ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS. The following are discussed in greater detail in other sections of labeling:o 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 Gland Pharma at 864-879-9994 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 drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.Adult PatientsDuring clinical investigations, 2904 immunocompetent adult patients were treated for non-CNS infections with Meropenem for Injection, USP (500 mg or gram every hours). Deaths in 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 ReactionsLocal 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 ReactionsSystemic 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 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 (5.3) and (5.9)]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 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 with Meropenem for Injection, USP, increased in patients with moderately severe renal impairment (creatinine clearance 10 to 26 mL/min) [see Dosage and Administration (2.2), Warnings and Precautions (5.9), Use in Specific Populations (8.5) and (8.6) and Clinical Pharmacology (12.3)]. Pediatric Patients:Systemic and Local Adverse ReactionsPediatric Patients with Serious Bacterial Infections (excluding Bacterial Meningitis)Meropenem for Injection, USP was studied in 515 pediatric patients (3 months to less than 13 years of age) with serious bacterial infections (excluding meningitis, see next section) at dosages of 10 mg/kg to 20 mg/kg every 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, USP and their rates of occurrence as follows: Diarrhea 3.5% Rash 1.6% Nausea and Vomiting 0.8%Pediatric Patients with Bacterial MeningitisMeropenem for Injection, USP was studied in 321 pediatric patients (3 months to less than 17 years of age) with meningitis at dosage of 40 mg/kg every hours. The types of systemic and local adverse events seen in these patients are similar to the adults, with the most common adverse reactions reported as possibly, probably, or definitely related to Meropenem for Injection, USP 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, USP treated group, 12/15 patients with seizures had late onset seizures (defined as occurring on day or later) versus 7/20 in the comparator arm. The meropenem group had statistically higher number of patients with transient elevation of liver enzymes.Pediatric Patients (Neonates and Infants less than months of Age)Meropenem for Injection, USP was studied in 200 neonates and infants less than months of age. The study was open-label, uncontrolled, 98% of the infants received concomitant medications, and the majority of adverse events were reported in neonates less than 32 weeks gestational age and critically ill at baseline, making it difficult to assess the relationship of the adverse events to Meropenem for Injection, USP.The adverse reactions seen in these patients that were reported and their rates of occurrence are as follows: Convulsion 5.0% Hyperbilirubinemia(Conjugated) 4.5% Vomiting 2.5%Adverse Laboratory Changes in Pediatric Patients:Laboratory changes seen in the pediatric studies, including the meningitis studies, were similar to those reported in the adult studies.. 6.2 Post-marketing Experience. The following adverse reactions have been identified during post-approval use of Meropenem for Injection, USP. Because these reactions are reported voluntarily from population of uncertain size, it is not always possible to reliably estimate their frequency or establish 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; positive direct or indirect Coombs test, and hemolytic anemia.Immune System Disorders: angioedema. Skin and Subcutaneous Disorders: Stevens-Johnson syndrome, toxic epidermal necrolysis, drug reaction with eosinophilia and systemic symptoms (DRESS), erythema multiforme and acute generalized exanthematous pustulosis.

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

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:In fertility studies, intravenous meropenem was administered to male rats beginning 11 weeks before mating and throughout mating and to female rats from weeks before mating through Gestation Day at doses of 240, 500, and 1000 mg/kg/day. There was no evidence of impaired fertility at doses up to 1000 mg/kg/day (on the basis of body surface area comparison, approximately 3.2 times to the MRHD of gram every hours).

