p-rms final assessment report procedure...

Meropenem 1/43 FAR AT/H/PSUR/0018/002

P-RMS FINAL

ASSESSMENT REPORT

Procedure number AT/H/PSUR/0018/002

Active substance Meropenem

Innovator name of product in the P-RMS Optinem

<for MRP products also procedure number> Nationally approved in AT

MRP: FR/H/467/01, FR/H/467/02

Pharmaceutical form(s)/strength i.v. 500 mg, i.v. 1 g

MAH(s) Astra Zeneca

HBD and DLP HBD: 17-08-1994

PSUR period 01-09-2009 to 31-08-2012

P-RMS AT

Assessor Dr. Claudia Reichelt

Contact point Dr. Claudia Reichelt Tel.: +43 (0)50 555 - 36269 Fax.: +43 (0)50 555 - 36207 mailto: [email protected]

TIME TABLE Procedure Start Date 07-01-2013

Date of preliminary AR – day 60 08-03-2013

Deadline for comments to P-RMS – day 90

07-04-2013

Clockstop / RFI / LoQ 22.04.2013

Procedure Restart Date 29.05.2013

Date of Draft Final AR 21.06.2013

Deadline for comments to P-RMS 21.07.2013

Date of Final AR 24.07.2013

Discussion at PhVWP

DLP of the next PSUR submission and period of PSUR

31-08-2015 (three years)

In addition to the innovator PSUR, the assessment report covers the following PSURs of additional

products authorised in the P-RMS:

MAHs MR procedure number

(if applicable)

Period covered by the PSUR

Sandoz GmbH NL/H/1727/1730/001-002/DC 01-09-2009 to 31-08-2012

Dr. Friedrich Eberth

Arzneimittel GmbH

UK/H/4098/01-02/DC 19-09-2011 to 31-08-2012

Actavis Group n/a 01-09-2009 to 31-08-2012

Hospira Deutschland GmbH DK/H/1699/001-002/DC 01-09-2009 to 31-08-2012

Fresenius Kabi Austria

GmbH

PT/H/0272/001-002/DC 01-06-2010 to 31-08-2012

Hikma Farmaceutica S.A. UK/H/2155/01-02/DC 28-09-2010 to 31-08-2012

Basics GmbH IE/H/0203/01-02/DC 16-06-2010 to 31-08-2012


The following PSURs of products not authorised in the P-RMS have been submitted as part of the

worksharing procedure:

MAHs MR procedure number (if

applicable)

Period covered by the PSUR

Recordati S.p.A. n/a 28. Nov. 2008 – 30. Nov. 2011

Pharmathen S.A. UK/H/4034/01-02/DC 09. Nov. 2011 – 31. Aug. 2012

INDICATIONS AUTHORISED IN THE P-RMS (INNOVATOR):

Optinem is indicated for the treatment of the following infections in adults and children over 3 months of age (see sections 4.4 and 5.1): · Pneumonia, including community acquired pneumonia and nosocomial pneumonia · Broncho-pulmonary infections in cystic fibrosis · Complicated urinary tract infections · Complicated intra-abdominal infections · Intra- and post-partum infections · Complicated skin and soft tissue infections · Acute bacterial meningitis Meronem may be used in the management of neutropenic patients with fever that is suspected to be due to a bacterial infection. Consideration should be given to official guidance on the appropriate use of antibacterial agents. 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: May 2010 Which sections of the reference safety document have been changed during the period covered by the PSUR?


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: The Core Data Sheet was updated twice. CDS 6 April 2010: Section 4.2 Posology and method of administration Statements were added to clarify the use and dosage of meropenem in the treatment of critically ill patients with infections known or suspected to be caused by Pseudomonas aeruginosa and/or Acinetobacter spp where the susceptibility of the pathogen is unknown. Statements were added to confirm that there is limited safety data available to support the administration of either a 2g bolus dose in adults or a 40 mg/kg bolus dose in children. The information on use in patients with impaired renal function has been modified to confirm that meropenem is cleared by hemofiltration as well as by haemodialysis. Section 4.4 Special Warnings and precautions for use Information was added to confirm that the rare hypersensitivity reactions which may occur with meropenem can be serious and occasionally fatal. A warning statement regarding concomitant administration of meropenem with valproic acid/sodium valproate was also added: ‘The concomitant use of valproic acid/sodium valproate and MERREM is not recommended’. Section 4.5 Interaction with other medicinal products and other forms of interaction More information was added on the nature of the drug/drug interaction between meropenem and valproic acid/sodium valproate: ‘decreases of valproic acid have been reported when it is co-administered with carbapenem agents resulting in a 60-100% decrease in valproic acid levels in about two days. Due to the rapid onset and the extent of the decrease, coadministration of MERREM in patients stabilised on valproic acid is not considered to be manageable and therefore should be avoided’. Section 4.8 Undesirable effects The adverse event tables have been reformatted. Instead of listing adverse effects by frequency of event first, then by system organ class, this information is now listed by system organ class first, then frequency of event (frequency is also now calculated using the CIOMS III frequency classification). Also, separate tables are presented for data generated from clinical studies and data generated from post-marketing clinical trials and spontaneous reports. Rare convulsions is considered to a be listed event and the footnote regarding a temporal association with MERREM/MERONEM has been removed. CDS 7 May 2010: Section 4.7 Effects on ability to drive and use machines A minor change has been made to clarify that although no studies on the ability to drive and use machines have been performed with meropenem, some of the recognised undesirable effects (headache, paraesthesia and convulsions) should be taken into account when driving or operating machines.


Selected differences between RSI and proposed CSP:


MAH Comment: This comparison document is prepared based upon the CDS in effect at the end of the reporting period of the PSUR, and therefore used as the reference document for the PSUR. The Core Data Sheet has subsequently been revised following the end of the PSUR reporting period and changes made in the revised CDS have been reflected in the proposed Core Safety Profile, as well as in the proposed QRD for the EU SmPC. This comparison document details where a difference between the proposed CSP and the CDS in effect at the end of reporting period, will be addressed by the updated CDS. Assessor’s comment: There are no essential differences between the text in the CDS and the text in the proposed CSP / QRD for the EU SmPC.

SUSPECTED ADVERSE DRUG REACTIONS (INNOVATOR) DURING THE PERIOD:

SBR: It can be calculated that during the period of the PSUR Summary Bridging Report that covers the period of 01-09-2009 to 31-08-2012 795 case reports met the criteria for inclusion in the PSURs, and these were associated with a total of 1386 adverse events. Total number of serious cases, incl. fatalities 962 Number of fatal cases 120 reports (initial and follow up cases)

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 79 33 11 8 131

Cardiac disorders - 17 - 5 22

Congenital and familial and genetic disorders - 2 - - 2


Ear and labyrinth disorders - 4 - 1 5

Endocrine disorders - - - - -

Eye disorders 1 3 1 1 6

Gastrointestinal disorders 14 14 29 11 68 General disorders and administration site conditions 5 88 2 43 138

Hepatobiliary disorders 8 77 1 71 157

Immune system disorders 28 5 4 - 37

Infections and infestations 21 52 4 4 81

Injury poisoning and procedural complications - 18 - 7 25

Investigations 79 55 98 79 311

Metabolism and nutrition disorders - 22 - 13 35 Musculoskeletal and connective tissue disorders - 12 - 1 13

Neoplasms benign, malignant and unspecified - 5 - - 5

Nervous system disorders 31 44 21 21 117

Pregnancy, puerperium and perinatal conditions - 10 - 1 11

Psychiatric disorders - 3 - 6 9

Renal and urinary disorders - 40 - 12 52

Reproductive system and breast disorders - - - 2 2

Respiratory thoracic and mediastinal disorders 1 46 - 6 53

Social circumstances - - - - -

Skin and subcutaneous tissue disorders 100 26 106 6 238

Surgical and medical procedure - 6 - 1 7

Vascular disorders - 12 3 5 21

Total 368 594 280 304 1546 Assessor’s comment: There is a difference between the number of adverse events mentioned in the PSUR (1386) and those in the table above. The MAH is requested to explain this difference. Comments and conclusion see Section F RFI / LoQ: REQUEST FOR FURTHER INFORMATION / LIST OF QUESTIONS

TABLE OF SELECTED* SERIOUS UNLISTED ADRs:

Serious unlisted ADRs (MedDRA PT in agreed SOC order)

Number of serious unlisted ADRs

Nervous system disorders -depressed level of consciousness 13 Renal and urinary disorders -renal failure acute -renal impairment

15 9

Respiratory thoracic and mediastinal disorders-intestinal lung disease 16 Hepatobiliary disorders -cholestasis -hepatic function abnormal -liver disorder

9 27 11

* 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

If yes, specify in table below:

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:

Meropenem Ranbaxy (Basics GmbH):

06 safety concerns have been identified from 04 reported cases & 02 published literature articles during the current reporting period, which Ranbaxy will monitor in future PSURs. These are:

Acute generalised exanthematous pustulosis Drug Rash With Eosinophilia And Systemic Symptoms (DRESS) Syndrome Metabolic Alkalosis and/or Hypokalemia Vanishing Bile Duct Syndrome Marked reactive plasmacytosis with drug eruption Drug interaction between meropenem and colistin leading to increase colistin neurotoxicity

Meropenem Hospira (Hospira Deutschland GmbH):

Hospira will continue to monitor cases reporting

vanishing bile duct syndrome interaction between meropenem and colistin

Assessor’s comment: This safety concern Vanishing Bile Duct Syndrome was also identified by MAH during the period covered by this SBR. However the MAH does not consider the amendment to the core prescribing information is required since the causal association has not yet been established. This area will continue to be kept under close surveillance by MAH and the MAH has already implemented a questionnaire to be sent for case reports potentially fulfilling the cholestasis criteria. Concerning the interaction between meropenem and colistin close monitoring is recommended, because this interaction may lead to increase colistin neurotoxicity.

