Data Sheet

Merrem IV

Meropenem, as the trihydrate.

Presentation

MERREM IV powder for intravenous injection or infusion is presented as a sterile white powder containing meropenem trihydrate equivalent to meropenem, 500 mg or 1 g, blended with sodium carbonate anhydrous for constitution. MERREM IV powder for intravenous injection or infusion contains 208 mg sodium carbonate anhydrous for each gram of meropenem (anhydrous potency).

Uses

Actions

Meropenem is a carbapenem antibiotic for parenteral use, that is stable to human dehydropeptidase-I (DHP-I). It is structurally similar to imipenem.

Meropenem exerts its bactericidal action by interfering with vital bacterial cell wall synthesis. The ease with which it penetrates bacterial cells, its high level of stability to all serine β-lactamases and its marked affinity for the 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.

A single set of meropenem susceptibility criteria are recommended based on pharmacokinetics and correlation of clinical and microbiological outcomes with zone diameter and minimum inhibitory concentrations (MIC) of the infection organisms.

The in vitro antibacterial spectrum of meropenem includes the majority of clinically significant Gram-positive and Gram-negative, aerobic and anaerobic strains of bacteria, as shown below:

Gram-positive aerobes

Bacillus spp., Corynebacterium diphtheriae, Enterococcus faecalis, Enterococcus liquifaciens, Enterococcus avium, Erysipelothrix rhusiopathiae, Listeria monocytogenes, Lactobacillus spp., Nocardia asteroides, Staphylococcus aureus (penicillinase negative and positive), Staphylococci (coagulase-negative); including Staphylococcus epidermidis, Staphylococcus saprophyticus, Staphylococcus capitis, Staphylococcus cohnii, Staphylococcus xylosus, Staphylococcus warneri, Staphylococcus hominis, Staphylococcus simulans, Staphylococcus intermedius, Staphylococcus sciuri, Staphylococcus lugdunensis, Streptococcus pneumoniae (penicillin susceptible and resistant), Streptococcus agalactiae, Streptococcus pyogenes, Streptococcus equi, Streptococcus bovis, Streptococcus mitis, Streptococcus mitior, Streptococcus milleri, Streptococcus sanguis, Streptococcus viridans, Streptococcus salivarius, Streptococcus morbillorum, Streptococcus cremoris, Streptococcus Group G, Streptococcus Group F, Rhodococcus equi.

Gram-negative aerobes

Achromobacter xylosoxidans, Acinetobacter anitratus, Acinetobacter lwoffii, Acinetobacter baumanii, Acinetobacter junii, Acinetobacter haemolyticus, Aeromonas hydrophilia, Aeromonas sorbria, Aeromonas caviae, Alcaligenes faecalis, Bordetella bronchiseptica, Brucella melitensis, Campylobacter coli, Campylobacter jejuni, Citrobacter freundii, Citrobacter diversus, Citrobacter koseri, Citrobacter amalonaticus, Enterobacter aerogenes, Enterobacter cloacae, Enterobacter sakazakii, Escherichia coli, Enterobacter (Pantoea) agglomerans, Escherichia hermannii, Gardnerella vaginalis, Haemophilus influenzae (including beta-lactamase positive and ampicillin-resistant strains), Haemophilus parainfluenzea, Haemophilus ducreyi, Helicobacter pylori, Neisseria meningitidis, Neisseria gonorrhoeae (including beta-lactamase positive, penicillin-resistant and spectinomycin-resistant strains), Hafnia alvei, Klebsiella pneumoniae, Klebsiella aerogenes, Klebsiella ozaenae, Klebsiella oxytoca, Moraxella (Branhamella) catarrhalis, Morganella morganii, Proteus mirabilis, Proteus vulgaris, Proteus penneri, Providencia rettgeri, Providencia stuartii, Providencia alcalifaciens, Pasteurella multocida, Plesiomonas shigelloides, Pseudomonas aeruginosa, Pseudomonas putida, Pseudomonas alcaligenes, Burkholderia (Pseudomonas) cepacia, Pseudomonas fluorescens, Pseudomonas stutzeri, Pseudomonas pickettii, Pseudomonas pseudomallei, Pseudomonas acidovorans, Salmonella spp. including Salmonella enteritidis/typhi, Serratia marcescens, Serratia liquefaciens, Serratia rubidaea, Shigella sonnei, Shigella flexneri, Shigella boydii, Shigella dysenteriae, Vibrio cholerae, Vibrio parahaemolyticus, Vibrio vulnificus, Yersinia enterocolitica.

