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All about: Merrem

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Generic Name: meropenem
Dosage Form: For injection

To reduce the development of drug-resistant bacteria and maintain the effectiveness of Merrem® I.V. (meropenem for injection) and other antibacterial drugs, Merrem I.V. should be used only to treat or prevent infections that are proven or strongly suspected to be caused by bacteria.

Merrem Description

Merrem® I.V. (meropenem for injection) is a sterile, pyrogen-free, synthetic, broad-spectrum, carbapenem antibiotic for intravenous administration. It is (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. Its empirical formula is C17H25N3O5S•3H2O with a molecular weight of 437.52. Its structural formula is:

Merrem I.V. is a white to pale yellow crystalline powder. The solution varies from colorless to yellow depending on the concentration. The pH of freshly constituted solutions is between 7.3 and 8.3. Meropenem is soluble in 5% monobasic potassium phosphate solution, sparingly soluble in water, very slightly soluble in hydrated ethanol, and practically insoluble in acetone or ether.

When constituted as instructed (see DOSAGE AND ADMINISTRATION; PREPARATION OF SOLUTION), each 1 g Merrem I.V. vial will deliver 1 g of meropenem and 90.2 mg of sodium as sodium carbonate (3.92 mEq). Each 500 mg Merrem I.V. vial will deliver 500 mg meropenem and 45.1 mg of sodium as sodium carbonate (1.96 mEq).

Merrem - Clinical Pharmacology

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

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

In subjects with normal renal function, the elimination half-life of Merrem I.V. is approximately 1 hour. Approximately 70% of the intravenously 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 after a 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.

Plasma protein binding of meropenem is approximately 2%.

There is one metabolite which is microbiologically inactive.

Meropenem penetrates well into most body fluids and tissues including cerebrospinal fluid, achieving concentrations matching or exceeding those required to inhibit most susceptible bacteria. After a single intravenous dose of Merrem I.V., the highest mean concentrations of meropenem were found in tissues and fluids at 1 hour (0.5 to 1.5 hours) after the start of infusion, except where indicated in the tissues and fluids listed in the table below.

Table 1Meropenem Concentrations in Selected Tissues (Highest Concentrations Reported)

Tissue

I.V. Dose (g)

Number of Samples

Mean [μg/mL or μg/(g)]*

Range [μg/mL or μg/(g)]

*
§
*
*at 1 hour unless otherwise noted
**obtained from blister fluid
***in pediatric patients of age 5 months to 8 years
§
****in pediatric patients of age 1 month to 15 years

Endometrium

0.5

7

4.2

1.7-10.2

Myometrium

0.5

15

3.8

0.4-8.1

Ovary

0.5

8

2.8

0.8-4.8

Cervix

0.5

2

7.0

5.4-8.5

Fallopian tube

0.5

9

1.7

0.3-3.4

Skin

0.5

22

3.3

0.5-12.6

Interstitial fluid**

0.5

9

5.5

3.2-8.6

Skin

1.0

10

5.3

1.3-16.7

Interstitial fluid**

1.0

5

26.3

20.9-37.4

Colon

1.0

2

2.6

2.5-2.7

Bile

1.0

7

14.6 (3 h)

4.0-25.7

Gall bladder

1.0

1

-

3.9

Peritoneal fluid

1.0

9

30.2

7.4-54.6

Lung

1.0

2

4.8 (2 h)

1.4-8.2

Bronchial mucosa

1.0

7

4.5

1.3-11.1

Muscle

1.0

2

6.1 (2 h)

5.3-6.9

Fascia

1.0

9

8.8

1.5-20

Heart valves

1.0

7

9.7

6.4-12.1

Myocardium

1.0

10

15.5

5.2-25.5

CSF (inflamed)

20 mg/kg***

40 mg/kg****

8

5

1.1 (2 h)

3.3 (3 h)

0.2-2.8

0.9-6.5

CSF (uninflamed)

1.0

4

0.2 (2 h)

0.1-0.3

The pharmacokinetics of Merrem I.V. in pediatric patients 2 years of age or older are essentially 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 are linear over the dose range from 10 to 40 mg/kg.

