NDC 0264-3185 Meropenem And Sodium Chloride

Meropenem And Sodium Chloride

NDC Product Code 0264-3185

NDC Product Information

Meropenem And Sodium Chloride with NDC 0264-3185 is a a human prescription drug product labeled by B. Braun Medical Inc.. The generic name of Meropenem And Sodium Chloride is meropenem and sodium chloride. The product's dosage form is injection, solution and is administered via intravenous form.

Labeler Name: B. Braun Medical Inc.

Dosage Form: Injection, Solution - A liquid preparation containing one or more drug substances dissolved in a suitable solvent or mixture of mutually miscible solvents that is suitable for injection.

Product Type: Human Prescription Drug What kind of product is this?
Indicates the type of product, such as Human Prescription Drug or Human Over the Counter Drug. This data element matches the “Document Type” field of the Structured Product Listing.

Meropenem And Sodium Chloride Active Ingredient(s)

What is the Active Ingredient(s) List?
This is the active ingredient list. Each ingredient name is the preferred term of the UNII code submitted.

  • MEROPENEM 1 g/50mL

Inactive Ingredient(s)

About the Inactive Ingredient(s)
The inactive ingredients are all the component of a medicinal product OTHER than the active ingredient(s). The acronym "UNII" stands for “Unique Ingredient Identifier” and is used to identify each inactive ingredient present in a product.

  • WATER (UNII: 059QF0KO0R)
  • WATER (UNII: 059QF0KO0R)

Administration Route(s)

What are the Administration Route(s)?
The translation of the route code submitted by the firm, indicating route of administration.

  • Intravenous - Administration within or into a vein or veins.

Pharmacological Class(es)

What is a Pharmacological Class?
These are the reported pharmacological class categories corresponding to the SubstanceNames listed above.

  • Carbapenems - [CS]
  • Penem Antibacterial - [EPC] (Established Pharmacologic Class)

Product Labeler Information

What is the Labeler Name?
Name of Company corresponding to the labeler code segment of the Product NDC.

Labeler Name: B. Braun Medical Inc.
Labeler Code: 0264
FDA Application Number: NDA202106 What is the FDA Application Number?
This corresponds to the NDA, ANDA, or BLA number reported by the labeler for products which have the corresponding Marketing Category designated. If the designated Marketing Category is OTC Monograph Final or OTC Monograph Not Final, then the Application number will be the CFR citation corresponding to the appropriate Monograph (e.g. “part 341”). For unapproved drugs, this field will be null.

Marketing Category: NDA - A product marketed under an approved New Drug Application. What is the Marketing Category?
Product types are broken down into several potential Marketing Categories, such as NDA/ANDA/BLA, OTC Monograph, or Unapproved Drug. One and only one Marketing Category may be chosen for a product, not all marketing categories are available to all product types. Currently, only final marketed product categories are included. The complete list of codes and translations can be found at www.fda.gov/edrls under Structured Product Labeling Resources.

Start Marketing Date: 04-30-2015 What is the Start Marketing Date?
This is the date that the labeler indicates was the start of its marketing of the drug product.

Listing Expiration Date: 12-31-2021 What is the Listing Expiration Date?
This is the date when the listing record will expire if not updated or certified by the product labeler.

Exclude Flag: N What is the NDC Exclude Flag?
This field indicates whether the product has been removed/excluded from the NDC Directory for failure to respond to FDA’s requests for correction to deficient or non-compliant submissions. Values = ‘Y’ or ‘N’.

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Information for Patients

Meropenem Injection

Meropenem Injection is pronounced as (mer oh pen' em)

Why is meropenem injection medication prescribed?
Meropenem injection is used to treat skin and abdominal (stomach area) infections caused by bacteria and meningitis (infection of the membranes that surround the brain an...
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Meropenem And Sodium Chloride Product Labeling Information

The product labeling information includes all published material associated to a drug. Product labeling documents include information like generic names, active ingredients, ingredient strength dosage, routes of administration, appearance, usage, warnings, inactive ingredients, etc.

Product Labeling Index

1.1 Complicated Skin And Skin Structure Infections (Adult Patients And Pediatric Patients 3 Months Of Age And Older Requiring The Full Adult Dose Only)

Meropenem for Injection USP and Sodium Chloride Injection USP is indicated for the treatment of complicated skin and skin structure infections (cSSSI) 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, and Peptostreptococcus species.

1.2  Complicated Intra-Abdominal Infections (Adult Patients And Pediatric Patients 3 Months Of Age And Older Requiring The Full Adult Dose Only)

Meropenem for Injection USP and Sodium Chloride Injection USP is indicated for the treatment of complicated appendicitis and peritonitis caused by viridans group streptococci, Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, Bacteroides fragilis, B. thetaiotaomicron, and Peptostreptococcus species.

1.3 Bacterial Meningitis (Pediatric Patients 3 Months Of Age And Older Requiring The Full Adult Dose Only)

Meropenem for Injection USP and Sodium Chloride Injection USP is indicated for the treatment of bacterial meningitis caused by Haemophilus influenzae, Neisseria meningitidis and penicillin-susceptible isolates of Streptococcus pneumoniae.Meropenem 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 Indications and Usage (1.1), (1.2) or (1.3); Dosage and Administration (2.3), and Adverse Reactions (6.1)].

1.4 Usage

To reduce the development of drug-resistant bacteria and maintain the effectiveness of Meropenem for Injection USP and Sodium Chloride Injection USP and other antibacterial drugs, Meropenem for Injection USP and Sodium Chloride Injection USP should only be used to treat 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.