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. Meropenem is an antibacterial drug [see Microbiology (12.4)]. 12.2 Pharmacodynamics. The percentage of time of dosing interval that unbound plasma concentration of meropenem exceeds the meropenem minimum inhibitory concentration (MIC) against the infecting organism has been shown to best correlate with efficacy in animal and in vitro models of infection.. 12.3 Pharmacokinetics. Plasma Concentrations At the end of 30-minute intravenous infusion of single dose of Meropenem for Injection, USP in healthy volunteers, mean peak plasma concentrations of meropenem are approximately 23 mcg/mL (range 14 to 26) for the 500 mg dose and 49 mcg/mL (range 39 to 58) for the gram dose. 5-minute intravenous bolus injection of Meropenem for Injection, USP in healthy volunteers results in mean peak plasma concentrations of approximately 45 mcg/mL (range 18 to 65) for the 500 mg dose and 112 mcg/mL (range 83 to 140) for the gram dose.Following intravenous doses of 500 mg, mean plasma concentrations of meropenem usually decline to approximately mcg/mL at hours after administration. No accumulation of meropenem in plasma was observed with regimens using 500 mg administered every hours or gram administered every hours in healthy volunteers with normal renal function.Distribution The plasma protein binding of meropenem is approximately 2%. After single intravenous dose of Meropenem for Injection, USP, the highest mean concentrations of meropenem were found in tissues and fluids at hour (0.5 hours to 1.5 hours) after the start of infusion, except where indicated in the tissues and fluids listed in Table below. Table 5: Meropenem Concentrations in Selected Tissues (Highest Concentrations Reported) TissueIntravenous Dose (gram)Number of SamplesMean [mcg/mL or mcg/(gram)]1 Range [mcg/mL or mcg/(gram)]Endometrium 0.5 4.2 1.7 to 10.2 Myometrium 0.5 15 3.8 0.4 to 8.1 Ovary 0.5 2.8 0.8 to 4.8 Cervix 0.5 7 5.4 to 8.5 Fallopian tube 0.5 1.7 0.3 to 3.4 Skin 0.5 22 3.3 0.5 to 12.6 Interstitial fluid2 0.5 5.5 3.2 to 8.6 Skin 10 5.3 1.3 to 16.7 Interstitial fluid2 5 26.3 20.9 to 37.4 Colon 2 2.6 2.5 to 2.7 Bile 7 14.6 (3 hours) to 25.7 Gall bladder 1 3.9 Peritoneal fluid 9 30.2 7.4 to 54.6 Lung 2 4.8 (2 hours) 1.4 to 8.2 Bronchial mucosa 7 4.5 1.3 to 11.1 Muscle 2 6.1 (2 hours) 5.3 to 6.9 Fascia 9 8.8 1.5 to 20 Heart valves 7 9.7 6.4 to 12.1 Myocardium 10 15.5 5.2 to 25.5 CSF (inflamed) 20 mg/kg3 40 mg/kg4 85 1.1 (2 hours)3.3 (3 hours) 0.2 to 2.80.9 to 6.5 CSF (uninflamed) 4 0.2 (2 hours) 0.1 to 0.3 at hour unless otherwise notedobtained from blister fluidin pediatric patients of age months to yearsin pediatric patients of age month to 15 yearsElimination In subjects with normal renal function, the elimination half-life of meropenem is approximately hour.Metabolism There is one metabolite of meropenem that is microbiologically inactive.Excretion Meropenem is primarily excreted unchanged by the kidneys. Approximately 70% (50% to 75%) of the dose is excreted unchanged within 12 hours. 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 hours after 500 mg dose.Specific Populations Patients with Renal Impairment Pharmacokinetic studies with Meropenem for Injection, USP 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 for Injection, USP is hemodialyzable. However, there is no information on the usefulness of hemodialysis to treat overdosage [see Overdosage (10)].Patients with Hepatic Impairment pharmacokinetic study with Meropenem for Injection, USP in patients with hepatic impairment has shown no effects of liver disease on the pharmacokinetics of meropenem.Geriatric Patients pharmacokinetic study with Meropenem for Injection, USP in elderly patients with renal impairment showed reduction in plasma clearance of meropenem that correlates with age-associated reduction in creatinine clearance.Pediatric Patients The pharmacokinetics of meropenem for injection, USP, in pediatric patients 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 months to years. The pharmacokinetics of meropenem in patients less than months of age receiving combination antibacterial drug therapy are given below.Table 6: Meropenem Pharmacokinetic Parameters in Patients Less Than Months of Age GA less than 32weeks PNA lessthan weeks(20 mg/kg every12 hours)GA less than 32 weeks PNA weeks or older (20 mg/kg every hours) GA 32 weeks or older PNA less than weeks (20 mg/kg every hours) GA 32 weeks or older PNA weeks or older (30 mg/kg every hours) Overall CL (L/h/kg) 0.089 0.122 0.135 0.202 0.119 (L/kg) 0.489 0.467 0.463 0.451 0.468 AUC0-24 (mcg-h/mL) 448 491 445 444 467 Cmax (mcg/mL) 44.3 46.5 44.9 61 46.9 Cmin (mcg/mL) 5.36 6.65 4.84 2.1 5.65 T1/2 (h) 3.82 2.68 2.33 1.58 2.68 Values are derived from population pharmacokinetic analysis of sparse data Drug Interactions Probenecid competes with meropenem for active tubular secretion and thus inhibits the renal excretion of meropenem. Following administration of probenecid with meropenem, the mean systemic exposure increased 56% and the mean elimination half-life increased 38% [see Drug Interactions (7.1)].. at hour unless otherwise noted. obtained from blister fluid. in pediatric patients of age months to years. in pediatric patients of age month to 15 years. 12.4 Microbiology. Mechanism of Action The 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 bind penicillin-binding-protein (PBP) targets. Meropenem binds to PBPs 2, and of Escherichia coli and Pseudomonas aeruginosa; and PBPs 1, and of Staphylococcus aureus. Bactericidal concentrations (defined as 3 log10 reduction in cell counts within 12 hours to 24 hours) are typically to times the bacteriostatic concentrations of meropenem, with the exception of Listeria monocytogenes, against which lethal activity is not observed. Meropenem does not have in vitro activity against methicillin-resistant Staphylococcus aureus (MRSA) or methicillin-resistant Staphylococcus epidermidis (MRSE). Resistance There 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--lactamases). Cross-resistance is sometimes observed with isolates resistant to other carbapenems. Interaction with Other Antimicrobials In vitro tests show meropenem to act synergistically with aminoglycoside antibacterial drugs against some isolates of Pseudomonas aeruginosa. Antimicrobial Activity Meropenem 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 bacteria Enterococcus faecalis (vancomycin-susceptible isolates only) Staphylococcus aureus (methicillin-susceptible isolates only) Streptococcus agalactiae Streptococcus pneumoniae (penicillin-susceptible isolates only) Streptococcus pyogenes Viridans group streptococciGram-negative bacteriaEscherichia coli Haemophilus influenzae Klebsiella pneumoniae Neisseria meningitidis Proteus mirabilis