: this case ( , SJS and TEN) has been described in Safety Topic Review section. Latency was of 27 days. An association of the AEs (SJS and TEN) with long-term therapy with sulbactam could not be enterely excluded, though the patient was on multiple medications. Off label use: No spontaneous cases of off-label use for sulbactam were reported during this period. Assessor s comment: No safety issues related to the special patient groups were identified. COMMENTS ON ANY CHANGE OF THE RISK BENEFIT BALANCE MAH conclusion: Analysis of the 17 cases received by the MAH between 01 December 2007 and 15 November 2010 identified no new safety information that altered the benefit-risk assessment of sulbactam. Assessors conclusions and comments: The P-RMS agrees that the risk/benefit balance remains positive but the MAH is expected to include SJS and TEN into the CSP. ACTION PLAN AND CONCLUSIONS A CHANGES OF THE BENEFIT RISK BALANCE Has the benefit risk balance changed? No Yes, please specify: Sulbactam 8/16 FAR

9 B CHANGES REQUIRED IN THE CSP Is the CSP acceptable? Yes No X If not, specify the necessary changes (specific wordings): - The MAH is expected to include SJS and TEN into the CSP and to provide a clean version of the updated CSP. MAH response: The MAH agrees to include SJS and TEN in section 4.8 of the CSP. Assessor`s comment: Issue resolved. - The MAH should discuss comments received from DE (see chapter D). MAH response: The MAH agrees to examine the clinical trial and post-marketing data available for sulbactam in order to determine the most appropriate frequencies for reported adverse events and to update Section 4.8 of the CSP accordingly. Assessor`s comment: Issue resolved. C REGULATORY ACTIONS * PROPOSED, IF ANY * Regulatory options may include urgent safety restrictions, variations, suspension or revocation. Topics for close monitoring should be mentioned below in section E. D SUMMARY OF COMMENTS FROM OTHER MSs Member State Comment Agreed action e.g. updating CSP, close monitoring DE comment on PAR Section 4.8 This section is currently not in line with SPC guideline. All adverse reactions which are mentioned in section 4.4 have to be amended with a reference (see section 4.4) or appropriate footnote. Adverse reactions should be displayed in a two-dimensional table format with frequencies given in separate columns which allow an easier view to both frequency and SOC. The CSP has to be further amended. DE comment on draft FAR Section 4.8 The German SPC for Combactam also listed the adverse reaction seizure (Frequency Not known ) under the SOC Nervous system disorders. The MAH should discuss this issue and update the CSP if necessary. Sulbactam 9/16 FAR

10 The following wordings are missing: The reactions considered at least possibly related to sulbactam are displayed by system organ class and frequency using the following convention: very common ( 1/10), common ( 1/100 to < 1/10), uncommon ( 1/1,000 to < 1/100) and not known (adverse reactions from post-marketing experience; cannot be estimated from the available data). The adverse reaction Pseudomembranous colitis should be added under the SOC Infections and infestations with the frequency Not known and a reference to section 4.4 (see section 4.4). The CSP has to be further amended. P-RMS final conclusion: As MAH did not respond to the German comments on draft FAR within the given time frame, the changes requested by DE are implemented. The majority of issues concerning 4.4 and 4.8 are already listed in the DE SmPC as well as in the AT SmPC. The CSP attached with the FAR is considered final. All adverse reactions which are mentioned in section 4.4 have to be amended with a reference (see section 4.4) this is still missing for the adverse reactions: fungal infection, Hypersensitivity and Anaphylactic shock. E POINTS TO BE ADDRESSED IN THE NEXT PSUR F RFI / LoQ: REQUEST FOR FURTHER INFORMATION / LIST OF QUESTIONS Sulbactam 10/16 FAR