2.1 Adult Patients

Meropenem for Injection USP and Sodium Chloride Injection USP in the DUPLEX® Container should be used only in patients who require the entire 500 mg or 1 gram dose and not any fraction thereof. The recommended dose of Meropenem for Injection USP and Sodium Chloride Injection USP is 500 mg given every 8 hours for skin and skin structure infections and 1 gram given every 8 hours for intra-abdominal infections. When treating complicated skin and skin structure infections caused by P. aeruginosa, a dose of 1 gram every 8 hours is recommended.Meropenem for Injection USP and Sodium Chloride Injection USP should be administered by intravenous infusion over approximately 15 to 30 minutes.

2.2 Use In Adult Patients With Renal Impairment

Dosage should be reduced in patients with creatinine clearance of 50 mL/min or less. (See dosing table below.)Dosage should be reduced in renal failure if less than a full dose (1 gram or 500 mg) is required and an alternative formulation should be used to avoid risk of overdose.When only serum creatinine is available, the following formula (Cockcroft and Gault equation)6 may be used to estimate creatinine clearance.Males: Creatinine Clearance (mL/min) =Weight (kg) x (140 - age)  72 x serum creatinine (mg/dL)Females: 0.85 x above valueTable 1: Recommended Meropenem for Injection Dosage Schedule for Adult Patients With Renal ImpairmentCreatinine Clearance (mL/min)  Dose (dependent on type of infection) Dosing Intervalgreater than 50 Recommended dose (500 mg cSSSI and 1 gram Intra-abdominal infection) Every 8 hours 26-50 Recommended dose Every 12 hours 10-25 One-half recommended dose Every 12 hoursless than 10 One-half recommended dose Every 24 hoursThere is inadequate information regarding the use of meropenem for injection in patients on hemodialysis or peritoneal dialysis.

2.3 Use In Pediatric Patients (3 Months Of Age And Older Only)

  • Meropenem for Injection USP and Sodium Chloride Injection USP in the DUPLEX® Container is designed to deliver a 500 mg or 1 gram dose of meropenem. To prevent unintentional overdose, this product should not be used in pediatric patients who require less than the full adult dose of meropenem.  Meropenem is not to be used in pediatric patients aged less than three months. For pediatric patients 3 months of age and older, the Meropenem for Injection USP and Sodium Chloride Injection USP dose is 10 mg/kg, 20 mg/kg or 40 mg/kg every 8 hours (maximum dose is 2 grams every 8 hours), depending on the type of infection (cSSSI, cIAI, intra-abdominal infection or meningitis). See dosing table 2 below. [see Use in Specific Populations (8.4)].   For pediatric patients weighing over 50 kg administer Meropenem for Injection USP and Sodium Chloride Injection USP at a dose of 500 mg every 8 hours for cSSSI, 1 gram every 8 hours for cIAI and 2 grams every 8 hours for meningitis. Administer Meropenem for Injection USP and Sodium Chloride Injection USP as an intravenous infusion over approximately 15 minutes to 30 minutes.Table 2: Recommended Meropenem for Injection Dosage Schedule for Pediatric Patients With Normal Renal Function Type of Infection Dose (mg/kg) Up to a Maximum Dose Dosing Interval Complicated Skin and Skin Structure Infections 10 500 mg Every 8 hours Complicated Intra-abdominal Infections 20 1 gram Every 8 hours Meningitis  40  2 grams Every 8 hours There is no experience in pediatric patients with renal impairment.When treating cSSSI caused by P. aeruginosa, a dose of 20 mg/kg (or 1 gram for pediatric patients weighing over 50 kg) every 8 hours is recommended.

2.4 Preparation And Administration Of Meropenem For Injection Usp And Sodium Chloride Injection Usp In Duplex® Container

  • Important Administration InstructionsDo not use in series connections. Such use would result in air embolism due to residual air being drawn from the primary container before administration of the fluid from the secondary container is complete. If administration is controlled by a pumping device, care must be taken to discontinue pumping action before the container runs dry or air embolism may result.Do not introduce additives into the DUPLEX® Container.Administer Meropenem for Injection USP and Sodium Chloride Injection USP intravenously over approximately 15 to 30 minutes.This reconstituted solution is for intravenous use only.Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration. Use only if solution is clear and container and seals are intact.DUPLEX® Container StorageTo avoid inadvertent activation, the DUPLEX® Container should remain in the folded position until activation is intended. Patient Labeling and Drug Powder/Diluent InspectionApply patient-specific label on foil side of container. Use care to avoid activation. Do not cover any portion of foil strip with patient label.Unlatch side tab and unfold DUPLEX® Container (see Diagram 1). Visually inspect diluent chamber for particulate matter. Use only if container and seals are intact.To inspect the drug powder for foreign matter or discoloration, peel foil strip from drug chamber (see Diagram 2).Protect from light after removal of foil strip.Note: If foil strip is removed, the container should be re-folded and the side tab latched until ready to activate. The product must then be used within 7 days at room temperature, but not beyond the labeled expiration date.Reconstitution (Activation)Do not use directly after storage by refrigeration, allow the product to equilibrate to room temperature before patient use. Unfold the DUPLEX® Container and point the set port in a downward direction. Starting at the hanger tab end, fold the DUPLEX® Container just below the diluent meniscus trapping all air above the fold. To activate, squeeze the folded diluent chamber until the seal between the diluent and powder opens, releasing diluent into the drug powder chamber (see Diagram 3). Agitate the liquid-powder mixture until the drug powder is completely dissolved.Note: Following reconstitution (activation), product must be used within 1 hour if stored at room temperature or within 15 hours if stored under refrigeration.AdministrationVisually inspect the reconstituted solution for particulate matter. Point the set port in a downwards direction. Starting at the hanger tab end, fold the DUPLEX® Container just below the solution meniscus trapping all air above the fold. Squeeze the folded DUPLEX® Container until the seal between reconstituted drug solution and set port opens, releasing liquid to set port (see Diagram 4).Prior to attaching the IV set, check for minute leaks by squeezing container firmly. If leaks are found, discard container and solution as sterility may be compromised. Using aseptic technique, peel foil cover from the set port and attach sterile administration set (see Diagram 5).Refer to directions for use accompanying the administration set.

