MERONEM IV 500MG

meropenem Read all of this leaflet carefully before you start taking this medicine. - Keep this leaflet. You may need to read it again. - If you have any further questions, ask your doctor or nurse. - This medicine has been prescribed for you. Do not pass it on to others. It may harm them, even if their symptoms are the same as yours. - If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please tell your doctor or nurse. In this leaflet: 1. What Meronem is and what it is used for 2. Before you use Meronem 3. How to use Meronem 4. Possible side effects 5. How to store Meronem 6. Further information 1.What Meronem is and what it is used for Meronem belongs to a group of medicines called carbapenem antibiotics. It works by killing bacteria, which can cause serious infections. Infection affecting the lungs (pneumonia). Lung and bronchial infections in patients suffering from cystic fibrosis. Complicated urinary tract infections. Complicated infections in the abdomen. Infections that you can catch during or after the delivery. Complicated skin and soft tissues infections. Acute bacterial infection of the brain (meningitis). Meronem may be used in the management of neutropenic patients with fever that is suspected to be due to a bacterial infection. 2.Before you use Meronem Do not use Meronem If you are allergic (hypersensitive) to meropenem or any of the other ingredients of Meronem (listed in Section 6Further information). If you are allergic (hypersensitive) to other antibiotics such as penicillins, cephalosporins, or carbapenems as you may also be allergic to meropenem. Take special care with Meronem Check with your doctor before using Meronem: If you have health problems, such as liver or kidney problems. If you have had severe diarrhoea after taking other antibiotics.
Medical Information Leaflet for Intravenous Administration 1. NAME OF THE MEDICINAL PRODUCT Meronem IV 2. QUALITATIVE AND QUANTITATIVE COMPOSITION Meronem IV 500mg Each vial contains meropenem trihydrate equivalent to 500mg anhydrous meropenem. Meronem IV 1g Each vial contains meropenem trihydrate equivalent to 1g anhydrous meropenem. Excipients: Each 500mg vial contains 104mg sodium carbonate which equates to approximately 2.0mEq of sodium (approximately 45mg). Each 1g vial contains 208mg sodium carbonate which equates to approximately 4.0mEq of sodium (approximately 90mg). For a full list of excipients, see section 6.1. 3. PHARMACEUTICAL FORM Powder for solution for injection or infusion. A white to light yellow powder. 4. CLINICAL PARTICULARS 4.1 Therapeutic indications Meronem is indicated for the treatment of the following infections in adults and children over 3months of age (see sections 4.4and 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. 4.2 Posology and method of administration The tables below provide general recommendations for dosing. The dose of meropenem administered and the duration of treatment should take into account the type of infection to be treated, including its severity, and the clinical response. A dose of up to 2g three times daily in adults and adolescents and a dose of up to 40mg/kg three times daily in children may be particularly appropriate when treating some types of infections, such as nosocomial infections due to Pseudomonas aeruginosa or Acinetobacter spp. Additional considerations for dosing are needed when treating patients with renal insufficiency (see further below). Adults and Adolescents Infection Dose to be administered every 8hours Pneumonia including community-acquired 500mg or 1g pneumonia and nosocomial pneumonia. Broncho-pulmonary infections in cystic fibrosis 2g

Meronem IV 500mg and 1g Powder for solution for injection or infusion

PACKAGE LEAFLET: INFORMATION FOR THE USER

You may develop a positive test (Coombs test) which indicates the presence of antibodies that may destroy red blood cells. Your doctor will discuss this with you. If you are not sure if any of the above applies to you, talk to your doctor or nurse before using Meronem. Using other medicines Please tell your doctor if you are taking or have recently taken any other medicines, including medicines obtained without a prescription and herbal medicines. This is because Meronem can affect the way some medicines work and some medicines can have an effect on Meronem. In particular, tell your doctor or nurse if you are taking any of the following medicines: Probenecid (used to treat gout). Sodium valproate (used to treat epilepsy). Meronem should not be used because it may decrease the effect of sodium valproate. Pregnancy and breast-feeding It is important that you tell your doctor if you are pregnant or are planning to become pregnant before receiving meropenem. It is preferable to avoid the use of meropenem during pregnancy. Your doctor will decide whether you should use meropenem. It is important that you tell your doctor if you are breast-feeding or if you intend to breast-feed before receiving meropenem. Small amounts of this medicine may pass into the breast milk and it may affect the baby. Therefore, your doctor will decide whether you should use meropenem while breastfeeding. Ask your doctor for advice before taking any medicine. Driving and using machines No studies on the effect on the ability to drive and use machines have been performed. Important information about some of the ingredients of Meronem Meronem contains sodium. Meronem 500mg: This medicinal product contains approximately 2.0mEq of sodium per 500mg dose which should be taken into consideration by patients on a controlled sodium diet. Meronem 1g: This medicinal product contains approximately 4.0mEq of sodium per 1.0g dose which should be taken into consideration by patients on a controlled sodium diet. If you have a condition which requires you to monitor your sodium intake please inform your doctor or nurse.

