Clinical Pharmacology Corner: FDA Approves VABOMERE (Meropenem and Vaborbactam)

FDA Approves VABOMERE™ (Meropenem and Vaborbactam) for Treatment of Patients 18 Years and Older with Complicated Urinary Tract Infections Including Pyelonephritis Caused by Designated Susceptible Bacteria On August 29, 2017, the U.S. Food and Drug Administration (FDA) approved VABOMERE (meropenem and vaborbactam) for treatment of patients 18 years and older with complicated urinary tract infections including pyelonephritis caused by the following susceptible microorganisms: Escherichia coli, Klebsiella pneumoniae, and Enterobacter cloacae species complex. The approved recommended dosage of VABOMERE is 4 grams (meropenem 2 grams and vaborbactam 2 grams) administered every 8 hours by intravenous (IV) infusion over 3 hours in patients 18 years of age and older with an estimated glomerular filtration rate (eGFR) ≥ 50 mL/min/1.73m2, as calculated using Modification of Diet in Renal Disease (MDRD) equation. The duration of treatment is for up to 14 days. Dosage modifications of VABOMERE for patients with renal impairment who have an eGFR < 50 mL/min/1.73m2 are described in the full prescribing information (link below). 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. Administer VABOMERE after a hemodialysis session for patients maintained on hemodialysis. 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. Serious and occasionally fatal hypersensitivity (anaphylactic) reactions and serious skin reactions have been reported. Seizures and other adverse central nervous system (CNS) experiences have been reported with meropenem, most commonly in patients with CNS disorders or with bacterial meningitis and/or compromised renal function. Close adherence to the recommended dosage regimens is recommended. Additional management and dosage modification information is described in the full prescribing information linked below. Mechanism of Action (MOA), General Pharmacokinetics (PK), and Pharmacodynamics (PD) MOA: VABOMERE is a combination of meropenem, a penem antibacterial, and vaborbactam, a beta lactamase inhibitor. General PK: Following 7 days of VABOMERE at the approved recommended dosage, the meropenem mean (SD) Cmax was 43.4 (8.8) mg/L and AUC was 138.0 (27.7) mg•h/L and the mean (SD) vaborbactam Cmax was 55.6 (11.0) mg/L and AUC was 196.0 (36.7) mg•h/L, in healthy adult subjects. There is no accumulation of meropenem or vaborbactam following multiple IV infusions administered every 8 hours for 7 days in subjects with normal renal function. Dose Proportionality: Cmax and AUC of meropenem and vaborbactam proportionally increased with dose across the dose ranges of 1 gram (0.5 times approved recommended dosage of meropenem) to 2 grams for meropenem and 0.25 grams (0.125 times approved recommended dosage of vaborbactam) to 2 grams for vaborbactam. Distribution: Plasma protein binding of meropenem is approximately 2% and of vaborbactam is approximately 33%. Elimination: Following multiple doses, the clearance of meropenem is 15.1 L/h and of vaborbactam is 10.9 L/h, in healthy subjects. Half-life is approximately 1.2 hours for meropenem and 1.7 hours for vaborbactam.  Metabolism: Hydrolysis of the beta-lactam ring is a minor metabolic pathway for meropenem. Vaborbactam does not undergo metabolism. Excretion: Meropenem and vaborbactam are primarily excreted via the kidneys. For meropenem, approximately 40 to 60% of the dose is excreted unchanged within 24 to 48 hours with a further 22% recovered as the microbiologically inactive hydrolysis product. For vaborbactam, 75 to 95% of the dose was excreted unchanged in the urine over a 24 to 48 hour period. Drug Interactions Co-administration of meropenem with valproic acid or divalproex sodium results in a reduction in valproic acid concentrations. Reduced valproic acid concentrations may increase the risk of breakthrough seizures. Co-administration of VABOMERE with probenecid results in increased plasma concentrations of meropenem from the competition of probenecid with meropenem for active tubular secretion. Co-administration of probenecid with VABOMERE is not recommended. Co-administration of meropenem and vaborbactam in healthy subjects did not result in a clinically significant change in the exposure of either drug. Use in Specific Populations Dosage adjustment for VABOMERE is recommended in patients with renal impairment (eGFR < 50 mL/min/1.73m2). Dosage adjustment for elderly patients should be based on renal function. Age, sex, race, and hepatic impairment did not have a clinically significant impact on the pharmacokinetics of VABOMERE. Efficacy and Safety The efficacy of VABOMERE was demonstrated in a randomized, double-blind, double dummy, multi-center trial comparing predefined end of treatment clinical and microbiological response of VABOMERE (approved recommended dosage) to piperacillin/tazobactam (piperacillin 4 grams/tazobactam 0.5 grams) IV every 8 hours (levofloxacin switch allowed after at least 15 doses). Additional information regarding the efficacy trial can be found in the full prescribing information linked below. Serious adverse reactions included hypersensitivity reactions, seizure potential, Clostridium difficile-associated diarrhea, increased risk of break-through seizures due to drug interaction with valproic acid, thrombocytopenia, neuromotor impairment, development of drug-resistant bacteria, and overgrowth of nonsusceptible organisms. The most frequently reported adverse reactions (≥ 3%) in patients receiving VABOMERE were headache, infusion site reactions, and diarrhea. Full prescribing information is available at https://go.usa.gov/xRAfB. Visit Drugs@FDA at http://go.usa.gov/cMsjT for prescribing and patient information, approval letters, reviews and other information for FDA-approved drug products, which are often available shortly following approval. Healthcare professionals should report all serious adverse events suspected to be associated with the use of any medicine and device to FDA's MedWatch Reporting System by completing a form online at http://www.fda.gov/medwatch/report.htm, by faxing (1-800-FDA-0178), or by mailing the postage-paid address form provided online, or by telephone (1-800-FDA-1088). We always welcome your thoughts regarding the format, content, and utility of the communication. Comments may be sent via email to ocp@fda.hhs.gov. This communication was prepared by Office of Clinical Pharmacology, Office of Translational Sciences, CDER, FDA. FDA/Center for Drug Evaluation and Research (CDER) Office of Translational Sciences Office of Clinical Pharmacology Email: ocp@fda.hhs.gov

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