EMBLAVEO

1 INDICATIONS AND USAGE EMBLAVEO is a combination of aztreonam, a monobactam antibacterial, and avibactam, a beta-lactamase inhibitor, that when used in combination with metronidazole, is indicated in patients 18 years and older who have limited or no alternative options for the treatment of complicated intra-abdominal infections (cIAI) including those caused by the following susceptible gram-negative microorganisms: Escherichia coli, Klebsiella pneumoniae, Klebsiella oxytoca, Enterobacter cloacae complex, Citrobacter freundii complex, and Serratia marcescens . Approval of this indication is based on limited clinical safety and efficacy data for EMBLAVEO. ( 1.1 ) Usage to Reduce Development of Drug-Resistant Bacteria To reduce the development of drug-resistant bacteria and maintain the effectiveness of EMBLAVEO and other antibacterial drugs, EMBLAVEO should be used only to treat infections that are proven or strongly suspected to be caused by bacteria. ( 1.2 ) 1.1 Complicated Intra-abdominal Infections EMBLAVEO, in combination with metronidazole, is indicated in patients 18 years and older who have limited or no alternative options for the treatment of complicated intra-abdominal infections (cIAI) including those caused by the following susceptible gram-negative microorganisms: Escherichia coli , Klebsiella pneumoniae , Klebsiella oxytoca , Enterobacter cloacae complex , Citrobacter freundii complex , and Serratia marcescens. Approval of this indication is based on limited clinical safety and efficacy data for EMBLAVEO [ see Clinical Studies ( 14.1 )] . 1.2 Usage to Reduce Development of Drug-Resistant Bacteria To reduce the development of drug-resistant bacteria and maintain the effectiveness of EMBLAVEO and other antibacterial drugs, EMBLAVEO should be used only to treat 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.

2 DOSAGE AND ADMINISTRATION Recommended Dosage in Adults based on Estimated Creatinine Clearance (C Lcr ) ( 2.1 , 2.2 ) Estimated C Lcr (mL/min) a Dose b Infusion Time Dosing Interval c Loading Maintenance Greater than 50 mL/min EMBLAVEO 2.67 g (aztreonam 2 grams and avibactam 0.67 grams) EMBLAVEO 2 g (aztreonam 1.5 grams and avibactam 0.5 grams) 3 hours Every 6 hours Greater than 30 to less than or equal to 50 mL/min EMBLAVEO 2.67 g (aztreonam 2 grams and avibactam 0.67 grams) EMBLAVEO 1 g (aztreonam 0.75 grams and avibactam 0.25 grams) 3 hours Every 6 hours Greater than 15 to less than or equal to 30 mL/min EMBLAVEO 1.8 g (aztreonam 1.35 grams and avibactam 0.45 grams) EMBLAVEO 0.9 g (aztreonam 0.675 grams and avibactam 0.225 grams) 3 hours Every 8 hours Less than or equal to 15 mL/min, including on hemodialysis d EMBLAVEO 1.33 g (aztreonam 1 gram and avibactam 0.33 grams) EMBLAVEO 0.9 g (aztreonam 0.675 grams and avibactam 0.225 grams) 3 hours Every 12 hours a Calculated using the Cockcroft-Gault formula. b Aztreonam-avibactam is a combination product in a fixed 3:1 ratio. A single loading dose is followed by maintenance doses beginning at the next dosing interval. c Dosing interval is calculated from the start of one infusion to the start of the subsequent infusion. d Both aztreonam and avibactam are removed by hemodialysis; thus, administer EMBLAVEO after hemodialysis, on hemodialysis days. For treatment of cIAI, administer metronidazole concurrently. ( 2.1 , 2.2 ) Recommended duration of treatment for cIAI: 5 to 14 days. ( 2.1 , 2.2 ) 2.1 Recommended Dosage in Adults with Estimated Creatinine Clearance G reater than 50 mL/min Table 1 shows the recommended dosage to be administered by intravenous (IV) infusion over 3 hours in adults with estimated creatinine clearance (CLcr) greater than 50 mL/min. Table 1. Recommended dosage for adults with estimated CLcr greater than 50 mL/min a Type of Infection Recommended Doses for EMBLAVEO (aztreonam and avibactam) b Dosing Interval c Treatment duration Complicated intra-abdominal infections (cIAI) d Loading EMBLAVEO 2.67 g (aztreonam 2 grams and avibactam 0.67 grams) Every 6 hours 5 to 14 days Maintenance EMBLAVEO 2 g (aztreonam 1.5 grams and avibactam 0.5 grams) a Calculated using the Cockcroft-Gault formula. b Aztreonam-avibactam is a combination product in a fixed 3:1 ratio. A single loading dose is followed by maintenance doses beginning at the next dosing interval. c Dosing interval is calculated from the start of one infusion to the start of the subsequent infusion. d For treatment of cIAI, administer metronidazole concurrently. 2.2 Recommended Dosage in Adults with Estimated Creatinine Clearance L ess than or E qual to 50 mL/min Table 2 shows the recommended dosage to be administered by intravenous (IV) infusion over 3 hours in adults with estimated creatinine clearance (CLcr) less than or equal to 50 mL/min. In patients with renal impairment, close monitoring of estimated CLcr is advised. In some patients, the CLcr estimated from serum creatinine can change quickly, especially early in the course of treatment for the infection. For treatment of cIAI, administer metronidazole concurrently. Table 2. Recommended dosage for adults with estimated CLcr less than or equal to 50 mL/min Estimated CLcr (mL/min) a Recommended Dose for EMBLAVEO (aztreonam and avibactam) b,c Dosing Interval d Greater than 30 to less than or equal to 50 mL/min Loading EMBLAVEO 2.67 g (aztreonam 2 grams and avibactam 0.67 grams) Every 6 hours Maintenance EMBLAVEO 1 g (aztreonam 0.75 grams and avibactam 0.25 grams) Greater than 15 to less than or equal to 30 mL/min Loading EMBLAVEO 1.8 g (aztreonam 1.35 grams and avibactam 0.45 grams) Every 8 hours Maintenance EMBLAVEO 0.9 g (aztreonam 0.675 grams and avibactam 0.225 grams) Less than or equal to 15, including on hemodialysis e Loading EMBLAVEO 1.33 g (aztreonam 1 gram and avibactam 0.33 grams) Every 12 hours Maintenance EMBLAVEO 0.9 g (aztreonam 0.675 gram…

