Meropenem

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{{DrugProjectFormSinglePage |authorTag=Stefano Giannoni [1] |genericName=Meropenem |aOrAn=a |drugClass=Carbapenem |indicationType=treatment |indication=complicated skin and skin structure infections, intra-abdominal infections, bacterial meningitis (pediatric patients). |blackBoxWarningTitle=TITLE |blackBoxWarningBody=Condition Name: (Content) |fdaLIADAdult=====Skin and Skin Structure Infections====

  • Dosage: 500 mg IV every 8 hours.

Is indicated as a single agent therapy for the treatment of complicated skin and skin structure infections due to:

Intra-abdominal Infections

  • 1 g IV every 8 hours

Is indicated as a single agent therapy for the treatment of complicated appendicitis and peritonitis caused by:

Meropenem for injection (I.V.) should be administered by intravenous infusion over approximately 15 to 30 minutes. Doses of 1 g may also be administered as an intravenous bolus injection (5 to 20 mL) over approximately 3-5 minutes.

Use in Adult Patients with Renal Impairment

There is inadequate information regarding the use of Meropenem for injection (I.V.) in patients on hemodialysis or peritoneal dialysis. |offLabelAdultGuideSupport=There is limited information regarding Off-Label Guideline-Supported Use of Meropenem in adult patients. |offLabelAdultNoGuideSupport=====Cystic Fibrosis====

  • 120 mg/kg IV t.i.d. (maximum 2 g/dose)[1]
  • In combination with tobramycin

Nosocomial Pneumonia

  • 1 g IV t.i.d.[2]
  • As monotherapy

Febrile Neutropenia

  • 1 g t.i.d.[3]
  • As monotherapy.

|fdaLIADPed=====Skin and Skin Structure Infections (Pediatric Patients ≥ 3 Months only)====

  • 10m/kg IV every 8 hours.
  • Up to a maximum Dose of 500 mg
  • Pediatric patients weighing over 50 kg should be administered Meropenem for injection (I.V.) at a dose of 500 mg every 8 hours for complicated skin and skin structure infections.

Is indicated as a single agent therapy for the treatment of complicated skin and skin structure infections due to:

Intra-abdominal Infections (Pediatric Patients ≥ 3 Months only)

  • 20 mg/kg IV every 8 hours
  • Up to a maximum dose of 1g
  • Pediatric patients weighing over 50 kg should be administered Meropenem for injection (I.V.) at a dose of 1 g every 8 hours for intra-abdominal infections.

Is indicated as a single agent therapy for the treatment of complicated appendicitis and peritonitis caused by:


Bacterial Meningitis (Pediatric Patients ≥ 3 Months only)

  • 40 mg IV every 8 hours.
  • Up to a maximum of 2 g.

Pediatric patients weighing over 50 kg should be administered Meropenem for injection (I.V.) at a dose of 2 g every 8 hours for meningitis. Meropenem for injection (I.V.) is indicated as a single agent therapy for the treatment of bacterial meningitis caused by:


Meropenem for injection (I.V.) should be given as intravenous infusion over approximately 15 to 30 minutes or as an intravenous bolus injection (5 to 20 mL) over approximately 3-5 minutes.

There is limited safety data available to support the administration of a 40 mg/kg (up to a maximum of 2 g) bolus dose. There is no experience in pediatric patients with renal impairment. |offLabelPedGuideSupport=There is limited information regarding Off-Label Guideline-Supported Use of Meropenem in pediatric patients. |offLabelPedNoGuideSupport=====Cystic Fibrosis====

  • 120 mg/kg IV t.i.d. (maximum 2 g/dose)[1]
  • In combination with tobramycin

Febrile Neutropenia

  • 60 mg/kg/day t.i.d.[4]
  • As monotherapy

|contraindications=*Hypersensitivity to any component of this product or to other drugs in the same class

|warnings=====Hypersensitivity Reactions====

Seizure Potential

  • Seizures and other adverse CNS experiences have been reported during treatment with Meropenem for injection (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 non-CNS infections 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.
  • Close adherence to the recommended dosage regimens is urged, especially in patients with known factors that predispose to convulsive activity.
  • Anti-convulsant therapy should be continued in patients with known seizure disorders.
  • If focal tremors, myoclonus, or seizures occur, patients should be evaluated neurologically, placed on anti-convulsant therapy if not already instituted, and the dosage of Meropenem for injection (I.V.) re-examined to determine whether it should be decreased or the antibiotic discontinued.