Pharmacokinetic studies with Merrem I.V. 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 - Use in Adults with Renal Impairment.) A pharmacokinetic study with Merrem I.V. in elderly patients with renal insufficiency has shown a reduction in plasma clearance of meropenem that correlates with age-associated reduction in creatinine clearance.

Meropenem I.V. is hemodialyzable. However, there is no information on the usefulness of hemodialysis to treat overdosage. (See OVERDOSAGE.)

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

Microbiology

Meropenem is a broad-spectrum carbapenem antibiotic. It is active against Gram-positive and Gram-negative bacteria.

The bactericidal activity of meropenem results from the inhibition of cell wall synthesis. Meropenem readily penetrates the cell wall of most Gram-positive and Gram-negative bacteria to reach penicillin-binding-protein (PBP) targets. Its strongest affinities are toward 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 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 of most categories, both penicillinases and cephalosporinases produced by Gram-positive and Gram-negative bacteria.

Meropenem should not be used to treat methicillin-resistant staphylococci (MRSA).

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

Mechanism of Action

Meropenem exerts its action by penetrating bacterial cells readily and interfering with the synthesis of vital cell wall components, which leads to cell death.

Resistance

Mechanism of 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 penicillin binding proteins (PBP), 3) increased expression of efflux pump components, and 4) production of antibiotic-destroying enzymes (carbapenems, metallo-β-lactamases).

Cross-Resistance

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

Lists of Microorganisms

Meropenem has been shown to be active against most isolates of the following microorganisms, both in vitro and in clinical infections as described in the INDICATIONS AND USAGE section.

Aerobic and facultative Gram-positive microorganisms

Enterococcus faecalis (excluding vancomycin-resistant isolates)

Staphylococcus aureus (β-lactamase and non-β-lactamase producing, methicillin-susceptible isolates only)

Streptococcus agalactiae

Streptococcus pneumoniae (penicillin-susceptible isolates only)

NOTE: Penicillin-resistant isolates had meropenem MIC90 values of 1 or 2 μg/mL, which is above the 0.12 μg/mL susceptible breakpoint for this species.

Streptococcus pyogenes

Viridans group streptococci

Aerobic and facultative Gram-negative microorganisms

Escherichia coli

Haemophilus influenzae (β-lactamase and non-β-lactamase producing)

Klebsiella pneumoniae

Neisseria meningitidis

Pseudomonas aeruginosa

Proteus mirabilis

Anaerobic microorganisms

Bacteroides fragilis

Bacteroides thetaiotaomicron

Peptostreptococcus species

The following in vitro data are available, but their clinical significance is unknown.

At least 90% of the following microorganisms exhibit an in vitro minimum inhibitory concentration (MIC) less than or equal to the susceptible breakpoints for meropenem. However, the safety and effectiveness of meropenem in treating clinical infections due to these microorganisms have not been established in adequate and well-controlled trials.

Aerobic and facultative Gram-positive microorganisms

Staphylococcus epidermidis (β-lactamase and non-β-lactamase-producing, methicillin-susceptible isolates only).

Aerobic and faculative Gram-negative

Microorganisms

Acinetobacter species

Aeromonas hydrophila

Campylobacter jejuni

Citrobacter diversus

Moraxella catarrhalis

(β-lactamase and non-β-lactamase-producing isolates)

Citrobacter freundii

Morganella morganii

Enterobacter cloacae

Pasteurella multocida

Haemophilus influenzae

(ampicillin-resistant, non-β-lactamase-producing isolates[BLNAR isolates])