2.5 Compatibility

Compatibility of Meropenem for Injection USP and Sodium Chloride Injection USP with other drugs has not been established. Meropenem for Injection USP and Sodium Chloride Injection USP should not be mixed with or physically added to solutions containing other drugs.

2.6 Stability And Storage

Freshly prepared solutions of Meropenem for Injection USP and Sodium Chloride Injection USP should be used. Following reconstitution (activation) in the DUPLEX® Container, the product maintains satisfactory potency for 1 hour at up to 25ºC (77ºF) or for 15 hours at up to 5ºC (41ºF). Solutions of intravenous Meropenem for Injection USP and Sodium Chloride Injection USP should not be frozen.

3 Dosage Forms And Strengths

  • Dual-chamber, single-use container:500 mg meropenem for injection USP (as a blend of sterile meropenem trihydrate USP and sterile sodium carbonate USP/NF) and 50 mL of sodium chloride injection USP
  • 1 gram meropenem for injection USP (as a blend of sterile meropenem trihydrate USP and sterile sodium carbonate USP/NF) and 50 mL of sodium chloride injection USP

4 Contraindications

Meropenem for Injection USP and Sodium Chloride Injection USP 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 beta-lactams.

5.1 Hypersensitivity Reactions

Serious and occasionally fatal hypersensitivity (anaphylactic) reactions have been reported in patients receiving therapy with beta-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 beta-lactam. Before initiating therapy with Meropenem for Injection USP and Sodium Chloride Injection USP, it is important to inquire about previous hypersensitivity reactions to penicillins, cephalosporins, other beta-lactams, and other allergens. If an allergic reaction to Meropenem for Injection USP and Sodium Chloride Injection USP occurs, discontinue the drug immediately.

5.2 Seizure Potential

Seizures and other adverse CNS experiences have been reported during treatment with meropenem for injection. 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 [see Adverse Reactions (6.1) and Drug Interactions (7.2)].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 adult patients with creatinine clearance of 50 mL/min or less [see Dosage and Administration (2.2)].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, evaluate neurologically, place on anti-convulsant therapy if not already instituted, and re-examine the dosage of Meropenem for Injection USP and Sodium Chloride Injection USP to determine whether it should be decreased or discontinued.

5.3 Risk Of Breakthrough Seizures Due To Drug Interaction With Valproic Acid

The concomitant use of meropenem and valproic acid or divalproex sodium is generally not recommended. 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. Consider administration of antibacterial drugs other than carbapenems to treat infections in patients whose seizures are well controlled on valproic acid or divalproex sodium. If administration of Meropenem for Injection USP and Sodium Chloride Injection USP is necessary, consider supplemental anti-convulsant therapy [see Drug Interactions (7.2)].

5.4 Clostridium Difficile–Associated Diarrhea

Clostridium difficile- associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including meropenem for injection, 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 antibacterial drug 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 antibacterial drug use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibacterial drug treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated.

5.5 Development Of Drug-Resistant Bacteria

Prescribing Meropenem for Injection USP and Sodium Chloride Injection USP in the absence of a proven or strongly suspected bacterial infection is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria.

5.6 Overgrowth Of Nonsusceptible Organisms

As with other broad-spectrum antibacterial drugs, 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.

5.7 Thrombocytopenia

In patients with renal impairment, thrombocytopenia has been observed but no clinical bleeding reported [see Dosage and Administration (2.2), Adverse Reactions (6.1), Use In Specific Populations (8.5) and (8.6), and Clinical Pharmacology (12.3)].

5.8 Potential For Neuromotor Impairment

Alert patients receiving meropenem for injection on an outpatient basis regarding adverse events such as seizures, delirium, 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 is well tolerated, advise patients not to operate machinery or motorized vehicles [see Adverse Reactions (6.1)].

5.9 High Sodium Load

Each 500 mg of Meropenem for Injection USP and Sodium Chloride Injection USP delivers 245.1 mg (10.7 mEq) of sodium and each 1 gram of Meropenem for Injection USP and Sodium Chloride Injection USP delivers 290.2 mg (12.6 mEq) of sodium. Avoid use of Meropenem for Injection USP and Sodium Chloride Injection USP in patients with congestive heart failure, elderly patients and patients requiring restricted sodium intake.

6 Adverse Reactions

  • The following are discussed in greater detail in other sections of labeling:Hypersensitivity Reactions [see Warnings and Precautions (5.1)]
  • Seizure Potential [see Warnings and Precautions (5.2)]
  • Risk of Breakthrough Seizures Due to Drug Interaction with Valproic Acid [see Warnings and Precautions (5.3)]
  • Clostridium difficile – Associated Diarrhea [see Warnings and Precautions (5.4)]
  • Development of Drug-Resistant Bacteria [see Warnings and Precautions (5.5)]
  • Overgrowth of Nonsusceptible Organisms [see Warnings and Precautions (5.6)]
  • Thrombocytopenia [see Warnings and Precautions (5.7)]
  • Potential for Neuromotor Impairment [see Warnings and Precautions (5.8)]
  • High Sodium Load [see Warnings and Precautions (5.9)]

