Zosyn in Galaxy Containers

6 ADVERSE REACTIONS 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) ] The most common adverse reactions (incidence >5%) are diarrhea, constipation, nausea, headache, and insomnia. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Pfizer Inc. at 1-800-438-1985 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 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 and tazobactam group and 198 (92.1%) in the imipenem/cilastatin group. Twenty-five (11.0%) patients in the piperacillin and 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 For adverse drug reactions that appeared in both studies the higher frequency is presented. 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%) Other Trials: Nephrotoxicity In a randomized, multicenter, controlled trial in 1200 adult critically ill patients, piperacillin and 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 1 [see Warnings and Precautions (5.6) ] . 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), 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. 6.3 Additional Experience with Piperacillin The following adverse reaction has also been reported for piperacillin for injection: Skeletal —prolonged neuromuscular blockade [see Drug Interactions (7.5) ].

4 CONTRAINDICATIONS ZOSYN is contraindicated in patients with a history of allergic reactions to any of the penicillins, cephalosporins, or beta-lactamase inhibitors. Patients with a history of allergic reactions to any of the penicillins, cephalosporins, or beta-lactamase inhibitors. ( 4 )

11 DESCRIPTION ZOSYN (piperacillin and tazobactam) Injection is an injectable antibacterial combination product consisting of the semisynthetic antibacterial piperacillin sodium and the beta-lactamase inhibitor tazobactam sodium for intravenous administration. Piperacillin sodium is derived from D(-)-α-aminobenzyl-penicillin. The chemical name of piperacillin sodium is sodium (2 S ,5 R ,6 R )-6-[( R )-2-(4-ethyl-2,3-dioxo-1-piperazine-carboxamido)-2-phenylacetamido]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate. The chemical formula is C 23 H 26 N 5 NaO 7 S and the molecular weight is 539.5. The chemical structure of piperacillin sodium is: Tazobactam sodium, a derivative of the penicillin nucleus, is a penicillanic acid sulfone. Its chemical name is sodium (2 S, 3 S, 5 R )-3-methyl-7-oxo-3-(1 H -1,2,3-triazol-1-ylmethyl)-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate-4,4-dioxide. The chemical formula is C 10 H 11 N 4 NaO 5 S and the molecular weight is 322.3. The chemical structure of tazobactam sodium is: ZOSYN Injection in the GALAXY Container is a frozen iso-osmotic sterile non-pyrogenic premixed solution. The components and dosage formulations are given in the table below: Table 6: ZOSYN In GALAXY Containers Premixed Frozen Solution Component Piperacillin and tazobactam are present in the formulation as sodium salts. Dextrose hydrous, sodium citrate dihydrate, and edetate disodium dihydrate amounts are approximate. Function Dosage Formulations 2.25 g/50 mL 3.375 g/50 mL 4.5 g/100 mL Piperacillin active ingredient 2 g 3 g 4 g Tazobactam beta-lactamase inhibitor 250 mg 375 mg 500 mg Dextrose Hydrous osmolality adjusting agent 1 g 350 mg 2 g Sodium Citrate Dihydrate buffering agent 100 mg 150 mg 200 mg Edetate Disodium Dihydrate metal chelator 0.5 mg 0.75 mg 1 mg Water for Injection solvent q.s. 50 mL q.s. 50 mL q.s. 100 mL ZOSYN contains a total of 2.84 mEq (65 mg) of sodium (Na + ) per gram of piperacillin in the combination product. Chemical Structure Chemical Structure

