Active ingredients: Meropenem
Merrem 500 mg powder for solution for injection for intravenous use
Merrem 1000 mg powder for solution for injection for intravenous use.
Why is Merrem used? What is it for?
Merrem belongs to a group of drugs called carbapenem antibiotics. It works by killing bacteria, which can cause serious infections.
- Infections 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 can be contracted during or after childbirth
- Complicated skin and soft tissue infections
- Acute bacterial infections of the brain (meningitis)
Merrem can be used to treat neutropenic patients with fever suspected of being due to bacterial infection.
Meropenem can be used to treat bacterial blood infection which may be associated with one type of the infections mentioned above.
Contraindications When Merrem should not be used
Do not use Merrem
- If you are allergic (hypersensitive) to meropenem or any of the other ingredients of Merrem
- If you are allergic (hypersensitive) to other antibiotics such as penicillins, cephalosporins or carbapenems, you may also be allergic to meropenem.
Precautions for use What you need to know before taking Merrem
Talk to your doctor or pharmacist or nurse before using Merrem if:
- have health problems, such as liver or kidney disease.
- have had severe diarrhea after taking other antibiotics.
He may develop a positive test (Coombs test) that indicates the presence of antibodies that can destroy red blood cells. Your doctor will discuss this with you.
If you have any further questions, ask your doctor or nurse before using Merrem.
Interactions Which drugs or foods can modify the effect of Merrem
Tell your doctor, pharmacist, or nurse if you are taking, have recently taken or might take any other medicines.
This is because Merrem can affect the way some medicines work, and some medicines can affect Merrem.
In particular, tell your doctor, pharmacist or nurse if you are taking any of the following medicines:
- Probenecid (used to treat gout).
- Valproic acid / sodium valproate / valpromide (used to treat epilepsy). Merrem should not be used as it may decrease the effect of sodium valproate.
- Oral anticoagulant agent (used to treat or prevent blood clots)
Warnings It is important to know that:
Pregnancy and breastfeeding
If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your doctor or pharmacist for advice before using this medicine.
It is preferable to avoid taking meropenem during pregnancy. Your doctor will decide if you should use meropenem.
It is important that you tell your doctor if you are breast-feeding or planning to breast-feed before taking meropenem. Small amounts of the drug can pass into breast milk and can affect the baby. Therefore, your doctor will decide whether you should use meropenem while breastfeeding.
Driving and using machines
No studies on the effect on the ability to drive or use machines have been performed.
Merrem contains sodium
Merrem 500 mg: This medicinal product contains approximately 2.0 mEq of sodium for the 500 mg dose, which should be taken into consideration by patients on a controlled sodium diet.
Merrem 1000 mg: This medicinal product contains approximately 4.0 mEq of sodium for the 1000 mg dose, which should be taken into consideration by patients on a controlled sodium diet.
If you have a condition that requires sodium intake to be monitored, consult your doctor, pharmacist or nurse.
Dose, Method and Time of Administration How to use Merrem: Posology
Always use this medicine exactly as your doctor or pharmacist has told you. If in doubt, consult your doctor or pharmacist.
Use in adults
- The dose depends on the type of infection you have, how it is located in the body and how severe it is. Your doctor will decide which dose is most appropriate for you.
- The usual adult dose ranges from 500 mg (milligrams) to 2 g (grams). Usually take one serving every 8 hours. However, you may still be given a dose less frequently if your kidneys are not working very well.
Use in children and adolescents
- The dose for children over 3 months of age and up to 12 years is decided on the basis of the age and weight of the child. The usual dose ranges from 10 mg to 40 mg of Merrem for each kilogram (kg) of weight of the child One dose is usually taken every 8 hours Children who weigh more than 50 kg will receive the same dosage as adults.
How to use Merrem
- Merrem will be given to you as an injection or infusion into a large vein.
- Your doctor or nurse will usually give you Merrem.
- However, some patients, relatives or caregivers have been trained on how to administer Merrem at home. Instructions for administration (in the section entitled "Instructions for" self-administration or giving Merrem to other people at home ") are given in this leaflet. Always use Merrem exactly as your doctor has told you. You should always consult your doctor if you are unsure.
