The Medicines Company Announces FDA Approval of VABOMERE™ (meropenem and vaborbactam)

30 Aug 2017

The Medicines Company (NASDAQ:MDCO) today announced that the U.S. Food and Drug Administration (FDA) has approved VABOMERE™ (meropenem and vaborbactam) for injection for the treatment of adult patients with complicated urinary tract infections (cUTI), including pyelonephritis, caused by designated susceptible Enterobacteriaceae – Escherichia coli, Klebsiella pneumoniae and Enterobacter cloacae species complex. VABOMERE is a drug containing meropenem, an antibacterial, and vaborbactam, which inhibits certain types of resistance mechanisms used by bacteria.

VABOMERE addresses gram-negative bacteria that produce beta-lactamase enzymes that have spread in the United States and Europe, particularly the Klebsiella pneumoniae carbapenemase (KPC) enzyme. KPC-producing bacteria are responsible for a large majority of all carbapenem-resistant Enterobacteriaceae in the United States and are classified by the U.S. Centers for Disease Control (CDC) to be an urgent antimicrobial resistance threat. VABOMERE was granted priority review and approval as a Qualified Infectious Disease Product (QIDP) in accordance with the Generating Antibiotics Incentives Now (GAIN) Act, which made VABOMERE eligible for the FDA’s fast-track program, and approval now secures a five-year regulatory extension of exclusivity under the Hatch-Waxman Act, which means that patent coverage and exclusivity in the United States are expected to extend into 2031. VABOMERE was developed by The Medicines Company’s Infectious Disease Business and is a key addition to its leading portfolio of infectious disease products that provide broad treatment coverage for many of the highest-priority, drug-resistant pathogens identified by the CDC and the World Health Organization (WHO).

“We are grateful to the FDA for working with us to advance the development and approval of VABOMERE for cUTI on an accelerated basis to make this important treatment available to physicians and patients, who carry significant risks of death and mortality, at the soonest possible time,” said Clive Meanwell, M.D., Ph.D., Chief Executive Officer of The Medicines Company. “VABOMERE represents a significant new advancement in addressing KPC-producing Enterobacteriaceae, for which there are currently limited treatment options. We look forward to a successful U.S. launch of VABOMERE, leveraging our established, fully dedicated commercial infrastructure, and to expanding VABOMERE into other global markets.”

Cornelius Clancy M.D., Associate Professor in the Division of Infectious Diseases at University of Pittsburgh and Chief of Infectious Diseases at the VA Pittsburgh Health System commented, “Carbapenem antibiotics have been the preferred drugs for treating serious infections, such as cUTI, due to Enterobacteriaceae-producing, extended-spectrum beta-lactamases. With the dissemination of the KPC enzyme, new drugs that address this resistance mechanism to carbapenems are a welcome addition to our armamentarium.”

The FDA approval of VABOMERE was supported by TANGO-1, a Phase III, multi-center, randomized, double-blind, double-dummy study to evaluate the efficacy, safety and tolerability of VABOMERE compared to piperacillin-tazobactam in the treatment of cUTI, including acute pyelonephritis, in adults. The trial enrolled 550 adult patients who were randomized 1:1 to receive VABOMERE (meropenem 2g - vaborbactam 2g) as a three-hour IV infusion every eight hours, or piperacillin 4g - tazobactam 500mg as a 30-minute IV infusion every eight hours, each for up to 10 days.

The primary assessment was performed in the microbiologic modified intent-to-treat (mMITT) patient population, and was defined as overall success of clinical outcome (cure or improvement) and microbiologic outcome of eradication (baseline bacterial pathogen reduced to < 104 CFU/ml). Overall success was observed in 183/186 patients (98.4%) in the meropenem-vaborbactam group and in 165/175 patients (94.3%) in the piperacillin-tazobactam group – a difference of 4.1% (95% CI: 0.3% to 8.8%). The most common adverse events for VABOMERE included headache, infusion site reactions and diarrhea.

Michael Dudley, PharmD, FIDSA, Senior Vice President, Head of R&D and Co-Leader for The Medicines Company’s Infectious Disease Business, noted, “We are grateful for the support of patients, families, and investigators that contributed to the rapid development of VABOMERE as it progressed from discovery in our laboratories to availability for patients in under eight years. This unprecedented speed has, in no small way, been due to our outstanding collaboration with, and support received from, the Biomedical Advanced Research and Development Authority (BARDA).”

Data from the TANGO clinical program, including data from TANGO-2, a multi-center, randomized, open-label clinical trial of VABOMERE versus “best available therapy” in subjects with known or suspected carbapenem-resistant Enterobacteriaceae (CRE), will be presented at IDWeek 2017, to be held October 4-8, 2017 in San Diego. Last month, the Company announced cessation of enrollment in TANGO-2 following a recommendation by the independent Data and Safety Monitoring Board, which concluded that a risk-benefit analysis of available data no longer supported randomization of additional patients to the “best available therapy” comparator arm.

