PEDIATRIC USE SECTION.

8.4 Pediatric Use. The safety and effectiveness of VABOMERE in pediatric patients (younger than 18 years of age) has not been established. Studies of VABOMERE have not been conducted in patients younger than 18 years of age.

GERIATRIC USE SECTION.

8.5 Geriatric Use. Of the 272 patients treated with VABOMERE in the Phase cUTI trial, 48 (18%) patients were 65 years of age and older, while 39 (14%) patients were 75 years of age and older. No overall differences in safety or effectiveness were observed between these patients and younger patients, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.Meropenem, component of VABOMERE, 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.Population pharmacokinetic (PK) analysis found no clinically relevant change in pharmacokinetic parameters in elderly patients. No dosage adjustment based on age is required. Dosage adjustment for elderly patients should be based on renal function [see Dosage and Administration (2.2) and Clinical Pharmacology (12.3)].

ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS. The following adverse reactions are discussed in greater detail in the Warnings and Precautions section:Hypersensitivity Reactions [see Warnings and Precautions (5.1)] Seizure Potential [see Warnings and Precautions (5.2)] Clostridioides difficile-associated Diarrhea [see Warnings and Precautions (5.3)]Risk of Breakthrough Seizures Due to Drug Interaction with Valproic Acid [see Warnings and Precautions (5.4)] Thrombocytopenia [see Warnings and Precautions (5.5)] Potential for Neuromotor Impairment [see Warnings and Precautions (5.6)] Development of Drug-Resistant Bacteria [see Warnings and Precautions (5.7)] Overgrowth of Nonsusceptible Organisms [see Warnings and Precautions (5.8)] Hypersensitivity Reactions [see Warnings and Precautions (5.1)] Seizure Potential [see Warnings and Precautions (5.2)] Clostridioides difficile-associated Diarrhea [see Warnings and Precautions (5.3)]. Risk of Breakthrough Seizures Due to Drug Interaction with Valproic Acid [see Warnings and Precautions (5.4)] Thrombocytopenia [see Warnings and Precautions (5.5)] Potential for Neuromotor Impairment [see Warnings and Precautions (5.6)] Development of Drug-Resistant Bacteria [see Warnings and Precautions (5.7)] Overgrowth of Nonsusceptible Organisms [see Warnings and Precautions (5.8)] The most frequently reported adverse reactions occurring in >=3% of patients treated with VABOMERE were headache, phlebitis/infusion site reactions, and diarrhea. (6.1)To report SUSPECTED ADVERSE REACTIONS, contact Melinta Therapeutics at 1-844-633-6568 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.. 6.1Clinical Trials Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction 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.VABOMERE was evaluated in Phase comparator-controlled clinical trial in cUTI, including pyelonephritis, which included 272 patients treated with VABOMERE and 273 patients treated with the comparator piperacillin/tazobactam 4.5 grams (piperacillin g/tazobactam 0.5 g) every hours. After minimum of 15 doses of IV therapy, patients could be switched to oral levofloxacin (500 mg daily every 24 hours) to complete the treatment course. Mean duration of IV therapy was days in both treatment groups. Mean duration of IV and oral therapy was 10 days; patients with baseline bacteremia could receive up to 14 days of treatment. The mean age of patients treated with VABOMERE was 53 years (range 18 to 92 years), and 32% of patients were 65 years of age or older. Patients were predominantly female (66.5%) and White (93.4%). Most patients were enrolled in Europe (89.7%).. Serious Adverse Reactions and Adverse Reactions Leading to DiscontinuationTreatment was discontinued due to adverse reactions in 2.9% (8/272) of patients receiving VABOMERE and in 5.1% (14/273) of patients receiving piperacillin/tazobactam. Most common adverse reactions resulting in discontinuation of VABOMERE included hypersensitivity, 1.1% (3/272) and infusion-related reactions, 0.7% (2/272). Death occurred in (0.7%) patients who received VABOMERE and in (0.7%) patients who received piperacillin/tazobactam.. Common Adverse ReactionsThe most frequently reported adverse reactions (3% or greater) in patients receiving VABOMERE in the Phase cUTI trial were headache, phlebitis/infusion site reactions, and diarrhea. Table provides adverse reactions occurring in 1% or greater of patients receiving VABOMERE in the Phase cUTI trial.Table 3:Adverse Reactions Occurring in 1% or Greater of Patients Receiving VABOMERE in the Phase Clinical Trial in cUTIAdverse ReactionsVABOMERE(N=272)%Piperacillin/TazobactamPiperacillin/tazobactam 4.5 grams (piperacillin g/tazobactam 0.5 g) IV infused over 30 minutes every hours. (N=273)%Headache8.84.4Phlebitis/Infusion site reactionsInfusion site reactions include infusion/injection site phlebitis, infusion site thrombosis, and infusion site erythema. 4.40.7Diarrhea3.34.4HypersensitivityHypersensitivity includes hypersensitivity, drug hypersensitivity, anaphylactic reaction, rash urticaria, and bronchospasm. 1.81.8Nausea1.81.5Alanine aminotransferase increased1.80.4Aspartate aminotransferase increased1.50.7Pyrexia1.50.7Hypokalemia1.11.5. Adverse Reactions Occurring in Less Than 1% of Patients Receiving VABOMERE in the Phase cUTI trial:Blood and lymphatic system disorders: leukopeniaGeneral disorders and administration site conditions: chest discomfortInfections and infestations: pharyngitis, vulvovaginal candidiasis, oral candidiasisInvestigations: creatinine phosphokinase increaseMetabolism and nutrition disorders: decreased appetite, hyperkalemia, hyperglycemia, hypoglycemiaNervous system disorders: dizziness, tremor, paresthesia, lethargyPsychiatric disorders: hallucination, insomniaRenal and urinary disorders: azotemia, renal impairmentVascular disorders: deep vein thrombosis, hypotension, vascular pain. Other Adverse Reactions Associated with MeropenemAdditionally, adverse reactions reported with meropenem alone that were not reported in VABOMERE-treated patients in the Phase clinical trial are listed below:Blood and lymphatic system disorders: thrombocytosis, neutropenia, eosinophilia, thrombocytopenia, agranulocytosis, hemolytic anemiaGastrointestinal disorders: abdominal painHepatobiliary disorders: jaundiceNervous system disorders: convulsionsInvestigations: blood alkaline phosphatase increased, blood lactate dehydrogenase increased, blood bilirubin increased, blood creatinine increased, blood urea increased, blood thromboplastin decreased, prothrombin time decreased, Direct and Indirect Coombs test positiveSkin and subcutaneous tissue disorders: pruritus, toxic epidermal necrolysis, Stevens Johnson syndrome, Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) syndrome, erythema multiformeImmune system disorders: angioedemaGeneral disorders and administration site conditions: pain.

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. CarcinogenesisLong-term carcinogenicity studies have not been performed with VABOMERE, meropenem, or vaborbactam.. Mutagenesis. MeropenemGenetic 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 mutation potential found in any of these tests. VaborbactamGenetic toxicity studies were performed with vaborbactam using the bacterial reverse mutation test, chromosomal aberration test and the mouse micronucleus test. There was no evidence of mutagenic potential found in any of these tests.. Impairment of Fertility. MeropenemReproductive studies were performed with meropenem in male and female rats at doses up to 1000 mg/kg/day with no evidence of impaired fertility (approximately equivalent to 1.6 times the MRHD based on body surface area comparison). In reproductive study in cynomolgus monkeys at doses of meropenem up to 360 mg/kg/day (on the basis of body surface area comparison, approximately equivalent to 1.2 times the MRHD) no reproductive toxicity was seen.. VaborbactamVaborbactam had no adverse effect on fertility in male and female rats at doses up to 1000 mg/kg/day, which is equivalent to approximately 1.6 times the MRHD based on body surface area comparison.

