Meropenem

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# Overview
Meropenem is a Carbapenem that is FDA approved for the treatment of complicated skin and skin structure infections, intra-abdominal infections, bacterial meningitis (pediatric patients)..   Common adverse reactions include headache, nausea, constipation, diarrhea, anemia, vomiting, and rash.

# Adult Indications and Dosage

## FDA-Labeled Indications and Dosage (Adult)

### 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:
- Staphylococcus aureus (methicillin-susceptible isolates only)
- Streptococcus pyogenes
- Streptococcus agalactiae
- Viridans group streptococci
- Enterococcus faecalis (vancomycin-susceptible isolates only)
- Pseudomonas aeruginosa
- Escherichia coli
- Proteus mirabilis
- Bacteroides fragilis
- Peptostreptococcus species

### 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:
- Viridans group streptococci
- Escherichia coli
- Klebsiella pneumoniae
- Pseudomonas aeruginosa
- Bacteroides fragilis
- B. thetaiotaomicron
- Peptostreptococcus species
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
- Dosage should be reduced in patients with creatinine clearance of 50 mL/min or less.
- When only serum creatinine is available, the following formula (Cockcroft and Gault equation) may be used to estimate creatinine clearance.
There is inadequate information regarding the use of Meropenem for injection (I.V.) in patients on hemodialysis or peritoneal dialysis.

## Off-Label Use and Dosage (Adult)

### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Meropenem in adult patients.

### NonGuideline-Supported Use

### Cystic Fibrosis
- 120 mg/kg IV t.i.d.  (maximum 2 g/dose)
- In combination with tobramycin

### Nosocomial Pneumonia
- 1 g IV t.i.d.
- As monotherapy

### Febrile Neutropenia
- 1 g t.i.d.
- As monotherapy.

# Pediatric Indications and Dosage

## FDA-Labeled Indications and Dosage (Pediatric)

### 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:
- Staphylococcus aureus (methicillin-susceptible isolates only)
- Streptococcus pyogenes
- Streptococcus agalactiae
- Viridans group streptococci
- Enterococcus faecalis (vancomycin-susceptible isolates only)
- Pseudomonas aeruginosa
- Escherichia coli
- Proteus mirabilis
- Bacteroides fragilis
- Peptostreptococcus species

### 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:
- Viridans group streptococci
- Escherichia coli
- Klebsiella pneumoniae
- Pseudomonas aeruginosa
- Bacteroides fragilis
- B. thetaiotaomicron
- Peptostreptococcus species

### 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:
- Streptococcus pneumoniae
- Haemophilus influenzae
- Neisseria meningitidis
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.

## Off-Label Use and Dosage (Pediatric)

### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Meropenem in pediatric patients.

### NonGuideline-Supported Use

### Cystic Fibrosis
- 120 mg/kg IV t.i.d. (maximum 2 g/dose)
- In combination with tobramycin

### Febrile Neutropenia
- 60 mg/kg/day t.i.d.
- As monotherapy

# Contraindications
- Hypersensitivity to any component of this product or to other drugs in the same class
- Demonstrated anaphylactic reactions to -lactams.

# Warnings

### Hypersensitivity Reactions
- Serious and occasionally fatal hypersensitivity (anaphylactic) reactions have been reported in patients receiving therapy with -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 -lactam.
- Before initiating therapy with Meropenem for injection (I.V.), careful inquiry should be made concerning previous hypersensitivity reactions to penicillins, cephalosporins, other -lactams, and other allergens. *If an allergic reaction to Meropenem for injection (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.

### 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
- 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 (I.V.) is necessary, supplemental anti-convulsant therapy should be considered.

### Clostridium difficileAssociated Diarrhea
- Clostridium difficile-associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including Meropenem for injection (I.V.), and may range in severity from mild diarrhea to fatal colitis.
- Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile.
- C. difficile produces toxins A and B which contribute to the development of CDAD.
- Hypertoxin producing isolates of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy.
- CDAD must be considered in all patients who present with diarrhea following antibiotic use.
- Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents.
- If CDAD is suspected or confirmed, ongoing antibiotic use not directed against C. difficile may need to be discontinued.
- Appropriate fluid and electrolyte management, protein supplementation, antibiotic treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated.

### 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
- In patients with renal impairment, thrombocytopenia has been observed but no clinical bleeding reported.

### Dialysis
- There is inadequate information regarding the use of Meropenem for injection (I.V.) in patients on hemodialysis or peritoneal 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.

