aeruginosa, a dose of 1 gram every 8 hours is recommended.
Meropenem should be administered by intravenous infusion over approximately 15 minutes to 30 minutes. Doses of 1 gram may also be administered as an intravenous bolus injection (5 mL to 20 mL) over approximately 3 minutes-5 minutes.

Recommended Meropenem I.V. Dosage Schedule for Adult Patients with Renal impairment

Regarding the use of Meropenem I.V.in patients on hemodialysis or peritoneal dialysis, there is inadequate information.

Pediatric patients weighing over 50 kg should be administered Meropenem. at a dose of 500 mg every 8 hours for complicated skin and skin structure infections, 1 gram every 8 hours for intra-abdominal infections and 2 grams every 8 hours for meningitis. Meropenem. should be given as intravenous infusion over approximately 15 minutes to 30 minutes or as an intravenous bolus injection (5 mL to 20 mL) over approximately 3 minutes-5 minutes. There is limited safety data available to support the administration of a 40 mg/kg (up to a maximum of 2 grams) bolus dose.
Recommended Meropenem I.V. Dosage Schedule for Pediatric Patients 3 Months of Age and Older with Normal Renal Function

Pediatric Patients Less Than 3 Months of Age
The Meropenem dose is based on gestational age (GA) and postnatal age (PNA) for pediatric patients (with normal renal function) less than 3 months of age, with intra-abdominal infections. Meropenem I.V. should be given as intravenous infusion over 30 minutes.
Recommended Meropenem Dosage Schedule for Pediatric Patients Less than 3 Months of Age with Complicated Intra-Abdominal Infections and Normal Renal Function

Preparation Of Solution
For Intravenous Bolus Administration
Constitute injection vials (500 mg and 1 gram) with sterile Water for Injection (see table below). Shake to dissolve and let stand until clear.

For Infusion
Infusion vials (500 mg and 1 gram) may be directly constituted with a compatible infusion fluid. Alternatively, an injection vial may be constituted, then the resulting solution added to an intravenous container and further diluted with an appropriate infusion
WARNING: Do not use flexible container in series connections.
Compatibility
Compatibility of Meropenem. with other drugs has not been established. Meropenem. should not be mixed with or physically added to solutions containing other drugs.
Stability And Storage
Freshly prepared solutions of Meropenem. should be used. However, constituted solutions of Meropenem maintain satisfactory potency under the conditions described below. Solutions of intravenous Meropenem. should not be frozen.
Intravenous Bolus Administration
Meropenem. injection vials constituted with sterile Water for Injection for bolus administration (up to 50 mg/mL of Meropenem may be stored for up to 3 hours at up to 25°C (77°F) or for 13 hours at up to 5°C (41°F).
Intravenous Infusion Administration
Solutions prepared for infusion Meropenem . concentrations ranging from 1 mg/mL to 20 mg/mL) constituted with Sodium Chloride Injection 0.9% may be stored for 1 hour at up to 25°C (77°F) or 15 hours at up to 5°C (41°F). Solutions prepared for infusion Meropenem concentrations ranging from 1 mg/mL to 20 mg/mL) constituted with Dextrose Injection 5% should be used immediately.
NOTE: Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

