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L3 5 CAMERO0 0 November 2013
Meropenem
for Injection, USP
500 mg and 1 g (Meropenem, USP) vials
For intravenous use
THERAPEUTIC CLASSIFICATION
500 mg
1000 mg
2000 mg
Time
(h)
Mean Conc. ± SD
(µg/mL)
Mean Conc. ± SD
(µg/mL)
Mean Conc. ± SD
(µg/mL)
3.5
1.28 ± 0.58
2.47 ± 1.07
–
4
0.91 ± 0.41
2.35 ± 0.98
–
4.5
0.57 ± 0.31
1.54 ± 0.86
–
5
0.40 ± 0.19
0.99 ± 0.63
3.33 ± 1.20
6
0.27 ± 0.15
0.60 ± 0.36
1.83 ± 0.65
7
0.14 ± 0.09
0.30 ± 0.23
1.03 ± 0.46
8
–
–
0.63 ± 0.32
10
–
–
0.21 ± 0.13
ND: Not detectable, Not measured
Antibiotic
ACTION AND CLINICAL PHARMACOLOGY
Meropenem is a broad spectrum, ß-lactamase-resistant, carbapenem antibiotic for
parenteral administration.
The bactericidal activity of meropenem results from the inhibition of bacterial cell wall
synthesis. Meropenem readily penetrates through the cell wall of most Gram-positive
and Gram-negative bacteria to reach penicillin-binding protein (PBP) targets. Its greatest
affinity is for PBP 2 of Escherichia coli, PBP 2 and 3 of Pseudomonas aeruginosa and
1, 2 and 4 of Staphylococcus aureus.
Meropenem is stable in the presence of most serine ß-lactamases (both penicillinases
and cephalosporinases) produced by Gram-positive and Gram-negative bacteria.
Pharmacokinetics
At the end of a 30 minute intravenous infusion of a single dose of meropenem in
healthy, male volunteers, mean peak plasma concentrations are approximately
23 μg/mL for the 500 mg dose, 49 μg/mL for the 1 g dose and 115 μg/mL for the 2 g
dose. The plasma concentration-time data for meropenem after a single 30 minute
infusion are presented in Table 1.
A 5 minute intravenous bolus injection of meropenem in healthy, male volunteers results
in mean peak plasma levels of approximately 52 μg/mL for the 500 mg dose and
112 μg/mL for the 1 g dose.
At doses of 500 mg, mean plasma levels of meropenem decline to 1 μg/mL or less,
6 hours after administration.
In subjects with normal renal function, the elimination half-life of meropenem is
approximately one hour. Approximately 70% of the administered dose is recovered
unchanged 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 at least 5 hours at the 500 mg dose. No clinically important 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. Plasma protein binding of meropenem is approximately 2%.
There is one metabolite which is microbiologically inactive. In healthy subjects, the AUC
for this metabolite was approximately 10% of the AUC for meropenem (Table 1).
Table 1 Plasma concentration-time values during and following single
30 minute infusion doses of meropenem in volunteers
500 mg
1000 mg
2000 mg
Time
(h)
Mean Conc. ± SD
(µg/mL)
Mean Conc. ± SD
(µg/mL)
Mean Conc. ± SD
(µg/mL)
Pre-dose
ND
ND
ND
0.083
5.43 ± 3.00
12.9 ± 3.62
–
0.167
–
–
48.4 ± 18.23
0.25
13.9 ± 2.74
28.6 ± 3.74
–
0.5
22.5 ± 4.86
48.6 ± 7.81
115.2 ± 23.5
0.75
15.5 ± 0.97
33.8 ± 1.99
78.8 ± 10.2
1
10.8 ± 1.46
24.6 ± 3.03
58.3 ± 8.93
1.5
6.84 ± 0.91
14.8 ± 2.17
36.9 ± 7.45
2
3.68 ± 0.81
11.1 ± 3.88
25.1 ± 4.62
2.5
2.92 ± 0.80
6.22 ± 1.40
–
3
1.95 ± 0.67
4.49 ± 1.02
12.5 ± 3.25
Meropenem penetrates well into most body fluids and tissues. However, it does
not penetrate readily into cerebrospinal fluid or aqueous humor in the absence of
inflammation at the sites. In children and adults with bacterial meningitis, meropenem
concentrations in the cerebrospinal fluid, after intravenous administration of
recommended doses, are in excess of those required to inhibit susceptible bacteria.