We expect that VABOMERE will be available in the fourth quarter of 2017. The FDA approval of VABOMERE triggered a $40 million milestone payment obligation to the former securityholders of Rempex Pharmaceuticals, Inc., which we acquired in December 2013.

About VABOMERE™ (meropenem and vaborbactam) for Injection

VABOMERE™ (meropenem and vaborbactam) 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.

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.

Highlights of Prescribing Information

Dosage and Administration

Recommended Dosage

The 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) greater than or equal to 50 mL/min/1.73m2. The duration of treatment is for up to 14 days.

Dosage 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 (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. For patients maintained on hemodialysis, administer VABOMERE after a hemodialysis session.

Table 1: Dosage of VABOMERE in Patients with Renal Impairment

                 
eGFRa
      <p class="bwcellpmargin">
        <b>(mL/min/1.73m2)</b>
      </p>
    </td>
    <td class="bwsinglebottom">
      &nbsp;
    </td>
    <td class="bwsinglebottom">
      &nbsp;
    </td>
    <td class="bwsinglebottom">
      &nbsp;
    </td>
    <td class="bwpadl0  bwvertalignt bwalignl bwsinglebottom">
      <p class="bwcellpmargin">
        <b>Recommended Dosage Regimen for</b><br><b>VABOMERE (meropenem 
        and</b><br><b>vaborbactam)b, c, d</b>
      </p>
    </td>
    <td class="bwsinglebottom">
      &nbsp;
    </td>
    <td class="bwsinglebottom">
      &nbsp;
    </td>
    <td class="bwsinglebottom">
      &nbsp;
    </td>
    <td class="bwpadl0  bwvertalignt bwalignl bwsinglebottom">
      <b>Dosing Interval</b>
    </td>
  </tr>
  <tr>
    <td class="bwpadl0  bwvertalignt bwalignl bwsinglebottom">
      30 to 49
    </td>
    <td class="bwsinglebottom">
      &nbsp;
    </td>
    <td class="bwsinglebottom">
      &nbsp;
    </td>
    <td class="bwsinglebottom">
      &nbsp;
    </td>
    <td class="bwpadl0  bwvertalignt bwalignl bwsinglebottom">
      <p class="bwcellpmargin">
        VABOMERE 2 grams (meropenem 1 gram and<br>vaborbactam 1 gram)
      </p>
    </td>
    <td class="bwsinglebottom">
      &nbsp;
    </td>
    <td class="bwsinglebottom">
      &nbsp;
    </td>
    <td class="bwsinglebottom">
      &nbsp;
    </td>
    <td class="bwpadl0  bwvertalignt bwalignl bwsinglebottom">
      Every 8 hours
    </td>
  </tr>
  <tr>
    <td class="bwpadl0  bwvertalignt bwalignl bwsinglebottom">
      15 to 29
    </td>
    <td class="bwsinglebottom">
      &nbsp;
    </td>
    <td class="bwsinglebottom">
      &nbsp;
    </td>
    <td class="bwsinglebottom">
      &nbsp;
    </td>
    <td class="bwpadl0  bwvertalignt bwalignl bwsinglebottom">
      <p class="bwcellpmargin">
        VABOMERE 2 grams (meropenem 1 gram and<br>vaborbactam 1 gram)
      </p>
    </td>
    <td class="bwsinglebottom">
      &nbsp;
    </td>
    <td class="bwsinglebottom">
      &nbsp;
    </td>
    <td class="bwsinglebottom">
      &nbsp;
    </td>
    <td class="bwpadl0  bwvertalignt bwalignl bwsinglebottom">
      Every 12 hours
    </td>
  </tr>
  <tr>
    <td class="bwpadl0  bwvertalignt bwalignl bwsinglebottom">
      Less than 15
    </td>
    <td class="bwsinglebottom">
      &nbsp;
    </td>
    <td class="bwsinglebottom">
      &nbsp;
    </td>
    <td class="bwsinglebottom">
      &nbsp;
    </td>
    <td class="bwpadl0  bwvertalignt bwalignl bwsinglebottom">
      <p class="bwcellpmargin">
        VABOMERE 1 gram (meropenem 0.5 grams<br>and vaborbactam 0.5 
        grams)
      </p>
    </td>
    <td class="bwsinglebottom">
      &nbsp;
    </td>
    <td class="bwsinglebottom">
      &nbsp;
    </td>
    <td class="bwsinglebottom">
      &nbsp;
    </td>
    <td class="bwpadl0  bwvertalignt bwalignl bwsinglebottom">
      Every 12 hours
    </td>
  </tr>
</tbody></table>
<table cellspacing="0" class="bwtablemarginb">
  <tbody><tr>
    <td class="bwpadl0  bwvertalignt bwalignl">
      a.
    </td>
    <td>
      &nbsp;
    </td>
    <td class="bwpadl0  bwvertalignt bwalignl">
      As calculated using the Modification of Diet in Renal Disease (MDRD) 
      formula as follows: eGFR (mL/min/1.73m2) = 175 x (serum 
      creatinine)-1.154 x (age)-0.203x (0.742 if female) x (1.212 if 
      African American).
    </td>