Pseudomonas aeruginosa Anaerobic bacteriaBacteroides fragilis Bacteroides thetaiotaomicron Peptostreptococcus speciesThe following in vitro data are available, but their clinical significance is unknown. At least 90% 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 bacteria have not been established in adequate and well-controlled clinical trials. Gram-positive bacteria Staphylococcus epidermidis (methicillin-susceptible isolates only)Gram-negative bacteriaAeromonas hydrophila Campylobacter jejuni Citrobacter freundii Citrobacter koseri Enterobacter cloacae Hafnia alvei Klebsiella oxytoca Moraxella catarrhalis Morganella morganii Pasteurella multocida Proteus vulgaris Serratia marcescensAnaerobic bacteriaBacteroides ovatus Bacteroides uniformis Bacteroides ureolyticus Bacteroides vulgatus Clostridium difficile Clostridium perfringens Eggerthella lenta Fusobacterium species Parabacteroides distasonis Porphyromonas asaccharolytica Prevotella bivia Prevotella intermedia Prevotella melaninogenica Propionibacterium acnes Susceptibility Testing For specific information regarding susceptibility test interpretive criteria and associated test methods and quality control standards recognized by FDA for this drug, please see: https://www.fda.gov/STIC.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. 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 randomized, multi-center, international, double-blind trial. The study evaluated meropenem at doses of 500 mg administered intravenously every hours and imipenem-cilastatin at doses of 500 mg administered intravenously every 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 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 the clinically evaluable population are provided in Table 7.Table 7: Success Rates at Test-of-Cure Visit for Clinically Evaluable Population with Complicated Skin and Skin Structure InfectionsPopulationMeropenem for Injection, USP n1/N2 (%)Imipenem-cilastatinn1/N2 (%)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 or older 35/43 (81) 33/46 (72) Men 130/148 (88) 137/172 (80) Women 95/113 (84) 101/115 (88) 1. n=number of patients with satisfactory response.2. N=number of patients in the clinically evaluable population or respective subgroup within treatment groups.The clinical efficacy rates by pathogen are provided in Table 8. 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 8: Clinical Efficacy Rates by Pathogen for Clinically Evaluable PopulationMICROORGANISMS1Meropenem for Injection, USPn2/N3 (%)4 Imipenem-cilastatinn2/N3 (%)4 Gram-positive aerobes Staphylococcus aureus, methicillin susceptible82/88 (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 faecalis9/12 (75) 14/20 (70) Viridans groupstreptococci 11/12 (92) 5/6 (83) Gram-negative aerobes Escherichia coli12/15 (80) 15/21 (71) Pseudomonas aeruginosa11/15 (73) 13/15 (87) Proteus mirabilis11/13 (85) 6/7 (86) Anaerobes Bacteroides fragilis10/11 (91) 9/10 (90) Peptostreptococcus Species10/13 (77) 14/16 (88) Patients may have more than one pretreatment pathogen.n=number of patients with satisfactory response.N=number of patients in the clinically evaluable population or subgroup within treatment groups.%= Percent of satisfactory clinical response at follow-up evaluation.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%).. Patients may have more than one pretreatment pathogen.. n=number of patients with satisfactory response.. N=number of patients in the clinically evaluable population or subgroup within treatment groups.. %= Percent of satisfactory clinical response at follow-up evaluation.. 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 or more days after completion of therapy, the presumptive microbiologic eradication/clinical cure rates and statistical findings are provided in Table 9:Table 9: Presumptive Microbiologic Eradication and Clinical Cure Rates at Test-of-Cure Visit in the Evaluable Population with Complicated Intra-Abdominal InfectionTreatment ArmNo. evaluable/ No. enrolled (%)Microbiologic Eradication RateClinical Cure RateOutcomemeropenem 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 control The finding that meropenem was not statistically equivalent to cefotaxime/metronidazole may have been due to uneven assignment of more seriously ill patients to the meropenem arm. Currently there is no additional information available to further interpret this observation.. 14.3 Bacterial Meningitis. Four hundred forty-six patients (397 pediatric patients months to less than 17 years of age) were enrolled in separate clinical trials and randomized to treatment with meropenem (n=225) at dose of 40 mg/kg every hours or comparator drug, i.e., cefotaxime (n=187) or ceftriaxone (n=34), at the approved dosing regimens. comparable number of patients were found to be clinically evaluable (ranging from 61 to 68%) and with 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 to 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 patients clinical status necessitated the addition of other antibacterial drugs.Either during or post-therapy, the patient developed large subdural effusion needing surgical drainage, or cerebral abscess, or bacteriologic relapse.Using the definition, the following efficacy rates were obtained, per organism (noted in Table 10). The values represent the number of patients clinically cured/number of clinically evaluable patients, with the percent cure in parentheses.Table 10: Efficacy rates by Pathogen in the Clinically Evaluable Population with Bacterial MeningitisMICROORGANISMSMeropenem for Injection, USPCOMPARATORS. pneumoniae17/24 (71) 19/30 (63) H. influenzae (+)18/10 (80) 6/6 (100) H. influenzae (-/NT)244/59 (75) 44/60 (73) N. meningitidis30/35 (86) 35/39 (90) Total (including others) 102/131 (78) 108/140 (77) (+) -lactamase-producing(-/NT) non--lactamase-producing or not testedSequelae were the most common reason patients were assessed as clinically not cured.Five patients were found to be bacteriologically not cured, in the comparator group (1 relapse and patients with cerebral abscesses) and in the meropenem group (1 relapse and 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 11: Hearing Loss at Post-Therapy in the Evaluable Population Treated with MeropenemDegree of Hearing Loss(in one or both ears)Meropenemn 128Comparatorn 135No loss 61% 56% 20 to 40 decibels 20% 24% Greater than 40 to 60 decibels 8% 7% Greater than 60 decibels 9% 10% At the to 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 patients clinical status necessitated the addition of other antibacterial drugs.. Either during or post-therapy, the patient developed large subdural effusion needing surgical drainage, or cerebral abscess, or bacteriologic relapse.. (+) -lactamase-producing. (-/NT) non--lactamase-producing or not tested.