Note: See PHARMACOLOGY, Human Pharmacology section of the Product
Monograph, Table 16 for Meropenem Concentrations in Selected Tissues or Body
Fluids. See MICROBIOLOGY section of the Product Monograph for susceptibility
break points.
The pharmacokinetics of meropenem for injection in children over age 2 years are
essentially similar to those in adults. The elimination half-life for meropenem was
approximately 1.5 hours in children of age 3 months to 2 years. The pharmacokinetics
for children are linear for doses of 10, 20 and 40 mg/kg and the peak plasma
concentrations and AUC values are similar to those seen in healthy adult volunteers
after 500 mg, 1 g and 2 g doses, respectively. (See PHARMACOLOGY, Human
Pharmacology, Pharmacokinetics section of the Product Monograph for details of
pharmacokinetics in adults and children.)
Pharmacokinetic studies of meropenem for injection in patients with renal insufficiency
have shown that the plasma clearance of meropenem correlates with creatinine
clearance. Dosage adjustments are necessary in subjects with renal impairment
(see DOSAGE AND ADMINISTRATION). A pharmacokinetic study with meropenem
for injection in elderly patients with renal insufficiency has shown that a reduction in
plasma clearance of meropenem correlates with age-associated reduction in creatinine
clearance.
A study in patients with alcoholic cirrhosis has shown no effects of liver disease on the
pharmacokinetics of meropenem.
INDICATIONS AND CLINICAL USE
Meropenem for Injection, USP is indicated for treatment of the following infections when
caused by susceptible strains of the designated micro-organisms:
Lower Respiratory Tract
Community-acquired pneumonia caused by Staphylococcus aureus (methicillinsusceptible strains only), Streptococcus pneumoniae, Escherichia coli and Haemophilus
influenzae (including ß-lactamase-producing strains).
Nosocomial pneumonia caused by Staphylococcus aureus (methicillin-susceptible
strains only), Escherichia coli, Haemophilus influenzae (non-ß-lactamase-producing),
Klebsiella pneumoniae and Pseudomonas aeruginosa.
Urinary Tract
Complicated urinary tract infections caused by Enterobacter cloacae, Escherichia coli,
Klebsiella pneumoniae, Pseudomonas aeruginosa and Serratia marcescens.
Intra-abdominal
Complicated intra-abdominal infections caused by Citrobacter freundii, Enterobacter
cloacae, Escherichia coli, Klebsiella oxytoca, Klebsiella pneumoniae, Morganella
morganii, Pseudomonas aeruginosa, Bacteroides fragilis, Bacteroides ovatus,
Bacteroides thetaiotaomicron, Bacteroides vulgatus, Clostridium perfringens, and
Peptostreptococcus species.
Gynecologic
Gynecologic infections caused by Staphylococcus aureus (methicillin-susceptible strains
only), Staphylococcus epidermidis (methicillin-susceptible strains only), Escherichia coli,
Prevotella bivia, and Peptostreptococcus species.
Pelvic inflammatory disease caused by Staphylococcus epidermidis (methicillinsusceptible strains only), Streptococcus agalactiae, Escherichia coli and Prevotella bivia.
NOTE: Meropenem for injection has no activity against Chlamydia trachomatis.
Additional antimicrobial coverage is required if this pathogen is expected.
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Uncomplicated Skin and Skin Structure
Uncomplicated skin and skin structure infections caused by Staphylococcus aureus
(methicillin-susceptible strains only), Streptococcus agalactiae, Streptococcus pyogenes
and Escherichia coli.
Complicated Skin and Skin Structure
Complicated skin and skin structure infections, except infected burns, due to
Staphylococcus aureus (methicillin-susceptible strains), Streptococcus pyogenes,
Streptococcus agalactiae, Viridans group streptococci, Escherichia coli, Pseudomonas
aeruginosa, Proteus mirabilis, Klebsiella pneumoniae, Peptostreptococcus species, and
Bacteroides fragilis.
