Xacduro- sulbactam and durlobactam
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Kosar Doraghi, M.D. [2]
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Black Box Warning
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Warnings: Hypersensitivity Reactions
See full prescribing information for complete Boxed Warning.
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
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Overview
Xacduro- sulbactam and durlobactam is a co-packaged product containing sulbactam, a beta-lactam antibacterial and beta lactamase inhibitor, and durlobactam, a beta lactamase inhibitor, that is FDA approved for the treatment of hospital-acquired bacterial pneumonia and ventilator-associated bacterial pneumonia (HABP/VABP), caused by susceptible isolates of Acinetobacter baumannii-calcoaceticus complex. There is a Black Box Warning for this drug as shown here. Common adverse reactions include liver test abnormalities, diarrhea, anemia, and hypokalemia.
Adult Indications and Dosage
FDA-Labeled Indications and Dosage (Adult)
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.
- Dosing regimen adjustments are recommended for CLcr less than 45 mL/min and CLcr greater than or equal to 130 mL/min.
- Administer all doses of XACDURO by IV infusion over 3 hours.
- 1 clear single-dose vial of sulbactam for injection 1 g and
- 2 amber single-dose vials of durlobactam for injection 0.5 g.
Off-Label Use and Dosage (Adult)
Pediatric Indications and Dosage
FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding Xacduro- sulbactam and durlobactam FDA-Labeled Indications and Dosage (Pediatric) in the drug label.
Off-Label Use and Dosage (Pediatric)
Contraindications
Known history of severe hypersensitivity to the components of XACDURO (sulbactam and durlobactam), or other beta-lactam antibacterial drugs
Warnings
|
Warnings: Hypersensitivity Reactions
See full prescribing information for complete Boxed Warning.
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
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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
- Clostridioides difficile-Associated Diarrhea (CDAD).
- XACDURO is not indicated for the treatment of HABP/VABP caused by pathogens other than susceptible isolates of Acinetobacter baumannii-calcoaceticus complex.
XACDURO should be used only to treat or prevent infections that are proven or strongly suspected to be caused by bacteria
Adverse Reactions
Clinical Trials Experience
- Hypersensitivity Reactions
- Clostridioides difficile-Associated Diarrhea
Clinical trials vary widely in their conditions, making direct comparisons of adverse reaction rates between drugs difficult and potentially misleading. The safety of durlobactam, with or without sulbactam, was assessed in multiple trials involving 380 adult subjects. These trials included patients with complicated urinary tract infections (cUTIs) and infections caused by Acinetobacter baumannii-calcoaceticus complex, such as hospital-acquired bacterial pneumonia (HABP), ventilator-associated bacterial pneumonia (VABP), and ventilated pneumonia (VP).
In a phase 3 trial comparing XACDURO to colistin, 91 patients received XACDURO intravenously every 6 hours, while 86 patients received colistin intravenously every 12 hours. Both groups also received imipenem/cilastatin as background therapy. Serious adverse reactions occurred in 40% of XACDURO patients and 49% of colistin patients, with discontinuation of treatment due to adverse reactions in 11% and 16% of patients, respectively. One XACDURO patient experienced anaphylactic shock leading to treatment discontinuation.
- Common adverse reactions (>10%) with XACDURO included liver test abnormalities, diarrhea, anemia, and hypokalemia. Table 2 details selected adverse reactions occurring at a frequency of over 5% in the trial.
Postmarketing Experience
There is limited information regarding Xacduro- sulbactam and durlobactam Postmarketing Experience in the drug label.
Drug Interactions
Organic Anion Transporter 1 (OAT1) Inhibitors: Concomitant administration with OAT1 inhibitors may increase plasma concentrations of XACDURO. Concomitant administration is not recommended.
Use in Specific Populations
Pregnancy
Pregnancy Category (FDA):
There is no FDA guidance on usage of Xacduro- sulbactam and durlobactam in women who are pregnant.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Xacduro- sulbactam and durlobactam in women who are pregnant.
Labor and Delivery
There is no FDA guidance on use of Xacduro- sulbactam and durlobactam during labor and delivery.
Nursing Mothers
There is no FDA guidance on the use of Xacduro- sulbactam and durlobactam in women who are nursing.
Pediatric Use
There is no FDA guidance on the use of Xacduro- sulbactam and durlobactam in pediatric settings.
Geriatic Use
In Trial 1, out of the 91 patients receiving XACDURO, 49 (54%) were aged 65 and older, with 17 (19%) being 76 years or older. However, there weren't enough elderly participants in XACDURO clinical studies to determine if they respond differently than younger patients. Since XACDURO is significantly eliminated through the kidneys and elderly individuals are more likely to have reduced renal function, dosage adjustments should be considered based on renal function in this population.
