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Guide
Drug Safety-related Labeling Changes (SrLC) Database
| ANDA | Abbreviated New Drug Application |
| BLA | Biologics License Application |
| CDER | Center for Drug Evaluation and Research |
| MG | Medication Guide |
| NDA | New Drug Application |
| PCI | Patient Counseling Information |
| PI | Patient Information |
| PLR | Physician Labeling Rule |
| PLLR | Pregnancy and Lactation Labeling Rule |
| Italics | For the most part, italics indicate an FDA comment such as:
Additions and/or revisions underlined These italics usually appear at the beginning of the section. In some cases, italics may be an inherent part of the label, and will most often appear in the body of the section. |
| Underlines | Any text that is underlined indicates text that has been added or revised. There are exceptions where underlining occurs in a section subtitle or heading. This is the case when there is just one word underlined in the body of the text. |
Sections
| BW | Box Warning |
| WP | Warnings and Precautions all in one section (PLR-format) Warnings as one section (pre-PLR format) Precautions as one section (pre-PLR format) |
| AR | Adverse Reactions (in pre-PLR format, this may be a subheading under precautions). |
| DI | Drug Interactions (in pre-PLR format, this may be a subheading under precautions). |
| USP | Use in Specific Populations (Inclusive on one or more of the following: Pregnancy; Lactation (PLLR- format); Nursing Mothers (pre-PLLR format); Females and Males of Reproductive Potential (PLLR format only); Pediatric Use, Geriatric Use, Renal Impairment, Hepatic Impairment, Sex, Race (these last six may be a subheading of precautions if label in pre-PLLR format. |
| PCI/PI/MG | Patient Counseling Information (PLR format only) - summarizes the information that a health care provider should convey to a patient (or caregiver when applicable) when a counseling discussion is taking place (e.g., a physician prescribing a drug during an office visit, a nurse providing discharge instructions at a hospital, or a pharmacist conveying information at a pharmacy). Patient Information - FDA approved patient labeling. Medication Guide - paper handouts that come with many prescription medicines. The guides address issues that are specific to particular drugs and drug classes, and they contain FDA-approved information that can help patients avoid serious adverse events. |
Only NDAs and CDER regulated BLAs are included in this database. ANDAs are not included.
Applications that remain active, even if the product has been discontinued, undergo safety-related labeling changes.
AVYCAZ (NDA-206494)
(AVIBACTAM SODIUM; CEFTAZIDIME)
Safety-related Labeling Changes Approved by FDA Center for Drug Evaluation and Research (CDER)
02/28/2025 (SUPPL-13)
6 Adverse Reactions
6.2 Postmarketing Experience
Additions and/or revisions underlined:
The following adverse reactions and altered laboratory tests have been identified during post approval use of ceftazidime (a component of AVYCAZ), or other cephalosporin-class antibacterial drugs. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Colitis, toxic nephropathy, hepatic dysfunction including cholestasis, hemorrhage, pancytopenia, aplastic anemia, prolonged prothrombin time, false-positive test for urinary glucose. Acute myocardial ischemia with or without myocardial infarction may occur as part of an allergic reaction.
01/26/2024 (SUPPL-12)
6 Adverse Reactions
6.1 Clinical Trials Experience
Additions and/or revisions underlined:
Other Adverse Reactions of AVYCAZ and Ceftazidime in Adults
Direct Coombs’ Test Seroconversion with AVYCAZ
In the Phase 3 trials, seroconversion from a negative to a positive direct Coombs’ test result among patients with an initial negative Coombs’ test and at least one follow up test occurred in 3% (cUTI), 12.9% (cIAI), and 21.4% (HABP/VABP) of patients receiving AVYCAZ and 0.9% (cUTI), 3% (cIAI) and 7% (HABP/VABP) of patients receiving a carbapenem comparator.
…
Adverse Reactions with Ceftazidime
Additionally, adverse reactions reported with ceftazidime alone that were not reported in AVYCAZ-treated patients in the Phase 3 trials are listed below:
…
Nervous system disorders – Paresthesia, seizures, encephalopathy, coma, asterixis, neuromuscular excitability, myoclonia
…
Hypersensitivity Reactions– Anaphylaxis, Angioedema, Erythema multiforme, Stevens-Johnson syndrome, Toxic epidermal necrolysis
Clinical Trials Experience in Pediatric Patients
Pediatric Patients Aged 3 months to less than 18 years
…
There were no deaths reported in the trials of cUTI, cIAI, and HABP/VABP in pediatric patients aged 3 months and older. Treatment discontinuation due to adverse reactions in the pediatric cUTI and cIAI trials occurred in 2.3% (3/128) of patients receiving AVYCAZ and 0/50 of patients receiving comparator drugs. The most common adverse reactions occurring in greater than 3% of pediatric patients aged 3 months to < 18 years treated with AVYCAZ were vomiting, diarrhea, rash, and infusion site phlebitis.