CONTRAINDICATIONS SECTION.

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()-lactams.. Known hypersensitivity to product components or anaphylactic reactions to -lactams. (4).

DESCRIPTION SECTION.

11 DESCRIPTION. Meropenem for Injection, USP is sterile, pyrogen-free, synthetic, carbapenem antibacterial for intravenous administration. It 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 C17H25N3O5So3H2O with molecular weight of 437.52. Its structural formula is: Meropenem for Injection, USP is white to pale yellow crystalline powder. The solution varies from colorless to yellow depending on the concentration. The pH of freshly constituted solutions is between 7.3 and 8.3. Meropenem is soluble in 5% monobasic potassium phosphate solution, sparingly soluble in water, very slightly soluble in hydrated ethanol, and practically insoluble in acetone or ether.When re-constituted as instructed, each gram Meropenem for Injection, USP vial will deliver gram of meropenem and 90.2 mg of sodium as sodium carbonate (3.92 mEq). Each 500 mg Meropenem for Injection, USP vial will deliver 500 mg meropenem and 45.1 mg of sodium as sodium carbonate (1.96 mEq) [see Dosage and Administration (2.4)]. image05.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. 500 mg every 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, dose of gram every hours is recommended. (2.1)1 gram every hours by intravenous infusion over 15 minutes to 30 minutes for intra-abdominal infections for adult patients. (2.1)1 gram every hours by intravenous bolus injection (5 mL to 20 mL) over minutes to 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 ImpairmentCreatinine Clearance (mL/min)Dose (dependent on type of infection)DosingIntervalGreater than 50 Recommended dose (500 mg cSSSI and gram Intra-abdominal) Every8 hours 26 to 50 Recommended dose Every12 hours 10 to 25 One-half recommended dose Every12 hours Less than 10 One-half recommended dose Every24 hours Pediatric patients months of age and olderRecommended Meropenem for Injection, USP Dosage Schedule for Pediatric Patients Months of Age and Older with Normal Renal Function (2.3) Type of InfectionDose(mg/kg)Up to aMaximum DoseDosingIntervalComplicated skin and skin structure 10 500 mg Every hours Intra-abdominal 20 gram Every hours Meningitis 40 grams Every hours 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 minutes to minutes.- There is no experience in pediatric patients with renal impairment.20 mg/kg (or gram for pediatric patients weighing over 50 kg) every hours is recommended when treating complicated skin and skin structure infections caused by P. aeruginosa. (2.3) Pediatric patients months of age and older Recommended Meropenem for Injection, USP Dosage Schedule for Pediatric Patients Less Than Months of Age with Complicated Intra-Abdominal Infections and Normal Renal Function (2.3)Age GroupDose (mg/kg)Dose IntervalInfants less than 32 weeks GA and PNA less than weeks 20 Every 12 hours Infants less than 32 weeks GA and PNA weeks and older 20 Every hours Infants 32 weeks and older GA and PNA less than weeks 20 Every hours Infants 32 weeks and older GA and PNA weeks and older 30 Every hours 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 500 mg every 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, dose of gram every hours is recommended. (2.1). gram every hours by intravenous infusion over 15 minutes to 30 minutes for intra-abdominal infections for adult patients. (2.1). gram every hours by intravenous bolus injection (5 mL to 20 mL) over minutes to minutes for adult patients. (2.1). Dosage should be reduced in adult patients with renal impairment. (2.2). 2.1 Adult Patients. The recommended dose of Meropenem for Injection, USP is 500 mg given every hours for skin and skin structure infections and gram given every hours for intra-abdominal infections. When treating complicated skin and skin structure infections caused by P. aeruginosa, dose of gram every hours is recommended. Meropenem for Injection, USP should be administered by intravenous infusion over approximately 15 minutes to 30 minutes. Doses of gram may also be administered as an intravenous bolus injection (5 mL to 20 mL) over approximately minutes to 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 valueTable 1:Recommended Meropenem for Injection, USP 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 gram Intra-abdominal) Every 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 There is inadequate information regarding the use of Meropenem for Injection, USP in patients on hemodialysis or peritoneal dialysis.. 