AVIBACTAM Drug Interactions: What You Need to Know

INTERACTIONS

7.1 Probenecid In vitro , avibactam is a substrate of OAT1 and OAT3 transporters which might contribute to the active uptake from the blood compartment, and thereby its excretion. As a potent OAT inhibitor, probenecid inhibits OAT uptake of avibactam by 56% to 70% in vitro and, therefore, has the potential to decrease the elimination of avibactam when co-administered. Because a clinical interaction study of AVYCAZ or avibactam alone with probenecid has not been conducted, co-administration of AVYCAZ with probenecid is not recommended [ see Clinical Pharmacology ( 12.3 ) ] .

7.2 Drug/Laboratory Test Interactions The administration of ceftazidime may result in a false-positive reaction for glucose in the urine with certain methods. It is recommended that glucose tests based on enzymatic glucose oxidase reactions be used.

AVYCAZ is contraindicated in patients with known serious hypersensitivity to the components of AVYCAZ (ceftazidime and avibactam), avibactam containing products, or other members of the cephalosporin class [see Warnings and Precautions ( 5.2 )] . AVYCAZ is contraindicated in patients with known serious hypersensitivity to the components of AVYCAZ (ceftazidime and avibactam), avibactam-containing products or other members of the cephalosporin class. ( 4 )

AND PRECAUTIONS Decreased Clinical Response in A dult cIAI P atients with B aseline CrC l of 30 to L ess T han or E qual to 50 mL/ min : Monitor CrCl at least daily in adult and pediatric patients with changing renal function and adjust the dosage of AVYCAZ accordingly. ( 5.1 ) Hypersensitivity R eactions : Includes anaphylaxis and serious skin reactions. Cross sensitivity may occur in patients with a history of penicillin allergy. If an allergic reaction occurs, discontinue AVYCAZ. ( 5.2 ) Clostrid io i des difficile -associated D iarrhea (CDAD) : CDAD has been reported with nearly all systemic antibacterial agents, including AVYCAZ. Evaluate if diarrhea occurs. ( 5.3 ) C entral Nervous System Reactions : Seizures and other neurologic events may occur, especially in patients with renal impairment. Adjust dose in patients with renal impairment. ( 5.4 )

5.1 Decreased Clinical Response in Adult cIAI Patients with Baseline Creatinine Clearance of 30 to Less Than or Equal to 50 mL/min In a Phase 3 cIAI trial in adult patients, clinical cure rates were lower in a subgroup of patients with baseline CrCl of 30 to less than or equal to 50 mL/min compared to those with CrCl greater than 50 mL/min (Table 10). The reduction in clinical cure rates was more marked in patients treated with AVYCAZ plus metronidazole compared to meropenem-treated patients. Within this subgroup, patients treated with AVYCAZ received a 33% lower daily dose than is currently recommended for patients with CrCl 30 to less than or equal to 50 mL/min. The decreased clinical response was not observed for patients with moderate renal impairment at baseline (CrCl of 30 to less than or equal to 50 mL/min) in the Phase 3 cUTI trials or the Phase 3 HABP/VABP trial. Monitor CrCl at least daily in adult and pediatric patients with changing renal function and adjust the dosage of AVYCAZ accordingly [ see Dosage and Administration ( 2.2 , 2.3 ) , and Adverse Reactions ( 6.1 ) ] .

Table

10.

Clinical Cure

Rate at Test of Cure in a Phase 3 cIAI Trial, by Baseline Renal Function – mMITT Population a AVYCAZ + Metronidazole % (n/N) Meropenem % (n/N) Normal function / mild impairment (CrCl greater than 50 mL/min) 85% (322/379) 86% (321/373) Moderate impairment (CrCl 30 to less than or equal to 50 mL/min) 45% (14/31) 74% (26/35) a Microbiological modified intent-to-treat (mMITT) population included patients who had at least one bacterial pathogen at baseline and received at least one dose of study drug. 5. 2 Hypersensitivity Reactions Serious and occasionally fatal hypersensitivity (anaphylactic) reactions and serious skin reactions have been reported in patients receiving beta-lactam antibacterial drugs. Before therapy with AVYCAZ is instituted, careful inquiry about previous hypersensitivity reactions to other cephalosporins, penicillins, or carbapenems should be made. Exercise caution if this product is to be given to a penicillin or other beta-lactam-allergic patient because cross sensitivity among beta-lactam antibacterial drugs has been established. Discontinue the drug if an allergic reaction to AVYCAZ occurs. 5. 3 Clostridi oides difficile- associated Diarrhea Clostridi oides difficile -associated diarrhea (CDAD) has been reported for nearly all systemic antibacterial drugs, including AVYCAZ, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial drugs alters the normal flora of the colon and may permit 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 use. Careful medical history is necessary because CDAD has been reported to occur more than 2 months after the administration of antibacterial drugs. If CDAD is suspected or confirmed, antibacterial drugs not directed against C. difficile may need to be discontinued. Manage fluid and electrolyte levels as appropriate, supplement protein intake, monitor antibacterial treatment of C. difficile , and institute surgical evaluation as clinically indicated. 5. 4 Central Nervous System Reactions Seizures, nonconvulsive status epilepticus (NCSE), encephalopathy, coma, asterixis, neuromuscular excitability, and myoclonia have been reported in patients treated with ceftazidime, particularly in the setting of renal impairment. Adjust dosing based on creatinine clearance [ see Dosage and Administration ( 2.2 ) ] . 5. 5 Development of Drug-Resistant Bacteria Prescribing AVYCAZ 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 [see Indications and Usage ( 1.4 )] .