- Your injection must not be mixed with or added to solutions containing other medicines.
- The injection can be given in about 5 minutes or in 15 to 30 minutes. Your doctor will tell you how to give Merrem.
- Usually the injections will be done at the same time every day.
Overdose What to do if you have taken too much Merrem
If you use more Merrem than you should
If you have accidentally taken more medication than prescribed, tell your doctor right away or go to the nearest hospital emergency room.
If you forget to use Merrem
If you miss an injection, you should give 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 taking Merrem
Do not stop taking Merrem until your doctor tells you that you can.
If you have any further questions on the use of this medicine, ask your doctor, pharmacist or nurse.
Side Effects What are the side effects of Merrem
Like all medicines, this medicine can cause side effects, although not everybody gets them.
Severe allergic reactions
If you experience a severe allergic reaction, stop taking Merrem and see your doctor immediately. You may need urgent medical attention. The signs of these allergic reactions include sudden onset of:
- Severe rash, itching or hives.
- Swelling of the face, lips, tongue or other parts of the body.
- Shortness of breath, asthmatic breathing or difficulty in breathing.
Damage to red blood cells (not known)
Signs of such damage include:
- Wheezing at unexpected moments.
- Red or brown discoloration of the urine.
If you notice any of the above signs, consult a doctor immediately.
Other possible side effects:
Common (may affect up to 1 in 10 patients)
- Abdominal (stomach) pains.
- Feeling sick (nausea).
- Being sick (vomiting).
- Diarrhea.
- Headache.
- Rash, itchy skin.
- Pain and inflammation.
- Increase in the number of platelets in the blood (determined in a blood test).
- Changes in blood tests, including those showing liver function.
Uncommon (may affect up to 1 in 100 patients)
- Blood disorders, which include a decrease in the number of platelets (which can make bruising easier), an increase in the number of some white blood cells, a decrease in the number of other white cells and an increase in a substance called 'bilirubin'. Your doctor will have blood tests done periodically.
- Changes in blood tests, including tests that show how well your kidneys are working.
- Tingling sensation (pins and needles).
- Infections of the mouth or vagina caused by a fungus (candidiasis).
- Intestinal inflammation with diarrhea.
- Pain in the veins when Merrem is injected.
- Other blood disorders. Symptoms include frequent infections, high body temperature, and sore throat. Your doctor will have blood tests done periodically.
- Sudden onset of severe rash or blistering or peeling of the skin. These manifestations can be associated with high fever and joint pain.
Rare (may affect up to 1 in 1,000 patients)
- Seizures (convulsions).
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.
If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting system at https://www.aifa.gov.it/content/segnalazioni-reazioni-avversei.
By reporting side effects you can help provide more information on the safety of this medicine.
Expiry and Retention
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 after "EXP". The expiry date refers to the last day of the month. Do not store above 30 ° C.
Injection
After reconstitution: The reconstituted solutions for intravenous injection should be used immediately. The time interval between the start of reconstitution and the end of the intravenous injection should not exceed 3 hours when stored at controlled room temperature (15-25 ° C).
Infusion
After reconstitution: The reconstituted solutions for intravenous infusion should be used immediately. The time interval between the start of reconstitution and the end of the intravenous infusion should not exceed:
- 6 hours if stored at controlled room temperature (15-25 ° C) when Merrem is dissolved in sodium chloride;
- 24 hours if stored at 2-8 ° C when Merrem is dissolved in sodium chloride. In this case, the prepared solution should be used within 2 hours from the moment it is taken out of the refrigerator;
- 1 hour when Merrem is dissolved in glucose (dextrose).
Do not freeze the reconstituted solution.
From a microbiological point of view, unless the method of opening / reconstitution / dilution excludes 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.
Do not throw any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. This will help protect the environment.
What Merrem contains
The active ingredient is meropenem. Each vial contains 500 mg of anhydrous meropenem as meropenem trihydrate.
The active substance is meropenem. Each vial contains 1000 mg of anhydrous meropenem as meropenem trihydrate.