Pediatric Patients less than 3 months of Age
AVYCAZ was also evaluated in a trial enrolling 46 pediatric patients less than three months of age as follows: infants > 28 days to < 3 months (N=17), term neonates from birth to 28 days, (N=13), pre-term neonates from birth (gestational age greater than or equal to 31 weeks) to 28 days (N=16). The median age of patients treated with AVYCAZ was 24 days. In this single-arm trial, 25 patients with a suspected or confirmed bacterial infection received a single- dose of AVYCAZ and 21 patients with suspected or confirmed serious gram-negative infections received multiple doses of AVYCAZ [see Dosage and Administration (2.2)]. The demographics of patients treated with AVYCAZ were female (54%), male (46%); racial groups of White (78%), Asian (11%), Black or African American (9%); ethnicities of Not Hispanic or Latino (91.3%); Hispanic or Latino (4.3%). In patients treated with multiple doses of AVYCAZ [see Dosage and Administration (2.2)], the mean treatment duration was 6 days and maximum treatment duration was 12 days.
There was one death reported in the trial for pediatric patients less than 3 months of age. There were no treatment discontinuations due to adverse reactions. The most common adverse reactions occurring in greater than 3% of pediatric patients less than 3 months of age were vomiting and increased transaminases.
The safety profile of AVYCAZ in pediatric patients was similar to adults with cIAI, cUTI, and HABP/VABP treated with AVYCAZ.
6.2 Postmarketing Experience
Newly added subsection:
The following adverse reactions and altered laboratory tests have been identified during post approval use of ceftazidime (a component of AVYCAZ), or other cephalosporin-class antibacterial drugs. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Colitis, toxic nephropathy, hepatic dysfunction including cholestasis, hemorrhage, pancytopenia, aplastic anemia, prolonged prothrombin time, false-positive test for urinary glucose.
8 Use in Specific Populations
8.4 Pediatric UseAdditions and/or revisions underlined:
The safety and effectiveness of AVYCAZ in the treatment of cUTI, cIAI, and HABP/VABP have been established in pediatric patients at least 31 weeks gestational age and older. Use of AVYCAZ is supported by evidence from adequate and well-controlled studies of AVYCAZ in adults with cUTI, cIAI, and HABP/VABP and additional pharmacokinetic and safety data from pediatric trials [see Clinical Pharmacology (12.3), Clinical Studies (14.1 and 14.2)].
The safety profile of AVYCAZ in pediatric patients was similar to adults with cIAI, cUTI, and HABP/VABP treated with AVYCAZ [see Adverse Reactions (6.1)].
The safety and effectiveness of AVYCAZ in the treatment of cUTI, cIAI, and HABP/VABP have not been established in pediatric patients less than 31 weeks gestational age.
12/20/2022 (SUPPL-11)
5 Warnings and Precautions
5.5 Development of Drug-Resistant BacteriaAdditions and revisions underlined:
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
. . .
Additions and revisions underlined:
Clinical Trials Experience in Pediatric Patients
. . .
An open-label single-dose pharmacokinetic (PK) and safety trial was conducted in pediatric patients with HABP/VABP and enrolled four patients aged 11.6 months to 9.4 years [see Clinical Pharmacology 12.3]
The safety profile of AVYCAZ in pediatric patients was similar to adults with cIAI, cUTI, and HABP/VABP treated with AVYCAZ.
There were no deaths reported in the pediatric trials. Treatment discontinuation due to adverse reactions in the pediatric cUTI and cIAI trials occurred in 2.3% (3/128) of patients receiving AVYCAZ and 0/50 of patients receiving comparator drugs.
. . .
8 Use in Specific Populations
8.4 Pediatric UseAdditions and revisions underlined:
The safety and effectiveness of AVYCAZ in the treatment of cUTI, cIAI, and HABP/VABP have been established in pediatric patients aged 3 months to less than 18 years. Use of AVYCAZ is supported by evidence from adequate and well-controlled studies of AVYCAZ in adults with cUTI, cIAI, and HABP/VABP and additional pharmacokinetic and safety data from pediatric trials [see Clinical Pharmacology (12.3), Clinical Studies (14.1 and 14.2)].