Bacterial Meningitis
Bacterial meningitis caused by Streptococcus pneumoniae, Haemophilus influenzae
(including ß-lactamase-producing strains) and Neisseria meningitidis.
NOTE: There is limited adult efficacy data for meropenem for injection in the treatment
of bacterial meningitis. Support for the adult meningitis indication is largely
provided by pediatric data.
Bacterial Septicemia
Bacterial septicemia caused by Escherichia coli.
Therapy with meropenem for injection may be initiated on the basis of clinical judgment
before results of sensitivity testing are available. Continuation of therapy should be
re-evaluated on the basis of bacteriological findings and on the patient’s clinical
condition. Regular sensitivity testing is recommended when treating Pseudomonas
aeruginosa infections.
Appropriate use of meropenem should be guided by local susceptibility data
accumulated for key bacterial pathogens.
Localised clusters of infections due to carbapenem-resistant bacteria have been
reported in some regions.
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.
CONTRAINDICATIONS
Meropenem for Injection, USP is contraindicated in patients with known hypersensitivity
to any component of this product or in patients who have demonstrated anaphylactic
reactions to ß-lactam antibiotics.
WARNINGS
SERIOUS AND OCCASIONALLY FATAL HYPERSENSITIVITY (ANAPHYLACTIC) REACTIONS
HAVE BEEN REPORTED IN PATIENTS RECEIVING THERAPY WITH ß-LACTAM ANTIBIOTICS.
THESE REACTIONS ARE MORE LIKELY TO OCCUR IN INDIVIDUALS WITH A HISTORY OF
SENSITIVITY TO MULTIPLE ALLERGENS.
THERE HAVE BEEN REPORTS OF INDIVIDUALS WITH A HISTORY OF PENICILLIN HYPER­
SENSITIVITY WHO HAVE EXPERIENCED SEVERE REACTIONS WHEN TREATED WITH
ANOTHER ß-LACTAM ANTIBIOTIC. BEFORE INITIATING THERAPY WITH MEROPENEM
FOR INJECTION, CAREFUL INQUIRY SHOULD BE MADE CONCERNING PREVIOUS
HYPER­SENSITIVITY REACTIONS TO PENICILLINS, CEPHALOSPORINS, OTHER ß-LACTAM
ANTIBIOTICS AND OTHER ALLERGENS. IF AN ALLERGIC REACTION TO MEROPENEM
FOR INJECTION OCCURS, DISCONTINUE THE DRUG IMMEDIATELY. ANAPHYLACTIC
REACTIONS REQUIRE IMMEDIATE TREATMENT WITH EPINEPHRINE. OXYGEN,
INTRAVENOUS STEROIDS, ANTIHISTAMINES AND AIRWAY MANAGEMENT,
INCLUDING INTUBATION, MAY BE REQUIRED.
Meropenem for Injection, USP should not be used to treat infections caused by
methicillin-resistant staphylococci.
Gastrointestinal
Clostridium difficile-associated disease
Clostridium difficile-associated disease (CDAD) has been reported with use of many
antibacterial agents, including meropenem for injection. CDAD may range in severity
from mild diarrhea to fatal colitis. It is important to consider this diagnosis in patients
who present with diarrhea, or symptoms of colitis, pseudomembranous colitis, toxic
megacolon, or perforation of colon subsequent to the administration of any antibacterial
agent. CDAD has been reported to occur over 2 months after the administration of
antibacterial agents.
Treatment with antibacterial agents may alter the normal flora of the colon and may
permit overgrowth of Clostridium difficile. C. difficile produces toxins A and B, which
contribute to the development of CDAD. CDAD may cause significant morbidity and
mortality. CDAD can be refractory to antimicrobial therapy.
If the diagnosis of CDAD is suspected or confirmed, appropriate therapeutic measures
should be initiated. Mild cases of CDAD usually respond to discontinuation of
antibacterial agents not directed against Clostridium difficile. In moderate to severe
cases, consideration should be given to management with fluids and electrolytes,
protein supplementation, and treatment with an antibacterial agent clinically
effective against Clostridium difficile. Surgical evaluation should be instituted as
clinically indicated, as surgical intervention may be required in certain severe cases
(see ADVERSE REACTIONS).
