Safety - Adverse Reactions

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, 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 also may not reflect rates observed in practice.

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 ≥20, indicating a high severity of illness for many patients enrolled in this trial.

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

Adverse Reactions Occurring in 2% or Greater of Patients Receiving ZERBAXA in a Phase 3 HABP/VABP Clinical Trial

Adverse Reactions
Adverse Reactions	ZERBAXA^aN=361 n (%)	Meropenem N=359 n (%)
Hepatic transaminase increased^b	43 (11.9)	26 (7.2)
Renal impairment/renal failure^c	32 (8.9)	22 (6.1)
Diarrhea	23 (6.4)	25 (7.0)
Intracranial hemorrhage^d	16 (4.4)	5 (1.4)
Vomiting	12 (3.3)	10 (2.8)
Clostridium difficile colitis^e	10 (2.8)	2 (0.6)

(a) The ZERBAXA for injection dose was 3 g intravenously every 8 hours, adjusted to match renal function where appropriate.
(b) Includes alanine aminotransferase increased, aspartate aminotransferase increased, hepatic enzyme increased, hypertransaminasaemia, liver function test abnormal.
(c) Includes acute renal failure, anuria, azotemia, oliguria, prerenal failure, renal failure, renal impairment.
(d) Includes cerebellar hemorrhage, cerebral hematoma, cerebral hemorrhage, hemorrhage intracranial, hemorrhagic stroke, hemorrhagic transformation stroke, intraventricular hemorrhage, subarachnoid hemorrhage, subdural hematoma.
(e) Includes Clostridium difficile colitis, Clostridium difficile infection, Clostridium test positive.

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.

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 treated with comparator (levofloxacin 750 mg daily in cUTI or meropenem 1 g every 8 hours in cIAI) for up to 14 days. The mean age of treated patients was 48 to 50 years (range 18 to 92 years), across treatment arms and indications. In both indications, about 25% of the subjects were 65 years of age or older. Most patients (75%) enrolled in the cUTI trial were female, and most patients (58%) enrolled in the cIAI trial were male. Most patients (>70%) in both trials were enrolled in Eastern Europe and were White.

The most common adverse reactions (5% or greater in either indication) occurring in patients receiving ZERBAXA were nausea, diarrhea, headache, and pyrexia. The table below lists adverse reactions occurring in 1% or greater of patients receiving ZERBAXA in Phase 3 cIAI and cUTI clinical trials.

Adverse Reactions Occurring in 1% or Greater of Patients Receiving ZERBAXA in Phase 3 cIAI and cUTI Clinical Trials

Preferred Term	Complicated Intra-abdominal Infections		Complicated Urinary Tract Infections, Including Pyelonephritis
Preferred Term	ZERBAXA^a(N=482) n (%)	Meropenem (N=497) n (%)	ZERBAXA^a(N=533) n (%)	Levofloxacin (N=535) n (%)
Nausea	38 (7.9)	29 (5.8)	15 (2.8)	9 (1.7)
Headache	12 (2.5)	9 (1.8)	31 (5.8)	26 (4.9)
Diarrhea	30 (6.2)	25 (5)	10 (1.9)	23 (4.3)
Pyrexia	27 (5.6)	20 (4)	9 (1.7)	5 (0.9)
Constipation	9 (1.9)	6 (1.2)	21 (3.9)	17 (3.2)
Insomnia	17 (3.5)	11 (2.2)	7 (1.3)	14 (2.6)
Vomiting	16 (3.3)	20 (4)	6 (1.1)	6 (1.1)
Hypokalemia	16 (3.3)	10 (2)	4 (0.8)	2 (0.4)
ALT increased	7 (1.5)	5 (1)	9 (1.7)	5 (0.9)
AST increased	5 (1)	3 (0.6)	9 (1.7)	5 (0.9)
Anemia	7 (1.5)	5 (1)	2 (0.4)	5 (0.9)
Thrombocytosis	9 (1.9)	5 (1)	2 (0.4)	2 (0.4)
Abdominal pain	6 (1.2)	2 (0.4)	4 (0.8)	2 (0.4)
Anxiety	9 (1.9)	7 (1.4)	1 (0.2)	4 (0.7)
Dizziness	4 (0.8)	5 (1)	6 (1.1)	1 (0.2)
Hypotension	8 (1.7)	4 (0.8)	2 (0.4)	1 (0.2)
Atrial fibrillation	6 (1.2)	3 (0.6)	1 (0.2)	0
Rash	8 (1.7)	7 (1.4)	5 (0.9)	2 (0.4)

(a) The ZERBAXA for injection dose was 1.5 g intravenously every 8 hours, adjusted to match renal function where appropriate. In the cIAI trials, ZERBAXA was given in conjunction with metronidazole.