The safety profile of AVYCAZ in pediatric patients was similar to adults with cIAI, cUTI, and HABP/VABP treated with AVYCAZ [see Adverse Reactions (6.1)].
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
PATIENT COUNSELING INFORMATIONAdditions and revisions underlined:
Antibacterial Resistance
Patients should be counseled that antibacterial drugs including AVYCAZ should only be used to treat bacterial infections.
03/14/2019 (SUPPL-5)
6 Adverse Reactions
6.1 Clinical Trials Experience(Additions and/or revisions are underlined)
Clinical Trials Experience in Pediatric Patients
AVYCAZ was evaluated in 128 pediatric patients aged 3 months to <18 years in two single-blind, randomized, active controlled clinical trials one in patients with cUTI and the other in patients with cIAI. Safety data from the two studies were pooled. The AVYCAZ dosing regimen was the same in each trial with a mean treatment duration of 6 days and a maximum of 14 days. The regimen was selected to result in pediatric drug exposure comparable to that of adults and in the cIAI trial metronidazole was administered concurrently with AVYCAZ. Patients were randomized 3:1 to receive AVYCAZ or comparator which was meropenem or cefepime in the cIAI and cUTI trials respectively. The median age of patients treated with AVYCAZ was 8.6 years and in the comparator group 7.4 years. The majority of patients treated with AVYCAZ were female (57%) and Caucasian (80%).
The safety profile of AVYCAZ in pediatric patients was similar to adults with cIAI and cUTI treated with AVYCAZ.
There were no deaths reported in either trial. Treatment discontinuation due to adverse reactions occurred in 2.3% (3/128) of patients receiving AVYCAZ and 0/50 of patients receiving comparator drugs.
The most common adverse reactions occurring in greater than 3% of pediatric patients treated with AVYCAZ were vomiting diarrhea rash and infusion site phlebitis.
8 Use in Specific Populations
8.3 Pediatric Use(Additions and/or revisions are underlined)
The safety and effectiveness of AVYCAZ in the treatment of cUTI and cIAI have been established in pediatric patients 3 months to less than 18 years. Use of AVYCAZ in these age groups is supported by evidence from adequate and well controlled studies of AVYCAZ in adults with cUTI and cIAI and additional pharmacokinetic and safety data from pediatric trials.
The safety profile of AVYCAZ in pediatric patients was similar to adults with cIAI and cUTI treated with AVYCAZ.
Safety and effectiveness in pediatric patients below the age of 3 months with cUTI or cIAI have not been established. There is insufficient information to recommend dosage adjustment for pediatric patients younger than 2 years of age with cIAI and cUTI and renal impairment.
Safety and effectiveness in pediatric patients less than 18 years of age with HABP VABP have not been established.
(Additions and/or revisions are underlined)
Dosage adjustment is also required in pediatric patients with cIAI or cUTI and renal impairment from 2 years to <18 years with eGFR 50 mL/min/1.73m^2 or less. There is insufficient information to recommend a dosing regimen for pediatric patients younger than 2 years of age with cIAI or cUTI and renal impairment.03/14/2019 (SUPPL-6)
6 Adverse Reactions
6.1 Clinical Trials Experience(Additions and/or revisions are underlined)
Clinical Trials Experience in Pediatric Patients
AVYCAZ was evaluated in 128 pediatric patients aged 3 months to <18 years in two single-blind, randomized, active controlled clinical trials one in patients with cUTI and the other in patients with cIAI. Safety data from the two studies were pooled. The AVYCAZ dosing regimen was the same in each trial with a mean treatment duration of 6 days and a maximum of 14 days. The regimen was selected to result in pediatric drug exposure comparable to that of adults and in the cIAI trial metronidazole was administered concurrently with AVYCAZ. Patients were randomized 3:1 to receive AVYCAZ or comparator which was meropenem or cefepime in the cIAI and cUTI trials respectively. The median age of patients treated with AVYCAZ was 8.6 years and in the comparator group 7.4 years. The majority of patients treated with AVYCAZ were female (57%) and Caucasian (80%).
The safety profile of AVYCAZ in pediatric patients was similar to adults with cIAI and cUTI treated with AVYCAZ.
