Merrem

• Astrazeneca

Before taking Merrem, tell your doctor about all of your medical conditions. Especially tell your doctor if you:

• are allergic to any ingredient in Merrem
• have or have had kidney problems
• take medication for seizures or bipolar disorder
• have or have had neurological (brain or nervous system) problems
• have gastrointestinal (stomach and bowel) problems, especially colitis
• are pregnant or breastfeeding

If this medication is administered by a healthcare provider in a medical setting, it is unlikely that an overdose will occur. However, if overdose is suspected, seek emergency medical attention.

• The dry powdered form of Merrem can be stored at room temperature at 15-25°C (59-77°F).
• Keep this and all medicines out of the reach of children.

Seek emergency medical attention or call the Poison Help line at 1-800-222-1222.

Distribution

Extent

Well distributed into body tissues and fluids, including bronchial mucosa, lung, bile, gynecologic tissue (endometrium, myometrium, ovary, cervix, fallopian tube), muscle, heart valves, skin, and interstitial and peritoneal fluid.1

Distributed into CSF.1

Plasma Protein Binding

Approximately 2%.1

Elimination

Metabolism

Partially metabolized; at least 1 metabolite is microbiologically active.1

Elimination Route

Eliminated in urine as unchanged drug.1 70% of an IV dose eliminated in urine as unchanged drug.1

Half-life

Adults with normal renal function: approximately 1 hour.1

Children 3 months to 2 years of age: approximately 1.5 hours.1

Special Populations

Pharmacokinetics not affected by hepatic impairment.1

Decreased clearance in patients with renal impairment.1

Storage

Parenteral

20–25°C.1 Do not freeze reconstituted or diluted solutions.1

Solutions for IV injection containing approximately 50 mg/mL prepared using water for injection are stable for 2 hours at 15–25°C or 12 hours at 4°C.1

Solutions for IV infusion containing 2.5–50 mg/mL prepared using 0.9% sodium chloride are stable for up to 2 hours at 15–25°C or 18 hours at 4°C; those prepared using 5% dextrose are stable for up to 1 hour at 15–25°C or 8 hours at 4°C.1 1

Compatibility

For information on systemic interactions resulting from concomitant use, see Interactions.

Parenteral

• Synthetic carbapenem β-lactam antibiotic; structurally and pharmacologically related to imipenem and ertapenem.1 2 3

• Usually bactericidal in action.1

• Like other β-lactam antibiotics, antibacterial activity results from inhibition of bacterial cell wall synthesis.1

• Spectrum of activity includes many gram-positive and -negative aerobic bacteria and some gram-positive and -negative anaerobic bacteria.1 Stable in the presence of a variety of β-lactamases (including penicillinases, cephalosporinases, and extended-spectrum β-lactamases).1

• Gram-positive aerobes: Active in vitro and in clinical infections against Streptococcus pneumoniae (penicillin-susceptible strains only) and viridans streptococci.1 Also active in vitro against Staphylococcus aureus and S. epidermidis.1 Oxacillin-resistant (methicillin-resistant) staphylococci are resistant.1

• Gram-negative aerobes: Active in vitro and in clinical infections against Escherichia coli, Haemophilus influenzae (including β-lactamase-producing strains), Klebsiella pneumoniae, Neisseria meningitidis and Pseudomonas aeruginosa.1 Also active in vitro against Acinetobacter, Aeromonas hydrophila, Campylobacter jejuni, Citrobacter, Enterobacter, H. influenzae (ampicillin-resistant, non-β-lactamase-producing strains; BLNAR), Havnia alvei, K. oxytoca, Moraxella catarrhalis, Morganella morganii, Pasteurella multocida, Proteus mirabilis, P. vulgaris, Salmonella, Shigella, Serratia marcescens, and Yersinia enterocolitica.1

• Anaerobes: Active in vitro and in clinical infections against Bacteroides fragilis, B. thetaiotaomicron, and Peptostreptococcus.1 Also active in vitro against B. distasonis, B. ovatus, B. uniformis, B. ureolyticus, B. vulgatus, Clostridium difficile, C. perfringens, Eubacterium lentum, Fusobacterium, Prevotella bivia, P. intermedia, P. melaninogenica, Porphyromonas asaccharolytica, and Propionibacterium acnes.1

• It is used to treat bacterial infections.