# Adverse Reactions

## Clinical Trials Experience
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 that were reported irrespective of the relationship to therapy with Meropenem for injection (I.V.) were as follows:
- Inflammation at the injection site 2.4%
- Injection site reaction 0.9%
- Phlebitis/thrombophlebitis 0.8%
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:
- Bleeding events were seen as follows: gastrointestinal hemorrhage (0.5%), melena (0.3%), epistaxis (0.2%), hemoperitoneum (0.2%), summing to 1.2%.
- Pain
- Abdominal pain
- Chest pain
- Fever
- Back pain
- Abdominal enlargement
- Chills
- Pelvic pain
- Heart failure
- Heart arrest
- Tachycardia
- Hypertension
- Myocardial infarction
- Pulmonary embolus
- Bradycardia
- Hypotension
- Syncope
- Oral moniliasis
- Anorexia
- Cholestatic jaundice/jaundice
- Flatulence
- Ileus
- Hepatic failure
- Dyspepsia
- Intestinal obstruction
- Anemia
- Hypochromic anemia
- Hypervolemia
- Peripheral edema
- Hypoxia
- Insomnia
- Agitation/delirium
- Confusion
- Dizziness
- Seizure
- Nervousness
- Paresthesia
- Hallucinations
- Somnolence
- Anxiety
- Depression
- Asthenia
- Respiratory disorder
- Dyspnea
- Pleural effusion
- Asthma
- Cough increased
- Lung edema
- Urticaria sweating
- Skin ulcer
- Dysuria
- Kidney failure
- Vaginal moniliasis
- Urinary incontinence
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:
- Increased SGPT (ALT), SGOT (AST), alkaline phosphatase, LDH, and bilirubin
- Increased platelets
- Increased eosinophils
- Decreased platelets
- Decreased hemoglobin
- Decreased hematocrit
- Decreased WBC
- Shortened prothrombin time and shortened partial thromboplastin time
- Leukocytosis
- Hypokalemia
- Increased creatinine
- Increased BUN
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).
- Presence of red blood cells
- Pain at the injection site 0.4%
- Edema at the injection site 0.2%
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:
- Headache (7.8%)
- Nausea (7.8%)
- Constipation (7%)
- Diarrhea (7%)
- Anemia (5.5%)
- Pain (5.1%)
Adverse events with an incidence of > 1%, and not listed above, include:
- Pharyngitis,
- Accidental injury
- Gastrointestinal disorder
- Hypoglycemia
- Peripheral vascular disorder
- Pneumonia

### Pediatric Patients
Meropenem for injection (I.V.) was studied in 515 pediatric patients ( 3 months to < 13 years of age) with serious bacterial infections (excluding meningitisinfections). 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:
- Diarrhea 3.5%
- Rash 1.6%
- Nausea and Vomiting 0.8%
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:
- Diarrhea 4.7%
- Rash (mostly diaper area moniliasis) 3.1%
- Oral Moniliasis 1.9%
- Glossitis 1%
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.
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 Experience
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.
- Agranulocytosis
- Neutropenia
- Leukopenia
- Positive direct or indirect Coombs test
- hemolytic anemia.
- Toxic epidermal necrolysis
- Stevens-Johnson Syndrome
- Angioedema
- Erythema multiforme

# Drug Interactions

### 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 acids 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.

# Use in Specific Populations

### Pregnancy
Pregnancy Category (FDA): 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.
Pregnancy Category (AUS): B2
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Meropenem in women who are pregnant.

### Labor and Delivery
There is no FDA guidance on use of Meropenem during labor and delivery.

### 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 Meropenem for injection (I.V.) is administered to a nursing woman.

### Pediatric Use
- 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.

### Geriatic Use
- 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.

### Gender
There is no FDA guidance on the use of Meropenem with respect to specific gender populations.

### Race
There is no FDA guidance on the use of Meropenem with respect to specific racial populations.

### Renal Impairment
- Dosage adjustment is necessary in patients with creatinine clearance 50 mL/min or less.
- Pharmacokinetic studies with Meropenem for injection (I.V.) in patients with renal impairment have shown that the plasma clearance of meropenem correlates with creatinine clearance.

### Hepatic Impairment
There is no FDA guidance on the use of Meropenem in patients with hepatic impairment.

### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Meropenem in women of reproductive potentials and males.

### Immunocompromised Patients
There is no FDA guidance one the use of Meropenem in patients who are immunocompromised.

# Administration and Monitoring

### 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.

# IV Compatibility
There is limited information regarding the compatibility of Meropenem and IV administrations.

# Overdosage
- 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.

# Pharmacology

## Mechanism of Action
- 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 -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).

