Meropenem and Sodium Chloride

RECENT MAJOR CHANGES Warnings and Precautions, Rhabdomyolysis ( 5.3 ) 12/2024

1 INDICATIONS AND USAGE Meropenem for Injection and Sodium Chloride Injection is a penem antibacterial indicated for the treatment of: Complicated skin and skin structure infections (adult patients and pediatric patients 3 months of age and older requiring the full adult dose only). ( 1.1 ) Complicated intra-abdominal infections (adult patients and pediatric patients 3 months of age and older requiring the full adult dose only). ( 1.2 ) Bacterial meningitis (pediatric patients 3 months of age and older requiring the full adult dose only). ( 1.3 ) To reduce the development of drug-resistant bacteria and maintain the effectiveness of Meropenem for Injection and Sodium Chloride Injection and other antibacterial drugs, Meropenem for Injection and Sodium Chloride Injection should only be used to treat or prevent infections that are proven or strongly suspected to be caused by bacteria. 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 and Sodium Chloride Injection 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 and Sodium Chloride Injection 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 and Sodium Chloride Injection 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 and Sodium Chloride Injection and other antibacterial drugs, Meropenem for Injection and Sodium Chloride Injection should only be used to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy.

2 DOSAGE AND ADMINISTRATION Use this formulation of meropenem only in patients who require the entire 500 mg or 1 gram dose and not any fraction thereof. ( 2.1 ) 500 mg every 8 hours by intravenous infusion over 15 to 30 minutes for complicated skin and skin structure infections (cSSSI) for adult patients. When treating infections caused by Pseudomonas aeruginosa , a dose of 1 gram every 8 hours is recommended ( 2.1 ). 1 gram every 8 hours by intravenous infusion over 15 to 30 minutes for intra-abdominal infections for adult patients. ( 2.1 ) Dosage should be reduced in adult patients with renal impairment. If less than a full dose (1 gram or 500 mg) is required, an alternative formulation should be used to avoid risk of overdose. ( 2.2 ) Recommended Meropenem for Injection Dosage Schedule for Adult Patients with Renal Impairment Creatinine Clearance (mL/min) Dose (dependent on type of infection) Dosing Interval greater 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 hours less than 10 One-half recommended dose Every 24 hours Meropenem for Injection and Sodium Chloride Injection 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. There is no experience in pediatric patients with renal impairment. Pediatric patients 3 months of age and older. ( 2.3 ) 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 20 mg/kg (or 1 gram for pediatric patients weighing over 50 kg) every 8 hours is recommended when treating complicated skin and skin structure infections caused by P. aeruginosa (2.3). 10 500 mg Every 8 hours Intra-abdominal 20 1 gram Every 8 hours Meningitis 40 2 grams Every 8 hours - Intravenous infusion is to be given over approximately 15 to 30 minutes. - There is no experience in pediatric patients with renal impairment. 2.1 Adult Patients Meropenem for Injection and Sodium Chloride Injection 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 and Sodium Chloride Injection 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 and Sodium Chloride Injection 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) 1 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 value Table 1: Recommended Meropenem for Injection Dosage Schedule for Adult Patients With Renal Impairment Creatinine Clearance (mL/min) Dose (dependent on type of infection) Dosing Interval greater 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 hours less than 10 One-half recommended dose Every 24 hours There is …

3 DOSAGE FORMS AND STRENGTHS Single-dose DUPLEX ® (Dual-chamber) 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 Single-dose DUPLEX ® Container consisting of: 500 mg Meropenem for Injection and 50 mL Sodium Chloride Injection 0.9% ( 3 ) 1 gram Meropenem for Injection and 50 mL Sodium Chloride Injection 0.9% ( 3 )

4 CONTRAINDICATIONS Meropenem for Injection and Sodium Chloride Injection 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. Known hypersensitivity to product components or anaphylactic reactions to beta-lactams. ( 4 ) Contraindicated where the administration of sodium or chloride could be clinically detrimental. ( 4 )