Proteus vulgaris

Salmonella species

Serratia marcescens

Hafnia alvei

Shigella species

Klebsiella oxytoca

Yersinia enterocolitica

Anaerobic microorganisms

Bacteroides distasonis

Eubacterium lentum

Bacteroides ovatus

Fusobacterium species

Bacteroides uniformis

Prevotella bivia

Bacteroides ureolyticus

Prevotella intermedia

Bacteroides vulgatus

Prevotella melaninogenica

Clostridium difficile Clostridium perfringens

Porphyromonas asaccharolytica

Propionibacterium acnes

Susceptibility Test Methods

When available, the clinical microbiology laboratory should provide cumulative results of 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 the most effective antimicrobial.

Dilution Techniques

Quantitative methods are used to determine antimicrobial minimum inhibitory concentrations (MICs). These MICs provide estimates of the susceptibility of bacteria to antimicrobial compounds. The MICs should be determined using a standardized procedure. Standardized procedures are based on a dilution method1,3 (broth or agar) or equivalent with standardized inoculum concentrations and standardized concentrations of meropenem powder. The MIC values should be interpreted according to the criteria provided in Table 2.

Diffusion Techniques

Quantitative methods that require measurement of zone diameters also provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. One such standardized procedure2,3 requires the use of standardized inoculum concentrations. This procedure uses paper disks impregnated with 10-µg of meropenem to test the susceptibility of microorganisms to meropenem. The disk diffusion interpretive criteria are provided in Table 2.

Streptococcus pneumoniae isolates should be tested using 1-µg/mL oxacillin disk. Isolates with oxacillin zone sizes of ≥ 20 mm are susceptible (MIC ≤ 0.06 μg/mL) to penicillin and can be considered susceptible to meropenem for approved indications, and meropenem need not be tested. A meropenem MIC should be determined on isolates of S. pneumoniae with oxacillin zone sizes of ≤19 mm. The disk test does not distinguish penicillin intermediate isolates (i.e., MIC’s = 0.12-1.0 μg/mL) from isolates that are penicillin resistant (i.e., MICs ≥ 2 μg/mL). Viridans group streptococci should be tested for meropenem susceptibility using an MIC method. Reliable disk diffusion tests for meropenem do not yet exist for testing streptococci.

Anaerobic techniques

For anaerobic bacteria, the susceptibility to meropenem as MICs can be determined by standardized test methods4. The MIC values obtained should be interpreted according to the criteria provided in Table 2.

Table 2Susceptibility Interpretive Criteria for Meropenem

Susceptibility Test Result Interpretive Criteria

Minimum Inhibitory Concentrations (μg/mL)

Disk Diffusion

(zone diameters in mm)

*
The current absence of data on resistant isolates precludes defining any category other than “Susceptible.”If isolates yield MIC results other than susceptible, they should be submitte
Staphylococci that are resistant to methicillin/oxacillin must be considered resistant to meropenem.
No Disk diffusion (zone diameter) interpretative criteria have been established for testing Streptococcus pneumoniae, Streptococcus agalactiae, and Streptococcus pyogenes. Use Dilution (MICs) techniques results.
§
MIC values using either Brucella blood or Wilkins Chalgren agar (former reference medium) are considered equivalent, based upon published in vitro literature and a multicenter collaborative trial for these antimicrobial agents.

Pathogen

S

I

R*

S

I

R*

Enterobacteriaceae, Acinetobacter spp. and Pseudomonas aeruginosa

≤ 4

8

≥ 16

≥ 16

14-15

≤ 13

Haemophilus influenzae

≤ 0.5

--

--

≥ 20

--

--

Staphylococcus aureus

≤ 4

8

≥ 16

≥ 16

14-15

≤ 13

Streptococcus pneumoniae

≤ 0.12

--

--

Streptococcus agalactiae and

Streptococcus pyogenes

≤ 0.5

--

--

Anaerobes§

≤ 4

8

≥ 16

No interpretative criteria have been established for testing enterococci and Neisseria meningitidis.