2.3 Use in Pediatric Patients. Pediatric Patients Months of Age and OlderFor pediatric patients months of age and older, the Meropenem for Injection, USP dose is 10 mg/kg, 20 mg/kg or 40 mg/kg every hours (maximum dose is grams every hours), depending on the type of infection (cSSSI, cIAI, intra-abdominal infection or meningitis). See dosing table below.For pediatric patients weighing over 50 kg administer Meropenem for Injection, USP at dose of 500 mg every hours for cSSSI, gram every hours for cIAI and grams every hours for meningitis.Administer Meropenem for Injection, USP as an intravenous infusion over approximately 15 minutes to 30 minutes or as an intravenous bolus injection (5 mL to 20 mL) over approximately minutes to minutes.There is limited safety data available to support the administration of 40 mg/kg (up to maximum of grams) bolus dose.Table 2: Recommended Meropenem for Injection, USP Dosage Schedule for Pediatric Patients Months of Age and Older with Normal Renal FunctionType of InfectionDose (mg/kg)Up to Maximum DoseDosing IntervalComplicated skin and skin structure infections 10 500 mg Every hours Complicated intra-abdominal infections 20 gram Every hours Meningitis 40 grams Every hours There is no experience in pediatric patients with renal impairment. When treating cSSSI caused by P. aeruginosa, dose of 20 mg/kg (or gram for pediatric patients weighing over 50 kg) every hours is recommended.Pediatric Patients Less Than Months of Age For pediatric patients (with normal renal function) less than months of age, with complicated intra-abdominal infections, the Meropenem for Injection, USP dose is based on gestational age (GA) and postnatal age (PNA). See dosing table below. Meropenem for Injection, USP should be given as intravenous infusion over 30 minutes.Table 3: Recommended Meropenem for Injection, USP Dosage Schedule for Pediatric Patients Less than Months of Age with Complicated Intra-abdominal Infections and Normal Renal FunctionAge GroupDose (mg/kg)Dose IntervalInfants less than 32 weeks GA and PNA less than weeks 20 Every 12 hours Infants less than 32 weeks GA and PNA weeks and older 20 Every hours Infants 32 weeks and older GA and PNA less than weeks 20 Every hours Infants 32 weeks and older GA and PNA weeks and older 30 Every hours There is no experience in pediatric patients with renal impairment. For pediatric patients months of age and older, the Meropenem for Injection, USP dose is 10 mg/kg, 20 mg/kg or 40 mg/kg every hours (maximum dose is grams every hours), depending on the type of infection (cSSSI, cIAI, intra-abdominal infection or meningitis). See dosing table below.. For pediatric patients weighing over 50 kg administer Meropenem for Injection, USP at dose of 500 mg every hours for cSSSI, gram every hours for cIAI and grams every hours for meningitis.. Administer Meropenem for Injection, USP as an intravenous infusion over approximately 15 minutes to 30 minutes or as an intravenous bolus injection (5 mL to 20 mL) over approximately minutes to minutes.. There is limited safety data available to support the administration of 40 mg/kg (up to maximum of grams) bolus dose.. 2.4 Preparation and Administration of Meropenem for Injection, USP. Important Administration InstructionsParenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. For Intravenous Bolus AdministrationRe-constitute injection vials (500 mg and gram) with Sterile Water for Injection (see table below). Shake to dissolve and let stand until clear.Table 4: Volume of Sterile Water for Injection for Reconstitution of Injection VialsVial SizeAmount of Diluent Added (mL)Approximate WithdrawableVolume (mL)Approximate Average Concentration (mg/mL)500 mg 10 10 50 gram 20 20 50 For InfusionInjection vials (500 mg and gram) may be directly re-constituted with compatible infusion fluid.Alternatively, an injection vial may be re-constituted, then the resulting solution added to an intravenous container and further diluted with an appropriate infusion fluid [see Dosage and Administration (2.5) and (2.6)]. Do not use flexible container in series connections.. Injection vials (500 mg and gram) may be directly re-constituted with compatible infusion fluid.. Alternatively, an injection vial may be re-constituted, then the resulting solution added to an intravenous container and further diluted with an appropriate infusion fluid [see Dosage and Administration (2.5) and (2.6)]. Do not use flexible container in series connections.. 2.5 Compatibility. Compatibility of Meropenem for Injection, USP with other drugs has not been established. Meropenem for 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 should be used. However, re-constituted solutions of Meropenem for Injection, USP maintain satisfactory potency under the conditions described below. Solutions of intravenous Meropenem for Injection, USP should not be frozen.Intravenous Bolus AdministrationMeropenem for Injection, USP vials re-constituted with Sterile Water for Injection for bolus administration (up to 50 mg/mL of Meropenem for Injection, USP) may be stored for up to hours at up to 25C (77F) or for 13 hours at up to 5C (41F).Intravenous Infusion AdministrationSolutions prepared for infusion (Meropenem for Injection, USP concentrations ranging from mg/mL to 20 mg/mL) re-constituted with Sodium Chloride Injection 0.9% may be stored for hour at up to 25C (77F) or 15 hours at up to 5C (41F). Solutions prepared for infusion (Meropenem for Injection, USP concentrations ranging from mg/mL to 20 mg/mL) re-constituted with Dextrose Injection 5% should be used immediately.