OVERALL ASSESSOR COMMENTS ON CASE REPORTS (INCL. LITERATURE CASES):

Describe and comment on ADRs of importance from individual case histories: The MAH calculated that during the period of the PSUR Summary Bridging Report 795 case reports met the criteria for inclusion in the PSURs, and these were associated with a total of 1386 adverse events.


Case reports with a fatal outcome (n =120)

There have been 120 reports (initial and follow up cases) with a fatal outcome during the 3 year period of the PSUR Summary Bridging Report.

The MAH concluded that in all cases where sufficient information has been provided and alternative causes or confounding factors (severity of the disease, concurrent conditions, age, concomitant medications) culminated in or contributed to the fatal outcome of the events. The MAH justifies this by the fact that meropenem is often used in the setting of severe infection for which a fatal outcome may not be unexpected. Assessor’s comment: This MAH conclusion can be accepted. Indeed, in the majority of case reports with a fatal outcome there are alternative causes or confounding factors (severity of the disease, concurrent conditions, concomitant medications, and patient’s age) which may have contributed to the fatal outcome of the events. In some of the cases meropenem was used in the setting of severe infection that may lead to the fatal outcome. The following topics have been reviewed during the period of this Summary Bridging Report:

atypical lung events, hepatobiliary disorders, renal dysfunction and electrolyte disturbances, pancytopenia, cardiac events, drug rash with eosinophilia, cholestasis, depressed level of consciousness

Atypical lung events: (Respiratory, thoracic and mediastinal disorders n = 53) The cumulative review by MAH up to 31 August 2010 identified a total of 399 events in 364 cases. MERREM/MERONEM lung events included in the cumulative review to 31 August 2010


As part of this review, the MAH implemented a questionnaire to obtain as complete information as possible for any potential reports of ‘atypical lung events’; according to the MAH this questionnaire continues to be used.


Atypical lung events in the period 01 September 2010 to 31 August 2012(This search produced 61 cases with 76 ILD-type events)

MAH review: The cases received during each period were reviewed in the respective PSURs but a cumulative review has been provided only for the period up to – 31 August 2010. Of the 61 cases reported in the above mentioned period (01 September 2010 – 31 August 2012), 23 did not have sufficient information with which to assess the case; important information such as disease indications, dose of MERREM/MEROPENEM, time to onset of events, the patient’s medical history, concomitant medications and outcomes of the adverse events were missing. For 3 cases, the patients were being treated with concomitant medications which could have contributed to the events. For 1 case, the time to onset of events was inconsistent with MERREM/MERONEM treatment. For 12 cases, the patients had a very short time to onset of events, and the adverse events themselves were indicative of a drug hypersensitivity of an anaphylaxis type I reaction which is known to be associated with MERREM/MERONEM. For 12 of these cases, the events described did not correspond to a clinical picture of ILD. The remaining 10 cases describe patients being treated with MERREM/MERONEM and experiencing ILD. However, these patients have underlying medical conditions which could provide alternative explanations for the events, conditions such as pneumonia, aspiration pneumonia, COPD, cancer, myocardial infarction and sepsis. In addition, these patients are on multiple concomitant medications which themselves are associated with lung events such as chemotherapy and other antibiotics as well as undergoing other procedures such as blood transfusion, radiotherapy or intubation. In some cases, important diagnostic test results are missing, such as DLST or diagnostic imaging with which to provide more information on a possible causal association between ILD and MERREM/MERONEM. The MAH concluded that there is insufficient evidence to establish a causal relationship between MERREM/MERONEM and atypical lung events and the MAH will continue to monitor this topic as part of our routine safety surveillance activities. In the PSUR period 01 September 2010 – 31 August 2011 all reports of interstitial lung disease (ILD) were from Japan and were reported as ‘interstitial pneumonia’ (preferred term = interstitial lung disease). There appears to be international differences in the prevalence of ILD in Japan that could be due to the fact that Japan has been found to preferentially use the term ‘pneumonia interstitial’ for events where other countries use ‘pneumonia’ (Koo LC et al 2005). Alternatively, there may be a specific increased genetic susceptibility to ILD amongst the Japanese population. Reviews of this topic in previous PSURs have found no


association between MERREM/MERONEM and ILD. In the latest PSUR (01 September 2011 – 31 August 2012) an update on cases received during 01 September 2010 to 31 August 2012 is provided. Based on this updated review, the MAH considered that there was insufficient evidence to support a possible causal relationship between MERREM/MERONEM and diffuse parenchymal lung disease. The MAH concluded that the analysis of the cases of ILD presented in this PSUR, which updates previous cumulative reviews of atypical lung events, does not provide evidence of a causal association between MERREM/MERONEM and ILD. This topic will continue to be kept under close surveillance by AstraZeneca and any further new information will be presented in the next PSUR. AstraZeneca will continue to monitor this topic as part of our close safety surveillance activities but will not present the topic in the next PSUR unless new safety data become available to change the assessment presented here. Assessor’s comment: Following the PSUR assessment in the procedure AT/H/PSUR/0018/001 the MAH was requested to provide a cumulative review of reports of atypical lung events. The cumulative review provided by the MAH covers the period up to 31 August 2010 and not up to 31 August 2012. Although the MAH implemented a questionnaire to obtain as complete information as possible for any potential reports of ‘atypical lung events’; the cumulative reviews have not been provided for the subsequent periods to allow independent review by assessor. Therefore no conclusions on causality association between meropenem and atypical lung events can be drawn. The MAH is requested to provide a cumulative review up to 31. August 2012. The analysis should include cases with sufficient information on patient´s age, gender, race, indications, time to onset, outcome and seriousness. A separate analysis should be performed for ILD including the aspects such as potential differences between Caucasians and Asians (Japanese). Comments and conclusion see Section F RFI / LoQ: REQUEST FOR FURTHER INFORMATION / LIST OF QUESTIONS Hepatobiliary disorders (n = 157) The cumulative review up to 31 August 2010 by MAH identified 462 unlisted hepatobiliary events in 436 cases.


MERREM/MERONEM unlisted hepatobiliary events (cumulative review to 31 August 2010)

Overview of confounding risk factors in unlisted hepatobiliary events (cumulative review to 31 August 2010)

A search of AstraZeneca’s worldwide safety database from 01 September 2010 to 31 August 2012 was carried out using the following HLGTs: Hepatic and biliary neoplasms benign; hepatic and hepatobiliary disorders; hepatobiliary disorders congenital; hepatobiliary investigations; hepatobiliary neoplasms; hepatobiliary neoplasms malignant and unspecified. This search produced 357 cases with 490 events:


Of the 490 events 273 (alanine aminotransferase, alanine aminotransferase increased, aspartate aminotransferase, aspartate aminotransferase increased, bilirubin conjugated increased, blood bilirubin increased, gamma-glutamyltransferase increased, hepatic enzyme increased, hypertransaminasaemia, hyperbilirubinaemia, transaminases increased) are considered to be listed events for MERREM/MERONEM. 171 events were reported as hepatic function abnormal, liver disorder, liver function test abnormal, liver injury were therefore considered to be consistent with listed events for MERREM/MERONEM (transaminases and bilirubin increases not fulfilling definition above). The remaining 46 events which relate to 31 case reports are shown below.

Twelve of these case reports did not have sufficient information with which to assess the case; important information such as disease indications, dose of MERREM/MEROPENEM, time to onset of events, the patient’s medical history, concomitant medications and outcomes of the adverse events were missing. For a further 2 case reports, the description of the event was inconsistent for the signal being evaluated. For the remaining 17 case reports, concomitant medication and/or background incidence, the disease under treatment or an underlying medical condition offered alternative explanations for the events. In conclusion, analysis of the cases presented in this PSUR, which updates the previous cumulative review and analysis of all cases of hepatobiliary events from AstraZeneca’s worldwide safety database, do not provide evidence of a causal association between unlisted hepatobiliary events and MERREM/MERONEM. The MAH stated that periodic reviews of hepatobiliary disorders have been performed for 2 of 3 PSURs period covered by this summary bridging report. The MAH considers that many of the events are listed for MERREM/MERONEM (elevations in serum transaminases, bilirubin, alkaline phosphatase, gamma-glutamyltransferase and lactate dehydrogenase), whilst there are alternative causes or confounding factors for the remaining reports (pre-existing conditions, underlying disease, concomitant medications). In the PSUR covering the period 01 September 2009 – 31 August 2010 a cumulative review was undertaken in response to a regulatory request during the EU PSUR Worksharing Procedure (AT/H/PSUR/0018/001) and the MAH concluded that there is insufficient evidence to establish that MERREM/MERONEM is associated with any unlisted hepatobiliary events. In the cumulative review to 31 August 2010, the MAH considers that all reports, where sufficient information has been provided, have significant confounding factors (underlying disease, history of hepatobiliary disorders, or concomitant use of drugs with known hepatic toxicities). Therefor the MAH proposes to monitor this safety topic as part of AstraZeneca’s routine safety surveillance activities. In the PSUR covering the period 01 September 2010 – 31 August 2011 it was noted that differences in reporting rates of hepatic events might also depend on the underlying prevalence of liver diseases in different parts of the world, like Asia, or differences on medical practice across regions, and finally genetic pre disposition and susceptibility to drug induced hepatic events.


