Vabomere

1 INDICATIONS AND USAGE VABOMERE (meropenem and vaborbactam) is a combination of meropenem, a penem antibacterial, and vaborbactam, a beta-lactamase inhibitor, indicated for the treatment of patients 18 years and older with complicated urinary tract infections (cUTI) including pyelonephritis caused by designated susceptible bacteria. 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. 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.

Administer VABOMERE 4 grams (meropenem 2 grams and vaborbactam 2 grams) every 8 hours by intravenous infusion over 3 hours for up to 14 days, in patients 18 years of age and older with an estimated glomerular filtration rate (eGFR) ≥50 mL/min/1.73m 2 . Dosage adjustment is recommended in patients with renal impairment who have an eGFR less than 50 mL/min/ 1.73m 2 . eGFR As calculated using the Modification of Diet in Renal Disease (MDRD) formula; (mL/min/ 1.73m 2 ) Recommended Dosage Regimen for VABOMERE (meropenem and vaborbactam) All doses of VABOMERE are administered intravenously over 3 hours; , Doses adjusted for renal impairment should be administered after a hemodialysis session; , The total duration of treatment is for up to 14 days. Dosing Interval 30 to 49 VABOMERE 2 grams (meropenem 1 gram and vaborbactam 1 gram) Every 8 hours 15 to 29 VABOMERE 2 grams (meropenem 1 gram and vaborbactam 1 gram) Every 12 hours Less than 15 VABOMERE 1 gram (meropenem 0.5 grams and vaborbactam 0.5 grams) Every 12 hours See Full Prescribing Information for instructions for constituting supplied dry powder and subsequent required dilution. See Full Prescribing Information for drug compatibilities.

2.1Recommended 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/1.73m 2 . The duration of treatment is for up to 14 days.

2.2Dosage Adjustments in Patients with Renal Impairment

Dosage adjustment is recommended in patients with renal impairment who have an eGFR less than 50 mL/min/1.73m 2 . The recommended dosage of VABOMERE in patients with varying degrees of renal function is presented in Table 1. 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 eGFR As calculated using the Modification of Diet in Renal Disease (MDRD) formula as follows: eGFR (mL/min/1.73m 2 ) = 175 × (serum creatinine) -1.154 × (age) -0.203 × (0.742 if female) × (1.212 if African American) (mL/min/ 1.73m 2 ) Recommended Dosage Regimen for VABOMERE (meropenem and vaborbactam) All doses of VABOMERE are administered intravenously over 3 hours. , Doses adjusted for renal impairment should be administered after a hemodialysis session. , The total duration of treatment is for up to 14 days.

Dosing Interval 30 to 49 VABOMERE 2 grams (meropenem 1 gram and vaborbactam 1 gram) Every 8 hours 15 to 29 VABOMERE 2 grams (meropenem 1 gram and vaborbactam 1 gram) Every 12 hours Less than 15 VABOMERE 1 gram (meropenem 0.5 grams and vaborbactam 0.5 grams) Every 12 hours

2.3Preparation and Administration of

VABOMERE for Intravenous Infusion Preparation VABOMERE is supplied as a dry powder in a single-dose vial that must be constituted and further diluted prior to intravenous infusion as outlined below. VABOMERE does not contain preservatives. Aseptic technique must be used for constitution and dilution. 1.

To prepare the required dose for intravenous infusion, constitute the appropriate number of vials, as determined from Table 2 below. Withdraw 20 mL of 0.9% Sodium Chloride Injection, USP, from an infusion bag and constitute each vial of VABOMERE. 2. Mix gently to dissolve. The constituted VABOMERE solution will have an approximate meropenem concentration of 0.05 gram/mL and an approximate vaborbactam concentration of 0.05 gram/mL. The final volume is approximately 21.3 mL. The constituted solution is not for direct injection. 3.

