wonderful [30:<15 ml/min/1.73 m 2 ). Vaborbactam exposure was higher when VABOMERE was administered after hemodialysis (AUC 0-inf ratio to subjects with normal renal function of 37.5) than when VABOMERE was administered before hemodialysis (AUC 0-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 Impairment A 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 Patients In 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 Patients Meropenem and vaborbactam C max and AUC were similar between males and females using a population pharmacokinetic analysis. Racial or Ethnic Groups No significant difference in mean meropenem or vaborbactam clearance was observed across race groups using a population pharmacokinetic analysis. Drug Interactions No 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 a 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 a 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 a substrate of OAT1, OAT3, OCT2, P gp, and BCRP. Meropenem is a 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 )]. 12.4 Microbiology Mechanism of Action The meropenem component of VABOMERE is a 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 a 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. Resistance Mechanisms 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 3 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 Antimicrobials In 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 Models Vaborbactam 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 Activity VABOMERE 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 complex Escherichia coli Klebsiella pneumoniae The 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 a 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 freundii Citrobacter koseri Enterobacter aerogenes Klebsiella oxytoca Morganella morganii Proteus mirabilis Providencia spp. Pseudomonas aeruginosa Serratia marcescens Susceptibility Test Methods When available, the clinical microbiology laboratory should provide cumulative reports of in vitro susceptibility test results for antimicrobial drugs used in local hospitals and practice areas as periodic reports that describe the susceptibility profile of nosocomial and community-acquired pathogens. These reports should aid in selecting the most appropriate antibacterial drug for treatment. Dilution Techniques Quantitative methods are used to determine antimicrobial MICs. These MICs provide estimates of the susceptibility of bacteria to antimicrobial compounds. The MICs should be determined using a standardized test method 2,3 (broth and/or agar). The MIC values should be determined using serial dilutions of meropenem combined with a fixed concentration of 8 mcg/mL of vaborbactam. The MIC values should be interpreted according to the criteria in Table 6. Diffusion Techniques Quantitative methods that require measurement of zone diameters can also provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. The zone size should be determined using a standardized method 3,4 . This procedure uses paper disks impregnated with 20 mcg of meropenem and 10 mcg vaborbactam to test the susceptibility of bacteria to meropenem and vaborbactam. The disk breakpoints are provided in Table 6. Table 6: Susceptibility Interpretive Criteria for Meropenem/Vaborbactam Pathogen Minimum Inhibitory Concentrations (mcg/mL) Disk Diffusion (zone diameters in mm) S I R S I R Enterobacteriaceae 4/8 8/8 16/8 17 14-16 13 S = Susceptible; I = Intermediate; R = Resistant A report of Susceptible (S) indicates that the antimicrobial drug is likely to inhibit growth of the pathogen if the antimicrobial drug reaches the concentration usually achievable at the site of infection. A report of Intermediate (I) indicates that the result should be considered equivocal, and, if the microorganism is not fully susceptible to alternative, clinically feasible drugs, the test should be repeated. This category implies possible clinical applicability in body sites where the drug is physiologically concentrated or in situations where a high dosage of the drug can be used. This category also provides a buffer zone that prevents small uncontrolled technical factors from causing major discrepancies in interpretation. A report of Resistant (R) indicates that the antimicrobial drug is not likely to inhibit growth of the pathogen if the antimicrobial drug reaches the concentrations usually achievable at the infection site; other therapy should be selected. Quality Control Standardized susceptibility test procedures require the use of laboratory controls to monitor and ensure the accuracy of supplies and reagents used in the assay, and the techniques of the individuals performing the test 2,3,4 . Standard meropenem and vaborbactam powder should provide the following range of MIC values noted in Table 7. For the diffusion technique