Emblaveo Drug Information

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 16 Anemia** 22 7 Diarrhea 16 5 Hypokalemia 16 4 Pyrexia*** 16 7 *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.

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.

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.

Pediatric Use The safety and effectiveness of EMBLAVEO in pediatric patients less than 18 years of age have not been established.

is contraindicated in patients with known hypersensitivity to the components of EMBLAVEO (aztreonam and avibactam) . Known hypersensitivity to the components of EMBLAVEO (aztreonam and avibactam).

There is no information on the clinical signs and symptoms associated with an overdose of EMBLAVEO. Aztreonam and avibactam can be partially removed by hemodialysis . No clinical information is available on the use of hemodialysis to treat EMBLAVEO overdosage.