Decreased Clinical Response in Patients with Baseline Creatinine Clearance of 30 to 50 mL/min In a Phase 3 cIAI trial, clinical cure rates were lower in a subgroup of patients with baseline CrCL of 30 to 50 mL/min compared to those with CrCL greater than 50 mL/min (Table 3). 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 50 mL/min. Monitor CrCL at least daily in patients with changing renal function and adjust the dosage of AVYCAZ accordingly [see DOSAGE AND ADMINISTRATION, and ADVERSE REACTIONS]. Table 3: Clinical Cure Rate at Test of Cure, by Baseline Renal Function – mMITT Population1
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 50 mL/min) 45% (14/31) 74% (26/35) 1Microbiological 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. 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. Clostridium Difficile-Associated Diarrhea Clostridium 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. Central Nervous System Reactions Seizures, nonconvulsive status epilepticus, 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]. Development Of Drug-Resistant Bacteria Prescribing AVYCAZ in the absence of a proven or strongly suspected bacterial infection is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria [see INDICATIONS AND USAGE]. Nonclinical Toxicology Carcinogenesis, Mutagenesis, Impairment Of Fertility Ceftazidime and avibactam were each evaluated for mutagenic potential in several in vitro and in vivo assays. Ceftazidime was negative for mutagenicity in a mouse micronucleus test and an Ames test. Avibactam was negative for genotoxicity in the Ames assay, unscheduled DNA synthesis, chromosomal aberration assay, and a rat micronucleus study. Avibactam had no adverse effects on fertility of male and female rats given up to 1 g/kg/day (approximately 20 fold higher than the recommended clinical dose on a body surface area basis). There was a dose-related increase in the percentage of pre-and post-implantation loss relative to controls, resulting in a lower mean litter size at doses 0.5 g/kg and greater with intravenous administration to female rats beginning 2 weeks prior to mating. Use In Specific Populations Pregnancy Pregnancy Category B Animal reproductive toxicity studies have been conducted with ceftazidime and with avibactam. However, there are no adequate and well-controlled studies of AVYCAZ, ceftazidime, or avibactam in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used in pregnancy only if clearly needed. Ceftazidime Reproduction studies have been performed in mice and rats at doses up to 40 times the human dose and showed no evidence of harm to the fetus due to ceftazidime. Avibactam Avibactam was not teratogenic in rats or rabbits. In the rat, intravenous studies showed no embryofetal toxicity at doses of 1000 mg/kg/day, approximately 9 times the human dose based on exposure (AUC). In a rat pre-and postnatal study at up to 825 mg/kg/day intravenously (11 times the human exposure based on AUC), there were no effects on pup growth and viability. A dose-related increase in the incidence of renal pelvic and ureter dilatation was observed in female weanling pups that was not associated with pathological changes to renal parenchyma or renal function, with renal pelvic dilatation persisting after female weanling pups became adults. Reproductive studies performed during early pregnancy in rabbits showed no effects on embryofetal development at doses of 100 mg/kg, twice the human exposure (AUC). At higher doses, increased post-implantation loss, lower mean fetal weights, delayed ossification of several bones and other anomalies were observed. Nursing Mothers Ceftazidime is excreted in human milk in low concentrations. It is not known whether avibactam is excreted into human milk, although avibactam was shown to be excreted in the milk of rats in a dose dependent manner. Exercise caution if AVYCAZ is to be administered to a nursing woman. Pediatric Use Safety and effectiveness in patients less than 18 years of age have not been established. Geriatric Use Of the 169 patients treated with AVYCAZ in the Phase 2 cIAI and cUTI trials, 18 (10.7%) were 65 years of age and older. Because of limited data, differences in outcomes or specific risks with AVYCAZ cannot be ruled out for patients 65 years of age and older. Ceftazidime and avibactam are excreted primarily by the kidney, and the risk of adverse reactions may be greater in patients with renal impairment. Because elderly patients are more likely to have renal impairment, care should be taken in dose selection in this age group and it may be useful to monitor renal function. Healthy elderly subjects had 17% greater exposure relative to healthy young subjects when administered the same single dose of avibactam, which may have been related to decreased renal function in the elderly subjects. Dosage adjustment for elderly patients should be based on renal function [see DOSAGE AND ADMINISTRATION and CLINICAL PHARMACOLOGY]. Renal Impairment Dosage adjustment is required in patients with moderately or severely impaired renal function (CrCL 50 mL/min or less). For patients with changing renal function, CrCL should be monitored at least daily and dosage of AVYCAZ adjusted accordingly. Both ceftazidime and avibactam are hemodialyzable; thus, AVYCAZ should be administered after hemodialysis on hemodialysis days [see DOSAGE AND ADMINISTRATION and CLINICAL PHARMACOLOGY]. Last reviewed on RxList: 3/10/2015
This monograph has been modified to include the generic and brand name in many instances.