  </tr>
  <tr>
    <td class="bwpadl0  bwvertalignt bwalignl">
      b.
    </td>
    <td>
    </td>
    <td class="bwpadl0  bwvertalignt bwalignl">
      All doses of VABOMERE are administered intravenously over 3 hours.
    </td>
  </tr>
  <tr>
    <td class="bwpadl0 bwnowrap bwpadr0 bwvertalignt bwalignl">
      c.
    </td>
    <td>
    </td>
    <td class="bwpadl0  bwvertalignt bwalignl">
      Doses adjusted for renal impairment should be administered after a 
      hemodialysis session.
    </td>
  </tr>
  <tr>
    <td class="bwpadl0  bwvertalignt bwalignl">
      d.
    </td>
    <td>
    </td>
    <td class="bwpadl0  bwvertalignt bwalignl">
      The total duration of treatment is for up to 14 days.
    </td>
  </tr>
  <tr>
    <td>
    </td>
    <td>
    </td>
    <td>
      &nbsp;
    </td>
  </tr>
</tbody></table>
<p>
  <i><b>Microbiology</b></i>
</p>
<p>
  <span class="bwuline">Mechanism of Action</span>
</p>
<p>
  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.
</p>
<p>
  The vaborbactam component of VABOMERE is a non-suicidal beta-lactamase 
  inhibitor that protects meropenem from degradation by certain serine 
  beta-lactamases such as <i>Klebsiella</i> <i>pneumoniae </i>carbapenemase 
  (KPC). Vaborbactam does not have any antibacterial activity. Vaborbactam 
  does not decrease the activity of meropenem against 
  meropenem-susceptible organisms.
</p>
<p>
  <span class="bwuline">Resistance</span>
</p>
<p>
  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.
</p>
<p>
  Clinical isolates may produce multiple beta-lactamases, express varying 
  levels of betalactamases, or have amino acid sequence variations, and 
  other resistance mechanisms that have not been identified.
</p>
<p>
  Culture and susceptibility information and local epidemiology should be 
  considered in selecting or modifying antibacterial therapy.
</p>
<p>
  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.
</p>
<p>
  In the Phase 3 cUTI trial with VABOMERE, some isolates of <i>E. coli</i>, 
  <i>K. pneumoniae, E. cloacae, C. freundii, P. mirabilis, P. stuartii</i> 
  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.
</p>
<p>
  Some beta-lactamases were also produced by an isolate of <i>K. pneumoniae</i> 
  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.
</p>
<p>
  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.
</p>
<p>
  <span class="bwuline">Interaction with Other Antimicrobials</span>
</p>
<p>
  In vitro synergy studies have not demonstrated antagonism between 
  VABOMERE and levofloxacin, tigecycline, polymyxin, amikacin, vancomycin, 
  azithromycin, daptomycin, or linezolid.
</p>
<p>
  <span class="bwuline">Activity against Meropenem Non-susceptible 
  Bacteria in Animal Infection Models</span>
</p>
<p>
  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.
</p>
<p>
  <span class="bwuline">Antimicrobial Activity</span>
</p>
<p>
  VABOMERE has been shown to be active against most isolates of the 
  following bacteria, both in vitro and in clinical infections.
</p>
<p>
  Gram-negative bacteria:
</p>
<ul>
  <li class="bwlistitemmargb">
    <i>Enterobacter cloacae species</i> complex
  </li>
  <li class="bwlistitemmargb">
    <i>Escherichia coli</i>
  </li>
  <li class="bwlistitemmargb">
    <i>Klebsiella pneumoniae</i>
  </li>
</ul>
<p>
  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.
</p>
<p>
  Gram-negative bacteria:
</p>
<ul>
  <li class="bwlistitemmargb">
    <i>Citrobacter freundii</i>
  </li>
</ul>
<ul>
  <li class="bwlistitemmargb">
    <i>Citrobacter koseri</i>
  </li>
</ul>
<ul>
  <li class="bwlistitemmargb">
    <i>Enterobacter aerogenes</i>
  </li>
  <li class="bwlistitemmargb">
    <i>Klebsiella oxytoca</i>
  </li>
</ul>
<ul>
  <li class="bwlistitemmargb">
    <i>Morganella morganii</i>
  </li>
</ul>
<ul>
  <li class="bwlistitemmargb">
    <i>Proteus mirabilis</i>
  </li>
</ul>
<ul>
  <li class="bwlistitemmargb">
    <i>Providencia spp.</i>
  </li>
</ul>
<ul>
  <li class="bwlistitemmargb">
    <i>Pseudomonas aeruginosa</i>
  </li>
</ul>
<ul>
  <li class="bwlistitemmargb">
    <i>Serratia marcescens</i>
  </li>
</ul>
<p>
  <span class="bwuline">Susceptibility Test Methods</span>
</p>
<p>
  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.
</p>
<p>
  <i>Dilution Techniques</i>
</p>
<p>
  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 (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 (below).