There were no deaths reported in either trial. Treatment discontinuation due to adverse reactions occurred in 2.3% (3/128) of patients receiving AVYCAZ and 0/50 of patients receiving comparator drugs.
The most common adverse reactions occurring in greater than 3% of pediatric patients treated with AVYCAZ were vomiting diarrhea rash and infusion site phlebitis.
8 Use in Specific Populations
8.3 Pediatric Use(Additions and/or revisions are underlined)
The safety and effectiveness of AVYCAZ in the treatment of cUTI and cIAI have been established in pediatric patients 3 months to less than 18 years. Use of AVYCAZ in these age groups is supported by evidence from adequate and well controlled studies of AVYCAZ in adults with cUTI and cIAI and additional pharmacokinetic and safety data from pediatric trials.
The safety profile of AVYCAZ in pediatric patients was similar to adults with cIAI and cUTI treated with AVYCAZ.
Safety and effectiveness in pediatric patients below the age of 3 months with cUTI or cIAI have not been established. There is insufficient information to recommend dosage adjustment for pediatric patients younger than 2 years of age with cIAI and cUTI and renal impairment.
Safety and effectiveness in pediatric patients less than 18 years of age with HABP VABP have not been established.
(Additions and/or revisions are underlined)
Dosage adjustment is also required in pediatric patients with cIAI or cUTI and renal impairment from 2 years to <18 years with eGFR 50 mL/min/1.73m^2 or less. There is insufficient information to recommend a dosing regimen for pediatric patients younger than 2 years of age with cIAI or cUTI and renal impairment.
02/01/2018 (SUPPL-4)
5 Warnings and Precautions
5.1 Decreased Clinical Response in cIAI Patients with Baseline Creatinine Clearance of 30 to Less Than or Equal to 50 mL/min(Additions and/or revisions are underlined)
In a Phase 3 cIAI trial, 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 8)…
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.
6 Adverse Reactions
6.1 Clinical Trial Experience(Additions and/or revisions are underlined)
…
AVYCAZ was evaluated in six active-controlled clinical trials in patients with cIAI, cUTI, including pyelonephritis, or HABP/VABP. These trials included two Phase 2 trials, one in cIAI and one in cUTI, as well as four Phase 3 trials, one in cIAI, one in cUTI (Trial 1), one in cIAI or cUTI due to ceftazidime non-susceptible pathogens (Trial 2) and one in HABP/VABP. Data from cUTI Trial 1 served as the primary dataset for AVYCAZ safety findings in cUTI as there was a single comparator. cUTI Trial 2 had an open-label design as well as multiple comparator regimens which prevented pooling, but provided supportive information. The six clinical trials included a total of 1809 adult patients treated with AVYCAZ and 1809 patients treated with comparators.
Complicated Intra-abdominal Infections
…
Table 9 lists adverse reactions occurring in 1% or more of patients receiving AVYCAZ plus metronidazole and with incidences greater than the comparator in the Phase 3 cIAI clinical trial.
Table 9. Incidence of Selected Adverse Reactions Occurring in 1% or more of Patients Receiving AVYCAZ in the Phase 3 cIAI Trial
Complicated Urinary Tract Infections, Including Pyelonephritis
The Phase 3 cUTI Trial 1 included 511 adult patients treated with AVYCAZ 2.5 grams (ceftazidime 2 grams and avibactam 0.5 grams) administered intravenously over 120 minutes every 8 hours and 509 patients treated with doripenem; in some patients parenteral therapy was followed by a switch to an oral antimicrobial agent. Median age of patients treated with AVYCAZ was 54 years (range 18 to 89 years) and 30.7% of patients were 65 years of age or older…
Table 10 lists adverse reactions occurring in 1% or more of patients receiving AVYCAZ and with incidences greater than the comparator in Trial 1.
Table 10. Incidence of Selected Adverse Drug Reactions Occurring in 1% or more of Patients Receiving AVYCAZ in the Phase 3 cUTI Trial 1
Hospital-acquired Bacterial Pneumonia/Ventilator-associated Bacterial Pneumonia
The Phase 3 HABP/VABP trial included 436 adult patients treated with AVYCAZ 2.5 grams (ceftazidime 2 grams and avibactam 0.5 grams) administered intravenously over 120 minutes and 434 patients treated with meropenem. The median age of patients treated with AVYCAZ was 66 years (range 18 to 89 years) and 54.1% of patients were 65 years of age or older. Patients were predominantly male (74.5%) and Asian (56.2%).