3.How to use Meronem Adults The dose depends on the type of infection that you have, where the infection is in the body and how serious the infection is. Your doctor will decide on the dose that you need. The dose for adults is usually between 500mg (milligrams) and 2g (gram). You will usually receive a dose every 8hours. However you may receive a dose less often if your kidneys do not work very well. Children and adolescents The dose for children over 3months old and up to 12years of age is decided using the age and weight of the child. The usual dose is between 10mg and 40mg of Meronem for each kilogram (kg) that the child weighs. A dose is usually given every 8hours. Children who weigh over 50kg will be given an adult dose. Meronem will be given to you as an injection or infusion into a large vein. Your doctor or nurse will normally give Meronem to you. However, some patients, parents and carers are trained to give Meronem at home. Instructions for doing this are provided in this leaflet (in the section called Instructions for giving Meronem to yourself or someone else at home). Always use Meronem exactly as your doctor has told you. You should check with your doctor if you are not sure. Your injection should not be mixed with or added to solutions that contain other medicines. The injection may take about 5minutes or between 15and 30minutes. Your doctor will tell you how to give Meronem. You should normally have your injections at the same times each day. If you use more Meronem than you should If you accidentally use more than your prescribed dose, contact your doctor or nearest hospital straight away. If you forget to use Meronem If you miss an injection, you should have it as soon as possible. However, if it is almost time for your next injection, skip the missed injection. Do not take a double dose (two injections at the same time) to make up for a forgotten dose. If you stop using Meropenem Do not stop having Meronem until your doctor tells you to. If you have any further questions on the use of this product, ask your doctor or nurse.
Children over 50kg body weight The adult dose should be administered. There is no experience in children with renal impairment. Meropenem is usually given by intravenous infusion over approximately 15to 30minutes (see sections 6.2, 6.3, and 6.6). Alternatively, meropenem doses of up to 20mg/kg may be given as an intravenous bolus over approximately 5minutes. There are limited safety data available to support the administration of a 40mg/kg dose in children as an intravenous bolus injection. 4.3 Contraindications Hypersensitivity to the active substance or to any of the excipients. Hypersensitivity to any other carbapenem antibacterial agent. Severe hypersensitivity (e.g. anaphylactic reaction, severe skin reaction) to any other type of betalactam antibacterial agent (e.g. penicillins or cephalosporins). 4.4 Special warnings and precautions for use The selection of meropenem to treat an individual patient should take into account the appropriateness of using a carbapenem antibacterial agent based on factors such as severity of the infection, the prevalence of resistance to other suitable antibacterial agents and the risk of selecting for carbapenem-resistant bacteria. As with all beta-lactam antibiotics, serious and occasionally fatal hypersensitivity reactions have been reported (see sections 4.3and 4.8). Patients who have a history of hypersensitivity to carbapenems, penicillins or other beta-lactam antibiotics may also be hypersensitive to meropenem. Before initiating therapy with meropenem, careful inquiry should be made concerning previous hypersensitivity reactions to beta-lactam antibiotics. If a severe allergic reaction occurs, the medicinal product should be discontinued and appropriate measures taken. Antibiotic-associated colitis and pseudomembranous colitis have been reported with nearly all anti-bacterial agents, including meropenem, and may range in severity from mild to life threatening. Therefore, it is important to consider this diagnosis in patients who present with diarrhoea during or subsequent to the administration of meropenem (see section 4.8). Discontinuation of therapy with meropenem and the administration of specific treatment for Clostridium difficile should be considered. Medicinal products that inhibit peristalsis should not be given. Seizures have infrequently been reported during treatment with carbapenems, including meropenem (see section 4.8). Hepatic function should be closely monitored during treatment with meropenem due to the risk of hepatic toxicity (hepatic dysfunction with cholestasis and cytolysis) (see section 4.8). Use in patients with liver disease: patients with pre-existing liver disorders should have liver function monitored during treatment with meropenem. There is no dose adjustment necessary (see section 4.2). A positive direct or indirect Coombs test may develop during treatment with meropenem. The concomitant use of meropenem and valproic acid/sodium valproate is not recommended (see section 4.5). Meronem contains sodium. Meronem 500mg: This medicinal product contains approximately 2.0mEq of sodium per 500mg dose which should be taken into consideration by patients on a controlled sodium diet. Meronem 1.0g: This medicinal product contains approximately 4.0mEq of sodium per 1.0g dose which should be taken into consideration by patients on a controlled sodium diet. 4.5 Interaction with other medicinal products and other forms of interaction No specific medicinal product interaction studies other than probenecid were conducted. Probenecid competes with meropenem for active tubular secretion and thus inhibits the renal excretion of meropenem with the effect of increasing the elimination half-life and plasma concentration of meropenem. Caution is required if probenecid is co-administered with meropenem.