The other excipient is anhydrous sodium carbonate.
Description of what Merrem looks like and contents of the pack
- Merrem is a white to pale yellow powder for solution for injection or infusion in a bottle. Pack sizes of 1 (not commercially) or 10 vials.
Medical notice / instructions
Antibiotics are used to treat infections caused by bacteria. They are not effective against infections caused by viruses. Sometimes an infection caused by bacteria does not respond to a course of antibiotic therapy. One of the most common reasons this happens is because the bacteria causing the infection are resistant to the antibiotic you are taking. This means that they can survive. and even multiply despite the antibiotic Bacteria can become resistant to antibiotics for many reasons. Using antibiotics correctly can help reduce the chance of bacteria becoming resistant.
When your doctor prescribes a course of antibiotic therapy, it is intended for the treatment of the current illness only. Paying attention to the following tips will help you to prevent the onset of bacterial resistance that can stop the action of the antibiotic.
- It is very important that you take the right dose of antibiotic, at the right times and for the right number of days. Read the instructions on the leaflet and if you do not understand something ask your doctor or pharmacist for an explanation.
- You should not take the antibiotic unless it has been prescribed specifically for you and you should only use it to treat the infection for which it was prescribed.
- You must not take antibiotics that have been prescribed for other people even if they have an infection similar to yours.
- You must not give antibiotics that have been prescribed for you to other people.
- If you are left with antibiotics when you have finished the course of therapy that your doctor has ordered you should take them to a pharmacy for proper disposal.
The following information is intended for medical or healthcare professionals only:
Instructions for self-administration or administration of Merrem to others at home
Some patients, parents or caregivers have been trained to administer Merrem at home.
Warning - This medicine can be self-administered or given to other people at home only after having received appropriate training from a doctor or nurse.
How to prepare this medicine
- The medicine must be mixed with another liquid (the solvent). Your doctor will tell you how much solvent to use.
- Use the medicine immediately after preparation. Do not freeze.
- Wash and dry your hands very well. Prepare a "clean work area."
- Remove the Merrem container (vial) from the package. Check the vial and the expiration date. Check that the vial is intact and does not show any signs of damage.
- Remove the colored ferrule and clean the gray rubber stopper with alcohol. Allow the rubber stopper to dry.
- Insert a new sterile needle into a new sterile syringe, without touching the ends.
- Withdraw the recommended amount of sterile "Water for Injections" and pour it into the syringe. The amount of liquid required is indicated in the table below:
Note: If the prescribed dose of Merrem is greater than 1 g, you will need to use more than one vial of Merrem. He can then withdraw the liquid and pour it into a syringe.
- Insert the needle of the syringe into the center of the gray rubber of the vial and inject the recommended amount of water for injections into the Merrem vial or vials.
- Remove the needle from the vial and shake the vial well for about 5 seconds, or until the powder is dissolved. Clean the gray rubber stopper again with alcohol and let the rubber stopper dry.
- With the plunger of the syringe completely inside the syringe barrel, put the needle back onto the gray rubber top. You must hold the syringe and the vial in your hand at the same time, and turn the vial upside down.
- Keeping the tip of the needle immersed in the liquid, pull back the plunger of the syringe and withdraw all the liquid contained in the vial into the syringe.
- Remove the needle and syringe from the vial and discard the empty vial in a safe place.
- Hold the syringe straight, with the tip of the needle pointing upwards. Tap on the syringe, in order to make any air bubbles rise to the surface.
- Remove any air in the syringe by gently pushing the plunger until all the air is gone.
- If you are using Merrem at home, dispose of used needles and infusion lines appropriately. If your doctor decides to stop treatment, dispose of unused Merrem appropriately.
How to inject
This medicine can also be given through a small cannula or venflon, or through a port-type catheter or central infusion line.
Administration of Merrem via a small cannula or venflon (needle cannula)
- Remove the needle from the syringe and dispose of the needle carefully in a container for stinging materials.
- Rub the tip of the small cannula or venflon with alcohol and allow to dry. Open the cannula cap and connect it to the syringe.