</p>
<p>
  <i>Diffusion Techniques</i>
</p>
<p>
  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. 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 (below).
</p>
<p>
  <b>Table 6:</b> <b>Susceptibility Interpretive Criteria for 
  Meropenem/Vaborbactam</b>
</p>
<table cellspacing="0" class="bwtablemarginb">
  <tbody><tr>
    <td class="bwsinglebottom">
      &nbsp;
    </td>
    <td class="bwsinglebottom">
      &nbsp;
    </td>
    <td class="bwsinglebottom">
      &nbsp;
    </td>
    <td class="bwsinglebottom">
      &nbsp;
    </td>
    <td class="bwsinglebottom" colspan="3">
      &nbsp;
    </td>
    <td class="bwsinglebottom">
      &nbsp;
    </td>
    <td class="bwsinglebottom">
      &nbsp;
    </td>
    <td class="bwsinglebottom">
      &nbsp;
    </td>
    <td class="bwsinglebottom" colspan="3">
      &nbsp;
    </td>
  </tr>
  <tr>
    <td class="bwpadl0  bwvertalignt bwalignl bwsinglebottom">
      <p class="bwcellpmargin">
        <b>Pathogen</b>
      </p>
    </td>
    <td class="bwsinglebottom">
      &nbsp;
    </td>
    <td class="bwsinglebottom">
      &nbsp;
    </td>
    <td class="bwsinglebottom">
      &nbsp;
    </td>
    <td class="bwpadl0  bwvertalignt bwalignl bwsinglebottom" colspan="3">
      <p class="bwcellpmargin">
        <b>Minimum Inhibitory</b><br><b>Concentrations (mcg/mL)</b>
      </p>
    </td>
    <td class="bwsinglebottom">
      &nbsp;
    </td>
    <td class="bwsinglebottom">
      &nbsp;
    </td>
    <td class="bwsinglebottom">
      &nbsp;
    </td>
    <td class="bwpadl0  bwvertalignt bwalignl bwsinglebottom" colspan="3">
      <p class="bwcellpmargin">
        Disk Diffusion<br>(zone diameters in mm)
      </p>
    </td>
  </tr>
  <tr>
    <td class="bwpadl0  bwvertalignt bwalignl">
      <p class="bwcellpmargin">
        Enterobacteriaceae
      </p>
    </td>
    <td>
      &nbsp;
    </td>
    <td>
      &nbsp;
    </td>
    <td>
      &nbsp;
    </td>
    <td class="bwpadl0  bwvertalignt bwalignc">
      S
    </td>
    <td class="bwpadl0  bwvertalignt bwalignc">
      I
    </td>
    <td class="bwpadl0  bwvertalignt bwalignc">
      R
    </td>
    <td>
      &nbsp;
    </td>
    <td>
      &nbsp;
    </td>
    <td>
      &nbsp;
    </td>
    <td class="bwpadl0  bwvertalignt bwalignc">
      <p class="bwcellpmargin">
        <b>S</b>
      </p>
    </td>
    <td class="bwpadl0  bwvertalignt bwalignc">
      <p class="bwcellpmargin">
        <b>I</b>
      </p>
    </td>
    <td class="bwpadl0  bwvertalignt bwalignc">
      <p class="bwcellpmargin">
        <b>R</b>
      </p>
    </td>
  </tr>
  <tr>
    <td class="bwpadl0  bwvertalignt bwalignl bwsinglebottom">
      &nbsp;
    </td>
    <td class="bwsinglebottom">
      &nbsp;
    </td>
    <td class="bwsinglebottom">
      &nbsp;
    </td>
    <td class="bwsinglebottom">
      &nbsp;
    </td>
    <td class="bwpadl0  bwvertalignt bwalignc bwsinglebottom">
      ?4/8
    </td>
    <td class="bwpadl0 bwnowrap bwpadr0 bwvertalignb bwalignc bwsinglebottom">
      8/8
    </td>
    <td class="bwpadl0  bwvertalignt bwalignc bwsinglebottom">
      ?16/8
    </td>
    <td class="bwsinglebottom">
      &nbsp;
    </td>
    <td class="bwsinglebottom">
      &nbsp;
    </td>
    <td class="bwsinglebottom">
      &nbsp;
    </td>
    <td class="bwpadl0  bwvertalignt bwalignc bwsinglebottom">
      <p class="bwcellpmargin">
        ?17
      </p>
    </td>
    <td class="bwpadl0 bwnowrap bwpadr0 bwvertalignb bwalignc bwsinglebottom">
      <p class="bwcellpmargin">
        14-16
      </p>
    </td>
    <td class="bwpadl0  bwvertalignt bwalignc bwsinglebottom">
      <p class="bwcellpmargin">
        ?13
      </p>
    </td>
  </tr>
</tbody></table>
<p>
  S = Susceptible; I = Intermediate; R = Resistant
</p>
<p>
  A report of <i>Susceptible (S) </i>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 <i>Intermediate (I) </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 <i>Resistant 
  (R) </i>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.
</p>
<p>
  <i>Quality Control</i>
</p>
<p>
  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. Standard meropenem and vaborbactam powder should 
  provide the following range of MIC values noted in Table 7 (below). For 
  the diffusion technique using the 20 mcg meropenem/10 mcg vaborbactam 