### Mechanism of Resistance
- There are several mechanisms of resistance to carbapenems:
- Decreased permeability of the outer membrane of Gram-negative bacteria (due to diminished production of porins) causing reduced bacterial uptake.
- Reduced affinity of the target PBPs.
- Increased expression of efflux pump components.
- Production of antibiotic destroying enzymes (carbapenemases, metallo--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-thio]-6--4-methyl-7-oxo-1-azabicyclohept-2-ene-2-carboxylic acid trihydrate. Its empirical formula is C17H25N3O5S3H2O 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).

## Pharmacodynamics
There is limited information regarding Meropenem Pharmacodynamics in the drug label.

## Pharmacokinetics
At the end of a 30-minute intravenous infusion of a single dose of Meropenem for injection (I.V.) in healthy volunteers, mean peak plasma concentrations of meropenem are approximately 23 mcg/mL (range 14-26) for the 500 mg dose and 49 mcg/mL (range 39-58) for the 1 g dose. A 5-minute intravenous bolus injection of Meropenem for injection (I.V.) in healthy volunteers results in mean peak plasma concentrations of approximately 45 mcg/mL (range 18-65) for the 500 mg dose and 112 mcg/mL (range 83-140) for the 1 g dose.
Following intravenous doses of 500 mg, mean plasma concentrations of meropenem usually decline to approximately 1 mcg/mL at 6 hours after administration.
No accumulation of meropenem in plasma was observed with regimens using 500 mg administered every 8 hours or 1 g administered every 6 hours in healthy volunteers with normal renal function.
The plasma protein binding of meropenem is approximately 2%.
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 Meropenem for injection (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.
There is one metabolite of meropenem that is microbiologically inactive.
In subjects with normal renal function, the elimination half-life of meropenem is approximately 1 hour. Meropenem is primarily excreted unchanged by the kidneys. Approximately 70% (50  75%) of the dose is excreted unchanged within 12 hours. A further 28% is recovered as the microbiologically inactive metabolite. Fecal elimination represents only approximately 2% of the dose. The measured renal clearance and the effect of probenecid show that meropenem undergoes both filtration and tubular secretion.

### Specific Populations
Pharmacokinetic studies with Meropenem for injection (I.V.) 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 I.V. is hemodialyzable. However, there is no information on the usefulness of hemodialysis to treat overdosage.
A pharmacokinetic study with Meropenem for injection (I.V.) in patients with hepatic impairment has shown no effects of liver disease on the pharmacokinetics of meropenem.
A pharmacokinetic study with Meropenem for injection (I.V.) in elderly patients with renal impairment showed a reduction in plasma clearance of meropenem that correlates with age-associated reduction in creatinine clearance.
The pharmacokinetics of meropenem 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.
Probenecid competes with meropenem for active tubular secretion and thus inhibits the renal excretion of meropenem. Following administration of probenecid with meropenem, the mean systemic exposure increased 56% and the mean elimination half-life increased 38%. Co-administration of probenecid with meropenem is not recommended.

## Nonclinical Toxicology

### Carcinogenesis, Mutagenesis, Impairment of Fertility
- Carcinogenesis studies have not been performed.
- 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.
- 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.

# Clinical Studies

### Complicated Skin and Skin Structure Infections
Adult patients with complicated skin and skin structure infections including complicated cellulitis, complex abscesses, perirectal abscesses, and skin infections requiring intravenous antimicrobials, hospitalization, and surgical intervention were enrolled in a randomized, multi-center, international, double-blind trial. The study evaluated meropenem at doses of 500 mg administered intravenously every 8 hours and imipenem-cilastatin at doses of 500 mg administered intravenously every 8 hours. The study compared the clinical response between treatment groups in the clinically evaluable population at the follow-up visit (test-of-cure). The trial was conducted in the United States, South Africa, Canada, and Brazil. At enrollment, approximately 37% of the patients had underlying diabetes, 12% had underlying peripheral vascular disease and 67% had a surgical intervention. The study included 510 patients randomized to meropenem and 527 patients randomized to imipenem-cilastatin. Two hundred and sixty-one (261) patients randomized to meropenem and 287 patients randomized to imipenem-cilastatin were clinically evaluable. The success rates in the clinically evaluable patients at the follow-up visit were 86% (225/261) in the meropenem arm and 83% (238/287) in imipenem-cilastatin arm.
The following table provides the results for the overall as well as subgroup comparisons in clinically evaluable population.
The following clinical efficacy rates were obtained, per organism. The values represent the number of patients clinically cured/number of clinically evaluable patients at the post-treatment follow-up visit, with the percent cure in parentheses (Fully Evaluable analysis set).
The proportion of patients who discontinued study treatment due to an adverse event was similar for both treatment groups (meropenem, 2.5% and imipenem-cilastatin, 2.7%).