It is important to inquire about previous hypersensitivity reactions to penicillins, cephalosporins, other β-lactams, and other allergens before initiating therapy with MEROPENEM I.V.
Discontinue the drug immediately, if an allergic reaction to MEROPENEM I.V. occurs. Serious anaphylactic reactions require immediate emergency treatment with epinephrine, intravenous steroids, oxygen, and airway management, including intubation. Other therapy may also be administered as indicated.
Seizure Potential
During treatment with MEROPENEM I.V, seizures and other adverse CNS reactions ((e.g., brain lesions or history of seizures) or with bacterial meningitis and/or compromised renal function) have been reported.
Often meropenem-treated patients with seizures had pre-existing contributing factors.
Especially in patients with known factors that predispose to convulsive activity, close adherence to the recommended dosage regimens is urged. In patients with known seizure disorders, continue anti-convulsant therapy. In patients with advanced age and/or reduced renal function, dosage adjustment is recommended.
If myoclonus, focal tremors, or seizures occur, evaluate neurologically, place the patient on anti-convulsant therapy if not already instituted, and determine whether Meropenem I.V should be decreased or the antibacterial drug discontinued. The dosage of Meropenem should be re-examined.
Interaction with Valproic Acid
It has been reported that concomitant use of carbapenems, including meropenem, in patients receiving valproic acid or divalproex sodium results in decreasing valproic acid concentrations. As a result of this interaction, the valproic acid concentrations may drop below the therapeutic range, thereby increasing the risk of breakthrough seizures.
To overcome this interaction, increasing the dose of valproic acid or divalproex sodium may not be sufficient. Co-administration of meropenem and valproic acid or divalproex sodium is generally not recommended.
In patients whose seizures are well controlled on valproic acid or divalproex sodium, anti-bacterials other than carbapenems should be considered to treat infections. Supplemental anticonvulsant therapy should be considered, if administration of Meropenem . is necessary.
Clostridium Difficile–Associated Diarrhea With use of nearly all antibacterial agents, including Meropenem , Clostridium difficile-associated diarrhea (CDAD) has been reported, and may range in severity from mild diarrhea to fatal colitis. The normal flora of the colon is altered leading to overgrowth of C. difficile with antibacterial treatment.
C. difficile produces toxins A and B which lead to the development of CDAD. Hyper-toxin producing isolates of C. difficile causes increased mortality and morbidity, as these infections can be refractory to antimicrobial therapy and may require colectomy. In all patients who present with diarrhea following antibacterial drug use, CDAD must be considered. CDAD has been reported to occur over two months after the administration of antibacterial agent’s careful medical history is necessary.
Ongoing antibacterial drug use not directed against C. difficile may need to be discontinued if CDAD is suspected or confirmed. Appropriate protein supplementation, fluid and electrolyte management, antibacterial drug treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated.
Development of Drug-Resistant Bacteria
Prescribing meropenem in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication , is unlikely to provide benefit to the patient and can increase the risk of the development of drug-resistant bacteria.
Overgrowth of Non-susceptible Organisms
Prolonged use of meropenem may result in overgrowth of non-susceptible organisms, as with other broad-spectrum antibacterial drugs. Repeated evaluation of the patient is required . Appropriate measures must be taken, if super-infection does occur during therapy.
Laboratory Tests
Periodic assessment of organ system functions, including renal, hepatic, and hematopoietic, is advisable during prolonged therapy as Meropenem possesses the characteristic low toxicity of the beta-lactam group of antibacterial drugs.
Patients with Renal Impairment
Thrombocytopenia has been observed but no clinical bleeding reported, in patients with renal impairment.
Dialysis
In patients on hemodialysis or peritoneal dialysis, there is inadequate information regarding the use of Meropenem .
Potential for Neuromotor Impairment
Patients receiving Meropenem . 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 is well tolerated, patients should not operate machinery or motorized vehicles
Carcinogenesis
Carcinogenesis studies have not been performed with meropenem
Mutagenesis
Genetic toxicity studies were performed with meropenem using the Chinese hamster ovary HGPRT assay, the bacterial reverse mutation test, the mouse micronucleus test, cultured human lymphocytes cytogenic assay, and no evidence of mutagenic potential was found in any of these tests.
Impairment of Fertility
There was no reproductive toxicity seen when Reproductive studies were performed with meropenem in animals (rats at doses up to 1000 mg/kg/day, and cynomolgus monkeys at doses up to 360 mg/kg/day ) .

Nursing Mothers

Caution should be exercised when Meropenem is administered to a nursing woman Meropenem has been reported to be excreted in human milk.

Pediatric Use
Meropenem safety and effectiveness has been established in pediatric patients 3 months of age and older diagnosed with bacterial meningitis, complicated skin and skin structure infections and for pediatric patients of all ages with complicated intra-abdominal infections.

Skin and Skin Structure Infections
In pediatric patients 3 months of age and older with complicated skin and skin structure infections, use of Meropenem is supported by evidence from an adequate and well-controlled study in adults and additional data from pediatric pharmacokinetics studies.

Intra-abdominal Infections
In pediatric patients 3 months of age and older with intra-abdominal infections use of Meropenem. is supported by evidence from adequate and well-controlled studies in adults with additional data from pediatric pharmacokinetics studies and controlled clinical trials in pediatric patients.

In pediatric patients less than 3 months of age with intra-abdominal infections use of Meropenem. is supported by evidence from adequate and well-controlled studies in adults with additional data from a pediatric pharmacokinetic and safety study

Bacterial Meningitis
In pediatric patients 3 months of age and older with bacterial meningitis use of Meropenem. is supported by evidence from adequate and well-controlled studies in the pediatric population.

Geriatric Use
The risk of adverse reactions to Meropenem may be increased in patients with renal impairment as Meropenem is known to be substantially excreted by the kidney. 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.

In elderly patients, a reduction in the plasma clearance of meropenem that correlates with age-associated reduction in creatinine clearance has been observed .

Patients with Renal Impairment
In patients with creatinine clearance 50 mL/min or less , dosage adjustment is essential .