4.Possible side effects Like all medicines, Meronem can cause side effects, although not everybody gets them. The frequency of possible side effects listed below is defined using the following convention: Very common (affects more than 1user in 10). Common (affects 1to 10users in 100). Uncommon (affects 1to 10users in 1,000). Rare (affects 1to 10users in 10,000). Very rare (affects less than 1user in 10,000). Not known (frequency cannot be estimated from the available data but this is rare or very rare). Severe allergic reactions If you have a severe allergic reaction, stop having Meronem and see a doctor straight away. You may need urgent medical treatment. The signs may include a sudden onset of: Severe rash, itching or hives on the skin. Swelling of the face, lips, tongue or other parts of the body. Shortness of breath, wheezing or trouble breathing. Damage to red blood cells (not known) The signs include: Being breathless when you do not expect it. Red or brown urine. If you notice any of the above, see a doctor straight away. Other possible side effects: Common Abdominal (stomach) pain. Feeling sick (nausea). Being sick (vomiting). Diarrhoea. Headache. Skin rash, itchy skin. Pain and inflammation. Increased numbers of platelets in your blood (shown in a blood test). Changes in blood tests, including tests that show how well your liver is working. Uncommon Changes in your blood. These include reduced numbers of platelets (which may make you bruise more easily), increased numbers of some white blood cells, decreased numbers of other white cells and increased amounts of a substance called bilirubin. Your doctor may do blood tests from time to time.
The potential effect of meropenem on the protein binding of other medicinal products or metabolism has not been studied. However, the protein binding is so low that no interactions with other compounds would be expected on the basis of this mechanism. Decreases in blood levels 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, co-administration of valproic acid with carbapenem agents is not considered to be manageable and therefore should be avoided (see section 4.4). Oral anti-coagulants Simultaneous administration of antibiotics with warfarin may augment its anti-coagulant effects. There have been many reports of increases in the anti-coagulant effects of orally administered anti-coagulant agents, including warfarin in patients who are concomitantly receiving antibacterial agents. The risk may vary with the underlying infection, age and general status of the patient so that the contribution of the antibiotic to the increase in INR (international normalised ratio) is difficult to assess. It is recommended that the INR should be monitored frequently during and shortly after co-administration of antibiotics with an oral anti-coagulant agent. 4.6 Pregnancy and lactation Pregnancy There are no or limited amount of data from the use of meropenem in pregnant women. Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity (see section 5.3). As a precautionary measure, it is preferable to avoid the use of meropenem during pregnancy. Lactation It is unknown whether meropenem is excreted in human milk. Meropenem is detectable at very low concentrations in animal breast milk. A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from meropenem therapy taking into account the benefit of therapy for the woman. 4.7 Effects on ability to drive and use machines No studies on the effect on the ability to drive and use machines have been performed. 4.8 Undesirable effects In a review of 4,872patients with 5,026meropenem treatment exposures, meropenem-related adverse reactions most frequently reported were diarrhoea (2.3 %), rash (1.4 %), nausea/vomiting (1.4 %) and injection site inflammation (1.1%). The most commonly reported meropenem-related laboratory adverse events were thrombocytosis (1.6%) and increased hepatic enzymes (1.5-4.3%). Adverse reactions listed in the table with a frequency of not known were not observed in the 2,367patients who were included in pre-authorisation clinical studies with intravenous and intramuscular meropenem but have been reported during the post-marketing period. In the table below all adverse reactions are listed by system organ class and frequency: very common (1/10); common (1/100to <1/10); uncommon (1/1,000to <1/100); rare (1/10,000to <1/1,000); very rare (<1/10,000) and not known (cannot be estimated from the available data). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness. Table 1 System Organ Class Infections and infestations Blood and lymphatic system disorders Immune system disorders Frequency Uncommon Common Uncommon Not known Not known Event oral and vaginal candidiasis thrombocythaemia eosinophilia, thrombocytopenia, leucopenia, neutropenia agranulocytosis, haemolytic anaemia angioedema, anaphylaxis (see sections 4.3and 4.4)

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Please turn over Changes in blood tests, including tests that show how well your kidneys are working. A tingling feeling (pins and needles). Infections of the mouth or the vagina that are caused by a fungus (thrush). Rare Fits (convulsions). Other possible side effects of unknown frequency Inflammation of the bowel with diarrhoea. Sore veins where Meronem is injected. Other changes in your blood. The symptoms include frequent infections, high temperature and sore throat. Your doctor may do blood tests from time to time. Sudden onset of a severe rash or blistering or peeling skin. This may be associated with a high fever and joint pains. If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please tell your doctor or nurse. 5.How to store Meronem Keep out of the reach and sight of children. Do not use Meronem after the expiry date which is stated on the container. The expiry date refers to the last day of that month. Do not store above 30C. Injection After reconstitution: The reconstituted solutions for intravenous injection should be used immediately. The time interval between the beginning of reconstitution and the end of intravenous injection should not exceed 3hours when stored at controlled room temperature (15-25C).