  disk, the criteria in Table 6 (above) should be achieved.
</p>
<p>
  <b>Table 7:</b> <b>Acceptable Quality Control Ranges for 
  Meropenem/Vaborbactam</b>
</p>
<table cellspacing="0" class="bwtablemarginb">
  <tbody><tr>
    <td class="bwsinglebottom">
      &nbsp;
    </td>
    <td class="bwsinglebottom">
      &nbsp;
    </td>
    <td class="bwsinglebottom">
      &nbsp;
    </td>
    <td class="bwsinglebottom">
      &nbsp;
    </td>
    <td class="bwsinglebottom">
      &nbsp;
    </td>
    <td class="bwsinglebottom">
      &nbsp;
    </td>
    <td class="bwsinglebottom">
      &nbsp;
    </td>
    <td class="bwsinglebottom">
      &nbsp;
    </td>
    <td class="bwsinglebottom">
      &nbsp;
    </td>
  </tr>
  <tr>
    <td class="bwpadl0  bwvertalignt bwalignl bwsinglebottom">
      <p class="bwcellpmargin">
        <b>Quality Control Strain</b>
      </p>
    </td>
    <td class="bwsinglebottom">
      &nbsp;
    </td>
    <td class="bwsinglebottom">
      &nbsp;
    </td>
    <td class="bwsinglebottom">
      &nbsp;
    </td>
    <td class="bwpadl0  bwvertalignt bwalignl bwsinglebottom">
      <p class="bwcellpmargin">
        <b>Minimum Inhibitory</b><br><b>Concentration</b><br><b>(mcg/mL)</b>
      </p>
    </td>
    <td class="bwsinglebottom">
      &nbsp;
    </td>
    <td class="bwsinglebottom">
      &nbsp;
    </td>
    <td class="bwsinglebottom">
      &nbsp;
    </td>
    <td class="bwpadl0  bwvertalignt bwalignl bwsinglebottom">
      <p class="bwcellpmargin">
        <b>Disk Diffusion</b><br><b>(zone diameter in mm)</b>
      </p>
    </td>
  </tr>
  <tr>
    <td class="bwpadl0  bwvertalignt bwalignl bwsinglebottom">
      <i>Klebsiella pneumoniae </i>ATCC BAA-1705*
    </td>
    <td class="bwsinglebottom">
      &nbsp;
    </td>
    <td class="bwsinglebottom">
      &nbsp;
    </td>
    <td class="bwsinglebottom">
      &nbsp;
    </td>
    <td class="bwpadl0 bwnowrap bwpadr0 bwvertalignb bwalignl bwsinglebottom">
      0.015/8-0.06/8
    </td>
    <td class="bwsinglebottom">
      &nbsp;
    </td>
    <td class="bwsinglebottom">
      &nbsp;
    </td>
    <td class="bwsinglebottom">
      &nbsp;
    </td>
    <td class="bwpadl0 bwnowrap bwpadr0 bwvertalignb bwalignl bwsinglebottom">
      21-27
    </td>
  </tr>
  <tr>
    <td class="bwpadl0  bwvertalignt bwalignl bwsinglebottom">
      <i>Klebsiella pneumoniae </i>ATCC BAA-2814*
    </td>
    <td class="bwsinglebottom">
      &nbsp;
    </td>
    <td class="bwsinglebottom">
      &nbsp;
    </td>
    <td class="bwsinglebottom">
      &nbsp;
    </td>
    <td class="bwpadl0 bwnowrap bwpadr0 bwvertalignb bwalignl bwsinglebottom">
      –
    </td>
    <td class="bwsinglebottom">
      &nbsp;
    </td>
    <td class="bwsinglebottom">
      &nbsp;
    </td>
    <td class="bwsinglebottom">
      &nbsp;
    </td>
    <td class="bwpadl0 bwnowrap bwpadr0 bwvertalignb bwalignl bwsinglebottom">
      16-20
    </td>
  </tr>
  <tr>
    <td class="bwpadl0  bwvertalignt bwalignl bwsinglebottom">
      <i>Pseudomonas aeruginosa </i>ATCC 27853
    </td>
    <td class="bwsinglebottom">
      &nbsp;
    </td>
    <td class="bwsinglebottom">
      &nbsp;
    </td>
    <td class="bwsinglebottom">
      &nbsp;
    </td>
    <td class="bwpadl0 bwnowrap bwpadr0 bwvertalignb bwalignl bwsinglebottom">
      0.12/8-1/8
    </td>
    <td class="bwsinglebottom">
      &nbsp;
    </td>
    <td class="bwsinglebottom">
      &nbsp;
    </td>
    <td class="bwsinglebottom">
      &nbsp;
    </td>
    <td class="bwpadl0 bwnowrap bwpadr0 bwvertalignb bwalignl bwsinglebottom">
      29-35
    </td>
  </tr>
  <tr>
    <td class="bwpadl0  bwvertalignt bwalignl bwsinglebottom">
      <i>Escherichia coli </i>ATCC 25922
    </td>
    <td class="bwsinglebottom">
      &nbsp;
    </td>
    <td class="bwsinglebottom">
      &nbsp;
    </td>
    <td class="bwsinglebottom">
      &nbsp;
    </td>
    <td class="bwpadl0 bwnowrap bwpadr0 bwvertalignb bwalignl bwsinglebottom">
      0.008/8-0.06/8
    </td>
    <td class="bwsinglebottom">
      &nbsp;
    </td>
    <td class="bwsinglebottom">
      &nbsp;
    </td>
    <td class="bwsinglebottom">
      &nbsp;
    </td>
    <td class="bwpadl0 bwnowrap bwpadr0 bwvertalignb bwalignl bwsinglebottom">
      31-37
    </td>
  </tr>
  <tr>
    <td class="bwpadl0  bwvertalignt bwalignl bwsinglebottom">
