ZERBAXA SIDE EFFECTS
- Generic Name: ceftolozane and tazobactam for injection
- Brand Name: Zerbaxa
- Drug Class: Cephalosporins, Other
SIDE EFFECTS
The following serious reactions are described in greater detail in the Warnings and Precautions section:
- Hypersensitivity reactions
- Clostridioides difficile-associated diarrhea
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.
Adult Patients
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. Table 1 lists adverse reactions occurring in 1% or greater of patients receiving ZERBAXA in Phase 3 cIAI and cUTI clinical trials.
Table 1: Adverse Reactions Occurring in 1% or Greater of Adult Patients (18 years and older) Receiving ZERBAXA in Phase 3 cIAI and cUTI Clinical Trials
| Adverse Reaction | Complicated Intra-abdominal Infections | Complicated Urinary Tract Infections, Including Pyelonephritis | ||
| ZERBAXA* (N=482) n (%) |
Meropenem (N=497) n (%) |
ZERBAXA* (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) |
| * 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
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.
Table 2 lists adverse reactions occurring in 2% or greater of patients receiving ZERBAXA in a Phase 3 HABP/VABP clinical trial.
Table 2: Adverse Reactions Occurring in 2% or Greater of Adult Patients (18 years and older) Receiving ZERBAXA in a Phase 3 HABP/VABP Clinical Trial
| Adverse Reactions | ZERBAXA* N=361 n (%) |
Meropenem N=359 n (%) |
| Hepatic transaminase increased1 | 43 (11.9) | 26 (7.2) |
| Renal impairment/renal failure2 | 32 (8.9) | 22 (6.1) |
| Diarrhea | 23 (6.4) | 25 (7.0) |
| Intracranial hemorrhage3 | 16 (4.4) | 5 (1.4) |
| Vomiting | 12 (3.3) | 10 (2.8) |
| Clostridioides difficile colitis4 | 10 (2.8) | 2 (0.6) |
| * The ZERBAXA for injection dose was 3 g intravenously every 8 hours, adjusted to match renal function where appropriate. 1 Includes alanine aminotransferase (ALT) increased, aspartate aminotransferase (AST) increased, hepatic enzyme increased, hypertransaminasaemia, liver function test abnormal. 2 Includes acute renal failure, anuria, azotemia, oliguria, prerenal failure, renal failure, renal impairment. 3 Includes cerebellar hemorrhage, cerebral hematoma, cerebral hemorrhage, hemorrhage intracranial, hemorrhagic stroke, hemorrhagic transformation stroke, intraventricular hemorrhage, subarachnoid hemorrhage, subdural hematoma. 4 Includes Clostridioides difficile colitis, Clostridioides difficile infection, Clostridioides test positive. |
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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
Pediatric Patients
Complicated Intra-abdominal Infections And Complicated Urinary Tract Infections, Including Pyelonephritis
ZERBAXA was evaluated in two blinded, randomized, active-controlled clinical studies in pediatric patients from birth to less than 18 years of age, one in cIAI and the other in cUTI, which included a total of 170 pediatric patients treated with ZERBAXA and 54 pediatric patients treated with the comparator. The ZERBAXA dosing regimen was the same in each trial. Patients were randomized 3:1 to receive ZERBAXA plus metronidazole or meropenem plus placebo in the cIAI study and ZERBAXA or meropenem in the cUTI study. In these pediatric patients, the type of adverse reactions were generally comparable to those observed in adults.
Table 3 lists adverse reactions occurring in 4% or greater of pediatric patients receiving ZERBAXA in either the pediatric cIAI or cUTI clinical trial.
Table 3: Adverse Reactions Occurring in 4% or Greater of Pediatric Patients (birth to less than 18 years of age) Receiving ZERBAXA in either the cIAI or cUTI Clinical Trial
| Adverse Reaction | Complicated Intra-abdominal Infections | Complicated Urinary Tract Infections, Including Pyelonephritis | ||
| ZERBAXA* (N=70) n (%) |
Meropenem (N=21) n (%) |
ZERBAXA (N=100) n (%) |
Meropenem (N=33) n (%) |
|
| Thrombocytosis1 | 11 (16) | 3 (14) | 9 (9) | 3 (9) |
| Diarrhea | 12 (17) | 5 (24) | 7 (7) | 3 (9) |
| Pyrexia2 | 9 (13) | 3 (14) | 7 (7) | 1 (3) |
| Leukopenia3 | 3 (4) | 0 (0) | 8 (8) | 0 (0) |
| Abdominal pain4 | 8 (11) | 0 (0) | 2 (2) | 1 (3) |
| AST increased | 5 (7) | 1 (5) | 4 (4) | 2 (6) |
| Vomiting | 7 (10) | 1 (5) | 1 (1) | 1 (3) |
| ALT increased | 4 (6) | 1 (5) | 4 (4) | 2 (6) |
| Anemia | 5 (7) | 0 (0) | 2 (2) | 0 (0) |
| Phlebitis5 | 4 (6) | 0 (0) | 1 (1) | 1 (3) |
| Hypertension | 3(4) | 0 (0) | 0 (0) | 1 (3) |
| Gastritis | 3 (4) | 0 (0) | 0 (0) | 0 (0) |
| Hypokalemia6 | 3 (4) | 0 (0) | 0 (0) | 0 (0) |
| Bradypnea7 | 3 (4) | 0 (0) | 0 (0) | 0 (0) |
| *In the cIAI trials, ZERBAXA was given in conjunction with metronidazole. 1 Includes platelet count increased. 2 Includes hyperthermia. 3 Includes neutropenia and neutrophil count decreased. 4 Includes upper abdominal pain. 5 Includes superficial phlebitis. 6 Includes blood potassium decreased. 7 Includes respiratory rate decreased. |
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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 adult 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 adult HABP/VABP clinical trial. The incidence of seroconversion to a positive direct Coombs test was 45.3% in patients receiving ZERBAXA and 33.3% in patients receiving meropenem in the pediatric cIAI clinical trial. The incidence of seroconversion to a positive direct Coombs test was 29.7% in patients receiving ZERBAXA and 8.7% in patients receiving meropenem in the pediatric cUTI clinical trial. In clinical trials, there was no evidence of hemolysis in patients who developed a positive direct Coombs test in any treatment group.
SRC: NLM .