Anaerobic bacteria

Actinomyces odontolyticus, Actinomyces meyeri, Actinomyces israelii, Bacteroides-Prevotella- Porphyromonas spp., Bacteroides fragilis, Bacteroides vulgatus, Bacteroides variabilis, Bacteroides pneumosintes, Bacteroides coagulans, Bacteroides uniformis, Bacteroides distasonis, Bacteroides ovatus, Bacteriodes thetaiotaomicron, Bacteriodes eggerthii, Bacteroides capsillosis, Bacteroides gracilis, Bacteroides levii, Bacteroides caccae, Bacteroides ureolyticus, Prevotella buccalis, Prevotella melaninogenica, Prevotella intermedia, Prevotella bivia, Prevotella corporis, Prevotella splanchnicus, Prevotella oralis, Prevotella disiens, Prevotella rumenicola, Prevotella oris, Prevotella buccae, Prevotella denticola, Porphyromonas asaccharolytica, Porphyromonas gingivalis, Bifidobacterium spp., Bilophila wadsworthia, Clostridium perfringens, Clostridium bifermentans, Clostridium ramosum, Clostridium sporogenes, Clostridium cadaveris, Clostridium difficile, Clostridium sordellii, Clostridium butyricum, Clostridium clostridiiformis, Clostridium innocuum, Clostridium subterminale, Clostridium tertium, Eubacterium lentum, Eubacterium aerofaciens, Fusobacterium mortiferum, Fusobacterium necrophorum, Fusobacterium nucleatum, Fusobacterium varium, Mobiluncus curtisii, Mobiluncus mulieris, Peptostreptococcus anaerobius, Peptostreptococcus micros, Peptostreptococcus saccharolyticus, Peptococcus saccharolyticus, Peptostreptococcus asaccharolyticus, Peptostreptococcus magnus, Peptostreptococcus prevotii, Propionibacterium acnes, Propionibacterium avidum, Propionibacterium granulosum, Veillonella parvula, Wolinella recta.

A comparision of the percentage of bacterial isolates fully susceptable to meropenem at 4 mg/L and at 8 mg/L (Table 1) at Dec 1993 and since then up to July 1998 shows that there have been no significant alterations in the activity of meropenem over this time period.

Table 1: Susceptibility data for meropenem judged by % of strains inhibited by 4 mg/L and 8 mg/L of meropenem at Dec 1993 and since then up to 1998.

* % susceptible

MS: methicillin-susceptible, PS: penicillin-susceptible, PR: penicillin-resistant

Meropenem and imipenem have a similar profile of clinical utility and activity against multi-resistant bacteria. However, meropenem is intrinsically more potent against Pseudomonas aeruginosa and may be active in vitro against imipenem-resistant strains.

Meropenem is active in vitro against many strains resistant to other beta-lactam antibiotics. This is explained in part by enhanced stability to beta-lactamases. Activity in vitro against strains resistant to unrelated classess of antibiotics such as aminoglycosides or quinolones is commonplace.

Enterococcus faecium, Stenotrophomonas (Xanthomonas) maltophilia and methicillin-resistant staphylococci have been found to be generally resistant to meropenem.

Pharmacokinetics

A 30 minute intravenous infusion of a single dose of MERREM in normal volunteers results in peak plasma levels of approximately 23 µg/mL for the 500 mg dose, 49 µg/mL for the 1 g dose and 115 µg/mL following the 2 g dose.

A 5 minute intravenous bolus injection of MERREM in normal volunteers results in peak plasma levels of approximately 52 µg/mL for the 500 mg dose and 112 µg/mL for the 1 g dose.

Intravenous infusions of 1 g of MERREM over 2 minutes, 3 minutes and 5 minutes were compared in a three-way crossover trial. These durations of infusion resulted in peak plasma levels of 110, 91 and 94 µg/mL, respectively.

After an intravenous dose of 500 mg, plasma levels of meropenem decline to values of 1 µg/mL or less, 6 hours after administration.

When multiple doses are administered at 8 hourly intervals to subjects with normal renal function, accumulation of meropenem does not occur.

In subjects with normal renal function, meropenem's elimination half-life is approximately one hour.

Plasma protein binding of meropenem is approximately 2%.