Complicated Skin and Skin Structure Infections (Adult Patients and Pediatric Patients 3 Months of Age and Older Only)

Merrem IV is indicated for the treatment of complicated skin and skin structure infections (cSSSI) due to Staphylococcus aureus (methicillin-susceptible isolates only), Streptococcus pyogenes, Streptococcus agalactiae, viridans group streptococci, Enterococcus faecalis (vancomycin-susceptible isolates only), Pseudomonas aeruginosa, Escherichia coli, Proteus mirabilis, Bacteroides fragilis, and Peptostreptococcus species.

Complicated Intra-abdominal Infections (Adult and Pediatric Patients)

Merrem IV is indicated for the treatment of complicated appendicitis and peritonitis caused by viridans group streptococci, Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, Bacteroides fragilis, B. thetaiotaomicron, and Peptostreptococcus species.

Bacterial Meningitis (Pediatric Patients 3 Months of Age and Older Only)

Merrem IV is indicated for the treatment of bacterial meningitis caused by Haemophilus influenzae, Neisseria meningitidis and penicillin-susceptible isolates of Streptococcus pneumoniae.

Merrem IV has been found to be effective in eliminating concurrent bacteremia in association with bacterial meningitis.

Usage

To reduce the development of drug-resistant bacteria and maintain the effectiveness of Merrem IV and other antibacterial drugs, Merrem IV should only be used to treat or prevent infections that are proven or strongly suspected

to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered

in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns

may contribute to the empiric selection of therapy.

Single dose clear glass vials of Merrem IV containing 500 mg or 1 gram (as the trihydrate blended with anhydrous sodium carbonate for re-constitution) of sterile meropenem powder.

Mechanism of Action

Meropenem is an antibacterial drug [see Microbiology (12.4)].

Pharmacokinetics

Plasma Concentrations

At the end of a 30-minute intravenous infusion of a single dose of Merrem IV in healthy volunteers, mean peak plasma concentrations of meropenem are approximately 23 mcg/mL (range 14-26) for the 500 mg dose and 49 mcg/mL (range 39-58) for the 1 gram dose. A 5-minute intravenous bolus injection of Merrem IV in healthy volunteers results in mean peak plasma concentrations of approximately 45 mcg/mL (range 18-65) for the 500 mg dose and 112 mcg/mL (range 83-140) for the 1 gram dose.

Following intravenous doses of 500 mg, mean plasma concentrations of meropenem usually decline to approximately 1 mcg/mL at 6 hours after administration.

No accumulation of meropenem in plasma was observed with regimens using 500 mg administered every 8 hours or 1 gram administered every 6 hours in healthy volunteers with normal renal function.

Distribution

The plasma protein binding of meropenem is approximately 2%.

After a single intravenous dose of Merrem IV, the highest mean concentrations of meropenem were found in tissues and fluids at 1 hour (0.5 hours to 1.5 hours) after the start of infusion, except where indicated in the tissues and fluids listed in Table 5 below.

Metabolism

There is one metabolite of meropenem that is microbiologically inactive.

Excretion

In subjects with normal renal function, the elimination half-life of meropenem is approximately 1 hour.

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. Fecal 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.

Urinary concentrations of meropenem in excess of 10 mcg/mL are maintained for up to 5 hours after a 500 mg dose.

Specific Populations

Renal Impairment

Pharmacokinetic studies with Merrem IV in patients with renal impairment have shown that the plasma clearance of meropenem correlates with creatinine clearance. Dosage adjustments are necessary in subjects with renal impairment (creatinine clearance 50 mL/min or less) [see Dosage and Administration (2.2) and Use in Specific Populations (8.6)].