using the 20 mcg meropenem/10 mcg vaborbactam disk, the criteria in Table 6 should be achieved Table 7: Acceptable Quality Control Ranges for Meropenem/Vaborbactam Quality Control Strain Minimum Inhibitory Concentration (mcg/mL) Disk Diffusion (zone diameter in mm) Klebsiella pneumoniae ATCC BAA-1705* 0.015/8-0.06/8 21-27 Klebsiella pneumoniae ATCC BAA-2814* - 16-20 Pseudomonas aeruginosa ATCC 27853 0.12/8-1/8 29-35 Escherichia coli ATCC 25922 0.008/8-0.06/8 31-37 Escherichia coli ATCC 35218 0.008/8-0.06/8 - Klebsiella pneumoniae ATCC 700603 0.015/8-0.06/8 29-35 Staphylococcus aureus ATCC 25923 - 32-38 Staphylococcus aureus ATCC 29213 0.03/8-0.12/8 - ATCC = American Type Culture Collection Nonclinical Toxicology 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis Long-term carcinogenicity studies have not been performed with VABOMERE, meropenem, or vaborbactam. Mutagenesis Meropenem 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 mutation potential found in any of these tests. Vaborbactam Genetic 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 Meropenem Reproductive 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 a 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. Vaborbactam Vaborbactam 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 Studies 14.1 Complicated Urinary Tract Infections (cUTI), including Pyelonephritis A total of 545 adults with cUTI, including pyelonephritis were randomized into a double blind, double dummy, multi center trial comparing VABOMERE (meropenem 2 grams and vaborbactam 2 grams) to piperacillin/tazobactam (piperacillin 4 grams/tazobactam 0.5 grams) intravenously every 8 hours. Switch to an oral antibacterial drug, such as levofloxacin was allowed after a 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 1 baseline uropathogen. Clinical and microbiological response at the end of IV treatment (EOIVT) required both a clinical outcome of cure or improvement and a microbiologic outcome of eradication (all baseline uropathogens at> 10 5 CFU/mL are to be reduced to <10 4 CFU/mL). Clinical and microbiological response was also assessed at the Test of Cure (TOC) visit (approximately 7 days after completion of treatment) in the m MITT population and required both a clinical outcome of cure and a 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/m 2 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 a non-removable and removable source of infection, respectively. Mean duration of IV treatment in both treatment groups was 8 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 a 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 8, 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 8. Table 8: Clinical and Microbiological Response Rates in a Phase 3 Trial of cUTI Including Pyelonephritis (m MITT Population) VABOMERE n/N (%) Piperacillin/ Tazobactam n/N (%) Difference (95% CI) Clinical cure or improvement AND microbiological eradication at the End of IV Treatment Visit* 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 7 days after completion of treatment** 124/162 (76.5) 2/153 (73.2) 3.3% (-6.2%, 13.0%) CI = confidence interval; EOIVT = End of Intravenous Treatment; TOC = Test of Cure *End of IV Treatment visit includes patients with organisms resistant to piperacillin/tazobactam at baseline **Test of Cure visit excludes patients with organisms resistant to piperacillin/tazobactam at baseline 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 a 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 3 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. REFERENCES Kawamura S, Russell AW, Freeman SJ, and Siddall, RA: Reproductive and Developmental Toxicity of Meropenem in Rats. Chemotherapy, 40:S238-250 (1992). Clinical and Laboratory Standards Institute (CLSI). Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria that Grow Aerobically; Approved Standard Tenth Edition. CLSI document M07 A10, Clinical and Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne, Pennsylvania 19087, USA, 2015. Clinical and Laboratory Standards Institute (CLSI). Performance Standards for Antimicrobial Susceptibility Testing; Twenty seventh Informational Supplement, CLSI document M100 S27, Clinical and Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne, Pennsylvania 19087, USA, 2017. Clinical and Laboratory Standards Institute (CLSI). Performance Standards for Antimicrobial Disk Diffusion Susceptibility Tests; Approved Standard Twelfth Edition. CLSI document M02-A12, Clinical and Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne, Pennsylvania 19087, USA, 2015. How Supplied/Storage and Handling VABOMERE 2 grams (meropenem and vaborbactam) for injection is supplied as a white to light yellow sterile powder for constitution in single dose, clear glass vials (NDC 65293 009 01) sealed with a rubber stopper (not made with