The constituted solution must be diluted further, immediately, in a 0.9% Sodium Chloride Injection, USP infusion bag before intravenous infusion. The intravenous infusion of the diluted solution must be completed within 4 hours if stored at room temperature or 22 hours if stored refrigerated at 2°C to 8°C (36°F to 46°F). 4. To dilute the constituted solution, withdraw the full or partial constituted vial contents from each vial and add it back into the infusion bag in accordance with Table 2 below.

Table 2: Preparation of VABOMERE Doses VABOMERE Dose (meropenem and vaborbactam) Number of Vials to Constitute for Further Dilution Volume to Withdraw from Each Constituted Vial for Further Dilution Volume of Infusion Bag Final Infusion Concentration of VABOMERE 4 grams (2 grams-2 grams) 2 vials Entire contents (approximately 21 mL) 250 mL 16 mg/mL 500 mL 8 mg/mL 1,000 mL 4 mg/mL 2 grams (1 gram-1 gram) 1 vial Entire contents (approximately 21 mL) 125 mL 16 mg/mL 250 mL 8 mg/mL 500 mL 4 mg/mL 1 gram (0.5 gram-0.5 gram) 1 vial 10.5 mL (discard unused portion) 70 mL 14.3 mg/mL 125 mL 8 mg/mL 250 mL 4 mg/mL 5. Visually inspect the diluted VABOMERE solution for particulate matter and discoloration prior to administration (the color of the VABOMERE infusion solution for administration ranges from colorless to light yellow). Discard unused portion after use.

2.4Drug Compatibility

VABOMERE solution for administration by 3-hour infusion is only compatible with 0.9% Sodium Chloride Injection, USP. Compatibility of VABOMERE solution for administration with other drugs has not been established.

Hypersensitivity reactions were reported with the use of VABOMERE. Serious and occasionally fatal hypersensitivity (anaphylactic) reactions have been reported in patients receiving beta-lactam antibacterial drugs. Discontinue infusion if signs of acute hypersensitivity occur. Seizures and other adverse Central Nervous System experiences have been reported during treatment with meropenem, a component of VABOMERE. Rhabdomyolysis: If signs or symptoms of rhabdomyolysis are observed, discontinue VABOMERE and initiate appropriate therapy. Clostridioides difficile -associated diarrhea has been reported with nearly all systemic antibacterial agents, including VABOMERE. Evaluate patients if diarrhea occurs. Co-administration of meropenem with valproic acid or divalproex sodium reduces the serum concentration of valproic acid potentially increasing the risk of breakthrough seizures. ( 5.5 , 7.1 )

5.1Hypersensitivity Reactions 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. These reactions are more likely to occur in individuals with a history of sensitivity to multiple allergens. 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.

Before initiating therapy with VABOMERE, it is important to inquire about previous hypersensitivity reactions to penicillins, cephalosporins, other beta-lactam antibacterial drugs, and other allergens. If an allergic reaction to VABOMERE occurs, discontinue the drug immediately.

5.2Seizure Potential Seizures and

other adverse Central Nervous System (CNS) experiences have been reported during treatment with meropenem, which is a component of VABOMERE. These experiences have occurred most commonly in patients with CNS disorders (e.g., brain lesions or history of seizures) or with bacterial meningitis and/or compromised renal function . Close adherence to the recommended dosage regimens is urged, especially in patients with known factors that predispose to convulsive activity. Continue anti-convulsant therapy in patients with known seizure disorders. If focal tremors, myoclonus, or seizures occur, evaluate neurologically, place on anti-convulsant therapy if not already instituted, and reexamine the dosage of VABOMERE to determine whether it should be decreased or discontinued.

5.3Rhabdomyolysis Rhabdomyolysis

has been reported with the use of meropenem, a component of VABOMERE . If signs or symptoms of rhabdomyolysis such as muscle pain, tenderness or weakness, dark urine, or elevated creatine phosphokinase are observed, discontinue VABOMERE and initiate appropriate therapy.

5.4Clostridioides

difficile -associated Diarrhea Clostridioides 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. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile . C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin-producing isolates of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibacterial drug use.

