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Guide
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.
ZOSYN (NDA-050684)
(PIPERACILLIN SODIUM; TAZOBACTAM SODIUM)
Safety-related Labeling Changes Approved by FDA Center for Drug Evaluation and Research (CDER)
05/01/2024 (SUPPL-104)
6 Adverse Reactions
6.2 Postmarketing ExperienceAdditions and revisions underlined:
. . .
Immune—hypersensitivity reactions, anaphylactic/anaphylactoid reactions (including shock), hemophagocytic lymphohistiocytosis (HLH), acute myocardial ischemia with or without myocardial infarction may occur as part of an allergic reaction
. . .
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, and linear IgA bullous dermatosis
04/08/2022 (SUPPL-100)
5 Warnings and Precautions
Newly added subsection:
5.3 Hemophagocytic Lymphohistiocytosis
Cases of hemophagocytic lymphohistiocytosis (HLH) have been reported in pediatric and adult patients treated with ZOSYN. Signs and symptoms of HLH may include fever, rash, lymphadenopathy, hepatosplenomegaly and cytopenia. If HLH is suspected, discontinue ZOSYN immediately and institute appropriate management.
6 Adverse Reactions
Newly added bulleted line listing:
The following clinically significant adverse reactions are described elsewhere in the labeling:
Hypersensitivity Adverse Reactions [see Warnings and Precautions (5.1)]
Severe Cutaneous Adverse Reactions [see Warnings and Precautions (5.2)]
Hemophagocytic Lymphohistiocytosis [see Warnings and Precautions (5.3)]
Hematologic Adverse Reactions [see Warnings and Precautions (5.4)]
Central Nervous System Adverse Reactions [see Warnings and Precautions (5.5)]
Nephrotoxicity in Critically Ill Patients [see Warnings and Precautions (5.6)]
- Clostridioides difficile-Associated Diarrhea [see Warnings and Precautions (5.8)]
6.2 Postmarketing Experience
Additions and/or revisions underlined:
Immune—hypersensitivity reactions, anaphylactic/anaphylactoid reactions (including shock), hemophagocytic lymphohistiocytosis (HLH)
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
PATIENT COUNSELING INFORMATIONNewly added information:
Hemophagocytic Lymphohistiocytosis
Prior to initiation of treatment with ZOSYN, inform patients that excessive immune activation may occur with ZOSYN and that they should report signs or symptoms such as fever, rash, or lymphadenopathy to a healthcare provider immediately [see Warnings and Precautions (5.3)].
07/29/2021 (SUPPL-98)
5 Warnings and Precautions
5.8 Development of Drug-Resistant BacteriaAdditions underlined
Prescribing ZOSYN in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of development of drug-resistant bacteria.
6 Adverse Reactions
6.3 Additional Experience with PiperacillinAdditions and/or revisions underlined
The following adverse reaction has also been reported for piperacillin for injection:
Skeletal—prolonged neuromuscular blockade [see Drug Interactions (7.5)].
7 Drug Interactions
7.5 VecuroniumAdditions and/or revisions underlined
Piperacillin when used concomitantly with vecuronium has been implicated in the prolongation of the neuromuscular blockade of vecuronium. ZOSYN could produce the same phenomenon if given along with vecuronium. Due to their similar mechanism of action, it is expected that the neuromuscular blockade produced by any of the non-depolarizing neuromuscular blockers could be prolonged in the presence of piperacillin. Monitor for adverse reactions related to neuromuscular blockade (see package insert for vecuronium bromide).
8 Use in Specific Populations
8.4 Pediatric UseAdditions underlined
…
Because of the limitations of the available strengths and administration requirements (i.e., administration of fractional doses is not recommended) of ZOSYN Injection supplied in GALAXY Containers, and to avoid unintentional overdose, this product is not recommended for use if a dose of ZOSYN Injection in GALAXY Containers that does not equal 2.25 g, 3.375 g, or 4.5 g is required and an alternative formulation of ZOSYN should be considered [see Dosage and Administration (2.1, 2.5, and 2.7)].
05/26/2020 (SUPPL-96)
6 Adverse Reactions
6.1 Clinical Trials ExperienceAdditions and/or revisions underlined:
Clinical Trials in Adult Patients
During the initial clinical investigations, 2621 patients worldwide were treated with ZOSYN in phase 3 trials …
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.
8 Use in Specific Populations
8.4 Pediatric UseAdditions and/or revisions underlined:
The safety and effectiveness of ZOSYN for intra-abdominal infections, and nosocomial pneumonia have been established in pediatric patients 2 months of age and older.
Use of ZOSYN in pediatric patients 2 months of age and older with intra-abdominal infections including appendicitis and/or peritonitis is supported by evidence from well-controlled studies and pharmacokinetic studies in adults and in pediatric patients. This includes a prospective, randomized, comparative, open-label clinical trial with 542 pediatric patients 2 to 12 years of age with intra-abdominal infections (including appendicitis and/or peritonitis), in which 273 pediatric patients received piperacillin/tazobactam [see Adverse Reactions (6.1) and Clinical Pharmacology (12.3)].
Use of ZOSYN in pediatric patients 2 months of age and older with nosocomial pneumonia is supported by evidence from well-controlled studies in adults with nosocomial pneumonia, a simulation study performed with a population pharmacokinetic model, and a retrospective, cohort study of pediatric patients with nosocomial pneumonia in which 140 pediatric patients were treated with ZOSYN and 267 patients treated with comparators (which included ticarcillin-clavulanate, carbapenems, ceftazidime, cefepime, or ciprofloxacin) [see Adverse Reactions (6.1) and Clinical Pharmacology (12.3)].