A report of Susceptible indicates that the antimicrobial is likely to inhibit growth of the pathogen if the antimicrobial compound in the blood reaches the concentrations usually achievable. 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 compound in the blood reaches the concentrations usually achievable; other therapy should be selected.

Quality control

Standardized susceptibility test procedures require the use of quality control microorganisms to control the technical aspects of the test procedures. Standard meropenem powder should provide the following range of values noted in Table 3.

Table 3Acceptable Quality Control Ranges for Meropenem

QC Strain

Minimum Inhibitory Concentrations

(MICs = μg/mL)

Disk Diffusion

(Zone diameters in mm)

*
*
d Using the Reference Agar Dilution procedure.

Staphylococcus aureus

ATCC 29213

0.03-0.12

Staphylococcus aureu

ATCC 25923

29-37

Streptococcus pneumoniae

ATCC 49619

0.06-0.25

28-35

Enterococcus faecalis

ATCC 29212

2.0-8.0

28-34

Escherichia coli

ATCC 25922

0.008-0.06

Haemophilus influenzae

ATCC 49766

0.03-0.12

Haemophilus influenzae

ATCC 49247

20-28

Pseudomonas aeruginosa

ATCC 27853

0.25-1.0

27-33

Bacteroides fragilisd

ATCC 25285

0.03-0.25

Bacteroides thetaiotaomicrond

ATCC 29741

0.125-0.5

Eubacterium lentumd

ATCC 43055

0.125-1

INDICATIONS AND USAGE

To reduce the development of drug-resistant bacteria and maintain the effectiveness of Merrem I.V. and other antibacterial drugs, Merrem I.V. 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.

Merrem I.V. is indicated as single agent therapy for the treatment of the following infections when caused by susceptible isolates of the designated microorganisms:

Skin and Skin Structure Infections

Complicated skin and skin structure infections due to Staphylococcus aureus (β-lactamase and non-β-lactamase producing, methicillin susceptible isolates only), Streptococcus pyogenes, Streptococcus agalactiae, viridans group streptococci, Enterococcus faecalis (excluding vancomycin-resistant isolates), Pseudomonas aeruginosa, Escherichia coli, Proteus mirabilis, Bacteroides fragilis, and Peptostreptococcus species.

Intra-abdominal Infections

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 only)

Bacterial meningitis caused by Streptococcus pneumoniae‡, Haemophilus influenzae (β-lactamase and non-β-lactamase-producing isolates), and Neisseria meningitidis.

‡ The efficacy of meropenem as monotherapy in the treatment of meningitis caused by penicillin nonsusceptible isolates of Streptococcus pneumoniae has not been established.

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

For information regarding use in pediatric patients (3 months of age and older) see PRECAUTIONS - Pediatrics , ADVERSE REACTIONS, and DOSAGE AND ADMINISTRATION sections.

Appropriate cultures should usually be performed before initiating antimicrobial treatment in order to isolate and identify the organisms causing infection and determine their susceptibility to Merrem I.V.

Merrem I.V. is useful as presumptive therapy in the indicated condition (i.e., intra-abdominal infections) prior to the identification of the causative organisms because of its broad spectrum of bactericidal activity.

Antimicrobial therapy should be adjusted, if appropriate, once the results of culture(s) and antimicrobial susceptibility testing are known.

CONTRAINDICATIONS

Merrem I.V. is contraindicated in patients with known hypersensitivity to any component of this product or to other drugs in the same class or in patients who have demonstrated anaphylactic reactions to β-lactams.