Meronem

Complicated urinary tract infections 500mg or 1g Complicated intra-abdominal infections 500mg or 1g Intra- and post-partum infections 500mg or 1g Complicated skin and soft tissue infections 500mg or 1g Acute bacterial meningitis 2g Management of febrile neutropenic patients 1g Meropenem is usually given by intravenous infusion over approximately 15to 30minutes (see section 6.2, 6.3and 6.6). Alternatively, doses up to 1 g can be given as an intravenous bolus injection over approximately 5minutes. There are limited safety data available to support the administration of a 2g dose in adults as an intravenous bolus injection. Renal impairment The dose for adults and adolescents should be adjusted when creatinine clearance is less than 51ml/min, as shown below. There are limited data to support the application of these dose adjustments for a unit dose of 2g. Dose Frequency (based on unit dose range of 500mg or 1g or 2g, see table above) 26-50 one unit dose every 12hours 10-25 half of one unit dose every 12hours <10 half of one unit dose every 24hours Meropenem is cleared by haemodialysis and haemofiltration. The required dose should be administered after completion of the haemodialysis cycle. There are no established dose recommendations for patients receiving peritoneal dialysis. Hepatic impairment No dose adjustment is necessary in patients with hepatic impairment (see section 4.4). Dose in elderly patients No dose adjustment is required for the elderly with normal renal function or creatinine clearance values above 50ml/min. Paediatric population Children under 3months of age The safety and efficacy of meropenem in children under 3months of age have not been established and the optimal dose regimen has not been identified. However, limited pharmacokinetic data suggest that 20mg/kg every 8hours may be an appropriate regimen (see section 5.2). Children from 3months to 11years of age and up to 50kg body weight The recommended dose regimens are shown in the table below: Infection Pneumonia including community-acquired pneumonia and nosocomial pneumonia Broncho-pulmonary infections in cystic fibrosis Complicated urinary tract infections Complicated intra-abdominal infections Complicated skin and soft tissue infections Acute bacterial meningitis Management of febrile neutropenic patients Dose to be administered every 8hours 10or 20mg/kg 40mg/kg 10or 20mg/kg 10or 20mg/kg 10or 20mg/kg 40mg/kg 20mg/kg Creatinine clearance (ml/min)

Nervous system disorders Common Uncommon Rare Gastrointestinal disorders Common Not known Hepatobiliary disorders Common Skin and subcutaneous tissue disorders Renal and urinary disorders General disorders and administration site conditions Uncommon Common Uncommon Not known Uncommon Common Uncommon Not known

headache paraesthesiae convulsions (see section 4.4) diarrhoea, vomiting, nausea, abdominal pain antibiotic-associated colitis (see section 4.4) transaminases increased, blood alkaline phosphatase increased, blood lactate dehydrogenase increased. blood bilirubin increased rash, pruritis urticaria toxic epidermal necrolysis, Stevens Johnson syndrome, erythema multiforme. blood creatinine increased, blood urea increased inflammation, pain thrombophlebitis pain at the injection site

4.9 Overdose Relative overdose may be possible in patients with renal impairment if the dose is not adjusted as described in section 4.2. Limited post-marketing experience indicates that if adverse reactions occur following overdose, they are consistent with the adverse reaction profile described in section 4.8, are generally mild in severity and resolve on withdrawal or dose reduction. Symptomatic treatments should be considered. In individuals with normal renal function, rapid renal elimination will occur. Haemodialysis will remove meropenem and its metabolite. 5. PHARMACOLOGICAL PROPERTIES 5.1 Pharmacodynamic properties Pharmacotherapeutic group: antibacterials for systemic use, carbapenems ATC code: J01DH02 Mode of action Meropenem exerts its bactericidal activity by inhibiting bacterial cell wall synthesis in Gram-positive and Gram-negative bacteria through binding to penicillin-binding proteins (PBPs). Pharmacokinetic/Pharmacodynamic (PK/PD) relationship Similar to other beta-lactam antibacterial agents, the time that meropenem concentrations exceed the MIC (T>MIC) has been shown to best correlate with efficacy. In preclinical models meropenem demonstrated activity when plasma concentrations exceeded the MIC of the infecting organisms for approximately 40% of the dosing interval. This target has not been established clinically. Mechanism of resistance Bacterial resistance to meropenem may result from: (1) decreased permeability of the outer membrane of Gram-negative bacteria (due to diminished production of porins) (2) reduced affinity of the target PBPs (3) increased expression of efflux pump components, and (4) production of beta-lactamases that can hydrolyse carbapenems. Localised clusters of infections due to carbapenem-resistant bacteria have been reported in the European Union. There is no target-based cross-resistance between meropenem and agents of the quinolone, aminoglycoside, macrolide and tetracycline classes. However, bacteria may exhibit resistance to more than one class of antibacterials agents when the mechanism involved include impermeability and/or an efflux pump(s).

