Meronem

Meropenem trihydrate.

Meropenem (MERONEM) IV is presented as a sterile white powder containing meropenem; 500 mg or 1 g as the trihydrate blended with anhydrous sodium carbonate for reconstitution. Meropenem (MERONEM) IV injection contains 208 mg sodium carbonate for each gram of meropenem (anhydrous potency). (See Table 1.)

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Excipients/Inactive Ingredients: Meropenem (MERONEM) IV includes the excipient anhydrous sodium carbonate.

Pharmacotherapeutic group: Antibacterials for systemic use, carbapenems. ATC Code: J01DH02.
Pharmacology: Pharmacodynamics: Meropenem is a carbapenem antibiotic for parenteral use, that is stable to human dehydropeptidase-I (DHP-I). It is structurally similar to imipenem.
Mechanism of action: Meropenem exerts its bactericidal action by interfering with bacterial cell wall synthesis. The ease with which it penetrates bacterial cells, its high level of stability to most serine β-lactamases and its high affinity for multiple Penicillin Binding Proteins (PBPs) explain the potent bactericidal activity of meropenem against a broad spectrum of aerobic and anaerobic bacteria. The bactericidal concentrations are generally within one doubling dilution of the minimum inhibitory concentrations (MICs).
Meropenem is stable in susceptibility tests and these tests can be performed using the normal routine systems. In vitro tests show that meropenem can act synergistically with various antibiotics. It has been demonstrated both in vitro and in vivo that meropenem has a post-antibiotic effect against Gram-positive and Gram-negative organisms.
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.
Mechanisms of resistance: Bacterial resistance to meropenem may result from one or more factors: (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 β-lactamases that can hydrolyse carbapenems.
Localised clusters of infections due to carbapenem-resistant bacteria have been reported in some regions.
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 antibacterial 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 as follows. (See Table 2.)

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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.
Antibacterial spectrum: The susceptibility to meropenem of a given clinical isolate should be determined by standard methods. Interpretations of test results should be made in accordance with local infectious diseases and clinical microbiology guidelines.
The antibacterial spectrum of meropenem includes the following species, based on clinical experience and therapeutic guidelines.
Commonly susceptible species: Gram-positive aerobes: Enterococcus faecalis (note that E. faecalis can naturally display intermediate susceptibility), Staphylococcus aureus (methicillin-susceptible strains only: methicillin-resistant staphylococci including MRSA are resistant to meropenem), Staphylococcus species including Staphylococcus epidermidis (methicillin-susceptible strains only: methicillin-resistant staphylococci including MRSE are resistant to meropenem), Streptococcus agalactiae (Group B streptococcus), Streptococcus milleri group (S. anginosus, S. constellatus, and S. intermedius), Streptococcus pneumoniae, Streptococcus pyogenes (Group A streptococcus).
Commonly susceptible species: Gram-negative aerobes: Citrobacter freundii, Citrobacter koseri, Enterobacter aerogenes, Enterobacter cloacae, Escherichia coli, Haemophilus influenzae, Klebsiella oxytoca, Klebsiella pneumoniae, Morganella morganii, Neisseria meningitidis, Proteus mirabilis, Proteus vulgaris, Serratia marcescens.
Commonly susceptible species: Gram-positive anaerobes: Clostridium perfringens, Peptoniphilus asaccharolyticus, Peptostreptococcus species (including P. micros, P anaerobius, P. magnus).
Commonly susceptible species: Gram-negative anaerobes: Bacteroides caccae, Bacteroides fragilis, Prevotella bivia, Prevotella disiens.
Species for which acquired resistance may be a problem: Gram-positive aerobes: Enterococcus faecium (E. faecium can naturally display intermediate susceptibility even without acquired resistance mechanisms.
Species for which acquired resistance may be a problem: Gram-negative aerobes: Acinetobacter species, Burkholderia cepacia, Pseudomonas aeruginosa.
Inherently resistant organisms: Gram-negative aerobes: Stenotrophomonas maltophilia, Legionella species.
Other inherently resistant organisms: Chlamydophila pneumoniae, Chlamydophila psittaci, Coxiella burnetii, Mycoplasma pneumoniae.
The published medical microbiology literature describes in-vitro meropenem-susceptibilities of many other bacterial species. However the clinical significance of such in-vitro findings is uncertain. Advice on the clinical significance of in-vitro findings should be obtained from local infectious diseases and clinical microbiology experts and local professional guidelines.
Meropenem is active in vitro against many strains resistant to other β-lactam antibiotics. This is explained in part by enhanced stability to β-lactamases. Activity in vitro against strains resistant to unrelated classes of antibiotics such as aminoglycosides or quinolones is common.
Pharmacokinetics: In healthy subjects the mean plasma half-life is approximately 1 hour; the mean volume of distribution is approximately 0.25 l/kg and the mean clearance is 239 mL/min at 500 mg falling to 205 mL/min at 2 g. Doses of 500, 1000 and 2000 mg doses infused over 30 minutes give mean Cmax values of approximately 23, 49 and 115 μg/mL respectively, corresponding AUC values were 39.3, 62.3 and 153 μg.h/mL. After infusion over 5 minutes Cmax values are 52 and 112 μg/mL after 500 and 1000 mg 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 1000 mg 8 hourly post-surgically for intra-abdominal 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. 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 β-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 Dosage & Administration).
Meropenem is cleared by haemodialysis with clearance during haemodialysis being approximately 4 times higher that in anuric patients.
Hepatic Insufficiency: A study in patients with alcoholic cirrhosis has shown 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 Cmax values approximating to those in adults following 500, 1000 and 2000 mg doses, respectively. Comparison showed consistent pharmacokinetics between the doses and half-lives similar to those observed in adults in all but the youngest subjects (<6 months t½ 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 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 2.9 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 Dosage & Administration).
Toxicology: 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 2000 mg/Kg and above.
Meropenem is generally well tolerated by the CNS. Effects were seen only at very high doses of 2000 mg/kg and above.
The i.v. LD₅₀ of meropenem in rodents is greater that 2000 mg/kg. In repeat dose studies of up to 6 months duration only minor effects were seen including a small decrease in red cell parameters and an increase in liver weight in dogs at 500 mg/kg.
There was no evidence of mutagenic potential in the 5 tests conducted and no evidence of reproductive toxicity including teratogenic potential in studies at the highest possible level in rats and monkeys. (The no effect dose level of a small reduction in F1 body weight in rat was 120 mg/kg.).
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 intramuscular formulation caused reversible injection site necrosis.
The sole metabolite of meropenem had a similar low profile of toxicity in animal studies.