A post-marketing investigation to determine if regional differences exist for hepatic adverse event reporting with AstraZeneca drugs in various drug classes revealed that the OR for hepatic AEs (n=3317) was significantly higher in Japan compared to the US (OR: 6.2;95% CI:5.7-6.8). The OR pattern for the individual drugs was consistent with the combined drug analysis across regions (Pasquale JJ 2006). In the latest PSUR (01 September 2011 – 31 August 2012) an update on cases received during 01 September 2010 to 31 August 2012 is provided. Based on this updated review, AstraZeneca considered that there was insufficient evidence to support a possible causal relationship between MERREM/MERONEM and hepatobiliary events. This topic will be will be monitored as part of AstraZeneca’s routine safety surveillance activities but will not be presented in the next PSUR unless new safety data become available to change the assessment presented here. Assessor’s comment: In response to the P-RMS request following the EU Worksharing Procedure (AT/H/PSUR/0018/001) the MAH provided a cumulative review for the period up to 31 August 2010 but not up to 31 August 2012. This can be accepted, because in the latest PSUR (01 September 2011 – 31 August 2012) an update on cases received during 01 September 2010 to 31 August 2012 is provided. Even if many of the reported events were considered to be consistent with listed events, they are not explicitly listed in the SmPC (hepatic function abnormal, liver disorder, and liver function test abnormal) and should be included in section 4.8 of the SmPC. Comments and conclusion see Section F RFI / LoQ: REQUEST FOR FURTHER INFORMATION / LIST OF QUESTIONS Renal dysfunction and electrolyte disturbances (Renal and urinary disorders n = 52) The cumulative review up to 31 August 2010 by MAH identified a total of 262 events in 225 cases. MERREM/MERONEM renal events (cumulative review to 31 August 2010)

Overview of confounding risk factors for renal events (cumulative review to 31 August 2010)


Renal dysfunction events 01 September 2010 to 31 August 2012

Of the 60 cases reported in the above mentioned period (01 September 2010 – 31 August 2012), 32 did not have sufficient information with which to assess the case; important information such as disease indications, dose of MERREM/MEROPENEM, time to onset of events, the patient’s medical history, concomitant medications and outcomes of the adverse events were missing. For 5 cases, the patients were being treated with concomitant medications which could have contributed to the events. Two of these cases are renal events in patients with underlying renal impairment. The remaining 23 cases describe patients being treated MERREM/MERONEM and experiencing renal dysfunction. However, it can be seen that these are seriously ill patients who have medical conditions such as sepsis, severe infection, diabetes, cancer and hypertension, conditions which put patients at significant risk of renal impairment or electrolyte disturbance, irrespective of treatments given. In addition, these patients are typically taking multiple concomitant medications, many of which are associated with renal impairment such as NSAIDs and other antibiotics such as vancomycin. In 2 of the cases, the patients were already suffering from renal impairment due to their medical conditions. This topic has been reviewed by MAH in 2 of the PSURs periods covered by this Summary Bridging Report including a cumulative review of renal events in the PSUR covering the period 01 September 2009 – 31 August 2010. The use of MERREM/MERONEM is restricted to hospitalized patients suffering from serious infections; this group is already at a significant risk of renal impairment, irrespective of the specific treatments given. Thus, a number of reports of renal impairment would be expected given the nature and range of patients exposed to MERREM/MERONEM. There have been no cases where there is a high probability that MERREM/MERONEM led directly to renal impairment. This safety topic will be monitored as part of AstraZeneca’s routine safety surveillance activities. In the latest PSUR (01 September 2011 – 31 August 2012) an update on cases received during 01 September 2010 to 31 August 2012 is provided. Based on this updated review, AstraZeneca considered that there was insufficient evidence to support a possible causal relationship between MERREM/MERONEM and renal events. This topic will be will be monitored as part of AstraZeneca’s routine safety surveillance activities but will not be presented in the next PSUR unless new safety data become available to change the assessment


presented here. Assessor’s comment: Again the cumulative review provided by the MAH covers the period up to 31 August 2010 and not up to 31 August 2012. The cases presented in the PSUR describe patients being treated with meropenem and experiencing renal dysfunction. In general, most of these patients are seriously ill and have medical conditions such as sepsis, severe infections, diabetes, cancer and hypertension, so that these patients have a significant risk of renal impairment. Additionally, these patients are taking multiple concomitant medications, many of which are associated with renal impairment such as NSAIDs and other antibiotics such as vancomycin. In 2 of the cases, the patients were already suffering from renal impairment due to their medical conditions. The MAH should however comment on the differences between the EU SmPC and US product information for Merrem (Astra Zeneca) and propose amendments to sections 4.4 and 4.8 of the EU SmPC with regard to renal adverse reactions and patients with renal impairment. The MAH should provide additional data concerning renal events, especially concerning time of onset. Any supplement information submitted and assessed in the ongoing renewal procedure in France should be taken into account. Comments and conclusion see Section F RFI / LoQ: REQUEST FOR FURTHER INFORMATION / LIST OF QUESTIONS Pancytopenia ( n = 10) Section 6.4 of the PSUR covering the period 01 September 2007 – 31 August 2008 included a reference to a cumulative review of pancytopenia which was undertaken in March 2008. It was concluded that a causal relationship could not be established however the topic would be kept under close surveillance. A periodic review of this topic was included in the PSUR covering the period 01 September 2008 – 31 August 2009 where it was concluded that none of the 3 additional cases were suggestive of a causal relationship between MERREM/MERONEM and pancytopenia and that the safety topic will continue to be kept under close surveillance but will not be presented in the next PSUR unless new safety data becomes available. However, in response to a regulatory request during the EU PSUR Worksharing Procedure (AT/H/PSUR/0018/001), an updated cumulative review was undertaken in the PSUR dated 01 September 2009 – 31 August 2010 which concluded that none of the reports are indicative of a causal association between MERREM/MERONEM and pancytopenia. This safety topic will be monitored as part of AstraZeneca’s routine safety surveillance activities. Overview of confounding risk factors for pancytopenia (cumulative review to 31 August 2010)


In the latest PSUR (01 September 2011 – 31 August 2012) an update on cases received during 01 September 2010 to 31 August 2012 is provided. Based on this updated review, AstraZeneca considered that there was insufficient evidence to support a possible causal relationship between MERREM/MERONEM and pancytopenia. In total for the cumulative reviews to date, there are 47 cases of pancytopenia in patients being treated with MERREM/MERONEM on AstraZeneca’s worldwide safety database at this time. Each case has been carefully reviewed. For 14 cases, there was insufficient information with which to assess the cases; information such as disease indications, dose of MERREM/MEROPENEM, time to onset of events, the patient’s medical history, concomitant medications and outcomes of the adverse events were missing. For 11 cases, the patient was being treated concomitantly with drugs which are known to cause pancytopenia, eg, vancomycin, carbimazole, tobramycin and immunosuppressant drugs. For 8 cases, the patient had a medical condition which could provide an alternative explanation for the event of pancytopenia, eg, sepsis, underlying severe infection, disseminated intravascular coagulation (DIC), viral haemophagocytic syndrome. For 1 case, the time to onset was inconsistent with MERREM/MERONEM treatment; pancytopenia started 1 month after MERREM/MERONEM discontinuation and MERREM/MERONEM was re-introduced with no further incidence of pancytopenia. For 13 cases, the patients had a combination of these factors, that is, they had both underlying medical conditions and concomitant medications which could have provided alternative explanations for the event of pancytopenia. Further analysis of the case details did not reveal a clustering of pancytopenia events for a particular dose or dose duration. Where the age of patient was known, the majority of cases were in adults and the elderly with little difference in numbers between either category. Where the outcome of the events was known, only 2 cases were fatal; the vast majority of patients recovered or were recovering. Where time to onset of the event is given, there are more cases of pancytopenia occurring within 7 days of commencing MERREM/MERONEM treatment; this timing is more consistent with an underlying disease process causing the event. This topic will be will be monitored as part of AstraZeneca’s routine safety surveillance activities but will not be presented in the next PSUR unless new safety data become available to change the assessment presented here. Assessor’s comment: This MAH conclusion can be accepted, however close monitoring on pancytopenia should be continued. Cardiac events (n = 22) This topic was reviewed in the PSUR covering the period 01 September 2008 – 31 August 2009 as several cases had been received during the PSUR period. In response to a regulatory request during the EU PSUR Worksharing Procedure (AT/H/PSUR/0018/001) a cumulative review of cardiac events reported in association with MERREM/MERONEM has been provided in the PSUR covering the period 01 September 2009 – 31 August 2010. The review concluded that there is insufficient evidence to establish a causal relationship with cardiac events and AstraZeneca will continue to monitor these reports as part of our routine safety surveillance activities. MERREM/MERONEM cardiac events (cumulative review to 31August 2010)


Overview of confounding risk factors for cardiac events (cumulative review to 31 August 2010)

In the latest PSUR (01 September 2011 – 31 August 2012) an update on cases received during 01 September 2010 to 31 August 2012 is provided. Based on this updated review, AstraZeneca considered that there was insufficient evidence to support a possible causal relationship between MERREM/MERONEM and cardiac events. These cases presented in this PSUR describe patients being treated with MERREM/MERONEM and experiencing cardiac events. However, these patients have underlying medical conditions which could provide alternative explanations for the events, conditions such as diabetes, hypertension, circulatory shock, infection, kidney failure and sepsis. In addition, these patients are on multiple concomitant medications which themselves are associated with cardiac events such as esomeprazole, ciprofloxacin, metronidazole and vancomycin. In such seriously ill patients their underlying medical conditions and multiple concomitant medications make a causal association between cardiac events and MERREM/MERONEM difficult. This topic will be will be monitored as part of AstraZeneca’s routine safety surveillance activities but will not be presented in the next PSUR unless new safety data become available to change the assessment presented here.