Death occurred in 9.6% (42/ 436) of patients who received AVYCAZ and in 8.3% (36/434) of patients who received meropenem. Treatment discontinuation due to an adverse reaction occurred in 3.7% (16/436) of patients receiving AVYCAZ and 3% (13/434) of patients receiving meropenem. There was no specific adverse reaction leading to discontinuation.
Adverse reactions occurring at 5% or greater in patients receiving AVYCAZ were diarrhea and vomiting.
Table 11 lists selected adverse reactions occurring in 1% or more of patients receiving AVYCAZ and with incidences greater than the comparator in the Phase 3 HABP/VABP clinical trial.
Table 11. Incidence of Selected Adverse Drug Reactions Occurring in 1% or more of Patients Receiving AVYCAZ in the Phase 3 HABP/VABP Trial (Table has been added; please refer to label)
Other Adverse Reactions of AVYCAZ and Ceftazidime
The following selected adverse reactions were reported in AVYCAZ-treated patients at a rate of less than 1% in
the Phase 3 trials and are not described elsewhere in the labeling.
Blood and lymphatic disorders - Thrombocytopenia, Thrombocytosis, Leukopenia
…
Laboratory Changes
In the Phase 3 trials, seroconversion from a negative to a positive direct Coombs’ test result among patients with an initial negative Coombs’ test and at least one follow up test occurred in 3.0% (cUTI), 12.9% (cIAI), and 21.4% (HABP/VABP) of patients receiving AVYCAZ and 0.9% (cUTI), 3% (cIAI) and 7% (HABP/VABP) of patients receiving a carbapenem comparator…
8 Use in Specific Populations
8.5 Geriatric Use(Additions and/or revisions are underlined)
Of the 1809 patients treated with AVYCAZ in the Phase 2 and Phase 3 clinical trials 621 (34.5%) were 65 years of age and older, including 302 (16.7 %) patients 75 years of age and older.
…
In the Phase 3 HABP/VABP trial, 54.1% (236/436) of patients treated with AVYCAZ were 65 years of age or older, including 129 (29.6%) patients 75 years of age or older. The incidence of adverse reactions in patients greater than or equal to 65 years of age was similar to patients < 65 years of age. The 28-day all-cause mortality was similar between treatment groups for patients 65 years of age or older (12.7% [29/229] for patients in the AVYCAZ arm and 11.3% [26/230] for patients in the meropenem arm).
01/26/2017 (SUPPL-3)
5 Warnings and Precautions
5.1 Decreased Clinical Response in cIAI Patients with Baseline Creatinine Clearance of 30 to Less Than or Equal to 50 mL/min(Additions and/or revisions are underlined; revised subsection title)
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.
6 Adverse Reactions
6.1 Clinical Trial Experience(Additions and/or revisions are underlined)
AVYCAZ was evaluated in five active-controlled clinical trials in patients with cIAI or cUTI, including pyelonephritis. These trials included two Phase 2 trials, one in cIAI and one in cUTI, as well as three Phase 3 trials, one in cIAI, one in cUTI (Trial 1), and one in cIAI or cUTI due to ceftazidime non-susceptible pathogens (Trial 2). Data from Trial 1 served as the primary dataset for AVYCAZ safety findings in cUTI as there was a single comparator. Trial 2 had an open-label design as well as multiple comparator regimens which prevented pooling, but provided supportive information. The five clinical trials included a total of 1373 adult patients treated with AVYCAZ and 1375 patients treated with comparators.
Complicated Urinary Tract Infections, Including Pyelonephritis
Trial 1 included 511 adult patients treated with AVYCAZ 2.5 grams (ceftazidime 2 grams and avibactam 0.5 grams) administered intravenously over 120 minutes every 8 hours and 509 patients treated with doripenem; in some patients parenteral therapy was followed by a switch to an oral antimicrobial agent. Median age of patients treated with AVYCAZ was 54 years (range 18 to 89 years). Patients were predominantly female (68.3%) and Caucasian (82.4%). Patients with CrCl less than 30 mL/min were excluded.
There were no deaths in Trial 1. Treatment discontinuation due to adverse reactions occurred in 1.4% (7/511) of patients receiving AVYCAZ and 1.2% (6/509) of patients receiving doripenem. There was no specific adverse reaction leading to discontinuation.