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Infusion After reconstitution: The reconstituted solutions for intravenous infusion should be used immediately. The time interval between the beginning of reconstitution and the end of intravenous infusion should not exceed: 6hours when stored at controlled room temperature (15-25C) when Meronem is dissolved in sodium chloride; 24hours when stored at 2-8C when Meronem is dissolved in sodium chloride. In this case, the prepared solution should be used within 2hours after it has left the refrigerator; 1hour when Meronem is dissolved in glucose (dextrose). Do not freeze the reconstituted solution. Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of medicines no longer required. These measures will help to protect the environment. 6.Further information What Meronem contains Each vial contains meropenem trihydrate equivalent to 500mg anhydrous meropenem. Each vial contains meropenem trihydrate equivalent to 1g anhydrous meropenem. The other ingredient is anhydrous sodium carbonate. What Meronem looks like and contents of the pack Meronem is a white to light yellow powder for solution for injection or infusion in a vial. Pack sizes of 1or 10vials. Marketing Authorisation Holder and Manufacturer The Marketing Authorisations for Meronem are held by AstraZeneca UK Ltd, 600Capability Green, Luton, LU13LU, UK. Meronem is manufactured by Corden Pharma S.p.A., Viale dell Industria, 3, 20040Caponago, Italy.
Breakpoints European Committee on Antimicrobial Susceptibility Testing (EUCAST) clinical breakpoints for MIC testing are presented below. EUCAST clinical MIC breakpoints for meropenem (2009-06-05, v 3.1) Organism Susceptible (S) Resistant (R) (mg/l) (mg/l) Enterobacteriaceae 2 >8 Pseudomonas 2 >8 Acinetobacter 2 >8 Streptococcus groups A, B, C, G 2 >2 Streptococcus pneumoniae1 2 >2 Other streptococci 2 2 Enterococcus --Staphylococcus2 note 3 note 3 Haemophilus influenzae1and Moraxella catarrhalis 2 >2 Neisseria meningitidis2,4 0.25 > 0.25 Gram-positive anaerobes 2 >8 Gram-negative anaerobes 2 >8 2 >8 Non-species related breakpoints5 1 Meropenem breakpoints for Streptococcus pneumoniae and Haemophilus influenzae in meningitis are 0.25/1mg/L. 2 Strains with MIC values above the S/I breakpoint are rare or not yet reported. The identification and antimicrobial susceptibility tests on any such isolate must be repeated and if the result is confirmed the isolate sent to a reference laboratory. Until there is evidence regarding clinical response for confirmed isolates with MIC above the current resistant breakpoint (in italics) they should be reported as resistant. 3 Susceptibility of staphylococci to meropenem is inferred from the methicillin susceptibility. 4 Meropenem breakpoints in Neisseria meningitidis relates to meningitis only. 5 Non-species related breakpoints have been determined mainly from PK/PD data and are independent of the MIC distributions of specific species. They are for use for species not mentioned in the table and footnotes. -- = Susceptibility testing not recommended as the species is a poor target for therapy with the medicinal product. The prevalence of acquired resistance may vary geographically and with time for selected species and local information on resistance is desirable, particularly when treating severe infections. As necessary, expert advice should be sought when the local prevalence of resistance is such that the utility of the agent in at least some types of infections is questionable. The following table of pathogens listed is derived from clinical experience and therapeutic guidelines. Commonly susceptible species Gram-positive aerobes Enterococcus faecalis$ Staphylococcus aureus (methicillin-susceptible) Staphylococcus species (methicillin-susceptible) including Staphylococcus epidermidis Streptococcus agalactiae (Group B) Streptococcus milleri group (S. anginosus, S. constellatus, and S. intermedius) Streptococcus pneumoniae Streptococcus pyogenes (Group A)

This medicinal product is authorised in the Member States of the EEA under the following names: Austria: Optinem Belgium: Meronem IV Bulgaria: Meronem Cyprus: MERONEM Czech Republic: MERONEM Denmark: MERONEM Estonia: Meronem Finland: Meronem France: MERONEM Germany: Meronem Greece: Meronem Hungary: Meronem Iceland: Meronem Ireland: Meronem IV Italy: MERREM Latvia: Meronem Lithuania: Meronem IV Luxembourg: Meronem IV Malta: Meronem IV Netherlands: Meronem i.v. Norway: Meronem Poland: Meronem Portugal: Meronem Romania: Meronem i.v. Slovak Republic: Meronem 500mg i.v. Slovenia: Meronem Spain: Meronem I.V. Sweden: Meronem United Kingdom: Meronem IV

To listen to or request a copy of this leaflet in Braille, large print or audio please call, free of charge: 08001985000(UK only) Please be ready to give the following information: Product name Reference number Meronem IV 500mg 17901/0029 Meronem IV 1g 17901/0030 This is a service provided by the Royal National Institute of Blind People.