Approximately 70% of the intravenous administered dose is recovered as unchanged meropenem in the urine over 12 hours, after which little further urinary excretion is detectable. Urinary concentrations of meropenem in excess of 10 µg/mL are maintained for up to 5 hours at the 500 mg dose. No accumulation of meropenem in plasma or urine was observed with regimens using 500 mg administered every 8 hours or 1 g administered every 6 hours in volunteers with normal renal function.

The only metabolite of meropenem is microbiologically inactive.

Meropenem penetrates well into most body fluids and tissues including cerebrospinal fluid of patients with bacterial meningitis, achieving concentrations in excess of those required to inhibit most bacteria.

Studies in infants and children have shown that the pharmacokinetics of MERREM IV in children are essentially similar to those in adults.

The elimination half-life for meropenem was increased to approximately 1.75 hours in 3-5 month old infants The concentrations of meropenem increase with increasing dose over the dose range of 10 to 40 mg/kg.

Pharmacokinetic studies in patients with renal insufficiency have shown the plasma clearance of meropenem correlates with creatinine clearance. Dosage adjustments are necessary in subjects with renal impairment.

Pharmacokinetic studies in the elderly have shown a reduction in plasma clearance of meropenem which correlated with age-associated reduction in creatinine clearance.

Pharmacokinetic studies in patients with liver disease have shown no effects of liver disease on the pharmacokinetics of meropenem.

Indications

MERREM is indicated for treatment, in adults and children, of the following infections caused by single or multiple susceptible bacteria and as empiric therapy prior to the identification of the causative organisms:

• Lower Respiratory Tract Infections
• Urinary Tract Infections, including complicated infections
• Intra-abdominal Infections
• Gynaecological Infections, including postpartum infections
• Skin and Skin Structure Infections
• Meningitis
• Septicaemia
• Empiric treatment, including initital monotherapy, for presumed bacterial infections in host-compromised, neutropenic patients

Because of its broad spectrum of bactericidal activity against Gram-positive and Gram-negative aerobic and anaerobic bacteria, MERREM is effective for the treatment of polymicrobial infections.

Dosage and Administration

A) Adults

Dosage range is 1.5 g - 6 g daily in three divided doses.

Usual dose

500 mg to 1 g by intravenous administration every 8 hours depending on type and severity of infection, the known or expected susceptibility of the pathogen(s) and the condition of the patient.

Exceptions

1. Febrile episodes in neutropenic patients - the dose should be 1 g every 8 hours.
2. Meningitis - the dose should be 2 g every 8 hours.

As with other antibiotics, caution may be required in using meropenem as monotherapy in critically ill patients with known or suspected Pseudomonas aeruginosa lower respiratory tract infections.

Regular sensitivity testing is recommended when treating Pseudomonas aeruginosa infections.

MERREM should be given as an intravenous bolus injection over approximately 5 minutes or by intravenous infusion over approximately 15 to 30 minutes (see Method of Administration).

Dosage Schedule for Adults with Impaired Renal Function

Dosage should be reduced in patients with creatinine clearance less than 51 mL/min, as scheduled below.

MERREM is cleared by haemodialysis. If continued treatment with MERREM is necessary, the unit dose (based on the type and severity of infection) 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 impaired hepatic metabolism.

B) Elderly

No dosage adjustment is required for the elderly with normal renal function or creatinine clearance values above 50 mL/min.

C) Children

For infants and children over 3 months and up to 12 years of age the recommended intravenous 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

1. Febrile episodes in neutropenic patients - the dose should be 20 mg/kg every 8 hours.
2. Meningitis the dose should be 40 mg/kg every 8 hours.

MERREM should be given as an IV bolus over approximately 5 minutes or by intravenous infusion over approximately 15 to 30 minutes.

There is no experience in children with renal impairment.

Method of Administration

MERREM to be used for bolus intravenous injection should be constituted with sterile water for injection (10 mL per 500 mg meropenem). This provides an approximate available concentration of 50 mg/mL. Constituted solutions are clear or pale yellow.

MERREM for intravenous infusion may be directly constituted with a compatible infusion fluid (see COMPATIBILITY) and then further diluted (50 to 200 mL) with the compatible infusion fluid, as needed.

Compatibility

MERREM IV is compatible with the following infusion fluids:

• 0.9% sodium chloride intravenous infusion
• 5% or 10% glucose intravenous infusion
• 5% glucose intravenous infusion with 0.02% sodium bicarbonate
• 5% glucose and 0.9% sodium chloride intravenous infusion
• 5% glucose with 0.225% sodium chloride intravenous infusion
• 5% glucose with 0.15% potassium chloride intravenous infusion
• 2.5% and 10% mannitol intravenous infusion
• normosol-M in 5% glucose intravenous infusion.