DOSAGE FORMS & STRENGTHS SECTION.

3 DOSAGE FORMS AND STRENGTHS. Single dose clear glass vials of Meropenem for Injection, USP containing 500 mg or gram (as the trihydrate blended with anhydrous sodium carbonate for re-constitution) of sterile meropenem powder.. 500 mg Meropenem for Injection Vial (3) gram Meropenem for Injection Vial (3).

DRUG INTERACTIONS SECTION.

7 DRUG INTERACTIONS. o Co-administration of Meropenem for Injection, USP with probenecid inhibits renal excretion of meropenem and is therefore not recommended. (7.1) The concomitant use of Meropenem for Injection, USP 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 reduction in valproic acid concentrations. The valproic acid concentrations may drop below the therapeutic range as result of this interaction, therefore increasing the risk of breakthrough seizures. Although the mechanism of this interaction is unknown, data from in vitro and animal studies suggest that carbapenems may inhibit the hydrolysis of valproic acids glucuronide metabolite (VPA-g) back to valproic acid, thus decreasing the serum concentrations of valproic acid. If administration of Meropenem for Injection, USP is necessary, then supplemental anti-convulsant therapy should be considered [see Warnings and Precautions (5.4)].

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL. NDC 68083-146-01 For Intravenous Use Only Meropenem for Injection, USP (I.V.) Equivalent to 500 mg/vial meropenem Contents are Sterile Rx Only NDC 68083-146-10 For Intravenous Use Only Meropenem for Injection, USP (I.V.) Equivalent to 500 mg/vial meropenem 10 500 mgSterile Vials NDC 68083-147-01 For Intravenous Use Only Meropenem for Injection, USP (I.V.) Equivalent to g/vial meropenem Contents are Sterile Rx Only NDC 68083-147-10 For Intravenous Use Only Meropenem for Injection, USP (I.V.) Equivalent to g/vial meropenem 10 1 gSterile Vials. image1. image2. image3. image4.

GERIATRIC USE SECTION.

8.5 Geriatric Use. Of the total number of subjects in clinical studies of Meropenem for Injection, USP, approximately 1100 (30%) were 65 years of age and older, while 400 (11%) were 75 years and older. Additionally, in 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, USP in elderly patients has shown reduction in the plasma clearance of meropenem that correlates with age-associated reduction in creatinine clearance [see Clinical Pharmacology (12.3)].

HOW SUPPLIED SECTION.

16 HOW SUPPLIED/STORAGE AND HANDLING. Meropenem for Injection, USP is supplied as follows:NDC Meropenem for Injection, USP Package Factor68083-146-10 500 mg Injection Vial 10 vials per carton68083-147-10 gram Injection Vial 10 vials per cartonMeropenem for Injection, USP is supplied in 20 mL and 30 mL injection vials containing sufficient meropenem to deliver 500 mg or gram for intravenous administration, respectively. Storage ConditionsStore at 20 to 25C (68 to 77F). [See USP Controlled Room Temperature.]Sterile, Nonpyrogenic, Preservative-free.The container closure is not made with natural rubber latex.

INDICATIONS & USAGE SECTION.

1 INDICATIONS AND USAGE. Meropenem for Injection, USP is penem antibacterial indicated for the treatment of: Complicated skin and skin structure infections (adult patients and pediatric patients months of age and older only). (1.1) Complicated intra-abdominal infections (adult and pediatric patients). (1.2) Bacterial meningitis (pediatric patients 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 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 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.

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. Counsel patients that antibacterial drugs including Meropenem for 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 is prescribed to treat bacterial infection, tell patients that although it is common to feel better early in the course of therapy, take the medication 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 or other antibacterial drugs in the future.Counsel patients that diarrhea is 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 (5.5)]. 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. If treatment with Meropenem for 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 (5.4)]. Patients receiving Meropenem for 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 is well tolerated, patients should not operate machinery or motorized vehicles [see Warnings and Precautions (5.9)]. Manufactured by:Gland Pharma Limited Pashamylaram, Patancheru, Hyderabad 502 307, India Revised: May 2019. Counsel patients that antibacterial drugs including Meropenem for 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 is prescribed to treat bacterial infection, tell patients that although it is common to feel better early in the course of therapy, take the medication 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 or other antibacterial drugs in the future.. Counsel patients that diarrhea is 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 (5.5)]. 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. If treatment with Meropenem for 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 (5.4)]. Patients receiving Meropenem for 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 is well tolerated, patients should not operate machinery or motorized vehicles [see Warnings and Precautions (5.9)].

LACTATION SECTION.

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 breast-fed child or on milk production. The developmental and health benefits of breastfeeding should be considered along with the mothers clinical need for Meropenem for Injection, USP and any potential adverse effects on the breast-fed child from Meropenem for Injection, USP or from the underlying maternal conditions.

MECHANISM OF ACTION SECTION.

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

NONCLINICAL TOXICOLOGY SECTION.

13 NONCLINICAL TOXICOLOGY. 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:In fertility studies, intravenous meropenem was administered to male rats beginning 11 weeks before mating and throughout mating and to female rats from weeks before mating through Gestation Day at doses of 240, 500, and 1000 mg/kg/day. There was no evidence of impaired fertility at doses up to 1000 mg/kg/day (on the basis of body surface area comparison, approximately 3.2 times to the MRHD of gram every hours).

OVERDOSAGE SECTION.

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 grams given intravenously every 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.

PEDIATRIC USE SECTION.

8.4 Pediatric Use. The safety and effectiveness of Meropenem for Injection, USP have been established for pediatric patients months of age and older with complicated skin and skin structure infections and bacterial meningitis, and for pediatric patients of all ages with complicated intra-abdominal infections. Skin and Skin Structure Infections Use of Meropenem for Injection, USP in pediatric patients months of age and older with complicated skin and skin structure infections is supported by evidence from an adequate and well-controlled study in adults and additional data from pediatric pharmacokinetics studies [see Indications and Usage (1.3), Dosage and Administration (2.3), Adverse Reactions (6.1), Clinical Pharmacology (12.3) and Clinical Studies (14.1)]. Intra-abdominal Infections Use of Meropenem for Injection, USP in pediatric patients months of age and older with intra-abdominal infections is supported by evidence from adequate and well-controlled studies in adults with additional data from pediatric pharmacokinetics studies and controlled clinical trials in pediatric patients. Use of Meropenem for Injection, USP in pediatric patients less than months of age with intra-abdominal infections is supported by evidence from adequate and well-controlled studies in adults with additional data from pediatric pharmacokinetic and safety study [see Indications and Usage (1.2), Dosage and Administration (2.3), Adverse Reactions (6.1), Clinical Pharmacology (12.3) and Clinical Studies (14.2)]. Bacterial Meningitis Use of Meropenem for Injection, USP in pediatric patients months of age and older with bacterial meningitis is supported by evidence from adequate and well-controlled studies in the pediatric population [see Indications and Usage (1.3), Dosage and Administration (2.3), Adverse Reactions (6.1), Clinical Pharmacology (12.3) and Clinical Studies (14.3)].