2 DOSAGE AND ADMINISTRATION • If a dose of ZOSYN is required that does not equal 2.25 g, 3.375 g, or 4.5 g, ZOSYN injection in GALAXY Containers is not recommended for use and an alternative formulation of ZOSYN should be considered. ( 2.1 ) • Adult Patients With Indications Other Than Nosocomial Pneumonia; The usual daily dosage of ZOSYN for adults is 3.375 g every six hours totaling 13.5 g (12.0 g piperacillin and 1.5 g tazobactam). ( 2.2 ) • Adult Patients with Nosocomial Pneumonia: Initial presumptive treatment of patients with nosocomial pneumonia should start with ZOSYN at a dosage of 4.5 g every six hours plus an aminoglycoside, totaling 18.0 g (16.0 g piperacillin and 2.0 g tazobactam). ( 2.3 ) • Adult Patients with Renal Impairment : Dosage in patients with renal impairment (creatinine clearance ≤40 mL/min) and dialysis patients should be reduced, based on the degree of renal impairment. ( 2.4 ) • Pediatric Patients by Indication and Age: See Table below ( 2.5 ) Recommended Dosage of ZOSYN for Pediatric Patients 2 months of Age and Older, Weighing up to 40 Kg and With Normal Renal Function Age Appendicitis and /or Peritonitis Nosocomial Pneumonia 2 months to 9 months 90 mg/kg (80 mg piperacillin and 10 mg tazobactam) every 8 ( eight ) hours 90 mg/kg (80 mg piperacillin and 10 mg tazobactam) every 6 ( six ) hours Older than 9 months 112.5 mg/kg (100 mg piperacillin and 12.5 mg tazobactam) every 8 ( eight) hours 112.5 mg/kg (100 mg piperacillin and 12.5 mg tazobactam) every 6 ( six) hours • Administer ZOSYN by intravenous infusion over 30 minutes to both adult and pediatric patients ( 2.2 , 2.3 , 2.4 , 2.5 ). • ZOSYN and aminoglycosides should be reconstituted, diluted, and administered separately. Co-administration via Y-site can be done under certain conditions. ( 2.7 ) See the full prescribing information for the preparation and administration instructions for ZOSYN Injection in GALAXY Containers. 2.1 Important Administration Instructions If a dose of ZOSYN is required that does not equal 2.25 g, 3.375 g, or 4.5 g, ZOSYN injection in GALAXY Containers is not recommended for use and an alternative formulation of ZOSYN should be considered. 2.2 Dosage in Adult Patients With Indications Other Than Nosocomial Pneumonia The usual total daily dosage of ZOSYN for adult patients with indications other than nosocomial pneumonia is 3.375 g every six hours [totaling 13.5 g (12.0 g piperacillin and 1.5 g tazobactam)], to be administered by intravenous infusion over 30 minutes. The usual duration of ZOSYN treatment is from 7 to 10 days. 2.3 Dosage in Adult Patients With Nosocomial Pneumonia Initial presumptive treatment of adult patients with nosocomial pneumonia should start with ZOSYN at a dosage of 4.5 g every six hours plus an aminoglycoside, [totaling 18.0 g (16.0 g piperacillin and 2.0 g tazobactam)], administered by intravenous infusion over 30 minutes. The recommended duration of ZOSYN treatment for nosocomial pneumonia is 7 to 14 days. Treatment with the aminoglycoside should be continued in patients from whom P. aeruginosa is isolated. 2.4 Dosage in Adult Patients With Renal Impairment In adult patients with renal impairment (creatinine clearance ≤ 40 mL/min) and dialysis patients (hemodialysis and CAPD), the intravenous dose of ZOSYN should be reduced based on the degree of renal impairment. The recommended daily dosage of ZOSYN for patients with renal impairment administered by intravenous infusion over 30 minutes is described in Table 1. Table 1: Recommended Dosage of ZOSYN in Patients with Normal Renal Function and Renal Impairment (As total grams piperacillin and tazobactam) Administer ZOSYN by intravenous infusion over 30 minutes. Creatinine clearance, mL/min All Indications (except nosocomial pneumonia) Nosocomial Pneumonia Greater than 40 mL/min 3.375 every 6 hours 4.5 every 6 hours 20 to 40 mL/min Creatinine clearance for patients not receiving hemodialysis 2.25 every 6 hours 3.375 every 6 hours Less than 20 mL/min 2.25 every 8 hours 2.25 every 6 hours Hemodialysis 0.75 g (0.67 g piperacillin and 0.08 g tazobactam) should be administered following each hemodialysis session on hemodialysis days 2.25 every 12 hours 2.25 every 8 hours CAPD 2.25 every 12 hours 2.25 every 8 hours For patients on hemodialysis, the maximum dose is 2.25 g every twelve hours for all indications other than nosocomial pneumonia and 2.25 g every eight hours for nosocomial pneumonia. Since hemodialysis removes 30% to 40% of the administered dose, an additional dose of 0.75 g ZOSYN (0.67 g piperacillin and 0.08 g tazobactam) should be administered following each dialysis period on hemodialysis days. No additional dosage of ZOSYN is necessary for CAPD patients. 