Meropenem

1 INDICATIONS AND USAGE Meropenem for Injection is a penem antibacterial indicated for the treatment of bacterial meningitis in pediatric patients 3 months of age and older only. ( 1.1 ) To reduce the development of drug-resistant bacteria and maintain the effectiveness of Meropenem for Injection and other antibacterial drugs, Meropenem for Injection should only be used to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria. ( 1.2 ) 1.1 Bacterial Meningitis (Pediatric Patients 3 Months of Age and Older Only) Meropenem for Injection is indicated for the treatment of bacterial meningitis caused by Haemophilus influenzae , Neisseria meningitidis andpenicillin-susceptible isolates of Streptococcus pneumoniae, in pediatric patients 3 months of age and older. Meropenem for injection has been found to be effective in eliminating concurrent bacteremia in association with bacterial meningitis. 1.2 Usage To reduce the development of drug-resistant bacteria and maintain the effectiveness of Meropenem for Injection and other antibacterial drugs, Meropenem for 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 • Pediatric patients 3 months of age and older with bacterial meningitis ( 2.1 ) Recommended Meropenem for Injection Dosage Schedule for Pediatric Patients 3 Months of Age and Older with Bacterial Meningitis and Normal Renal Function (2.1) Type of Infection Dose (mg/kg) Up to a Maximum Dose Dosing Interval Bacterial Meningitis 40 2 grams Every 8 hours - Intravenous infusion is to be given over approximately 15 minutes to 30 minutes. - There is no experience with the use of Meropenem for Injection in pediatric patients with renal impairment. 2.1 Recommended Dosage in Pediatric Patients 3 Months of Age and Older with Bacterial Meningitis • For pediatric patients 3 months of age and older with bacterial meningitis, the Meropenem for Injection recommended dosage is 40 mg/kg every 8 hours (maximum dosage is 2 grams every 8 hours). • For pediatric patients weighing over 50 kg administer Meropenem for Injection at a dosage of 2 grams every 8 hours for bacterial meningitis. • Administer diluted Meropenem for Injection as an intravenous infusion over approximately 15 minutes to 30 minutes [see Dosage and Administration ( 2.2 )] . • There is limited safety data available to support the administration of a 40 mg/kg (up to a maximum of 2 grams) intravenous bolus injection. There is no experience with the use of Meropenem for Injection in pediatric patients with renal impairment [see Clinical Pharmacology ( 12.3 )] . 2.2 Preparation and Administration of Meropenem for Injection Preparation instructions for Intravenous Infusion (Reconstitution and Dilution) • Reconstitute Meropenem for Injection vial (2 grams) with Sterile Water for Injection according to the instructions in Table 1 below. • Shake well to dissolve and let stand until clear. Table 1: Volume of Sterile Water for Injection for Reconstitution of Injection Vials Vial Size Amount of Diluent Added (mL) Approximate Withdrawable Volume (mL) Approximate Average Concentration (mg/mL) 2 grams 40 mL 40 mL 50 mg/mL • Add the resulting reconstituted solution to an intravenous container and further dilute with an appropriate infusion fluid [see Dosage and Administration( 2.3 )and ( 2.4 )] . • Discard unused portion. • Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. When reconstituted, the solution varies from colorless to yellow depending on the concentration. • Do not use flexible container in series connections. Administration Instructions for Meropenem Intravenous Infusion Solution After reconstitution and dilution of Meropenem for Injection, administer the appropriate dose of diluted Meropenem solution as an intravenous infusion over approximately 15 minutes to 30 minutes [see Dosage and Administration ( 2.1 )]. 2.3 Compatibility Compatibility of Meropenem for Injection with other drugs has not been established. Meropenem for Injection should not be mixed with or physically added to solutions containing other drugs. 2.4 Stability and Storage Reconstituted Solution with Sterile Water for Injection Use the reconstituted solution with Sterile Water for Injection immediately. However, re-constituted solutions of Meropenem for Injection maintain satisfactory potency under the conditions described below. Do not freeze reconstituted solutions of Meropenem for Injection. Reconstituted Solution Diluted with Sodium Chloride Injection, 0.9 % Solutions prepared for infusion (meropenem concentrations ranging from 1 mg/mL to 20 mg/mL) reconstituted with Water for Injection and further diluted with Sodium Chloride Injection 0.9% may be stored for 1 hour at up to 25°C (77°F) or 2 hours at up to 5°C (41°F). Reconstituted Solution Diluted with Dextrose Injection, 5 % Immediately use solutions (meropenem concentrations ranging from 1 mg/mL to 20 mg/mL) reconstituted with Water for Injection and subsequently diluted with Dextrose Injection 5%.