6.1 Adverse Reactions From Clinical Trials

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 (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.The following adverse reaction frequencies were derived from the clinical trials in the 2904 patients treated with meropenem for injection.Local Adverse ReactionsLocal adverse reactions that were reported with meropenem for injection 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 ReactionsSystemic adverse events that were reported with meropenem for injection 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 systemic adverse reactions that were reported with meropenem for injection 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%).Body as a Whole: pain, abdominal pain, chest pain, fever, back pain, abdominal enlargement, chills, pelvic painCardiovascular: heart failure, heart arrest, tachycardia, hypertension, myocardial infarction, pulmonary embolus, bradycardia, hypotension, syncopeDigestive System: oral moniliasis, anorexia, cholestatic jaundice/jaundice, flatulence, ileus, hepatic failure, dyspepsia, intestinal obstructionHemic/Lymphatic: anemia, hypochromic anemia, hypervolemiaMetabolic/Nutritional: peripheral edema, hypoxiaNervous System: insomnia, agitation, delirium, confusion, dizziness, seizure, nervousness, paresthesia, hallucinations, somnolence, anxiety, depression, asthenia [see Warnings and Precautions (5.2) and (5.8)]Respiratory: respiratory disorder, dyspnea, pleural effusion, asthma, cough increased, lung edemaSkin and Appendages: urticaria, sweating, skin ulcerUrogenital System: dysuria, kidney failure, vaginal moniliasis, urinary incontinenceAdverse Laboratory ChangesAdverse laboratory changes that were reported and occurring in greater than 0.2% of the patients were as follows:Hepatic: increased alanine transaminase (ALT), aspartate transaminase (AST), alkaline phosphatase, lactate dehydrogenase (LDH), and bilirubinHematologic: increased platelets, increased eosinophils, decreased platelets, decreased hemoglobin, decreased hematocrit, decreased white blood cell (WBC), shortened prothrombin time and shortened partial thromboplastin time, leukocytosis, hypokalemiaRenal: increased creatinine and increased blood urea nitrogen (BUN)Urinalysis: presence of red blood cellsComplicated Skin and Skin Structure InfectionsIn 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 greater than 5% of the patients were: headache (7.8%), nausea (7.8%), constipation (7.0%), diarrhea (7.0%), anemia (5.5%), and pain (5.1%). Adverse events with an incidence of greater than 1%, and not listed above, include: pharyngitis, accidental injury, gastrointestinal disorder, hypoglycemia, peripheral vascular disorder, and pneumonia.Patients with Renal Impairment: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, increased in patients with moderately severe renal impairment (creatinine clearance greater than 10 to 26 mL/min) [see Dosage and Administration (2.2), Warnings and Precautions (5.8), Use in Specific Populations (8.5) and (8.6) and Clinical Pharmacology (12.3)].Pediatric PatientsSystemic and Local Adverse ReactionsPediatric Patients with Serious Bacterial Infections (excluding Bacterial Meningitis):Meropenem for injection was studied in 515 pediatric patients (3 months of age and older to below 13 years of age) with serious bacterial infections (excluding meningitis, see next section) at dosages of 10 to 20 mg/kg every 8 hours. The types of systemic and local 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 and their rates of occurrence as follows:Diarrhea 3.5%Rash 1.6%Nausea and Vomiting 0.8%Pediatric Patients with Bacterial Meningitis:Meropenem for injection was studied in 321 pediatric patients (3 months of age and older to below 17 years of age) with meningitis at a dosage of 40 mg/kg every 8 hours. The types of systemic and local 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 and their rates of occurrence as follows:Diarrhea  4.7%Rash (mostly diaper area moniliasis) 3.1%Oral Moniliasis 1.9%Glossitis 1.0%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 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. The meropenem group had a statistically higher number of patients with transient elevation of liver enzymes.

6.2 Post-Marketing Experience

The following adverse reactions have been identified during post-approval use of meropenem for injection. 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 from Clinical Trials section of this prescribing information and reported as possibly, probably, or definitely drug related are listed within each body system in order of decreasing severity. Blood and Lymphatic System Disorders: agranulocytosis, neutropenia, and leukopenia; a positive direct or indirect Coombs test, and hemolytic anemia.Immune System Disorders: angioedema and drug rash with eosinophilia and systemic symptoms (DRESS syndrome). Skin and Subcutaneous Disorders: toxic epidermal necrolysis, Stevens-Johnson syndrome, and erythema multiforme.

7.1 Probenecid

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

7.2  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 is necessary, then supplemental anti-convulsant therapy should be considered [see Warnings and Precautions (5.3)].

Risk Summary

There are insufficient human data to establish whether there is a drug-associated risk of major birth defects or miscarriages with meropenem in pregnant women. No fetal toxicity or malformations were observed in pregnant rats and cynomolgus macaques administered intravenous meropenem during organogenesis at doses up to 3.2 and 2.3 times the maximum recommended human dose based on body surface area comparison, respectively.  In rats administered intravenous meropenem in late pregnancy and during the lactation period, there were no adverse effects on offspring at doses equivalent to approximately 3.2 times the maximum recommended human dose based on body surface area comparison  [see Data].The background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4 % and 15-20%, respectively.

Meropenem has been reported to be excreted in human milk. No information is available on the effects of meropenem on the breastfed –child or on milk production.  The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for Meropenem for Injection USP and Sodium Chloride Injection USP in the DUPLEX® Container and any potential adverse effects on the breastfed-child from Meropenem for Injection USP and Sodium Chloride Injection USP in the DUPLEX® Container or from the underlying maternal conditions.