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. VABOMERE is an antibacterial drug [see Microbiology (12.4)].. 12.2 Pharmacodynamics. Similar to other beta-lactam antibacterial drugs, the percentage of time of dosing interval that unbound plasma concentration of meropenem exceeds the meropenem-vaborbactam minimum inhibitory concentration (MIC) against the infecting organism has been shown to best correlate with efficacy in animal and in vitro models of infection. The ratio of the 24-hour unbound plasma vaborbactam AUC to meropenem-vaborbactam MIC is the index that best predicts efficacy of vaborbactam in combination with meropenem in animal and in vitro models of infection.. Cardiac ElectrophysiologyAt dose of and times the maximum approved recommended dose, Vabomere (meropenem and vaborbactam) does not prolong the QT interval to any clinically relevant extent.. 12.3 Pharmacokinetics. Pharmacokinetic (PK) ParametersThe mean PK parameters of meropenem and vaborbactam in healthy adults with normal renal function after single and multiple 3-hour infusions of VABOMERE grams (meropenem grams and vaborbactam grams) administered every hours are summarized in Table 4.The PK parameters of meropenem and vaborbactam were similar for single and multiple dose administration of VABOMERE.Table 4:Pharmacokinetic Parameters (Mean [SD]) of Meropenem and Vaborbactam Following Administration of VABOMERE grams (meropenem grams and vaborbactam grams) by 3-hour Infusion in Healthy Adult SubjectsParameterMeropenemVaborbactamSingle VABOMERE gramMeropenem grams and vaborbactam grams administered as 3-hour infusion Dose(N=8)Multiple VABOMERE gram Doses Administered Every hours for Days (N=8)Single VABOMERE gram Dose(N=8)Multiple VABOMERE gram Doses Administered Every hours for Days (N=8)Cmax maximum observed concentration; CL plasma clearance; AUC area under the concentration time curve; 1/2 half-life.Cmax (mg/L)46.0 (5.7)43.4 (8.8)50.7 (8.4)55.6 (11.0)CL (L/h)14.6 (2.7)15.1 (2.8)12.3 (2.2)10.9 (1.8)AUC (mgh/L)AUC0-inf reported for single-dose administration; AUC0-8 reported for multiple-dose administration; AUC0 24 is 414 mgh/L for meropenem and 588 mgh/L for vaborbactam. 142.0 (28.0)138.0 (27.7)168.0 (32.2)196.0 (36.7)T1/2 (h)1.50 (1.0)1.22 (0.3)1.99 (0.8)1.68 (0.4)The maximum plasma concentration (Cmax) and area under the plasma drug concentration time curve (AUC) of meropenem and vaborbactam proportionally increased with dose across the dose range studied (1 gram to grams for meropenem and 0.25 grams to grams for vaborbactam) when administered as single 3-hour intravenous infusion. There is no accumulation of meropenem or vaborbactam following multiple intravenous infusions administered every hours for days in subjects with normal renal function.The mean population PK parameters of meropenem and vaborbactam in 295 patients (including 35 patients with reduced renal function) after 3-hour infusions of VABOMERE grams (meropenem grams and vaborbactam grams) administered every hours (or dose adjusted based on renal function) are summarized in Table 5.Table 5:Population Pharmacokinetic Parameters (Mean [SD]) of Meropenem and Vaborbactam Following Administration of VABOMERE grams (meropenem grams and vaborbactam grams) by 3-hour Infusion in PatientsMeropenem grams and vaborbactam grams administered as 3-hour infusion. ParameterMeropenemVaborbactamCmax (mg/L)57.3 (23.0)71.3 (28.6)AUC0-24, Day (mgh/L)637 (295)821 (369)AUC0-24, steady-state (mgh/L)650 (364)835 (508)CL (L/h)10.5 (6.4)7.95 (4.3)T1/2 (h)2.30 (2.5)2.25 (2.1). DistributionThe plasma protein binding of meropenem is approximately 2%. The plasma protein binding of vaborbactam is approximately 33%.The steady-state volumes of distribution of meropenem and vaborbactam in patients were 20.2 and 18.6 L, respectively.. EliminationThe clearance of meropenem in healthy subjects following multiple doses is 15.1 L/h and for vaborbactam is 10.9 L/h. The t1/2 is 1.22 hours and 1.68 hours for meropenem and vaborbactam, respectively.. MetabolismA minor pathway of meropenem elimination is hydrolysis of the beta-lactam ring (meropenem open lactam), which accounts for 22% of dose eliminated via the urine.Vaborbactam does not undergo metabolism.. ExcretionBoth meropenem and vaborbactam are primarily excreted via the kidneys.Approximately 40-60% of meropenem dose is excreted unchanged within 24-48 hours with further 22% recovered as the microbiologically inactive hydrolysis product. The mean renal clearance for meropenem was 7.8 L/h. The mean non-renal clearance for meropenem was 7.3 L/h which comprises both fecal elimination (~2% of dose) and degradation due to hydrolysis.For vaborbactam, 75 to 95% of the dose was excreted unchanged in the urine over 24 to 48 hour period. The mean renal clearance for vaborbactam was 8.9 L/h. The mean non-renal clearance for vaborbactam was 2.0 L/h indicating nearly complete elimination of vaborbactam by the renal route.. Specific Populations. Patients with Renal ImpairmentFollowing single dose of VABOMERE, pharmacokinetic studies with meropenem and vaborbactam in subjects with renal impairment have shown that meropenem AUC0-inf ratios to subjects with normal renal function are 1.28, 2.07, and 4.63 for subjects with mild (eGFR of 60 to 89 mL/min/1.73m2), moderate (eGFR of 30 to 59 mL/min/1.73m2), and severe (eGFR <30 mL/min/1.73m2) renal impairment, respectively; vaborbactam AUC0-inf ratios to subjects with normal renal function are 1.18, 2.31, and 7.8 for subjects with mild, moderate, and severe renal impairment, respectively [see Dosing and Administration (2.2)]. Hemodialysis removed 38% of the meropenem dose and 53% of the vaborbactam dose. Vaborbactam exposure was high in subjects with ESRD (eGFR <15 ml/min/1.73 m2). Vaborbactam exposure was higher when VABOMERE was administered after hemodialysis (AUC0-inf ratio to subjects with normal renal function of 37.5) than when VABOMERE was administered before hemodialysis (AUC0-inf ratio to subjects with normal renal function of 10.2) [see Use in Specific Populations (8.6) and Dosing and Administration (2.2)]. Patients with Hepatic ImpairmentA pharmacokinetic study conducted with an intravenous formulation of meropenem in patients with hepatic impairment has shown no effects of liver disease on the pharmacokinetics of meropenem.Vaborbactam does not undergo hepatic metabolism. Therefore, the systemic clearance of meropenem and vaborbactam is not expected to be affected by hepatic impairment. Geriatric PatientsIn elderly patients with renal impairment, plasma clearances of meropenem and vaborbactam were reduced, correlating with age-associated reduction in renal function [see Dosage and Administration (2.2) and Use in Specific Populations (8.5)].. Male and Female PatientsMeropenem and vaborbactam Cmax and AUC were similar between males and females using population pharmacokinetic analysis.. Racial or Ethnic GroupsNo significant difference in mean meropenem or vaborbactam clearance was observed across race groups using population pharmacokinetic analysis.. Drug InteractionsNo drug-drug interaction was observed between meropenem and vaborbactam in clinical studies with healthy subjects.Based upon the in vitro and in vivo data available to date, there is low potential for clinically significant drug interactions with vaborbactam.Vaborbactam at clinically relevant concentrations does not inhibit the cytochrome P450 isoforms CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4 in vitro human liver microsomes. Vaborbactam showed no potential for in vitro induction of CYP1A2, CYP2B6, and CYP3A4 in human hepatocytes. Studies evaluating the potential for meropenem to interact with CYP450 enzymes or active transport systems have not been conducted. However, carbapenems as class have not shown the potential for inhibition or induction CYP450 enzymes and clinical experience suggests that such effects are unlikely.Vaborbactam does not inhibit the following hepatic and renal transporters in vitro at clinically relevant concentrations: P-gp, BCRP, OAT1, OAT3, OCT1, OCT2, OATP1B1, OATP1B3 or BSEP. Vaborbactam was not substrate of OAT1, OAT3, OCT2, P-gp, and BCRP.Meropenem is substrate of OAT1 and OAT3 and as such, 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 (7.2)].Concomitant administration of meropenem and valproic acid has been associated with reductions in valproic acid concentrations with subsequent loss in seizure control [see Drug Interactions (7.1)].. 