Meropenem (MERONEM) IV is indicated for treatment of the following infections caused by single or multiple susceptible bacteria and as empiric therapy prior to the identification of the causative organisms: Meropenem (MERONEM) IV: (Adults and children): Lower respiratory tract infections; Urinary tract infections including complicated infections; Intra-abdominal infections; Gynaecological infections including postpartum infections; Skin and skin structure infections; Septicaemia; Meningitis.
Empiric treatment including initial monotherapy for presumed bacterial infections in host-compromised neutropenic patients.
Polymicrobial Infections: because of its broad spectrum of bactericidal activity against Gram-positive and Gram-negative aerobic and anaerobic bacteria, meropenem is effective for the polymicrobial infections.
Intravenous meropenem has been used effectively in patients with cystic fibrosis and chronic lower respiratory tract infections, either as monotherapy or in combination with other antibacterial agents. Eradication of the organism was not always established.

Adults: The dosage range is 1.5 g to 6 g daily in three divided doses.
Usual dose: 500 mg to 1 g by intravenous administration every 8 hours depending on the type and severity of infection, the known or expected susceptibility of the pathogen(s), and the condition of the patient.
Exceptions: Febrile episodes in neutropenic patients: the dose should be 1 g every 8 hours.
Meningitis/Cystic Fibrosis: the dose should be 2 g every 8 hours.
When treating infections known or suspected to be caused by Pseudomonas aeruginosa, a dose of at least 1 g every 8 hours in adults (maximum approved dose is 6 g daily given in 3 divided doses) and a dose of at least 20 mg/kg every 8 hours in children (maximum approved dose is 120 mg/kg daily given in 3 divided doses) are recommended.
Regular sensitivity testing is recommended when treating Pseudomonas aeruginosa infections.
Meropenem (MERONEM) IV should be given as an intravenous bolus injection over approximately 5 minutes or by intravenous infusion over approximately 15 to 30 minutes (see Incompatibilities under Cautions for Usage and Storage for the reconstitution details). There is limited safety data available to support the administration of a 2g bolus dose.
Dosage Schedule for Adults with Impaired Renal Function: Dosage should be reduced in patients with creatinine clearance less than 51 mL/min, as scheduled as follows. (See Table 3.)