11 Questions to be addressed by the MAH: - The MAH is expected to include SJS and TEN into the CSP and to provide a clean version of the updated CSP. MAH response: The MAH agrees to include SJS and TEN in section 4.8 of the CSP. Assessor`s comment: Issue resolved. - The MAH should provide a short safety conclusion of this trial (A : Post marketing surveillance on the efficacy, safety and tolerability of cefoperazone/sulbactam (sulperazone)1:1 ratio in the treatment of bacterial systemic infection in adults). Assessor`s comment: The MAH provided a short conclusion of this trial. No new safety concerns were identified. - MAH should discuss comments received from DE (see chapter D). MAH response: The MAH agrees to examine the clinical trial and post-marketing data available for sulbactam in order to determine the most appropriate frequencies for reported adverse events and to update Section 4.8 of the CSP accordingly. Discussion One of the issues with determining adverse event frequencies is that Combactam is always used in combination with beta-lactam antibiotics. It is therefore difficult to distinguish the safety profile due to the sulbactam component alone from that typically seen with the antibiotic component. In order to verify the side effect profile and to estimate frequency data, it was necessary to examine the original clinical trial data present in the MAA. Prior to the authorisation of Combactam, two sulbactam fixed combination products were available, namely Unasyn (a combination of sulbactam and ampicillin in a 1:2 ratio) and Sulperazone (a combination of sulbactam and cefoperazone in 1:1 and 1:2 ratio). The registration of sulbactam was supported by extensive premarketing and post-marketing clinical safety and efficacy data with two fixed combination products along with the new clinical data involving 483 patients on the other combinations of sulbactam and widely used beta-lactam antibiotics (penicillin G, mezlocillin, piperacillin and cefotaxime). In addition, post marketing experiences with two fixed combinations were utilized to support sulbactam registration. Adverse events and lab abnormalities observed with all newly studied sulbactam combinations, as well as with sulbactam/ampicillin and sulbactam/cefoperazone, were similar in type, severity, and incidence to those occurring with beta-lactams alone. A summary table of specific adverse events and lab abnormalities possibly related to four newly studied sulbactam combinations (483 patients) was documented in the MAA. These were considered a representative data set of crude incidence rates of adverse experiences with sulbactam combinations and one where patient numbers could be definitely assigned, also where a medical assessment of probable relatedness had been carried out. Thus, this was determined as the data source for the assessment of AE frequencies and determinations of AE frequencies were carried out by applying the following criteria. Data Source Sulbactam Sodium Parenteral/Original MAA (June 1989): Volume 3.1 of Part IV Clinical Documentation Criteria Frequencies based on incidence rates of adverse events and lab abnormalities possibly related to sulbactam combinations, which are derived from pooled studies, are used to assign frequency category. If an AE was not reported in the aforementioned documentation, with the possibility that it is seen with beta-lactams alone or with other sulbactam combination where a frequency cannot be estimated from the available data, the category Frequency not known is used according to the EU SmPC guideline dated September 2009 Assessor`s comment: The MAH provided a revised CSP with a single table format with the estimated frequency of those AE s in the current CSP and any additional AE s not listed previously and extracted from the examination of the clinical trials. The CSP is considered acceptable. Issue resolved. Sulbactam 11/16 FAR

12 FINAL CONCLUSION (SUMMARY OF A-F) The benefit / risk profile remains favourable. The CSP (annex 1) is considered final. The issues from sections A-E are considered resolved. DATE AND CONCLUSION OF PHVWP DISCUSSION CONCERNING THIS PSUR, IF ANY: Annex I - CSP : separately attached In PAR: Proposed CSP with assessor comments, if any In Draft FAR: Proposed CSP with assessor comments In FAR: Agreed CSP Sulbactam 12/16 FAR

13 Annex I: Sulbactam EU Core Safety Profile 4.3 Contraindications Combactam is contraindicated in patients with known hypersensitivity to sulbactam or the coadministered ß-lactam antibiotic. A possible cross allergy between penicillins and cephalosporins should be considered. In addition, the contraindications of the co-administered antibiotic have to be considered. In case of intramuscular injection, the contraindications of lidocaine should be considered, if applicable. 4.4 Special Warnings and Precautions for Use Sulbactam s activity in children under the age of one year has not been completely clarified yet. Therefore, Combactam should be used in this patient population only after a careful benefit-risk assessment. Caution is required in patients with bronchial asthma, urticaria, and hay fever. Serious and occasionally fatal hypersensitivity (anaphylactic) reactions have been reported in patients on ß-lactam antibiotic therapy. These reactions are more apt to occur in individuals with a history of hypersensitivity reactions to multiple allergens. If an allergic reaction occurs, the drug should be discontinued and the appropriate therapy instituted. Serious anaphylactic reactions require immediate emergency treatment with epinephrine. Oxygen, intravenous steroids and airway management including intubation should be administered as indicated. As with any antibiotic preparation, constant observation for signs of overgrowth of nonsusceptible organisms, including fungi, is essential. Should superinfection occur, the drug should be discontinued and/or appropriate therapy instituted. Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including sulbactam sodium, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile. C. difficile produces toxins A and B which contribute to the development of CDAD. Sulbactam 13/16 FAR

