Xacduro
(Sulbactam And Durlobactam)Dosage & Administration
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Xacduro Prescribing Information
XACDURO is a co-packaged product containing sulbactam, a beta-lactam antibacterial and beta lactamase inhibitor, and durlobactam, a beta lactamase inhibitor, indicated in patients 18 years of age and older for the treatment of hospital-acquired bacterial pneumonia and ventilator-associated bacterial pneumonia (HABP/VABP), caused by susceptible isolates of
XACDURO is indicated in patients 18 years of age and older for the treatment of hospital-acquired bacterial pneumonia and ventilator-associated bacterial pneumonia (HABP/VABP), caused by susceptible isolates of
XACDURO is not indicated for the treatment of HABP/VABP caused by pathogens other than susceptible isolates of
XACDURO is not indicated for the treatment of HABP/VABP caused by pathogens other than susceptible isolates of
XACDURO is indicated in patients 18 years of age and older for the treatment of hospital-acquired bacterial pneumonia and ventilator-associated bacterial pneumonia (HABP/VABP), caused by susceptible isolates of
XACDURO is not indicated for the treatment of HABP/VABP caused by pathogens other than susceptible isolates of
A total of 177 hospitalized adults with documented
The primary efficacy endpoint for the study was 28-day all-cause mortality in the patients who received any amount of study medication with a confirmed baseline infection with carbapenem-resistant
The demographic and baseline characteristics were comparable between treatment groups among 125 patients in the analysis: 74% male, 50% White, and 44% Asian; the mean age was 63 (±17) years. The majority of patients had pneumonia as the baseline infection (53% VABP and 43% HABP); 2% had bacteremia. The mean Acute Physiology and Chronic Health Evaluation II (APACHE II) score at baseline was 17, and 26% of patients had an APACHE II score ≥ 20. At randomization, 64% of patients had been in the ICU ≥5 days, 26% of patients had been in the ICU for >14 days, and 75% were mechanically ventilated. Approximately 39% of patients had CLcr less than 90 mL/min at baseline. The mean duration of treatment was 9 days for the XACDURO group and 8 days for the colistin group.
Table 5 shows results for the primary endpoint of Day 28 all-cause mortality in the CRABC m-MITT population. XACDURO was non-inferior to colistin with regard to Day 28 all-cause mortality.
| XACDURO n/NPercentage was calculated using N, the number of patients in the specified population, as the denominator.(%) | Colistin n/N(%) | Treatment Difference (95% CI)The 95% CI (2-sided) was computed using a continuity-corrected z statistic. | |
|---|---|---|---|
| CI = Confidence Interval | |||
Day 28 All-Cause Mortality | 12/63 (19.0%) | 20/62 (32.3%) | -13.2% (-30.0, 3.5) |
Clinical cure rates were also evaluated. Clinical cure was defined as complete resolution or significant improvement of signs and symptoms that were present at baseline and no new symptoms, such that no additional gram-negative antimicrobial therapy was warranted. Clinical cure rates in the CRABC m-MITT population at the Test of Cure (TOC) Visit that was 7 days (±2 days) after the end of treatment were 39/63 (61.9%) for XACDURO versus 25/62 (40.3%) for colistin.
To reduce the development of drug-resistant bacteria and maintain the effectiveness of XACDURO and other antibacterial drugs, XACDURO should be used only to treat or prevent infections that are proven or strongly suspected to be caused by bacteria. (
To reduce the development of drug-resistant bacteria and maintain the effectiveness of XACDURO and other antibacterial drugs, XACDURO should be used only to treat or prevent 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.
- Administer XACDURO (1 g of sulbactam, 1 g of durlobactam) every 6 hours by intravenous (IV) infusion over 3 hours in patients with creatinine clearance (CLcr) of 45 to 129 mL/min. ()
2.1 Recommended DosageXACDURO is a co-packaged product containing sulbactam for injection and durlobactam for injection. The recommended dosage of XACDURO is 1 gram (g) of sulbactam and 1 g of durlobactam every 6 hours administered by intravenous (IV) infusion over 3 hours in adults with a creatinine clearance (CLcr) of 45 to 129 mL/min.
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
[see Dosage and Administration (2.2)].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.