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 need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibacterial drug treatment of C. difficile , and surgical evaluation should be instituted as clinically indicated.

5.5Risk of Breakthrough Seizures Due to Drug

Interaction with Valproic Acid 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.

Increasing the dose of valproic acid or divalproex sodium may not be sufficient to overcome this interaction. Consider administration of antibacterial drugs other than carbapenems to treat infections in patients whose seizures are well controlled on valproic acid or divalproex sodium. If administration of VABOMERE is necessary, consider supplemental anticonvulsant therapy .

5.6Thrombocytopenia In

patients with renal impairment, thrombocytopenia has been observed in patients treated with meropenem, but no clinical bleeding has been reported .

5.7Potential for Neuromotor Impairment 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. Until it is reasonably well established that VABOMERE is well tolerated, advise patients not to operate machinery or motorized vehicles .

5.8Development of Drug-Resistant Bacteria 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 .

5.9Overgrowth of Non-susceptible Organisms As with

other antibacterial drugs, prolonged use of VABOMERE may result in overgrowth of non-susceptible organisms. Repeated evaluation of the patient is essential. If superinfection does occur during therapy, appropriate measures should be taken.

4 CONTRAINDICATIONS 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 . Known hypersensitivity to the components of VABOMERE (meropenem and vaborbactam) or anaphylactic reactions to beta-lactams.

8.1Pregnancy Risk Summary Fetal

malformations were observed in vaborbactam-treated rabbits, therefore advise pregnant women of the potential risks to the fetus. There are insufficient human data to establish whether there is a drug-associated risk of major birth defects or miscarriages with VABOMERE, meropenem, or vaborbactam in pregnant women. Malformations (supernumerary lung lobes, interventricular septal defect) were observed in offspring from pregnant rabbits administered intravenous vaborbactam during the period of organogenesis at doses approximately equivalent to or above the maximum recommended human dose (MRHD) based on plasma AUC comparison.

The clinical relevance of the malformations is uncertain. No similar malformations or fetal toxicity were observed in offspring from pregnant rats administered intravenous vaborbactam during organogenesis or from late pregnancy and through lactation at a dose equivalent to approximately 1.6 times the MRHD based on body surface area comparison . No fetal toxicity or malformations were observed in pregnant rats and cynomolgus monkeys administered intravenous meropenem during organogenesis at doses up to 1.6 and 1.2 times the MRHD based on body surface area comparison, respectively. In rats administered intravenous meropenem in late pregnancy and during the lactation period, there were no adverse effects on offspring at doses equivalent to approximately 1.6 times the MRHD based on body surface area comparison . The background risk of major birth defects and miscarriage for the indicated population is unknown.

In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. Data Animal Data Meropenem Reproductive studies have been performed with meropenem in rats at doses of up to 1000 mg/kg/day and in cynomolgus monkeys at doses of up to 360 mg/kg/day (on the basis of body surface area comparisons, approximately 1.6 times and 1.2 times higher, respectively, than the MRHD of 2 grams every 8 hours). These studies revealed no evidence of harm to the fetus due to meropenem, although there were slight changes in fetal body weight at doses of 250 mg/kg/day (equivalent to approximately 0.4 times the MRHD of 2 grams every 8 hours based on body surface area comparison) and above in rats.

In a published study 1 , meropenem administered to pregnant rats from Gestation Day 6 to Gestation Day 17, was associated with mild maternal weight loss at all doses, but did not produce malformations or fetal toxicity. The no-observed-adverse-effect-level (NOAEL) for fetal toxicity in this study was considered to be the high dose of 750 mg/kg/day (equivalent to approximately 1.2 times the MRHD based on body surface area comparison). In a peri-postnatal study in rats described in the published literature 1 , intravenous meropenem was administered to dams from Gestation Day 17 until Postpartum Day 21.