- Slowly push the plunger of the syringe to administer the antibiotic steadily for approximately 5 minutes.
- Once you have finished administering the antibiotic and with the syringe empty, remove the syringe and wash the area as recommended by your doctor or nurse.
- Close the cannula cap and dispose of the syringe carefully in a container for stinging materials.
Administration of Merrem via a port-type catheter or central infusion line
- Remove the cap from the port or line, wipe the end of the line with alcohol and allow to dry.
- Connect the syringe and gently push the plunger into the syringe to administer the antibiotic steadily for approximately 5 minutes.
- Once you have finished administering the antibiotic, remove the syringe and wash the area as recommended by your doctor or nurse.
- Place a new, clean cap on the center infusion line and dispose of the syringe carefully in a pungent container.
Source Package Leaflet: AIFA (Italian Medicines Agency). Content published in January 2016. The information present may not be up-to-date.
To have access to the most up-to-date version, it is advisable to access the AIFA (Italian Medicines Agency) website. Disclaimer and useful information.
01.0 NAME OF THE MEDICINAL PRODUCT
MERREM POWDER FOR SOLUTION FOR INJECTION FOR INTRAVENOUS USE
02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION
Merrem 500 mg
Each vial contains meropenem trihydrate equivalent to 500 mg of anhydrous meropenem.
Merrem 1000 mg
Each vial contains meropenem trihydrate equivalent to 1000 mg anhydrous meropenem.
Excipients:
Each 500 mg vial contains 104 mg of sodium carbonate which corresponds to approximately 2.0 mEq of sodium (approximately 45 mg).
Each 1000 mg vial contains 208 mg of sodium carbonate which corresponds to approximately 4.0 mEq of sodium (approximately 90 mg).
For the full list of excipients, see section 6.1.
03.0 PHARMACEUTICAL FORM
Powder for solution for injection or infusion.
White to pale yellow powder.
04.0 CLINICAL INFORMATION
04.1 Therapeutic indications
Merrem 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):
• Severe pneumonia, including hospital-acquired pneumonia and ventilator-associated pneumonia
• Bronchopulmonary infections in cystic fibrosis
• Complicated urinary tract infections
• Complicated intra-abdominal infections
• Intra and postpartum infections
• Complicated skin and soft tissue infections
• Acute bacterial meningitis
Merrem can be used in the management of neutropenic patients with fever of suspected bacterial infection.
Treatment of patients with bacteraemia that occurs in association with, or appears to be associated with, any of the infections listed above.
Official guidelines on the appropriate use of antibacterial agents should be consulted.
04.2 Posology and method of administration
The tables below provide general dosing recommendations.
The dose of meropenem administered and the duration of treatment should take into account the type of infection to be treated, including severity and clinical response.
A dose of up to 2 g three times a day in adults and adolescents and a dose of up to 40 mg / kg three times a day in children may be particularly appropriate in the treatment of certain types of infections such as infections with insensitive bacterial species ( eg.Enterobacteriaceae, Pseudomonas aeruginosa, Acinetobacter spp) or very serious infections.
Additional dosing considerations are needed when treating patients with renal insufficiency (see further below).
Adults and adolescents
Meropenem is usually administered by intravenous infusion lasting approximately 15 to 30 minutes (see sections 6.2, 6.3 and 6.6).
Alternatively, doses up to 1 g can be administered as an intravenous bolus injection lasting 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.
Kidney failure
The dose in adults and adolescents should be adjusted when creatinine clearance is less than 51 ml / min as reported below. There are limited data to support the application of these dose adjustments for a unit dose of 2 g.
Meropenem is removed by hemodialysis and haemofiltration. The required dose should be administered after completion of the hemodialysis cycle.
There are no established dose recommendations for patients on peritoneal dialysis.
Hepatic insufficiency
No dose adjustment is necessary in patients with hepatic insufficiency (see section 4.4).
Dose in elderly patients
No dose adjustment is required in elderly patients with normal renal function or creatinine clearance values above 50 ml / min.
Pediatric 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 dosing 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 and with a body weight up to 50 kg
The recommended dosing regimen is shown in the table below:
Children over 50 kg in weight
The adult dose should be used.