PRECAUTIONS
General
As with other broad-spectrum antibiotics, prolonged use of meropenem for injection
may result in overgrowth of nonsusceptible organisms. Repeated evaluation of the
patient is essential. If super-infection does occur during therapy, appropriate measures
should be taken.
Meropenem for injection, like all ß-lactam antibiotics, has the potential to cause
seizures. Diminished renal function and central nervous system lesions may increase
the risk of seizures. When meropenem for injection is indicated in patients with
these risk factors, caution is advised. Convulsions have been observed in a temporal
association with use of meropenem for injection.
Use of meropenem for injection may lead to the development of a positive direct or
indirect Coombs’ test.
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,
paresthesia, and convulsions have been reported for meropenem for injection.
When treating infections known or suspected to be caused by Pseudomonas
aeruginosa, higher doses are recommended based on pharmacokinetic/
pharmacodynamics modeling and probability of target attainment simulation for
susceptible strains of Pseudomonas aeruginosa (MIC ≤ 2 µg/mL) (see DOSAGE AND
ADMINISTRATION and MICROBIOLOGY section of the Product Monograph). Caution
may be required in critically ill patients with known or suspected Pseudomonas
aeruginosa lower respiratory tract infections.
Valproic Acid Interaction
Case reports in the literature have shown that co-administration of carbapenems,
including meropenem, to patients receiving valproic acid or divalproex sodium results
in a reduction in valproic acid concentrations. The valproic acid concentrations may
drop below the therapeutic range as a result of this interaction, therefore increasing the
risk of breakthrough seizures. Increasing the dose of valproic acid or divalproex sodium
may not be sufficient to overcome this interaction. The concomitant use of meropenem
and valproic acid or divalproex sodium is generally not recommended. Antibacterials
other than carbapenems should be considered to treat infections in patients whose
seizures are well controlled on valproic acid or divalproex sodium. If administration of
meropenem for injection is necessary, supplemental anti-convulsant therapy should be
considered. The concomitant use of valproic acid/sodium valproate and meropenem for
injection is not recommended (see PRECAUTIONS, Drug Interactions).
Pediatrics
The safety and effectiveness of meropenem for injection in the pediatric population
3 months of age and older have been established. Meropenem for injection is not
recommended for use in infants under the age of 3 months.
The use of meropenem for injection in pediatric patients with bacterial meningitis
is supported by evidence from adequate and well controlled studies in the pediatric
population. Use of meropenem for injection in pediatric patients for all other indications,
as listed in the INDICATIONS section, is supported by evidence from adequate and well
controlled studies in adults with additional data from pediatric pharmacokinetic studies
and controlled clinical trials in pediatric patients (see DOSAGE AND ADMINISTRATION,
Children).
NOTE: Inadequate data are available to support the pediatric indications for nosocomial
pneumonia, septicemia and complicated skin and skin structure infections.
Pregnancy
There are no adequate and well-controlled studies in pregnant women. Because
animal reproduction studies are not always predictive of human response, this drug
should be used during pregnancy only if clearly needed. Reproduction studies have
been performed in rats and Cynomolgous monkeys at doses up to 1000 mg/kg/day
(approximately 16 times the usual human dose of 1 g every 8 hours). These studies
revealed no evidence of impaired fertility or harm to the fetus due to meropenem
although there were slight changes in fetal body weight at doses of 240 mg/kg/day and
above in rats.
Nursing Mothers
Meropenem for injection is detected in animal breast milk; however, it is not known
whether meropenem is excreted in human milk. Meropenem for injection should not be
given to breast-feeding women unless the potential benefit justifies the potential risk
to the baby.
Liver Disease
Patients with pre-existing liver disorders should have their liver function monitored
during treatment with meropenem for injection.
Renal Impairment
Dosage adjustment is recommended for patients with renal insufficiency (see DOSAGE
AND ADMINISTRATION).
Drug 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 for injection. The co-administration of probenecid
with meropenem for injection is neither required nor recommended.
Other than probenecid, no specific drug interaction studies were conducted.