Advice/medical education Antibiotics are used to treat infections caused by bacteria. They have no effect against infections caused by viruses. Sometimes an infection caused by bacteria does not respond to a course of an antibiotic. One of the commonest reasons for this to occur is because the bacteria causing the infection are resistant to the antibiotic that is being taken. This means that they can survive and even multiply despite the antibiotic. Bacteria can become resistant to antibiotics for many reasons. Using antibiotics carefully can help to reduce the chance of bacteria becoming resistant to them. When your doctor prescribes a course of an antibiotic it is intended to treat only your current illness. Paying attention to the following advice will help prevent the emergence of resistant bacteria that could stop the antibiotic working. 1. It is very important that you take the antibiotic at the right dose, at the right times and for the right number of days. Read the instructions on the label and if you do not understand anything ask your doctor or pharmacist to explain. 2. You should not take an antibiotic unless it has been prescribed specifically for you and you should use it only to treat the infection for which it was prescribed. 3. You should not take antibiotics that have been prescribed for other people even if they had an infection that was similar to yours. 4. You should not give antibiotics that were prescribed for you to other people. 5. If you have any antibiotic left over when you have taken the course as directed by your doctor you should take the remainder to a pharmacy for appropriate disposal. This leaflet was last updated in April 2011 AstraZeneca 2011 Meronem is a trade mark of the AstraZeneca group of companies. INF 100021 The following information is intended for medical or healthcare professionals only: Instructions for giving Meronem to yourself or someone else at home Some patients, parents and carers are trained to give Meronem at home.

Warning You should only give this medicine to yourself or someone else at home after a doctor or nurse has trained you. The medicine must be mixed with another liquid (the diluent). Your doctor will tell you how much of the diluent to use. Use the medicine straight after preparing it. Do not freeze it. How to prepare this medicine 1. Wash your hands and dry them very well. Prepare a clean working area. 2. Remove the Meronem bottle (vial) from the packaging. Check the vial and the expiry date. Check that the vial is intact and has not been damaged. 3. Remove the coloured cap and clean the grey rubber stopper with an alcohol wipe. Allow the rubber stopper to dry. 4. Connect a new sterile needle to a new sterile syringe, without touching the ends. 5. Draw up the recommended amount of sterile Water for Injections into the syringe. The amount of liquid that you need is shown in the table below: Dose of Meronem 500mg (milligrams) 1g (gram) 1.5g 2g Please note: Amount of Water for Injections needed for dilution 10ml (millilitres) 20ml 30ml 40ml

I f your prescribed dose of Meronem is more than 1g, you will need to use more than 1vial of Meronem. You can then draw the liquid in the vials into the one syringe. 6. Put the needle of the syringe through the centre of the grey rubber stopper and inject the recommended amount of Water for Injections into the vial or vials of Meronem. 7. Remove the needle from the vial and shake the vial well for about 5seconds, or until all the powder has dissolved. Clean the grey rubber stopper once more with a new alcohol wipe and allow the rubber stopper to dry. 8. With the plunger of the syringe pushed fully into the syringe, put the needle back through the grey rubber stopper. You must then hold both the syringe and the vial and turn the vial upside down.

9. Keeping the end of the needle in the liquid, pull back the plunger and draw all the liquid in the vial into the syringe. 10.Remove the needle and syringe from the vial and throw the empty vial away in a safe place. 11.Hold the syringe upright, with the needle pointing upwards. Tap the syringe so that any bubbles in the liquid rise to the top of the syringe. 12.Remove any air in the syringe by gently pushing the plunger until all the air has gone. 13.If you are using Meronem at home, dispose of any needles and infusion lines that you have used in an appropriate way. If your doctor decides to stop your treatment, dispose of any unused Meronem in an appropriate way. Giving the injection You can either give this medicine through a short cannula or venflon, or through a port or central line. Giving Meronem through a short cannula or venflon 1. Remove the needle from the syringe and throw the needle away carefully in your sharps bin. 2. Wipe the end of the short cannula or venflon with an alcohol wipe and allow it to dry. Open the cap on your cannula and connect the syringe. 3. Slowly push the plunger of the syringe to give the antibiotic steadily over about 5minutes. 4. Once you have finished giving the antibiotic and the syringe is empty, remove the syringe and use a flush as recommended by your doctor or nurse. 5. Close the cap of your cannula and carefully throw the syringe away in your sharps bin. Giving Meronem through a port or central line 1. Remove the cap on the port or line, clean the end of the line with an alcohol wipe and allow it to dry. 2. Connect the syringe and slowly push the plunger on the syringe to give the antibiotic steadily over about 5minutes. 3. Once you have finished giving the antibiotic, remove the syringe and use a flush as recommended by your doctor or nurse. 4. Place a new clean cap on your central line and carefully throw the syringe away in your sharps bin.