12.4Microbiology. Mechanism of ActionThe meropenem component of VABOMERE is penem antibacterial drug. The bactericidal action 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 is stable to hydrolysis by most beta-lactamases, including penicillinases and cephalosporinases produced by gram-negative and gram-positive bacteria, with the exception of carbapenem hydrolyzing beta-lactamases.The vaborbactam component of VABOMERE is non-suicidal beta-lactamase inhibitor that protects meropenem from degradation by certain serine beta-lactamases such as Klebsiella pneumoniae carbapenemase (KPC). Vaborbactam does not have any antibacterial activity. Vaborbactam does not decrease the activity of meropenem against meropenem-susceptible organisms.. ResistanceMechanisms of beta-lactam resistance may include the production of beta-lactamases, modification of PBPs by gene acquisition or target alteration, up-regulation of efflux pumps, and loss of outer membrane porin. VABOMERE may not have activity against gram-negative bacteria that have porin mutations combined with overexpression of efflux pumps.Clinical isolates may produce multiple beta-lactamases, express varying levels of beta-lactamases, or have amino acid sequence variations, and other resistance mechanisms that have not been identified.Culture and susceptibility information and local epidemiology should be considered in selecting or modifying antibacterial therapy.VABOMERE demonstrated in vitro activity against Enterobacteriaceae in the presence of some beta-lactamases and extended-spectrum beta-lactamases (ESBLs) of the following groups: KPC, SME, TEM, SHV, CTX-M, CMY, and ACT. VABOMERE is not active against bacteria that produce metallo-beta lactamases or oxacillinases with carbapenemase activity. In the Phase cUTI trial with VABOMERE, some isolates of E. coli, K. pneumoniae, E. cloacae, C. freundii, P. mirabilis, P. stuartii that produced beta-lactamases, were susceptible to VABOMERE (minimum inhibitory concentration <=4 mcg /mL). These isolates produced one or more beta-lactamases of the following enzyme groups: OXA (non-carbapenemases), KPC, CTX-M, TEM, SHV, CMY, and ACT. Some beta-lactamases were also produced by an isolate of K. pneumoniae that was not susceptible to VABOMERE (minimum inhibitory concentration >=32 mcg/mL). This isolate produced beta-lactamases of the following enzyme groups: CTX-M, TEM, SHV, and OXA.No cross-resistance with other classes of antimicrobials has been identified. Some isolates resistant to carbapenems (including meropenem) and to cephalosporins may be susceptible to VABOMERE.. Interaction with Other AntimicrobialsIn vitro synergy studies have not demonstrated antagonism between VABOMERE and levofloxacin, tigecycline, polymyxin, amikacin, vancomycin, azithromycin, daptomycin, or linezolid.. Activity against Meropenem Non-susceptible Bacteria in Animal Infection ModelsVaborbactam restored activity of meropenem in animal models of infection (e.g., mouse thigh infection, urinary tract infection and pulmonary infection) caused by some meropenem non-susceptible KPC-producing Enterobacteriaceae. Antimicrobial ActivityVABOMERE has been shown to be active against most isolates of the following bacteria, both in vitro and in clinical infections [see Indications and Usage (1.1)].Gram-negative bacteria:Enterobacter cloacae species complexEscherichia coliKlebsiella pneumoniaeThe following in vitro data are available, but their clinical significance is unknown. At least 90 percent of the following bacteria exhibit an in vitro MIC less than or equal to the susceptible breakpoint for VABOMERE against isolates of similar genus or organism group. However, the efficacy of VABOMERE in treating clinical infections due to these bacteria has not been established in adequate and well-controlled clinical trials.Gram-negative bacteria:Citrobacter freundiiCitrobacter koseriEnterobacter aerogenesKlebsiella oxytocaMorganella morganiiProteus mirabilisProvidencia spp.Pseudomonas aeruginosaSerratia marcescens. Enterobacter cloacae species complex. Escherichia coli. Klebsiella pneumoniae. Citrobacter freundii. Citrobacter koseri. Enterobacter aerogenes. Klebsiella oxytoca. Morganella morganii. Proteus mirabilis. Providencia spp.. Pseudomonas aeruginosa. Serratia marcescens. Susceptibility Test MethodsFor 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. 14.1Complicated Urinary Tract Infections (cUTI), including Pyelonephritis. total of 545 adults with cUTI, including pyelonephritis were randomized into double-blind, double dummy, multi-center trial comparing VABOMERE (meropenem grams and vaborbactam grams) to piperacillin/tazobactam (piperacillin grams/tazobactam 0.5 grams) intravenously every hours. Switch to an oral antibacterial drug, such as levofloxacin was allowed after minimum of 15 doses of IV therapy.The microbiologically modified intent to treat population (m-MITT) included all randomized patients who received any study drug and had at least baseline uropathogen. Clinical and microbiological response at the end of IV treatment (EOIVT) required both clinical outcome of cure or improvement and microbiologic outcome of eradication (all baseline uropathogens at >105 CFU/mL are to be reduced to <104 CFU/mL). Clinical and microbiological response was also assessed at the Test of Cure (TOC) visit (approximately days after completion of treatment) in the m-MITT population and required both clinical outcome of cure and microbiological outcome of eradication.Patient demographic and baseline characteristics were balanced between treatment groups in the m-MITT population. Approximately 93% of patients were Caucasian and 66% were females in both treatment groups. The mean age was 54 years with 32% and 42% patients greater than 65 years of age in VABOMERE and piperacillin/tazobactam treatment groups, respectively. Mean body mass index was approximately 26.5 kg/m2 in both treatment groups. Concomitant bacteremia was identified in 12 (6%) and 15 (8%) patients at baseline in VABOMERE and piperacillin/tazobactam treatment groups respectively. The proportion of patients with diabetes mellitus at baseline was 17% and 19% in VABOMERE and piperacillin/tazobactam treatment groups, respectively. The majority of patients (approximately 90%) were enrolled from Europe, and approximately 2% of patients were enrolled from North America. Overall, in both treatment groups, 59% of patients had pyelonephritis and 40% had cUTI, with 21% and 19% of patients having non-removable and removable source of infection, respectively.Mean duration of IV treatment in both treatment groups was days and mean total treatment duration (IV and oral) was 10 days; patients with baseline bacteremia could receive up to 14 days of therapy. Approximately 10% of patients in each treatment group in the m-MITT population had levofloxacin-resistant pathogen at baseline and received levofloxacin as the oral switch therapy. This protocol violation may have impacted the assessment of the outcomes at the TOC visit. These patients were not excluded from the analysis presented in Table 6, as the decision to switch to oral levofloxacin was based on post-randomization factors.VABOMERE demonstrated efficacy with regard to clinical and microbiological response at the EOIVT visit and TOC visits in the m-MITT population as shown in Table 6.Table 6:Clinical and Microbiological Response Rates in Phase Trial of cUTI Including Pyelonephritis (m-MITT Population) VABOMEREn/N (%)Piperacillin/Tazobactamn/N (%)Difference(95% CI)CI confidence interval; EOIVT End of Intravenous Treatment; TOC Test of CureClinical cure or improvement AND microbiological eradication at the End of IV Treatment VisitEnd of IV Treatment visit includes patients with organisms resistant to piperacillin/tazobactam at baseline 183/186 (98.4)165/175 (94.3) 4.1%(0.3%, 8.8%)Clinical cure AND microbiological eradication at the Test of Cure visit approximately days after completion of treatmentTest of Cure visit excludes patients with organisms resistant to piperacillin/tazobactam at baseline 124/162 (76.5)112/153 (73.2)3.3%(-6.2%, 13.0%) In the m-MITT population, the rate of clinical and microbiological response in VABOMERE- treated patients with concurrent bacteremia at baseline was 10/12 (83.3%).In subset of the E. coli and K. pneumoniae isolates, genotypic testing identified certain ESBL groups (e.g., TEM, CTX-M, SHV and OXA) in both treatment groups of the Phase cUTI trial. The rates of clinical and microbiological response were similar in the ESBL-positive and ESBL-negative subset at EOIVT; at TOC, clinical and microbiological response was lower in the ESBL-positive as compared to ESBL-negative subset in both treatment groups.