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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 in patients stabilized on valproic acid is not considered
to be manageable and therefore should be avoided (see PRECAUTIONS, General).
General disorders and administration site conditions
Abdominal pain, chills, infection, injection site pain and injection site edema
Metabolism and nutrition disorders
Peripheral edema
Nervous system disorders
Agitation, convulsions, dizziness, hallucinations, neuropathy, taste perversion
ADVERSE REACTIONS
Adverse Drug Reaction (ADR) Overview
Meropenem for injection is generally well tolerated. Many patients receiving
meropenem for injection are severely ill, have multiple background diseases,
physiological impairments and receive multiple other drug therapies. In such seriously
ill patients, it is difficult to establish the relationship between adverse events and
meropenem for injection.
Serious adverse reactions include occasionally fatal hypersensitivity (anaphylactic)
reactions, severe skin reactions (erythema multiforme, Stevens-Johnson syndrome,
toxic epidermal necrolysis) which require immediate discontinuation of the drug and
standard of care treatment. The most commonly reported drug-related adverse events
in the clinical trial programme were inflammation at the site of injection, diarrhea,
nausea and vomiting, and rash. The most commonly reported laboratory adverse events
included increased levels of ALT and AST and increased platelets.
Renal and urinary disorders
Renal impairment
Skin and subcutaneous tissue disorders
Sweating
Abnormal Hematologic and Clinical Chemistry Findings
Adverse laboratory changes that were reported in clinical trials by the investigator as
possibly, probably or definitely related to meropenem occurring in greater than 0.2% of
the patients are summarised in Table 3.
Table 3 Meropenem-Related Adverse Chemical and Hematologic Laboratory
Changes with Frequency ≥ 0.2% (N = 3187 patients)
Adverse Laboratory Change1
Frequency2
Clinical Trial Adverse Drug Reactions
Because clinical trials are conducted under very specific conditions, the adverse drug
reaction rates observed in the clinical trials may not reflect the rates observed in
practice and should not be compared to the rates in the clinical trials of another drug.
Adverse drug reaction information from clinical trials is useful for identifying drugrelated adverse events and for approximating rates.
The safety of meropenem has been evaluated in a clinical trial program of 3187 adults
and children, in a range of bacterial infections including pneumonia, complicated urinary
tract, intra-abdominal and skin/skin structure infections, gynecological infections and
meningitis.
A subsequent safety review on an expanded clinical trial database of 4872 patients
treated intravenously or intramuscularly with meropenem (5026 treatment exposures)
was generally consistent with earlier findings.
The following Table 2 presents a summary of clinical trial adverse drug reactions,
judged by the investigator to be related to therapy with meropenem (possibly, probably
or definitely), that occurred at frequencies greater than 0.2% in the 3187 patients
treated intravenously with meropenem, plus those reactions only observed in the
expanded clinical trial database at frequencies greater than or equal to 0.1%.
Chemistry:
Eosinophil count increased
Common
Table 2 Meropenem Clinical Trial Adverse Drug Reactions with Frequency
≥ 0.2% (N = 3187 patients)
Partial thromboplastin time abnormal
Uncommon
Alanine aminotransferase increased
Common
Alkaline phosphatase increased
Common
Aspartate aminotransferase increased
Common
Blood bilirubin increased
Uncommon
Blood urea nitrogen increased
Uncommon
Blood creatinine increased
Uncommon
Lactate dehydrogenase increased
Common
Transaminases increased
Common
Hematology:
Platelet count decreased
Uncommon
System Organ Class
Frequency1
Reaction2
Platelet count increased
Common
Blood and lymphatic
system disorders
Common
thrombocythemia3
Prothrombin time abnormal
Uncommon
Uncommon
eosinophilia, thrombocytopenia,
leucopenia, neutropenia
White blood cell count decreased
Uncommon
Gastrointestinal
disorders
Common
diarrhea (2.5%), nausea/vomiting (1.2%)
General disorders and
administration site
conditions
Common
fever, injection site inflammation (1.6%)
Medical Dictionary for Regulatory Activities preferred term level
2 CIOMS III frequency classification: 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%)
Uncommon
injection site phlebitis/
thrombophlebitis (0.5%),
injection site reaction (0.4%)
Pediatric Patients
Drug-related increases in platelets (7.0%) appear to occur more frequently in pediatric
patients than in adults treated with meropenem.