Gender
There is no FDA guidance on the use of Xacduro- sulbactam and durlobactam with respect to specific gender populations.
Race
There is no FDA guidance on the use of Xacduro- sulbactam and durlobactam with respect to specific racial populations.
Renal Impairment
No dosage adjustment of XACDURO is recommended in patients with CLcr 45 to 129 mL/min. The recommended dosage of XACDURO in patients aged 18 and older varies based on renal function, as outlined in TABLE 1. Adjustments to the dosing regimen are advised for patients with creatinine clearance (CLcr) below 45 mL/min or those with augmented renal clearance (CLcr equal to or greater than 130 mL/min). For patients undergoing intermittent hemodialysis (HD), initiate XACDURO dosing immediately after the completion of HD. Further details can be found in the sections "Use in Specific Populations" and "Clinical Pharmacology."
Hepatic Impairment
There is no FDA guidance on the use of Xacduro- sulbactam and durlobactam in patients with hepatic impairment.
Females of Reproductive Potential and Males
There is no FDA guidance on the use of Xacduro- sulbactam and durlobactam in women of reproductive potentials and males.
Immunocompromised Patients
There is no FDA guidance one the use of Xacduro- sulbactam and durlobactam in patients who are immunocompromised.
Administration and Monitoring
Administration
XACDURO is a combined product containing sulbactam and durlobactam for injection. In adults with a creatinine clearance (CLcr) of 45 to 129 mL/min, the recommended dosage is 1 gram (g) of sulbactam and 1 g of durlobactam every 6 hours via intravenous (IV) infusion over 3 hours. Dosing adjustments are advised for patients with CLcr less than 45 mL/min or equal to or greater than 130 mL/min.
The duration of XACDURO treatment is typically 7 to 14 days, guided by the patient's clinical condition. Dosage of XACDURO (Sulbactam and Durlobactam) in Patients (18 Years of Age and Older) Based on Renal Function: [Image: To prepare XACDURO for intravenous administration:
Reconstitute the sulbactam 1 g single-dose vial with 5 mL of Sterile Water for Injection. Gently shake to dissolve. Each reconstituted vial contains 1 g of sulbactam per 5 mL of clear, colorless to slightly yellow solution. This solution is not for direct injection and must be diluted before 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. Gently shake to dissolve. Each reconstituted vial contains 0.5 g of durlobactam per 2.5 mL of clear, light yellow to orange solution. This solution is not for direct injection and must be diluted before infusion. Dilution must occur within 1 hour of reconstitution. To prepare the required dose, withdraw 5 mL of reconstituted sulbactam and 5 mL (2.5 mL from each vial) of reconstituted durlobactam. Add both volumes to a 100 mL infusion bag of 0.9% Sodium Chloride Injection, USP. Discard any unused portion of the prepared solution.
Monitoring
There is limited information regarding Xacduro- sulbactam and durlobactam Monitoring in the drug label.
IV Compatibility
There is limited information regarding the compatibility of Xacduro- sulbactam and durlobactam and IV administrations.
Overdosage
There is limited information regarding Xacduro- sulbactam and durlobactam overdosage. If you suspect drug poisoning or overdose, please contact the National Poison Help hotline (1-800-222-1222) immediately.
Pharmacology
There is limited information regarding Xacduro- sulbactam and durlobactam Pharmacology in the drug label.
Mechanism of Action
XACDURO is an antibacterial drug
Structure
XACDURO (sulbactam for injection and durlobactam for injection) is an antibacterial co-packaged product containing sulbactam sodium, a penicillin derivative beta-lactam antibacterial and beta-lactamase inhibitor, and durlobactam sodium, a diazabicyclooctane beta-lactamase inhibitor, for intravenous administration.