There is no experience in children with renal insufficiency.
Meropenem is usually administered by intravenous infusion lasting approximately 15 to 30 minutes (see sections 6.2, 6.3 and 6.6). Alternatively, doses up to 20 mg / kg of meropenem can be administered as an intravenous bolus injection lasting 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.
04.3 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 reactions, severe skin reactions) to any other type of beta-lactam antibacterial agent (e.g. penicillins or cephalosporins).
04.4 Special warnings and appropriate precautions for use
The choice of meropenem to treat an individual patient must take into account the appropriateness of use of a bacterial carbapenem agent based on factors such as the severity of the infection, the prevalence of resistance to other appropriate antibacterial agents, and the risk of selection for the carbapenem-resistant bacteria.
Resistance to Enterobacteriaceae, Pseudomonas aeruginosa And Acinetobacter spp
Resistance to the penemes of Enterobacteriaceae, Pseudomonas aeruginosa And Acinetobacter spp. varies across the European Union. Physicians are advised to consider the local prevalence of resistance of these bacteria to penemas.
Hypersensitivity reactions
As with all beta-lactam antibiotics, serious and occasionally fatal hypersensitivity reactions have been reported (see sections 4.3 and 4.8).
Patients with a history of hypersensitivity to carbapenems, penicillins or other beta-lactam antibiotics may also be hypersensitive to meropenem. Before initiating therapy with meropenem, very careful research should be done regarding 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
Antibiotic-associated colitis and pseudomembranous colitis have been reported, as with all antibacterial agents, including meropenem, and can range in severity from moderate to life-threatening. Consequently, it is important to consider this diagnosis in patients who present with diarrhea during or following administration of meropenem (see section 4.8). The discontinuation of meropenem therapy and the administration of a specific treatment for the Clostridium difficile must be considered. Medicinal products that inhibit peristalsis should not be administered.
Convulsions
Convulsions have been reported infrequently during treatment with carbapenems (see section 4.8).
Monitoring of liver function
During treatment with meropenem, hepatic function should be closely monitored for 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 disease require careful monitoring of liver function during treatment with meropenem. No dose adjustment is necessary (see section 4.2).
Serum conversion to direct antiglobulin test (Coombs test)
A positive direct or indirect Coombs test may occur during treatment with meropenem.
Concomitant use of meropenem with valproic acid / sodium valproate / valpromide
The concomitant use of meropenem with valproic acid / sodium valproate / valpromide is not recommended (see section 4.5).
Merrem contains sodium.
Merrem 500 mg: This medicinal product contains approximately 2.0 mEq of sodium for the 500 mg dose which should be considered by patients on a controlled sodium diet.
Merrem 1000 mg: This medicinal product contains approximately 4.0 mEq of sodium for the 1.0 g dose which should be considered by patients on a controlled sodium diet.
04.5 Interactions with other medicinal products and other forms of interaction
No specific interaction studies with medicinal products have been performed, with the exception of probenecid. Probenecid competes with meropenem in active tubular secretion, thereby inhibiting the renal excretion of meropenem resulting in increased elimination half-life and plasma concentration. Caution is required if probenecid is co-administered with meropenem.
The potential effect of meropenem on the protein binding of other medicinal products or their metabolism has not been studied. However, the protein binding is so low that no interactions with other compounds are expected based on this mechanism.
Decreases in blood valproic acid levels have been reported when co-administered with carbapenem agents resulting in a 60-100% reduction in valproic acid levels in approximately two days. Due to the rapid onset and extent of the decrease, co-administration of valproic acid / sodium valproate / valpromide with carbapenem agents cannot be considered manageable and therefore should be avoided (see section 4.4).
Oral anticoagulants
Co-administration of antibiotics with warfarin may increase its anticoagulant effect. There are many reports of the "increased" anticoagulant effect of orally administered anticoagulants, including warfarin, in patients receiving concomitant antibacterial agents. The risk may vary with an "underlying infection, age and general status of the patient so that it is difficult to assess the contribution of the antibiotic to the increase in the INR" (International Normalized Ratio). It is recommended to check the INR frequently during and immediately after co-administration of antibiotics with an oral anticoagulant agent.
