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Package leaflet: Information for the user

Meropenem 500 mg, powder for solution for injection/infusion

Meropenem

Read all of this leaflet carefully before you start taking this medicine because it contains important information for you.

-    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 only. Do not pass it on to others. It may harm them, even if their signs of illness are the same as yours.

-    If you get any side effects, talk to your doctor or nurse. This includes any possible side effects not listed in this leaflet. See section 4.

What is in this leaflet

1.    What Meropenem is and what it is used for

2.    What you need to know before you use Meropenem

3.    How to use Meropenem

4.    Possible side effects

5.    How to store Meropenem

6.    Contents of the pack and other information

1. What Meropenem is and what it is used for

Meropenem 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 tissue infections

Acute bacterial infection of the brain (meningitis)

Meropenem may be used in the management of neutropenic patients with fever that is suspected to be due to a bacterial infection.

2. What you need to know before you use Meropenem Do not use Meropenem:

-    if you are allergic to meropenem or any of the other ingredients of this medicine (listed in section 6)

-    if you are allergic to other antibiotics such as penicillins, cephalosporins, or carbapenems as you may also be allergic to meropenem

Warnings and precautions

Talk to your doctor before using Meropenem

-    if you have health problems, such as liver or kidney problems

-    if you have had severe diarrhoea after taking other antibiotics

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 Meropenem.

Children

Meropenem should not be used in children below 3 months of age.

Other medicines and Meropenem

Tell your doctor if you are taking, have recently taken or might take any other medicines.

This is because Meropenem can affect the way some medicines work and some medicines can have an effect on Meropenem.

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). Meropenem should not be used because it may decrease the effect of sodium valproate

Pregnancy and breast-feeding

If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your doctor for advice before taking this medicine.

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 breastfeed 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.

Meropenem contains sodium

This medicinal product contains approximately 2.0 mEq of sodium per 500 mg 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 Meropenem

Always use this medicine exactly as your doctor has told you. Check with your doctor if you are not sure.

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 500 mg (milligrams) and 2 g (gram). You will usually receive a dose every 8 hours. However you may receive a dose less often if your kidneys do not work very well.

Use in children and adolescents

-    The dose for children over 3 months old and up to 12 years of age is decided using the age and weight of the child. The usual dose is between 10 mg and 40 mg of Meropenem for each kilogram (kg) that the child weighs. A dose is usually given every 8 hours. Children who weigh over 50 kg will be given an adult dose.

-    Meropenem will be given to you as an injection or infusion into a large vein.

-    Your doctor or nurse will normally give Meropenem to you.

-    However, some patients, parents and carers are trained to give Meropenem at home. Instructions for doing this are provided in this leaflet (in the section called ‘Instructions for giving Meropenem to yourself or someone else at home’). Always use Meropenem 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 5 minutes or between 15 and 30 minutes. Your doctor will tell you how to give Meropenem.

-    You should normally have your injections at the same times each day.

If you use more Meropenem 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 Meropenem

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 Meropenem until your doctor tells you to.

If you have any further questions on the use of this medicine, ask your doctor or nurse.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them.

Severe allergic reactions

If you have a severe allergic reaction, stop having Meropenem 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 (affects 1 to 10 users in 100)

-    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 (affects 1 to 10 users in 1,000)

-    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

-    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 (affects 1 to 10 users in 10,000)

- Fits (convulsions)

Not known (cannot be estimated from the available data)

-    Inflammation of the bowel with diarrhoea

-    Sore veins where Meropenem 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

Reporting of side effects

If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via

Yellow Card Scheme

Website: www.mhra.gov.uk/yellowcard.

By reporting side effects you can help provide more information on the safety of this medicine.

5. How to store Meropenem

Keep this medicine out of the sight and reach of children.

Do not use this medicine after the expiry date which is stated on the container. The expiry date refers to the last day of that month.

This medicine does not require any special storage conditions.

After reconstitution: The reconstituted solutions for intravenous injection or infusion should be used immediately. The time interval between the beginning of reconstitution and the end of intravenous injection should not exceed one hour.

Do not freeze the reconstituted solution

Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. These measures will help protect the environment.

6. Contents of the pack and other information What Meropenem contains

-    The active substance is meropenem.

Each vial contains meropenem trihydrate equivalent to 500 mg anhydrous meropenem.

-    The other ingredient is anhydous sodium carbonate.

What Meropenem looks like and contents of the pack

Meropenem is a white to light yellow crystalline powder.

Pack sizes of 1 or 10 vials

Not all pack sizes may be marketed.

Marketing Authorisation Holder and Manufacturer

Marketing Authorisation Holder:

ACIC Europe Limited

Leontiou, 163, CLERIMOS BUILIDING, 2nd floor

3022 Limassol

Cyprus

Manufacturer:

Geryon Pharma Limited 18 Owen Drive Liverpool L24 1YL United Kingdom

Distributor:

Creo Pharma Ltd Felsted Business Centre

The following information is intended for healthcare professionals only:

Instructions for giving Meropenem to yourself or someone else at home

Some patients, parents and carers are trained to give Meropenem at home.