Gram-negative aerobes Citrobacter freudii Citrobacter koseri Enterobacter aerogenes Enterobacter cloacae Escherichia coli Haemophilus influenzae Klebsiella oxytoca Klebsiella pneumoniae Morganella morganii Neisseria meningitides Proteus mirabilis Proteus vulgaris Serratia marcescens Gram-positive anaerobes Clostridium perfringens Peptoniphilus asaccharolyticus Peptostreptococcus species (including P. micros, P anaerobius, P. magnus) Gram-negative anaerobes Bacteroides caccae Bacteroides fragilis group Prevotella bivia Prevotella disiens Species for which acquired resistance may be a problem Gram-positive aerobes Enterococcus faecium$ Gram-negative aerobes Acinetobacter species Burkholderia cepacia Pseudomonas aeruginosa Inherently resistant organisms Gram-negative aerobes Stenotrophomonas maltophilia Legionella species Other micro-organisms Chlamydophila pneumoniae Chlamydophila psittaci Coxiella burnetii Mycoplasma pneumoniae $ Species that show natural intermediate susceptibility All methicillin-resistant staphylococci are resistant to meropenem Resistance rate 50% in one or more EU countries. 5.2 Pharmacokinetic properties In healthy subjects the mean plasma half-life is approximately 1hour; the mean volume of distribution is approximately 0.25l/kg (11-27l) and the mean clearance is 287ml/min at 250 mg falling to 205ml/min at 2g. Doses of 500, 1000and 2000mg doses infused over 30minutes give mean Cmax values of approximately 23, 49and 115g/ml respectively, corresponding AUC values were 39.3, 62.3and 153g.h/ml. After infusion over 5minutes Cmax values are 52and 112g/ml after 500and

1000mg doses respectively. When multiple doses are administered 8-hourly to subjects with normal renal function, accumulation of meropenem does not occur. A study of 12patients administered meropenem 1000mg 8hourly post-surgically for intra-abdominal infections showed a comparable Cmax and half-life to normal subjects but a greater volume of distribution 27l. Distribution The average plasma protein binding of meropenem was approximately 2% and was independent of concentration. After rapid administration (5minutes or less) the pharmacokinetics are biexponential but this is much less evident after 30minutes infusion. Meropenem has been shown to penetrate well into several body fluids and tissues: including lung, bronchial secretions, bile, cerebrospinal fluid, gynaecological tissues, skin, fascia, muscle, and peritoneal exudates. Metabolism Meropenem is metabolised by hydrolysis of the beta-lactam ring generating a microbiologically inactive metabolite. In vitro meropenem shows reduced susceptibility to hydrolysis by human dehydropeptidase-I (DHP-I) compared to imipenem and there is no requirement to co-administer a DHP-I inhibitor. Elimination Meropenem is primarily excreted unchanged by the kidneys; approximately 70% (5075%) of the dose is excreted unchanged within 12hours. A further 28% is recovered as the microbiologically inactive metabolite. Faecal elimination represents only approximately 2% of the dose. The measured renal clearance and the effect of probenecid show that meropenem undergoes both filtration and tubular secretion. Renal insufficiency Renal impairment results in higher plasma AUC and longer half-life for meropenem. There were AUC increases of 2.4fold in patients with moderate impairment (CrCL 33-74ml/min), 5fold in severe impairment (CrCL 4-23ml/min) and 10fold in haemodialysis patients (CrCL <2ml/min) when compared to healthy subjects (CrCL >80ml/min). The AUC of the microbiologically inactive ring opened metabolite was also considerably increased in patients with renal impairment. Dose adjustment is recommended for patients with moderate and severe renal impairment (see section 4.2). Meropenem is cleared by haemodialysis with clearance during haemodialysis being approximately 4times higher than in anuric patients. Hepatic insufficiency A study in patients with alcoholic cirrhosis shows no effect of liver disease on the pharmacokinetics of meropenem after repeated doses. Adult patients Pharmacokinetic studies performed in patients have not shown significant pharmacokinetic differences versus healthy subjects with equivalent renal function. A population model developed from data in 79patients with intra-abdominal infection or pneumonia, showed a dependence of the central volume on weight and the clearance on creatinine clearance and age. Paediatrics The pharmacokinetics in infants and children with infection at doses of 10, 20and 40mg/kg showed Cmax values approximating to those in adults following 500, 1000and 2000mg doses, respectively. Comparison showed consistent pharmacokinetics between the doses and half-lives similar to those observed in adults in all but the youngest subjects (<6months t1/21.6hours). The mean meropenem clearance values were 5.8ml/min/kg (6-12years), 6.2ml/min/kg (2-5years), 5.3ml/min/kg (6-23months) and 4.3ml/min/kg (2-5months). Approximately 60% of the dose is excreted in urine over 12hours as meropenem with a further 12% as metabolite. Meropenem concentrations in the CSF of children with meningitis are approximately 20% of concurrent plasma levels although there is significant inter-individual variability.