2.5 Dosage in Pediatric Patients With Appendicitis/Peritonitis or Nosocomial Pneumonia The recommended dosage for pediatric patients with appendicitis and/or peritonitis or nosocomial pneumonia aged 2 months of age and older, weighing up to 40 kg, and with normal renal function, is described in Table 2 [see Use in Specific Populations (8.4) and Clinical Pharmacology (12.3) ] . Table 2: Recommended Dosage of ZOSYN in Pediatric Patients 2 Months of Age and Older, Weighing Up to 40 kg, and With Normal Renal Function Administer ZOSYN by intravenous infusion over 30 minutes If a dose of ZOSYN is required that does not equal 2.25 g, 3.375 g, or 4.5 g, ZOSYN injection in GALAXY Containers is not recommended for use and an alternative formulation of ZOSYN should be considered [see Use in Specific Populations (8.4) ] . Age Appendicitis and/or Peritonitis Nosocomial Pneumonia 2 months to 9 months 90 mg/kg (80 mg piperacillin and 10 mg tazobactam) every 8 ( eight ) hours 90 mg/kg (80 mg piperacillin and 10 mg tazobactam) every 6 ( six ) hours Older than 9 months of age 112.5 mg/kg (100 mg piperacillin and 12.5 mg tazobactam) every 8 ( eight ) hours 112.5 mg/kg (100 mg piperacillin and 12.5 mg tazobactam) every 6 ( six ) hours Pediatric patients weighing over 40 kg and with normal renal function should receive the adult dose [see Dosage and Administration (2.2 , 2.3) ] . Dosage of ZOSYN in pediatric patients with renal impairment has not been determined. 2.6 Directions for Use of ZOSYN Injection Important Administration Instructions for ZOSYN Injection in GALAXY Containers Administer ZOSYN Injection in GALAXY Containers using sterile equipment, after thawing to room temperature. ZOSYN containing EDTA is compatible for co-administration via a Y-site intravenous tube with Lactated Ringer's injection, USP. Do NOT add supplementary medication. Unused portions of ZOSYN Injection should be discarded. Do NOT use plastic containers in series connections. Such use could result in air embolism due to residual air being drawn from the primary container before administration of the fluid from the secondary container is complete. Handle frozen product containers with care. Product containers may be fragile in the frozen state. Thawing of Plastic Container Thaw frozen container at room temperature 20°C to 25°C [68°F to 77°F] or under refrigeration (2°C to 8°C [36°F to 46°F]). Do not force thaw by immersion in water baths or by microwave irradiation. Check for minute leaks by squeezing container firmly. If leaks are detected, discard solution as sterility may be impaired. The container should be visually inspected. Components of the solution may precipitate in the frozen state and will dissolve upon reaching room temperature with little or no agitation. Potency is not affected. Agitate after solution has reached room temperature. If after visual inspection, the solution remains cloudy or if an insoluble precipitate is noted or if any seals or outlet ports are not intact, the container should be discarded. Administration Instructions for ZOSYN Injection in GALAXY Containers to Adult Patients Administer by infusion over a period of at least 30 minutes. During the infusion it is desirable to discontinue the primary infusion solution. Administration Instruction for ZOSYN Injection in GALAXY Containers to Pediatric Patients Weighing up to 40 kg If a dose of ZOSYN is required that does not equal 2.25 g, 3.375 g, or 4.5 g, ZOSYN injection in GALAXY Containers is not recommended for use and an alternative formulation of ZOSYN should be considered. Storage of ZOSYN Injection Store in a freezer capable of maintaining a temperature of -20°C (-4°F). For GALAXY Containers, the thawed solution is stable for 14 days under refrigeration (2°C to 8°C [36°F to 46°F]) or 24 hours at room temperature 20°C to 25°C [68°F to 77°F]. Do not refreeze thawed ZOSYN Injection. 2.7 Compatibility With Aminoglycosides Due to the in vitro inactivation of aminoglycosides by piperacillin, ZOSYN and aminoglycosides are recommended for separate administration. ZOSYN and aminoglycosides should be reconstituted, diluted, and administered separately when concomitant therapy with aminoglycosides is indicated [see Drug Interactions (7.1) ] . In circumstances where co-administration via Y-site is necessary, ZOSYN formulations containing EDTA are compatible for simultaneous co-administration via Y-site infusion only with the following aminoglycosides under the following conditions: Table 3: Compatibility with Aminoglycosides Aminoglycoside ZOSYN Dose (grams) Aminoglycoside Concentration Range The concentration ranges in Table 3 are based on administration of the aminoglycoside in divided doses (10–15 mg/kg/day in two daily doses for amikacin and 3–5 mg/kg/day in three daily doses for gentamicin). Administration of amikacin or gentamicin in a single daily dose or in doses exceeding those stated above via Y-site with ZOSYN containing EDTA has not been evaluated. See package insert for each aminoglycoside for complete Dosage and Administration instructions. (mg/mL) Acceptable Diluents Amikacin 2.25 3.375 4.5 1.75 – 7.5 0.9% sodium chloride or 5% dextrose Gentamicin 2.25 3.375 ZOSYN 3.375 g per 50 mL GALAXY Containers are NOT compatible with gentamicin for co-administration via a Y-site due to the higher concentrations of piperacillin and tazobactam. 4.5 0.7 – 3.32 0.9% sodium chloride or 5% dextrose Only the concentration and diluents for amikacin or gentamicin with the dosages of ZOSYN listed above have been established as compatible for co-administration via Y-site infusion. Simultaneous co-administration via Y-site infusion in any manner other than listed above may result in inactivation of the aminoglycoside by ZOSYN. ZOSYN is not compatible with tobramycin for simultaneous co-administration via Y-site infusion. Compatibility of ZOSYN with other aminoglycosides has not been established. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