The safety and effectiveness of ZOSYN have not been established in pediatric patients less than 2 months of age [see Clinical Pharmacology (12) and Dosage and Administration (2)].
Dosage of ZOSYN in pediatric patients with renal impairment has not been determined.
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
PATIENT COUNSELING INFORMATIONThis product's labeling may have been updated. For the most recent prescribing information, please visit http://www.pfizer.com.
04/13/2020 (SUPPL-95)
5 Warnings and Precautions
5.4 Central Nervous System Adverse Reactions(Additions and/or revisions underlined)
As with other penicillins, ZOSYN may cause neuromuscular excitability or convulsions (seizures). Patients receiving higher doses, especially patients with renal impairment may be at greater risk for central nervous system adverse reactions. Closely monitor patients with renal impairment or seizure disorders for signs and symptoms of neuromuscular excitability or convulsions (seizures).
(Subsection title revised; Additions and/or revisions underlined)
Clostridioides difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including ZOSYN, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile.
C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibacterial drug use. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents.
If CDAD is suspected or confirmed, ongoing antibacterial drug use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibacterial treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated.
6 Adverse Reactions
6.2 Postmarketing Experience(Additions and/or revisions underlined)
In addition to the adverse drug reactions identified in clinical trials in Table 3 and Table 4, 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—seizure
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
05/10/2019 (SUPPL-94)
6 Adverse Reactions
6.2 Post-Marketing Experience(Additions and/or revisions are underlined)
In addition to the adverse drug reactions identified in clinical trials in Table 3 and Table 4, 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.
Psychiatric disorders—delirium
05/05/2017 (SUPPL-88)
5 Warnings and Precautions
5.5 Nephrotoxicity in Critically Ill Patients(new subsection added)
The use of ZOSYN was found to be an independent risk factor for renal failure and was associated with delayed recovery of renal function as compared to other beta-lactam antibacterial drugs in a randomized, multicenter, controlled trial in critically ill patients . Based on this study, alternative treatment options should be considered in the critically ill population. If alternative treatment options are inadequate or unavailable, monitor renal function during treatment with ZOSYN.
Combined use of piperacillin/tazobactam and vancomycin may be associated with an increased incidence of acute kidney injury.
6 Adverse Reactions
6.1 Clinical Trials Experience(additions underlined)
…
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 drugs.
…
05/05/2017 (SUPPL-89)
8 Use in Specific Populations
8.1 Pregnancy(PLLR conversion, please refer to label)
(PLLR conversion, additions underlined)
Risk Summary
Piperacillin is excreted in human milk; tazobactam concentrations in human milk have not been studied. No information is available on the effects of piperacillin and tazobactam on the breast- fed child or on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for ZOSYN and any potential adverse effects on the breastfed child from ZOSYN or from the underlying maternal condition.
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
PATIENT COUNSELING INFORMATION(addition underlined)
…
Counsel patients that ZOSYN can cross the placenta in humans and is excreted in human milk.
05/05/2017 (SUPPL-90)
5 Warnings and Precautions
5.5 Nephrotoxicity in Critically Ill Patients(new subsection added)
The use of ZOSYN was found to be an independent risk factor for renal failure and was associated with delayed recovery of renal function as compared to other beta-lactam antibacterial drugs in a randomized, multicenter, controlled trial in critically ill patients . Based on this study, alternative treatment options should be considered in the critically ill population. If alternative treatment options are inadequate or unavailable, monitor renal function during treatment with ZOSYN.
Combined use of piperacillin/tazobactam and vancomycin may be associated with an increased incidence of acute kidney injury.
06/10/2016 (SUPPL-84)
5 Warnings and Precautions
Electrolyte Effects- Change ZOSYN contains a total of 2.79 mEq (64 mg) of Na+ per gram of piperacillin in the combination product to ZOSYN contains a total of 2.84 mEq (65 mg) of Na+ (sodium) per gram of piperacillin in the combination product.
7 Drug Interactions
Vancomycin (new section added)- A limited number of retrospective studies have detected an increased incidence of acute kidney injury in patients concomitantly administered piperacillin/tazobactam and vancomycin as compared to vancomycin alone. Monitor kidney function in patients concomitantly administered with piperacillin/tazobactam and vancomycin.
- No pharmacokinetic interactions have been noted between piperacillin/tazobactam and vancomycin.
8 Use in Specific Populations
Geriatric Use- ZOSYN contains 65 mg (2.84 mEq) of sodium per gram of piperacillin in the combination product. At the usual recommended doses, patients would receive between 780 and 1040 mg/day (34.1 and 45.5 mEq) of sodium.
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
PCI - Serious Hypersensitivity Reactions (addition)- Advise patients, their families, or caregivers that serious hypersensitivity reactions, including serious allergic cutaneous reactions, could occur that require immediate treatment. Ask them about any previous hypersensitivity reactions to ZOSYN, other beta-lactams (including cephalosporins), or other allergens.
06/10/2016 (SUPPL-86)
6 Adverse Reactions
Post-Marketing ExperienceRespiratory—eosinophilic pneumonia (addition of new subheading)
Skin and Appendages (addition to subsection):
- dermatitis exfoliative
System Organ Class
Skin and subcutaneous tissue disorders
- add Purpura (?1%)
Respiratory, thoracic and mediastinal disorders (new section)
- Epistaxis (?1%)
System Organ Class
Psychiatric disorders (new section)
- Insomnia (4.5%)