The pharmacokinetics of meropenem in neonates requiring anti-infective treatment showed greater clearance in neonates with higher chronological or gestational age with an overall average half-life of 2.9hours. Monte Carlo simulation based on a population PK model showed that a dose regimen of 20mg/kg 8hourly achieved 60%T>MIC for P. aeruginosa in 95% of pre-term and 91% of full term neonates. Elderly Pharmacokinetic studies in healthy elderly subjects (65-80years) have shown a reduction in plasma clearance, which correlated with age-associated reduction in creatinine clearance, and a smaller reduction in non-renal clearance. No dose adjustment is required in elderly patients, except in cases of moderate to severe renal impairment (see section 4.2). 5.3 Preclinical safety data Animal studies indicate that meropenem is well tolerated by the kidney. Histological evidence of renal tubular damage was seen in mice and dogs only at doses of 2000mg/kg and above after a single administration and above and in monkeys at 500mg/kg in a 7-day study. Meropenem is generally well tolerated by the central nervous system. Effects were seen in acute toxicity studies in rodent at doses exceeding 1000mg/kg. The IV LD50of meropenem in rodents is greater that 2000mg/kg. In repeat dose studies of up to 6months duration only minor effects were seen including a decrease in red cell parameters in dogs. There was no evidence of mutagenic potential in a conventional test battery and no evidence of reproductive toxicity including teratogenic potential in studies in rats up to 750mg/kg and in monkeys up to 360mg/kg. There was increased evidence of abortions at 500mg/kg in a preliminary study in monkeys. There was no evidence of increased sensitivity to meropenem in juveniles compared to adult animals. The intravenous formulation was well tolerated in animal studies. The sole metabolite of meropenem had a similar profile of toxicity in animal studies. 6. PHARMACEUTICAL PARTICULARS 6.1 List of excipients Meronem 500mg: anhydrous sodium carbonate Meronem 1g: anhydrous sodium carbonate 6.2 Incompatibilities This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6. 6.3 Shelf life 4years After reconstitution: Intravenous bolus injection administration A solution for bolus injection is prepared by dissolving the drug product Meronem in water for injection to a final concentration of 50mg/ml. Chemical and physical in-use stability for a prepared solution for bolus injection has been demonstrated for 3hours at controlled room temperature (15-25C). From a microbiological point of view, unless the method of opening/reconstitution/dilution precludes the risk of microbiological contamination, the product should be used immediately. If not used immediately in-use storage times and conditions are the responsibility of the user. Intravenous infusion administration A solution for infusion is prepared by dissolving the drug product Meronem in either 0.9% sodium chloride solution for infusion or 5% glucose (dextrose) solution for infusion to a final concentration of 1to 20mg/ml.

Chemical and physical in-use stability for a prepared solution for infusion using 0.9% sodium chloride solution has been demonstrated for 6hours at controlled room temperature (15-25C) or 24hours at 2-8C. The prepared solution should, if refrigerated, be used within 2hours after it has left the refrigerator. From a microbiological point of view, unless the method of opening/reconstitution/dilution precludes the risk of microbiological contamination, the product should be used immediately. If not used immediately in-use storage times and conditions are the responsibility of the user. Reconstituted solution of Meronem in 5% glucose (dextrose) solution should be used immediately, i.e. within one hour following reconstitution. 6.4 Special precautions for storage Do not store above 30C. Do not freeze the reconstituted solution. 6.5 Nature and contents of container Meronem 500mg 674mg powder in a 20ml Type 1glass vial with stopper (grey halobutilic rubber with an aluminium cap) Meronem 1g 1348mg powder in a 30ml Type 1glass vial with stopper (grey halobutilic rubber with an aluminium cap) The medicinal product is supplied in pack sizes of 1or 10vials. Not all pack sizes may be marketed. 6.6 Special precautions for disposal Injection Meropenem to be used for bolus intravenous injection should be constituted with sterile water for injection. Infusion For intravenous infusion meropenem vials may be directly constituted with 0.9% sodium chloride or 5% glucose solutions for infusion. Each vial is for single use only. Standard aseptic techniques should be used for solution preparation and administration. The solution should be shaken before use. Any unused product or waste material should be disposed of in accordance with local requirements. 7. MARKETING AUTHORISATION HOLDER AstraZeneca UK Ltd 600Capability Green Luton LU13LU United Kingdom 8. MARKETING AUTHORISATION NUMBER(S) Meronem IV 500mg PL 17901/0029 Meronem IV 1g PL 17901/0030 9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 09February 2009 10. DATE OF REVISION OF THE TEXT April 2011 INF 100021

299374-A03 23-05-11 330034 LC09_LEAFLET_F46_D300.049_V2 354 Meronem Leaflet Combined UK

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