The most common adverse reactions occurring in 3% of cUTI patients treated with AVYCAZ were nausea and diarrhea.
Table 6 lists adverse reactions occurring in 1% or more of patients receiving AVYCAZ and with incidences greater than the comparator in Trial 1. (Table revised; please refer to label)
Other Adverse Reactions of AVYCAZ and Ceftazidime
The following selected adverse reactions were reported in AVYCAZ-treated patients at a rate of less than 1% in the Phase 3 trials and are not described elsewhere in the labeling.
Renal and urinary disorders - Acute renal failure, Renal impairment, Nephrolithiasis
Psychiatric disorders - Anxiety
Additionally, adverse reactions reported with ceftazidime alone that were not reported in AVYCAZ-treated patients in the Phase 3 trials are listed below:
Blood and lymphatic disorders - Agranulocytosis, Hemolytic anemia, Leukopenia, Lymphocytosis, Neutropenia, Thrombocytosis, Eosinophilia
Investigations - Increased blood lactate dehydrogenase, Prolonged prothrombin time
Laboratory Changes
Seroconversion from a negative to a positive direct Coombs’ test result at any time up to the last visit occurred in 31/240 (12.9%) of patients receiving AVYCAZ plus metronidazole with initial negative Coombs’ test and at least one follow up test and in 7/235 (3.0%) of patients receiving meropenem in the Phase 3 cIAI trial.
Seroconversion from a negative to a positive direct Coombs’ test result at any time up to the last visit occurred in 7/216 (3.2%) of patients receiving AVYCAZ with initial negative Coombs’ test and at least one follow up test and 2/214 (0.9%) of patients receiving doripenem in the Phase 3 cUTI trial.
8 Use in Specific Populations
8.5 Geriatric Use(Additions and/or revisions are underlined)
Of the 1373 patients treated with AVYCAZ in the Phase 2 and Phase 3 clinical trials 385 (28%) were 65 years of age and older, including 173 (15.3 %) patients 75 years of age and older.
In the pooled Phase 2 and Phase 3 cIAI AVYCAZ clinical trials, 20% (126/630) of patients treated with AVYCAZ were 65 years of age and older, including 49 (7.8%) patients 75 years of age and older.
In the Phase 3 cUTI trial, 30.7% (157/511) of patients treated with AVYCAZ were 65 years of age or older, including 78 (15.3%) patients 75 years of age or older. The incidence of adverse reactions in both treatment groups was lower in older patients (greater than or equal to 65 years of age) and similar between treatment groups. Among patients 65 years of age or older in the Phase 3 cUTI trial, 66.1% (82/124) of patients treated with AVYCAZ had symptomatic resolution at Day 5 compared with 56.6% (77/136) of patients treated with doripenem. The combined response (microbiological cure and symptomatic response) observed at the test-of-cure (TOC) visit for patients 65 years of age or older were 58.1% (72/124) in the AVYCAZ arm and 58.8% (80/136) in the doripenem arm.
06/22/2016 (SUPPL-2)
6 Adverse Reactions
Clinical Trial Experience- (addition of new paragraph) AVYCAZ was evaluated in four active-controlled clinical trials in patients with cIAI or cUTI, including pyelonephritis. These trials included two Phase 2 trials, one in cIAI and one in cUTI, as well as two Phase 3 trials, one in cIAI and one in cIAI or cUTI due to ceftazidime-resistant pathogens. The four clinical trials included a total of 862 adult patients treated with AVYCAZ and 866 patients treated with comparators.
- The Phase 3 cIAI trial included 529 adult patients treated with AVYCAZ 2.5 grams (ceftazidime 2 grams and avibactam 0.5 grams) administered intravenously over 120 minutes every 8 hours plus 0.5 grams metronidazole administered intravenously over 60 minutes every 8 hours and 529 patients treated with meropenem. The median age of patients treated with AVYCAZ was 50 years (range 18 to 90 years) and 22.5% of patients were 65 years of age or older. Patients were predominantly male (62%) and Caucasian (76.6%).
- Treatment discontinuation due to an adverse reaction occurred in 2.6% (14/529) of patients receiving AVYCAZ plus metronidazole and 1.3% (7/529) of patients receiving meropenem. There was no specific adverse reaction leading to discontinuation.
- Adverse reactions occurring at 5% or greater in patients receiving AVYCAZ plus metronidazole were diarrhea, nausea and vomiting.