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Meropenem (MERONEM) IV is cleared by haemodialysis and haemofiltration; if continued treatment with Meropenem (MERONEM) IV is necessary, the unit dose based on the infection type and severity is recommended at the completion of the haemodialysis procedure to re-institute effective treatment.
There is no experience with peritoneal dialysis.
Use in Adults with Hepatic Insufficiency: No dosage adjustment is necessary in patients with hepatic impairment.
Elderly: No dosage adjustment is required for the elderly with normal renal function or creatinine clearance values above 50 mL/min.
Children: For infants and children over 3 months and up to 12 years of age the IV dose is 10 to 40 mg/kg every 8 hours depending on type and severity of infection, the known or suspected susceptibility of the pathogen(s), and the condition of the patient. In children over 50 kg weight, adult dosage should be used.
Exceptions: Febrile episodes in neutropenic patients: the dose should be 20 mg/kg every 8 hours.
Meningitis/Cystic Fibrosis: the dose should be 40 mg/kg every 8 hours.
Meropenem (MERONEM) IV should be given as an IV bolus over approximately 5 min or by intravenous infusion over approximately 15 to 30 minutes (see Incompatibilities under Cautions for Usage and Storage for the reconstitution details). There is limited safety data available to support the administration of a 40 mg/kg bolus dose.
There is no experience in children with renal impairment.
Method of Administration: Reconstitution and Compatibility: Meropenem (MERONEM) IV to be used for bolus intravenous injection should be reconstituted with sterile water for injection (10 mL for each 500 mg). This provides an approximate available concentration of 50 mg/mL. Reconstituted solutions are clear or pale yellow.
For intravenous infusion Meropenem (MERONEM) IV vials may be directly reconstituted with a compatible infusion fluid (as listed in Storage) and then further diluted with the compatible infusion fluid, as needed.
Freshly prepared solutions of Meropenem (MERONEM) IV should be used whenever possible. However, reconstituted solutions of Meropenem (MERONEM) IV maintain satisfactory potency at room temperature (15-25 degrees C) or under refrigeration (4 degrees C) as shown in Storage.
Meropenem (MERONEM) IV should not be mixed with or physically added to solutions containing other drugs.
Solutions of Meropenem (MERONEM) IV should not be frozen.

Intentional overdosing of Meropenem (MERONEM) IV is unlikely, although overdosing could occur particularly in patients with renal impairment. Limited post-marketing experience indicates that if adverse events occur following over dosage, they are consistent with the adverse event profile described in Adverse Reactions, are generally mild in severity and resolve on withdrawal or dose reduction. Symptomatic treatments should be considered.
In normal individuals rapid renal elimination will occur.
Haemodialysis will remove Meropenem (MERONEM) IV and its metabolite.

Meropenem (MERONEM) IV is contraindicated in patients who have demonstrated hypersensitivity to this product.

Patients who have a history of hypersensitivity to carbapenems, penicillins or other β-lactam antibiotics may also be hypersensitive to Meropenem (MERONEM) IV. As with all β-lactam antibiotics rare hypersensitivity reactions (serious and occasionally fatal) have been reported (see Adverse Reactions).
Severe cutaneous adverse reactions (SCAR), such as Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS), erythema multiforme (EM) and acute generalised exanthematous pustulosis (AGEP) have been reported in patients receiving Meropenem (MERONEM) IV (see Adverse Reactions). If signs and symptoms suggestive of these reactions appear, meropenem should be withdrawn immediately and an alternative treatment should be considered.
As with other antibiotics, overgrowth of non-susceptible organisms may occur and repeated evaluation of each patient is necessary. Rarely, pseudomembranous colitis has been reported on Meropenem (MERONEM) IV as with virtually all antibiotics; therefore, its diagnosis should be considered in patients who develop diarrhoea in association with the use of Meropenem (MERONEM) IV.
The concomitant use of valproic acid/sodium valproate and Meropenem (MERONEM) IV is not recommended. Meropenem (MERONEM) IV may reduce serum valproic acid levels. Subtherapeutic levels may be reached in some patients (see Interactions).
Effects on ability to drive and use machines: No studies on the ability to drive and use machines have been performed. However when driving or operating machines, it should be taken into account that headache, paraesthesia, and convulsions have been reported for Meropenem (MERONEM) IV.
Use in patients with renal insufficiency: Refer to dosage recommendations for Meropenem (MERONEM) IV.
Use in patients with liver disease: Patients with pre-existing liver disorders should have liver function monitored during treatment with Meropenem (MERONEM) IV.A positive direct or indirect Coombs test may develop.
Use in Children: Efficacy and tolerability in infants under 3 months old have not been established; therefore, Meropenem (MERONEM) IV is not recommended for use below this age.