Assessor’s comment: The MAH should provide a cumulative review of cardiac events up to 2012 including a separate discussion regarding tachycardia The MAH should discuss the temporal association, the clinical outcome in relation to drug continuation or discontinuation, the presence of potential alternative causes and concomitant drugs. Any supplement documents submitted in the ongoing renewal procedure in France should be provided. Comments and conclusion see Section F RFI / LoQ: REQUEST FOR FURTHER INFORMATION / LIST OF QUESTIONS Drug rash with eosinophilia and systemic symptoms (DRESS) and Drug induced hypersensitivity syndrome (DIHS) (n = 5) Drug rash with eosinophilia and systemic symptoms was reviewed in the PSUR dated 01 September 2008 – 31 August 2009 as several cases had been received during the PSUR period. It was concluded that where sufficient information was provided, the cases contain alternative causes for the event. In the PSUR covering the period 01 September 2009 – 31 August 2010, as a result of detailed follow up information received for 1 of the cases (2007AP00902), AstraZeneca undertook a full cumulative review of the extended topic (drug rash with eosinophilia and systemic symptoms and drug induced hypersensitivity syndrome). The MAH concluded that there is insufficient evidence to establish a causal relationship between these events and MERREM/MERONEM but AstraZeneca continues to closely monitor such reports. In the latest PSUR (01 September 2011 – 31 August 2012) an update on cases received during 01 September 2010 to 31 August 2012 is provided. Based on this updated review, AstraZeneca considered that there was insufficient evidence to support a possible causal relationship between MERREM/MERONEM and events of DRESS and DIHS. During this PSUR period, 5 cases were reported either as DRESS or DIHS and 1 case of serum sickness-like reaction identified as fulfilling the criteria for DRESS, although not reported as such. In four of these cases, the patient was reported as having received a concomitant medication (vancomycin, phenytoin) that is known to cause DRESS syndrome. The fifth case described DRESS syndrome and Stevens-Johnsons syndrome in a patient receiving multiple concomitant medications and also did not include information on definitive diagnostic tests with which to identify the culprit drug. This topic will be will be monitored as part of AstraZeneca’s close safety surveillance activities but will not be presented in the next PSUR unless new safety data become available to change the assessment presented here. A follow-up questionnaire is currently in use to capture further information from reports that could indicate DRESS syndrome or DIHS. This topic will continue to be kept under close surveillance and any cases which fulfill either criteria will be presented in the next PSUR. Assessor’s comment: In the next PSUR the cases of Drug rash with eosinophilia and systemic symptoms (DRESS) and Drug induced hypersensitivity syndrome (DIHS) should be presented and based on the evaluation of information provided by the questionnaires a re-evaluation of these cases should be provided and the MAH should discuss the update of section 4.8 of the SmPC. Cholestasis (n = 9) In the PSUR covering the period 01 September 2010 to 31 August 2011 cholestasis was identified as a subject for review for MERREM/MERONEM by pharmacovigilance processes internal to AstraZeneca after a literature report of vanishing bile duct syndrome (VBDS) was identified (Schumaker 2010). This was the first report in the medical and scientific literature of cholestasis and VBDS reported as related to MERREM/MERONEM. VBDS is a rare and potentially life-threatening disorder in which progressive destruction and disappearance of small intra hepatic bile ducts occur, with resultant cholestasis. Following the cumulative review, AstraZeneca considers that based on the current available data there is


insufficient evidence to suggest a causal relationship between cholestasis and MERREM/MERONEM and no amendment to the core prescribing information of MERREM/MERONEM is required, as a causal association had not been established. In order to obtain the most comprehensive information on any future reports of cholestasis in association with MERREM/MERONEM, AstraZeneca continues to closely monitor such reports and has implemented a questionnaire to be sent for case reports potentially fulfilling the cholestasis criteria. In the latest PSUR (01 September 2011 – 31 August 2012) 2 new cases were received. These two reports appear to be a duplicate of the same case. Based review of these 2 new cases, AstraZeneca considered that there was insufficient evidence to support a possible causal relationship between MERREM/MERONEM and cholestasis. 2011SE18006/2012SE21407: cholestasis This is a Regulatory report of a 30 year old female patient with mucoviscidosis, cystic fibrosis-related diabetes, arterial hypertension, steroid-induced osteoporosis, nephropathy and aggravated oesophageal reflux. The patient’s concomitant medications included prednisolone, tacrolimas, mycophenolate mofetil, ramipril, amlodipine/valsartan, urapidil, furosemide, atenolol, valganciclovir, sodium polystyrene sulphonate, levetiracetam, pancrelipase, esomeprazole, cyamepromazine, paroxetine, calcium carbonate and insulin. The patient had a medical history of lung transplant in 2002 due to muscoviscidosis. Nine years later, on 04 February 2011, the patient was hospitalised in intensive care unit for septic shock secondary to pneumonia. Two weeks previously, the patient had undergone a renal puncture biopsy for nephrotic syndrome which was complicated by peri-renal haematoma and haemorrhagic shock. The biopsy showed vascular lesions related to diabetic nephropathy, arterial hypertension and tacrolimus treatment, there was also an indication of tacrolimus overdose. At hospital admission the patient presented with moderate cholestasis. Two days later the patient’s cholestasis worsened. Hepatic workup showed a very gradual improvement of liver function with fluctuations. Abdominal untrasonography showed no intra- and extrahepatic bile duct dilatation. In March 2011, Cholangio-Magnetic Resonance Imaging showed no bile duct abnormalities. In February 2012, follow-up of hepatic work-up showed improving blood ALP level with persistent cholestasis [ALP level at 277 IU/L (Normal value < 80 IU/L)]. AstraZeneca comment: Cholestasis is not known to be associated with MERREM/MERONEM, but transaminases increases are. The concomitant use of tacrolimus which is known to cause cholestasis, several other medications, the underlying cystic fibrosis and infection associated with the renal impairment which contributed to possible overdose of tracolimus offer alternative explanations for the events. The patient presented with cholestasis at hospital admission, which indicates development of hepatic injury by underlying disease and other factors previously. Assessor’s comment: This MAH conclusion can be accepted. This topic will be will be monitored as part of AstraZeneca’s close safety surveillance activities but will not be presented in the next PSUR unless new safety data become available to change the assessment presented here. Assessor’s comment: In order to obtain the comprehensive information on reports of cholestasis in association with meropenem the MAH implemented a questionnaire to be sent for case reports potentially fulfilling cholestasis criteria. This measure is considered sufficient at this moment. Depressed level of consciousness(n= 14) In the latest PSUR (01 September 2011 – 31 August 2012) depressed level of consciousness was been identified as an area of concern from pharmacovigilance processes internal to AstraZeneca. During this PSUR period a cumulative review of all events describing a possible depressed level of consciousness reported in patients treated with MERREM/MERONEM was conducted. Of the 44 case reports received which describe events of depressed level of consciousness, 12 case reports were excluded from further review as they provided insufficient information to allow review or described events that occurred prior to treatment with MERREM/MERONEM. Of the remaining 32 case reports where sufficient information has been provided, 28 case reports document confounding factors (eg. underlying disease, medical history of CNS disorders, or co-administration of medications known to depress


consciousness) which compromises interpretation of these events. The remaining 4 case reports describe events where the reporter has either suggested that the patient recovered from the event following dialysis or that increased MERREM/MERONEM serum levels due to reduced clearance of MERREM/MERONEM in patients with impaired renal function may have contributed to onset of the event. Although it is recognised that exposure to MERREM/MERONEM is known to be increased in patients with renal impairment and MERREM/MERONEM is known cleared by dialysis. Evidence that this has contributed to these events is not conclusive, these case reports are confounded by concurrent convulsions, hypotensive episodes and suspected meningitis which may provide alternative plausible aetiologies for the events described. Limited information is available regarding serum levels of MERREM/MERONEM or whether dosage of MERREM/MERONEM was adjusted for renal impairment in these patients. The cases presented in the latest PSUR period (01 September 2011 – 31 August 2012) do not indicate that MERREM/MERONEM is associated with depressed level of consciousness. AstraZeneca will continue to monitor depressed level of consciousness and will review this topic as part of our routine safety surveillance activities. Additionally all events reported from patients with renal impairment are reviewed on an ongoing basis. Any new information will be presented in the next PSUR. Assessor’s comment: In the next PSUR the cases of Depressed level of consciousness should be re-evaluated and the MAH should discuss an update of section 4.8 of the SmPC. Analysis of individual case histories PSUR period 01 September 2011 – 31 August 2012: These individual case histories were selected based on the presentation of the events and their clinical relevance (eg, particular serious or unanticipated findings, including their nature, medical significance, mechanism, reporting frequency, etc); difficulties in determining causality (eg, due to many confounding factors); the involvement of safety topics that are kept under close surveillance; the previous knowledge and understanding of the safety profile of MERREM/MERONEM. 2012SE02636: Insulin autoimmune syndrome This is a spontaneous report concerning a 78 year old, female patient receiving MERREM/MERONEM, clindamycin, cefazolin, cefmetazole sodium for sepsis. The patient’s medical history included cerebral haemorrhage in 2006. In 2006, the patient started to receive dialysis for chronic renal failure (3 times/week) it is reported that she did not have diabetes and the renal failure was caused by renal sclerosis. On 18 June 2011 she was hospitalised for haemorrhagic duodenal ulcer and received blood transfusion, developed sepsis concurrently and MERREM/MERONEM 0.5g/day was started. Her general condition improved and 5 days later MERREM/MERONEM was discontinued. She received MERREM/MERONEM again from 9 to 15 July 2011 for sepsis. On 28 July 2011 hypoglycaemic coma was detected. Blood sugar level was 34mg/dL. She improved with intravenous infusion of 50% glucose solution 20ml; however infusion of dextrose solution was maintained during the night. Anti-insulin antibody was more than 5000 nU/ml, insulin binding ratio was more than 90%.Insulinoma was unlikely and patient was diagnosed with insulin autoimmune syndrome. Approximately 2 months later anti insulin antibody level remained high at more than 5000nU/ml and binding ratio was more than 90%. AstraZeneca Comment: Insulin autoimmune syndrome may be related to sulfhydryl compounds, as reported by Uchigata (Uchigata et al 1994) on 43% of the 197 cases in Japan since the 1970s, had received these compounds previously to the development of the syndrome; only 21 cases were reported in Europe or USA. MERREM/MERONEM is not one of these compounds. Also, several other antibiotics were administered prior to the development of the adverse event and it is not possible to conclude fully on causality. There is insufficient information on differential diagnostic tests performed and the event persisted after MERREM/MERONEM was discontinued. Assessor’s comment: This MAH conclusion can be accepted. 2011SE40211: Polyarteritis nodosa This case is a spontaneous report of a female patient with chronic renal disease, hepatic abcess and bacterial infection. The patient received MERREM/MERONEM 1 g daily starting on 01 March 2011 for


