Xacduro Drug Information

Recommended Dosage XACDURO is a co-packaged product containing sulbactam for injection and durlobactam for injection. Adjustments to the dosing regimen for XACDURO are recommended for patients with CLcr less than 45 mL/min and for patients with CLcr greater than or equal to 130 mL/min. The recommended duration of treatment with XACDURO is 7 to 14 days.

The duration of therapy should be guided by the patient's clinical status.

Dosage in Patients (18 Years of Age and Older) Based on Renal Function See Table 1 for the recommended dosage of XACDURO in patients (18 years of age and older) based on renal function. For patients undergoing intermittent hemodialysis (HD), start the dosing of XACDURO immediately after the completion of HD. For patients with fluctuating renal function, monitor CLcr and adjust dosage accordingly.

Table 1: Dosage of XACDURO (Sulbactam and Durlobactam) in Patients (18 Years of Age and Older) Based on Renal Function

Administration

The prepared XACDURO solution should be brought to ambient room temperature (over 15 to 30 min) prior to infusion to the patient. Administer all doses of XACDURO by intravenous (IV) infusion over 3 hours.

Preparation of XACDURO for Intravenous Administration XACDURO is a co-packaged kit containing 1 clear single-dose vial of sulbactam 1g and 2 amber single-dose vials of durlobactam 0.5g as sterile powders that must be reconstituted and further diluted using aseptic technique prior to intravenous infusion. XACDURO does not contain a bacteriostatic preservative and the prepared solution must be used within 24 hours when stored refrigerated at 2°C to 8°C (36°F to 46°F). Discard unused portion.

Items required to prepare XACDURO: XACDURO kit (includes one sulbactam 1 g single-dose vial and two durlobactam 0.5 g single-dose vials) 100 mL infusion bag containing 0.9% Sodium Chloride Injection, USP 10 mL Sterile Water for Injection, USP 10 mL sterile syringe and alcohol wipes Preparation of XACDURO: Reconstitute the sulbactam 1 g single-dose vial with 5 mL of Sterile Water for Injection and gently shake to dissolve. Each reconstituted vial contains 1 g of sulbactam per 5 mL of clear, colorless to slightly yellow solution. The reconstituted solution is not for direct injection and must be diluted before intravenous infusion.

Dilution must occur within 1 hour of reconstitution. Each reconstituted vial contains 0.5 g of durlobactam per 2.5 mL of clear, light yellow to orange solution. To prepare the required XACDURO dose, withdraw 5 mL of reconstituted sulbactam and 5 mL (2.5 mL from each vial) of reconstituted durlobactam.

Add the withdrawn volume of both sulbactam and durlobactam to a 100 mL infusion bag of 0.9% Sodium Chloride for Injection, USP. Discard unused portion. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

The prepared XACDURO solution should appear as a clear, light yellow to orange solution, free of particulates. If the XACDURO solution is cloudy or contains particulates, do not administer.

Compatibility XACDURO is compatible with 0.9% Sodium Chloride Injection, USP. The compatibility of XACDURO for administration with solutions containing other drugs or other diluents has not been established. XACDURO should not be mixed with other drugs or physically added to solutions containing other drugs.

Storage of Prepared Solution in Infusion Bag Store the prepared bag in the refrigerator at 2°C to 8°C (36°F to 46°F) until administration. The time between starting the reconstitution of the powders and the conclusion of the infusion should not exceed 24 hours. Do not freeze.

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). 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. One patient treated with XACDURO developed anaphylactic shock which led to discontinuation of treatment.

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.

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 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 respectively. 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. 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.

XACDURO 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.

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.