- Table 5 lists adverse reactions occurring in 1% or more of patients receiving AVYCAZ plus metronidazole and with incidences greater than the comparator in the Phase 3 cIAI clinical trial.
- Table 5: Has extensively changed; please refer to label.
- Adverse reactions occurring 10% or greater in patients receiving AVYCAZ were constipation and anxiety. Table 6 lists adverse reactions occurring in 5% or more of patients receiving AVYCAZ and with incidences greater than the comparator in the Phase 2 cUTI trial.
- Addition of Table 6: Incidence of Selected Adverse Drug Reactions Occurring in 5% or more of Patients Receiving AVYCAZ in the Phase 2 cUTI Trial; please see label for information.
(updated figures are bolded)
- Among a subgroup of patients with baseline CrCl 30 to less than or equal to 50 mL/min, death occurred in 19.5% (8/41) of patients who received AVYCAZ plus metronidazole and in 7.0% (3/43) of patients who received meropenem.
- In patients with normal renal function or mild renal impairment (baseline CrCl greater than 50 mL/min), death occurred in 1.0% (5/485) of patients who received AVYCAZ plus metronidazole and in 1.0% (5/484) of patients who received meropenem.
- (updated sentence) Seroconversion from a negative to a positive direct Coombs’ test result occurred in 31/240 (12.9%) of patients receiving AVYCAZ plus metronidazole with initial negative Coombs’ test and at least one follow up test and in 7/235 (3.0%) of patients receiving meropenem in the Phase 3 cIAI trial…
The following selected adverse reactions were reported in AVYCAZ-treated subjects at a rate of less than 1% in the Phase 3 cIAI trial or less than 5% in the Phase 2 cUTI trial and are not described elsewhere in the labeling.
- Blood and lymphatic disorders - Eosinophilia, Thrombocytopenia
- General disorders and administration site conditions - Injection site phlebitis
- Infections and infestations - Candidiasis
- Investigations - Increased aspartate aminotransferase, Increased alanine aminotransferase, Increased gamma-glutamyltransferase, Prolonged prothrombin time
- Metabolism and nutrition disorders - Hypokalemia
- Nervous system disorders - Dysgeusia
- Renal and urinary disorders - Acute renal failure, Renal impairment
- Skin and subcutaneous tissue disorders - Rash, Rash maculo-papular, Urticaria, Pruritus
Additionally, adverse reactions reported with ceftazidime alone that were not reported in any AVYCAZ-treated subjects in any AVYCAZ clinical trials are listed below:
- Blood and lymphatic disorders - Agranulocytosis, Hemolytic anemia, Leukopenia, Lymphocytosis,
- Neutropenia, Thrombocytosis
- General disorders and administration site conditions - Infusion site inflammation, Injection site hematoma, Injection site thrombosis
- Hepatobiliary disorders – Jaundice
- Investigations - Increased blood lactate dehydrogenase
- Nervous system disorders - Paresthesia
- Renal and urinary disorders - Tubulointerstitial nephritis
- Reproductive and breast disorders - Vaginal inflammation
- Skin and subcutaneous tissue disorders - Angioedema, Erythema multiforme, Stevens-Johnson syndrome, Toxic epidermal necrolysis
8 Use in Specific Populations
Geriatric Use- (addition) Of the 630 patients in the pooled Phase 2 and Phase 3 cIAI CAZ-AVI clinical trials who were treated with AVYCAZ, 126 (20%) were 65 years of age and older, including 49 (7.8%) 75 years of age and older. In the pooled Phase 2 and Phase 3 cIAI trials, the incidence of adverse reactions in both treatment groups was higher in older patients (= 65 years of age) and similar in both treatment groups. In the Phase 3 cIAI trial, clinical cure rates for patients 65 years of age or older were 73.0% (73/100) in the AVYCAZ plus metronidazole arm and 78.6% (77/98) in the meropenem arm.
- (addition) In the Phase 2 cUTI clinical trial, 11/68 (16.2%) of patients receiving AVYCAZ were 65 years of age or older, including 5/68 (8.8%) 75 years of age or older. Because of limited clinical data in cUTI patients, differences in outcomes or specific risks with AVYCAZ cannot be ruled out for cUTI patients 65 years of age and older.
- (Updates and additions) Ceftazidime and avibactam are known to be substantially excreted by the kidney; therefore, the risk of adverse reactions to ceftazidime and avibactam may be greater in patients with decreased renal function… Dosage adjustment for elderly patients should be based on renal function.