04.6 Pregnancy and lactation
Pregnancy
There are no or limited amount of data on the use of meropenem in pregnant women.
Animal studies do not indicate direct or indirect harmful effects related to reproductive toxicity (see section 5.3).
As a precautionary measure, it is preferable to avoid the use of meropenem during pregnancy.
Feeding time
It is not known whether meropenem is excreted in human milk. Meropenem is detectable at very low concentrations in breast-fed animals. 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.
04.7 Effects on ability to drive and use machines
No studies on the ability to drive and use machines have been performed.
04.8 Undesirable effects
Summary of the safety profile
In a review of 4,872 patients with 5,026 exposures to meropenem treatment, the most frequently reported meropenem-related adverse reactions were diarrhea (2.3%), rash (1.4%), nausea / vomiting (1.4%). and inflammation at the injection site (1.1%). The most common laboratory adverse events related to meropenem were thrombocytosis (1.6%) and elevated liver enzymes (1.5-4.3%).
Table containing the list of adverse reactions
In the table below, all adverse reactions are listed by organ and system class and frequency: very common (≥ 1/10); common (≥ 1/100 y
Table 1
Reporting of suspected adverse reactions
Reporting of suspected adverse reactions occurring after authorization of the medicinal product is important as it allows continuous monitoring of the benefit / risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system. "address https://www.aifa.gov.it/content/segnalazioni-reazioni-avverse.
04.9 Overdose
Relative overdose may be possible in patients with renal insufficiency if the dose is not adjusted as described in section 4.2. Limited post-marketing experience indicates that if adverse reactions occur after overdose, they fall within the adverse reaction profile described in section 4.8 and are generally mild in nature and resolve with dose interruption or reduction. symptomatic treatment.
In subjects with normal renal function, rapid renal elimination will occur.
Hemodialysis is able to remove meropenem and its metabolite.
05.0 PHARMACOLOGICAL PROPERTIES
05.1 Pharmacodynamic properties
Pharmacotherapeutic group: antibacterials for systemic use, carbapenems.
ATC code: J01DH02.
Mechanism of action
Meropenem exerts its bactericidal activity by inhibiting cell wall synthesis in Gram-positive and Gram-negative bacteria through binding to penicillin-binding proteins (PBPs).
Pharmacokinetic / pharmacodynamic relationship (PK / PD)
As with other beta-lactam antibacterial agents, the length of time meropenem concentration remains above the MIC (T> MIC) was shown to be better correlated with efficacy. In preclinical models meropenem showed activity when plasma concentrations exceeded the MIC of the infecting organism for approximately 40% of the dose interval. This has not been clinically established.
Resistance mechanism
Bacterial resistance to meropenem can result from:
decreased permeability of the outer membrane of Gram-negative bacteria (due to a decrease in the production of porins),
reduced affinity for target PBPs,
increased expression of efflux pump components, e
production of beta-lactamases which can hydrolyze carbapenems.
Localized strains of infections due to carbapenem-resistant bacteria have been reported in the European Union.
There is no cross-resistance at the target site between meropenem and agents such as quinolones, aminoglycosides, macrolides and classes of tetracyclines. However, bacteria may show resistance to one or more classes of antibacterial agents when the mechanism involved includes impermeability and / or one (s) of efflux pumps.
Breakpoints
The European Committee on Antimicrobial Susceptibility Testing (EUCAST) clinical breakpoints for MIC measurement are presented below.
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. If necessary, when local spread of resistance is such that the drug's utility in certain types of infections is questionable, an expert should be consulted.
The following table of listed pathogens is taken from clinical experience and therapeutic guidelines.
Glanders and myyloidosis: The use of meropenem in humans is based on in vitro susceptibility data from B. mallei and B. pseudomallei and limited human data. Physicians should refer to national and / or international consensus documents regarding the treatment of glanders and myloidosis.
