Xacduro Drug Information

Clinical Trials Experience Clinical trials are conducted under widely varying conditions, therefore

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. The safety of durlobactam with or without sulbactam was evaluated in 380 adult subjects across six phase 1 trials, one phase 2 trial in patients with complicated urinary tract infections (cUTIs) including acute pyelonephritis, and one phase 3 trial (also referred to as Trial 1) in adult patients with infections caused by Acinetobacter baumannii-calcoaceticus complex including hospital-acquired bacterial pneumonia (HABP), ventilator-associated bacterial pneumonia (VABP), and ventilated pneumonia (VP). In the randomized, active-controlled portion of the phase 3 trial, 91 patients received XACDURO (1 g sulbactam and 1 g durlobactam, or renally adjusted dose) intravenously over 3 hours every 6 hours and 86 patients were treated with colistin 2.5 mg/kg (or renally adjusted dose) intravenously over 30 minutes every 12 hours after an initial loading dose of colistin 2.5 to 5 mg/kg. Both treatment arms also received 1 g imipenem/1 g cilastatin (or renally adjusted dose) intravenously every 6 hours as background therapy for potential HABP/VABP pathogens other than Acinetobacter baumannii-calcoaceticus complex.

The mean duration of XACDURO therapy was 9 days versus 8 days for colistin. Serious Adverse Reactions and Discontinuation of Treatment Thirty-six patients (40%) in the XACDURO treatment group and 42 patients (49%) in the colistin treatment group experienced serious adverse reactions. Discontinuation of treatment due to any adverse reaction occurred in 10/91 (11%) patients treated with XACDURO and in 14/86 (16%) patients treated with colistin.

One patient treated with XACDURO developed anaphylactic shock which led to discontinuation of treatment. Common Adverse Reactions Adverse reactions were reported in 88% (80/91) of patients in the XACDURO treatment group and 94% (81/86) of patients in the colistin treatment group. The most common adverse reactions reported in >10% of patients treated with XACDURO were liver test abnormalities, diarrhea, anemia, and hypokalemia.

Table 2 lists selected adverse reactions occurring at a frequency of >5% in Trial 1. Table 2. Selected Adverse Reactions Occurring at a Frequency of >5% in Trial 1 Adverse Reaction XACDURO (N=91) n (%) Colistin (N=86) n (%) Any Adverse Reaction 80 81 Liver test abnormalities Liver test abnormalities includes the following adverse reactions: liver function test abnormal, hepatic function abnormal, increased transaminases, ALT increased, and AST increased; Acute kidney injury includes the following adverse reactions: renal impairment, blood Cr increased, toxic nephropathy, renal failure and acute kidney injury. 17 18 Diarrhea 15 9 Anemia 12 12 Hypokalemia 11 9 Arrhythmia 8 8 Acute kidney injury 5 31 Thrombocytopenia 5 3 Constipation 5 5

Organic Anion Transporter 1 (OAT1) Inhibitors

Concomitant administration with OAT1 inhibitors may increase plasma concentrations of sulbactam. Concomitant administration of OAT1 inhibitors (e.g., probenecid) with XACDURO is not recommended. .

Pregnancy Risk Summary XACDURO There are no available data on the use of XACDURO in pregnancy to evaluate for a drug-associated risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes. Individual Components of XACDURO Sulbactam: Available published data from case reports and case series with sulbactam use in combination with ampicillin during pregnancy over many decades have not identified a drug-associated risk of major birth defects, miscarriage or other adverse maternal or fetal outcomes. The published literature reports that sulbactam crosses the human placenta.

Reproduction studies have been performed in mice, rats, and rabbits at doses up to ten times the human dose and have revealed no evidence of harm to the fetus due to sulbactam (see Data ). Durlobactam: There are no available data on the use of durlobactam in pregnancy to evaluate for a drug-associated risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes. Durlobactam administered to pregnant mice and rats during organogenesis, showed no drug-induced fetal malformations but an increased incidence of skeletal variations was observed in mice at 2- and 4-times the Maximum Recommended Human Dose (MRHD) (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 U.S. general population, the estimated background risk of major birth defects and miscarriages in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Data Animal Data Sulbactam: Reproduction studies have been performed in mice, rats, and rabbits at doses up to ten times the human dose and have revealed no evidence of harm to the fetus due to sulbactam sodium/ampicillin sodium. Durlobactam: Daily administration of durlobactam at 400, 800, or 1600 mg/kg/day (administered as four doses per day) via subcutaneous injection to pregnant mice from gestation day (GD) 6 through 15 resulted in durlobactam-related, increased incidence of skeletal variations (unossified calcaneum) of the hindlimb and asymmetrical ossification of the sternebrae and supernumerary ribs at 800 and/or 1600 mg/kg, equivalent to 2- and 4-times the maximum recommended human dose based on area under the curve (AUC) comparisons.

No adverse effects on mean body weight, reproductive performance, or cesarean section parameters were observed in any pregnant mice. IV infusion (2 hours/day) of durlobactam to pregnant female Sprague Dawley rats from GD 6 to weaning on Lactation Day 20 at a dose level of 300 or 1000 mg/kg/day was well tolerated with no adverse maternal effects in either group. Similarly, there was no adverse effect of maternal treatment in either group on embryo-fetal, perinatal or postnatal development up to 1000 mg/kg/day (approximately 4 times the MRHD based on AUC).

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

is contraindicated in patients with a history of known severe hypersensitivity to the components of XACDURO (sulbactam and durlobactam), or other beta-lactam antibacterial drugs . Known history of severe hypersensitivity to the components of XACDURO (sulbactam and durlobactam), or other beta-lactam antibacterial drugs.

There is no information on the clinical signs and symptoms associated with an overdose of XACDURO. Neurological adverse reactions, including convulsions, may occur with the attainment of high CSF levels of beta-lactams. Sulbactam and durlobactam are removed by hemodialysis. No clinical information is available on the use of hemodialysis to treat overdosage.