Sulbactam Sodium
Sulbactam sodium is a beta-lactam antibacterial and a beta-lactamase inhibitor. Chemically, sulbactam sodium is sodium penicillinate sulfone; sodium (2S, 5R)-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo [3.2.0] heptane-2-carboxylate 4,4-dioxide. Sulbactam is a white to off-white crystalline powder that is freely soluble in water and its empirical formula is C8H10NNaO5S with a molecular weight of 255.22. [Image: Durlobactam Sodium
Durlobactam is a beta-lactamase inhibitor antibacterial drug. Chemically, durlobactam sodium is sodium (2S,5R)-2-carbamoyl-3-methyl-7-oxo-1,6-diazabicyclo[3.2.1]oct-3-en-6-yl sulfate. Durlobactam sodium is the pure (2S,5R)-enantiomer of the trans diastereoisomer. It is a white to yellow amorphous powder that is freely soluble in water. The empirical formula is C8H10N3NaO6S and the molecular weight (sodium salt) is 299.23. [Image:
Pharmacodynamics
For sulbactam, the percent time of dosing interval that unbound plasma concentrations of sulbactam exceed the minimum inhibitory concentration (MIC) of A. baumannii has been shown to be the best predictor of efficacy in animal and in vitro models of infection. For durlobactam, the ratio of the 24-hour unbound plasma durlobactam AUC to the sulbactam-durlobactam MIC (fAUC0–24/MIC) best predicts the activity in in vivo and in vitro models of infection.
- Cardiac Electrophysiology
At a dose 4 times the maximum recommended single dose, durlobactam does not prolong the QTc interval to any clinically relevant extent.
Pharmacokinetics
Sulbactam and durlobactam exhibit similar pharmacokinetics after both single and multiple doses. The maximum plasma concentration (Cmax) and area under the concentration-time curve (AUC) of sulbactam increase proportionally to the dose, ranging from 0.5 times to the recommended single dose up to 1 g. Durlobactam also displays dose-proportional pharmacokinetics over the studied dose range, which extends from 0.25 times to 2 times the recommended single dose, administered over 3 hours every 6 hours.
Nonclinical Toxicology
Durlobactam was negative in genetic toxicology studies including the Salmonella typhimurium bacterial reverse mutation assay, in vivo and in vitro micronucleus assays, and the in vivo Pig-A assay in rats.
Clinical Studies
- Treatment of Hospital-acquired and Ventilator-associated Bacterial Pneumonia Caused by Acinetobacter baumannii-calcoaceticus Complex Organisms
No drug-drug interactions were observed among durlobactam, sulbactam, imipenem, and cilastatin in a clinical study in healthy subjects.
- In vitro studies on cytochrome P450 (CYP) enzymes revealed that durlobactam, at therapeutic plasma concentrations, does not inhibit a range of CYP enzymes, nor does it induce them. No in vitro studies on CYP450 and sulbactam were conducted.
Regarding membrane transporter systems, in vitro data showed that neither sulbactam nor durlobactam inhibit several transporters at therapeutic plasma concentrations. However, sulbactam is a substrate of OAT1, and inhibition of OAT1 may increase sulbactam plasma concentrations. No clinical studies have explored the interaction between XACDURO and OAT1 inhibitors. In terms of microbiology, XACDURO, containing sulbactam and durlobactam, demonstrated in vitro activity against Acinetobacter baumannii-calcoaceticus complex (ABC) isolates expressing various beta-lactamases. It exhibited broad-spectrum activity against these enzymes, including extended spectrum beta-lactamases (ESBLs) and carbapenemases.
- Resistance mechanisms in ABC isolates may involve beta-lactamases, target site modifications, up-regulation of efflux pumps, or loss of outer membrane porin. XACDURO is not active against ABC isolates producing metallo-beta-lactamases or with modifications of the sulbactam active target site.
In vitro studies showed no antagonism between XACDURO and various antibacterial drugs, including ceftazidime-avibactam, imipenem, meropenem, and others.
How Supplied
XACDURO is a co-packaged product containing sulbactam for injection and durlobactam for injection. XACDURO is supplied as a kit (NDC 68547-111-10) containing the following single-dose vials each containing sterile powder for reconstitution:
- 1 g sulbactam in one clear glass single-dose vial
- 1 g durlobactam in two amber glass single-dose vials (0.5 g durlobactam in each single-dose vial)
Storage
XACDURO does not contain a bacteriostatic preservative, so the prepared solution must be used within 24 hours when stored refrigerated at 2°C to 8°C (36°F to 46°F). Any unused portion should be discarded. Make sure to follow aseptic technique throughout the preparation process
Images
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Patient Counseling Information
There is limited information regarding Xacduro- sulbactam and durlobactam Patient Counseling Information in the drug label.
Precautions with Alcohol
Alcohol-Xacduro- sulbactam and durlobactam interaction has not been established. Talk to your doctor regarding the effects of taking alcohol with this medication.
Brand Names
There is limited information regarding Xacduro- sulbactam and durlobactam Brand Names in the drug label.
Look-Alike Drug Names
There is limited information regarding Xacduro- sulbactam and durlobactam Look-Alike Drug Names in the drug label.
Drug Shortage Status
Price
References
The contents of this FDA label are provided by the National Library of Medicine.