05.2 Pharmacokinetic properties
Absorption
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 with 250 mg decreasing at 205 ml / min with 2 g.Doses of 500, 1000 and 2000 mg infused in 30 minutes determine average Cmax values of approximately 23, 49 and 115 mcg / ml respectively; the corresponding AUC values were 39.3, 62.3 and 153 mcg.h / ml. After a 5-minute infusion, Cmax values are 52 and 112 mcg / ml after doses of 500 and 1000 mg, respectively. In subjects with normal renal function, multiple doses administered at 8 hour intervals did not result in accumulation of meropenem.
A study in 12 patients post-surgically treated with 1000 mg of meropenem at 8 hour intervals for intra-abdominal infections showed comparable Cmax and half-life to those of normal subjects, but a volume of distribution greater than 27l.
Distribution
The mean plasma protein binding of meropenem is approximately 2% and is independent of concentration. After rapid administration (5 minutes or less) the pharmacokinetics are bi-exponential, but this is much less evident after 30 minutes of infusion. Meropenem has been shown to have good penetration into most body fluids and tissues, including lungs, bronchial secretions, bile, cerebrospinal fluid, gynecological tissues, skin, fascia, muscles and peritoneal exudates.
Metabolism
Meropenem is metabolised by hydrolysis of the beta-lactam ring which generates a microbiologically inactive metabolite. In vitro meropenem exhibits reduced sensitivity to human dihydropeptidase-I (DHP-I) hydrolysis compared to imipenem and there is no need for co-administration of a DHP-I inhibitor.
Elimination
Meropenem is mainly excreted unchanged by the kidneys; about 70% (50 - 75%) of the dose is excreted unchanged over 12 hours. A further 28% is found as a microbiologically inactive metabolite. Faecal elimination accounts for only about 2% of the administered dose. The measured renal clearance and the effect of probenecid show that meropenem is subject to both filtration and tubular secretion.
Kidney failure
Renal impairment results in higher plasma AUC values and a prolonged half-life for meropenem. There were 2.4-fold increases in AUC in patients with moderate renal impairment (CrCL 33-74 mL / min), 5-fold in severe impairment (CrCL 4-23 mL / min), and 10-fold in hemodialysis patients. (CrCL 80 mL / min) The AUC of microbiologically inactive open-loop metabolites is also significantly increased in patients with impaired renal function. Dose adjustment is recommended in patients with moderate to severe renal impairment (see section 4.2).
Meropenem is removed from the circulation by hemodialysis, with a clearance during hemodialysis approximately 4 times greater than in anuric patients.
Hepatic insufficiency
A study in patients with alcoholic cirrhosis showed no liver disease-related effects on the pharmacokinetics of meropenem after repeat dosing.
Adult patients
Pharmacokinetic studies performed in patients did not show significant pharmacokinetic differences compared to healthy subjects with equivalent renal function. A population model, developed from data from 79 patients with intra-abdominal infection or pneumonia, showed a central volume dependence on weight, creatinine clearance and age.
Pediatric patients
Pharmacokinetics in infants and children with infections at doses of 10, 20 and 40 mg / kg showed Cmax values close to those recorded in adults after doses of 500, 1000 and 2000 mg, respectively. The comparison showed consistent pharmacokinetics between doses and half-lives similar to that observed in adults in all subjects except the youngest (12-hour urine as meropenem, while an additional 12% as metabolite. meropenem in the cerebrospinal fluid of children with meningitis are approximately 20% of the concomitant plasma levels, although there is significant interindividual variability.
The pharmacokinetics of meropenem in infants requiring anti-infective treatment showed higher clearance in infants with a greater chronological or gestational age, with a mean total half-life of 2.9 hours. Monte Carlo simulation based on a population pharmacokinetic model showed that a dosing regimen of 20 mg / kg at 8 hour intervals achieved 60% T> MIC for P. aeruginosa in 95% of preterm infants and 91% of full term infants.
Senior citizens
Pharmacokinetic studies in healthy elderly subjects (65-80 years) have shown a reduction in plasma clearance, related to the age-associated reduction in creatinine clearance, and with a minor reduction for non-renal clearance. No adjustment of the plasma is required. dose in elderly patients except in moderate to severe renal impairment (see section 4.2).