### Complicated Intra-Abdominal Infections
One controlled clinical study of complicated intra-abdominal infection was performed in the United States where meropenem was compared with clindamycin/tobramycin. Three controlled clinical studies of complicated intra-abdominal infections were performed in Europe; meropenem was compared with imipenem (two trials) and cefotaxime/metronidazole (one trial).
Using strict evaluability criteria and microbiologic eradication and clinical cures at follow-up which occurred 7 or more days after completion of therapy, the following presumptive microbiologic eradication/clinical cure rates and statistical findings were obtained:
The finding that meropenem was not statistically equivalent to cefotaxime/metronidazole may have been due to uneven assignment of more seriously ill patients to the meropenem arm. Currently there is no additional information available to further interpret this observation.

### Bacterial Meningitis
Four hundred forty-six patients (397 pediatric patients  3 months to < 17 years of age) were enrolled in 4 separate clinical trials and randomized to treatment with meropenem (n = 225) at a dose of 40 mg/kg every 8 hours or a comparator drug, i.e., cefotaxime (n = 187) or ceftriaxone (n = 34), at the approved dosing regimens. A comparable number of patients were found to be clinically evaluable (ranging from 61-68%) and with a similar distribution of pathogens isolated on initial CSF culture.
Patients were defined as clinically not cured if any one of the following three criteria were met:
At the 5-7 week post-completion of therapy visit, the patient had any one of the following: moderate to severe motor, behavior or development deficits, hearing loss of > 60 decibels in one or both ears, or blindness.
During therapy the patients clinical status necessitated the addition of other antibiotics.
Either during or post-therapy, the patient developed a large subdural effusion needing surgical drainage, or a cerebral abscess, or a bacteriologic relapse.
Using the definition, the following efficacy rates were obtained, per organism. The values represent the number of patients clinically cured/number of clinically evaluable patients, with the percent cure in parentheses.
Sequelae were the most common reason patients were assessed as clinically not cured.
Five patients were found to be bacteriologically not cured, 3 in the comparator group (1 relapse and 2 patients with cerebral abscesses) and 2 in the meropenem group (1 relapse and 1 with continued growth of Pseudomonas aeruginosa).
The adverse events seen were comparable between the two treatment groups both in type and frequency. The meropenem group did have a statistically higher number of patients with transient elevation of liver enzymes. Rates of seizure activity during therapy were comparable between patients with no CNS abnormalities who received meropenem and those who received comparator agents. 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.
With respect to hearing loss, 263 of the 271 evaluable patients had at least one hearing test performed post-therapy. The following table shows the degree of hearing loss between the meropenem-treated patients and the comparator-treated patients.

# How Supplied
- Meropenem for Injection, USP (I.V.) is supplied in 20 mL and 30 mL injection vials containing sufficient meropenem to deliver 500 mg or 1 g for intravenous administration, respectively.

## Storage
- The dry powder should be stored at controlled room temperature 20-25oC (68-77oF)

# Images

## Drug Images

## Package and Label Display Panel

# Patient Counseling Information
- Patients should be counseled that antibacterial drugs including Meropenem for injection (I.V.) should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When Meropenem for injection (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 Meropenem for injection (I.V.) or other antibacterial drugs in the future.
- Patients should be counseled that diarrhea is a common problem caused by ntibiotics which usually ends when the antibiotic is discontinued.
- Sometimes after starting treatment with antibiotics, patients can develop watery and bloody stools (with or without stomach cramps and fever) even as late as two or more months after having taken the last dose of the antibiotic. If this occurs, patients should contact their physician as soon as possible
- Patients should be counseled to inform their physician if they are taking valproic acid or divalproex sodium. Valproic acid concentrations in the blood may drop below the therapeutic range upon co-administration with Meropenem for injection (I.V.).
- If treatment with Meropenem for injection (I.V.) is necessary and continued, alternative or supplemental anti-convulsant medication to prevent and/or treat seizures may be needed.
- 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.

# Precautions with Alcohol
Alcohol-Meropenem interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.

# Brand Names
- Merrem IV 

# Look-Alike Drug Names
There is limited information regarding Meropenem Look-Alike Drug Names in the drug label.

# Drug Shortage Status

# Price