Elements for a Public Summary. VI.2.1 Overview of disease epidemiology

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1 VI.2 Elements for a Public Summary VI.2.1 Overview of disease epidemiology Pneumonia: Pneumonia (lung inflammation caused by infection) is a major public health problem. WHO report has shown that pneumonia accounted for approximately one-fifth (19%) of the 2 million deaths with 90% of these occurring in the developing world; 50% of these deaths occur in Africa alone. Pneumonia is common at both extremes of age. In adults, the incidence varies among countries from 1.6 to 11 per 1,000 adults. Individual 65 years old are at higher risk of pneumonia. It is a leading cause of death among children worldwide and children

2 under age of 5 years are major concern. Among comorbidities (associated serious diseases), chronic obstructive pulmonary disease (disease with long term obstruction of lung airflow) is the most frequent. Ventilator-associated pneumonia (pneumonia occurring from use of breathing machine in patients) is the most common infection observed in patients who require treatment in ICU (Intensive Care Unit). Most of the available data suggest that ventilatorassociated pneumonia is seen on average in 1 to 4 patients out of 10 who undergo process of ventilation [Bonten M et al, 2004; Polverino E & Marti T, 2011; Deshpande A, 2012; Johnson WBR &Abdulkarim AA, 2013]. Cystic fibrosis: Cystic fibrosis (CF) is a lethal genetic disorder. It is estimated that approximately 30,000 persons in the United States have CF. A study showed that in Europe, there were 35,806 CF patients identified in a total population (mean prevalence of per 10,000). In CF patients, lung disease is one of the most challenging problems and accounts for more than 90% of deaths. Males with CF tend to have a longer life expectancy than that of females. [Rosenfeld M et al 1997; Farrell PM, 2008; Flume PA, 2009; Lipuma JJ, 2010] Urinary tract infections: Urinary tract infections (UTIs) are among the most common bacterial infections acquired in the community and in hospitals. UTIs are mostly found in women, occurring in an 8:1 ratio in women to men. Among women aged 18 years and older, the estimated incidence was 12.6%; for men, this incidence was only 3%. UTIs have a higher frequency among the very young and a gradual increase with age in both men and women. An estimated 1 million cases of hospital-acquired UTIs occur in the USA annually of which 80% are attributed to catheters (small tubes for withdrawing or introducing fluids). Catheter-associated UTIs account for 40% of all hospital-acquired infections. UTIs are generally associated with minimal morbidity (associated serious disease) except among specific subpopulations. [Foxman B, 2003; Rahn DD, 2008; Foxman B, 2010] Intra-abdominal infections: Intra-abdominal infections (IAI) are serious clinical problems that generally occur secondary to problems in the gastrointestinal tract like injury, intrinsic diseases, or surgery. These infections comprise a group of conditions ranging from appendicitis (inflammation of appendix) to conditions such as infected pancreatic necrosis (death of cells of pancreas), peritonitis (inflammation of the membrane lining the cavity of the abdomen) and intestinal infarction (death of part of the intestine due to its blood supply being cut off) that are associated with substantial morbidity (associated serious disease) and death-rate. Peritonitis is the most frequently reported type of IAI. Appendicitis and diverticulitis (inflammation of divertuiculum that is tube leading from a colon cavity) are among the most common diseases that precede intra-abdominal sepsis and these conditions are responsible for more than 25% of the total cases of intraabdominal abscess. The elderly population suffers from intraabdominal infections more frequently than younger. [Nichols RL, 1985; Cooper GS, 1994; Marshall JC, 2004]