Treatment discontinuation due to adverse events occurred in 2.0% (20/1015) of patients receiving ZERBAXA and 1.9% (20/1032) of patients receiving comparator drugs. Renal impairment (including the terms renal impairment, renal failure, and renal failure acute) led to discontinuation of treatment in 5/1015 (0.5%) subjects receiving ZERBAXA and none in the comparator arms.

Increased Mortality

In the cIAI trials (Phase 2 and 3), death occurred in 2.5% (14/564) of patients receiving ZERBAXA and in 1.5% (8/536) of patients receiving meropenem. The causes of death varied and included worsening and/or complications of infection, surgery and underlying conditions.

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

The following selected adverse reactions were reported in ZERBAXA-treated subjects at a rate of less than 1%:

Cardiac disorders: tachycardia, angina pectoris
Gastrointestinal disorders: gastritis, abdominal distension, dyspepsia, flatulence, ileus paralytic
General disorders and administration site conditions: infusion site reactions
Infections and infestations: candidiasis including oropharyngeal and vulvovaginal, fungal urinary tract infection
Investigations: increased serum gamma-glutamyl transpeptidase (GGT), increased serum alkaline phosphatase, positive Coombs test
Metabolism and nutrition disorders: hyperglycemia, hypomagnesemia, hypophosphatemia
Nervous system disorders: ischemic stroke
Renal and urinary system: renal impairment, renal failure
Respiratory, thoracic and mediastinal disorders: dyspnea
Skin and subcutaneous tissue disorders: urticaria
Vascular disorders: venous thrombosis

Indications

ZERBAXA is indicated for the treatment of patients 18 years and older with hospital-acquired bacterial pneumonia and ventilator-associated bacterial pneumonia (HABP/VABP), caused by the following susceptible Gram-negative microorganisms: Enterobacter cloacae, Escherichia coli, Haemophilus influenzae, Klebsiella oxytoca, Klebsiella pneumoniae, Proteus mirabilis, Pseudomonas aeruginosa, and Serratia marcescens.

ZERBAXA is indicated for the treatment of patients 18 years and older with complicated urinary tract infections (cUTI), including pyelonephritis, caused by the following susceptible Gram-negative microorganisms: Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, and Pseudomonas aeruginosa.

ZERBAXA used in combination with metronidazole is indicated for the treatment of patients 18 years and older with complicated intra-abdominal infections (cIAI) caused by the following susceptible Gram-negative and Gram-positive microorganisms: Enterobacter cloacae, Escherichia coli, Klebsiella oxytoca, Klebsiella pneumoniae, Proteus mirabilis, Pseudomonas aeruginosa, Bacteroides fragilis, Streptococcus anginosus, Streptococcus constellatus, and Streptococcus salivarius.

Usage

To reduce the development of drug-resistant bacteria and maintain the effectiveness of ZERBAXA and other antibacterial drugs, ZERBAXA should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy.