Infections and
infestations
Uncommon
oral (0.3%) and vaginal (0.7%)
candidiasis, vaginitis (0.3%)
Nervous system
disorders
Common
headache
Uncommon
paresthesia
Postmarket Adverse Drug Reactions
The following adverse reactions have been identified during post-approval use of
meropenem. These reactions were reported voluntarily from a population of uncertain
size, so it is not possible to reliably estimate their frequency. A causal relationship could
not be excluded in spite of concomitant medications and/or illnesses.
Skin and subcutaneous
tissue disorders
Common
rash (1.1%), pruritus
Uncommon
urticaria (0.3%)
IOMS III frequency classification: very common (≥1/10; ≥10%); common
C
(≥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%)
2 Medical Dictionary for Regulatory Activities preferred term level
3 Observed in the expanded clinical trial database at ≥0.1%, n = 4872 patients
(5026 meropenem treatment exposures)
1
Less Common Clinical Trial Adverse Drug Reactions (< 0.2%)
Blood and lymphatic system disorders
Agranulocytosis
Gastrointestinal disorders
Constipation
1
Blood and the lymphatic system disorders
Thrombocytopenia with bleeding, hemolytic anemia
Gastrointestinal disorders
Pseudomembranous colitis
Hepatobiliary disorders
Cholestasis, hepatitis
Investigations
Hypokalemia, hypomagnesemia
Immune system disorders
Severe hypersensitivity reactions of angioedema and anaphylaxis
Skin and subcutaneous tissue disorders
Severe skin reactions such as erythema multiforme, Stevens-Johnson syndrome and
toxic epidermal necrolysis
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SYMPTOMS AND TREATMENT OF OVERDOSAGE
For management of a suspected drug overdose, please contact your regional Poison
Control Centre immediately.
Intentional overdosing of meropenem for injection is unlikely, although accidental
overdosing might occur particularly in patients with reduced renal function. The largest
dose of meropenem administered in clinical trials has been 2 g given intravenously
every 8 hours to adult patients with normal renal function and 40 mg/kg every 8 hours
to children with normal renal function. At these dosages, no adverse pharmacological
effects were observed.
Limited postmarketing experience indicates that if adverse events occur following
overdosage, they are generally consistent with the adverse event profile described
under ADVERSE REACTIONS.
In the event of an overdose, meropenem for injection should be discontinued and
general supportive treatment given until renal elimination takes place. Meropenem
for injection and its metabolite are readily dialyzable and effectively removed by
hemodialysis; however, no information is available on the use of hemodialysis to treat
overdosage.
The intravenous LD50 of meropenem in mice and rats is more than 2500 mg/kg and is
approximately 2000 mg/kg in dogs.
DOSAGE AND ADMINISTRATION
Elderly
Dosage adjustment is recommended for the elderly with an estimated or measured
creatinine clearance value below 50 mL/min (see section on Impaired Renal Function).
Children
For infants and children over 3 months of age and weighing up to 50 kg, the recom­
mended dose of Meropenem for Injection, USP is 10 to 40 mg/kg every 8 hours,
depending on type and severity of infection, the known or suspected susceptibility of the
pathogens and the condition of the patient (see Table 6). Children weighing over 50 kg
require the adult dosage. Meropenem for injection should be given as an intravenous
infusion over approximately 15 to 30 minutes or as an intravenous bolus injection
(5 to 20 mL) over approximately 5 minutes (see PHARMACEUTICAL INFORMATION,
Intravenous Bolus Administration and Infusion).
When treating infections known or suspected to be caused by Pseudomonas
aeruginosa, 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) is recommended. This dose is based
on pharmacokinetic/pharmacodynamic modeling and probability of target attainment
simulation for susceptible strains of Pseudomonas aeruginosa (MIC ≤ 2 µg/mL).
There is limited safety data available to support the administration of a 40 mg/kg bolus
dose.