1 INDICATIONS AND USAGE ZOSYN is a combination of piperacillin, a penicillin-class antibacterial and tazobactam, a beta-lactamase inhibitor, indicated for the treatment of: • Intra-abdominal infections in adult and pediatric patients 2 months of age and older ( 1.1 ) • Nosocomial pneumonia in adult and pediatric patients 2 months of age and older ( 1.2 ) • Skin and skin structure infections in adults ( 1.3 ) • Female pelvic infections in adults ( 1.4 ) • Community-acquired pneumonia in adults ( 1.5 ) To reduce the development of drug-resistant bacteria and maintain the effectiveness of ZOSYN and other antibacterial drugs, ZOSYN should be used only to treat or prevent infections that are proven or strongly suspected to be caused by bacteria. ( 1.6 ) 1.1 Intra-abdominal Infections ZOSYN is indicated in adults and pediatric patients (2 months of age and older) for the treatment of appendicitis (complicated by rupture or abscess) and peritonitis caused by beta-lactamase producing isolates of Escherichia coli or the following members of the Bacteroides fragilis group: B. fragilis , B. ovatus , B. thetaiotaomicron , or B. vulgatus . 1.2 Nosocomial Pneumonia ZOSYN is indicated in adults and pediatric patients (2 months of age and older) for the treatment of nosocomial pneumonia (moderate to severe) caused by beta-lactamase producing isolates of Staphylococcus aureus and by piperacillin and tazobactam-susceptible Acinetobacter baumannii , Haemophilus influenzae , Klebsiella pneumoniae , and Pseudomonas aeruginosa (Nosocomial pneumonia caused by P. aeruginosa should be treated in combination with an aminoglycoside) [see Dosage and Administration (2) ] . 1.3 Skin and Skin Structure Infections ZOSYN is indicated in adults for the treatment of uncomplicated and complicated skin and skin structure infections, including cellulitis, cutaneous abscesses and ischemic/diabetic foot infections caused by beta-lactamase producing isolates of Staphylococcus aureus . 1.4 Female Pelvic Infections ZOSYN is indicated in adults for the treatment of postpartum endometritis or pelvic inflammatory disease caused by beta-lactamase producing isolates of Escherichia coli . 1.5 Community-acquired Pneumonia ZOSYN is indicated in adults for the treatment of community-acquired pneumonia (moderate severity only) caused by beta-lactamase producing isolates of Haemophilus influenzae . 1.6 Usage To reduce the development of drug-resistant bacteria and maintain the effectiveness of ZOSYN and other antibacterial drugs, ZOSYN should be used only to treat or prevent infections that are proven or strongly suspected to be caused by 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.

10 OVERDOSAGE There have been postmarketing reports of overdose with piperacillin and tazobactam. The majority of those events experienced, including nausea, vomiting, and diarrhea, have also been reported with the usual recommended dosages. Patients may experience neuromuscular excitability or seizures if higher than recommended doses are given intravenously (particularly in the presence of renal failure) [see Warnings and Precautions (5.5) ] . Treatment should be supportive and symptomatic according to the patient's clinical presentation. Excessive serum concentrations of either piperacillin or tazobactam may be reduced by hemodialysis. Following a single 3.375 g dose of piperacillin and tazobactam, the percentage of the piperacillin and tazobactam dose removed by hemodialysis was approximately 31% and 39%, respectively [see Clinical Pharmacology (12) ] .

7 DRUG INTERACTIONS • ZOSYN administration can significantly reduce tobramycin concentrations in hemodialysis patients. Monitor tobramycin concentrations in these patients. ( 7.1 ) • Probenecid prolongs the half-lives of piperacillin and tazobactam and should not be co-administered with ZOSYN unless the benefit outweighs the risk. ( 7.2 ) • Co-administration of ZOSYN with vancomycin may increase the incidence of acute kidney injury. Monitor kidney function in patients receiving ZOSYN and vancomycin. ( 7.3 ) • Monitor coagulation parameters in patients receiving ZOSYN and heparin or oral anticoagulants. ( 7.4 ) • ZOSYN may prolong the neuromuscular blockade of vecuronium and other non-depolarizing neuromuscular blockers. Monitor for adverse reactions related to neuromuscular blockade. ( 7.5 ) 7.1 Aminoglycosides Piperacillin may inactivate aminoglycosides by converting them to microbiologically inert amides. In vivo inactivation : When aminoglycosides are administered in conjunction with piperacillin to patients with end-stage renal disease requiring hemodialysis, the concentrations of the aminoglycosides (especially tobramycin) may be significantly reduced and should be monitored. Sequential administration of ZOSYN and tobramycin to patients with either normal renal function or mild to moderate renal impairment has been shown to modestly decrease serum concentrations of tobramycin but no dosage adjustment is considered necessary. In vitro inactivation : Due to the in vitro inactivation of aminoglycosides by piperacillin, ZOSYN and aminoglycosides are recommended for separate administration. ZOSYN and aminoglycosides should be reconstituted, diluted, and administered separately when concomitant therapy with aminoglycosides is indicated. ZOSYN, which contains EDTA, is compatible with amikacin and gentamicin for simultaneous Y-site infusion in certain diluents and at specific concentrations. ZOSYN is not compatible with tobramycin for simultaneous Y-site infusion [see Dosage and Administration (2.7) ] . 7.2 Probenecid Probenecid administered concomitantly with ZOSYN prolongs the half-life of piperacillin by 21% and that of tazobactam by 71% because probenecid inhibits tubular renal secretion of both piperacillin and tazobactam. Probenecid should not be co-administered with ZOSYN unless the benefit outweighs the risk. 7.3 Vancomycin Studies have detected an increased incidence of acute kidney injury in patients concomitantly administered piperacillin and tazobactam and vancomycin as compared to vancomycin alone [see Warnings and Precautions (5.6) ] . Monitor kidney function in patients concomitantly administered with piperacillin and tazobactam and vancomycin. No pharmacokinetic interactions have been noted between piperacillin and tazobactam and vancomycin. 7.4 Anticoagulants Coagulation parameters should be tested more frequently and monitored regularly during simultaneous administration of high doses of heparin, oral anticoagulants, or other drugs that may affect the blood coagulation system or the thrombocyte function [see Warnings and Precautions (5.4) ] . 7.5 Vecuronium 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). 7.6 Methotrexate Limited data suggests that co-administration of methotrexate and piperacillin may reduce the clearance of methotrexate due to competition for renal secretion. The impact of tazobactam on the elimination of methotrexate has not been evaluated. If concurrent therapy is necessary, serum concentrations of methotrexate as well as the signs and symptoms of methotrexate toxicity should be frequently monitored. 7.7 Effects on Laboratory Tests There have been reports of positive test results using the Bio-Rad Laboratories Platelia Aspergillus EIA test in patients receiving piperacillin and tazobactam injection who were subsequently found to be free of Aspergillus infection. Cross-reactions with non-Aspergillus polysaccharides and polyfuranoses with the Bio-Rad Laboratories Platelia Aspergillus EIA test have been reported. Therefore, positive test results in patients receiving piperacillin and tazobactam should be interpreted cautiously and confirmed by other diagnostic methods. As with other penicillins, the administration of ZOSYN may result in a false-positive reaction for glucose in the urine using a copper-reduction method (CLINITEST ® ). It is recommended that glucose tests based on enzymatic glucose oxidase reactions be used.