Animal Data

Reproductive studies have been performed with meropenem in rats at doses of up to 1000 mg/kg/day and in cynomolgus monkeys at doses of up to 360 mg/kg/day (on the basis of body surface area comparisons, approximately 3.2 times and 2.3 times higher, respectively, than the maximum recommended human dose of 1 gram every 8 hours). These studies revealed no evidence of harm to the fetus due to meropenem, although there were slight changes in fetal body weight at doses of 250 mg/kg/day (equivalent to approximately 0.8 times the maximum recommended human dose of 1 gram every 8 hours based on body surface area comparison) and above in rats. In a published study1, meropenem administered to pregnant rats from Gestation Day 6  to Gestation Day 17, was associated with mild maternal weight loss at all doses, but did not produce malformations or fetal toxicity. The no-observed-adverse-effect-level (NOAEL) for fetal toxicity in this study was considered to be the high dose of 750 mg/kg/day (equivalent to approximately 2.4 times the highest recommended human dose based on body surface area comparison).In a peri-postnatal study in rats described in the published literature1, intravenous meropenem was administered to dams from Gestation Day 17 until Postpartum Day 21. There were no adverse effects in the dams and no adverse effects in the first generation offspring (including developmental, behavioral, and functional assessments and reproductive parameters) except that female offspring exhibited lowered body weights which continued during gestation and nursing of the second generation offspring. Second generation offspring showed no meropenem-related effects. The NOAEL value was considered to be 1000 mg/kg/day (approximately 3.2 times the highest recommended clinical dose based on body surface area comparisons).

8.4 Pediatric Use

Meropenem for Injection USP and Sodium Chloride Injection USP in the DUPLEX® Container is designed to deliver a 500 mg or 1 gram dose of meropenem. To prevent unintentional overdose, this product should not be used in pediatric patients who require less than the full adult dose of meropenem. Meropenem is not to be used in pediatric patients aged less than three months. [see Dosage and Administration (2.3)].    Use of meropenem for injection in pediatric patients with bacterial meningitis is supported by evidence from adequate and well-controlled studies in the pediatric population. Use of meropenem for injection in pediatric patients 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 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 Indications and Usage (1), Dosage and Administration (2.3), Adverse Reactions (6.1), Clinical Pharmacology (12.3) and Clinical Studies (14)].

8.5 Geriatric Use

Of the total number of subjects in clinical studies of meropenem for injection, 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.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 in elderly patients has shown a reduction in the plasma clearance of meropenem that correlates with age-associated reduction in creatinine clearance [see Clinical Pharmacology (12.3)].Each 500 mg of Meropenem for Injection USP and Sodium Chloride Injection USP delivers 245.1 mg (10.7 mEq) of sodium and each 1 gram of Meropenem for Injection USP and Sodium Chloride Injection USP delivers 290.2 mg (12.6 mEq) of sodium. At the usual recommended doses of 500 mg or 1000 mg every 8 hours, patients would receive between 735 mg/day and 870 mg/day (32 mEq and 38 mEq) of sodium. The geriatric population may respond with a blunted natriuresis to salt loading. This may be clinically important with regard to such diseases as congestive heart failure [see Contraindications (4)  and Warnings and Precautions (5.11)].

8.6 Patients With Renal Impairment

Dosage adjustment is necessary in patients with creatinine clearance 50 mL/min or less [see Dosage and Administration (2.2), Warnings and Precautions (5.7), and Clinical Pharmacology (12.3)].

10 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 USP and Sodium Chloride Injection USP 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 grams 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.

11 Description

Meropenem for injection is a sterile, pyrogen-free, synthetic, carbapenem antibacterial drug for intravenous administration. Meropenem 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 is a white to pale yellow crystalline powder containing meropenem trihydrate and sodium carbonate. The constituted 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. Meropenem for Injection USP and Sodium Chloride Injection USP is supplied as a sterile, nonpyrogenic, single-use packaged combination of meropenem (drug chamber) and 50 mL of sodium chloride (diluent) in the DUPLEX® sterile container. When reconstituted as instructed, each 1 gram Meropenem for injection in the DUPLEX® Container will deliver 1 gram of meropenem and a total sodium content of 290.2 mg (12.6 mEq). Each 500 mg Meropenem for injection in the DUPLEX® Container will deliver 500 mg of meropenem and a total sodium content of 245.1 mg (10.7 mEq) [see Dosage and Administration (2.4)]. The osmolality of the reconstituted solution of Meropenem for Injection USP and Sodium Chloride Injection USP is approximately 356 mOsmol/kg for the 500 mg dose and approximately 417 mOsmol/kg for the 1 gram dose.The DUPLEX® Container is a flexible dual chamber container. After removing the peelable foil strip, activating the seals, and thoroughly mixing, the reconstituted drug product is hyperosmotic and is intended for single intravenous use. The product (diluent and drug) contact layer is a mixture of thermoplastic rubber and a polypropylene ethylene copolymer that contains no plasticizers.Not made with natural rubber latex, PVC or Di(2-ethylhexyl)phthalate (DEHP).

12.1 Mechanism Of Action

Meropenem is an antibacterial drug [see Microbiology (12.4)].