Table 6 Dosage in Pediatric Patients
Adults
The usual dose is 500 mg to 1 g by intravenous infusion every 8 hours, depending on
type and severity of infection, the known or suspected susceptibility of the pathogens
and the condition of the patient (see Table 4). Doses up to 2 g every 8 hours have
been used. Meropenem for Injection, USP should be given by intravenous infusion over
approximately 15 to 30 minutes or as an intravenous bolus injection (5 to 20 mL) over
approximately 5 minutes (see PHARMACEUTICAL INFORMATION, Intravenous Bolus
Administration and Infusion).
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) is recommended. This dose is based on
pharmacokinetic/pharmacodynamic modeling and probability of target attainment
simulation for susceptible strains of Pseudomonas aeruginosa (MIC ≤ 2 µg/mL).
There is limited safety data available to support the administration of a 2 g bolus dose.
The recommended dose to be given for adults is as in Table 4.
Table 4 Recommended Dose in Adults
Type of Infection
Adults with Hepatic Insufficiency
No dosage adjustment is necessary in patients with hepatic dysfunction as long as
renal function is normal.
Dose
Dosage Interval
Complicated urinary tract
500 mg
every 8 hours
Uncomplicated skin and skin structure
500 mg
every 8 hours
Complicated skin and skin structure
500 mg
every 8 hours
Gynecologic and Pelvic Inflammatory Disease
500 mg
every 8 hours
Lower respiratory
Community-acquired pneumonia
Nosocomial pneumonia
500 mg
1g
every 8 hours
every 8 hours
Complicated intra-abdominal
1g
every 8 hours
Meningitis
2g
every 8 hours
Septicemia
1g
every 8 hours
Impaired Renal Function
Dosage should be reduced in patients with creatinine clearance less than 51 mL/min
(Table 5).
Table 5 Dosage in Patients with Creatinine Clearance Less than 51 mL/min
Creatinine Clearance
(mL/min)
Dose
(dependent on type of infection)
Dosing
Interval
26 - 50
Recommended dose
(500 mg to 2000 mg)
every 12 hours
10 - 25
one-half recommended dose
every 12 hours
< 10
one-half recommended dose
every 24 hours
Meropenem is removed by hemodialysis and hemofiltration; if continued treatment with
Meropenem for Injection, USP is necessary, the dose, based on the infection type and
severity, should be administered at the completion of the hemodialysis procedure to
reinstitute effective treatment.
There are no data on appropriate doses in patients requiring peritoneal dialysis.
Type of Infection
Dose (mg/kg)
Dosing Interval
10
every 8 hours
Uncomplicated skin and skin structure
10 - 20
every 8 hours
Community acquired pneumonia
Complicated urinary tract
10 - 20
every 8 hours
Complicated intra-abdominal
20
every 8 hours
Meningitis
40
every 8 hours
There are no data on appropriate doses for children with renal impairment.
PHARMACEUTICAL INFORMATION
Drug Substance
Proper namemeropenem
Chemical Name(-)-(4R,5S,6S)-3-[[(3S,5S)-5-(dimethylcarbamoyl)-3-pyrrolidinyl]
thio]-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3,2,0]
hept-2-ene-2-carboxylic acid trihydrate
Structural Formula
Molecular FormulaC17H31N3O8S
Molecular Weight 437.51 g/mol
DescriptionMeropenem is a white to light yellow, crystalline powder which
is soluble in 5% sodium bicarbonate solution, sparingly soluble
in water, very slightly soluble in absolute ethanol and practically
insoluble in ether.
The pH of a 1% w/v solution in water ranges from 4.0 to 6.0.
The pKa values are 2.9 and 7.4. The melting point is difficult to
determine because decomposition and colour changes occur
before melting. The n-octanol: water partition coefficient is small
(< 1x 10-3).
Composition
Each 1 g vial of Meropenem for Injection, USP will deliver 1 g of meropenem anhydrous
as meropenem trihydrate and 90.2 mg of sodium as sodium carbonate, and each
500 mg vial will deliver 500 mg meropenem anhydrous as meropenem trihydrate and
45.1 mg of sodium as sodium carbonate.
Stability and Storage Recommendations
Store between 15°C and 30°C. Do not freeze.