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action ZOSYN is an antibacterial drug [see Microbiology (12.4) ] . 12.2 Pharmacodynamics The pharmacodynamic parameter for piperacillin and tazobactam that is most predictive of clinical and microbiological efficacy is time above MIC. 12.3 Pharmacokinetics The mean and coefficients of variation (CV%) for the pharmacokinetic parameters of piperacillin and tazobactam after multiple intravenous doses are summarized in Table 7. Table 7: Mean (CV%) Piperacillin and Tazobactam PK Parameters C max : maximum observed concentration, AUC: Area under the curve, CL=clearance, CL R = Renal clearance V=volume of distribution, T 1/2 = elimination half-life Piperacillin Piperacillin and Tazobactam Dose Piperacillin and tazobactam were given in combination, infused over 30 minutes. C max (mcg/mL) AUC Numbers in []parentheses are coefficients of variation [CV%]. (mcg∙h/mL) CL (mL/min) V (L) T 1/2 (h) CL R (mL/min) 2.25 g 134 131 [14] 257 17.4 0.79 -- 3.375 g 242 242 [10] 207 15.1 0.84 140 4.5 g 298 322 [16] 210 15.4 0.84 -- Tazobactam Piperacillin and Tazobactam Dose C max (mcg/mL) AUC (mcg∙h/mL) CL (mL/min) V (L) T 1/2 (h) CL R (mL/min) 2.25 g 15 16.0 [21] 258 17.0 0.77 -- 3.375 g 24 25.0 [8] 251 14.8 0.68 166 4.5 g 34 39.8 [15] 206 14.7 0.82 -- Peak plasma concentrations of piperacillin and tazobactam are attained immediately after completion of an intravenous infusion of ZOSYN. Piperacillin plasma concentrations, following a 30-minute infusion of ZOSYN, were similar to those attained when equivalent doses of piperacillin were administered alone. Steady-state plasma concentrations of piperacillin and tazobactam were similar to those attained after the first dose due to the short half-lives of piperacillin and tazobactam. Distribution Both piperacillin and tazobactam are approximately 30% bound to plasma proteins. The protein binding of either piperacillin or tazobactam is unaffected by the presence of the other compound. Protein binding of the tazobactam metabolite is negligible. Piperacillin and tazobactam are widely distributed into tissues and body fluids including intestinal mucosa, gallbladder, lung, female reproductive tissues (uterus, ovary, and fallopian tube), interstitial fluid, and bile. Mean tissue concentrations are generally 50% to 100% of those in plasma. Distribution of piperacillin and tazobactam into cerebrospinal fluid is low in subjects with non-inflamed meninges, as with other penicillins (see Table 8). Table 8: Piperacillin and Tazobactam Concentrations in Selected Tissues and Fluids after Single 4 g/0.5 g 30-min IV Infusion of ZOSYN Tissue or Fluid N Each subject provided a single sample. Sampling period Time from the start of the infusion (h) Mean PIP Concentration Range (mg/L) Tissue:Plasma Range Tazo Concentration Range (mg/L) Tazo Tissue:Plasma Range Skin 35 0.5 – 4.5 34.8 – 94.2 0.60 – 1.1 4.0 – 7.7 0.49 – 0.93 Fatty Tissue 37 0.5 – 4.5 4.0 – 10.1 0.097 – 0.115 0.7 – 1.5 0.10 – 0.13 Muscle 36 0.5 – 4.5 9.4 – 23.3 0.29 – 0.18 1.4 – 2.7 0.18 – 0.30 Proximal Intestinal Mucosa 7 1.5 – 2.5 31.4 0.55 10.3 1.15 Distal Intestinal Mucosa 7 1.5 – 2.5 31.2 0.59 14.5 2.1 Appendix 22 0.5 – 2.5 26.5 – 64.1 0.43 – 0.53 9.1 – 18.6 0.80 – 1.35 Metabolism Piperacillin is metabolized to a minor microbiologically active desethyl metabolite. Tazobactam is metabolized to a single metabolite that lacks pharmacological and antibacterial activities. Excretion Following single or multiple ZOSYN doses to healthy subjects, the plasma half-life of piperacillin and of tazobactam ranged from 0.7 to 1.2 hours and was unaffected by dose or duration of infusion. Both piperacillin and tazobactam are eliminated via the kidney by glomerular filtration and tubular secretion. Piperacillin is excreted rapidly as unchanged drug with 68% of the administered dose excreted in the urine. Tazobactam and its metabolite are eliminated primarily by renal excretion with 80% of the administered dose excreted as unchanged drug and the remainder as the single metabolite. Piperacillin, tazobactam and desethyl piperacillin are also secreted into the bile. Specific Populations Renal Impairment After the administration of single doses of piperacillin and tazobactam to subjects with renal impairment, the half-life of piperacillin and of tazobactam increases with decreasing creatinine clearance. At creatinine clearance below 20 mL/min, the increase in half-life is twofold for piperacillin and fourfold for tazobactam compared to subjects with normal renal function. Dosage adjustments for ZOSYN are recommended when creatinine clearance is below 40 mL/min in patients receiving the usual recommended daily dose of ZOSYN. See Dosage and Administration (2) for specific recommendations for the treatment of patients with renal-impairment. Hemodialysis removes 30% to 40% of a piperacillin and tazobactam dose with an additional 5% of the tazobactam dose removed as the tazobactam metabolite. Peritoneal dialysis removes approximately 6% and 21% of the piperacillin and tazobactam doses, respectively, with up to 16% of the tazobactam dose removed as the tazobactam metabolite. For dosage recommendations for patients undergoing hemodialysis [see Dosage and Administration (2) ] . Hepatic Impairment The half-life of piperacillin and of tazobactam increases by approximately 25% and 18%, respectively, in patients with hepatic cirrhosis compared to healthy subjects. However, this difference does not warrant dosage adjustment of ZOSYN due to hepatic cirrhosis. Pediatrics Piperacillin and tazobactam pharmacokinetics were studied in pediatric patients 2 months of age and older. The clearance of both compounds is slower in the younger patients compared to older children and adults. In a population PK analysis, estimated clearance for 9 month-old to 12 year-old patients was comparable to adults, with a population mean (SE) value of 5.64 (0.34) mL/min/kg. The piperacillin clearance estimate is 80% of this value for pediatric patients 2 – 9 months old. In patients younger than 2 months of age, clearance of piperacillin is slower compared to older children; however, it is not adequately characterized for dosing recommendations. The population mean (SE) for piperacillin volume of distribution is 0.243 (0.011) L/kg and is independent of age. Geriatrics The impact of age on the pharmacokinetics of piperacillin and tazobactam was evaluated in healthy male subjects, aged 18 – 35 years (n=6) and aged 65 to 80 years (n=12). Mean half-life for piperacillin and tazobactam was 32% and 55% higher, respectively, in the elderly compared to the younger subjects. This difference may be due to age-related changes in creatinine clearance. Race The effect of race on piperacillin and tazobactam was evaluated in healthy male volunteers. No difference in piperacillin or tazobactam pharmacokinetics was observed between Asian (n=9) and Caucasian (n=9) healthy volunteers who received single 4/0.5 g doses. Drug Interactions The potential for pharmacokinetic drug interactions between ZOSYN and aminoglycosides, probenecid, vancomycin, heparin, vecuronium, and methotrexate has been evaluated [see Drug Interactions (7) ] . 12.4 Microbiology Mechanism of Action Piperacillin sodium exerts bactericidal activity by inhibiting septum formation and cell wall synthesis of susceptible bacteria. In vitro, piperacillin is active against a variety of gram-positive and gram-negative aerobic and anaerobic bacteria. Tazobactam sodium has little clinically relevant in vitro activity against bacteria due to its reduced affinity to penicillin-binding proteins. It is, however, a beta-lactamase inhibitor of the Molecular class A enzymes, including Richmond-Sykes class III (Bush class 2b & 2b') penicillinases and cephalosporinases. It varies in its ability to inhibit class II and IV (2a & 4) penicillinases. Tazobactam does not induce chromosomally-mediated beta-lactamases at tazobactam concentrations achieved with the recommended dosage regimen. Antimicrobial Activity ZOSYN has been shown to be active against most isolates of the following microorganisms, both in vitro and in clinical infections [see Indications and Usage (1) ] : Aerobic bacteria Gram-positive bacteria Staphylococcus aureus (methicillin susceptible isolates only) Gram-negative bacteria Acinetobacter baumannii Escherichia coli Haemophilus influenzae (excluding beta-lactamase negative, ampicillin-resistant isolates) Klebsiella pneumoniae Pseudomonas aeruginosa (given in combination with an aminoglycoside to which the isolate is susceptible) Anaerobic bacteria Bacteroides fragilis group ( B. fragilis, B. ovatus, B. thetaiotaomicron, and B. vulgatus ) The following in vitro data are available, but their clinical significance is unknown. At least 90 percent of the following bacteria exhibit an in vitro minimum inhibitory concentration (MIC) less than or equal to the susceptible breakpoint for piperacillin and tazobactam against isolates of similar genus or organism group. However, the efficacy of ZOSYN in treating clinical infections caused by these bacteria has not been established in adequate and well-controlled clinical trials. Aerobic bacteria Gram-positive bacteria Enterococcus faecalis (ampicillin or penicillin-susceptible isolates only) Staphylococcus epidermidis (methicillin susceptible isolates only) Streptococcus agalactiae These are not beta-lactamase producing bacteria and, therefore, are susceptible to piperacillin alone. Streptococcus pneumoniae (penicillin-susceptible isolates only) Streptococcus pyogenes Viridans group streptococci Gram-negative bacteria Citrobacter koseri Moraxella catarrhalis Morganella morganii Neisseria gonorrhoeae Proteus mirabilis Proteus vulgaris Serratia marcescens Providencia stuartii Providencia rettgeri Salmonella enterica Anaerobic bacteria Clostridium perfringens Bacteroides distasonis Prevotella melaninogenica Susceptibility Testing For specific information regarding susceptibility test interpretive criteria, and associated test methods and quality control standards recognized by FDA for this drug, please see: https://www.fda.gov/STIC .

