EMBLAVEO

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 )].

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, hypertransaminasemia, transaminases increased, hepatic enzyme increased, liver injury **Includes anemia, hemoglobin decreased ***Includes pyrexia, hyperpyrexia, hyperthermia, body temperature increased Hepatic Adverse Reactions In Trial 1, 40/275 patients (15%) in the EMBLAVEO arm had hepatic adverse reactions compared to 16/137 (12%) in the comparator arm receiving meropenem with or without colistin. In Trial 1, 10 (3.8%) patients in the EMBLAVEO arm compared to 4 (3.1%) patients in the comparator arm had an ALT elevation greater than or equal to 5 x ULN. No Hy’s Law cases in the EMBLAVEO or comparator arm were seen in Trials 1, 2, and 3. EMBLAVEO was discontinued due to hepatic enzyme elevations in 4 patients in Trials 1, 2, and 3. The transaminase elevations resolved when EMBLAVEO was discontinued. The following adverse reactions were reported in EMBLAVEO-treated patients at a rate of less than 5% in Trial 1: Vascular disorders: Phlebitis, flushing, hypotension Skin and subcutaneous tissue disorders: Rash (includes rash and rash macular), dermatitis (includes dermatitis allergic, dermatitis), erythema Gastrointestinal Disorders: Vomiting, nausea, abdominal pain (includes abdominal pain, abdominal pain upper, abdominal pain lower), constipation Nervous System Disorders: Mental status change (includes mental status changes, delirium, confusional state, and disorientation), dizziness, headache, sleep disorder (includes sleep disorder, insomnia), ageusia, asthenia Infectious Diseases: Clostridioides difficile infection (includes Clostridioides difficile infection and Clostridioides difficile colitis) Hematologic: Coagulopathy, leukocytosis (includes white blood cell count increased and leukocytosis), thrombocytopenia (includes thrombocytopenia, platelet count decreased); thrombocytosis (includes thrombocytosis, platelet count increased), eosinophilia Hypersensitivity: Bronchospasm Additionally, adverse reactions that have been reported with aztreonam alone that were not reported in EMBLAVEO-treated patients in Trial 1 are listed below: Hypersensitivity: Anaphylaxis, angioedema Hematologic: Pancytopenia, neutropenia Dermatologic: Purpura, erythema multiforme, exfoliative dermatitis, urticaria, petechiae, pruritus, diaphoresis Cardiovascular: Transient ECG changes (ventricular bigeminy and PVC) Respiratory: Wheezing, dyspnea, chest pain Hepatobiliary: Hepatitis, jaundice Nervous System: Seizure, encephalopathy, vertigo, paresthesia Musculoskeletal: Muscular aches Special Senses: Tinnitus, diplopia, numb tongue, sneezing, nasal congestion, halitosis Other: Vaginal candidiasis, vaginitis, breast tenderness Body as a Whole: Malaise Adverse Laboratory Changes reported with aztreonam alone that were not reported in EMBLAVEO-treated patients in Trial 1 are listed below: Hematologic: Positive Coombs’ test Renal: Increases in serum creatinine Trial 2 was a noncomparative study of EMBLAVEO in 34 subjects with cIAI. Trial 3 was a comparative study of EMBLAVEO versus best available therapy in patients with serious infections due to multi-drug resistant gram-negative bacteria producing metallo-beta-lactamases (not an approved indication for EMBLAVEO); 12 patients were treated in the EMBLAVEO arm and 2 patients were treated in the comparator arm. The safety findings for the EMBLAVEO treatment arm in Trials 2 and 3 were similar to those of Trial 1.

<table><caption>Table 5: Adverse Reactions Occurring in &gt; 5% of Patients in the EMBLAVEO Treatment Arm in Trial 1</caption><col width="240"/><col width="176"/><col width="208"/><tbody><tr><td styleCode="Toprule Lrule Rrule "><content styleCode="bold">Adverse Reactions </content></td><td styleCode="Toprule Lrule Rrule " align="center"><content styleCode="bold">EMBLAVEO &#xB1; Metronidazole</content> <content styleCode="bold">(N=275)</content> <content styleCode="bold">n (%)</content></td><td styleCode="Toprule Lrule Rrule " align="center"><content styleCode="bold">Meropenem &#xB1; Colistin</content> <content styleCode="bold">(N=137)</content> <content styleCode="bold">n (%)</content></td></tr><tr><td styleCode="Toprule Lrule Rrule ">Hepatic adverse reactions*</td><td styleCode="Toprule Lrule Rrule " align="center">40 (14.5)</td><td styleCode="Toprule Lrule Rrule " align="center">16 (11.7)</td></tr><tr><td styleCode="Toprule Lrule Rrule ">Anemia**</td><td styleCode="Toprule Lrule Rrule " align="center">22 (8.0)</td><td styleCode="Toprule Lrule Rrule " align="center">7 (5.1)</td></tr><tr><td styleCode="Toprule Lrule Rrule ">Diarrhea</td><td styleCode="Toprule Lrule Rrule " align="center">16 (5.8)</td><td styleCode="Toprule Lrule Rrule " align="center">5 (3.6)</td></tr><tr><td styleCode="Toprule Lrule Rrule ">Hypokalemia</td><td styleCode="Toprule Lrule Rrule " align="center">16 (5.8)</td><td styleCode="Toprule Lrule Rrule " align="center">4 (2.9)</td></tr><tr><td styleCode="Toprule Lrule Rrule ">Pyrexia***</td><td styleCode="Toprule Lrule Rrule " align="center">16 (5.8)</td><td styleCode="Toprule Lrule Rrule " align="center">7 (5.1)</td></tr><tr><td styleCode="Toprule " colspan="3">*Includes AR terms alanine aminotransferase increased, aspartate aminotransferase increased, hepatic function abnormal, hypertransaminasemia, transaminases increased, hepatic enzyme increased, liver injury **Includes anemia, hemoglobin decreased ***Includes pyrexia, hyperpyrexia, hyperthermia, body temperature increased</td></tr></tbody></table>