Vabomere Injection

1.1 Complicated Urinary Tract Infections (cUTI), including Pyelonephritis

VABOMERE™ 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.

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 containing meropenem 1 gram (equivalent to 1.14 grams meropenem trihydrate) and vaborbactam 1 gram.

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)]
• Clostridium 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)]

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a 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 a Phase 3 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 4 g/tazobactam 0.5 g) every 8 hours. After a 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 8 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 Discontinuation

Treatment 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 2 (0.7%) patients who received VABOMERE and in 2 (0.7%) patients who received piperacillin/tazobactam.

Common Adverse Reactions

The most frequently reported adverse reactions (3% or greater) in patients receiving VABOMERE in the Phase 3 cUTI trial were headache, phlebitis/infusion site reactions, and diarrhea. Table 3 provides adverse reactions occurring in 1% or greater of patients receiving VABOMERE in the Phase 3 cUTI trial.

a Piperacillin/tazobactam 4.5 grams (piperacillin 4 g/tazobactam 0.5 g) IV infused over 30 minutes every 8 hours.

b Infusion site reactions include infusion/injection site phlebitis, infusion site thrombosis, and infusion site erythema.

c Hypersensitivity includes hypersensitivity, drug hypersensitivity, anaphylactic reaction, rash urticaria, and bronchospasm

Adverse Reactions Occurring in Less Than 1% of Patients Receiving VABOMERE in the Phase 3 cUTI trial:

Blood and lymphatic system disorders: leukopenia

General disorders and administration site conditions: chest discomfort

Infections and infestations: pharyngitis, vulvovaginal candidiasis, oral candidiasis

Investigations: creatinine phosphokinase increase

Metabolism and nutrition disorders: decreased appetite, hyperkalemia, hyperglycemia, hypoglycemia

Nervous system disorders: dizziness, tremor, paresthesia, lethargy

Psychiatric disorders: hallucination, insomnia

Renal and urinary disorders: azotemia, renal impairment

Vascular disorders: deep vein thrombosis, hypotension, vascular pain

Other Adverse Reactions Associated with Meropenem

Additionally, adverse reactions reported with meropenem alone that were not reported in VABOMERE-treated patients in the Phase 3 clinical trial are listed below:

Blood and lymphatic system disorders: thrombocytosis, neutropenia, eosinophilia, thrombocytopenia, agranulocytosis, hemolytic anemia

Gastrointestinal disorders: abdominal pain

Hepatobiliary disorders: jaundice

Nervous system disorders: convulsions

Investigations: 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 positive

Skin and subcutaneous tissue disorders: pruritus, toxic epidermal necrolysis, Stevens Johnson syndrome, Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) syndrome, erythema multiforme

Immune system disorders: angioedema

General disorders and administration site conditions: pain

VABOMERE (meropenem and vaborbactam) for injection is a combination product that contains meropenem, a synthetic penem antibacterial drug and vaborbactam, a cyclic boronic acid beta-lactamase inhibitor, for intravenous administration.

Meropenem, present as a trihydrate, is a white to light yellow crystalline powder, with a molecular weight of 437.52. The chemical name for meropenem trihydrate is (4 R,5 S,6 S)-3-[[(3 S,5 S)-5-(dimethylcarbamoyl)-3-pyrrolidinyl]thio]-6-[(1 R)-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 C 17H 25N 3O 5S·3H 2O and its chemical structure is:

Figure 1: Structure of Meropenem Trihydrate

Vaborbactam is a white to off-white powder, with a molecular weight of 297.14. The chemical name for vaborbactam is (3 R,6 S)-2-hydroxy-3-[[2-(2-thienyl)acetyl]amino]-1,2-oxaborinane-6-acetic acid. Its empirical formula is C 12H 16BNO 5S and its chemical structure is:

Figure 2: Structure of Vaborbactam

VABOMERE is supplied as a white to light yellow sterile powder for constitution that contains meropenem trihydrate, vaborbactam, and sodium carbonate. Each 50 mL glass 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. 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 a colorless to light yellow solution [see Dosage and Administration ( 2.3)].

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

MEROPENEM: On day 6 postpartum, a mother started meropenem 1 g IV every 8 hours for 7 days; her newborn was exclusively breastfed. From day 6 to day 9 postpartum, 5 samples of hindmilk were collected over 37 hours; over this period, the highest, lowest, and average meropenem levels in breast milk were 644, 246, and 480 mcg/L, respectively. Estimated average and maximum infant intake were 71 mcg/kg/day (0.13% of weight-adjusted maternal dose) and 97 mcg/kg/day (0.18% of weight-adjusted maternal dose), respectively. When asked later, the mother stated her infant had no oral thrush, watery diarrhea, or diaper dermatitis requiring antifungal therapy during the month after her meropenem therapy. An infant was breastfed (extent not provided) until the 4th month postpartum. At 2 months of age, his mother was given tobramycin and meropenem (dose not provided) for 2 weeks for a cystic fibrosis exacerbation. The infant's stool pattern did not change during maternal therapy and he had normal renal function at 6 months of age.

Benefit should outweigh risk. Excreted into human milk: Yes (meropenem); Unknown (vaborbactam) Excreted into animal milk: Data not available (vaborbactam) Comments: -Developmental and health benefits of breastfeeding should be considered as well as the mother's clinical need for this drug. -The effects in the nursing infant are unknown; potential side effects in the breastfed child due to this drug or the mother's underlying condition should be considered. -While no data are available on the use of meropenem during breastfeeding, beta-lactams are generally not expected to cause harmful effects in nursing infants. -Disruption of infant's gastrointestinal flora (resulting in diarrhea or thrush) reported occasionally with beta-lactams; such effects have not been adequately evaluated.