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ZOSYN® (piperacillin, tazobactam) Adverse Reactions

6 ADVERSE REACTIONS

6.1 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 4: 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 5: Adverse Reactions from ZOSYN Plus Aminoglycoside Clinical Trials*
System Organ Class
  Adverse Reaction
*
For adverse drug reactions that appeared in both studies the higher frequency is presented.
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%)

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 [see Warnings and Precautions (5.5)].

Adverse Laboratory Changes (Seen During Clinical Trials)

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:

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 intra-abdominal 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.

6.2 Postmarketing Experience

In addition to the adverse drug reactions identified in clinical trials in Table 4 and Table 5, 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)

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.

6.3 Additional Experience with Piperacillin

The following adverse reaction has also been reported for piperacillin for injection:

Skeletal—prolonged muscle relaxation [see Drug Interactions (7.5)].

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