DRUG INTERACTIONS-

1. 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. 

BRIEF SUMMARY

SULBACTAM/DURLOBACTAM (May 2023)

Indication- To treat hospital -acquired bacterial pneumonia and ventilator  associated bacterial pneumonia caused by susceptible complex

Dosage-  a co-packaged kit containing the following two components as sterile powders for reconstitution-   1 clear single-dose vial of sulbactam for injection 1 g and 2 amber single-dose vials of durlobactam for injection 0.5 g. 

ADR-  most common adverse reactions (incidence > 10%) were liver test abnormalities, diarrhea, anemia, and hypokalemia.

CI-  Known history of severe hypersensitivity to the components (sulbactam and durlobactam), or other beta-lactam antibacterial drugs.

WARNINGS-

 • Hypersensitivity Reactions: Serious and occasionally fatal hypersensitivity (anaphylactic) reactions have been reported with beta-lactam antibacterial drugs.

Pat inform-  Serious Diarrhea- Advise the patient, their families, or caregivers that diarrhea is a common problem caused by antibacterial drugs.

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U.S. FDA APPROVED  DRUGS DURING 2023

Sr.No-  19

ADVERSE REACTIONS-

 The most common adverse reactions (incidence > 10%) were liver test abnormalities, diarrhea, anemia, and hypokalemia.

CONTRAINDICATIONS-

 Known history of severe hypersensitivity to the components of XACDURO (sulbactam and durlobactam), or other beta-lactam antibacterial drugs.

WARNINGS AND PRECAUTIONS-

 • 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.

• Clostridioides difficile-Associated Diarrhea (CDAD):

CDAD has been reported with nearly all systemic antibacterial agents, including XACDURO. Evaluate if diarrhea occurs. 

DOSAGE FORMS AND STRENGTHS-

 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 1 g and

• 2 amber single-dose vials of durlobactam for injection 0.5 g. 

 PATIENT COUNSELING INFORMATION

Serious Allergic Reactions -

Advise the patient, their families, or caregivers that allergic reactions, including serious allergic reactions, could occur and that serious reactions require immediate treatment.

Ask them about any previous hypersensitivity reactions to XACDURO (sulbactam and durlobactam), other betaReference ID: 5179574 17 lactams (including cephalosporins) or other allergens.

Potentially Serious Diarrhea Advise the patient, their families, or caregivers that diarrhea is a common problem caused by antibacterial drugs, including XACDURO.

Sometimes, frequent watery or bloody diarrhea may occur and may be a sign of a more serious intestinal infection.

If severe watery or bloody diarrhea develops, tell them to contact their healthcare provider

Antibacterial Resistance-                                                                                             Patients should be counseled that antibacterial drugs, including XACDURO, should only be used to treat bacterial infections.

They do not treat viral infections (e.g., the common cold).

Patients should be told that the medication should be administered exactly as directed. 

Distributed by: La Jolla Pharmaceutical Company, Waltham, MA 02451 XACDURO is a registered trademark of Entasis Therapeutics Ltd. Copyright ©2023, Entasis Therapeutics Ltd. All rights reserved.

CLINICAL PHARMACOLOGY-

1. Mechanism of Action -

XACDURO is an antibacterial drug 

2. 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.

Cardiac Electrophysiology -

At a dose 4 times the maximum recommended single dose, durlobactam does not prolong the QTc interval to any clinically relevant extent.

3. Pharmacokinetics-

Sulbactam and durlobactam pharmacokinetics are similar following single- and multiple-dose administrations.

Distribution- % Bound to human plasma protein 38% 10% AUC0-6 ELF/plasma ratio 0.5 0.37 Vss (L)* 25.4 ± 11.3 30.3 ± 12.9

Metabolism- Minimally metabolized Elimination CL (L/h)* 11.6 ± 5.64 9.96 ± 3.11 T1/2 (h)* 2.15 ± 1.16 2.52 ± 0.77

Excretion- Major route of elimination Renal % excreted unchanged in urine 75% to 85% 78%

Specific Populations -No clinically significant differences in the pharmacokinetics of sulbactam or durlobactam were observed based on age (18-91 years), gender, weight (35-150 kg), and race (White, Black, Asian, American Indian/Alaska Native, Other).

Patients with Renal Impairment- In a single-dose trial evaluating the effect of renal impairment on the pharmacokinetics of sulbactam and durlobactam, dose normalized systemic exposures of sulbactam and durlobactam were higher at all levels of renal impairment compared to healthy subjects with CLcr greater than or equal to 90 mL/min

Use in Specific Populations-

 Patients with Hepatic Impairment Sulbactam and durlobactam are primarily cleared renally; therefore, hepatic impairment is not likely to have any effect on XACDURO exposures.

Drug Interaction Studies-                                                                                              Clinical Studies No drug-drug interactions were observed among durlobactam, sulbactam, imipenem, and cilastatin in a clinical study in healthy subjects.

 USE IN SPECIFIC POPULATIONS

1. Pregnancy Risk Summary

XACDURO There are no available data on the use of XACDURO in pregnancy to evaluate for a drugassociated 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 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.

2. Lactation Risk Summary-

There are no data on the presence of durlobactam in human or animal milk. Sulbactam is present in human milk in low concentrations.

There are no data on the effects of XACDURO, sulbactam, or durlobactam on the breastfed infant or on milk production.

The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for XACDURO and any potential adverse effects on the breastfed child from XACDURO or from the underlying maternal condition.

3. Pediatric Use-

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

4.Geriatric Use-

Of the 91 patients treated with XACDURO in Trial 1, 49 (54%) were 65 years of age and older, including 17 (19%) patients 76 years of age and older.

Clinical studies of XACDURO did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently than younger patients

5. Renal Impairment-

 Patients with CLcr 45 to 129 mL/min No dosage adjustment of XACDURO is recommended in patients with CLcr 45 to 129 mL/min.

Patients with CLcr Less Than 45 mL/min Including Patients Receiving Intermittent HD Adjustments to the XACDURO dosing regimen are required in patients with CLcr less than 45 mL/min. In patients requiring HD, complete HD at the latest possible time before the start of XACDURO dosin.

Monitor renal function regularly and adjust the dosage of XACDURO accordingly as renal function may change during the course of therapy.

Patients Receiving Continuous Renal Replacement Therapy-

(CRRT) Limited information is available to provide a dosage recommendation in this setting and therapy should be guided by the patient’s clinical status.

While on CRRT, a patient’s residual renal function may change, which may warrant a change in XACDURO dosage.

Monitor renal function regularly and adjust the dosage of XACDURO accordingly as renal function may change during the course of therapy.

Monitor renal function regularly and adjust the dosage of XACDURO accordingly as renal function may change during the course of therapy.

6..Hepatic Impairment- -

The effects of hepatic impairment on the pharmacokinetics of sulbactam and durlobactam have not been evaluated.

Hepatic impairment is not expected to alter the elimination of XACDURO as neither sulbactam nor durlobactam undergo substantial hepatic metabolism/excretion.

Dosage adjustments are not necessary in patients with impaired hepatic function. 

OVERDOSAGE

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.