12.1 Mechanism of Action ZOSYN is an antibacterial drug [see Microbiology (12.4) ] .

12.2 Pharmacodynamics The pharmacodynamic parameter for piperacillin and tazobactam that is most predictive of clinical and microbiological efficacy is time above MIC.

12.3 Pharmacokinetics The mean and coefficients of variation (CV%) for the pharmacokinetic parameters of piperacillin and tazobactam after multiple intravenous doses are summarized in Table 7. Table 7: Mean (CV%) Piperacillin and Tazobactam PK Parameters C max : maximum observed concentration, AUC: Area under the curve, CL=clearance, CL R = Renal clearance V=volume of distribution, T 1/2 = elimination half-life Piperacillin Piperacillin and Tazobactam Dose Piperacillin and tazobactam were given in combination, infused over 30 minutes. C max (mcg/mL) AUC Numbers in []parentheses are coefficients of variation [CV%]. (mcg∙h/mL) CL (mL/min) V (L) T 1/2 (h) CL R (mL/min) 2.25 g 134 131 [14] 257 17.4 0.79 -- 3.375 g 242 242 [10] 207 15.1 0.84 140 4.5 g 298 322 [16] 210 15.4 0.84 -- Tazobactam Piperacillin and Tazobactam Dose C max (mcg/mL) AUC (mcg∙h/mL) CL (mL/min) V (L) T 1/2 (h) CL R (mL/min) 2.25 g 15 16.0 [21] 258 17.0 0.77 -- 3.375 g 24 25.0 [8] 251 14.8 0.68 166 4.5 g 34 39.8 [15] 206 14.7 0.82 -- Peak plasma concentrations of piperacillin and tazobactam are attained immediately after completion of an intravenous infusion of ZOSYN. Piperacillin plasma concentrations, following a 30-minute infusion of ZOSYN, were similar to those attained when equivalent doses of piperacillin were administered alone. Steady-state plasma concentrations of piperacillin and tazobactam were similar to those attained after the first dose due to the short half-lives of piperacillin and tazobactam. Distribution Both piperacillin and tazobactam are approximately 30% bound to plasma proteins. The protein binding of either piperacillin or tazobactam is unaffected by the presence of the other compound. Protein binding of the tazobactam metabolite is negligible. Piperacillin and tazobactam are widely distributed into tissues and body fluids including intestinal mucosa, gallbladder, lung, female reproductive tissues (uterus, ovary, and fallopian tube), interstitial fluid, and bile. Mean tissue concentrations are generally 50% to 100% of those in plasma. Distribution of piperacillin and tazobactam into cerebrospinal fluid is low in subjects with non-inflamed meninges, as with other penicillins (see Table 8). Table 8: Piperacillin and Tazobactam Concentrations in Selected Tissues and Fluids after Single 4 g/0.5 g 30-min IV Infusion of ZOSYN Tissue or Fluid N Each subject provided a single sample. Sampling period Time from the start of the infusion (h) Mean PIP Concentration Range (mg/L) Tissue:Plasma Range Tazo Concentration Range (mg/L) Tazo Tissue:Plasma Range Skin 35 0.5 – 4.5 34.8 – 94.2 0.60 – 1.1 4.0 – 7.7 0.49 – 0.93 Fatty Tissue 37 0.5 – 4.5 4.0 – 10.1 0.097 – 0.115 0.7 – 1.5 0.10 – 0.13 Muscle 36 0.5 – 4.5 9.4 – 23.3 0.29 – 0.18 1.4 – 2.7 0.18 – 0.30 Proximal Intestinal Mucosa 7 1.5 – 2.5 31.4 0.55 10.3 1.15 Distal Intestinal Mucosa 7 1.5 – 2.5 31.2 0.59 14.5 2.1 Appendix 22 0.5 – 2.5 26.5 – 64.1 0.43 – 0.53 9.1 – 18.6 0.80 – 1.35 Metabolism Piperacillin is metabolized to a minor microbiologically active desethyl metabolite. Tazobactam is metabolized to a single metabolite that lacks pharmacological and antibacterial activities. Excretion Following single or multiple ZOSYN doses to healthy subjects, the plasma half-life of piperacillin and of tazobactam ranged from 0.7 to 1.2 hours and was unaffected by dose or duration of infusion. Both piperacillin and tazobactam are eliminated via the kidney by glomerular filtration and tubular secretion. Piperacillin is excreted rapidly as unchanged drug with 68% of the administered dose excreted in the urine. Tazobactam and its metabolite are eliminated primarily by renal excretion with 80% of the administered dose excreted as unchanged drug and the remainder as the single metabolite. Piperacillin, tazobactam and desethyl piperacillin are also secreted into the bile. Specific Populations Renal Impairment After the administration of single doses of piperacillin and tazobactam to subjects with renal impairment, the half-life of piperacillin and of tazobactam increases with decreasing creatinine clearance. At creatinine clearance below 20 mL/min, the increase in half-life is twofold for piperacillin and fourfold for tazobactam compared to subjects with normal renal function. Dosage adjustments for ZOSYN are recommended when creatinine clearance is below 40 mL/min in patients receiving the usual recommended daily dose of ZOSYN. See Dosage and Administration (2) for specific recommendations for the treatment of patients with renal-impairment. Hemodialysis removes 30% to 40% of a piperacillin and tazobactam dose with an additional 5% of the tazobactam dose removed as the tazobactam metabolite. Peritoneal dialysis removes approximately 6% and 21% of the piperacillin and tazobactam doses, respectively, with up to 16% of the tazobactam dose removed as the tazobactam metabolite. For dosage recommendations for patients undergoing hemodialysis [see Dosage and Administration (2) ] . Hepatic Impairment The half-life of piperacillin and of tazobactam increases by approximately 25% and 18%, respectively, in patients with hepatic cirrhosis compared to healthy subjects. However, this difference does not warrant dosage adjustment of ZOSYN due to hepatic cirrhosis. Pediatrics Piperacillin and tazobactam pharmacokinetics were studied in pediatric patients 2 months of age and older. The clearance of both compounds is slower in the younger patients compared to older children and adults. In a population PK analysis, estimated clearance for 9 month-old to 12 year-old patients was comparable to adults, with a population mean (SE) value of 5.64 (0.34) mL/min/kg. The piperacillin clearance estimate is 80% of this value for pediatric patients 2 – 9 months old. In patients younger than 2 months of age, clearance of piperacillin is slower compared to older children; however, it is not adequately characterized for dosing recommendations. The population mean (SE) for piperacillin volume of distribution is 0.243 (0.011) L/kg and is independent of age. Geriatrics The impact of age on the pharmacokinetics of piperacillin and tazobactam was evaluated in healthy male subjects, aged 18 – 35 years (n=6) and aged 65 to 80 years (n=12). Mean half-life for piperacillin and tazobactam was 32% and 55% higher, respectively, in the elderly compared to the younger subjects. This difference may be due to age-related changes in creatinine clearance. Race The effect of race on piperacillin and tazobactam was evaluated in healthy male volunteers. No difference in piperacillin or tazobactam pharmacokinetics was observed between Asian (n=9) and Caucasian (n=9) healthy volunteers who received single 4/0.5 g doses. Drug Interactions The potential for pharmacokinetic drug interactions between ZOSYN and aminoglycosides, probenecid, vancomycin, heparin, vecuronium, and methotrexate has been evaluated [see Drug Interactions (7) ] .