Meropenem IV is hemodialyzable. However, there is no information on the usefulness of hemodialysis to treat overdosage [see Overdosage (10)].

Hepatic Impairment

A pharmacokinetic study with Merrem IV in patients with hepatic impairment has shown no effects of liver disease on the pharmacokinetics of meropenem.

Geriatric Patients

A pharmacokinetic study with Merrem IV in elderly patients with renal impairment showed a reduction in plasma clearance of meropenem that correlates with age-associated reduction in creatinine clearance.

Pediatric Patients

The pharmacokinetics of meropenem for injection IV, in pediatric patients 2 years of age or older, are similar to those in adults. The elimination half-life for meropenem was approximately 1.5 hours in pediatric patients of age 3 months to 2 years.

The pharmacokinetics of meropenem in patients less than 3 months of age receiving combination antibacterial drug therapy are given below.

Drug Interactions

Probenecid competes with meropenem for active tubular secretion and thus inhibits the renal excretion of meropenem. Following administration of probenecid with meropenem, the mean systemic exposure increased 56% and the mean elimination half-life increased 38%. Co-administration of probenecid with meropenem is not recommended.

Microbiology

Mechanism of Action

The bactericidal activity of meropenem results from the inhibition of cell wall synthesis. Meropenem penetrates the cell

wall of most gram-positive and gram-negative bacteria to reach penicillin-binding-protein (PBP) targets. Meropenem

binds to PBPs 2, 3 and 4 of Escherichia coli and Pseudomonas aeruginosa; and PBPs 1, 2 and 4 of Staphylococcus

aureus. Bactericidal concentrations (defined as a 3 log10 reduction in cell counts within 12 hours to 24 hours) are typically

1-2 times the bacteriostatic concentrations of meropenem, with the exception of Listeria monocytogenes, against which

lethal activity is not observed.

Meropenem has significant stability to hydrolysis by β-lactamases, both penicillinases and cephalosporinases produced by gram-positive and gram-negative bacteria.

Meropenem does not have in vitro activity against methicillin-resistant Staphylococcus aureus (MRSA) or methicillin-resistant Staphylococcus epidermidis (MRSE).

Resistance

There are several mechanisms of resistance to carbapenems: 1) decreased permeability of the outer membrane of gram-negative bacteria (due to diminished production of porins) causing reduced bacterial uptake, 2) reduced affinity of the target PBPs, 3) increased expression of efflux pump components, and 4) production of antibacterial drug-destroying enzymes (carbapenemases, metallo-β-lactamases).

Cross-Resistance

Cross-resistance is sometimes observed with isolates resistant to other carbapenems.

Interactions with Other Antibacterial Drugs

In vitro tests show meropenem to act synergistically with aminoglycoside antibacterials against some isolates of Pseudomonas aeruginosa.

Antimicrobial Activity

Meropenem has been shown to be active against most isolates of the following bacteria, both in vitro and in clinical infections [see Indications and Usage (1)].

Gram-positive bacteria

Enterococcus faecalis (vancomycin-susceptible isolates only)

Staphylococcus aureus (methicillin-susceptible isolates only)

Streptococcus agalactiae

Streptococcus pneumoniae (penicillin-susceptible isolates only)

Streptococcus pyogenes

Viridans group streptococci

Gram-negative bacteria

Escherichia coli

Haemophilus influenzae

Klebsiella pneumoniae

Neisseria meningitidis

Proteus mirabilis

Pseudomonas aeruginosa

Anaerobic bacteria

Bacteroides fragilis

Bacteroides thetaiotaomicron

Peptostreptococcus species

Greater than 90% of the following microorganisms exhibit activity in vitro with a minimum inhibitory concentration (MIC) less than or equal to the meropenem-susceptible breakpoint for organisms of similar genus shown in Table 7. The safety and effectiveness of meropenem in treating clinical infections due to these microorganisms have not been established in adequate and well-controlled clinical trials.