Interaction with Valproic Acid

Clostridium difficile–Associated Diarrhea

Development of Drug-Resistant Bacteria

  • Prescribing Meropenem for injection (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.

Overgrowth of Nonsusceptible Organisms

  • 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 Meropenem for injection (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.

Patients with Renal Impairment

Dialysis

Potential for Neuromotor Impairment

  • Patients receiving Meropenem for injection (I.V.) on an outpatient basis may develop adverse events such as seizures, headaches and/or paresthesias that could interfere with mental alertness and/or cause motor impairment.
  • Until it is reasonably well established that Meropenem for injection (I.V.) is well tolerated, patients should not operate machinery or motorized vehicles.

|clinicalTrials=Because clinical trials are conducted under widely varying conditions, adverse reactions rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Adult Patients

  • During clinical investigations, 2904 immunocompetent adult patients were treated for non-CNS infections with Meropenem for injection (I.V.) (500 mg or 1000 mg every 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 Meropenem for injection (I.V.).

The following adverse reaction frequencies were derived from the clinical trials in the 2904 patients treated with Meropenem for injection (I.V.)

Local Adverse Reactions

Local adverse reactions that were reported irrespective of the relationship to therapy with Meropenem for injection (I.V.) were as follows:

Systemic Adverse Reactions

Systemic adverse reactions that were reported irrespective of the relationship to Meropenem for injection (I.V.) occurring in greater than 1% 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 systemic adverse reactions that were reported irrespective of relationship to therapy with Meropenem for injection (I.V.) and occurring in less than or equal to 1% but greater than 0.1% of the patients are listed below within each body system in order of decreasing frequency:

Body as a Whole
Cardiovascular
Digestive System
Hemic/Lymphatic
Metabolic/Nutritional
Nervous System
Respiratory
Skin and Appendages
Urogenital System
Adverse Laboratory Changes

Adverse laboratory changes that were reported irrespective of relationship to Meropenem for injection (I.V.) and occurring in greater than 0.2% of the patients were as follows:

Hepatic
Hematologic
Renal


For patients with varying degrees of renal impairment, the incidence of heart failure, kidney failure, seizure and shock reported irrespective of relationship to Meropenem for injection (I.V.), increased in patients with moderately severe renal impairment (creatinine clearance > 10 to 26 mL/min).

Urinalysis
Complicated Skin and Skin Structure Infections

In a study of complicated skin and skin structure infections, the adverse reactions were similar to those listed above. The most common adverse events occurring in > 5% of the patients were:

Adverse events with an incidence of > 1%, and not listed above, include:


Pediatric Patients

Clinical Adverse Reactions

Meropenem for injection (I.V.) was studied in 515 pediatric patients (≥ 3 months to < 13 years of age) with serious bacterial infections (excluding meningitis. At dosages of 10 to 20 mg/kg every 8 hours. The types of clinical adverse events seen in these patients are similar to the adults, with the most common adverse events reported as possibly, probably, or definitely related to Meropenem for injection (I.V.) and their rates of occurrence as follows:

Meropenem for injection (I.V.) was studied in 321 pediatric patients (≥ 3 months to < 17 years of age) with meningitis at a dosage of 40 mg/kg every 8 hours. The types of clinical adverse events seen in these patients are similar to the adults, with the most common adverse events reported as possibly, probably, or definitely related to Meropenem for injection (I.V.) and their rates of occurrence as follows:

In the meningitis studies, the rates of seizure activity during therapy were comparable between patients with no CNS abnormalities who received meropenem and those who received comparator agents (either cefotaxime or ceftriaxone). In the Meropenem for injection (I.V.) treated group, 12/15 patients with seizures had late onset seizures (defined as occurring on day 3 or later) versus 7/20 in the comparator arm.

