Drug Safety-related Labeling Changes (SrLC)

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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.

ZERBAXA (NDA-206829)

(CEFTOLOZANE SULFATE; TAZOBACTAM SODIUM)

Safety-related Labeling Changes Approved by FDA Center for Drug Evaluation and Research (CDER)

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04/21/2022 (SUPPL-11)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.1 Decreased Efficacy in Patients with Baseline Creatinine Clearance of 30 to 50 mL/min

Additions and/or revisions underlined:

In a subgroup analysis of a Phase 3 cIAI trial of adult patients, clinical cure rates were lower in patients with baseline CrCl of 30 to 50 mL/min compared to those with CrCl greater than 50 mL/min (Table 5). The reduction in clinical cure rates was more marked in the ZERBAXA plus metronidazole arm compared to the meropenem arm. A similar trend was also seen in the cUTI trial. Monitor CrCl at least daily in patients with changing renal function and adjust the dosage of ZERBAXA accordingly [see Dosage and Administration (2.2)].

Table 5: Clinical Cure Rates in a Phase 3 Trial of Adult cIAI Patients by Baseline Renal Function (MITT Population)

…

5.3 Clostridioides difficile-associated Diarrhea

Subsection title revised; Additions and/or revisions underlined:

Clostridioides difficile-associated diarrhea (CDAD) has been reported for nearly all systemic antibacterial agents, including ZERBAXA, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon and may permit overgrowth of C. difficile.

…

6 Adverse Reactions

Additions and/or revisions underlined:

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

Hypersensitivity reactions [see Warnings and Precautions (5.2)]
Clostridioides difficile-associated diarrhea [see Warnings and Precautions (5.3)]

6.1 Clinical Trials Experience

Extensive changes; please refer to label

8 Use in Specific Populations

8.4 Pediatric Use

Additions and/or revisions underlined:

Complicated Intra-abdominal Infections (cIAI) and Complicated Urinary Tract Infections (cUTI), including Pyelonephritis

The safety and effectiveness of ZERBAXA for the treatment of cIAI and cUTI have been established in pediatric patients aged birth to less than 18 years old. Use of ZERBAXA in these age groups is supported by evidence from adequate and well-controlled studies of ZERBAXA in adults with cUTI and cIAI and additional pharmacokinetic and safety data from pediatric trials [see Clinical Pharmacology (12.3) and Clinical Studies (14.1 and 14.2)].

The safety profile of ZERBAXA in pediatric patients was similar to adults with cIAI and cUTI, treated with ZERBAXA [see Adverse Reactions (6.1)].

There is insufficient information to recommend dosage adjustment for pediatric patients younger than 18 years of age with cIAI and cUTI with eGFR 50 mL/min/1.73m2 or less [see Dosage and Administration (2.4) and Clinical Pharmacology (12.3)].

ZERBAXA is not recommended in pediatric patients who have an eGFR 50 mL/min/1.73m2 or less. Pediatric patients born at term or pre-term may not have an eGFR of 50 mL/min/1.73m2 or greater at birth or within the first few months of life.

Hospital-acquired Bacterial Pneumonia and Ventilator-associated Bacterial Pneumonia (HABP/VABP)

The safety and effectiveness of ZERBAXA in pediatric patients have not been established for the treatment of HABP and VABP.

8.6 Patients with Renal Impairment

Additions and/or revisions underlined:

Adult Patients

Dosage adjustment is required in adult patients with CrCl 50 mL/min or less, including adult patients with ESRD on HD [see Dosage and Administration (2.2), Warnings and Precautions (5.1) and Clinical Pharmacology (12.3)].

Pediatric Patients

No dose adjustment has been established in pediatric patients aged birth to less than 18 years of age with eGFR 50 mL/min/1.73 m2 or less [see Clinical Pharmacology (12.3)].

04/21/2022 (SUPPL-12)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.1 Decreased Efficacy in Patients with Baseline Creatinine Clearance of 30 to 50 mL/min

Additions and/or revisions underlined:

Table 5: Clinical Cure Rates in a Phase 3 Trial of Adult cIAI Patients by Baseline Renal Function (MITT Population)

…

5.3 Clostridioides difficile-associated Diarrhea

Subsection title revised; Additions and/or revisions underlined:

…

6 Adverse Reactions

Additions and/or revisions underlined:

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

Hypersensitivity reactions [see Warnings and Precautions (5.2)]
Clostridioides difficile-associated diarrhea [see Warnings and Precautions (5.3)]

6.1 Clinical Trials Experience

Extensive changes; please refer to label

8 Use in Specific Populations

8.4 Pediatric Use

Additions and/or revisions underlined:

Complicated Intra-abdominal Infections (cIAI) and Complicated Urinary Tract Infections (cUTI), including Pyelonephritis

The safety profile of ZERBAXA in pediatric patients was similar to adults with cIAI and cUTI, treated with ZERBAXA [see Adverse Reactions (6.1)].