WARNINGS

SERIOUS AND OCCASIONALLY FATAL HYPERSENSITIVITY (ANAPHYLACTIC) REACTIONS HAVE BEEN REPORTED IN PATIENTS RECEIVING THERAPY WITH β-LACTAMS. 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 HYPERSENSITIVITY WHO HAVE EXPERIENCED SEVERE HYPERSENSITIVITY REACTIONS WHEN TREATED WITH ANOTHER β-LACTAM. BEFORE INITIATING THERAPY WITH Merrem I.V., CAREFUL INQUIRY SHOULD BE MADE CONCERNING PREVIOUS HYPERSENSITIVITY REACTIONS TO PENICILLINS, CEPHALOSPORINS, OTHER β-LACTAMS, AND OTHER ALLERGENS. IF AN ALLERGIC REACTION TO Merrem I.V. OCCURS, DISCONTINUE THE DRUG IMMEDIATELY. SERIOUS ANAPHYLACTIC REACTIONS REQUIRE IMMEDIATE EMERGENCY TREATMENT WITH EPINEPHRINE, OXYGEN, INTRAVENOUS STEROIDS, AND AIRWAY MANAGEMENT, INCLUDING INTUBATION. OTHER THERAPY MAY ALSO BE ADMINISTERED AS INDICATED.

Seizures and other CNS adverse experiences have been reported during treatment with Merrem I.V. (See PRECAUTIONS and ADVERSE REACTIONS.)

Pseudomembranous colitis has been reported with nearly all antibacterial agents, including meropenem, and may range in severity from mild to life-threatening. Therefore, it is important to consider this diagnosis in patients who present with diarrhea subsequent to the administration of antibacterial agents.

Treatment with antibacterial agents alters the normal flora of the colon and may permit overgrowth of clostridia. Studies indicate that a toxin produced by Clostridium difficile is a primary cause of “antibiotic-associated colitis”.

After the diagnosis of pseudomembranous colitis has been established, therapeutic measures should be initiated. Mild cases of pseudomembranous colitis usually respond to drug discontinuation alone. In moderate-to-severe cases, consideration should be given to management with fluids and electrolytes, protein supplementation, and treatment with an antibacterial drug clinically effective against Clostridium difficile colitis.

PRECAUTIONS

General

Prescribing Merrem I.V. in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria.

Seizures and other adverse CNS experiences have been reported during treatment with Merrem I.V. These experiences have occurred most commonly in patients with CNS disorders (e.g., brain lesions or history of seizures) or with bacterial meningitis and/or compromised renal function.

During clinical investigations, 2904 immunocompetent adult patients were treated for infections outside the CNS, with the overall seizure rate being 0.7% (based on 20 patients with this adverse event). All meropenem-treated patients with seizures had pre-existing contributing factors. Among these are included prior history of seizures or CNS abnormality and concomitant medications with seizure potential. Dosage adjustment is recommended in patients with advanced age and/or reduced renal function. (See DOSAGE AND ADMINISTRATION - Use in Adults with Renal Impairment.)

Close adherence to the recommended dosage regimens is urged, especially in patients with known factors that predispose to convulsive activity. Anticonvulsant therapy should be continued in patients with known seizure disorders. If focal tremors, myoclonus, or seizures occur, patients should be evaluated neurologically, placed on anticonvulsant therapy if not already instituted, and the dosage of Merrem I.V. re-examined to determine whether it should be decreased or the antibiotic discontinued.

In patients with renal dysfunction, thrombocytopenia has been observed but no clinical bleeding reported. (See DOSAGE AND ADMINISTRATION - Use in Adults with Renal Impairment.)

There is inadequate information regarding the use of Merrem I.V. in patients on hemodialysis.

As with other broad-spectrum antibiotics, prolonged use of meropenem may result in overgrowth of nonsusceptible organisms. Repeated evaluation of the patient is essential. If superinfection does occur during therapy, appropriate measures should be taken.

Laboratory Tests

While Merrem I.V. possesses the characteristic low toxicity of the beta-lactam group of antibiotics, periodic assessment of organ system functions, including renal, hepatic, and hematopoietic, is advisable during prolonged therapy.

