VABOMERE (Page 6 of 6)

13 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.

14 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.

15 REFERENCES

  1. Kawamura S, Russell AW, Freeman SJ, and Siddall, RA: Reproductive and Developmental Toxicity of Meropenem in Rats. Chemotherapy, 40:S238-250 (1992).
  2. 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.
  3. 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.
  4. 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.

16 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)].

17 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

packaging-carton
(click image for full-size original)

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

packaging-vial
(click image for full-size original)

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 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 Multilevel Packaging
1 NDC:65293-009-06 6 VIAL, SINGLE-DOSE in 1 CARTON contains a VIAL, SINGLE-DOSE (65293-009-01)
1 NDC:65293-009-01 2 g in 1 VIAL, SINGLE-DOSE This package is contained within the CARTON (65293-009-06)
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

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