CONTRAINDICATIONS SECTION.

4 CONTRAINDICATIONS. VABOMERE is contraindicated in patients with known hypersensitivity to any components of VABOMERE (meropenem and vaborbactam), or to other drugs in the same class or in patients who have demonstrated anaphylactic reactions to beta-lactam antibacterial drugs [see Warnings and Precautions (5.1)].. Known hypersensitivity to the components of VABOMERE (meropenem and vaborbactam) or anaphylactic reactions to beta-lactams. (4).

DESCRIPTION SECTION.

11 DESCRIPTION. VABOMERE (meropenem and vaborbactam) for injection is combination product that contains meropenem, synthetic penem antibacterial drug and vaborbactam, cyclic boronic acid beta-lactamase inhibitor, for intravenous administration.Meropenem, present as trihydrate, is white to light yellow crystalline powder, with molecular weight of 437.52. The chemical name for meropenem trihydrate 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. The empirical formula of meropenem trihydrate is C17H25N3O5S3H2O and its chemical structure is:Figure 1:Structure of Meropenem TrihydrateVaborbactam is white to off-white powder, with molecular weight of 297.14. The chemical name for vaborbactam is (3R,6S)-2-hydroxy-3-[[2-(2-thienyl)acetyl]amino]-1,2-oxaborinane-6-acetic acid. Its empirical formula is C12H16BNO5S and its chemical structure is:Figure 2:Structure of VaborbactamVABOMERE is supplied as white to light yellow sterile powder for constitution that contains meropenem trihydrate, vaborbactam, and sodium carbonate. Each 50 mL glass vial contains gram of meropenem (equivalent to 1.14 grams of meropenem trihydrate), gram of vaborbactam, and 0.575 gram of sodium carbonate. The total sodium content of the mixture is approximately 0.25 grams (10.9 mEq)/vial.Each vial is constituted and further diluted with 0.9% Sodium Chloride Injection, USP. Both the constituted solution and the diluted solution for intravenous infusion should be colorless to light yellow solution [see Dosage and Administration (2.3)]. Chemical Structure. Chemical Structure.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. Administer VABOMERE grams (meropenem grams and vaborbactam grams) every hours by intravenous infusion over hours for up to 14 days, in patients 18 years of age and older with an estimated glomerular filtration rate (eGFR) >=50 mL/min/1.73m2. (2.1)Dosage adjustment is recommended in patients with renal impairment who have an eGFR less than 50 mL/min/ 1.73m2. (2.2) eGFRAs calculated using the Modification of Diet in Renal Disease (MDRD) formula; (mL/min/ 1.73m2)Recommended Dosage Regimen for VABOMERE(meropenem and vaborbactam) All doses of VABOMERE are administered intravenously over hours; Doses adjusted for renal impairment should be administered after hemodialysis session; The total duration of treatment is for up to 14 days. Dosing Interval30 to 49VABOMERE grams (meropenem gram and vaborbactam gram)Every hours15 to 29VABOMERE grams (meropenem gram and vaborbactam gram)Every 12 hoursLess than 15VABOMERE gram (meropenem 0.5 grams and vaborbactam 0.5 grams)Every 12 hoursSee Full Prescribing Information for instructions for constituting supplied dry powder and subsequent required dilution. (2.3)See Full Prescribing Information for drug compatibilities. (2.4). Administer VABOMERE grams (meropenem grams and vaborbactam grams) every hours by intravenous infusion over hours for up to 14 days, in patients 18 years of age and older with an estimated glomerular filtration rate (eGFR) >=50 mL/min/1.73m2. (2.1). Dosage adjustment is recommended in patients with renal impairment who have an eGFR less than 50 mL/min/ 1.73m2. (2.2) See Full Prescribing Information for instructions for constituting supplied dry powder and subsequent required dilution. (2.3). See Full Prescribing Information for drug compatibilities. (2.4). 2.1 Recommended Dosage. The recommended dosage of VABOMERE is grams (meropenem grams and vaborbactam grams) administered every hours by intravenous (IV) infusion over hours in patients 18 years of age and older with an estimated glomerular filtration rate (eGFR) greater than or equal to 50 mL/min/1.73m2. The duration of treatment is for up to 14 days.. 2.2Dosage Adjustments in Patients with Renal Impairment. Dosage adjustment is recommended in patients with renal impairment who have an eGFR less than 50 mL/min/1.73m2. The recommended dosage of VABOMERE in patients with varying degrees of renal function is presented in Table 1. For patients with changing renal function, monitor serum creatinine concentrations and eGFR at least daily and adjust the dosage of VABOMERE accordingly [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)].Meropenem and vaborbactam are removed by hemodialysis [see Clinical Pharmacology (12.3)]. For patients maintained on hemodialysis, administer VABOMERE after hemodialysis session. Table 1:Dosage of VABOMERE in Patients with Renal ImpairmenteGFRAs calculated using the Modification of Diet in Renal Disease (MDRD) formula as follows: eGFR (mL/min/1.73m2) 175 (serum creatinine)-1.154 (age)-0.203x (0.742 if female) (1.212 if African American) (mL/min/ 1.73m2)Recommended Dosage Regimen for VABOMERE (meropenem and vaborbactam)All doses of VABOMERE are administered intravenously over hours. Doses adjusted for renal impairment should be administered after hemodialysis session. The total duration of treatment is for up to 14 days. Dosing Interval30 to 49VABOMERE grams (meropenem gram and vaborbactam gram)Every hours15 to 29VABOMERE grams (meropenem gram and vaborbactam gram)Every 12 hoursLess than 15VABOMERE gram (meropenem 0.5 grams and vaborbactam 0.5 grams)Every 12 hours. 2.3Preparation and Administration of VABOMERE for Intravenous Infusion. PreparationVABOMERE is supplied as dry powder in single-dose vial that must be constituted and further diluted prior to intravenous infusion as outlined below. VABOMERE does not contain preservatives. Aseptic technique must be used for constitution and dilution.1. To prepare the required dose for intravenous infusion, constitute the appropriate number of vials, as determined from Table below. Withdraw 20 mL of 0.9% Sodium Chloride Injection, USP, from an infusion bag and constitute each vial of VABOMERE. 2. Mix gently to dissolve. The constituted VABOMERE solution will have an approximate meropenem concentration of 0.05 gram/mL and an approximate vaborbactam concentration of 0.05 gram/mL. The final volume is approximately 21.3 mL. The constituted solution is not for direct injection. 3. The constituted solution must be diluted further, immediately, in 0.9% Sodium Chloride Injection, USP infusion bag before intravenous infusion. The intravenous infusion of the diluted solution must be completed within hours if stored at room temperature or 22 hours if stored refrigerated at 2C to 8C (36F to 46F).4. To dilute the constituted solution, withdraw the full or partial constituted vial contents from each vial and add it back into the infusion bag in accordance with Table below.Table 2:Preparation of VABOMERE DosesVABOMERE Dose(meropenem and vaborbactam)Number of Vials to Constitute for Further DilutionVolume to Withdraw from Each Constituted Vial for Further DilutionVolume of Infusion BagFinal Infusion Concentration of VABOMERE4 grams(2 grams-2 grams)2 vialsEntire contents(approximately 21 mL)250 mL16 mg/mL500 mL8 mg/mL1,000 mL4 mg/mL2 grams(1 gram-1 gram)1 vialEntire contents(approximately 21 mL)125 mL16 mg/mL250 mL8 mg/mL500 mL4 mg/mL1 gram(0.5 gram-0.5 gram)1 vial10.5 mL(discard unused portion)70 mL14.3 mg/mL125 mL8 mg/mL250 mL4 mg/mL5. Visually inspect the diluted VABOMERE solution for particulate matter and discoloration prior to administration (the color of the VABOMERE infusion solution for administration ranges from colorless to light yellow). Discard unused portion after use.. 2.4Drug Compatibility. VABOMERE solution for administration by 3-hour infusion is only compatible with 0.9% Sodium Chloride Injection, USP.Compatibility of VABOMERE solution for administration with other drugs has not been established.

DOSAGE FORMS & STRENGTHS SECTION.

3 DOSAGE FORMS AND STRENGTHS. VABOMERE grams (meropenem and vaborbactam) for injection, is supplied as white to light yellow sterile powder for constitution in single-dose, clear glass vials containing meropenem gram (equivalent to 1.14 grams meropenem trihydrate) and vaborbactam gram.. VABOMERE grams (meropenem and vaborbactam) for injection, is supplied as sterile powder for constitution in single-dose vials containing meropenem gram (equivalent to 1.14 grams of meropenem trihydrate) and vaborbactam1 gram. (3).

DRUG INTERACTIONS SECTION.