20230315

1

3 DOSAGE FORMS AND STRENGTHS ZOSYN ® (piperacillin and tazobactam) Injection is supplied in GALAXY Containers as a frozen, iso-osmotic, sterile, non-pyrogenic solution in single-dose plastic containers: 2.25 g (piperacillin sodium equivalent to 2 g piperacillin and tazobactam sodium equivalent to 0.25 g tazobactam) in 50 mL. 3.375 g (piperacillin sodium equivalent to 3 g piperacillin and tazobactam sodium equivalent to 0.375 g tazobactam) in 50 mL. 4.5 g (piperacillin sodium equivalent to 4 g piperacillin and tazobactam sodium equivalent to 0.5 g tazobactam) in 100 mL. ZOSYN ® Injection: 2.25 g in 50 mL, 3.375 g in 50 mL, and 4.5 g in 100 mL frozen solution in single-dose GALAXY Containers. ( 3 , 16 )

Zosyn in Galaxy Containers TAZOBACTAM SODIUM and PIPERACILLIN SODIUM TAZOBACTAM SODIUM TAZOBACTAM PIPERACILLIN SODIUM PIPERACILLIN ANHYDROUS DEXTROSE MONOHYDRATE SODIUM CITRATE, UNSPECIFIED FORM EDETATE DISODIUM SODIUM BICARBONATE HYDROCHLORIC ACID WATER Zosyn in Galaxy Containers TAZOBACTAM SODIUM and PIPERACILLIN SODIUM TAZOBACTAM SODIUM TAZOBACTAM PIPERACILLIN SODIUM PIPERACILLIN ANHYDROUS DEXTROSE MONOHYDRATE SODIUM CITRATE, UNSPECIFIED FORM EDETATE DISODIUM SODIUM BICARBONATE HYDROCHLORIC ACID WATER Zosyn in Galaxy Containers TAZOBACTAM SODIUM and PIPERACILLIN SODIUM TAZOBACTAM SODIUM TAZOBACTAM PIPERACILLIN SODIUM PIPERACILLIN ANHYDROUS DEXTROSE MONOHYDRATE SODIUM CITRATE, UNSPECIFIED FORM EDETATE DISODIUM SODIUM BICARBONATE HYDROCHLORIC ACID WATER

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis Long-term carcinogenicity studies in animals have not been conducted with piperacillin and tazobactam, piperacillin, or tazobactam. Mutagenesis Piperacillin and tazobactam was negative in microbial mutagenicity assays, the unscheduled DNA synthesis (UDS) test, a mammalian point mutation (Chinese hamster ovary cell HPRT) assay, and a mammalian cell (BALB/c-3T3) transformation assay. In vivo , piperacillin and tazobactam did not induce chromosomal aberrations in rats. Fertility Reproduction studies have been performed in rats and have revealed no evidence of impaired fertility when piperacillin and tazobactam is administered intravenously up to a dose of 1280/320 mg/kg piperacillin and tazobactam, which is similar to the maximum recommended human daily dose based on body-surface area (mg/m 2 ).

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis Long-term carcinogenicity studies in animals have not been conducted with piperacillin and tazobactam, piperacillin, or tazobactam. Mutagenesis Piperacillin and tazobactam was negative in microbial mutagenicity assays, the unscheduled DNA synthesis (UDS) test, a mammalian point mutation (Chinese hamster ovary cell HPRT) assay, and a mammalian cell (BALB/c-3T3) transformation assay. In vivo , piperacillin and tazobactam did not induce chromosomal aberrations in rats. Fertility Reproduction studies have been performed in rats and have revealed no evidence of impaired fertility when piperacillin and tazobactam is administered intravenously up to a dose of 1280/320 mg/kg piperacillin and tazobactam, which is similar to the maximum recommended human daily dose based on body-surface area (mg/m 2 ).

NDA050750

Zosyn in Galaxy Containers

TAZOBACTAM SODIUM and PIPERACILLIN SODIUM

0206-8860

HUMAN PRESCRIPTION DRUG

INTRAVENOUS

12.4 Microbiology Mechanism of Action Piperacillin sodium exerts bactericidal activity by inhibiting septum formation and cell wall synthesis of susceptible bacteria. In vitro, piperacillin is active against a variety of gram-positive and gram-negative aerobic and anaerobic bacteria. Tazobactam sodium has little clinically relevant in vitro activity against bacteria due to its reduced affinity to penicillin-binding proteins. It is, however, a beta-lactamase inhibitor of the Molecular class A enzymes, including Richmond-Sykes class III (Bush class 2b & 2b') penicillinases and cephalosporinases. It varies in its ability to inhibit class II and IV (2a & 4) penicillinases. Tazobactam does not induce chromosomally-mediated beta-lactamases at tazobactam concentrations achieved with the recommended dosage regimen. Antimicrobial Activity ZOSYN has been shown to be active against most isolates of the following microorganisms, both in vitro and in clinical infections [see Indications and Usage (1) ] : Aerobic bacteria Gram-positive bacteria Staphylococcus aureus (methicillin susceptible isolates only) Gram-negative bacteria Acinetobacter baumannii Escherichia coli Haemophilus influenzae (excluding beta-lactamase negative, ampicillin-resistant isolates) Klebsiella pneumoniae Pseudomonas aeruginosa (given in combination with an aminoglycoside to which the isolate is susceptible) Anaerobic bacteria Bacteroides fragilis group ( B. fragilis, B. ovatus, B. thetaiotaomicron, and B. vulgatus ) The following in vitro data are available, but their clinical significance is unknown. At least 90 percent of the following bacteria exhibit an in vitro minimum inhibitory concentration (MIC) less than or equal to the susceptible breakpoint for piperacillin and tazobactam against isolates of similar genus or organism group. However, the efficacy of ZOSYN in treating clinical infections caused by these bacteria has not been established in adequate and well-controlled clinical trials. Aerobic bacteria Gram-positive bacteria Enterococcus faecalis (ampicillin or penicillin-susceptible isolates only) Staphylococcus epidermidis (methicillin susceptible isolates only) Streptococcus agalactiae These are not beta-lactamase producing bacteria and, therefore, are susceptible to piperacillin alone. Streptococcus pneumoniae (penicillin-susceptible isolates only) Streptococcus pyogenes Viridans group streptococci Gram-negative bacteria Citrobacter koseri Moraxella catarrhalis Morganella morganii Neisseria gonorrhoeae Proteus mirabilis Proteus vulgaris Serratia marcescens Providencia stuartii Providencia rettgeri Salmonella enterica Anaerobic bacteria Clostridium perfringens Bacteroides distasonis Prevotella melaninogenica Susceptibility Testing For specific information regarding susceptibility test interpretive criteria, and associated test methods and quality control standards recognized by FDA for this drug, please see: https://www.fda.gov/STIC .