endocarditis infection secondary to hepatic abscess. At the time of reporting the patient was presenting with various nodular lesions in her legs for 1 week. The lesions were nodular, painful and circular in shape, predominantly on their thighs. She improved but 1 month later she had the same clinical presentation. She received MERREM/MERONEM for a second time. The patient stopped MERREM/MERONEM and after 3 weeks the lesions were remitting and the symptoms disappeared. When MERREM/MERONEM was reintroduced the events reappeared. AstraZeneca Comment: There is insufficient information on symptoms (including neuro and muscular), signs (blood pressure, weight) and diagnostic evaluation (HBV, renal) including skin biopsy which makes a full assessment difficult. The report describes only skin lesions, no other symptom or sign is provided. Assessor’s comment: A Follow-up on this case and close monitoring on Polyarthritis nodosa should be performed and described in the next PSUR. 2011SE66360: Leukocytoclastic vasculitis This regulatory report concerns a 61 year old female patient urgently admitted to hospital on 10 January 2008 after she had twisted her left ankle. The patient’s concurrent diseases included smoking and hypertension. A radiograph of the left ankle showed a fractured leg and ankle, which was treated with osteosynthesis. She received cefuroxime as a single dose for antibiotic therapy. Nineteen days later there was a large area of dead tissue in the surgical scar and she was treated with dicloxacillin. Approximately 3 months later the blue colour of lower leg with blistering on both feet went up along both legs to the abdomen and lower back. The patient was hospitalised, received treatment with gentamicin and cefuroxime. Staphillococci was identified and she then received treatment with MERREM/MERONEM, clindamycin and cefalexin. It was reported that approximately 1 year previously the patient had a wound on her right leg, which included the outer ankle. The wound took approximately 6 months to heal. A month later the patient was discharged with the diagnosis of leucocytoclastic vasculitis. AstraZeneca Comment: Leukocytoclastic vasculitis is not known to be associated with MERREM/MERONEM use, but rash is. Leukocytoclastic vasculitis (LCV), also known as hypersensitivity vasculitis and hypersensitivity angiitis, is a histopathologic term commonly used to denote a small vessel vasculitis. Iit has many causes, but no cause is identified in up to 50% of patients with this condition. The most common drugs that can cause cutaneous vasculitis are antibiotics and this patient has received several courses of antibiotics, which might have contributed to the event, various infections may also be associated with vasculitis. The previous episode of difficult wound healing reported indicates that LCV might have started before MERREM/MERONEM use, which makes a causal relationship less likely. Assessor’s comment: In the next PSUR period a close monitoring and cumulative review on leukocytoclastic vasculitis should be performed. The MAH should review cases of vascular inflammation and discuss a need for an update of section 4.8 of the SmPC. 2011SE75029: Idiopathic pulmonary fibrosis; Mycobacterium chelonae infection; Post procedural infection; Infection This 49 year old male with idiopathic pulmonary fibrosis has received MERREM/MERONEM 1g every 8 hours since 29 November 2011 for Mycobacterium chelonae post procedural infection, 4 months after a bilateral lung transplantation carried out on 20 August 2011. A CT of chest on 20 October 2011 showed loculated fluid collection in medial right chest. He then underwent an incision and drainage of the chest wall on 03 November 2011. The action taken with MERREM/MERONEM was unknown. The outcome of the events was unknown. AstraZeneca comment: The underlying idiopathic pulmonary fibrosis and mycobacterium chelonae infection and surgical site infection post bilateral lung transplantation appear to pre-date the use of MERREM/MERONEM. The lung transplant was performed on the 20 August 2011. A CT chest on the 20 October 2011 showed signs of the infection and MERREM/MERONEM was started on 29 November 2011. Assessor’s comment: This MAH conclusion can be accepted.


OVERALL ASSESSOR COMMENTS ON MAH SPONSORED STUDIES:

Describe and comment on studies of relevance to safety of the product(s): There are no newly analysed studies with significant safety information. OVERALL ASSESSOR COMMENTS ON STUDIES FROM THE LITERATURE: Describe and comment on literature studies of relevance to safety of the product(s): On February 27, 2012 the Food and Drug Administration (FDA) announced the opening of a public docket (FDA report on paediatric study 2012) to make available to the public a report of the paediatric study of MERREM/MERONEM that was conducted in accordance with section 409I of the Public Health Service Act (PHS Act) and submitted to the Director of the National Institutes of Health (NIH) and the Commissioner of Food and Drugs by Duke University on behalf of the NIH. This is a study for an off-label indication of MERREM/MERONEM as the children age for the study was defined as under 3 months old (<91 days of age). This study evaluated the safety, tolerability and PK-PD of MERREM/MERONEM in infants <91 days of age with suspected and complicated intra-abdominal infections. The dosing of MERREM/MERONEM, stratified by gestational age (GA) and postnatal age (PNA) was predicted to provide therapeutic exposure in the majority of infants. Infants were enrolled in four GA/PNA strata. Safety was assessed in real time by the MERREM/MERONEM Off-Patent Drug Studies (MPODS) Clinical Events Safety Committee and by an independent Data Monitoring Committee (DMC). The FDA is analyzing the data further and will provide AstraZeneca its recommendation based on the study in 2013.

A Phase III study (independent study sites: D4280C00001, D4280C00005) is currently in progress to assess the noninferiority of ceftazidime-avibactam (CAZ-AVI) plus metronidazole compared to MERREM/MERONEM with respect to clinical cure at Test-of-Cure (TOC) visit in patients who have at least 1 identified pathogen. This is a prospective, randomized, multicenter, double blind, double-dummy, parallel group, comparative study to determine the efficacy, safety, and tolerability of CAZ-AVI plus metronidazole versus MERREM/MERONEM in the treatment of hospitalised adults with Complicated Intra- Abdominal Infections (cIAIs), defined as infections that require surgical intervention and extend beyond the hollow viscus into the peritoneal space. Approximately 1106 hospitalized patients (18 to 90 years of age, inclusive) with a presumed (preoperative) or definitive (intra-operative or postoperative) diagnosis of cIAI will be enrolled. Estimated date of first patient enrolled: November 2011; Estimated date of last patient completed: September 2013. Assessor’s comment: The results of these studies should be discussed in the next PSUR. OVERALL ASSESSOR COMMENTS ON NEW INFORMATION REGARDING: Special populations: Children MERREM/MERONEM is licensed for use in children over 3 months of age. There is no evidence of an increased risk of any ADRs in children. All reports received were consistent with events observed in the adult population. Other special patient groups There is no evidence of an increased risk of any ADRs in other special patient groups eg, elderly patients or in those with impaired organ function. No clustering of adverse event terms was observed in either the hepatically impaired or renally impaired patient groups and the pattern of adverse events was in line with the expected safety profile of MERREM/MERONEM.


Pregnancy/lactation: There were 29 reports of pregnancy during this PSUR period. Two of these were reviewed in the PSUR covering the period 01 September 2009 – 31 August 2010. No details were provided regarding outcome in 2 cases; in the remaining case the mother gave birth at 38 weeks to a premature healthy male baby. Thirteen reports were reviewed in the PSUR covering the period 01 September 2010 – 31 August 2011. Seven of these resulted in healthy babies and in 4 the outcome was unknown but reports were considered to be non-serious. Of the 2 remaining cases, 1 patient had a non-viable foetus identified at 24 weeks’ gestation however she was receiving concomitant cytotoxic medications for non-Hodgkins lymphoma and causality is most likely attributed to this medication. The final pregnancy resulted in stillbirth. The patient had underlying serious infection and disseminated intravascular coagulation that offered an alternative explanation for the pregnancy outcome. The remaining 14 reports were reviewed in the PSUR covering the period 01 September 2011 – 31 August 2012. Five of these resulted in healthy babies and in 4 the outcome was unknown but reports were considered to be non-serious. Of the remaining 5 cases, 1 was an elective abortion; 1 case was given MERREM/MERONEM for treatment of pyelonephritis caused by ESBL creating E-coli. Patient experienced syncope, pressure over the chest, chest pain, dyspnoea, angioedema and nausea. Patient recovered from the events and outcome of the pregnancy was unknown; 1 case report resulted in premature delivery of a non-healthy baby. The patient had underlying infections and complications from surgical procedures that offer alternative explanations for the pregnancy outcome; 1 case report of a preterm baby, for which minimal information was provided; 1 case report of an abnormal delivery of a non-healthy baby. Minimal information was provided which precludes a causal assessment. Assessor’s comment: No safety concerns arise from the above mentioned cases. Drug interaction: There have been 44 reports of interactions involving the use of MERREM/MERONEM during the period of this Summary Bridging Report. Thirty three of these involved an interaction with sodium valproate. This is a recognised interaction which is documented in Sections 4.4 and 4.5 of the CDS. A further 3 reports are of an interaction with an anti-convulsant drug, details of which are not provided but are likely to be valproic acid. The 8 remaining interactions reported are documented as follows: PSUR period 01 September 2009 – 31 August 2010 (1 report of potential interaction with ciprofloxacin and 1 report of interaction in a patient taking MERREM/MERONEM together with warfarin, aspirin, clopidogrel, erythromycin, ciprofloxacin, and metronidazole). With regard to the patient taking ciprofloxacin the timing of the medications made an interaction less likely. It was concluded that an interaction with warfarin could not be confirmed. Also, it was concluded that there is a known interaction between erythromycin, ciprofloxacin, metronidazole and warfarin which offer alternative explanations for the reported events (headache, severe pain, hyphaemia of the left eye, fever, nausea and anorexia) in this case. PSUR period 01 September 2010 – 31 August 2011 (1 report of potential interaction with Colistin as the patient had unexpected high blood levels of Colistin). Colistin has been taken concomitantly with MERREM\MERONEM in a number of adverse event reports and there have not been any other specific reports of drug interaction with this drug combination. The patient had a severe underlying medical condition, had undergone surgery and was receiving multiple concomitant medications which could have contributed to the events. PSUR period 01 September 2011 – 31 August 2012 (1 report of potential interaction with sirolimus, 1 report of a potential interaction between 22 concomitant medications, 1 report of potential interaction with amiodarone, 1 report of cross sensitivity with piperacillintazobactam and 1 report of potential interaction with nitrofurantoin and warfarin sodium). With regard to the interaction with sirolimus, and also the interaction amiodarone, it was considered likely that the underlying conditions and/or the concomitant medications might have contributed to the event. With regard to the interaction between 22 concomitant medications, patients’ medical history (leukaemia and infections) and the large number of concomitant medications which might cause adverse events individually, provide plausible explanations for the reported events.