Adverse Laboratory Changes

Laboratory changes seen in the pediatric studies, including the meningitis studies, were similar to those reported in the adult studies.

There is no experience in pediatric patients with renal impairment. |postmarketing=The following adverse reactions have been identified during post-approval use of Meropenem for injection (I.V.). Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Worldwide post-marketing adverse reactions not otherwise listed in the Adverse Reactions section of this product label and reported as possibly, probably, or definitely drug related are listed within each body system in order of decreasing severity.

Hematologic
Skin

|drugInteractions=====Probenecid====

  • Probenecid competes with meropenem for active tubular secretion, resulting in increased plasma concentrations of meropenem.
  • Co-administration of probenecid with meropenem is not recommended.

Other Antibiotics

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

Valproic Acid

  • 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.
  • Although the mechanism of this interaction is unknown, data from in vitro and animal studies suggest that carbapenems may inhibit the hydrolysis of valproic acid’s glucuronide metabolite (VPA-g) back to valproic acid, thus decreasing the serum concentrations of valproic acid.
  • If administration of Meropenem for injection (I.V.) is necessary, then supplemental anti-convulsant therapy should be considered.

|FDAPregCat=B |useInPregnancyFDA=*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.

|useInNursing=*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 Meropenem for injection (I.V.) is administered to a nursing woman.

|useInPed=*The safety and effectiveness of Meropenem for injection (I.V.) have been established for pediatric patients ≥ 3 months of age.

  • Use of Meropenem for injection (I.V.) 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 (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 Meropenem for injection (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.

|useInGeri=*Of the total number of subjects in clinical studies of Meropenem for injection (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 complicatedskin 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.
  • Meropenem is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with renal impairment.
  • 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.
  • A pharmacokinetic study with Meropenem for injection (I.V.) in elderly patients has shown a reduction in the plasma clearance of meropenem that correlates with age-associated reduction in creatinine clearance.

|useInRenalImpair=*Dosage adjustment is necessary in patients with creatinine clearance 50 mL/min or less. |administration=*Intravenous |monitoring=While Meropenem for injection (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. |overdose=*In mice and rats, large intravenous doses of meropenem (2200-4000 mg/kg) have been associated with ataxia, dyspnea, convulsions, and mortalities.

  • Intentional overdosing of Meropenem for injection (I.V.) is unlikely, although accidental overdosing might occur if large doses are given to patients with reduced renal function.
  • The largest dose of meropenem administered in clinical trials has been 2 g given intravenously every 8 hours.
  • At this dosage, no adverse pharmacological effects or increased safety risks have been observed.
  • Limited post-marketing experience indicates that if adverse events occur following overdosage, they are consistent with the adverse event profile described in the Adverse Reactions section and are generally mild in severity and resolve on withdrawal or dose reduction.
  • Symptomatic treatments should be considered.
  • In individuals with normal renal function, rapid renal elimination takes place.
  • Meropenem and its metabolite are readily dialyzable and effectively removed by hemodialysis; however, no information is available on the use of hemodialysis to treat overdosage.

|drugBox=

Chemical structure of Meropenem
Meropenem
Systematic (IUPAC) name
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Identifiers
CAS number ?
ATC code ?
PubChem 64778
DrugBank APRD01097
Chemical data
Formula Template:OrganicBox atomTemplate:OrganicBox atomTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBox atomTemplate:OrganicBoxTemplate:OrganicBox atomTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBox atomTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBox 
Mol. mass ?
Pharmacokinetic data
Bioavailability ?
Metabolism ?
Half life ?
Excretion ?
Therapeutic considerations
Pregnancy cat.

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Legal status
Routes ?

|mechAction=*The bactericidal activity of meropenem results from the inhibition of cell wall synthesis.