Also see SPECIAL PRECAUTIONS FOR STORAGE

Contraindications

MERREM is contraindicated in patients who have demonstrated hypersensitivity to this product.

Warnings and Precautions

Patients who have a history of hypersensitivity to carbapenems, penicillins or other beta-lactam antibiotics may also be hypersensitive to MERREM. As with all beta-lactam antibiotics rare hypersensitivity reactions have been reported (see ADVERSE EFFECTS).

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 with MERREM as with virtually all antibiotics; therefore, its diagnosis should be considered in patients who develop diarrhoea in association with the use of MERREM.

MERREM may reduce serum valproic acid levels. Subtherapeutic levels may be reached in some patients.

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, MERREM is not recommended for use below this age.

Use in Patients with Renal Insufficiency

See DOSAGE AND ADMINISTRATION.

Use in Patients with Liver Disease

Patients with pre-existing liver disorders should have liver function monitored during treatment with MERREM.

Use in Pregnancy

The safety of MERREM in human pregnancy has not been established, although animal studies have not shown an adverse effect on the developing foetus. MERREM should not be used in pregnancy unless the potential benefit justifies the potential risk to the foetus.

Use in Lactation

Meropenem is detectable at very low concentrations in animal breast milk. MERREM should not be used in breast-feeding women unless the potential benefit justifies the potential risk to the baby.

Effect on Ability to Drive or Operate Machinery

No data are available, but it is not anticipated that MERREM will affect the ability to drive and operate machinery.

Adverse Effects

MERREM is generally well tolerated. Adverse events rarely lead to cessation of treatment. Serious adverse events are rare.

Table 1 Frequency of Adverse Reactions

* Convulsions have been observed in a temporal association with the administration of Merrem; a causal relationship with MERREM has not been established.

Interactions

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 MERREM dosed without probenecid are adequate the co-administration of probenecid with MERREM is not recommended. The potential effect of MERREM on the protein binding of other medicines or metabolism has not been studied. However, the protein binding is so low (approximately 2%) that no interactions with other compounds would be expected on the basis of this mechanism.

MERREM has been administered concomitantly with many other medications without apparent adverse interaction. MERREM may reduce serum valproic acid levels. Subtherapeutic levels may be reached in some patients. However, no specific drug interaction studies other than with probenecid were conducted.

Overdosage

Intentional overdosing of MERREM is unlikely, although overdosing could occur during therapy particularly in patients with renal impairment. Limited post-marketing experience indicates that if adverse events occur following overdosage, they are consistent with the adverse event profile described in ADVERSE EFFECTS, 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 MERREM and its metabolite.

Pharmaceutical Precautions

Shelf-life

4 years

Special precautions for storage

Prior to constitution, store MERREM powder for intravenous injection or infusion packs below 25°C.

To reduce microbiological hazard, solutions of MERREM IV should be used as soon as practicable after reconstitution. If storage is necessary, hold at 2 to 8°C for not more than 24 hours, or the period shown in the following table, whichever is the lesser.

Solutions of MERREM should not be frozen.

Incompatibilities

MERREM is compatible with the infusion solutions listed in SPECIAL PRECAUTIONS FOR STORAGE and should not be mixed with or physically added to solutions containing other medicines.

Medicine Classification

Prescription Medicine

Package Quantities

MERREM powder for intravenous injection or infusion packs

10 vials of meropenem trihydrate/sodium carbonate anhydrous blend as sterile powder:

20 mL vial

meropenem trihydrate equivalent to meropenem 500 mg, sodium carbonate anhydrous 104 mg as buffer

30 mL vial

meropenem trihydrate equivalent to meropenem 1 g, sodium carbonate anhydrous 208 mg as buffer

Further Information

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 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 small decrease in red cell parameters and an increase in liver weight in dogs at 500 mg/kg.

There was not 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 rats was 120 mg/kg).

There was increased evidence 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 intramuscular formulation caused reversible injection site necrosis.

The sole metabolite of meropenem had a similar low profile of toxicity in animal studies.

Name and Address

AstraZeneca Limited
303 Manukau Road, Epsom
P O Box 1301
Auckland

Telephone: (09) 623-6300

Date of Preparation

21 December 2006

CDS  09/06

Copyright - No part may be reproduced by any process without the prior written permission of AstraZeneca Limited