With regard to the interaction with piperacillin-azobactam, the events started before MERREM/MERONEM treatment which makes a causal relationship with MERREM/MERONEM less likely. It was concluded that the concomitant use of warfarin as it interacts with food, therefore changes in diet can potentially affect control of anticoagulation and for which haemorrhage is a known adverse effect, offers an alternative explanation for the events. Assessor’s comment: Concerning the interaction between meropenem and colistin close monitoring is recommended, because this interaction may lead to increase colistin neurotoxicity. No other safety concerns arise from the above mentioned cases. Overdose: There have been 4 reports of overdose during the period of the PSUR Summary Bridging Report. In the PSUR period 01 September 2009 – 31 August 2010 there were 2 reports of overdose: 1 accidental overdose containing limited information; the remaining case involving a patient with chronic renal failure who developed hypotension, abnormal decrease in white blood cell count, vomiting, disturbed orientation, tremor in hands and involuntary movement of tongue. No information was provided regarding the creatinine clearance therefore it is not possible to determine whether the dosage had been reduced in accordance with the information provided in the CDS. In the PSUR period 01 September 2010 – 31 August 2011 there was 1 report of suspected overdose in a patient with underlying renal impairment. The patient experienced disturbance of consciousness, an event that has been associated with concomitant Maxipime; the event stopped following discontinuation of Maxipime. In the PSUR period 01 September 2011 – 31 August 2012 there was 1 report of suspected overdose that experienced renal failure acute, renal adverse events have been associated with concomitant vancomycin. Also rechallenge with MERREM/MERONEM was negative. Assessor’s comment: No safety concerns arise from the above mentioned cases. Abuse or misuse: MERREM/MERONEM is unlikely to have any potential for abuse. There were 2 reports (1 drug filtered before being given, 1 off-label use in babies under 3 months of age) of drug abuse or misuse with MERREM/MERONEM received by AstraZeneca during the period of this PSUR, both of which experienced no associated adverse events. Medication errors: A total of 28 prescription/medication errors have been received or updated during the period the Summary Bridging Report. The PSUR covering the period 01 September 2009 – 31 August 2010 contained 7 reports of prescription/medication errors, again of a diverse nature, 4 of these were reports without associated adverse events (1 counterfeit drug, 1 relating to drug solution, 1 where the patient drank their medication, 1 who received incorrectly prepared drug); 1 contained minimal information reporting a patient who became ‘ill’; the remaining 2 included a nonserious report of MERREM/MERONEM being administered subcutaneously instead of intravenously and a serious report of a patient requiring arm arteriogram, venogram, thrombectomy and fasciotomy with planned amputation as a result of MERREM/MERONEM together with ciprofloxacin being incorrectly administered intra-arterially. The PSUR covering the period 01 September 2010 – 31 August 2011 contained 12 reports of prescription/medical errors of a diverse nature: 10 with no associated adverse events (1 accidental exposure to eye; 1 incorrect drug reconstitution, 1 incorrect dose, 1 incorrect dosing schedule, 1 incorrect storage of drug, 1 incorrect infusion time, 2 incorrect route of drug, 1 with minimal information, 1 where MERREM/MERONEM was infused into the cranial ventricular drain line). Of the remaining 2 reports, 1 involved the known interaction of concomitant use with sodium valproate where the patient experienced convulsions and 1 report of lack of effect where possible counterfeit MERREM/MERONEM was used. The PSUR covering the period 01 September 2011 – 31 August 2012 contained 9 reports of prescription/medical errors of a diverse nature: 8 with no associated adverse events (1 paravenous administration, 2 wrong technique used in reconstituting process, 1 exposure to the skin, 2 intramuscular


administration, 1 MERREM/MERONEM got into an epidural catheter, 1 incorrect infusion time). The remaining report experienced hyperaemia and face oedema but no details of the drug prescribing error were provided. Long-term treatment: There is no significant new information on the effects of long-term treatment with MERREM/MERONEM. Off label use: There are no safety concerns arising from off-label use at this time. Assessor’s comment: No safety concerns arise from the above mentioned cases. COMMENTS ON ANY CHANGE OF THE RISK BENEFIT BALANCE: MAH conclusion: A comprehensive review has been presented of clinical studies and post-marketing experience, as well as regulatory and manufacturer’s actions over the period of the PSUR Summary Bridging Report. During the period of the PSUR Summary Bridging Report safety information has been continually monitored and updated. Drug rash with eosinophilia and systemic symptoms (DRESS), Drug induced hypersensitivity syndrome (DIHS), atypical lung events and cholestasis will continue to be kept under close surveillance. Hepatobiliary disorders, renal dysfunction and electrolyte disturbances, pancytopenia, cardiac disorders and depressed level of consciousness will be monitored as part of AstraZeneca’s routine safety surveillance activities. Assessor’s conclusions and comments: It can be agreed that the risk-benefit of the product remains unchanged, but the EU product information needs further amendments regarding renal adverse reactions, patients with renal impairment and hepatic function abnormal, liver disorder, and liver function test abnormal. Comments and conclusion see Section F RFI / LoQ: REQUEST FOR FURTHER INFORMATION / LIST OF QUESTIONS ACTION PLAN AND CONCLUSIONS

A CHANGES OF THE BENEFIT RISK BALANCE Has the benefit risk balance changed? No Yes , please specify:

B CHANGES REQUIRED IN THE CSP Is the CSP acceptable? Yes No


If not, specify the necessary changes (specific wordings): Assessor’s comments: Section 4.8: For ADRs identified only in the post marketing period a definition “not known” is no longer considered

acceptable according to the Guideline on Summary of Product Characteristics (SmPC). If an adverse reaction has never been observed in clinical trials, then the upper limit of the 95% confidence interval is not higher than 3/X, with X representing the total sample size summed up across all relevant clinical trials and studies.

The PTs hepatic function abnormal, liver disorder and liver function test abnormal should be included in 4.8 of the SmPC.

Concerning the urogenital system: the PTS dysuria, kidney failure, urinary incontinence should be included in 4.8 of the SmPC.

Section 4.4: Amendments with regard to renal adverse reactions and patients with renal impairment. Sections 4.4 and 4.8 : For better readability it is recommended to include headings. Comments and conclusion see Section F RFI / LoQ: REQUEST FOR FURTHER INFORMATION / LIST OF QUESTIONS

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

Ireland We fully endorse report of the P-RMS and have no additional comments.

Germany The P-RMS conclusion has been endorsed. With regard to renal dysfunction DE would like to refer to the US SmPC for Merrem (Astra Zeneca) which lists the following additional renal adverse reactions and Information: Urogenital System: dysuria, kidney failure, urinary incontinence NOTE: For patients with varying degrees of renal impairment, the incidence of heart failure, kidney failure, seizure and shock reported irrespective of relationship to MERREM I.V., increased in patients with moderately severe renal impairment (creatinine clearance

P-RMS conclusion: The MAH is requested to propose the amendments of sections 4.4 and 4.8 of the EU SmPCs with regard to renal adverse reactions and patients with renal impairment. The MAH should also consider any supplement information submitted under the scope of the ongoing renewal in France (see FR comments).


>10 to 26 mL/min) [see Dosage and Administration (2.2), Warnings and Precautions (5.8), Use in Specific Populations (8.5) and (8.6) and Clinical Pharmacology (12.3)]. Additionally, the following adverse reactions are listed for centrally authorised ertapenem (Invanz) and should be taken into account for assessment of causality: Rare: Renal insufficiency, acute renal insufficiency DE proposes to amend the EU SmPCs in line with the US product information which also includes a warning for thrombocytopenia in patients with renal impairment (http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/050706s031lbl.pdf).

France The P-RMS conclusion has been endorsed. The additional comments are related to the ongoing assessment of the MAH’s response of the renewal procedure: Regarding atypical lung events it can be endorsed that this topic would be monitored with routine safety surveillance but a cumulative safety review regarding cases of interstitial pneumonia should be addressed in the next PSUR.

Regarding renal events, based on the provided data from MAH’s response of the renewal procedure which is assessed in parallel, we consider that in the next PSUR even if a cumulative safety review is indeed not relevant, the MAH should continue to closely monitor this topic and present new cases of renal dysfunction presenting a possible causal relationship.

Regarding cardiac events, we fully support the P-RMS’s opinion to continue the close monitoring of cases of cardiac events. Moreover cumulatively the MAH has reported

P-RMS conclusion: The requested cumulative review should include a separate analysis for ILD including the aspects such as potential differences between Caucasians and Asians (Japanese). The MAH should provide additional data concerning renal events, especially concerning time of onset. The MAH should provide a cumulative review of cardiac events up to 2012 including a separate discussion regarding tachycardia. Any supplement documents submitted in the ongoing


13 cases of tachycardia (including ventricular tachycardia). Based on the short time relationship among 6 of the 13 cumulative reported cases of tachycardia, on the recover after withdrawal of meropenem in two cases and positive rechallenge in one case without apparent confounding factor, we consider that tachycardia should be added as listed cardiac disorder with an unknown frequency.