Drug Interactions

Probenecid competes with meropenem for active tubular secretion and thus inhibits the renal excretion of meropenem. This led to statistically significant increases in the elimination half-life (38%) and in the extent of systemic exposure (56%). Therefore, the coadministration of probenecid with meropenem is not recommended.

There is evidence that meropenem may reduce serum levels of valproic acid to subtherapeutic levels (therapeutic range considered to be 50 to 100 µg/mL total valproate).

Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

Carcinogenesis studies have not been performed.

Mutagenesis

Genetic toxicity studies were performed with meropenem using the bacterial reverse mutation test, the Chinese hamster ovary HGPRT assay, cultured human lymphocytes cytogenic assay, and the mouse micronucleus test. There was no evidence of mutagenic potential found in any of these tests.

Impairment of fertility

Reproductive studies were performed with meropenem in rats at doses up to 1000 mg/kg/day, and cynomolgus monkeys at doses up to 360 mg/kg/day (on the basis of AUC comparisons, approximately 1.8 times and 3.7 times, respectively, to the human exposure at the usual dose of 1 g every 8 hours). There was no reproductive toxicity seen.

Pregnancy Category B

Reproductive studies have been performed with meropenem in rats at doses of up to 1000 mg/kg/day, and cynomolgus monkeys at doses of up to 360 mg/kg/day (on the basis of AUC comparisons, approximately 1.8 times and 3.7 times, respectively, to the human exposure at the usual 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 250 mg/kg/day (on the basis of AUC comparisons, 0.4 times the human exposure at a dose of 1 g every 8 hours) and above in rats. There are, however, 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.

Pediatric Use

The safety and effectiveness of Merrem I.V. have been established for pediatric patients ≥ 3 months of age. Use of Merrem I.V. in pediatric patients with bacterial meningitis is supported by evidence from adequate and well-controlled studies in the pediatric population. Use of Merrem I.V. in pediatric patients with intra-abdominal infections is supported by evidence from adequate and well-controlled studies with adults with additional data from pediatric pharmacokinetics studies and controlled clinical trials in pediatric patients. Use of Merrem I.V. in pediatric patients with complicated skin and skin structure infections is supported by evidence from an adequate and well-controlled study with adults and additional data from pediatric pharmacokinetics studies. (See CLINICAL PHARMACOLOGY, INDICATIONS AND USAGE, ADVERSE REACTIONS, DOSAGE AND ADMINISTRATION, and CLINICAL STUDIES sections.)

Nursing Mothers

It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Merrem I.V. is administered to a nursing woman.

Geriatric Use

Of the total number of subjects in clinical studies of Merrem I.V., approximately 1100 (30%) were 65 years of age and older, while 400 (11%) were 75 years and older. Additionally, in a study of 511 patients with complicated skin and skin structure infections 93 (18%) were 65 years of age and older, while 38 (7%) were 75 years and older. No overall differences in safety or effectiveness were observed between these subjects and younger subjects; spontaneous reports and other reported clinical experience have not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

A pharmacokinetic study with Merrem I.V. in elderly patients with renal insufficiency has shown a reduction in plasma clearance of meropenem that correlates with age-associated reduction in creatinine clearance. (See DOSAGE AND ADMINISTRATION; Use in Adults with Renal Impairment).

Merrem I.V. is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.

Information For Patients

Patients should be counseled that antibacterial drugs including Merrem I.V. should only be used to treat bacterial infections. They do not treat viral infections (eg, the common cold). When Merrem I.V. is prescribed to treat a bacterial infection, patients should be told that although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed. Skipping doses or not completing the full course of therapy may (1) decrease the effectiveness of the immediate treatment and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by Merrem I.V. or other antibacterial drugs in the future.