Digestive System: anorexia, dyspepsia, cholestatic jaundice/jaundice, ileus, oral moniliasis, flatulence, hepatic failure, intestinal obstruction
Hemic/Lymphatic: hypochromic anemia, anemia, hypervolemia
Metabolic/Nutritional: hypoxia, peripheral edema,
Nervous System: agitation/delirium, insomnia, anxiety, nervousness, dizziness, seizure, paresthesia, hallucinations, somnolence, depression, confusion, asthenia
Respiratory: cough increased, dyspnea, pleural effusion, respiratory disorder, asthma, lung edema
Skin and Appendages: sweating, urticaria, skin ulcer Urogenital System: kidney failure, vaginal moniliasis, dysuria, urinary incontinence
Hepatic: increased SGOT (AST), SGPT (ALT), LDH, alkaline phosphatase, and bilirubin
Hematologic: increased eosinophils, decreased platelets, decreased WBC, increased platelets, decreased hemoglobin, decreased hematocrit, shortened prothrombin time and shortened partial thromboplastin time, hypokalemia, leukocytosis
Renal: increased BUN and increased creatinine
NOTE: For patients with varying degrees of renal impairment, the incidence of kidney failure, heart failure, seizure and shock reported irrespective of relationship to Meropenem I.V., increased in patients with moderately severe renal impairment (creatinine clearance >10 to 26 mL/min). Urinalysis: presence of red blood cells
Hematologic – neutropenia, agranulocytosis, and leukopenia.
Skin –Stevens-Johnson Syndrome, angioedema, toxic epidermal necrolysis, and erythema multiform

In clinical trials, the largest dose of meropenem administered has been 2 grams given intravenously every 8 hours. No adverse pharmacological effects or increased safety risks have been observed, at this dosage.
Limited post-marketing experience indicates that occur following overdosage if adverse events, they are consistent with the adverse event profile and are generally mild in severity and resolve on withdrawal or dose reduction.
Treatment Consider symptomatic treatment. Rapid renal elimination takes place in individuals with normal renal function.
Meropenem and its metabolite are readily dialyzable and effectively removed by hemodialysis; however, to treat overdosage no information is available on the use of hemodialysis.

Pharmacodynamic Properties:
Meropenem exerts its action by penetrating bacterial cells readily and interfering with the synthesis of vital cell wall components, which leads to cell death.
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.
Meropenem has significant stability to hydrolysis by β-lactamases, both penicillinases and cephalosporinases produced by Gram-positive and Gram-negative bacteria. Meropenem should not be used to treat methicillin-resistant Staphylococcus aureus (MRSA) or methicillin-resistant Staphylococcus epidermidis (MRSE).

Spectrum of Activity

Meropenem has been shown to be active against most isolates of the following bacteria, both in vitro and in clinical infections

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
Pseudomonas aeruginosa
Proteus mirabilis

Anaerobic Bacteria

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 bacteria have exhibited in vitro minimum inhibitory concentrations (MICs) less than or equal to the susceptible breakpoints for meropenem.

Gram-negative Bacteria

Aeromonas hydrophila
Campylobacter jejuni
Citrobacter koseri (formerly diversus)
Citrobacter freundii
Enterobacter cloacae
Hafnia alvei
Klebsiella oxytoca
Moraxella catarrhalis
Morganella morganii
Pasteurella multocida
Proteus vulgaris
Serratia marcescens
Anaerobic Bacteria
Bacteroides distasonis
Bacteroides ovatus
Bacteroides uniformis
Bacteroides ureolyticus
Bacteroides vulgatus
Clostridium difficile
Clostridium perfringens
Eubacterium lentum
Fusobacterium species
Prevotella bivia
Prevotella intermedia
Prevotella melaninogenica
Porphyromonas asaccharolytica
Propionibacterium acnes

Pharmacokinetic Properties:

Pharmacokinetics in special patient populations
Specific Populations
Renal Impairment
Pharmacokinetic studies with Meropenem 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)
Meropenem is hemodialyzable. But there is no information regarding the usefulness of hemodialysis to treat overdosage
Hepatic Impairment
A pharmacokinetic study with Meropenem. in patients with hepatic impairment has demonstrated no effects of liver disease on the pharmacokinetics of meropenem.
Geriatric Patients
A pharmacokinetic study with Meropenem 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 I.V., 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.

Meropenem is generally well tolerated by the central nervous system. Effects were seen in acute toxicity studies in rodent at doses exceeding 1000 mg/kg.
The IV LD50 of meropenem in rodents is greater than 2000 mg/kg.
In repeat dose studies of up to 6 months duration only minor effects were seen including a decrease in red cell parameters in dogs.
There was no evidence of mutagenic potential in a conventional test battery and no evidence of reproductive toxicity including teratogenic potential in studies in rats up to 750 mg/kg and in monkeys up to 360 mg/kg.
There was no evidence of increased sensitivity to meropenem in juveniles compared to adult animals. The intravenous formulation was well tolerated in animal studies.
The sole metabolite of meropenem had a similar profile of toxicity in animal studies.