PHARMACODYNAMICS SECTION.

12.2 Pharmacodynamics. The percentage of time of dosing interval that unbound plasma concentration of meropenem exceeds the meropenem minimum inhibitory concentration (MIC) against the infecting organism has been shown to best correlate with efficacy in animal and in vitro models of infection.

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. Plasma Concentrations At the end of 30-minute intravenous infusion of single dose of Meropenem for Injection, USP in healthy volunteers, mean peak plasma concentrations of meropenem are approximately 23 mcg/mL (range 14 to 26) for the 500 mg dose and 49 mcg/mL (range 39 to 58) for the gram dose. 5-minute intravenous bolus injection of Meropenem for Injection, USP in healthy volunteers results in mean peak plasma concentrations of approximately 45 mcg/mL (range 18 to 65) for the 500 mg dose and 112 mcg/mL (range 83 to 140) for the gram dose.Following intravenous doses of 500 mg, mean plasma concentrations of meropenem usually decline to approximately mcg/mL at hours after administration. No accumulation of meropenem in plasma was observed with regimens using 500 mg administered every hours or gram administered every hours in healthy volunteers with normal renal function.Distribution The plasma protein binding of meropenem is approximately 2%. After single intravenous dose of Meropenem for Injection, USP, the highest mean concentrations of meropenem were found in tissues and fluids at hour (0.5 hours to 1.5 hours) after the start of infusion, except where indicated in the tissues and fluids listed in Table below. Table 5: Meropenem Concentrations in Selected Tissues (Highest Concentrations Reported) TissueIntravenous Dose (gram)Number of SamplesMean [mcg/mL or mcg/(gram)]1 Range [mcg/mL or mcg/(gram)]Endometrium 0.5 4.2 1.7 to 10.2 Myometrium 0.5 15 3.8 0.4 to 8.1 Ovary 0.5 2.8 0.8 to 4.8 Cervix 0.5 7 5.4 to 8.5 Fallopian tube 0.5 1.7 0.3 to 3.4 Skin 0.5 22 3.3 0.5 to 12.6 Interstitial fluid2 0.5 5.5 3.2 to 8.6 Skin 10 5.3 1.3 to 16.7 Interstitial fluid2 5 26.3 20.9 to 37.4 Colon 2 2.6 2.5 to 2.7 Bile 7 14.6 (3 hours) to 25.7 Gall bladder 1 3.9 Peritoneal fluid 9 30.2 7.4 to 54.6 Lung 2 4.8 (2 hours) 1.4 to 8.2 Bronchial mucosa 7 4.5 1.3 to 11.1 Muscle 2 6.1 (2 hours) 5.3 to 6.9 Fascia 9 8.8 1.5 to 20 Heart valves 7 9.7 6.4 to 12.1 Myocardium 10 15.5 5.2 to 25.5 CSF (inflamed) 20 mg/kg3 40 mg/kg4 85 1.1 (2 hours)3.3 (3 hours) 0.2 to 2.80.9 to 6.5 CSF (uninflamed) 4 0.2 (2 hours) 0.1 to 0.3 at hour unless otherwise notedobtained from blister fluidin pediatric patients of age months to yearsin pediatric patients of age month to 15 yearsElimination In subjects with normal renal function, the elimination half-life of meropenem is approximately hour.Metabolism There is one metabolite of meropenem that is microbiologically inactive.Excretion Meropenem is primarily excreted unchanged by the kidneys. Approximately 70% (50% to 75%) of the dose is excreted unchanged within 12 hours. 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 hours after 500 mg dose.Specific Populations Patients with Renal Impairment Pharmacokinetic studies with Meropenem for Injection, USP 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 for Injection, USP is hemodialyzable. However, there is no information on the usefulness of hemodialysis to treat overdosage [see Overdosage (10)].Patients with Hepatic Impairment pharmacokinetic study with Meropenem for Injection, USP in patients with hepatic impairment has shown no effects of liver disease on the pharmacokinetics of meropenem.Geriatric Patients pharmacokinetic study with Meropenem for Injection, USP in elderly patients with renal impairment showed reduction in plasma clearance of meropenem that correlates with age-associated reduction in creatinine clearance.Pediatric Patients The pharmacokinetics of meropenem for injection, USP, in pediatric patients 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 months to years. The pharmacokinetics of meropenem in patients less than months of age receiving combination antibacterial drug therapy are given below.Table 6: Meropenem Pharmacokinetic Parameters in Patients Less Than Months of Age GA less than 32weeks PNA lessthan weeks(20 mg/kg every12 hours)GA less than 32 weeks PNA weeks or older (20 mg/kg every hours) GA 32 weeks or older PNA less than weeks (20 mg/kg every hours) GA 32 weeks or older PNA weeks or older (30 mg/kg every hours) Overall CL (L/h/kg) 0.089 0.122 0.135 0.202 0.119 (L/kg) 0.489 0.467 0.463 0.451 0.468 AUC0-24 (mcg-h/mL) 448 491 445 444 467 Cmax (mcg/mL) 44.3 46.5 44.9 61 46.9 Cmin (mcg/mL) 5.36 6.65 4.84 2.1 5.65 T1/2 (h) 3.82 2.68 2.33 1.58 2.68 Values are derived from population pharmacokinetic analysis of sparse data Drug Interactions Probenecid competes with meropenem for active tubular secretion and thus inhibits the renal excretion of meropenem. Following administration of probenecid with meropenem, the mean systemic exposure increased 56% and the mean elimination half-life increased 38% [see Drug Interactions (7.1)].. at hour unless otherwise noted. obtained from blister fluid. in pediatric patients of age months to years. in pediatric patients of age month to 15 years.