There were no adverse effects in the dams and no adverse effects in the first generation offspring (including developmental, behavioral, and functional assessments and reproductive parameters) except that female offspring exhibited lowered body weights which continued during gestation and nursing of the second generation offspring. Second generation offspring showed no meropenem-related effects. The NOAEL value was considered to be 1000 mg/kg/day (approximately 1.6 times the MRHD based on body surface area comparisons).

Vaborbactam In a rat embryo-fetal toxicology study, intravenous administration of vaborbactam during Gestation Days 6-17 showed no evidence of maternal or embryofetal toxicity at doses up to 1000 mg/kg, which is equivalent to approximately 1.6 times the MRHD based on body surface area comparisons. In the rabbit, intravenous administration of vaborbactam during Gestation Days 7–19 at doses up to 1000 mg/kg/day (approximately 5 times the MRHD based on AUC exposure comparison) was not associated with maternal toxicity or fetal weight loss. A low incidence of malformations occurred in the 300 mg/kg/day mid-dose group (two fetuses from different litters with interventricular septal defects, one fetus with a fused right lung lobe and one fetus with a supernumerary lung lobe), and in the 1000 mg/kg/day high-dose group (two fetuses from different litters with supernumerary lobes).

The NOAEL was considered to be 100 mg/kg/day which is equivalent to 0.3 times the MRHD based on plasma AUC exposure comparison and 6-times the MRHD based on maximum plasma concentration (C max ) comparison. The clinical relevance of the malformations is uncertain. Vaborbactam C max values may have influenced malformations in the rabbit study, and the recommended 3-hour infusion time for clinical administration of vaborbactam is associated with lower plasma C max values than the 30-minute infusions in rabbits.

In a peri-postnatal study in rats, vaborbactam administered intravenously to pregnant dams from Gestation Day 6 to Lactation Day 20 caused no adverse effects on the dams, or in first and second generation offspring. The NOAEL was considered to be 1000 mg/kg/day (equivalent to approximately 1.6 times the MRHD based on body surface area comparison).

The following adverse reactions are discussed in greater detail in the Warnings and Precautions section: Hypersensitivity Reactions Seizure Potential Rhabdomyolysis Clostridioides difficile -associated Diarrhea Risk of Breakthrough Seizures Due to Drug Interaction with Valproic Acid Thrombocytopenia Potential for Neuromotor Impairment Development of Drug-Resistant Bacteria Overgrowth of Non-susceptible Organisms The most frequently reported adverse reactions occurring in ≥3% of patients treated with VABOMERE were headache, phlebitis/infusion site reactions, and diarrhea. To report SUSPECTED ADVERSE REACTIONS, contact Melinta Therapeutics at 1-844-633-6568 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

6.1Clinical 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. Table 3: Adverse Reactions Occurring in 1% or Greater of Patients Receiving VABOMERE in the Phase 3 Clinical Trial in cUTI Adverse Reactions VABOMERE (N=272) % Piperacillin/Tazobactam Piperacillin/tazobactam 4.5 grams (piperacillin 4 g/tazobactam 0.5 g) IV infused over 30 minutes every 8 hours. (N=273) % Headache 8.8

4.4Phlebitis/Infusion

site reactions Infusion site reactions include infusion/injection site phlebitis, infusion site thrombosis, and infusion site erythema. 4.4

0.7Diarrhea

3.3

4.4Hypersensitivity Hypersensitivity

includes hypersensitivity, drug hypersensitivity, anaphylactic reaction, rash urticaria, and bronchospasm. 1.8

1.8Nausea

1.8

1.5Alanine

aminotransferase increased 1.8

0.4Aspartate

aminotransferase increased 1.5

0.7Pyrexia

1.5

0.7Hypokalemia

1.1

1.5Adverse 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

6.2Postmarketing Experience The

following adverse reactions have been identified during post approval use of meropenem, a component of VABOMERE, or with VABOMERE. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Musculoskeletal Disorders : rhabdomyolysis Hepatobiliary Disorders : drug-induced liver injury (DILI), including hepatitis and liver failure