ZOSYN SIDE EFFECTS
- Generic Name: piperacillin and tazobactam injection
- Brand Name: Zosyn
- Drug Class: Penicillins, Extended-Spectrum
SIDE EFFECTS
The following clinically significant adverse reactions are described elsewhere in the labeling:
- Hypersensitivity Adverse Reactions
- Severe Cutaneous Adverse Reactions
- Hemophagocytic Lymphohistiocytosis
- Hematologic Adverse Reactions
- Central Nervous System Adverse Reactions
- Nephrotoxicity in Critically Ill Patients
- 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 may not reflect the rates observed in practice.
Clinical Trials In Adult Patients
During the initial clinical investigations, 2621 patients worldwide were treated with ZOSYN in phase 3 trials. In the key North American monotherapy clinical trials (n=830 patients), 90% of the adverse events reported were mild to moderate in severity and transient in nature. However, in 3.2% of the patients treated worldwide, ZOSYN was discontinued because of adverse events primarily involving the skin (1.3%), including rash and pruritus; the gastrointestinal system (0.9%), including diarrhea, nausea, and vomiting; and allergic reactions (0.5%).
Table 1: Adverse Reactions from ZOSYN Monotherapy Clinical Trials
| System Organ Class/ Adverse Reaction | |
| Gastrointestinal disorders | |
| Diarrhea | (11.3%) |
| Constipation | (7.7%) |
| Nausea | (6.9%) |
| Vomiting | (3.3%) |
| Dyspepsia | (3.3%) |
| Abdominal pain | (1.3%) |
| General disorders and administration site conditions | |
| Fever | (2.4%) |
| Injection site reaction | (≤1%) |
| Rigors | (≤1%) |
| Immune system disorders | |
| Anaphylaxis | (≤1%) |
| Infections and infestations | |
| Candidiasis | (1.6%) |
| Pseudomembranous colitis | (≤1%) |
| Metabolism and nutrition disorders | |
| Hypoglycemia | (≤1%) |
| Musculoskeletal and connective tissue disorders | |
| Myalgia | (≤1%) |
| Arthralgia | (≤1%) |
| Nervous system disorders | |
| Headache | (7.7%) |
| Psychiatric disorders | |
| Insomnia | (6.6%) |
| Skin and subcutaneous tissue disorders | |
| Rash | (4.2%, including maculopapular, bullous, and urticarial) |
| Pruritus | (3.1%) |
| Purpura | (≤1%) |
| Vascular disorders | |
| Phlebitis | (1.3%) |
| Thrombophlebitis | (≤1%) |
| Hypotension | (≤1%) |
| Flushing | (≤1%) |
| Respiratory, thoracic and mediastinal disorders | |
| Epistaxis | (≤1%) |
Nosocomial Pneumonia Trials
Two trials of nosocomial lower respiratory tract infections were conducted. In one study, 222 patients were treated with ZOSYN in a dosing regimen of 4.5 g every 6 hours in combination with an aminoglycoside and 215 patients were treated with imipenem/cilastatin (500 mg/500 mg every 6 hours) in combination with an aminoglycoside. In this trial, treatment-emergent adverse events were reported by 402 patients, 204 (91.9%) in the piperacillin/tazobactam group and 198 (92.1%) in the imipenem/cilastatin group. Twenty-five (11.0%) patients in the piperacillin/tazobactam group and 14 (6.5%) in the imipenem/cilastatin group (p > 0.05) discontinued treatment due to an adverse event.
The second trial used a dosing regimen of 3.375 g given every 4 hours with an aminoglycoside.
Table 2: Adverse Reactions from ZOSYN Plus Aminoglycoside Clinical Trials System Organ Class Adverse Reaction *
| System Organ Class/Adverse Reaction | |
| Blood and lymphatic system disorders | |
| Thrombocythemia | (1.4%) |
| Anemia | (≤1%) |
| Thrombocytopenia | (≤1%) |
| Eosinophilia | (≤1%) |
| Gastrointestinal disorders | |
| Diarrhea | (20%) |
| Constipation | (8.4%) |
| Nausea | (5.8%) |
| Vomiting | (2.7%) |
| Dyspepsia | (1.9%) |
| Abdominal pain | (1.8%) |
| Stomatitis | (≤1%) |
| General disorders and administration site conditions | |
| Fever | (3.2%) |
| Injection site reaction | (≤1%) |
| Infections and infestations | |
| Oral candidiasis | (3.9%) |
| Candidiasis | (1.8%) |
| Investigations | |
| BUN increased | (1.8%) |
| Blood creatinine increased | (1.8%) |
| Liver function test abnormal | (1.4%) |
| Alkaline phosphatase increased | (≤1%) |
| Aspartate aminotransferase increased | (≤1%) |
| Alanine aminotransferase increased | (≤1%) |
| Metabolism and nutrition disorders | |
| Hypoglycemia | (≤1%) |
| Hypokalemia | (≤1%) |
| Nervous system disorders | |
| Headache | (4.5%) |
| Psychiatric disorders | |
| Insomnia | (4.5%) |
| Renal and urinary disorders | |
| Renal failure | (≤1%) |
| Skin and subcutaneous tissue disorders | |
| Rash | (3.9%) |
| Pruritus | (3.2%) |
| Vascular disorders | |
| Thrombophlebitis | (1.3%) |
| Hypotension | (1.3%) |
| * For adverse drug reactions that appeared in both studies the higher frequency is presented | |
Other Trials: Nephrotoxicity
In a randomized, multicenter, controlled trial in 1200 adult critically ill patients, piperacillin/tazobactam was found to be a risk factor for renal failure (odds ratio 1.7, 95% CI 1.18 to 2.43), and associated with delayed recovery of renal function as compared to other beta-lactam antibacterial drugs1.