14 Hypertoxin producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibiotic use. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents. As with any potent systemic agent, it is advisable to check periodically for organ system dysfunction during extended therapy; this includes renal, hepatic, and hematopoietic systems. This is particularly important in neonates, especially when premature, and other infants. In patients who have to restrict their sodium intake, it should be considered that a dry-fill vial of Combactam 1 g contains approximately 4.4 mmol sodium. 4.5 Interaction with Other Medicinal Products and Other Forms of Interaction Probenecid: Oral probenecid administered shortly before or concomitantly with sulbactam sodium competitively inhibits renal tubular secretion of sulbactam and produces higher and prolonged serum concentrations of the drug. All interactions reported in combination with Combactam are possible interactions of the antibiotic component. Interactions related to the selected antibiotic have to be considered. 4.6 Fertility, Pregnancy and Lactation Pregnancy: Reproduction studies in animals have revealed no evidence of impaired fertility and no teratological findings. Sulbactam diffuses readily into most body tissues and fluids in the human, and crosses the placental barrier. There are, however, no adequate and well controlled studies in pregnant women. Therefore, sulbactam should be used during pregnancy only if the potential benefits outweigh the potential risk. Lactation period: Lactation should be discontinued during sulbactam therapy. 4.7 Effects on Ability to Drive and Use Machines No studies have been performed with regard to the effects on the ability to drive and use Sulbactam 14/16 FAR

15 machines. It should be considered that dizziness may occasionally occur after administration of antibiotics 4.8 Undesirable Effects In clinical trials of sulbactam co-administered with ß-lactam antibiotics (n=483), the following adverse events and frequencies were observed. The reactions considered at least possibly related to sulbactam are displayed by system organ class and frequency using the following convention: very common ( 1/10), common ( 1/100 to < 1/10), uncommon ( 1/1,000 to < 1/100) and not known (adverse reactions from post-marketing experience; cannot be estimated from the available data). Infections and Infestations Blood and lymphatic disorders Immune system disorders Nervous system disorders Gastrointestinal disorders Hepato-biliary disorders Skin and subcutaneous tissue disorders common ( 1/100 to < 1/10) uncommon ( 1/1,000 to < 1/100) Frequency not known Fungal Pseudomembranous infection/stomatitis (see colitis (see section 4.4) section 4.4) Eosinophilia Thrombocytopenia, Thrombocytosis, Leukopenia Leukocytosis, Neutropenia, Anaemia, Bleeding time prolonged, Purpura Hypersensitivity (see Anaphylactic shock (see section 4.4) section 4.4) Dizziness Headache Seizure Diarrhoea Vomiting Gastrointestinal disorders Nausea Decreased appetite Flatulence Transaminases Blood bilirubin increased increased Skin reaction Stevens-Johnson Syndrome Toxic epidermal Sulbactam 15/16 FAR

16 Musculosceletal and connective tissue disorders Renal and urinary disorder General disorders and administration site conditions Thrombophlebitis Injection site pain necrolysis Muscle spasms Blood creatinine increased Tubulointerstitial nephritis Studies to date with sulbactam in combination with β-lactam antibiotics have shown no evidence that the addition of sulbactam results in any side effects not seen with the ß-lactams administered alone. All side effects reported for combination therapy with sulbactam are possible side effects of the antibiotic component. 4.9 Overdose Symptoms of intoxication: Sulbactam and ß-lactam antibiotics show a broad therapeutic range. Intoxications in the narrow sense are not known. Certain risk constellations and administration of very high doses may lead to central nervous agitation, myoclonia and cramps, as also described for other ß-lactams. In patients with severely impaired renal function, epilepsy or meningitis, the risk of developing such undesired reactions is increased. Emergency treatment: In cases of central nervous side effects, e.g. cramps, sedation with diazepam is recommended. Anaphylactic reactions require the usual emergency treatment, which should be initiated at the very first signs of shock. Hemodialysis may accelerate excretion of sulbactam. Sulbactam 16/16 FAR