natural rubber latex) and an aluminum overseal. Each vial is supplied in cartons of 6 vials (NDC 65293 009 06). Each vial contains 1 gram of meropenem (equivalent to 1.14 grams of meropenem trihydrate), 1 gram of vaborbactam, and 0.575 gram of sodium carbonate. Store VABOMERE vials at 20 C to 25 C (68 F to 77 F); excursions are permitted to 15 C to 30 C (59 F to 86 F) [see USP, Controlled Room Temperature (CRT)]. Patient Counseling Information Serious Allergic Reactions Advise 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 )] . Seizures Patients 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 Diarrhea Counsel patients that diarrhea is a 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 Acid 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 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 Resistance Counsel 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 a 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 )] . PRINICIPAL DISPLAY PANEL - VABOMERETM - Carton Rx Only VABOMERE TM (meropenem and vaborbactam) for injection 2 g per vial * *Meropenem 1 gram (equivalent to 1.14 g meropenem trihydrate) and vaborbactam 1 g For Intravenous Infusion Only Single Dose Only Discard Unused Portion After Use PN 1502 NDC 65293-009-06 MUST BE CONSTITUTED THEN DILUTED See prescribing information for constitution and dilution instructions and complete directions for use. Storage: Store at 20 C to 25 C (68 F to 77 F); excursions are permitted to 15 C to 30 C (59 F to 86 F) [See USP Controlled Room Temperature] Manufactured by: Facta Farmaceutici S.p.A. Nucleo Industriale S. Atto S. Nicolo a Tordino 64100 Teramo (TE) Italy Marketed by: The Medicines Company Parsippany, NJ 07054 Product of Italy Contains 6 single dose 2 g vials PRINCIPAL DISPLAY PANEL - VABOMERE TM - Vial Rx Only NDC 65293-009-01 VABOMERE TM (meropenem and vaborbactam) for injection 2 g per vial* *Meropenem 1 gram (equivalent to 1.14 g meropenem trihydrate) and vaborbactam 1 g For Intravenous Infusion Only Single Dose Only Discard Unused Portion After Use MUST BE CONSTITUTED THEN DILUTED See prescribing information for constitution and dilution instructions and complete directions for use. Each vial contains meropenem 1 g, vaborbactam 1 g, and sodium carbonate 0.575 g. The total sodium content of themixture is approximately 0.35 g (10.9 mEq). Storage : Store at 20 C to 25 C (68 F to 77 F); excursions are permitted to 15 C to 30 C (59 F to 86 F) [See USP Controlled Room Temperature] Manufactured by: Facta Farmaceutici S.p.A. Nucleo Industriale S. Atto S. Nicolo a Tordino 64100 Teramo (TE), Italy Marketed by: The Medicines Company Parsippany, NJ 07054 Product of Italy PN 1501 VABOMERE meropenem-vaborbactam injection, powder, for solution Product Information Product Type HUMAN PRESCRIPTION DRUG LABEL Item Code (Source) NDC:65293-009 Route of Administration INTRAVENOUS DEA Schedule Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength VABORBACTAM (VABORBACTAM) VABORBACTAM 1 g in 2 g MEROPENEM (MEROPENEM ANHYDROUS) MEROPENEM 1 g in 2 g Inactive Ingredients Ingredient Name Strength SODIUM CARBONATE 575 mg in 2 g Product Characteristics Color white (White to light yellow) Score Shape Size Flavor Imprint Code Contains Packaging # Item Code Package Description 1 NDC:65293-009-06 6 VIAL, SINGLE-DOSE in 1 CARTON 1 NDC:65293-009-01 2 g in 1 VIAL, SINGLE-DOSE Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date NDA NDA209776 10/02/2017 Labeler - The Medicines Company (040861601) Registrant - The Medicines Company (040861601) Establishment Name Address ID/FEI Operations Facta Farmaceutici S.p.A. 434623333 manufacture(65293-009) Revised: 08/2017 The Medicines Company Next Interactions Print this page Add to My Med List More about meropenem/vaborbactam Side Effects During Pregnancy Drug Interactions Support Group 0 Reviews Add your own review/rating Drug class: carbapenems/beta-lactamase inhibitors Consumer resources Meropenem and vaborbactam Professional resources Meropenem and Vaborbactam (AHFS Monograph) Other brands: Vabomere Related treatment guides Urinary Tract Infection> ]} FEATURED: CAR-T Cell Therapy Overview Mechanism of Action KTE-C19 Studies KTE-C19 Cancer Targets Adverse Events Manufacturing Drug Status Rx Availability Prescription only Approval History Drug history at FDA Drug Class Carbapenems / beta-lactamase inhibitors Related Drugs carbapenems / beta-lactamase inhibitors Vabomere , meropenem / vaborbactam Urinary Tract Infection ciprofloxacin , amoxicillin , doxycycline , Augmentin , Levaquin , levofloxacin , Bactrim , nitrofurantoin , cranberry , sulfamethoxazole / trimethoprim , Macrobid , ceftriaxone , cefuroxime , Acidophilus , Rocephin , Ceftin , amoxicillin / clavulanate , cefazolin , Amoxil , Bactrim DS , ampicillin , Zosyn , More... 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