3 Intrapartum and postpartum infections: Infection during pregnancy is a major cause of maternal death (death of a woman while pregnant) and morbidity (associated serious disease) worldwide. On average, out of total cases of infection in pregnancy, 10.3% are intrapartum (during childbirth) and 46.2% are postpartum (shortly after childbirth). Chorioamnionitis (inflammation occurring in unborn baby due to a bacterial infection) is a common complication during intrapartum period and is associated with postpartum maternal infections and other severe conditions. Overall, 1 to 4% of all births in the USA are complicated by chorioamnionitis. Postpartum infections include endometritis (inflammation of membranes lining the womb), infections related to the urinary tract, breast abscess and other infections. Up to one in four women will experience postpartum infection. The incidence of postpartum infection has been estimated to be 1 to 4% after vaginal delivery and 10 to 20% after caesarean section. Postpartum infection accounts for more than 12% of maternal deaths, particularly in women undergoing caesarean sections. [Van Benedenet al, 2007; Tita AT & Andrews WW, 2010; Ahnfeldt-Mollerupet al, 2012; Bamfo, 2013; Bianco A et al, 2013] Skin and soft tissue infections: Skin and soft tissue infections (SSTIs) collectively refer to several microbial invasions of the skin layers and of the underlying soft tissue. SSTIs are one of the most common causes of infection among groups of different ages. It is difficult to make an assessment of the exact incidence and prevalence of SSTI, probably because of their variable presentation and their short duration. Complicated skin and soft tissue infections (csstis) typically involve deep soft tissue and occur in patients with underlying disease, often requiring intravenous antibiotic therapy, surgical treatment, or both. csstis are among the most rapidly increasing reasons for hospitalization. Approximately 7% to 10% of hospitalized patients are affected by SSTIs. In the emergency care setting, SSTIs represent the third most common diagnosis after chest pain and asthma. There is an increased prevalence among men (60% to 70% of all cases) and patients between 45 and 64 years of age. [Ki V &Rotstein C, 2008; Zervos MJ et al, 2012; Tognetti L et al, 2012] Bacterial meningitis: Bacterial meningitis (inflammation of the membranes that line the skull) is a life-threatening disease which accounts for an estimated deaths worldwide per year. Bacterial meningitis is essentially a disease of young children, mainly due to attenuated immunologic response in this age group. Nearly 95% of cases occur between 1 month and 5 years of age. Among these, children less than 2 years of age are at high risk of bacterial meningitis. A study showed that the average patient with bacterial meningitis has increased from 15 months of age to 25 years of age. In past few years, the vaccination programs have been shown to be important in preventing meningitis. [Aneja S &Aggarwal A, 1997; Snyder RD, 2003; Tzanakaki G &Mastrantonio P, 2007; Makwana N & Riordan FA, 2007; Nudelman Y &Tunkel A, 2009; Kim KS, 2010] Febrile neutropenia:

4 Febrile neutropenia is a condition in which there is development of fever, often with infection, in a patient with neutropenia (an abnormally low number of neutrophil granulocytes that is a type of white blood cell). It is a serious complication of cancer chemotherapy (treatment of cancer), and is a major cause of morbidity (associated serious disease). A neutropenic patient with certain low white blood cell levels (of <500/mm 3 ) who develops fever has a greater than 60% chance of being infected. The number of patients at risk of infection continues to grow as the intensity and duration of complicated chemotherapy regimens are extended. Death rate from febrile neutropenia are 5% in patients with solid tumors (masses of abnormal tissue that originate in organs) (1% in patients with low risk) and as high as 11% in some haematological malignancies (the types of cancer that affect blood related system of body). [Hathorn JW & Lyke K, 1997; Marti FM et al, 2009] VI.2.2 Summary of treatment benefits No pivotal clinical efficacy and safety studies were conducted for Meropenem ELC Group 500 mg & 1 g Powder for solution for injection/infusion considering this is a generic product. The available medical literature is considered sufficient to evaluate the safety of Meropenem ELC Group 500 mg & 1 g Powder for solution for injection/infusion in the proposed therapeutic indications. VI.2.3 Unknowns relating to treatment benefits The safety and efficacy of meropenem in children under 3 months of age have not been established. There are limited safety data available to support the administration of a 40 mg/kg meropenem dose in children as an intravenous bolus injection. The effect of intravenous meropenem in children with renal impairment has not been studied. There are no or limited amount of data from the use of meropenem in pregnant women and excretion in human milk. VI.2.4 Summary of safety concerns Important identified risks: Risk What is known Preventability Disturbance in proper functioning of liver (Hepatic dysfunction) Allergic problems (Hypersensitivity reactions) In clinical studies, it has been commonly observed in patients taking meropenem that there are changes in blood tests that show how well patient s liver is working. Serious and occasionally danger hypersensitivity reactions have been reported with all meropenem type of Yes, during treatment with meropenem, laboratory tests related to liver functioning should be performed in order to monitor proper functioning of liver. Yes, before initiating treatment with meropenem, physician should take patient history concerning previous