7 DRUG INTERACTIONS. 7.1Valproic 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 VABOMERE is necessary, then supplemental anti-convulsant therapy should be considered [see Warnings and Precautions (5.4)].. 7.2Probenecid. Probenecid competes with meropenem for active tubular secretion, resulting in increased plasma concentrations of meropenem. Co-administration of probenecid with VABOMERE is not recommended.

HOW SUPPLIED SECTION.

16 HOW SUPPLIED/STORAGE AND HANDLING. VABOMERE grams (meropenem and vaborbactam) for injection is supplied as white to light yellow sterile powder for constitution in single-dose, clear glass vials (NDC 70842-120-01) sealed with rubber stopper (not made with natural rubber latex) and an aluminum overseal. Each vial is supplied in cartons of vials (NDC 70842-120-06). Each vial contains gram of meropenem (equivalent to 1.14 grams of meropenem trihydrate), gram of vaborbactam, and 0.575 gram of sodium carbonate.. Store VABOMERE vials at 20C to 25C (68F to 77F); excursions are permitted to 15C to 30C (59F to 86F) [see USP, Controlled Room Temperature (CRT)].

INDICATIONS & USAGE SECTION.

1 INDICATIONS AND USAGE. VABOMERE (meropenem and vaborbactam) is combination of meropenem, penem antibacterial, and vaborbactam, beta-lactamase inhibitor, indicated for the treatment of patients 18 years and older with complicated urinary tract infections (cUTI) including pyelonephritis caused by designated susceptible bacteria. (1.1)To reduce the development of drug-resistant bacteria and maintain the effectiveness of VABOMERE and other antibacterial drugs, VABOMERE should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria. (1.2). 1.1.Complicated Urinary Tract Infections (cUTI), including Pyelonephritis. VABOMERE(R) is indicated for the treatment of patients 18 years of age and older with complicated urinary tract infections (cUTI) including pyelonephritis caused by the following susceptible microorganisms: Escherichia coli, Klebsiella pneumoniae, and Enterobacter cloacae species complex. 1.2.Usage. To reduce the development of drug-resistant bacteria and maintain the effectiveness of VABOMERE and other antibacterial drugs, VABOMERE should be used only 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. Serious Allergic ReactionsAdvise patients that allergic reactions, including serious allergic reactions, could occur and that serious reactions require immediate treatment. Ask patient about any previous hypersensitivity reactions to VABOMERE (meropenem and vaborbactam), penicillins, cephalosporins, other beta-lactams, or other allergens [see Warnings and Precautions (5.1)].. SeizuresPatients receiving VABOMERE 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 VABOMERE is well tolerated, patients should not operate machinery or motorized vehicles [see Warnings and Precautions (5.2)].. Potentially Serious DiarrheaCounsel patients that diarrhea is common problem caused by antibacterial drugs including VABOMERE, 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 (5.3)].. Interaction with Valproic AcidCounsel 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 VABOMERE. If treatment with VABOMERE 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)].. Antibacterial ResistanceCounsel patients that antibacterial drugs, including VABOMERE, should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When VABOMERE 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 VABOMERE or other antibacterial drugs in the future [see Warnings and Precautions (5.7)].

LACTATION SECTION.

8.2 Lactation. Meropenem has been reported to be excreted in human milk. It is unknown whether vaborbactam is excreted in human milk. No information is available on the effects of meropenem and vaborbactam 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 VABOMERE and any potential adverse effects on the breast-fed child from VABOMERE or from the underlying maternal condition.

MECHANISM OF ACTION SECTION.

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

MICROBIOLOGY SECTION.

12.4Microbiology. Mechanism of ActionThe meropenem component of VABOMERE is penem antibacterial drug. The bactericidal action 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 is stable to hydrolysis by most beta-lactamases, including penicillinases and cephalosporinases produced by gram-negative and gram-positive bacteria, with the exception of carbapenem hydrolyzing beta-lactamases.The vaborbactam component of VABOMERE is non-suicidal beta-lactamase inhibitor that protects meropenem from degradation by certain serine beta-lactamases such as Klebsiella pneumoniae carbapenemase (KPC). Vaborbactam does not have any antibacterial activity. Vaborbactam does not decrease the activity of meropenem against meropenem-susceptible organisms.. ResistanceMechanisms of beta-lactam resistance may include the production of beta-lactamases, modification of PBPs by gene acquisition or target alteration, up-regulation of efflux pumps, and loss of outer membrane porin. VABOMERE may not have activity against gram-negative bacteria that have porin mutations combined with overexpression of efflux pumps.Clinical isolates may produce multiple beta-lactamases, express varying levels of beta-lactamases, or have amino acid sequence variations, and other resistance mechanisms that have not been identified.Culture and susceptibility information and local epidemiology should be considered in selecting or modifying antibacterial therapy.VABOMERE demonstrated in vitro activity against Enterobacteriaceae in the presence of some beta-lactamases and extended-spectrum beta-lactamases (ESBLs) of the following groups: KPC, SME, TEM, SHV, CTX-M, CMY, and ACT. VABOMERE is not active against bacteria that produce metallo-beta lactamases or oxacillinases with carbapenemase activity. In the Phase cUTI trial with VABOMERE, some isolates of E. coli, K. pneumoniae, E. cloacae, C. freundii, P. mirabilis, P. stuartii that produced beta-lactamases, were susceptible to VABOMERE (minimum inhibitory concentration <=4 mcg /mL). These isolates produced one or more beta-lactamases of the following enzyme groups: OXA (non-carbapenemases), KPC, CTX-M, TEM, SHV, CMY, and ACT. Some beta-lactamases were also produced by an isolate of K. pneumoniae that was not susceptible to VABOMERE (minimum inhibitory concentration >=32 mcg/mL). This isolate produced beta-lactamases of the following enzyme groups: CTX-M, TEM, SHV, and OXA.No cross-resistance with other classes of antimicrobials has been identified. Some isolates resistant to carbapenems (including meropenem) and to cephalosporins may be susceptible to VABOMERE.. Interaction with Other AntimicrobialsIn vitro synergy studies have not demonstrated antagonism between VABOMERE and levofloxacin, tigecycline, polymyxin, amikacin, vancomycin, azithromycin, daptomycin, or linezolid.. Activity against Meropenem Non-susceptible Bacteria in Animal Infection ModelsVaborbactam restored activity of meropenem in animal models of infection (e.g., mouse thigh infection, urinary tract infection and pulmonary infection) caused by some meropenem non-susceptible KPC-producing Enterobacteriaceae. Antimicrobial ActivityVABOMERE has been shown to be active against most isolates of the following bacteria, both in vitro and in clinical infections [see Indications and Usage (1.1)].Gram-negative bacteria:Enterobacter cloacae species complexEscherichia coliKlebsiella pneumoniaeThe following in vitro data are available, but their clinical significance is unknown. At least 90 percent of the following bacteria exhibit an in vitro MIC less than or equal to the susceptible breakpoint for VABOMERE against isolates of similar genus or organism group. However, the efficacy of VABOMERE in treating clinical infections due to these bacteria has not been established in adequate and well-controlled clinical trials.Gram-negative bacteria:Citrobacter freundiiCitrobacter koseriEnterobacter aerogenesKlebsiella oxytocaMorganella morganiiProteus mirabilisProvidencia spp.Pseudomonas aeruginosaSerratia marcescens. Enterobacter cloacae species complex. Escherichia coli. Klebsiella pneumoniae. Citrobacter freundii. Citrobacter koseri. Enterobacter aerogenes. Klebsiella oxytoca. Morganella morganii. Proteus mirabilis. Providencia spp.. Pseudomonas aeruginosa. Serratia marcescens. Susceptibility Test MethodsFor 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.

NONCLINICAL TOXICOLOGY SECTION.

13 NONCLINICAL TOXICOLOGY. 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. CarcinogenesisLong-term carcinogenicity studies have not been performed with VABOMERE, meropenem, or vaborbactam.. Mutagenesis. MeropenemGenetic 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 mutation potential found in any of these tests. VaborbactamGenetic toxicity studies were performed with vaborbactam using the bacterial reverse mutation test, chromosomal aberration test and the mouse micronucleus test. There was no evidence of mutagenic potential found in any of these tests.. Impairment of Fertility. MeropenemReproductive studies were performed with meropenem in male and female rats at doses up to 1000 mg/kg/day with no evidence of impaired fertility (approximately equivalent to 1.6 times the MRHD based on body surface area comparison). In reproductive study in cynomolgus monkeys at doses of meropenem up to 360 mg/kg/day (on the basis of body surface area comparison, approximately equivalent to 1.2 times the MRHD) no reproductive toxicity was seen.. VaborbactamVaborbactam had no adverse effect on fertility in male and female rats at doses up to 1000 mg/kg/day, which is equivalent to approximately 1.6 times the MRHD based on body surface area comparison.