12.3 Pharmacokinetics

Plasma ConcentrationsAt the end of a 30-minute intravenous infusion of a single dose of meropenem for injection 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 gram 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 gram administered every 6 hours in healthy volunteers with normal renal function.DistributionThe plasma protein binding of meropenem is approximately 2%.After a single intravenous dose of meropenem for injection, 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 table 3 below.Table 3: Meropenem Concentrations in Selected Tissues (Highest Concentrations Reported)TissueIntravenous Dose (gram) Number of Samples Mean [mcg/mL or mcg/(g)]at 1 hour unless otherwise noted   Range [mcg/mL or mcg/(g)]Endometrium0.5  7 4.21.7–10.2 Myometrium  0.5 15 3.8 0.4–8.1Ovary  0.5 8 2.8 0.8–4.8Cervix  0.52  7 5.4–8.5Fallopian tube 0.59  1.7 0.3-3.4Skin  0.522  3.3 0.5–12.6Interstitial fluidobtained from blister fluid   0.5 9 5.53.2-8.6 Skin  1 105.3  1.3–16.7Interstitial fluid 1 526.3 20.9–37.4 Colon 12  2.6 2.5–2.7Bile  1 7 14.6 (3 hours)4.0–25.7 Gall bladder 1 1—  3.9Peritoneal fluid1 9 30.2 7.4–54.6Lung 1 2 4.8 (2 hours) 1.4–8.2Bronchial mucosa  1 74.5  1.3–11.1Muscle 12 6.1 (2 hours) 5.3–6.9 Fascia 1 98.8  1.5–20Heart valves  1 7 9.7 6.4–12.1Myocardium 110  15.5 5.2–25.5CSF (inflamed) 20 mg/kgin pediatric patients of age 5 months to 8 years  8 1.1 (2 hours)  0.2-2.8  40 mg/kgin pediatric patients of age 1 month to 15 years  5  3.3 (3 hours) 0.9-6.5CSF (uninflamed)  14  0.2 (2 hours)0.1–0.3 MetabolismThere is one metabolite of meropenem that is microbiologically inactive.ExcretionIn 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.Urinary concentrations of meropenem in excess of 10 mcg/mL are maintained for up to 5 hours after a 500 mg dose.Specific PopulationsRenal ImpairmentPharmacokinetic studies with meropenem for injection 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) [see Dosage and Administration (2.2) and Use In Specific Populations (8.6)].Meropenem is hemodialyzable. However, there is no information on the usefulness of hemodialysis to treat overdosage [see Overdosage (10)].Hepatic ImpairmentA pharmacokinetic study with meropenem for injection in patients with hepatic impairment has shown no effects of liver disease on the pharmacokinetics of meropenem.Geriatric PatientsA pharmacokinetic study with meropenem for injection in elderly patients with renal impairment showed a reduction in plasma clearance of meropenem that correlates with age-associated reduction in creatinine clearance.Pediatric PatientsThe pharmacokinetics of meropenem 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.Drug InteractionsProbenecid 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.

12.4 Microbiology

  • Mechanism of ActionThe bactericidal activity of meropenem results from the inhibition of cell wall synthesis. Meropenem penetrates the cell wall of most Gram-positive and Gram-negative bacteria to reach penicillin-binding-protein (PBP) targets. Meropenem binds to 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 beta-lactamases, both penicillinases and cephalosporinases produced by Gram-positive and Gram-negative bacteria.Meropenem does not have in-vitro activity against methicillin-resistant Staphylococcus aureus (MRSA) or methicillin-resistant Staphylococcus epidermidis (MRSE).ResistanceThere 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, and 4) production of antibacterial drug-destroying enzymes (carbapenemases, metallo-beta-lactamases).Cross-ResistanceCross-resistance is sometimes observed with isolates resistant to other carbapenems.Interaction with Other AntimicrobialsIn vitro tests show meropenem to act synergistically with aminoglycoside antibacterial drugs against some isolates of Pseudomonas aeruginosa.Antimicrobial ActivityMeropenem has been shown to be active against most isolates of the following microorganisms, both in vitro and in clinical infections [see Indications and Usage (1)].Gram-positive bacteriaEnterococcus faecalis (vancomycin-susceptible isolates only) Staphylococcus aureus (methicillin-susceptible isolates only) Streptococcus agalactiae Streptococcus pneumoniae (penicillin-susceptible isolates only) Streptococcus pyogenesViridans group streptococciGram-negative bacteriaEscherichia coliHaemophilus influenzaeKlebsiella pneumoniaeNeisseria meningitidisProteus mirabilisPseudomonas aeruginosaAnaerobic bacteriaBacteroides fragilisBacteroides thetaiotaomicronPeptostreptococcus speciesThe following in vitro data are available, but their clinical significance is unknown. At least 90 percent of the following bacteria exhibit an in vitro minimum inhibitory concentration (MIC) less than or equal to the susceptible breakpoint for meropenem against isolates of similar genus or organism group. However, the efficacy of meropenem in treating clinical infections caused by these microorganisms has not been established in adequate and well-controlled clinical trials.Gram-positive bacteriaStaphylococcus epidermidis (methicillin-susceptible isolates only)Gram-negative bacteriaAeromonas hydrophilaCampylobacter jejuniCitrobacter freundiiCitrobacter koseriEnterobacter cloacaeHafnia alveiKlebsiella oxytocaMoraxella catarrhalisMorganella morganiiPasteurella multocidaProteus vulgarisSerratia marcescensAnaerobic bacteriaBacteroides ovatusBacteroides uniformisBacteroides ureolyticusBacteroides vulgatusClostridium difficileClostridium perfringensEggerthella lentaFusobacterium speciesParabacteroides distasonisPorphyromonas asaccharolyticaPrevotella biviaPrevotella intermediaPrevotella melaninogenica Propionibacterium acnesSusceptibility Test MethodsWhen available, the clinical microbiology laboratory should provide cumulative reports of in vitro susceptibility test results for antimicrobial drugs used in local hospitals and practice areas as periodic reports that describe the susceptibility profile of nosocomial and community-acquired pathogens. These reports should aid in the selection of an appropriate antibacterial drug for treatment.Dilution TechniquesQuantitative methods are used to determine antimicrobial MICs. These MICs provide estimates of the susceptibility of bacteria to antimicrobial compounds. The MICs should be determined using a standardized test method (broth or agar)1,3. The MIC values should be interpreted according to the criteria provided in Table 4.Diffusion TechniquesQuantitative methods that require measurement of zone diameters can also provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. The zone size should be determined using a standardized test method.2,3 This procedure uses paper disks impregnated with 10-mcg of meropenem to test the susceptibility of bacteria to meropenem. The disk diffusion breakpoints are provided in Table 4.Anaerobic TechniquesFor anaerobic bacteria, the susceptibility to meropenem can be determined by a standardized test method.2,4 The MIC values obtained should be interpreted according to the criteria provided in Table 4.Table 4: Susceptibility Test Interpretive Criteria for Meropenem  Minimum Inhibitory Concentrations (mcg/mL)Disk Diffusion(zone diameters in mm) Pathogen S I R SI  R Enterobacteriaceae  < 1 2 >4 >23 20-22 < 19 Pseudomonas aeruginosaThe interpretive criteria for P. aeruginosa are based upon the dosing of 1 gram every 8 hours  < 2 4 >8 >1916–18 < 15 Haemophilus influenzaeThe 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 submitted to a reference laboratory for additional testing. < 0.5 — — > 20 — — Neisseria meningitides  < 0.25 — — > 30 — — Streptococcus pneumoniaFor nonmeningitis isolates of S. pneumoniae a penicillin MIC of ≤ 0.06 mcg/mL or oxacillin zone ≥ 20 mm can predict susceptibility to meropenem. MIC testing should be performed on isolates that do not test as susceptible by either of these methods, and on all meningitis S. pneumoniae isolates.Reliable disk diffusion tests for meropenem do not yet exist for testing streptococci  < 0.25 0.5 >1 — — — Streptococcus agalactiae and Streptococcus pyogenes   < 0.5 — — — — — Viridans group streptococci    < 0.5——— —— AnaerobesMIC values using either Brucella blood or Wilkins Chalgren agar (former reference medium) are considered equivalent. Broth microdilution is only recommended for testing the B. fragilis group. MIC values for agar or broth microdilution are considered equivalent for that group. < 4 8 >16 — — —S = Susceptible, I = Intermediate, R = Resistant               No interpretative criteria have been established for testing enterococci.Susceptibility of staphylococci to meropenem may be deduced from testing either cefoxitin or oxacillin.A report of Susceptible indicates that the antimicrobial is likely to inhibit growth of the pathogen if the antimicrobial drug reaches the concentration usually achievable at the site of infection. 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 drug is not likely to inhibit growth of the pathogen if the antimicrobial drug reaches the concentration usually achievable at the infection site; other therapy should be selected.Quality ControlStandardized susceptibility test procedures require the use of laboratory controls to monitor and ensure the accuracy and precision of supplies and reagents used in the assay, and the techniques of the individuals performing the test.2,3,4,5 Standard meropenem powder should provide the following range of MIC values noted in Table 5. For the diffusion technique using the 10-mcg meropenem disk, the criteria in Table 5 should be achieved.Table 5: Acceptable Quality Control Ranges for Meropenem Quality Control Strain Minimum Inhibitory Concentrations(mcg/mL)Disk Diffusion(zone diameters in mm) Staphylococcus aureus ATCC® 292130.03-0.12  —Staphylococcus aureus ATCC® 25923—29–37Streptococcus pneumoniae ATCC® 496190.03-0.2528–35 Enterococcus faecalis ATCC® 292122–8  Escherichia coli ATCC® 259220.008-0.06 28–35 Haemophilus influenzae ATCC® 497660.03-0.12  Haemophilus influenzae ATCC® 49247 — 20–28 Pseudomonas aeruginosa ATCC® 278530.12-127–33 Bacteroides fragilisUsing the Reference Agar Dilution procedure. ATCC® 252850.03–0.25 Bacteroides thetaiotaomicron ATCC® 29741 0.125-0.5  Eggerthella lenta ATCC® 430550.125-1  Clostridium difficile ATCC® 7000570.5-4  ATCC=American Type Culture Collection