Selected Safety Information

Patients with renal impairment: Decreased efficacy of ZERBAXA has been observed in patients with baseline CrCl of 30 to ≤ 50 mL/min. In a clinical trial, patients with cIAIs with CrCl > 50 mL/min had a clinical cure rate of 85.2% when treated with ZERBAXA plus metronidazole vs 87.9% when treated with meropenem. In the same trial, patients with CrCl 30 to ≤ 50 mL/min had a clinical cure rate of 47.8% when treated with ZERBAXA plus metronidazole vs 69.2% when treated with meropenem. A similar trend was also seen in the cUTI trial. Dose adjustment is required for patients with CrCl 50 mL/min or less. All doses of ZERBAXA are administered over 1 hour. Monitor CrCl at least daily in patients with changing renal function and adjust the dose of ZERBAXA accordingly.
Hypersensitivity: ZERBAXA is contraindicated in patients with known serious hypersensitivity to the components of ZERBAXA (ceftolozane/tazobactam), piperacillin/tazobactam, or other members of the beta-lactam class. Serious and occasionally fatal hypersensitivity (anaphylactic) reactions have been reported in patients receiving beta-lactam antibacterials. Before initiating therapy with ZERBAXA, make careful inquiry about previous hypersensitivity reactions to cephalosporins, penicillins, or other beta-lactams. If an anaphylactic reaction to ZERBAXA occurs, discontinue use and institute appropriate therapy.
Clostridium difficile-associated diarrhea (CDAD), ranging from mild diarrhea to fatal colitis, has been reported with nearly all systemic antibacterial agents, including ZERBAXA. Careful medical history is necessary because CDAD has been reported to occur more than 2 months after the administration of antibacterial agents. If CDAD is confirmed, antibacterial use not directed against C. difficile should be discontinued, if possible.
Development of drug-resistant bacteria: Prescribing ZERBAXA in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and risks the development of drug-resistant bacteria.
Adverse reactions: The most common adverse reactions occurring in ≥5% of patients in the HABP/VABP trial were hepatic transaminase increased (11.9%), renal impairment/renal failure (8.9%), and diarrhea (6.4%).
The most common adverse reactions occurring in ≥5% of patients in the cUTI and cIAI trials were headache (5.8%) in the cUTI trial, and nausea (7.9%), diarrhea (6.2%), and pyrexia (5.6%) in the cIAI trial.

Before prescribing ZERBAXA, please read the accompanying Prescribing Information.

Indications

Usage

Selected Safety Information

Patients with renal impairment: Decreased efficacy of ZERBAXA has been observed in patients with baseline CrCl of 30 to ≤ 50 mL/min. In a clinical trial, patients with cIAIs with CrCl > 50 mL/min had a clinical cure rate of 85.2% when treated with ZERBAXA plus metronidazole vs 87.9% when treated with meropenem. In the same trial, patients with CrCl 30 to ≤ 50 mL/min had a clinical cure rate of 47.8% when treated with ZERBAXA plus metronidazole vs 69.2% when treated with meropenem. A similar trend was also seen in the cUTI trial. Dose adjustment is required for patients with CrCl 50 mL/min or less. All doses of ZERBAXA are administered over 1 hour. Monitor CrCl at least daily in patients with changing renal function and adjust the dose of ZERBAXA accordingly.
Hypersensitivity: ZERBAXA is contraindicated in patients with known serious hypersensitivity to the components of ZERBAXA (ceftolozane/tazobactam), piperacillin/tazobactam, or other members of the beta-lactam class. Serious and occasionally fatal hypersensitivity (anaphylactic) reactions have been reported in patients receiving beta-lactam antibacterials. Before initiating therapy with ZERBAXA, make careful inquiry about previous hypersensitivity reactions to cephalosporins, penicillins, or other beta-lactams. If an anaphylactic reaction to ZERBAXA occurs, discontinue use and institute appropriate therapy.
Clostridium difficile-associated diarrhea (CDAD), ranging from mild diarrhea to fatal colitis, has been reported with nearly all systemic antibacterial agents, including ZERBAXA. Careful medical history is necessary because CDAD has been reported to occur more than 2 months after the administration of antibacterial agents. If CDAD is confirmed, antibacterial use not directed against C. difficile should be discontinued, if possible.
Development of drug-resistant bacteria: Prescribing ZERBAXA in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and risks the development of drug-resistant bacteria.
Adverse reactions: The most common adverse reactions occurring in ≥5% of patients in the HABP/VABP trial were hepatic transaminase increased (11.9%), renal impairment/renal failure (8.9%), and diarrhea (6.4%).
The most common adverse reactions occurring in ≥5% of patients in the cUTI and cIAI trials were headache (5.8%) in the cUTI trial, and nausea (7.9%), diarrhea (6.2%), and pyrexia (5.6%) in the cIAI trial.

Before prescribing ZERBAXA, please read the accompanying Prescribing Information.

US-ZER-0014107/19