OVERDOSAGE SECTION.

10 OVERDOSAGE. In the event of overdose, discontinue VABOMERE and institute general supportive treatment.Meropenem and vaborbactam can be removed by hemodialysis. In subjects with end-stage renal disease (ESRD) administered meropenem gram and vaborbactam gram, the mean total recovery in dialysate following hemodialysis session was 38% and 53% of the administered dose of meropenem and vaborbactam, respectively.No clinical information is available on the use of hemodialysis to treat VABOMERE overdosage.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

PRINCIPAL DISPLAY PANEL 2 Vial Carton. Rx onlyNDC 70842-120-06VABOMERE(R)(meropenem and vaborbactam)for injection2 per vialMeropenem gram (equivalentto 1.14 meropenem trihydrate)and vaborbactam gFor Intravenous Infusion OnlySingle Dose OnlyDiscard Unused Portion After UseMUST BE CONSTITUTED THEN DILUTEDSee prescribing information for constitutionand dilution instructions and completedirections for use.Each vial contains meropenem g, vaborbactam g, and sodium carbonate 0.575 g. The total sodium content of the mixture is approximately 0.25 (10.9 mEq).Storage:Store at 20C to 25C (68F to 77F);excursions are permitted to 15C to 30C(59F to 86F) [See USP ControlledRoom Temperature]MEL042-R002Contains single dose g vials. PRINCIPAL DISPLAY PANEL 2 Vial Carton.

PHARMACODYNAMICS SECTION.

12.2 Pharmacodynamics. Similar to other beta-lactam antibacterial drugs, the percentage of time of dosing interval that unbound plasma concentration of meropenem exceeds the meropenem-vaborbactam minimum inhibitory concentration (MIC) against the infecting organism has been shown to best correlate with efficacy in animal and in vitro models of infection. The ratio of the 24-hour unbound plasma vaborbactam AUC to meropenem-vaborbactam MIC is the index that best predicts efficacy of vaborbactam in combination with meropenem in animal and in vitro models of infection.. Cardiac ElectrophysiologyAt dose of and times the maximum approved recommended dose, Vabomere (meropenem and vaborbactam) does not prolong the QT interval to any clinically relevant extent.

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. Pharmacokinetic (PK) ParametersThe mean PK parameters of meropenem and vaborbactam in healthy adults with normal renal function after single and multiple 3-hour infusions of VABOMERE grams (meropenem grams and vaborbactam grams) administered every hours are summarized in Table 4.The PK parameters of meropenem and vaborbactam were similar for single and multiple dose administration of VABOMERE.Table 4:Pharmacokinetic Parameters (Mean [SD]) of Meropenem and Vaborbactam Following Administration of VABOMERE grams (meropenem grams and vaborbactam grams) by 3-hour Infusion in Healthy Adult SubjectsParameterMeropenemVaborbactamSingle VABOMERE gramMeropenem grams and vaborbactam grams administered as 3-hour infusion Dose(N=8)Multiple VABOMERE gram Doses Administered Every hours for Days (N=8)Single VABOMERE gram Dose(N=8)Multiple VABOMERE gram Doses Administered Every hours for Days (N=8)Cmax maximum observed concentration; CL plasma clearance; AUC area under the concentration time curve; 1/2 half-life.Cmax (mg/L)46.0 (5.7)43.4 (8.8)50.7 (8.4)55.6 (11.0)CL (L/h)14.6 (2.7)15.1 (2.8)12.3 (2.2)10.9 (1.8)AUC (mgh/L)AUC0-inf reported for single-dose administration; AUC0-8 reported for multiple-dose administration; AUC0 24 is 414 mgh/L for meropenem and 588 mgh/L for vaborbactam. 142.0 (28.0)138.0 (27.7)168.0 (32.2)196.0 (36.7)T1/2 (h)1.50 (1.0)1.22 (0.3)1.99 (0.8)1.68 (0.4)The maximum plasma concentration (Cmax) and area under the plasma drug concentration time curve (AUC) of meropenem and vaborbactam proportionally increased with dose across the dose range studied (1 gram to grams for meropenem and 0.25 grams to grams for vaborbactam) when administered as single 3-hour intravenous infusion. There is no accumulation of meropenem or vaborbactam following multiple intravenous infusions administered every hours for days in subjects with normal renal function.The mean population PK parameters of meropenem and vaborbactam in 295 patients (including 35 patients with reduced renal function) after 3-hour infusions of VABOMERE grams (meropenem grams and vaborbactam grams) administered every hours (or dose adjusted based on renal function) are summarized in Table 5.Table 5:Population Pharmacokinetic Parameters (Mean [SD]) of Meropenem and Vaborbactam Following Administration of VABOMERE grams (meropenem grams and vaborbactam grams) by 3-hour Infusion in PatientsMeropenem grams and vaborbactam grams administered as 3-hour infusion. ParameterMeropenemVaborbactamCmax (mg/L)57.3 (23.0)71.3 (28.6)AUC0-24, Day (mgh/L)637 (295)821 (369)AUC0-24, steady-state (mgh/L)650 (364)835 (508)CL (L/h)10.5 (6.4)7.95 (4.3)T1/2 (h)2.30 (2.5)2.25 (2.1). DistributionThe plasma protein binding of meropenem is approximately 2%. The plasma protein binding of vaborbactam is approximately 33%.The steady-state volumes of distribution of meropenem and vaborbactam in patients were 20.2 and 18.6 L, respectively.. EliminationThe clearance of meropenem in healthy subjects following multiple doses is 15.1 L/h and for vaborbactam is 10.9 L/h. The t1/2 is 1.22 hours and 1.68 hours for meropenem and vaborbactam, respectively.. MetabolismA minor pathway of meropenem elimination is hydrolysis of the beta-lactam ring (meropenem open lactam), which accounts for 22% of dose eliminated via the urine.Vaborbactam does not undergo metabolism.. ExcretionBoth meropenem and vaborbactam are primarily excreted via the kidneys.Approximately 40-60% of meropenem dose is excreted unchanged within 24-48 hours with further 22% recovered as the microbiologically inactive hydrolysis product. The mean renal clearance for meropenem was 7.8 L/h. The mean non-renal clearance for meropenem was 7.3 L/h which comprises both fecal elimination (~2% of dose) and degradation due to hydrolysis.For vaborbactam, 75 to 95% of the dose was excreted unchanged in the urine over 24 to 48 hour period. The mean renal clearance for vaborbactam was 8.9 L/h. The mean non-renal clearance for vaborbactam was 2.0 L/h indicating nearly complete elimination of vaborbactam by the renal route.. Specific Populations. Patients with Renal ImpairmentFollowing single dose of VABOMERE, pharmacokinetic studies with meropenem and vaborbactam in subjects with renal impairment have shown that meropenem AUC0-inf ratios to subjects with normal renal function are 1.28, 2.07, and 4.63 for subjects with mild (eGFR of 60 to 89 mL/min/1.73m2), moderate (eGFR of 30 to 59 mL/min/1.73m2), and severe (eGFR <30 mL/min/1.73m2) renal impairment, respectively; vaborbactam AUC0-inf ratios to subjects with normal renal function are 1.18, 2.31, and 7.8 for subjects with mild, moderate, and severe renal impairment, respectively [see Dosing and Administration (2.2)]. Hemodialysis removed 38% of the meropenem dose and 53% of the vaborbactam dose. Vaborbactam exposure was high in subjects with ESRD (eGFR <15 ml/min/1.73 m2). Vaborbactam exposure was higher when VABOMERE was administered after hemodialysis (AUC0-inf ratio to subjects with normal renal function of 37.5) than when VABOMERE was administered before hemodialysis (AUC0-inf ratio to subjects with normal renal function of 10.2) [see Use in Specific Populations (8.6) and Dosing and Administration (2.2)]. Patients with Hepatic ImpairmentA pharmacokinetic study conducted with an intravenous formulation of meropenem in patients with hepatic impairment has shown no effects of liver disease on the pharmacokinetics of meropenem.Vaborbactam does not undergo hepatic metabolism. Therefore, the systemic clearance of meropenem and vaborbactam is not expected to be affected by hepatic impairment. Geriatric PatientsIn elderly patients with renal impairment, plasma clearances of meropenem and vaborbactam were reduced, correlating with age-associated reduction in renal function [see Dosage and Administration (2.2) and Use in Specific Populations (8.5)].. Male and Female PatientsMeropenem and vaborbactam Cmax and AUC were similar between males and females using population pharmacokinetic analysis.. Racial or Ethnic GroupsNo significant difference in mean meropenem or vaborbactam clearance was observed across race groups using population pharmacokinetic analysis.. Drug InteractionsNo drug-drug interaction was observed between meropenem and vaborbactam in clinical studies with healthy subjects.Based upon the in vitro and in vivo data available to date, there is low potential for clinically significant drug interactions with vaborbactam.Vaborbactam at clinically relevant concentrations does not inhibit the cytochrome P450 isoforms CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4 in vitro human liver microsomes. Vaborbactam showed no potential for in vitro induction of CYP1A2, CYP2B6, and CYP3A4 in human hepatocytes. Studies evaluating the potential for meropenem to interact with CYP450 enzymes or active transport systems have not been conducted. However, carbapenems as class have not shown the potential for inhibition or induction CYP450 enzymes and clinical experience suggests that such effects are unlikely.Vaborbactam does not inhibit the following hepatic and renal transporters in vitro at clinically relevant concentrations: P-gp, BCRP, OAT1, OAT3, OCT1, OCT2, OATP1B1, OATP1B3 or BSEP. Vaborbactam was not substrate of OAT1, OAT3, OCT2, P-gp, and BCRP.Meropenem is substrate of OAT1 and OAT3 and as such, 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 (7.2)].Concomitant administration of meropenem and valproic acid has been associated with reductions in valproic acid concentrations with subsequent loss in seizure control [see Drug Interactions (7.1)].