Regarding the cases of polyarteritis nodosa and leukocytoclastic vasculitis which are both related to inflammation of vessels, since these ADRs could be difficult to be diagnosed, it could be requested to extend the cumulative safety review regarding cases of vascular inflammation.

renewal procedure in France should be provided. The MAH should provide a broader discussion on causal association of meropenem and vascular inflammation.

E POINTS TO BE ADDRESSED IN THE NEXT PSUR <E.g. agreed topic(s) for close monitoring / review to be included in next PSUR.> The following topics should be closely monitored in the next PSUR period:

- Vanishing Bile Duct Syndrome and Cholestasis - interaction between meropenem and colistin - Leukocytoclastic vasculitis

- Drug rash with eosinophilia and systemic symptoms (DRESS) - Drug induced hypersensitivity syndrome (DIHS) - Depressed level of consciousness - Pancytopenia - Cardiac disorders, especially arrhythmias and conduction abnormalities - Polyarteritis nodosa - Atypical lung events and ILD - liver disorder / serious hepatic events - renal events

The MAH is asked to provide with the next PSUR a cumulative review for:

- Leukocytoclastic vasculitis / vascular inflammation

– The topics Drug rash with eosinophilia and systemic symptoms (DRESS) and Drug induced hypersensitivity syndrome (DIHS) and depressed level of consciousness should be re-evaluated and the MAH should discuss the update of section 4.4 and 4.8 of the SmPC.

The following information should be provided in the next PSUR:


- A Follow-up on the case 2011SE40211 - Polyarteritis nodosa should be performed and discussed in

the next PSUR.

The results of the studies “FDA report on paediatric study 2012” and “A Phase III study should be presented and discussed in the next PSUR.

F RFI / LoQ: REQUEST FOR FURTHER INFORMATION / LIST OF QUESTIONS

Questions to be addressed by the MAH:

There is a difference between the number of adverse events mentioned in the SBR-PSUR (n = 1386) and those provided in the table “ADVERSE DRUG REACTIONS” (n = 1546). The MAH is requested to explain this difference.

Summary of MAH response: The Adverse Drug Reaction (ADR) table for the SBR period of 01 September 2009 – 31 August 2012 was generated on 23 January 2013. The data is not static as the safety database is not locked. It is a dynamic database and can change according to any additional information or events. If significant follow-up data has been obtained which is relevant to the interpretation of the case, the updated case report could be included in more than 1 PSUR. Other criteria that could change the qualification for inclusion could be a change in the causality assessment for a clinical study case or the receipt of medical confirmation on a consumer case etc. Assessor´s conclusion:

Acknowledged.

The MAH is requested to provide a cumulative review concerning atypical lung events up to 31.

August 2012 including a cumulative review of interstitial pneumonia. The review should include information on indications, patient´s age, gender, race, time to onset, outcome of AE and seriousness.(See comments to atypical lung events and ILD).

Summary of MAH response: The analysis of cases presented describe patients being treated with MERREM/MERONEM and experiencing ILD. However, these patients have underlying medical conditions which could provide alternative explanations for the events, conditions such as pneumonia, aspiration pneumonia, bronchiectasis, cancer and infection. In addition, these patients are on multiple concomitant medications which themselves are associated with lung events such as chemotherapy and other antibiotics as well as medications which have ILD and ILD-type events as listed events. In some cases, important diagnostic test results are missing, such as diagnostic imaging and perhaps a Drug Lymphocyte Stimulation Test (DLST) with which to provide more information on a possible causal association between ILD and MERREM/MERONEM. Concerning the separate analysis for ILD including the aspects such as potential differences between Caucasians and Asians (Japanese), the observed differences are thought to be cultural differences in AE reporting, different medical practice patterns across regions, differences in earlier editions of coding systems, underlying prevalence of diseases in different regions, differences in the genetic predisposition across regions, increase in general pharmacovigilance awareness and reporting, a tendency of an increase of AE reporting in some regions, implementation of follow up questionnaires, differences in labeling. There is no indication from the cumulative reviews of a safety reason underlying this increased rate in Japan against the rest of the world. A cumulative search of all cases of atypical lung events in patients being treated withMERREM/MERONEM was carried out till 22 October 2012 and this search retrieved 428 cases. Out of these cases 58 cases did


describe a clinical picture of ILD or AEs consistent with a clinical picture of ILD such as pneumonitis, eosinophilic pneumonia acute, eosinophilic pneumonia, pulmonary fibrosis and pulmonary eosinophilia. In conclusion, analysis of the cases of ILD presented does not provide evidence of a causal association between MERREM/MERONEM and ILD. Assessor´s conclusion:

The MAH conclusion can be agreed. In the cases described, the patients had underlying medical conditions or were being treated concomitantly with drugs which are known to cause ILD. Even in four cases where a temporal relationship between the AE and the administration of MERREM/MERONEM was seen, the underlying medical condition and/or concomitant medication are possible explanations for the occurrence of ILD. Nevertheless this topic should be kept under close surveillance by the MAH and - especially cases with positive dechallange should be presented in the next PSUR. The MAH should also come up with the proposal how the cases of atypical lung events could be further investigated.

The MAH should add in section 4.8 of the SmPC: hepatic function abnormal, liver disorder, and liver function test abnormal.

Summary of MAH response: The current EU Summary of Product Characteristics (SmPC) for MERONEM contains the following information related to ‘hepatobiliary disorders’ in section 4.8, ‘Undesirable effects’. Common: transaminases increased, blood alkaline phosphatase increased, blood lactate dehydrogenase increased. Uncommon: blood bilirubin increased. The term ‘liver / hepatic function tests’ is commonly applied to a variety of blood tests that assess the general state of the liver and biliary system. ‘Hepatic function abnormal’ is defined as any abnormality in the liver function tests with/without associated clinical features like fatigue, nausea, vomiting, right upper quadrant pain, itching, skin rash, jaundice, weakness, anorexia, weight loss and ascites (Aithal et al 2011). ‘Liver disorder’ is a non-specific term related to diseases affecting the liver, of varied aetiology and includes a wide spectrum of clinical signs and symptoms and investigations. There is no evidence to suggest a causal association between the PTs ‘hepatic function abnormal’, ‘liver disorder’ and ‘liver function test abnormal’ and MERREM/MERONEM and AstraZeneca does not consider that the requested changes to the SmPC are warranted. Assessor´s conclusion:

The MAH`s statement not to include hepatic function abnormal, and liver function test abnormal in section 4.8 of the SmPC can be accepted. As regard the liver disorders the MAH should discuss measures in the next PSUR how the cases of liver disorder can be further characterised concerning the kind of liver disease.

Serious hepatic events should be kept under close monitoring.

The MAH should provide additional data concerning renal events, especially concerning time of

onset and provide a proposal for amendment of EU SmPCs with regard to renal adverse reactions and patients with renal impairment.

Summary of MAH response: Despite use of MERREM/MERONEM for over 20 years there are relatively few case reports of renal dysfunction. The majority of case reports received 75% (216 of 288 case reports) describe AEs of prerenal aetiology, considering the indication for MERREM/MERONEM and as such its use in severely ill patients many with predisposing factors such as hypotension due to sepsis, or hypovolaemia due to trauma or surgery this is not unexpected. There are no mechanisms by which MERREM/MERONEM could be


expected to contribute renal failure from prerenal causes. Indeed treatment of the underlying infection would be anticipated to improve the patient’s condition and improve their renal outcomes. Where possible AEs reported that are associated with intrinsic renal disease or damage including injury to the renal vasculature, nephron or interstitium have been identified as such and evaluated separately. The most common cause of renal dysfunction attributed to medications is nephritis. Very few reports of nephritis have been received concerning patients receiving meropenem (16 of 288). No clear pattern of onset can be observed from these reports. Where diagnosis is supported by biopsy and pattern of presentation, convincing alternative aetiologies are present. Few reports of nephrotic syndrome, renal tubular disorders and hepatorenal disease have been received and have been evaluated. These do not indicate a change to the safety profile of MERREM/MERONEM. Regarding updating the section 4.8 of EU SmPC with the events of dysuria, kidney failure, urinary incontinence, the cumulative review of the AstraZeneca global safety data till 12 October 2012 does not support a causality association due to MERREM/MERONEM. Regarding updating the section 4.4 of the EU SmPC with warnings related to administration of MERREM/MERONEM in renal patients, the current EU SmPC sections 4.2 and 5.2 clearly describes the precautions and dose changes that need to be followed in renal impaired patients, which is considered adequate. AstraZeneca acknowledges that there are variations in the labelling in different countries. AstraZeneca has established a Core Data Sheet based upon a rigorous and continuous review of all available data. After careful review of the cumulative data it is concluded that the requested changes are not supported by the data available and AstraZeneca does not consider that changes to the EU SmPC are warranted. Assessor´s conclusion:

The MAH conclusion can be agreed, the MAH should continue to closely monitor this topic and present new cases of renal events presenting a possible causal relationship in the next PSUR.