5 WARNINGS AND PRECAUTIONS Hypersensitivity Reactions : Hypersensitivity reactions were noted in patients treated with EMBLAVEO including rash, flushing, and bronchospasm. In case of hypersensitivity reactions, immediately discontinue EMBLAVEO and initiate appropriate medications and/or supportive care. ( 5.1 ) Serious Skin Disorders: Cases of toxic epidermal necrolysis have been reported in association with aztreonam (a component of EMBLAVEO) in patients undergoing bone marrow transplant with multiple risk factors. Discontinue EMBLAVEO if serious skin reaction occurs. ( 5.2 ) Hepatic Adverse Reactions: Elevations in hepatic transaminases have been observed during treatment with EMBLAVEO. If transaminase elevations are noted, consider discontinuation of EMBLAVEO, if clinically indicated, and monitor the patient for resolution of any pertinent clinical and laboratory findings. ( 5.3 ) Clostridioides Difficile -Associated Diarrhea (CDAD): CDAD has been reported with nearly all systemic antibacterial agents, including EMBLAVEO. Evaluate if diarrhea occurs. ( 5.4 ) 5. 1 Hypersensitivity Reactions Hypersensitivity reactions were noted in patients treated with EMBLAVEO, including rash, flushing, and bronchospasm [see Adverse Reactions ( 6.1 )]. Prior to treatment, it should be established if the patient has a history of hypersensitivity reactions to components of EMBLAVEO (aztreonam and avibactam). In case of hypersensitivity reactions, immediately discontinue EMBLAVEO and initiate appropriate medications and/or supportive care. 5. 2 Serious Skin Disorders Cases of toxic epidermal necrolysis have been reported in association with aztreonam (a component of EMBLAVEO) in patients undergoing bone marrow transplant with multiple risk factors including sepsis, radiation therapy, and other concomitantly administered drugs associated with toxic epidermal necrolysis. Discontinue EMBLAVEO if a serious skin reaction occurs. 5. 3 Hepatic Adverse Reactions Elevations in hepatic transaminases have been observed during treatment with EMBLAVEO [see Adverse Reactions ( 6.1 )]. Monitoring of liver-related laboratory tests is recommended while on treatment, particularly in patients with baseline liver comorbidities or on concomitant hepatotoxic medications. If transaminase elevations are noted, consider discontinuing EMBLAVEO, if clinically indicated, and monitor the patient for resolution of any pertinent clinical and laboratory findings. 5. 4 Clostridioides Difficile -Associated Diarrhea Clostridioides difficile - associated diarrhea (CDAD) has been reported for nearly all systemic antibacterial drugs, including EMBLAVEO, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial drugs alters the normal flora of the colon and may permit overgrowth of C. difficile . C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin producing strains 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 use. Careful medical history is necessary because CDAD has been reported to occur more than 2 months after the administration of antibacterial drugs. If CDAD is suspected or confirmed, antibacterial drugs not directed against C. difficile may need to be discontinued. Manage fluid and electrolyte levels as appropriate, supplement protein intake, monitor antibacterial treatment of C. difficile , and institute surgical evaluation as clinically indicated. 5.5 Development of Drug-Resistant Bacteria Prescribing EMBLAVEO in the absence of a proven or strongly suspected bacterial infection is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria [see Indications and Usage ( 1.2 )].