Hospital-acquired Bacterial Pneumonia and Ventilator-associated Bacterial Pneumonia (HABP/VABP)

The safety and effectiveness of ZERBAXA in pediatric patients have not been established for the treatment of HABP and VABP.

8.6 Patients with Renal Impairment

Additions and/or revisions underlined:

Adult Patients

Pediatric Patients

No dose adjustment has been established in pediatric patients aged birth to less than 18 years of age with eGFR 50 mL/min/1.73 m2 or less [see Clinical Pharmacology (12.3)].

06/03/2019 (SUPPL-8)

Approved Drug Label (PDF)

6 Adverse Reactions

6.1 Clinical Trials Experience

Additions and/or revisions underlined:

Complicated Intra-abdominal Infections and Complicated Urinary Tract Infections, Including Pyelonephritis

ZERBAXA was evaluated in Phase 3 comparator-controlled clinical trials of cIAI and cUTI, which included a total of 1015 patients treated with ZERBAXA (1.5 g every 8 hours, adjusted based on renal function where appropriate) and 1032 patients …

Table 5 lists adverse reactions occurring in 1% or greater of patients receiving ZERBAXA in Phase 3 cIAI and cUTI clinical trials.

Less Common Adverse Reactions in Phase 3 cIAI and cUTI Clinical Trials

The following selected adverse reactions …

Newly added information:

Hospital-acquired Bacterial Pneumonia and Ventilator-associated Bacterial Pneumonia (HABP/VABP)

ZERBAXA was evaluated in a Phase 3 comparator-controlled clinical trial for HABP/VABP, which included a total of 361 patients treated with ZERBAXA (3 g every 8 hours, adjusted based on renal function where appropriate) and 359 patients treated with comparator (meropenem 1 g every 8 hours) for up to 14 days. The mean age of treated patients was 60 years (range 18 to 98 years), across treatment arms. About 44% of the subjects were 65 years of age or older. Most patients (71%) enrolled in the trial were male. All subjects were mechanically ventilated at randomization and 92% were in an intensive care unit (ICU) at randomization. The median APACHE II score was 17, and 33% of subjects had a baseline APACHE II score of greater than or equal to 20, indicating a high severity of illness for many patients enrolled in this trial.

Table 6 lists adverse reactions occurring in 2% or greater of patients receiving ZERBAXA in a Phase 3 HABP/VABP clinical trial.

Table 6: Adverse Reactions Occurring in 2% or Greater of Patients Receiving ZERBAXA in a Phase 3 HABP/VABP Clinical Trial Newly added table; please refer to label for complete information.

Treatment discontinuation due to adverse reactions occurred in 1.1% (4/361) of patients receiving ZERBAXA and 1.4% (5/359) of patients receiving meropenem.

Less Common Adverse Reactions in a Phase 3 HABP/VABP Clinical Trial

The following selected adverse reactions were reported in ZERBAXA-treated subjects at a rate of less than 2%: Investigations: blood alkaline phosphatase increased, gamma-glutamyltransferase increased, Coombs direct test positive.

Laboratory Values

The development of a positive direct Coombs test may occur during treatment with ZERBAXA. The incidence of seroconversion to a positive direct Coombs test was 0.2% in patients receiving ZERBAXA and 0% in patients receiving the comparator in the cUTI and cIAI clinical trials. The incidence of seroconversion to a positive direct Coombs test was 31.2% in patients receiving ZERBAXA and 3.6% in patients receiving meropenem in the HABP/VABP clinical trial. In clinical trials, there was no evidence of hemolysis in patients who developed a positive direct Coombs test in any treatment group.

8 Use in Specific Populations

8.1 Pregnancy

8.2 Lactation

PLLR conversion; please refer to label for complete information.

8.5 Geriatric Use

Additions and/or revisions underlined:

Of the 361 patients treated with ZERBAXA in the Phase 3 HABP/VABP clinical trial, 160 (44.3%) were 65 years or older, including 83 (23%) 75 years or older. The incidence of adverse events in both treatment groups was higher in older subjects (65 years or older). In the trial, Day 28 all-cause mortality rates in the elderly (aged 65 years and older) were comparable between treatment arms:50/160 (31.3%) in the ZERBAXA arm and 54/160 (33.8%) in the comparator arm.

ZERBAXA is substantially excreted by the kidney and the risk of adverse reactions to ZERBAXA may be greater in patients with renal impairment. Because elderly patients …

8.6 Patient with Renal Impairment

Additions and/or revisions underlined:

Dosage adjustment is required in patients with CrCl 50 mL/min or less, including patients with ESRD on HD.

09/06/2016 (SUPPL-2)

Approved Drug Label (PDF)

6 Adverse Reactions

Clinical Trials Experience

Less Common Adverse Reactions

Infections and infestations:

candidiasis (including oropharyngeal and vulvovaginal) (addition in parenthesis)