13.1 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 performed with meropenem in rats at doses up to 1000 mg/kg/day, (approximately 1.8 times the human exposure at a dose of 1 gram every 8 hours based on AUC) showed no evidence of fertility impairment.

14.1 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 success rates for clinically evaluable population are provided in Table 6.Table 6: Success Rates at Test-of-Cure Visit for Clinically Evaluable Population with Complicated Skin and Skin Structure Infections Population Meropenem for Injection nn=number of patients with satisfactory response./NN=number of patients in the clinically evaluable population or respective subgroup within treatment groups.(%)  Imipenem-cilastatin n/N(%) Total  225/261 (86) 238/287 (83) Diabetes mellitus 83/97 (86) 76/105 (72) No diabetes mellitus 142/164 (87) 162/182 (89) Less than 65 years of age 190/218 (87)205/241 (85) 65 years of age and older 35/43 (81)  33/46 (72) Men 130/148 (88) 137/172 (80) Women95/113 (84)101/115 (88)The clinical efficacy rates by pathogen are provided in Table 7. 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).Table 7: Clinical Efficacy Rates by Pathogen for Clinically Evaluable Population MICROORGANISMSPatients may have more than one pretreatment pathogen. Meropenem for Injectionnn=number of patients with satisfactory response./NN=number of patients in the clinically evaluable population or subgroup within treatment groups.(%)%= Percent of satisfactory clinical response at follow-up evaluation.  Imipenem-cilastatinn/N (%)  Gram-positive aerobes   Staphylococcus aureus, methicillin susceptible 82/88 (93) 84/100 (84) Streptococcus pyogenes (Group A) 26/29 (90) 28/32 (88) Streptococcus agalactiae (Group B) 12/17 (71) 16/19 (84) Enterococcus faecalis 9/12 (75) 14/20 (70) Viridans group streptococci 11/12 (92) 5/6 (83) Gram-negative aerobes   Escherichia coli 12/15 (80) 15/21 (71) Pseudomonas aeruginosa 11/15 (73) 13/15 (87) Proteus mirabilis 11/13 (85) 6/7 (86) Anaerobes   Bacteroides fragilis 10/11 (91) 9/10 (90) Peptostreptococcus spp. 10/13 (77) 14/16 (88)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%).