4 CONTRAINDICATIONS EMBLAVEO is contraindicated in patients with known hypersensitivity to the components of EMBLAVEO (aztreonam and avibactam) [see Warnings and Precautions ( 5.1 )] . Known hypersensitivity to the components of EMBLAVEO (aztreonam and avibactam). ( 4 )

7 DRUG INTERACTIONS 7.1 OAT 1 and 3 Transport Inhibitors Concomitant use of organic anion transporter (OAT) 1 and OAT 3 transporter inhibitors (e.g., probenecid) with EMBLAVEO is not recommended. There is insufficient information to characterize the effect of concomitant use of OAT 1/3 transport inhibitors with EMBLAVEO [see Clinical Pharmacology ( 12.3 )].

8.1 Pregnancy Risk Summary There are no data on the effects of EMBLAVEO use in pregnant women to evaluate for a drug-associated risk of major birth defects, miscarriage or other adverse maternal or fetal outcomes. Available data from case reports over several decades with aztreonam and over approximately a decade with avibactam have not identified a drug-associated risk of major birth defects, miscarriage or other maternal or fetal outcomes. Aztreonam Developmental toxicity studies in pregnant rats and rabbits with daily doses of aztreonam revealed no evidence of embryotoxicity, fetotoxicity, or fetal malformations at doses 2.7- and 3.6-fold greater, respectively, than the maximum recommended human dose (MRHD) for adults of 6.5 g per day. In a peri/postnatal development (PPND) study in rats, no aztreonam-induced changes in any maternal, fetal, or neonatal parameters were observed at a dose 2.7-fold greater than the MRHD. Avibactam Avibactam administered to pregnant rats was not associated with fetal malformations at doses 6 times the MRHD of 2.17 g per day. In pregnant rabbits, avibactam administered in doses greater than or equal to 5 times the MRHD was associated with increased post-implantation loss, lower mean fetal weights, delayed ossification of several bones and other anomalies. In a rat PPND study, there were no effects on pup growth and viability at doses up to 8 times the avibactam MRHD. A dose-related increase in the incidence of renal pelvic and ureter dilatation was observed in female weaning pups with renal pelvic dilatation persisting into adulthood (see Data). The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss or other adverse outcomes. In the US general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Data Animal Data Aztreonam Developmental toxicity studies in pregnant rats and rabbits with daily doses of aztreonam up to 1800 and 1200 mg/kg, respectively, revealed no evidence of embryotoxicity or fetotoxicity or fetal malformations. These doses, based on body surface area, are 2.7- and 3.6-fold greater than the MRHD for adults of 6.5 g per day. A peri/postnatal study in rats revealed no drug-induced changes in any maternal, fetal, or neonatal parameters. The highest dose used in this study, 1800 mg/kg/day, is 2.7 times the MRHD based on body surface area comparison. Avibactam Avibactam did not produce fetal malformations in pregnant rats or rabbits. In the rat, intravenous studies with 0, 250, 500 and 1000 mg/kg/day of avibactam during gestation days 6-17 showed no embryo-fetal toxicity at doses up to 1000 mg/kg/day, approximately 6 times the MRHD (2.17 g/day) based on exposure (AUC). Pregnant rabbits administered intravenous avibactam on gestation days 6-19 at 0, 100, 300 and 1000 mg/kg/day showed no effects on embryo-fetal development at a dose of 100 mg/kg, twice the MRHD based on AUC comparison. At doses greater than or equal to 300 mg/kg/day (5 times the MRHD based on AUC comparison), increased post-implantation loss, lower mean fetal weights, delayed ossification of several bones and other anomalies were observed. In a rat pre-and post-natal study at up to 825 mg/kg/day intravenously (8 times the MRHD based on AUC), there were no effects on pup growth and viability. A dose-related increase in the incidence of renal pelvic and ureter dilatation was observed in female weaning pups that was not associated with pathological changes to renal parenchyma or renal function, with renal pelvic dilatation persisting after female weaning pups became adults.