      <i>Escherichia coli </i>ATCC 35218
    </td>
    <td class="bwsinglebottom">
      &nbsp;
    </td>
    <td class="bwsinglebottom">
      &nbsp;
    </td>
    <td class="bwsinglebottom">
      &nbsp;
    </td>
    <td class="bwpadl0 bwnowrap bwpadr0 bwvertalignb bwalignl bwsinglebottom">
      0.008/8-0.06/8
    </td>
    <td class="bwsinglebottom">
      &nbsp;
    </td>
    <td class="bwsinglebottom">
      &nbsp;
    </td>
    <td class="bwsinglebottom">
      &nbsp;
    </td>
    <td class="bwpadl0 bwnowrap bwpadr0 bwvertalignb bwalignl bwsinglebottom">
      –
    </td>
  </tr>
  <tr>
    <td class="bwpadl0  bwvertalignt bwalignl bwsinglebottom">
      <i>Klebsiella pneumoniae </i>ATCC 700603
    </td>
    <td class="bwsinglebottom">
      &nbsp;
    </td>
    <td class="bwsinglebottom">
      &nbsp;
    </td>
    <td class="bwsinglebottom">
      &nbsp;
    </td>
    <td class="bwpadl0 bwnowrap bwpadr0 bwvertalignb bwalignl bwsinglebottom">
      0.015/8-0.06/8
    </td>
    <td class="bwsinglebottom">
      &nbsp;
    </td>
    <td class="bwsinglebottom">
      &nbsp;
    </td>
    <td class="bwsinglebottom">
      &nbsp;
    </td>
    <td class="bwpadl0 bwnowrap bwpadr0 bwvertalignb bwalignl bwsinglebottom">
      29-35
    </td>
  </tr>
  <tr>
    <td class="bwpadl0  bwvertalignt bwalignl bwsinglebottom">
      <i>Staphylococcus aureus </i>ATCC 25923
    </td>
    <td class="bwsinglebottom">
      &nbsp;
    </td>
    <td class="bwsinglebottom">
      &nbsp;
    </td>
    <td class="bwsinglebottom">
      &nbsp;
    </td>
    <td class="bwpadl0 bwnowrap bwpadr0 bwvertalignb bwalignl bwsinglebottom">
      –
    </td>
    <td class="bwsinglebottom">
      &nbsp;
    </td>
    <td class="bwsinglebottom">
      &nbsp;
    </td>
    <td class="bwsinglebottom">
      &nbsp;
    </td>
    <td class="bwpadl0 bwnowrap bwpadr0 bwvertalignb bwalignl bwsinglebottom">
      32-38
    </td>
  </tr>
  <tr>
    <td class="bwpadl0  bwvertalignt bwalignl bwsinglebottom">
      <i>Staphylococcus aureus </i>ATCC 29213
    </td>
    <td class="bwsinglebottom">
      &nbsp;
    </td>
    <td class="bwsinglebottom">
      &nbsp;
    </td>
    <td class="bwsinglebottom">
      &nbsp;
    </td>
    <td class="bwpadl0 bwnowrap bwpadr0 bwvertalignb bwalignl bwsinglebottom">
      0.03/8-0.12/8
    </td>
    <td class="bwsinglebottom">
      &nbsp;
    </td>
    <td class="bwsinglebottom">
      &nbsp;
    </td>
    <td class="bwsinglebottom">
      &nbsp;
    </td>
    <td class="bwpadl0 bwnowrap bwpadr0 bwvertalignb bwalignl bwsinglebottom">
      –
    </td>
  </tr>
</tbody></table>
<table cellspacing="0" class="bwtablemarginb">
  <tbody><tr>
    <td class="bwpadl0  bwvertalignt bwalignl">
      ATCC = American Type Culture Collection
    </td>
  </tr>
  <tr>
    <td class="bwpadl0  bwvertalignt bwalignl">
      *KPC-producing K. pneumoniae included for the QC of vaborbactam 
      activity
    </td>
  </tr>
  <tr>
    <td>
      &nbsp;
    </td>
  </tr>
</tbody></table>
<p>
  <b>IMPORTANT SAFETY INFORMATION</b>
</p>
<p>
  <b>Contraindications</b>
</p>
<p>
  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.
</p>
<p>
  <b>Warnings and Precautions</b>
</p>
<ul>
  <li class="bwlistitemmargb">
    Hypersensitivity reactions were reported in patients treated with 
    VABOMERE in the clinical trials. Serious and occasionally fatal 
    hypersensitivity (anaphylactic) reactions and serious skin reactions 
    have been reported in patients receiving therapy with beta-lactam 
    antibacterial drugs. There have been reports of individuals with a 
    history of penicillin hypersensitivity who have experienced severe 
    hypersensitivity reactions when treated with another beta-lactam 
    antibacterial drug. If an allergic reaction to VABOMERE occurs, 
    discontinue the drug immediately.
  </li>
  <li class="bwlistitemmargb">
    Seizures and other adverse Central Nervous System (CNS) experiences 
    have been reported during treatment with meropenem, which is a 
    component of VABOMERE. Close adherence to the recommended dosage 
    regimens is urged, especially in patients with known factors that 
    predispose to convulsive activity.
  </li>
  <li class="bwlistitemmargb">
    Clostridium 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. 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 ne45ed to be discontinued.