-    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.

How to prepare this medicine

1.    Wash your hands and dry them very well. Prepare a clean working area.

2.    Remove the Meropenem 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 Meropenem	Amount of “Water for Injections” needed for dilution
500 mg (milligrams)	10 ml (millilitres)
1 g (gram)	20 ml
15 g	30 ml
2 g	40 ml

Please note:    If your prescribed dose of Meropenem is more than 1 g, you will need to

use more than 1 vial of Meropenem. 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 Meropenem.

7.    Remove the needle from the vial and shake the vial well for about 5 seconds, 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 Meropenem 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 Meropenem 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 Meropenem 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 5 minutes.

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

Giving Meropenem 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 5 minutes.

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.

MEDICAL INFORMATION LEAFLET

Meropenem

for Intravenous Administration

1.    NAME OF THE MEDICINAL PRODUCT

Meropenem 500 mg, powder for solution for injection/infusion

2.    QUALITATIVE AND QUANTITATIVE COMPOSITION

Each vial contains meropenem trihydrate equivalent to 500 mg anhydrous meropenem.

Excipients with known effect:

Each 500 mg vial contains 104 mg sodium carbonate which equates to approximately 2.0 mEq of sodium (approximately 45 mg).

For a full list of excipients, see section 6.1.

3.    PHARMACEUTICAL FORM

Powder for solution for injection/infusion

A white to light yellow crystalline powder.

4.    CLINICAL PARTICULARS

4.1 Therapeutic indications

Meropenem 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

Meropenem 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.

Posology

A dose of up to 2 g three times daily in adults and adolescents and a dose of up to 40 mg/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 8 hours
Pneumonia including community-acquired pneumonia and nosocomial pneumonia.	500 mg or 1 g
Broncho-pulmonary infections in cystic fibrosis	2 g
Complicated urinary tract infections	500 mg or 1 g
Complicated intra-abdominal infections	500 mg or 1 g
Intra- and post-partum infections	500 mg or 1 g
Complicated skin and soft tissue infections	500 mg or 1 g
Acute bacterial meningitis	2 g
Management of febrile neutropenic patients	1 g

Meropenem is usually given by intravenous infusion over approximately 15 to 30 minutes (see sections 6.2, 6.3 and 6.6).

Alternatively, doses up to 1 g can be given as an intravenous bolus injection over approximately 5 minutes. There are limited safety data available to support the administration of a 2 g 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 51 ml/min, as shown below. There are limited data to support the application of these dose adjustments for a unit dose of 2 g.

Creatinine clearance Dose (based on “unit” dose range of Frequency (ml/min)    500 mg or 1 g or 2 g, see table

above)

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 50 ml/min.

Paediatric population Children under 3 months of age

The safety and efficacy of meropenem in children under 3 months of age have not been established and the optimal dose regimen has not been identified. However, limited pharmacokinetic data suggest that 20 mg/kg every 8 hours may be an appropriate regimen (see section 5.2).

Children from 3 months to 11 years of age and up to 50 kg body weight The recommended dose regimens are shown in the table below:

Infection	Dose to be administered every 8 hours
Pneumonia including community-acquired pneumonia and nosocomial pneumonia	10 or 20 mg/kg
Broncho-pulmonary infections in cystic fibrosis	40 mg/kg
Complicated urinary tract infections	10 or 20 mg/kg
Complicated intra-abdominal infections	10 or 20 mg/kg
Complicated skin and soft tissue infections	10 or 20 mg/kg
Acute bacterial meningitis	40 mg/kg
Management of febrile neutropenic patients	20 mg/kg

Children over 50 kg body weight The adult dose should be administered.

There is no experience in children with renal impairment.

Method of administration

Meropenem is usually given by intravenous infusion over approximately 15 to 30 minutes (see sections 6.2, 6.3, and 6.6). Alternatively, meropenem doses of up to 20 mg/kg may be given as an intravenous bolus over approximately 5 minutes. There are limited safety data available to support the administration of a 40 mg/kg dose in children as an intravenous bolus injection.

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. 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 4.3 and 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).

Meropenem 500 mg powder for solution for injection or infusion contains sodium.

This medicinal product contains approximately 2.0 mEq of sodium per 500 mg 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.

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 Fertility, pregnancy and lactation

Fertility

There are no data available regarding potential effects of meropenem on male or female fertility.