PREGNANCY SECTION.

8.1 Pregnancy. Risk SummaryFetal malformations were observed in vaborbactam-treated rabbits, therefore advise pregnant women of the potential risks to the fetus. There are insufficient human data to establish whether there is drug-associated risk of major birth defects or miscarriages with VABOMERE, meropenem, or vaborbactam in pregnant women.Malformations (supernumerary lung lobes, interventricular septal defect) were observed in offspring from pregnant rabbits administered intravenous vaborbactam during the period of organogenesis at doses approximately equivalent to or above the maximum recommended human dose (MRHD) based on plasma AUC comparison. The clinical relevance of the malformations is uncertain. No similar malformations or fetal toxicity were observed in offspring from pregnant rats administered intravenous vaborbactam during organogenesis or from late pregnancy and through lactation at dose equivalent to approximately 1.6 times the MRHD based on body surface area comparison [see Data].No fetal toxicity or malformations were observed in pregnant rats and cynomolgus monkeys administered intravenous meropenem during organogenesis at doses up to 1.6 and 1.2 times the 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 1.6 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. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.. Data. Animal Data. MeropenemReproductive studies have been performed with meropenem in rats at doses of up to 1000 mg/kg/day and in cynomolgus monkeys at doses of up to 360 mg/kg/day (on the basis of body surface area comparisons, approximately 1.6 times and 1.2 times higher, respectively, than the MRHD of grams every hours). These studies revealed no evidence of harm to the fetus due to meropenem, although there were slight changes in fetal body weight at doses of 250 mg/kg/day (equivalent to approximately 0.4 times the MRHD of grams every hours based on body surface area comparison) and above in rats. In published study1, meropenem administered to pregnant rats from Gestation Day to Gestation Day 17, was associated with mild maternal weight loss at all doses, but did not produce malformations or fetal toxicity. The no-observed-adverse-effect-level (NOAEL) for fetal toxicity in this study was considered to be the high dose of 750 mg/kg/day (equivalent to approximately 1.2 times the MRHD based on body surface area comparison).In peri-postnatal study in rats described in the published literature1, intravenous meropenem was administered to dams from Gestation Day 17 until Postpartum Day 21. There were no adverse effects in the dams and no adverse effects in the first generation offspring (including developmental, behavioral, and functional assessments and reproductive parameters) except that female offspring exhibited lowered body weights which continued during gestation and nursing of the second generation offspring. Second generation offspring showed no meropenem-related effects. The NOAEL value was considered to be 1000 mg/kg/day (approximately 1.6 times the MRHD based on body surface area comparisons).. VaborbactamIn rat embryo-fetal toxicology study, intravenous administration of vaborbactam during Gestation Days 6-17 showed no evidence of maternal or embryofetal toxicity at doses up to 1000 mg/kg, which is equivalent to approximately 1.6 times the MRHD based on body surface area comparisons. In the rabbit, intravenous administration of vaborbactam during Gestation Days 7-19 at doses up to 1000 mg/kg/day (approximately times the MRHD based on AUC exposure comparison) was not associated with maternal toxicity or fetal weight loss. low incidence of malformations occurred in the 300 mg/kg/day mid-dose group (two fetuses from different litters with interventricular septal defects, one fetus with fused right lung lobe and one fetus with supernumerary lung lobe), and in the 1000 mg/kg/day high-dose group (two fetuses from different litters with supernumerary lobes). The NOAEL was considered to be 100 mg/kg/day which is equivalent to 0.3 times the MRHD based on plasma AUC exposure comparison and 6-times the MRHD based on maximum plasma concentration (Cmax) comparison. The clinical relevance of the malformations is uncertain. Vaborbactam Cmax values may have influenced malformations in the rabbit study, and the recommended 3-hour infusion time for clinical administration of vaborbactam is associated with lower plasma Cmax values than the 30-minute infusions in rabbits.In peri-postnatal study in rats, vaborbactam administered intravenously to pregnant dams from Gestation Day to Lactation Day 20 caused no adverse effects on the dams, or in first and second generation offspring. The NOAEL was considered to be 1000 mg/kg/day (equivalent to approximately 1.6 times the MRHD based on body surface area comparison).

REFERENCES SECTION.

15 REFERENCES. Kawamura S, Russell AW, Freeman SJ, and Siddall, RA: Reproductive and Developmental Toxicity of Meropenem in Rats. Chemotherapy, 40:S238-250 (1992). Kawamura S, Russell AW, Freeman SJ, and Siddall, RA: Reproductive and Developmental Toxicity of Meropenem in Rats. Chemotherapy, 40:S238-250 (1992).

SPL UNCLASSIFIED SECTION.

1.1.Complicated Urinary Tract Infections (cUTI), including Pyelonephritis. VABOMERE(R) is indicated for the treatment of patients 18 years of age and older with complicated urinary tract infections (cUTI) including pyelonephritis caused by the following susceptible microorganisms: Escherichia coli, Klebsiella pneumoniae, and Enterobacter cloacae species complex.

STORAGE AND HANDLING SECTION.

Store VABOMERE vials at 20C to 25C (68F to 77F); excursions are permitted to 15C to 30C (59F to 86F) [see USP, Controlled Room Temperature (CRT)].