Adverse Laboratory Changes
Of the trials reported, including that of nosocomial lower respiratory tract infections in which a higher dose of ZOSYN was used in combination with an aminoglycoside, changes in laboratory parameters include:
For adverse drug reactions that appeared in both studies the higher frequency is presented.
Hematologic – decreases in hemoglobin and hematocrit, thrombocytopenia, increases in platelet count, eosinophilia, leukopenia, neutropenia. These patients were withdrawn from therapy; some had accompanying systemic symptoms (e.g., fever, rigors, chills)
Coagulation – positive direct Coombs’ test, prolonged prothrombin time, prolonged partial thromboplastin time
Hepatic – transient elevations of AST (SGOT), ALT (SGPT), alkaline phosphatase, bilirubin
Renal – increases in serum creatinine, blood urea nitrogen
Additional laboratory events include abnormalities in electrolytes (i.e., increases and decreases in sodium, potassium, and calcium), hyperglycemia, decreases in total protein or albumin, blood glucose decreased, gamma-glutamyltransferase increased, hypokalemia, and bleeding time prolonged.
Clinical Trials In Pediatric Patients
Clinical studies of ZOSYN in pediatric patients suggest a similar safety profile to that seen in adults.
In a prospective, randomized, comparative, open-label clinical trial of pediatric patients, 2 to 12 years of age, with intraabdominal infections (including appendicitis and/or peritonitis), 273 patients were treated with ZOSYN 112.5 mg/kg given IV every 8 hours and 269 patients were treated with cefotaxime (50 mg/kg) plus metronidazole (7.5 mg/kg) every 8 hours. In this trial, treatment-emergent adverse events were reported by 146 patients, 73 (26.7%) in the ZOSYN group and 73 (27.1%) in the cefotaxime/metronidazole group. Six patients (2.2%) in the ZOSYN group and 5 patients (1.9%) in the cefotaxime/metronidazole group discontinued due to an adverse event.
In a retrospective, cohort study, 140 pediatric patients 2 months to less than 18 years of age with nosocomial pneumonia were treated with ZOSYN and 267 patients were treated with comparators (which included ticarcillin-clavulanate, carbapenems, ceftazidime, cefepime, or ciprofloxacin). The rates of serious adverse reactions were generally similar between the ZOSYN and comparator groups, including patients aged 2 months to 9 months treated with ZOSYN 90 mg/kg IV every 6 hours and patients older than 9 months and less than 18 years of age treated with ZOSYN 112.5 mg/kg IV every 6 hours.
Postmarketing Experience
In addition to the adverse drug reactions identified in clinical trials in Table 6 and Table 7, the following adverse reactions have been identified during post-approval use of ZOSYN. 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.
Hepatobiliary – hepatitis, jaundice
Hematologic – hemolytic anemia, agranulocytosis, pancytopenia
Immune – hypersensitivity reactions, anaphylactic/anaphylactoid reactions (including shock), hemophagocytic lymphohistiocytosis (HLH)
Renal – interstitial nephritis
Nervous system disorders – seizures
Psychiatric disorders – delirium
Respiratory – eosinophilic pneumonia
Skin and Appendages – erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, drug reaction with eosinophilia and systemic symptoms, (DRESS), acute generalized exanthematous pustulosis (AGEP), dermatitis exfoliative
Postmarketing experience with ZOSYN in pediatric patients suggests a similar safety profile to that seen in adults.
Additional Experience With Piperacillin
The following adverse reaction has also been reported for piperacillin for injection:
Skeletal – prolonged neuromuscular blockade.
SRC: NLM .