Parenteral Products
Compatibility of meropenem for injection with other drugs has not been established.
Meropenem for injection should not be mixed with or physically added to solutions
containing other drugs.
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Freshly prepared solutions of meropenem for injection should be used whenever
possible. Constituted solutions of meropenem for injection should not be frozen.
All vials are for single use only. Standard aseptic technique should be employed during
constitution and administration. Shake constituted solution before use.
Parenteral drug products should be inspected visually for particulate matter and
discolouration prior to administration, whenever solution and container permit.
Intravenous Bolus Administration
A solution for bolus injection is prepared by dissolving the drug product meropenem
for injection with sterile Water for Injection to a final concentration of 50 mg/mL
(see Table 7). Shake to dissolve and let stand until clear.
Table 7 Reconstitution Volume
Vial
Size
Amount of
Diluent Added
(mL)
Approximate
Withdrawable
Volume (mL)
Approximate Average
Concentration
(mg/mL)
500 mg/20 mL
10
10
50
1 g/20 mL
20
20
50
REPORTING SUSPECTED SIDE EFFECTS
REPORTING SUSPECTED SIDE EFFECTS
You can report any suspected adverse reactions associated with the use of health
products to the Canada Vigilance Program by one of the following 3 ways:
• Report online at www.healthcanada.gc.ca/medeffect
• Call toll-free at 1-866-234-2345
• Complete a Canada Vigilance Reporting Form and:
– Fax toll-free to 1-866-678-6789, or
– Mail to: Canada Vigilance Program
Health Canada
Postal Locator 0701E
Ottawa, ON K1A 0K9
Postage paid labels, Canada Vigilance Reporting Form and the adverse reaction
reporting guidelines are available on the MedEffect™ Canada Web site at
www.healthcanada.gc.ca/medeffect.
NOTE: Should you require information related to the management of side effects,
contact your health professional. The Canada Vigilance Program does not provide
medical advice.
Stability in Glass Vials
Meropenem for injection vials reconstituted with sterile Water for Injection for bolus
administration (up to 50 mg/mL of meropenem) may be stored for up to 3 hours at
controlled room temperature (15°C to 25°C) or for up to 16 hours under refrigerated
conditions (2°C to 8°C).
Infusion
A solution for infusion is prepared by dissolving the drug meropenem for injection
(500 mg/20 mL and 1 g/20 mL) in either 0.9% Sodium Chloride Injection or 5% Glucose
(Dextrose) Injection, then the resulting solution is added to an i.v. container and further
diluted to a final concentration of 1 to 20 mg/mL (see Table 8).
Stability in Plastic i.v. Bags
Solutions prepared for infusion (meropenem for injection concentrations ranging from
1 to 20 mg/mL) may be stored in plastic i.v. bags with diluents as shown in Table 8
below. Meropenem for injection reconstituted with 0.9% Sodium Chloride Injection
may be stored for up to 3 hours at controlled room temperature (15°C to 25°C) or
for up to 24 hours under refrigerated conditions (2°C to 8°C). Constituted solutions
of meropenem for injection in 5% Glucose (Dextrose) Injection should be used
immediately.
From a microbiological point of view, unless the method of opening/constitution/
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.
Diluted intravenous infusion solutions should be inspected visually for discolouration,
haziness, particulate matter and leakage prior to administration, whenever solution and
container permit.
Discard unused portion.
Table 8 Number of Hours Stable after Reconstitution
Diluent
Number of Hours Stable
at Controlled Room
Temperature
15°C to 25°C
Number of Hours
Stable at
2°C to 8°C
0.9% Sodium Chloride Injection
3
24
5% Glucose (Dextrose) Injection
Use Immediately
Use Immediately
AVAILABILITY OF DOSAGE FORMS
Meropenem for Injection, USP is supplied in 20 mL glass vials capped with latex-free
stoppers and violet colour flip-off seal for the 500 mg and grey colour for the 1 g
strength, containing sufficient meropenem to deliver 500 mg and 1 g of meropenem
anhydrous respectively for intravenous administration.
PHARMACEUTICAL PARTNERS OF CANADA INC.
Richmond Hill, ON L4B 3P6
? 1-877-821-7724
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