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 PBPs. 3)Increased expression of efflux pump components. 4)Production of antibiotic-destroying enzymes (carbapenemases, metallo-β-lactamases). Localized clusters of infections due to carbapenem-resistant bacteria have been reported in some regions. |structure=*Meropenem for Injection, USP (I.V.) 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:
  • Meropenem for Injection, USP (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, each 500 mg Meropenem for Injection, USP (I.V.) vial will deliver 500 mg meropenem and 45.1 mg of sodium as sodium carbonate (1.96 mEq). Each 1 g Meropenem for Injection, USP (I.V.) vial will deliver 1 g of meropenem and 90.2 mg of sodium as sodium carbonate (3.92 mEq).

|nonClinToxic=====Carcinogenesis, Mutagenesis, Impairment of Fertility====

Carcinogenesis
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.

|alcohol=Alcohol-Meropenem interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. |brandNames=*Merrem IV }}

Meropenem
MERREM® FDA Package Insert
Description
Clinical Pharmacology
Microbiology
Indications and Usage
Contraindications
Warnings
Precautions
Adverse Reactions
Overdosage
Clinical Studies
Dosage and Administration
Compatibility, Reconstitution, and Stability
How Supplied
Labels and Packages

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [2]; Associate Editor(s)-in-Chief: Sheng Shi, M.D. [3]

Overview

Meropenem is an ultra-broad spectrum injectable antibiotic used to treat a wide variety of infections, including meningitis and pneumonia. It is a beta-lactam and belongs to the subgroup of carbapenem, similar to imipenem and ertapenem. Meropenem gained FDA approval in July 1996. It penetrates well into many tissues and body fluids including the cerebrospinal fluid,bile, heart valves, lung, and peritoneal fluid.[5]

Category

Carbapenem

US Brand Names

MERREM®

FDA Package Insert

Description | Clinical Pharmacology | Microbiology | Indications and Usage | Contraindications | Warnings | Precautions | Adverse Reactions | Overdosage | Clinical Studies | Dosage and Administration | Compatibility, Reconstitution, and Stability | How Supplied | Labels and Packages

Mechanism of action

Meropenem is bactericidal except against Listeria monocytogenes where it is bacteriostatic. It inhibits bacterial wall synthesis like other beta-lactam antibiotics. In contrast to other beta-lactams, it is highly resistant to degradation by beta-lactamase or cephalosporinase. Resistance generally arises due to mutations in penicillin binding proteins, production of metallo-beta-lactamases, or resistance to diffusion across the bacterial outer membrane.[6] Unlike imipenem, it is stable to dehydropeptidase-1 and can therefore be given without cilastatin.

References

  1. ↑ 1.0 1.1 Latzin P, Fehling M, Bauernfeind A, Reinhardt D, Kappler M, Griese M (2008). "Efficacy and safety of intravenous meropenem and tobramycin versus ceftazidime and tobramycin in cystic fibrosis". J Cyst Fibros. 7 (2): 142–6. doi:10.1016/j.jcf.2007.07.001. PMID 17766190.
  2. ↑ Alvarez Lerma F, Serious Infection Study Group (2001). "Efficacy of meropenem as monotherapy in the treatment of ventilator-associated pneumonia". J Chemother. 13 (1): 70–81. doi:10.1179/joc.2001.13.1.70. PMID 11233804.
  3. ↑ "Equivalent efficacies of meropenem and ceftazidime as empirical monotherapy of febrile neutropenic patients. The Meropenem Study Group of Leuven, London and Nijmegen". J Antimicrob Chemother. 36 (1): 185–200. 1995. PMID 8537265.
  4. ↑ Oguz A, Karadeniz C, Citak EC, Cil V, Eldes N (2006). "Experience with cefepime versus meropenem as empiric monotherapy for neutropenia and fever in pediatric patients with solid tumors". Pediatr Hematol Oncol. 23 (3): 245–53. doi:10.1080/08880010500506867. PMID 16517540.
  5. ↑ AHFS DRUG INFORMATION® 2006 (2006 ed ed.). American Society of Health-System Pharmacists. 2006.
  6. ↑ Mosby's Drug Consult 2006 (16 ed ed.). Mosby, Inc. 2006.
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