Pregnancy: The safety of Meropenem (MERONEM) IV in human pregnancy has not been established, although animal studies have not shown an adverse effect on the developing foetus. Meropenem (MERONEM) should not be used in pregnancy unless the potential benefit justifies the potential risk to the foetus.
Lactation: Meropenem has been reported to be excreted in human milk. Meropenem (MERONEM) IV should not be used in breast-feeding women unless the potential benefit justifies the potential risk to the baby.

Meropenem (MERONEM) IV is generally well tolerated. Adverse reactions rarely lead to cessation of treatment. Serious adverse reactions are rare.
The following adverse reactions have been identified following clinical studies with Meropenem (MERONEM) IV. Their frequency is presented in Table 4 Frequency of Adverse Reactions (data derived from clinical trial data sources) using CIOMS III frequency classification and then listed by MedDRA SOC and at the preferred level. Frequencies of occurrence of undesirable effects are defined as: very common (≥1/10; ≥10%); common (≥1/100 to <1/10; ≥1% to <10%); uncommon (≥1/1,000 to <1/100; ≥0.1% to <1%); rare (≥1/10,000 to <1/1,000; ≥0.01% to <0.1%); very rare (<1/10,000; <0.01%). (See Table 4.)

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The following adverse reactions have been identified from post-marketing clinical trials and spontaneous reports. Their frequency is presented in Table 5: Reporting Rate of Adverse Reactions (data derived from a combination of post-marketing clinical trial and spontaneous sources) using CIOMS III frequency classification and then listed by MedDRA SOC and at the preferred level. Frequencies of occurrence of undesirable effects are defined as: very common (≥1/10; ≥10%); common (≥1/100 to <1/10; ≥1% to <10%); uncommon (≥1/1,000 to <1/100; ≥0.1% to <1%); rare (≥1/10,000 to <1/1,000; ≥0.01% to <0.1%); very rare (<1/10,000; <0.01%); not known (cannot be estimated from the available data). (See Table 5.)

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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. As the potency and duration of action of Meropenem (MERONEM) IV dosed without probenecid are adequate the co-administration of probenecid with Meropenem (MERONEM) IV is not recommended. The potential effect of Meropenem (MERONEM) IV on the protein binding of other drugs 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 Meropenem (MERONEM) IV in patients stabilised on valproic acid is not considered to be manageable and therefore should be avoided (see Precautions).
Meropenem (MERONEM) IV has been administered concomitantly with many other medications without apparent adverse interaction. However, no specific drug interaction studies other than probenecid were conducted.

Incompatibilities: Meropenem (MERONEM) IV is compatible with the infusion fluids listed in Storage.
Meropenem (MERONEM) IV should not be mixed with or physically added to solutions containing other drugs.
Instructions for use, handling and disposal: Refer to Incompatibilities previously and Storage as follows. Shake the reconstituted solution before use.
All vials are for single use only.
Standard aseptic technique should be employed during reconstitution and administration.

Store at a temperature not exceeding 30°C.
Do not freeze.
A solution for bolus injection is prepared by dissolving the drug product Meropenem (MERONEM) IV in water for injection to a final concentration of 50 mg/mL. Chemical and physical in-use stability for a prepared solution for bolus injection has been demonstrated for 3 hours at up to 25°C or 16 hours under refrigerated conditions (2-8ºC).
A solution for infusion is prepared by dissolving the drug product Meropenem (MERONEM) IV in either 0.9% sodium chloride solution for infusion or 5% glucose (dextrose) solution for infusion to a final concentration of 1 to 20 mg/mL. Chemical and physical in-use stability for a prepared solution for infusion using 0.9% sodium chloride solution has been demonstrated for 3 hours at up to 25°C or 24 hours under refrigerated conditions (2-8ºC). Reconstituted solutions of Meropenem (MERONEM) IV in 5% glucose (dextrose) solution should be used immediately.
The reconstituted solutions should not be frozen.
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.

Other Beta-Lactams

J01DH02 - meropenem ; Belongs to the class of carbapenems. Used in the systemic treatment of infections.

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