5 WARNINGS AND PRECAUTIONS • Serious and occasionally fatal hypersensitivity (anaphylactic) reactions have been reported in patients receiving β-lactams. ( 5.1 ) • Severe cutaneous adverse reactions have been reported in patients receiving meropenem for injection. ( 5.2 ) • Rhabdomyolysis: If signs or symptoms of rhabdomyolysis are observed, discontinue meropenem for injection and initiate appropriate therapy. ( 5.3 ) • Seizures and other adverse CNS experiences have been reported during treatment. ( 5.4 ) • Co-administration of meropenem for injection with valproic acid or divalproex sodium reduces the serum concentration of valproic acid potentially increasing the risk of breakthrough seizures. ( 5.5 , 7.2 ) • Clostridioides difficile -associated diarrhea (ranging from mild diarrhea to fatal colitis) has been reported. Evaluate if diarrhea occurs. ( 5.6 ) • In patients with renal dysfunction, thrombocytopenia has been observed ( 5.9 ) 5.1 Hypersensitivity Reactions Serious and occasionally fatal hypersensitivity (anaphylactic) reactions have been reported in patients receiving therapy with β-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 β-lactam. Before initiating therapy with meropenem for injection, it is important to inquire about previous hypersensitivity reactions to penicillins, cephalosporins, other β-lactams, and other allergens. If an allergic reaction to meropenem for injection occurs, discontinue the drug immediately. 5.2 Severe Cutaneous Adverse Reactions Severe cutaneous adverse reactions (SCAR) such as Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS), erythema multiforme (EM) and acute generalized exanthematous pustulosis (AGEP) have been reported in patients receiving meropenem for injection [ see Adverse Reactions ( 6.2 ) ]. If signs and symptoms suggestive of these reactions appear, meropenem should be withdrawn immediately and an alternative treatment should be considered. 5.3 Rhabdomyolysis Rhabdomyolysis has been reported with the use of meropenem [see Adverse Reactions ( 6.2 )] . If signs or symptoms of rhabdomyolysis such as muscle pain, tenderness or weakness, dark urine, or elevated creatine phosphokinase are observed, discontinue meropenem for injection and initiate appropriate therapy. 5.4 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 included a prior history of seizures or CNS abnormality and concomitant medications with seizure potential. Close adherence to the recommended dosage regimens is urged, especially in patients with known factors that predispose to convulsive activity. Continue anti-convulsant therapy in patients with known seizure disorders. If focal tremors, myoclonus, or seizures occur, evaluate neurologically, placed on anti-convulsant therapy if not already instituted, and re-examine the dosage of meropenem for injection to determine whether it should be decreased or discontinued. 5.5 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 repo…

4 CONTRAINDICATIONS Meropenem for 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 (β)-lactams. • Known hypersensitivity to product components or other drugs in the same class or in patients who have demonstrated anaphylactic reactions to beta (β)-lactams. ( 4 )

7 DRUG INTERACTIONS • Co-administration of meropenem for injection with probenecid inhibits renal excretion of meropenem and therefore Meropenem for Injection is not recommended ( 7.1 ) • The concomitant use of Meropenem for Injection 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. ( 5.4 , 7.2 ) 7.1 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. 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( 5.4 ) ].

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 monkeys administered intravenous meropenem during organogenesis at doses up to 2.4 and 2.3 times the maximum recommended human dose (MRHD) 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 MRHD based on body surface area comparison ( see Data ). The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Data Meropenem administered to pregnant rats during organogenesis (Gestation Day 6 to Gestation Day 17) in intravenous doses of 240, 500, and 750 mg/kg/day 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 MRHD of 1 gram every 8 hours based on body surface area comparison). Meropenem administered intravenously to pregnant Cynomolgus monkeys during organogenesis from Day 20 to 50 after mating at doses of 120, 240, and 360 mg/kg/day did not produce maternal or fetal toxicity at the NOAEL dose of 360 mg/kg/day (approximately 2.3 times the MRHD 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 Lactation Day 21 at doses of 240, 500, and 1000 mg/kg/day. 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 MRHD based on body surface area comparisons).

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 )] Most common adverse reactions (incidence ≥ 1%) are: diarrhea, rash (mostly diaper area moniliasis), oral moniliasis, and glossitis ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact WG Critical Care, LLC at 1-866-562-4708 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 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. Adverse Reactions in Pediatric Patients with Bacterial Meningitis Meropenem for injection was studied in 321 pediatric patients (3 months to less than 17 years of age) with bacterial meningitis at a dosage of 40 mg/kg every 8 hours. The most common adverse reactions and their rates of occurrence were as follows: Diarrhea 4.7% Rash (mostly diaper area moniliasis) 3.1% Oral Moniliasis 1.9% Glossitis 1% In these studies, the rates of seizure activity during therapy were comparable between patients with no CNS abnormalities who received meropenem for injection 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 (seizures that occurred on day 3 or later) versus 7/20 patients in the comparator arm. The meropenem for injection group had a statistically higher number of patients than the comparator with transient elevation of liver enzymes. Adverse Reactions from Studies of Meropenem for Injectionin Other Serious Bacterial Infections (not bacterial meningitis) The following adverse reactions occurred in studies of 2,904 immunocompetent adult patients who received meropenem for injection (500 mg or 1 gram every 8 hours) for the treatment of other serious bacterial infections (not bacterial meningitis). This meropenem for injection product is indicated only for the treatment of bacterial meningitis caused by certain organisms in pediatric patients 3 months of age and older [see Indications and Usage ( 1.1 )]. Many patients in these studies 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. Deaths in 5 patients were assessed as possibly related to meropenem for injection; 36 (1.2%) patients had meropenem for injection discontinued because of adverse events. 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%), and edema at the injection site (0.2%) Systemic Adverse Reactions Systemic adverse reactions that occurred in greater than 1% of the meropenem for injection-treated patients were diarrhea (4.8%), nausea/vomiting (3.6%), headache (2.3%), rash (1.9%), sepsis (1.6%), const…