05.3 Preclinical safety data
Animal studies indicate that meropenem is well tolerated by the kidney. Histological evidence of renal tubular damage was observed only in mice and dogs at doses of 2000 mg / kg or more after a single administration and beyond and in monkeys. to 500 mg / kg in a 7-day study.
Meropenem is generally well tolerated in the central nervous system. Effects were observed in acute toxicity studies in rodents at doses above 1000 mg / kg.
The LD50 of intravenous meropenem in rodents is greater than 2000 mg / kg.
In repeated dose toxicity studies up to 6 months only minor effects were observed, including a decrease in red blood cell parameters in dogs.
There was no evidence of mutagenic potential in a battery of conventional tests and of reproductive and teratogenic toxicity in rat studies up to 750 mg / kg and in monkeys up to 360 mg / kg.
An increase in miscarriages was found in a preliminary study in monkeys at a dose of 500 mg / kg.
There was no evidence of increased sensitivity to meropenem in juvenile compared to adult animals. The intravenous formulation was well tolerated in animal studies.
The unique metabolite of meropenem showed a similar toxicity profile in animal studies.
06.0 PHARMACEUTICAL INFORMATION
06.1 Excipients
Merrem 500 mg: anhydrous sodium carbonate.
Merrem 1000 mg: anhydrous sodium carbonate.
06.2 Incompatibility
This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.
06.3 Period of validity
4 years.
After reconstitution:
Administration by intravenous bolus injection
A bolus injection solution is prepared by dissolving the drug in water for injection to a final concentration of 50 mg / ml.
Chemical and physical stability in use of a solution prepared for bolus injection has been demonstrated for 3 hours up to 25 ° C or 12 hours in a refrigerator (2 - 8 ° C).
From a microbiological point of view, unless the method of opening / reconstitution / dilution excludes 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.
Administration by intravenous infusion
A solution for infusion is prepared by dissolving the drug in 0.9% sodium chloride solution for infusion or 5% dextrose solution for infusion to a final concentration of 1 to 20 mg / ml.
Chemical and physical in-use stability of a solution prepared for infusion using 0.9% sodium chloride solution has been demonstrated for 3 hours up to 25 ° C or 24 hours in a refrigerator (2 - 8 ° C).
From a microbiological point of view, unless the method of opening / reconstitution / dilution excludes 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.
The reconstituted solution of the product in 5% dextrose solution should be used immediately.
Reconstituted solutions should not be frozen.
06.4 Special precautions for storage
Do not store above 30 ° C.
Do not freeze the reconstituted solution.
06.5 Nature of the immediate packaging and contents of the package
Merrem 500 mg
674 mg of powder in a 20 ml type I glass vial with a stopper (gray halobutyl rubber with aluminum cap).
Merrem 1000 mg
1348 mg powder in a 30 ml type I glass vial with a stopper (gray halobutyl rubber with aluminum cap).
This medicine is available in packs of 1 or 10 vials.
Not all pack sizes may be marketed.
06.6 Instructions for use and handling
Injection
Meropenem for intravenous bolus use must be reconstituted with sterile water for injections.
Infusion
For intravenous infusion meropenem vials can be directly reconstituted with 0.9% sodium chloride or 5% dextrose solution for infusion.
Each vial is for single use only.
Standard aseptic techniques should be employed for preparation of the solution and administration.
The solution must be shaken before use.
Unused medicine and waste derived from this medicine must be disposed of in accordance with local regulations.
07.0 MARKETING AUTHORIZATION HOLDER
AstraZeneca S.p.A.
Ferraris Palace
Via Ludovico il Moro 6 / C
Basiglio (MI) 20080
Italy
08.0 MARKETING AUTHORIZATION NUMBER
Merrem 500 mg powder for solution for injection for intravenous use 10 vials 500 mg - AIC 028949081
Merrem 1 g powder for solution for injection for intravenous use 10 vials 1000 mg - AIC 028949093
09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION
GU n. 202 of 31.08.2001 - Renewal: October 2014
10.0 DATE OF REVISION OF THE TEXT
19 September 2015