6 ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in the Warnings and Precautions section: Hypersensitivity Reactions [see Warnings and Precautions ( 5.1 )] Serious Skin Disorders [see Warnings and Precautions ( 5.2 )] Hepatic Adverse Reactions [see Warnings and Precautions ( 5.3 )] Clostridioides Difficile -Associated Diarrhea [see Warnings and Precautions ( 5.4 )] The most common adverse reactions occurring at an incidence of greater than 5% were hepatic adverse reactions, anemia, diarrhea, hypokalemia, and pyrexia. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact AbbVie Inc. at 1-800-633-9110 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 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. Clinical Trials Experience in Adult Patients Three clinical trials, Trial 1, Trial 2, and Trial 3, underly the EMBLAVEO clinical development program. Trial 1 was a randomized, comparative trial conducted in patients with cIAI and hospital-acquired bacterial pneumonia/ventilator-associated bacterial pneumonia (HABP/VABP) (not an approved indication for EMBLAVEO), while Trials 2 and 3 were smaller, noncomparative trials conducted in patients with cIAI as well as other serious infections caused by gram negative pathogens expressing metallo-beta-lactamases. The safety data from Trial 1 are summarized below. In Trial 1, EMBLAVEO was evaluated in a comparative clinical trial in patients with cIAI or HABP/VABP; note that EMBLAVEO is not approved for the treatment of HABP/VABP. Trial 1 evaluated 275 patients treated with EMBLAVEO and 137 patients treated with comparator (meropenem +/- colistin); 203 EMBLAVEO-treated patients had a diagnosis of cIAI while 72 EMBLAVEO-treated patients had a diagnosis of HABP/VABP (not an approved indication for EMBLAVEO). Patients received treatment with EMBLAVEO 2 grams (aztreonam 1.5 grams and avibactam 0.5 grams) or comparator for 5 to 14 days. Patients randomized to EMBLAVEO received a loading dose of aztreonam and avibactam administered by intravenous infusion over 30 minutes immediately followed by an extended loading dose infused over 3 hours, followed by maintenance doses infused over 3 hours every 6 hours based on the participant’s creatinine clearance. Patients with cIAI randomized to EMBLAVEO also received metronidazole 500 mg administered by intravenous infusion over 60 minutes every 8 hours. The median age of patients in Trial 1 treated with EMBLAVEO was 58 years, ranging between 18 and 87 years old. Patients treated with EMBLAVEO were predominantly male (66%) and White (59%). Approximately 40% (22% of cIAI and 89% of HABP/VABP; not an approved indication) of patients treated with EMBLAVEO had an APACHE II score greater than 10 at baseline. Death occurred in 6.9% (19/275) of patients who received EMBLAVEO and in 8% (11/137) of patients who received comparator. In patients with cIAI, death occurred in 3.0% (6/203) of patients treated with EMBLAVEO and 2.9% (3/103) in patients treated with comparator. Overall, 3.6% (10/275) of the patients who received EMBLAVEO discontinued treatment due to an adverse reaction, compared with 3.6% (5/137) of patients treated with comparator. Common adverse reactions occurring in greater than 5% of patients are noted in the table below. Table 5: Adverse Reactions Occurring in > 5% of Patients in the EMBLAVEO Treatment Arm in Trial 1 Adverse Reactions EMBLAVEO ± Metronidazole (N=275) n (%) Meropenem ± Colistin (N=137) n (%) Hepatic adverse reactions* 40 (14.5) 16 (11.7) Anemia** 22 (8.0) 7 (5.1) Diarrhea 16 (5.8) 5 (3.6) Hypokalemia 16 (5.8) 4 (2.9) Pyrexia*** 16 (5.8) 7 (5.1) *Includes AR terms alanine aminotransferase increased, aspartate aminotransferase increased, hepatic function abnormal…