  </li>
  <li class="bwlistitemmargb">
    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 a 
    reduction in valproic acid concentrations. The valproic acid 
    concentrations may drop below the therapeutic range as a result of 
    this interaction, therefore increasing the risk of breakthrough 
    seizures. If administration of VABOMERE is necessary, consider 
    supplemental anticonvulsant therapy.
  </li>
  <li class="bwlistitemmargb">
    In patients with renal impairment, thrombocytopenia has been observed 
    in patients treated with meropenem, but no clinical bleeding has been 
    reported.
  </li>
  <li class="bwlistitemmargb">
    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.
  </li>
  <li class="bwlistitemmargb">
    Prescribing VABOMERE in the absence of a proven or strongly suspected 
    bacterial infection is unlikely to provide benefit to the patient and 
    increases the risk of drug-resistant bacteria.
  </li>
  <li class="bwlistitemmargb">
    As with other antibacterial drugs, prolonged use of VABOMERE may 
    result in overgrowth of nonsusceptible organisms.
  </li>
</ul>
<p>
  <b>Adverse Reactions</b>
</p>
<p>
  The most frequently reported adverse reactions occurring in ?3% of 
  patients treated with VABOMERE were headache, phlebitis/infusion site 
  reactions, and diarrhea.
</p>
<p>
  Please see <a href="http://cts.businesswire.com/ct/CT?id=smartlink&amp;url=http%3A%2F%2Fwww.vabomere.com&amp;esheet=51675962&amp;newsitemid=20170830005417&amp;lan=en-US&amp;anchor=www.vabomere.com&amp;index=1&amp;md5=f97dc88fb9a87600b8791af5341f98a0" rel="nofollow">www.vabomere.com</a> 
  for the full prescribing information.
</p>
<p>
  <b>About The Infectious Disease Business</b>
</p>
<p>
  The Medicines Company Infectious Disease Business (MDCO IDC) is 
  committed to bringing life-saving antimicrobial products to patients 
  with the most serious drug-resistant infections – infections caused by 
  “super bugs” which are no longer treatable with available antibiotics. 
  MDCO IDC encompasses basic research and drug discovery focused on 
  bacterial mechanisms of drug resistance; drug development focused on the 
  most threatening bacterial diseases; and a distribution and commercial 
  infrastructure that serves the leading hospitals and healthcare 
  facilities in the United States. MDCO IDC also has a leading pipeline of 
  novel agents directed towards existing and emerging multidrug-resistant 
  bacteria.
</p>
<p>
  In addition to the development and approval of VABOMERE, MDCO IDC has, 
  since 2014, successfully developed and launched two antibiotics against 
  serious infections: ORBACTIV<sup>® </sup>(oritavancin) for the treatment 
  of acute bacterial skin and skin-structure infections in adults, caused 
  by designated pathogens, including methicillin-resistant Staphylococcus 
  aureus, and a new formulation of MINOCIN<sup>®</sup> (minocycline) for 
  Injection, which is among the few FDA-approved agents for the treatment 
  of infections due to <i>Acinetobacter spp., </i>a pathogen classified by 
  the CDC to be a serious antimicrobial resistance threat. For more 
  information on these products, including their respective important 
  safety information and package inserts, please see <a href="http://cts.businesswire.com/ct/CT?id=smartlink&amp;url=http%3A%2F%2Fwww.orbactiv.com%2F&amp;esheet=51675962&amp;newsitemid=20170830005417&amp;lan=en-US&amp;anchor=www.orbactiv.com&amp;index=2&amp;md5=783f12d390567faf70488217f3a9e79e" rel="nofollow">www.orbactiv.com</a> 
  and <a href="http://cts.businesswire.com/ct/CT?id=smartlink&amp;url=http%3A%2F%2Fwww.minociniv.com%2F&amp;esheet=51675962&amp;newsitemid=20170830005417&amp;lan=en-US&amp;anchor=www.minociniv.com&amp;index=3&amp;md5=1bcf7e6b03399951b9bca0293f90600e" rel="nofollow">www.minociniv.com</a>.
</p>
<p>
  <b>About BARDA</b>
</p>
<p>
  In February 2014, The Medicines Company Infectious Disease Business was 
  awarded a cost-sharing contract by the Biomedical Advanced Research and 
  Development Authority (BARDA), a division of the Office of the Assistant 
  Secretary for Preparedness and Response within the U.S. Department of 
  Health and Human Services (HHS), of which $55.8 million in federal funds 
  have been obligated to date to support the development of VABOMERE.
</p>
<p>
