XACDURO Kit for injection Ref.[107381] Active ingredients: Sulbactam Sulbactam and Durlobactam

5.1 Hypersensitivity Reactions

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 [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.

5.2 Clostridioides 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 of C. difficile.

C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin producing strains of C. difficile cause 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.

5.3 Development of Drug-Resistant Bacteria

Prescribing XACDURO in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria.

The following serious adverse reactions are described in greater detail in the Warnings and Precautions section:

• Hypersensitivity Reactions [see Warnings and Precautions (5.1)]
• Clostridioides difficile-Associated Diarrhea (CDAD) [see Warnings and Precautions (5.2)]

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) [see Clinical Studies (14)].

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:

^* 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.

7.1 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 [see Clinical Pharmacology (12.3)].

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 (10) 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 (10) 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).

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. Published data report sulbactam in breastmilk at an estimated maximum daily infant dose of 560 mcg/kg/day (1% to 2% of adult weight-adjusted dose), assuming mean milk consumption of 200 mL/kg/day. 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.

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

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.

XACDURO is known to be substantially excreted by the kidney and elderly patients are more likely to have decreased renal function. Adjust dosing regimen for elderly patients based on renal function [see Dosage and Administration (2.2), Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)].

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 dosing [see Dosage and Administration (2.2) and Clinical Pharmacology (12.3)]. 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.

Patients with CLcr 130 mL/min or Greater

CLcr 130 mL/min or greater may be seen in seriously ill patients who are receiving intravenous fluid resuscitation. Dosage adjustment of XACDURO is required in patients with CLcr 130 mL/min or greater [see Dosage and Administration (2.2) and Clinical Pharmacology (12.3)]. Monitor renal function regularly and adjust the dosage of XACDURO accordingly as renal function may change during the course of therapy.

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.