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. 8.1 Pregnancy. Risk SummaryFetal malformations were observed in vaborbactam-treated rabbits, therefore advise pregnant women of the potential risks to the fetus. There are insufficient human data to establish whether there is drug-associated risk of major birth defects or miscarriages with VABOMERE, meropenem, or vaborbactam in pregnant women.Malformations (supernumerary lung lobes, interventricular septal defect) were observed in offspring from pregnant rabbits administered intravenous vaborbactam during the period of organogenesis at doses approximately equivalent to or above the maximum recommended human dose (MRHD) based on plasma AUC comparison. The clinical relevance of the malformations is uncertain. No similar malformations or fetal toxicity were observed in offspring from pregnant rats administered intravenous vaborbactam during organogenesis or from late pregnancy and through lactation at dose equivalent to approximately 1.6 times the MRHD based on body surface area comparison [see Data].No fetal toxicity or malformations were observed in pregnant rats and cynomolgus monkeys administered intravenous meropenem during organogenesis at doses up to 1.6 and 1.2 times the 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 1.6 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. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.. Data. Animal Data. MeropenemReproductive studies have been performed with meropenem in rats at doses of up to 1000 mg/kg/day and in cynomolgus monkeys at doses of up to 360 mg/kg/day (on the basis of body surface area comparisons, approximately 1.6 times and 1.2 times higher, respectively, than the MRHD of grams every hours). These studies revealed no evidence of harm to the fetus due to meropenem, although there were slight changes in fetal body weight at doses of 250 mg/kg/day (equivalent to approximately 0.4 times the MRHD of grams every hours based on body surface area comparison) and above in rats. In published study1, meropenem administered to pregnant rats from Gestation Day to Gestation Day 17, was associated with mild maternal weight loss at all doses, but did not produce malformations or fetal toxicity. The no-observed-adverse-effect-level (NOAEL) for fetal toxicity in this study was considered to be the high dose of 750 mg/kg/day (equivalent to approximately 1.2 times the MRHD based on body surface area comparison).In peri-postnatal study in rats described in the published literature1, intravenous meropenem was administered to dams from Gestation Day 17 until Postpartum Day 21. There were no adverse effects in the dams and no adverse effects in the first generation offspring (including developmental, behavioral, and functional assessments and reproductive parameters) except that female offspring exhibited lowered body weights which continued during gestation and nursing of the second generation offspring. Second generation offspring showed no meropenem-related effects. The NOAEL value was considered to be 1000 mg/kg/day (approximately 1.6 times the MRHD based on body surface area comparisons).. VaborbactamIn rat embryo-fetal toxicology study, intravenous administration of vaborbactam during Gestation Days 6-17 showed no evidence of maternal or embryofetal toxicity at doses up to 1000 mg/kg, which is equivalent to approximately 1.6 times the MRHD based on body surface area comparisons. In the rabbit, intravenous administration of vaborbactam during Gestation Days 7-19 at doses up to 1000 mg/kg/day (approximately times the MRHD based on AUC exposure comparison) was not associated with maternal toxicity or fetal weight loss. low incidence of malformations occurred in the 300 mg/kg/day mid-dose group (two fetuses from different litters with interventricular septal defects, one fetus with fused right lung lobe and one fetus with supernumerary lung lobe), and in the 1000 mg/kg/day high-dose group (two fetuses from different litters with supernumerary lobes). The NOAEL was considered to be 100 mg/kg/day which is equivalent to 0.3 times the MRHD based on plasma AUC exposure comparison and 6-times the MRHD based on maximum plasma concentration (Cmax) comparison. The clinical relevance of the malformations is uncertain. Vaborbactam Cmax values may have influenced malformations in the rabbit study, and the recommended 3-hour infusion time for clinical administration of vaborbactam is associated with lower plasma Cmax values than the 30-minute infusions in rabbits.In peri-postnatal study in rats, vaborbactam administered intravenously to pregnant dams from Gestation Day to Lactation Day 20 caused no adverse effects on the dams, or in first and second generation offspring. The NOAEL was considered to be 1000 mg/kg/day (equivalent to approximately 1.6 times the MRHD based on body surface area comparison).. 8.2 Lactation. Meropenem has been reported to be excreted in human milk. It is unknown whether vaborbactam is excreted in human milk. No information is available on the effects of meropenem and vaborbactam 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 VABOMERE and any potential adverse effects on the breast-fed child from VABOMERE or from the underlying maternal condition.. 8.4 Pediatric Use. The safety and effectiveness of VABOMERE in pediatric patients (younger than 18 years of age) has not been established. Studies of VABOMERE have not been conducted in patients younger than 18 years of age.. 8.5 Geriatric Use. Of the 272 patients treated with VABOMERE in the Phase cUTI trial, 48 (18%) patients were 65 years of age and older, while 39 (14%) patients were 75 years of age and older. No overall differences in safety or effectiveness were observed between these patients and younger patients, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.Meropenem, component of VABOMERE, 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.Population pharmacokinetic (PK) analysis found no clinically relevant change in pharmacokinetic parameters in elderly patients. No dosage adjustment based on age is required. Dosage adjustment for elderly patients should be based on renal function [see Dosage and Administration (2.2) and Clinical Pharmacology (12.3)].. 8.6Renal Impairment. Pharmacokinetic studies conducted with meropenem and vaborbactam in subjects with renal impairment have shown that the plasma exposures of both meropenem and vaborbactam increased with decreasing renal function [see Clinical Pharmacology (12.3)]. Dosage adjustment for VABOMERE is recommended in patients with renal impairment (eGFR less than 50 mL/min/1.73m2) [see Dosage and Administration (2.2)]. For patients with changing renal function, monitor serum creatinine concentrations and eGFR at least daily and adjust the dosage of VABOMERE accordingly. Meropenem and vaborbactam are removed by hemodialysis. Following single dose of VABOMERE, vaborbactam exposure was substantially greater when VABOMERE was administered after hemodialysis than before hemodialysis [see Clinical Pharmacology (12.3)].

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. Hypersensitivity reactions were reported with the use of VABOMERE. Serious and occasionally fatal hypersensitivity (anaphylactic) reactions have been reported in patients receiving beta-lactam antibacterial drugs. Discontinue infusion if signs of acute hypersensitivity occur. (5.1)Seizures and other adverse Central Nervous System experiences have been reported during treatment with meropenem, component of VABOMERE. (5.2)Clostridioides difficile-associated diarrhea has been reported with nearly all systemic antibacterial agents, including VABOMERE. Evaluate patients if diarrhea occurs. (5.3)Co-administration of meropenem with valproic acid or divalproex sodium reduces the serum concentration of valproic acid potentially increasing the risk of breakthrough seizures. (5.4, 7.1). Hypersensitivity reactions were reported with the use of VABOMERE. Serious and occasionally fatal hypersensitivity (anaphylactic) reactions have been reported in patients receiving beta-lactam antibacterial drugs. Discontinue infusion if signs of acute hypersensitivity occur. (5.1). Seizures and other adverse Central Nervous System experiences have been reported during treatment with meropenem, component of VABOMERE. (5.2). Clostridioides difficile-associated diarrhea has been reported with nearly all systemic antibacterial agents, including VABOMERE. Evaluate patients if diarrhea occurs. (5.3). Co-administration of meropenem with valproic acid or divalproex sodium reduces the serum concentration of valproic acid potentially increasing the risk of breakthrough seizures. (5.4, 7.1). 5.1Hypersensitivity Reactions. Hypersensitivity reactions were reported in patients treated with VABOMERE in the clinical trials [see Adverse Reactions (6.1)]. Serious and occasionally fatal hypersensitivity (anaphylactic) reactions and serious skin reactions have been reported in patients receiving therapy with beta-lactam antibacterial drugs. 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 beta-lactam antibacterial drug. Before initiating therapy with VABOMERE, it is important to inquire about previous hypersensitivity reactions to penicillins, cephalosporins, other beta-lactam antibacterial drugs, and other allergens. If an allergic reaction to VABOMERE occurs, discontinue the drug immediately.. 5.2Seizure Potential. Seizures and other adverse Central Nervous System (CNS) experiences have been reported during treatment with meropenem, which is component of VABOMERE. 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 (7.1)].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, place on anti-convulsant therapy if not already instituted, and reexamine the dosage of VABOMERE to determine whether it should be decreased or discontinued.. 5.3Clostridioides difficile-associated Diarrhea. Clostridioides difficile-associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including VABOMERE, 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.. 5.4Risk of Breakthrough Seizures Due to Drug Interaction with Valproic Acid. The concomitant use of VABOMERE 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 VABOMERE is necessary, consider supplemental anticonvulsant therapy [see Drug Interactions (7.1)].. 5.5Thrombocytopenia. In patients with renal impairment, thrombocytopenia has been observed in patients treated with meropenem, but no clinical bleeding has been 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)].. 5.6Potential for Neuromotor Impairment. Alert patients receiving VABOMERE on an outpatient basis regarding adverse reactions 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 VABOMERE is well tolerated, advise patients not to operate machinery or motorized vehicles [see Adverse Reactions (6.1) ].. 5.7Development of Drug-Resistant Bacteria. Prescribing VABOMERE in the absence of proven or strongly suspected bacterial infection is unlikely to provide benefit to the patient and increases the risk of drug-resistant bacteria [see Indications and Usage (1.2)].. 5.8Overgrowth of Nonsusceptible Organisms. As with other antibacterial drugs, prolonged use of VABOMERE 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.