6 ADVERSE REACTIONS The following are discussed in greater detail in other sections of labeling: Hypersensitivity Reactions [see Warnings and Precautions (5.1) ] Severe Cutaneous Adverse Reactions [see Warnings and Precautions (5.2)] Rhabdomyolysis [see Warnings and Precautions (5.3) ] Seizure Potential [see Warnings and Precautions (5.4) ] Risk of Breakthrough Seizures Due to Drug Interaction with Valproic Acid [see Warnings and Precautions (5.5) ] Clostridioides difficile – Associated Diarrhea [see Warnings and Precautions (5.6) ] Development of Drug-Resistant Bacteria [see Warnings and Precautions (5.7) ] Overgrowth of Nonsusceptible Organisms [see Warnings and Precautions (5.8) ] Thrombocytopenia [see Warnings and Precautions (5.9) ] Potential for Neuromotor Impairment [see Warnings and Precautions (5.10) ] High Sodium Load [see Warnings and Precautions (5.11) ] Most common adverse reactions (greater than or equal to 2%) are: headache, nausea, constipation, diarrhea, anemia, vomiting, and rash ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact B. Braun Medical Inc. at 1-800-854-6851 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 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 Reactions Local 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 Reactions Systemic 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 pain Cardiovascular: heart failure, heart arrest, tachycardia, hypertension, myocardial infarction, pulmonary embolus, bradycardia, hypotension, syncope Digestive System: oral moniliasis, anorexia, cholestatic jaundice/jaundice, flatulence, ileus, hepatic failure, dyspepsia, intestinal obstruction Hemic/Lymphatic: anemia, hypochromic anemia, hypervolemia Metabolic/Nutritional: peripheral edema, hypoxia Nervous System: insomnia, agitation, delirium, confusion, dizziness, seizure, nervousness, paresthesia, hallucinations, somnolence, anxiety, depression, asthenia [see Warnings and Precautions (5.4) and (5.10) ] Respiratory: respiratory disorder, dyspnea, pleural effus …

7 DRUG INTERACTIONS Co-administration of Meropenem for Injection with probenecid inhibits renal excretion of meropenem and is therefore not recommended. ( 7.1 ) The concomitant use of Meropenem and valproic acid or divalproex sodium is generally not recommended. Antibacterial drugs other than carbapenems should be considered to treat infections in patients whose seizures are well controlled on valproic acid or divalproex sodium. ( 5.5 , 7.2 ) 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 (5.5) ].

8 USE IN SPECIFIC POPULATIONS Pediatric use: Meropenem for Injection and Sodium Chloride Injection should not be used in pediatric patients who require less than the full adult dose of meropenem. ( 8.4 ) Renal Impairment: Dose adjustment is necessary, if creatinine clearance is 50 mL/min or less. ( 2.2 , 8.6 ) 8.1 Pregnancy 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. Data 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 study 2 , 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 literature 1 , 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). 8.2 Lactation Risk Summary 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 and Sodium Chloride Injection in the DUPLEX® Container and any potential adverse effects on the breastfed-child from Meropenem for Injection and Sodium Chloride Injection in the DUPLEX® Container or from the underlying maternal conditions. 8.4 Pediatric Use Meropenem for Injection and Sodium Chloride Injection 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 fu …

12.1 Mechanism of Action Meropenem is an antibacterial drug [see Microbiology (12.4) ].

11 DESCRIPTION Meropenem for injection is a sterile, pyrogen-free, synthetic, carbapenem antibacterial drug for intravenous administration. Meropenem is (4 R ,5 S ,6 S )-3- [[(3 S ,5 S )-5-(Dimethylcarbamoyl)-3-pyrrolidinyl]thio]-6-[(1 R )-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid trihydrate. Its empirical formula is C 17 H 25 N 3 O 5 S•3H 2 O 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-dose 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). structural formula

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 and Sodium Chloride Injection 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.

16 HOW SUPPLIED/STORAGE AND HANDLING Meropenem for Injection USP and Sodium Chloride Injection USP in the DUPLEX® Container is a flexible dual chamber single-dose 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 500 Anhydrous 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 mL Store the unactivated unit at 20°C–25°C (68°F–77°F). Excursion permitted to 15°C-30°C. [See USP Controlled Room Temperature.] Protect from freezing. Use only if prepared solution is clear and free from particulate matter.