Gram-positive bacteria

Staphylococcus epidermidis (methicillin-susceptible isolates only)

Gram-negative bacteria

Aeromonas hydrophila

Campylobacter jejuni

Citrobacter freundii

Citrobacter koseri

Enterobacter cloacae

Hafnia alvei

Klebsiella oxytoca

Moraxella catarrhalis

Morganella morganii

Pasteurella multocida

Proteus vulgaris

Anaerobic bacteria

Bacteroides ovatus

Bacteroides uniformis

Bacteroides ureolyticus

Bacteroides vulgatus

Clostridium difficile

Clostridium perfringens

Eggerthella lenta

Fusobacterium species

Parabacteroides distasonis

Porphyromonas asaccharolytica

Prevotella bivia

Prevotella intermedia

Prevotella melaninogenica

Susceptibility Test Methods

When available, the clinical microbiology laboratory should provide in vitro susceptibility test results for antimicrobial drugs used in local hospitals and practice areas to the physician as periodic reports that describe the susceptibility profile of nosocomial and community-acquired pathogens. These reports should aid the physician in selecting an antimicrobial drug product for treatment.

Dilution Techniques:

Quantitative methods are used to determine antimicrobial MICs. These MICs provide estimates of the susceptibility of bacteria to antimicrobial compounds. The MICs should be determined using a standardized test method (broth or agar)1,3. The MIC values should be interpreted according to the criteria provided in Table 7.

Diffusion Techniques:

Quantitative methods that require measurement of zone diameters also provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. The zone size provides an estimate of the susceptibility of bacteria to antimicrobial compounds. The zone size should be determined using a standardized test method 2,3 and requires the use of standardized inoculum concentrations. This procedure uses paper disks impregnated with 10-mcg of meropenem to test the susceptibility of microorganisms to meropenem. The disk diffusion interpretive criteria are provided in Table 7.

Anaerobic Techniques:

For anaerobic bacteria, the susceptibility to meropenem as MICs can be determined by a standardized test method.2,4 The MIC values obtained should be interpreted according to the criteria provided in Table 7.

A report of Susceptible indicates that the antimicrobial is likely to inhibit growth of the pathogen if the antimicrobial drug reaches the concentration usually achievable at the site of infection. A report of Intermediate indicates that the result should be considered equivocal, and, if the microorganism is not fully susceptible to alternative, clinically feasible drugs, the test should be repeated. This category implies possible clinical applicability in body sites where the drug is physiologically concentrated or in situations where a high dosage of drug can be used. This category also provides a buffer zone that prevents small uncontrolled technical factors from causing major discrepancies in interpretation. A report of Resistant indicates that the antimicrobial is not likely to inhibit growth of the pathogen if the antimicrobial drug reaches concentrations usually achievable at the infection site; other therapy should be selected.

Quality Control

Standardized susceptibility test procedures require the use of quality controls to monitor and ensure the accuracy and precision of supplies and reagents used in the assay, and the techniques of the individuals performing the test. Standard meropenem powder should provide the following range of values provided in Table 8.

Merrem IV is supplied in 20 mL and 30 mL injection vials containing sufficient meropenem to deliver 500 mg or 1 gram for intravenous administration, respectively. The dry powder should be stored at controlled room temperature 20º-25ºC (68º-77ºF) [see USP].

Merrem (meropenem) is an antibiotic that fights bacteria.

Merrem is used to treat severe infections of the skin or stomach. Merrem is also used to treat bacterial meningitis (infection of brain or spinal cord).

Merrem may also be used for purposes not listed in this medication guide.

Use the missed dose as soon as you remember. Skip the missed dose if it is almost time for your next scheduled dose. Do not use extra medicine to make up the missed dose.