  In September 2016, The Medicines Company entered into a new strategic 
  partnership with BARDA that will provide the Company with the potential 
  for up to $132 million to support the development of new antibiotics to 
  fight drug-resistant, gram-negative infections (HHSO100201600026C). The 
  partnership was established under HHS’s Other Transactional Authority 
  (OTA), and is a distinctive, flexible, portfolio-based approach to 
  funding drug development. The Medicines Company was awarded $32 million 
  in initial funding, and up to an additional $100 million (pending the 
  availability of funding) over approximately five years, if all options 
  to extend the partnership are exercised by BARDA and The Medicines 
  Company. The initial $32 million award supports further development of 
  VABOMERE as well as advancement of the Company’s early stage pipeline. 
  Funding provided under any subsequent options exercised by BARDA and The 
  Medicines Company, will also support the advancement of antibiotics in 
  MDCO IDC’s portfolio of new antibiotic drug candidates targeting drug 
  resistant bacteria.
</p>
<p>
  <b>About The Medicines Company</b>
</p>
<p>
  The Medicines Company is a biopharmaceutical company driven by an 
  overriding purpose – to save lives, alleviate suffering and contribute 
  to the economics of healthcare. The Company’s mission is to create 
  transformational solutions to address the most pressing healthcare needs 
  facing patients, physicians and providers in serious infectious disease 
  care and cardiovascular care. The Company is headquartered in 
  Parsippany, New Jersey, with global innovation centers in California and 
  Switzerland.
</p>
<p>
  <b>Forward-Looking Statements</b>
</p>
<p>
  Statements contained in this press release that are not purely 
  historical may be deemed to be forward-looking statements for purposes 
  of the safe harbor provisions under The Private Securities Litigation 
  Reform Act of 1995. Without limiting the foregoing, the words 
  "believes," "anticipates," "expects," “potential,” and similar 
  expressions are intended to identify forward-looking statements. These 
  forward-looking statements involve known and unknown risks and 
  uncertainties that may cause the Company's actual results, levels of 
  activity, performance or achievements to be materially different from 
  those expressed or implied by these forward-looking statements. 
  Important factors that may cause or contribute to such differences 
  include the timing and success of a commercial launch of VABOMERE in the 
  United States; the Company’s broader commercial strategy and competition 
  for VABOMERE; whether additional clinical trials for VABOMERE will 
  advance on a timely basis, or at all, or succeed in achieving their 
  specified endpoints; whether physicians, patients and other key decision 
  makers will accept clinical trial results; whether physicians will 
  prescribe and patients will use VABOMERE, once available; whether the 
  Company will make additional regulatory submissions for VABOMERE on a 
  timely basis, or at all; whether the Company’s regulatory submissions 
  will receive approvals from regulatory agencies on a timely basis, or at 
  all; and such other factors as are set forth in the risk factors 
  detailed from time to time in the Company's periodic reports and 
  registration statements filed with the Securities and Exchange 
  Commission, including, without limitation, the risk factors detailed in 
  the Company's Quarterly Report on Form 10-Q filed with the Securities 
  and Exchange Commission on August 9, 2017, which are incorporated herein 
  by reference. The Company specifically disclaims any obligation to 
  update these forward-looking statements.
</p>


Contacts

The Medicines Company
Media
Meg Langan, 973-290-6319
Vice President
margaret.langan@themedco.com
or
Investors
Krishna Gorti, M.D., 973-290-612
Vice President, Investor Relations
Krishna.Gorti@themedco.com

Contact Us

The Medicines Company
8 Sylvan Way
Parsippany, NJ 07054 USA
Tel 973 290 6000
Toll-free 800 388 1183
Global Medical Information

Human Resources
Verification of employment
Tel 973 290 6361
Fax 862 207 6361

Investors Relations

Krishna Gorti, MD
Tel 973 290 6122
krishna.gorti@themedco.com

Media Inquiries

Michael Blash
Tel 973 290 6100
michael.blash@themedco.com