Adverse Reactions

Adult Patients

During clinical investigations, 2904 immunocompetent adult patients were treated for infections outside the CNS with Merrem I.V. (500 mg or 1000 mg q 8 hours). Deaths in 5 patients were assessed as possibly related to meropenem; 36 (1.2%) patients had meropenem discontinued because of adverse events. Many patients in these trials were severely ill and had multiple background diseases, physiological impairments and were receiving multiple other drug therapies. In the seriously ill patient population, it was not possible to determine the relationship between observed adverse events and therapy with Merrem I.V.

The following adverse reaction frequencies were derived from the clinical trials in the 2904 patients treated with Merrem I.V.

Local Adverse Reactions

Local adverse reactions that were reported irrespective of the relationship to therapy with Merrem I.V. were as follows:

Inflammation at the injection site

2.4%

Injection site reaction

0.9%

Phlebitis/thrombophlebitis

0.8%

Pain at the injection site

0.4%

Edema at the injection site

0.2%

Systemic Adverse Reactions

Systemic adverse clinical reactions that were reported irrespective of the relationship to Merrem I.V. occurring in greater than 1.0% of the patients were diarrhea (4.8%), nausea/vomiting (3.6%), headache (2.3%), rash (1.9%), sepsis (1.6%), constipation (1.4%), apnea (1.3%), shock (1.2%), and pruritus (1.2%).

Additional adverse systemic clinical reactions that were reported irrespective of relationship to therapy with Merrem I.V. and occurring in less than or equal to 1.0% but greater than 0.1% of the patients are listed below within each body system in order of decreasing frequency:

Bleeding events were seen as follows: gastrointestinal hemorrhage (0.5%), melena (0.3%), epistaxis (0.2%), hemoperitoneum (0.2%), summing to 1.2%.

Body as a Whole: pain, abdominal pain, chest pain, fever, back pain, abdominal enlargement, chills, pelvic pain.

Cardiovascular: heart failure, heart arrest, tachycardia, hypertension, myocardial infarction, pulmonary embolus

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Generic Name: Benzoyl Peroxide Wash (BEN-zoyl per-OX-ide) Brand Name: Examples include Benzac AC and EthexDERM BPWEthexDERM BPW Wash is used for:Treating acne. EthexDERM BPW Wash is a keratolytic agent with antibacterial actions. The effectiveness of benzoyl peroxide appears to be due to its an more...

Leflunomide Leflunomide
Dosage Form: Tablets CONTRAINDICATIONS AND WARNINGS PREGNANCY MUST BE EXCLUDED BEFORE THE START OF TREATMENT WITH Leflunomide TABLETS. Leflunomide TABLETS ARE CONTRAINDICATED IN PREGNANT WOMEN, OR WOMEN OF CHILDBEARING POTENTIAL WHO ARE NOT USING RELIABLE CONTRACEPTION. (SEE CONTRAINDICATIONS AN more...

Micatin Spray Micatin Spray
Generic Name: Miconazole Spray and Spray Powder (mi-KON-a-zole) Brand Name: Examples include Desenex Spray and MicatinMicatin Spray is used for:Treating athlete's foot, jock itch, or ringworm and relieving the itching, scaling, burning, and discomfort due to those conditions. It may also be use more...

Neutrogena Healthy Scalp Dandruff Shampoo Neutrogena Healthy Scalp Dandruff Shampoo
Generic Name: salicylic acid topical (sah lih SIH lick AH sid) Brand Names: Compound W, Duofilm, Duoplant, Fungi-Nail, Ionil Shampoo, Keralyt, Mediplast, Neutrogena Acne Wash Oil Free, Neutrogena Healthy Scalp Dandruff Shampoo, Occlusal-HP, Oxy Clean Maximum Strength, Oxy Clean Medicated, more...

Plan B Plan B
Generic Name: Levonorgestrel Tablets (LEE-voe-nor-JESS-truhl) Brand Name: Plan BPlan B is used for:Preventing pregnancy after unprotected sexual intercourse or suspected birth control failure. Plan B is a progestin. How it works is not fully known. It may prevent pregnancy by inhibiting ovulat more...