Meropenem

1 INDICATIONS AND USAGE Meropenem for Injection, USP 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 only). ( 1.1 ) Complicated intra-abdominal infections (adult and pediatric patients). ( 1.2 ) Bacterial meningitis (pediatric patients 3 months of age and older only). ( 1.3 ) To reduce the development of drug-resistant bacteria and maintain the effectiveness of Meropenem for Injection, USP and other antibacterial drugs, Meropenem for Injection, USP should only be used to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria. 1.1 Complicated Skin and Skin Structure Infections (Adult Patients and Pediatric Patients 3 Months of Age and Older Only) Meropenem for 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 and Pediatric Patients) Meropenem for 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 Only) Meropenem for Injection, USP is indicated for the treatment of bacterial meningitis caused by Haemophilus influenzae, Neisseria meningitidis and penicillin-susceptible isolates of Streptococcus pneumoniae. Meropenem for Injection, USP has been found to be effective in eliminating concurrent bacteremia in association with bacterial meningitis. 1.4 Usage To reduce the development of drug-resistant bacteria and maintain the effectiveness of Meropenem for Injection, USP and other antibacterial drugs, Meropenem for Injection, USP 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.

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

2 DOSAGE AND ADMINISTRATION 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 minutes to 30 minutes for intra-abdominal infections for adult patients. ( 2.1 ) 1 gram every 8 hours by intravenous bolus injection (5 mL to 20 mL) over 3 minutes to 5 minutes for adult patients. ( 2.1 ) Dosage should be reduced in adult patients with renal impairment. ( 2.2 ) Recommended Meropenem for Injection, USP 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) Every 8 hours 26 to 50 Recommended dose Every 12 hours 10 to 25 One-half recommended dose Every 12 hours Less than 10 One-half recommended dose Every 24 hours Pediatric patients 3 months of age and older Recommended Meropenem for Injection, USP Dosage Schedule for Pediatric Patients 3 Months of Age and Older with Normal Renal Function ( 2.3 ) Type of Infection Dose (mg/kg) Up to a Maximum Dose Dosing Interval - Intravenous infusion is to be given over approximately 15 minutes to 30 minutes. - Intravenous bolus injection (5 mL to 20 mL) is to be given over approximately 3 minutes to 5 minutes. - There is no experience in pediatric patients with renal impairment. 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 gram Every 8 hours Pediatric patients less than 3 months of age Recommended Meropenem for Injection, USP Dosage Schedule for Pediatric Patients Less Than 3 Months of Age with Complicated Intra-Abdominal Infections and Normal Renal Function ( 2.3 ) Age Group Dose (mg/kg) Dose Interval - Intravenous infusion is to be given over 30 minutes. - There is no experience in pediatric patients with renal impairment. GA: gestational age and PNA: postnatal age Infants less than 32 weeks GA and PNA less than 2 weeks 20 Every 12 hours Infants less than 32 weeks GA and PNA 2 weeks and older 20 Every 8 hours Infants 32 weeks and older GA and PNA less than 2 weeks 20 Every 8 hours Infants 32 weeks and older GA and PNA 2 weeks and older 30 Every 8 hours 2.1 Adult Patients The recommended dose of Meropenem for 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 should be administered by intravenous infusion over approximately 15 minutes to 30 minutes. Doses of 1 gram may also be administered as an intravenous bolus injection (5 mL to 20 mL) over approximately 3 minutes to 5 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.) 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) × (140 - age) 72 × serum creatinine (mg/dL) Females: 0.85 × above value Table 1: Recommended Meropenem for Injection, USP 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) Every 8 hours 26 to 50 Recommended dose Every 12 hours 10 to 25 One-half recommended dose Every 12 hours Less than 10 On

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) ] Seizure Potential [see Warnings and Precautions (5.3) ] Risk of Breakthrough Seizures Due to Drug Interaction with Valproic Acid [see Warnings and Precautions (5.4) ] Clostridium difficile – associated Diarrhea [see Warnings and Precautions (5.5) ] Development of Drug-Resistant Bacteria [see Warnings and Precautions (5.6) ] Overgrowth of Nonsusceptible Organisms [see Warnings and Precautions (5.7) ] Thrombocytopenia [see Warnings and Precautions (5.8) ] Potential for Neuromotor Impairment [see Warnings and Precautions (5.9) ] Most common adverse reactions (2% or less) are: headache, nausea, constipation, diarrhea, anemia, vomiting, and rash. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Xellia Pharmaceuticals USA, LLC at [email protected] or 1-833-295-6953, 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, USP (500 mg or 1 gram 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, USP. The following adverse reaction frequencies were derived from the clinical trials in the 2904 patients treated with Meropenem for Injection, USP. Local Adverse Reactions Local adverse events that were reported with Meropenem for Injection, USP 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, USP 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 events that were reported with Meropenem for Injection, USP 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 (5.3) and (5.9) ] Respiratory: respiratory disorder, dyspnea, pleural effusion, asthma, cough increased, lung edema Skin and Appendages: urticaria, s

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, USP. ( 5.2 ) Seizures and other adverse CNS experiences have been reported during treatment. ( 5.3 ) Co-administration of Meropenem for Injection, USP with valproic acid or divalproex sodium reduces the serum concentration of valproic acid potentially increasing the risk of breakthrough seizures. ( 5.4 , 7.2 ) Clostridium difficile- associated diarrhea (ranging from mild diarrhea to fatal colitis) has been reported. Evaluate if diarrhea occurs. ( 5.5 ) In patients with renal dysfunction, thrombocytopenia has been observed. ( 5.8 ) 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, USP, 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, USP 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, USP [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 Seizure Potential Seizures and other adverse CNS experiences have been reported during treatment with Meropenem for Injection, USP. 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. 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, USP to determine whether it should be decreased or discontinued. 5.4 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 resul

4 CONTRAINDICATIONS Meropenem for 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 (β)-lactams. Known hypersensitivity to product components or anaphylactic reactions to β-lactams. ( 4 )

10 OVERDOSAGE In mice and rats, large intravenous doses of meropenem (2200 mg/kg to 4000 mg/kg) have been associated with ataxia, dyspnea, convulsions, and mortalities. Intentional overdosing of Meropenem for 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 postmarketing 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. Consider symptomatic treatments. 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.