The MAH should provide a cumulative review of cardiac events up to 31- 08-2012 including a

separate analysis for cases of tachycardia. Summary of MAH response:

A cumulative search of all cases of cardiac events in patients being treated with MERREM/MERONEM on the AstraZeneca worldwide safety database was carried out on 12 October 2012. This search identified 469 cases. Of these 469 cases, 129 cases included AEs which were not specifically of cardiac origin (eg, events such as dizziness, laryngeal and other localised oedema, respiratory distress) and which the narratives described drug hypersensitivity or allergic reactions of the patient to either MERREM/MERONEM or another concomitant medication. A further 250 cases were from unsponsored clinical trial sources and were considered unrelated to MERREM/MERONEM by the investigators. The remaining 90 cases describe 107 cardiac events or events suggestive of a cardiac condition. Sudden death For the 3 cases of sudden death, there was insufficient information with which to assess the cases; information such as disease indications, dose of MERREM/MERONEM, time to onset of events, the patient’s medical history, concomitant medications and outcomes of the AEs were missing. Cardiac arrest, cardiorespiratory arrest There are 19 cases with 19 events describing cardiac arrest and cardiorespiratory arrest. Most of these cases have confounding factors and do not provide a clear effect of MERREM/MERONEM on the heart to induce cardiac arrest or cardiorespiratory arrest. However 2 cases are of interest because of the temporal relationship between the AE and the administration of MERREM/MERONEM. Arrhythmias and conduction abnormalities There are 34 cases with 39 events describing arrhythmias and conduction abnormalities. Most of these cases have confounding factors and do not provide a clear effect of MERREM/MERONEM on the heart to give arrhythmias and other conduction abnormalities.


However 3 cases (see below) are of interest because of the temporal relationship between the AE and the administration of MERREM/MERONEM. 1996AP19894 is a report of a 57-year-old female being treated with MERREM/MERONEM for infection. The patient had a medical history of renal dysfunction, mycosis, ovarian cancer, infection and acute myeloid leukemia. The patient was in the terminal stages of cancer and was on multiple concomitant medications. After the administration of an infusion of MERREM/MERONEM the patient experienced ventricular fibrillation with loss of consciousness and cardiac and respiratory arrest. The patient was stabilized and treated with further medications. MERREM/MERONEM was discontinued. The patient subsequently died due to her worsening condition. A causal association with the event of ventricular fibrillation and MERREM/MERONEM was suspected because of the temporal association however the patient’s extensive medical history and concomitant medications make a causal assessment difficult. The patient’s concomitant medications included fluconazole, haloperidol, imipenem and idarubicin which are all listed for arrhythmias. 2001UW02885 is a report of a 49-year-old female being treated with MERREM/MERONEM for cryptococcal meningitis. The patient had a medical history which included HIV infection and a possible penicillin allergy. Her concomitant medications included metronidazole, linezolid, fluconazole, metoprolol, famotidine, potassium, paracetamol, heparin, ibuprofen and pseudoephedrine. The patient started treatment with MERREM/MERONEM (1000 mg) and 45 minutes later experienced atrioventricular block and ECG T-wave inversion. She was intubated in the Intensive Care Unit. The patient was taking metoprolol which is listed for cardiac arrhythmias however the temporal relationship of the events with MERREM/MERONEM makes a causal relationship possible. Although the temporal relationship exists, there is no information on the outcome of the AE and no further information given with which to assess the case. 2005UW00995 is a report of a 35-week-old female pediatric patient being treated with MERREM/MERONEM for an Enterobacter aerogenes infection. Previous treatment included gentamycin and clavulanate/ticarcillin. She also received erythromycin and ranitidine for a short time. Treatment with MERREM/MERONEM was initiated 20 mg/kg every 8 hours. After 3 weeks of treatment, the patient started to have periods of apnoea with bradycardia. MERREM/MERONEM was reduced to 20 mg/kg every 12 hours. Sometimes the periods of apnoea would correspond with MERREM/MERONEM treatment but sometime it didn't. MERREM/MERONEM was discontinued and the periods of apnoea and bradycardia stopped at this time. A gastronomy tube was inserted. The reporter stated that it was difficult to assess if the events were related to MERREM/MERONEM or if the patient was experiencing episodes of reflux that were relieved by the gastronomy tube. Assessor´s conclusion:

Even if in these three cases a temporal relationship between the AEs and the administration of MERREM/MERONEM cannot be excluded these cases have confounding factors. This topic should be kept under review.

Tachycardia There are 13 cases reports in which the PT of tachycardia was reported among the patients treated with MERREM/MERONEM (including 2 cases of ventricular tachycardia). All of these cases had insufficient information with which to assess the cases; have confounding factors or underlying medical conditions and do not provide a clear effect of MERREM/MERONEM on the heart to induce tachycardia.

Cardiac failure There are 20 cases with 22 events of cardiac failure or signs suggesting cardiac failure. Most of these cases have confounding factors and do not provide a clear effect of MERREM/MERONEM on the heart to induce cardiac failure. However 2 cases (see below) are of interest because of the temporal relationship between the AE and the administration of MERREM/MERONEM. 1999UW02584 is a report of a 15-year-old female. This paediatric patient had cystic fibrosis and received MERREM/MERONEM for Pseudomonas aeruginosa-resistant bronchitis for 4 days, 400 mg every 8 hours, reduced to 300 mg every 8 hours. Six days after being discharged from hospital the patient was re-hospitalised with congestive heart failure. Twenty days later the patient died due to cardiomyopathy and respiratory failure secondary to congestive heart failure and pneumonia. The physician stated that ‘they did


not know the cause of the patient’s cardiomyopathy, this is the first time the patient has been treated with meropenem and [we] are curious to see if it played a role.’ Although the temporal relationship exists, no further information on diagnostic laboratory tests is provided which makes a causal assessment difficult. 2000AP03508 is a report of a 51-year-old female. The patient had a medical history of necrotizing fasciitis, diabetic nephropathy, acute renal failure and proteinuria. Concomitant medication included diltiazem, citalopram, captopril and bromazepam. She received MERREM/MERONEM for necrotizing fasciitis. Approximately 6 weeks later she developed acute heart failure with acute pulmonary oedema and was hospitalized. Treatment with furosemide, nitrates, digoxin and oxygen was given. MERREM/MERONEM was withdrawn and the patient's condition was improving. Other causes of cardiac failure such as ischemic disease, myocarditis and sepsis were absent. Events occurred 6 weeks after starting MERREM/MERONEM. The reporter noted a positive dechallenge but also could not exclude ischemic heart disease. However, although ischemic heart disease could provide an alternative explanation for the event, further information necessary to differentiate between these two hypotheses are not provided. Assessor´s conclusion:

In these two cases a temporal relationship between the AEs and the administration of MERREM/MERONEM cannot be excluded. Additionally a positive dechallenge is reported in one case. The MAH should come up with a proposal for further investigation of cardiac events associated with meropenem.

Myocardial infarction There are 3 cases of myocardial infarction in patients being treated with MERREM/MERONEM (including 2 associated events of cardiogenic shock). These cases were considered to be related to the patient’s medical conditions. Other cardiac disorders These cases all have confounding factors and do not provide a clear effect of MERREM/MERONEM on the heart to induce cardiac failure. However one case is of interest because of the temporal relationship between the AE and the administration of MERREM/MERONEM.

MAH Conclusion In conclusion, a careful and thorough cumulative analysis of cardiac events in patients being treated with MERREM/MERONEM was provided. There is no evidence to suggest a causal association between any of the medical concepts discussed and MERREM/MERONEM. Assessor´s conclusion:

Concerning the PTs “sudden death, cardiac arrest, cardiorespiratory arrest, tachycardia and myocardial infarction” the MAHs conclusion can be agreed. These cases all have confounding factors or there was insufficient information and underlying medical conditions and do not provide a clear effect of MERREM/MERONEM on the heart. Nevertheless close monitoring of cases of cardiac events should be continued.

FINAL CONCLUSION (SUMMARY OF A-F)


CHANGES REQUIRED IN THE SmPC: Section 4.8: For ADRs identified only in the post marketing period a definition “not known” is no longer considered

acceptable according to the Guideline on Summary of Product Characteristics (SmPC). If an adverse reaction has never been observed in clinical trials, then the upper limit of the 95% confidence interval is not higher than 3/X, with X representing the total sample size summed up across all relevant clinical trials and studies.

Sections 4.4 and 4.8 : For better readability it is recommended to include headings. POINTS TO BE ADDRESSED IN THE NEXT PSUR: The following topics should be closely monitored in the next PSUR period:

- Vanishing Bile Duct Syndrome and Cholestasis - interaction between meropenem and colistin - Leukocytoclastic vasculitis - Drug rash with eosinophilia and systemic symptoms (DRESS) - Drug induced hypersensitivity syndrome (DIHS) - Depressed level of consciousness - Pancytopenia - Cardiac disorders, especially arrhythmias and conduction abnormalities - Polyarteritis nodosa - Atypical lung events and ILD - liver disorder / serious hepatic events - renal events

The MAH is asked to provide with the next PSUR a cumulative review for: Leukocytoclastic vasculitis / vascular inflammation (Additionally a discussion on causal association of

meropenem and vascular inflammation should be provided in the next PSUR). The topics Drug rash with eosinophilia and systemic symptoms (DRESS) and Drug induced

hypersensitivity syndrome (DIHS) and depressed level of consciousness should be re-evaluated and the MAH should discuss the update of section 4.4 and 4.8 of the SmPC.

The following information should be provided in the next PSUR:

A Follow-up on the case 2011SE40211 - Polyarteritis nodosa should be performed and discussed in the next PSUR.

The results of the studies “FDA report on paediatric study 2012” and “A Phase III study” should be

presented and discussed in the next PSUR.

ILD should be kept under close surveillance by the MAH and - especially cases with positive dechallange should be presented in the next PSUR. The MAH should also come up with the proposal how the cases of atypical lung events could be further investigated.

Concerning liver disorders the MAH should discuss measures in the next PSUR how the cases of liver

disorder can be further characterised concerning the kind of liver disease.

Cases of renal events presenting a possible causal relationship should be presented in the next

PSUR.


Concerning cardiac failure the MAH should come up with a proposal for further investigation of these

events associated with merropenem.

DATE AND CONCLUSION OF PHVWP DISCUSSION CONCERNING THIS PSUR, IF ANY:

p-rms final assessment report procedure...

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