5 Risk What is known Preventability Inflammation of the bowel with diarrhoea due to antibiotic type of medicines (Antibiotic-associated colitis) No response of bacteria to meropenem (Bacterial resistance to meropenem) Use of meropenem at the same time as valproic acid/sodium valproate (medicines used to treat epilepsy) Important potential risks: antibiotic medicines. Antibiotic-associated colitis has been reported with nearly all anti-bacterial type of medicines including meropenem. Bacteria can become resistant to treatment with meropenem by developing certain mechanisms and thus can survive and even multiply despite meropenem treatment. This resistance causes reduction in effectiveness of meropenem to treat infections caused by bacteria. Meropenem can reduce the levels of valproic acid in the blood. allergic problems after use of beta-lactam type of antibiotic medicines and if found positive, the treatment should not be started. Yes, before initiating treatment with meropenem careful patient history should be taken for severe diarrhoea after taking any antibiotic type of medicines. The patient should be informed that if he/she develops severe diarrhoea during treatment, he/she must report immediately to the physician. Yes, it should be evaluated how severe the infection is before starting treatment with meropenem. The type of bacteria responsible for the infection to be cured should be taken into account. The patient should be informed that improper use of anti-bacterial type of medicines including meropenem can cause development of resistant by bacteria and reduction in effectiveness of these medicines to treat infection. Yes, the patient is informed that meropenem and sodium valproate should not be used together.

6 Risk Use of meropenem in patients on a controlled salt (sodium) diet Use of meropenem with warfarin (a medicine used to treat blood clots) What is known Meropenem ELC Group contains sodium which should be taken into consideration by patients on a controlled sodium diet. Meropenem can interfere with the bloodclotting effects of warfarin. Missing information: Risk Dose recommendations for patients receiving peritoneal dialysis (used to treat patients with kidney disease) Use of meropenem in children under 3 months of age Use of meropenem in children with kidney disease (renal impairment) Use of meropenem in pregnancy and breastfeeding What is known There are no established dose recommendations for patients receiving peritoneal dialysis. The safety and effectiveness of meropenem has not been established in children aged under 3 months of age. There is no experience of meropenem treatment in children with renal impairment. There are no or limited amount of data from the use of meropenem in pregnant women. It is unknown whether meropenem is excreted in human milk. Meropenem is detectable at very low concentrations in animal breast milk. VI.2.5 Summary of additional risk minimization measures by safety concern Summary of Product Characteristics (SmPC) of Meropenem ELC Group 500 mg & 1 g Powder for solution for injection/infusion provides physicians, pharmacists and other health care professionals with details on how to use the medicine, the risks and recommendations for minimising them. An abbreviated version of this in lay language is provided in the form of the package leaflet (PL). All these risk minimization measures are given in SmPC and PL of Meropenem ELC Group 500 mg & 1 g Powder for solution for injection/infusion. This medicine has no additional risk minimization measures. VI.2.6 Planned post authorisation development plan No post authorisation study is planned for this product. VI.2.7 Summary of changes to the Risk Management Plan over time Version Date (dd-mmyyyy) Indications Comment Meropenem is indicated for the Nil

7 treatment of the following infections in adults and children over 3 months of age: 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 Meropenem may be used in the management of neutropenic (..) bacterial infection. Consideration should (..) antibacterial agents Following indication modified From Pneumonia, including community acquired pneumonia and nosocomial pneumonia to Severe pneumonia, including hospital and ventilator-associated pneumonia. In response to agency review (Day 70 and Day 100 review). Following added as new indication: Treatment of patients with bacteraemia that occurs in association with, or is suspected to be associated with, any of the infections listed above