14.2 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 presumptive microbiologic eradication/clinical cure rates and statistical findings are provided in Table 8.Table 8: Presumptive Microbiologic Eradication and Clinical Cure Rates at Test-of-Cure Visit in the Evaluable population with Complicated intra-abdominal infectionsTreatment Arm No. evaluable/No. enrolled (%)Microbiologic Eradication RateClinical Cure RateOutcome meropenem 146/516 (28%) 98/146 (67%) 101/146 (69%)  imipenem 65/220 (30%) 40/65 (62%) 42/65 (65%) Meropenem equivalent to control cefotaxime/metronidazole 26/85 (30%) 22/26 (85%) 22/26 (85%) Meropenem not equivalent to control clindamycin/tobramycin 50/212 (24%) 38/50 (76%) 38/50 (76%) Meropenem equivalent to controlThe 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.

14.3 Bacterial Meningitis

  • Four hundred forty-six patients (397 pediatric patients 3 months of age and older to below 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 greater than 60 decibels in one or both ears, or blindness.
  • During therapy the patient’s clinical status necessitated the addition of other antibacterial drugs.
  • 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 (noted in Table 9). The values represent the number of patients clinically cured/number of clinically evaluable patients, with the percent cure in parentheses.Table 9: Efficacy Rates by Pathogen in the Clinically Evaluable Population with Bacterial Meningitis MICROORGANISMS MEROPENEM FOR INJECTION COMPARATOR   S. pneumoniae 17/24 (71) 19/30 (63)   H. influenzae (+)(+) beta-lactamase-producing 8/10 (80) 6/6 (100)   H. influenzae (-/NT)(-/NT) non-beta-lactamase-producing or not tested 44/59 (75) 44/60 (73)   N. meningitidis 30/35 (86)  35/39 (90)   Total (including others) 102/131 (78)  108/140 (77)  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).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.Table 10: Hearing Loss at Post-Therapy in the Evaluable Population treated with MeropenemDegree of Hearing Loss (in one or both ears)   Meropenem n = 128 Comparator n = 135   No loss 61%  56% 20-40 decibels  20% 24%greater than 40-60 decibels  8%  7%greater than 60 decibels 9%  10%

15 References

  • Kawamura S, Russell AW, Freeman SJ, and Siddall, RA: Reproductive and Developmental Toxicity of Meropenem in Rats. Chemotherapy, 40:S238-250 (1992).Clinical and Laboratory Standards Institute (CLSI). Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria that Grow Aerobically; Approved Standard -Tenth Edition. CLSI document M07-A10, Clinical and Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne, Pennsylvania 19087, USA, 2015.  Clinical and Laboratory Standards Institute (CLSI). Performance Standards for Antimicrobial Disk Diffusion Susceptibility Tests; Approved Standard – Twelfth Edition CLSI document M02-A12, Clinical and Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne, Pennsylvania 19087, USA, 2015.  Clinical and Laboratory Standards Institute (CLSI). Performance Standards for Antimicrobial Susceptibility Testing; Twenty-seventh Informational Supplement, CLSI document M100-S27, Clinical and Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne, Pennsylvania 19087, USA, 2017. Clinical and Laboratory Standards Institute (CLSI). Methods for Antimicrobial Susceptibility Testing of Anaerobic Bacteria; Approved Standard -Eight Edition. CLSI document M11-A8. Clinical and Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne, Pennsylvania 19087 USA, 2012.  Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine.  Nephron. 1976; 16:31-41.

16 How Supplied/Storage And Handling

Meropenem for Injection USP and Sodium Chloride Injection USP in the DUPLEX® Container is a flexible dual chamber container supplied in two concentrations. The diluent chamber contains approximately 50 mL of 0.9% Sodium Chloride Injection USP. After reconstitution, the delivered doses are equivalent to 500Anhydrous basis. mg and 1 gram meropenem.Meropenem for Injection USP and Sodium Chloride Injection USP is supplied sterile and nonpyrogenic in the DUPLEX® Container packaged 24 units per case. NDC REF Dose Volume 0264-3183-11 3183-11 500 mg 50 mL 0264-3185-11 3185-11 1 gram 50 mLStore the unactivated unit at 20–25°C (68–77°F). Excursion permitted to 15-30°C. [See USP Controlled Room Temperature.] Protect from freezing.Use only if prepared solution is clear and free from particulate matter.

17 Patient Counseling Information

  • Counsel patients that antibacterial drugs including Meropenem for Injection USP and Sodium Chloride Injection USP should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When Meropenem for Injection USP and Sodium Chloride Injection USP 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 USP and Sodium Chloride Injection USP or other antibacterial drugs in the future.
  • Counsel patients that diarrhea is a common problem caused by antibacterial drugs which usually ends when the antibacterial drug is discontinued. Sometimes after starting treatment with antibacterial drugs, 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 antibacterial drug. If this occurs, patients should contact their physician as soon as possible [see Warnings and Precautions (5.4)].
  • Counsel patients 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 USP and Sodium Chloride Injection USP. If treatment with Meropenem for Injection USP and Sodium Chloride Injection USP is necessary and continued, alternative or supplemental anti-convulsant medication to prevent and/or treat seizures may be needed [see Warnings and Precautions (5.3)].
  • Patients receiving Meropenem for Injection USP and Sodium Chloride Injection USP on an outpatient basis must be alerted of adverse events such as seizures, delirium, 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 USP and Sodium Chloride Injection USP is well tolerated, patients should not operate machinery or motorized vehicles [see Warnings and Precautions (5.10)].Meropenem for Injection USP and Sodium Chloride Injection USP contains a high sodium load. Instruct patients to inform or report symptoms of difficulty breathing, swelling, or increased weight [see Warnings and Precautions (5.11)].

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