- Dosing regimen adjustments are recommended for CLcr less than 45 mL/min and CLcr greater than or equal to 130 mL/min. ()
2.2 Dosage in Patients (18 Years of Age and Older) Based on Renal FunctionSee Table 1for the recommended dosage of XACDURO in patients (18 years of age and older) based on renal function
[see Use in Specific Populations (8.6)and Clinical Pharmacology (12.3)].Adjustments to the dosing regimen are recommended for patients with creatinine clearance (CLcr) less than 45 mL/min and patients with augmented renal clearance (CLcr greater than or equal to 130 mL/min). 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
[see Use in Specific Populations (8.6)].Table 1: Dosage of XACDURO (Sulbactam and Durlobactam) in Patients (18 Years of Age and Older) Based on Renal Function Dose of Sulbactam and Durlobactam (g) Estimated CLcr (mL/min)CLcr = creatinine clearance estimated by Cockcroft-Gault equation Frequency sulbactam 1 g and durlobactam 1 g Greater than or equal to 130 Every 4 hours 45 to 129 Every 6 hours 30 to 44 Every 8 hours 15 to 29 Every 12 hours less than 15For patients on hemodialysis, the dose should be administered after the dialysis session has ended For patients initiating XACDURO: Every 12 hours for the first 3 doses (0, 12, and 24 hours), followed by every 24 hours after the third dose
For patients currently receiving XACDURO whose CLcr declines to less than 15 mL/min: Every 24 hours - Administer all doses of XACDURO by IV infusion over 3 hours. ()
2.3 AdministrationThe prepared XACDURO solution
[see Dosage and Administration (2.4)]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. - See full prescribing information for instructions on the preparation of the intravenous solution. ()
2.4 Preparation of XACDURO for Intravenous AdministrationXACDURO 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.
- Reconstitute each durlobactam 0.5 g single-dose vial with 2.5 mL of Sterile Water for Injection and gently shake to dissolve. Each reconstituted vial contains 0.5 g of durlobactam per 2.5 mL of clear, light yellow to orange solution. The reconstituted solution is not for direct injection and must be diluted before intravenous infusion. Dilution must occur within 1 hour of reconstitution.
- 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
notadminister.
XACDURO is a co-packaged kit containing the following two components as sterile powders for reconstitution:
- 1 clear single-dose vial of sulbactam for injection 1g (as white to off-white powder) and
- 2 amber single-dose vials of durlobactam for injection 0.5g (as solid cake or powder) in each vial.
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
Serious and occasionally fatal hypersensitivity (anaphylactic) reactions and serious skin reactions have been reported in patients receiving beta-lactam antibacterial drugs. These reactions are more likely to occur in individuals with a history of beta-lactam hypersensitivity and/or a history of sensitivity to multiple allergens. Hypersensitivity was observed in patients treated with XACDURO in clinical trials
- Hypersensitivity Reactions: Serious and occasionally fatal hypersensitivity (anaphylactic) reactions have been reported with beta-lactam antibacterial drugs. Hypersensitivity was observed in patients treated with XACDURO. If an allergic reaction occurs, discontinue XACDURO. ()
5.1 Hypersensitivity ReactionsSerious and occasionally fatal hypersensitivity (anaphylactic) reactions and serious skin reactions have been reported in patients receiving beta-lactam antibacterial drugs. These reactions are more likely to occur in individuals with a history of beta-lactam hypersensitivity and/or a history of sensitivity to multiple allergens. Hypersensitivity was observed in patients treated with XACDURO in clinical trials
[see Adverse Reactions (6.1)]. Before initiating therapy with XACDURO, careful inquiry should be made concerning previous hypersensitivity reactions to carbapenems, penicillins, cephalosporins, other beta lactams, and other allergens. Discontinue XACDURO if an allergic reaction occurs. - Clostridioides difficile-Associated Diarrhea (CDAD):CDAD has been reported with nearly all systemic antibacterial agents, including XACDURO. Evaluate if diarrhea occurs. ()
5.2Clostridioides difficile-Associated Diarrhea (CDAD)Clostridioides difficile-associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including XACDURO, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth ofC. difficile.C. difficileproduces toxins A and B which contribute to the development of CDAD. Hypertoxin producing strains ofC. difficilecause 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 drug use. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents.If CDAD is suspected or confirmed, the risk/benefit of continuing treatment with XACDURO should be assessed. Appropriate fluid and electrolyte management, protein supplementation, antibacterial drug treatment of
C. difficile, and surgical evaluation should be instituted as clinically indicated.