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 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 4,872 patients with 5,026 meropenem 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 2,367 patients 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 (> 1/100 to <1/10); uncommon (> 1/1,000 to <1/100); rare (> 1/10,000 to <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	Frequency	Event
Infections and infestations	Uncommon	oral and vaginal candidiasis
Blood and lymphatic system	Common	thrombocythaemia
disorders	Uncommon	eosinophilia, thrombocytopenia, leucopenia, neutropenia
	Not known	agranulocytosis, haemolytic anaemia
Immune system disorders	Not known	angioedema, anaphylaxis (see sections 4.3 and 4.4)
Nervous system disorders	Common	headache
	Uncommon	paraesthesiae
	Rare	convulsions (see section 4.4)
Gastrointestinal disorders	Common	diarrhoea, vomiting, nausea, abdominal pain
	Not known	antibiotic-associated colitis (see section 4.4)
Hepatobiliary disorders	Common	transaminases increased,

Skin and subcutaneous tissue disorders	Uncommon Common Uncommon	blood alkaline phosphatase increased, blood lactate dehydrogenase increased blood bilirubin increased rash, pruritis urticaria
	Not known	toxic epidermal necrolysis, Stevens Johnson syndrome, erythema multiforme
Renal and urinary disorders	Uncommon	blood creatinine increased, blood urea increased
General disorders and	Common	inflammation, pain
administration site conditions	Uncommon	thrombophlebitis
	Not known	pain at the injection site

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via

Yellow Card Scheme

Website: www.mhra.gov.uk/yellowcard

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 Grampositive 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).

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 influenzae1 and Moraxella catarrhalis	< 2	> 2
Neisseria meningitidis2 4	< 0.25	> 0.25
Gram-positive anaerobes	< 2	> 8
Gram-negative anaerobes	< 2	> 8

Non-species related breakpoints⁵    < 2

¹    Meropenem breakpoints for Streptococcus pneumoniae and Haemophilus influenzae in meningitis are 0.25/1 mg/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)

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 1 hour; the mean volume of distribution is approximately 0.25 l/kg (11-27 l) and the mean clearance is 287 ml/min at 250 mg falling to 205 ml/min at 2 g. Doses of 500, 1000 and 2000 mg doses infused over 30 minutes give mean C_max values of approximately 23, 49 and 115 pg/ml respectively, corresponding AUC values were 39.3, 62.3 and 153 pg-h/ml. After infusion over 5 minutes C_max values are 52 and 112 pg/ml after 500 and 1 g doses respectively. When multiple doses are administered 8-hourly to subjects with normal renal function, accumulation of meropenem does not occur.

A study of 12 patients administered meropenem 1 g 8 hourly post-surgically for intraabdominal infections showed a comparable Cmax and half-life to normal subjects but a greater volume of distribution 27 l.

Distribution

The average plasma protein binding of meropenem was approximately 2 % and was independent of concentration. After rapid administration (5 minutes or less) the pharmacokinetics are biexponential but this is much less evident after 30 minutes 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 % (50 -75 %) of the dose is excreted unchanged within 12 hours. 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 2.4 fold in patients with moderate impairment (CrCL 33-74 ml/min),

5 fold in severe impairment (CrCL 4-23 ml/min) and 10 fold in haemodialysis patients (CrCL

<2 ml/min) when compared to healthy subjects (CrCL >80 ml/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 4 times 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 79 patients 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, 20 and 40 mg/kg showed C_max values approximating to those in adults following 500, 1000 and 2000 mg doses, respectively. Comparison showed consistent pharmacokinetics between the doses and halflives similar to those observed in adults in all but the youngest subjects (<6 months t1/2 1.6 hours). The mean meropenem clearance values were 5.8 ml/min/kg (6-12 years), 6.2 ml/min/kg (2-5 years), 5.3 ml/min/kg (6-23 months) and 4.3 ml/min/kg (2-5 months). Approximately 60 % of the dose is excreted in urine over 12 hours 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 interindividual 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 2.9 hours. Monte Carlo simulation based on a population PK model showed that a dose regimen of 20 mg/kg 8 hourly 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 (65-80 years) 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 at doses of 2000 mg/kg and above after a single administration and above and in monkeys at 500 mg/kg in a 7-day study.

Meropenem is generally well tolerated by the central nervous system. Effects were seen in acute toxicity studies in rodents at doses exceeding 1000 mg/kg.

The IV LD₅₀ of meropenem in rodents is greater than 2000 mg/kg.

In repeat dose studies of up to 6 months 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 was observed in rats up to 750 mg/kg and in monkeys up to 360 mg/kg.

However, there was an increased incidence of abortions at 500 mg/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

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

36 months

After reconstitution:

The reconstituted solutions for intravenous injection or infusion should be used immediately. The time interval between the beginning of reconstitution and the end of intravenous injection of infusion should not exceed one hour.

6.4 Special precautions for storage

This medicinal product does not require any special storage conditions

For storage conditions after reconstitution of the medicinal product, see section 6.3.

Do not freeze the reconstituted solution.

6.5    Nature and contents of container

674 mg powder in a 20 ml Type I borosilicate glass vial with a grey chlorobutyl rubber stopper and sealed with an aluminium cap in a cardboard carton.

The medicinal product is supplied in pack sizes of 1 vial or 10 vials.

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 medicinal product or waste material should be disposed of in accordance with local requirements.

7. MARKETING AUTHORISATION HOLDER

ACIC Europe Limited

Leontiou, 163, CLERIMOS BUILIDING, 2nd floor 3022 Limassol

Cyprus

8.    MARKETING AUTHORISATION NUMBER(S)

41697/0001

9.    DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

01/11/2013

10.    DATE OF REVISION OF THE TEXT

February 2016