PREGNANCY SECTION.

8.1 Pregnancy. Risk Summary There are insufficient human data to establish whether there is 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 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 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 gram every 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 peri-postnatal study in rats described in the published literature2, 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).

RECENT MAJOR CHANGES SECTION.

Warnings and Precautions, Severe Cutaneous Adverse Reactions (5.2) 6/2018.

REFERENCES SECTION.

15 REFERENCES. Cockcroft DW, MH Gault, 1976, Prediction of creatinine clearance from serum creatinine, Nephron, 16:31-41.Kawamura S, AW Russell, SJ Freeman, and RA Siddall, 1992, Reproductive and Developmental Toxicity of Meropenem in Rats, Chemotherapy, 40:S238-250. Cockcroft DW, MH Gault, 1976, Prediction of creatinine clearance from serum creatinine, Nephron, 16:31-41.. Kawamura S, AW Russell, SJ Freeman, and RA Siddall, 1992, Reproductive and Developmental Toxicity of Meropenem in Rats, Chemotherapy, 40:S238-250.

SPL UNCLASSIFIED SECTION.

1.1 Complicated Skin and Skin Structure Infections (Adult Patients and Pediatric Patients 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.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. 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 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 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 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 gram every 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 peri-postnatal study in rats described in the published literature2, 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).. 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 breast-fed child or on milk production. The developmental and health benefits of breastfeeding should be considered along with the mothers clinical need for Meropenem for Injection, USP and any potential adverse effects on the breast-fed child from Meropenem for Injection, USP or from the underlying maternal conditions.. 8.4 Pediatric Use. The safety and effectiveness of Meropenem for Injection, USP have been established for pediatric patients months of age and older with complicated skin and skin structure infections and bacterial meningitis, and for pediatric patients of all ages with complicated intra-abdominal infections. Skin and Skin Structure Infections Use of Meropenem for Injection, USP in pediatric patients months of age and older with complicated skin and skin structure infections is supported by evidence from an adequate and well-controlled study in adults and additional data from pediatric pharmacokinetics studies [see Indications and Usage (1.3), Dosage and Administration (2.3), Adverse Reactions (6.1), Clinical Pharmacology (12.3) and Clinical Studies (14.1)]. Intra-abdominal Infections Use of Meropenem for Injection, USP in pediatric patients months of age and older with intra-abdominal infections is supported by evidence from adequate and well-controlled studies in adults with additional data from pediatric pharmacokinetics studies and controlled clinical trials in pediatric patients. Use of Meropenem for Injection, USP in pediatric patients less than months of age with intra-abdominal infections is supported by evidence from adequate and well-controlled studies in adults with additional data from pediatric pharmacokinetic and safety study [see Indications and Usage (1.2), Dosage and Administration (2.3), Adverse Reactions (6.1), Clinical Pharmacology (12.3) and Clinical Studies (14.2)]. Bacterial Meningitis Use of Meropenem for Injection, USP in pediatric patients months of age and older with bacterial meningitis is supported by evidence from adequate and well-controlled studies in the pediatric population [see Indications and Usage (1.3), Dosage and Administration (2.3), Adverse Reactions (6.1), Clinical Pharmacology (12.3) and Clinical Studies (14.3)]. 8.5 Geriatric Use. Of the total number of subjects in clinical studies of Meropenem for Injection, USP, approximately 1100 (30%) were 65 years of age and older, while 400 (11%) were 75 years and older. Additionally, in 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, USP in elderly patients has shown reduction in the plasma clearance of meropenem that correlates with age-associated reduction in creatinine clearance [see Clinical Pharmacology (12.3)]. 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 (5.8), and Clinical Pharmacology (12.3)].

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. Serious and occasionally fatal hypersensitivity (anaphylactic) reactions have been reported in patients receiving -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 -lactams. These reactions are more likely to occur in individuals with history of sensitivity to multiple allergens. There have been reports of individuals with history of penicillin hypersensitivity who have experienced severe hypersensitivity reactions when treated with another -lactam. Before initiating therapy with Meropenem for Injection, USP, it is important to inquire about previous hypersensitivity reactions to penicillins, cephalosporins, other -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 reduction in valproic acid concentrations. The valproic acid concentrations may drop below the therapeutic range as 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 is necessary, consider supplemental anti-convulsant therapy [see Drug Interactions (7.2)].. 5.5 Clostridium difficile-associated Diarrhea. Clostridium difficile-associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including Meropenem for Injection, USP, 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 and 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.. 5.6 Development of Drug-Resistant Bacteria. Prescribing Meropenem for Injection, USP in the absence of proven or strongly suspected bacterial infection or prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria.. 5.7 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.. 5.8 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)].. 5.9 Potential for Neuromotor Impairment. Alert patients receiving Meropenem for Injection, USP 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, USP is well tolerated, advise patients not to operate machinery or motorized vehicles [see Adverse Reactions (6.1)].