PRINCIPAL DISPLAY PANEL – 2.25 g Container ZOSYN ® (Piperacillin and Tazobactam Injection) 2.25 g Rx only GALAXY Single Dose Container 50 mL Iso-osmotic NDC 0206-8860-01 Code 2G3575 Sterile Nonpyrogenic Store at or below -20°C/-4°F. Thaw at room temperature 20° to 25°C (68° to 77°F) or under refrigeration 2° to 8°C (36° to 46°F). DO NOT FORCE THAW BY IMMERSION IN WATER BATHS OR BY MICROWAVE IRRADIATION. Thawed solution remains stable for 14 days under refrigeration or 24 hours at room temperature. Do not refreeze. Handle frozen product containers with care. Product containers may be fragile in the frozen state. Dosage and Use: For intravenous use only. As directed by a physician. See Package Insert. Cautions: Do not add supplementary medication or additives. Must not be used in series connections. Check for minute leaks and solution clarity. Each 50 mL contains: Piperacillin Sodium equivalent to 2 g Piperacillin and Tazobactam Sodium equivalent to 0.25 g Tazobactam in Water for Injection. Approximately 1 g Dextrose Hydrous added to adjust osmolality. Approximately 100 mg Sodium Citrate Dihydrate added as a buffer. pH adjusted with sodium bicarbonate and hydrochloric acid. pH 5.5 - 6.8 Each 50 mL also contains approximately 0.5 mg Edetate Disodium Dihydrate added as a metal chelator. GALAXY is a registered trademark of Baxter International Inc. Distributed by Wyeth Pharmaceuticals LLC A subsidiary of Pfizer Inc Philadelphia, PA 19101 PL 2040 Plastic 14715600 0734001604 Pfizer Hospital PRINCIPAL DISPLAY PANEL – 2.25 g Container

Warnings and Precautions, Hemophagocytic Lymphohistiocytosis ( 5.3 ) 4/2022

17 PATIENT COUNSELING INFORMATION Serious Hypersensitivity Reactions Advise patients, their families, or caregivers that serious hypersensitivity reactions, including serious allergic cutaneous reactions, could occur with use of ZOSYN that require immediate treatment. Ask them about any previous hypersensitivity reactions to ZOSYN, other beta-lactams (including cephalosporins), or other allergens [see Warnings and Precautions (5.2) ]. 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) ] . Diarrhea Advise patients, their families, or caregivers that diarrhea is a common problem caused by antibacterial drugs, including ZOSYN, which usually ends when the drug is discontinued. Sometimes after starting treatment with antibacterial drugs, patients can develop watery and bloody stools (with or without stomach cramps and fever) even as late as two or more months after having taken the last dose of the drug. If this occurs, patients should contact their physician as soon as possible [see Warnings and Precautions (5.8) ] . Antibacterial Resistance Patients should be counseled that antibacterial drugs including ZOSYN should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When ZOSYN is prescribed to treat a bacterial infection, patients should be told that although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed. Skipping doses or not completing the full course of therapy may (1) decrease the effectiveness of the immediate treatment and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by ZOSYN or other antibacterial drugs in the future. Pregnancy and Lactation Patients should be counseled that ZOSYN can cross the placenta in humans and is excreted in human milk [see Use in Specific Populations (8.1 , 8.2) ] . This product's labeling may have been updated. For the most recent prescribing information, please visit http://www.pfizer.com . CLINITEST ® is a registered trademark of Siemens Healthcare Diagnostics Inc. GALAXY is a registered trademark of Baxter International Inc. LAB-1527-1.0 Figure Figure Logo

15 REFERENCES 1. Jensen J-US, Hein L, Lundgren B, et al. BMJ Open 2012; 2:e000635. doi:10.1136.

8.5 Geriatric Use Patients over 65 years are not at an increased risk of developing adverse effects solely because of age. However, dosage should be adjusted in the presence of renal impairment [see Dosage and Administration (2) ] . In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. 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. The geriatric population may respond with a blunted natriuresis to salt loading. This may be clinically important with regard to such diseases as congestive heart failure. This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.

8.4 Pediatric Use 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 and 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) ]. 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 2.6) ] . 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.

8.1 Pregnancy Risk Summary Piperacillin and tazobactam cross the placenta in humans. However, there are insufficient data with piperacillin and/or tazobactam in pregnant women to inform a drug-associated risk for major birth defects and miscarriage. No fetal structural abnormalities were observed in rats or mice when piperacillin and tazobactam was administered intravenously during organogenesis at doses 1 to 2 times and 2 to 3 times the human dose of piperacillin and tazobactam, respectively, based on body-surface area (mg/m 2 ). However, fetotoxicity in the presence of maternal toxicity was observed in developmental toxicity and peri/postnatal studies conducted in rats (intraperitoneal administration prior to mating and throughout gestation or from gestation day 17 through lactation day 21) at doses less than the maximum recommended human daily dose based on body-surface area (mg/m 2 ) (see Data ) . The background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2–4% and 15–20%, respectively. Data Animal Data In embryo-fetal development studies in mice and rats, pregnant animals received intravenous doses of piperacillin and tazobactam up to 3000/750 mg/kg/day during the period of organogenesis. There was no evidence of teratogenicity up to the highest dose evaluated, which is 1 to 2 times and 2 to 3 times the human dose of piperacillin and tazobactam, in mice and rats respectively, based on body-surface area (mg/m 2 ). Fetal body weights were reduced in rats at maternally toxic doses at or above 500/62.5 mg/kg/day, minimally representing 0.4 times the human dose of both piperacillin and tazobactam based on body-surface area (mg/m 2 ). A fertility and general reproduction study in rats using intraperitoneal administration of tazobactam or the combination piperacillin and tazobactam prior to mating and through the end of gestation, reported a decrease in litter size in the presence of maternal toxicity at 640 mg/kg/day tazobactam (4 times the human dose of tazobactam based on body-surface area), and decreased litter size and an increase in fetuses with ossification delays and variations of ribs, concurrent with maternal toxicity at ≥640/160 mg/kg/day piperacillin and tazobactam (0.5 times and 1 times the human dose of piperacillin and tazobactam, respectively, based on body-surface area). Peri/postnatal development in rats was impaired with reduced pup weights, increased stillbirths, and increased pup mortality concurrent with maternal toxicity after intraperitoneal administration of tazobactam alone at doses ≥320 mg/kg/day (2 times the human dose based on body surface area) or of the combination piperacillin and tazobactam at doses ≥640/160 mg/kg/day (0.5 times and 1 times the human dose of piperacillin and tazobactam, respectively, based on body-surface area) from gestation day 17 through lactation day 21.

8 USE IN SPECIFIC POPULATIONS Dosage in patients with renal impairment (creatinine clearance ≤40 mL/min) should be reduced based on the degree of renal impairment. ( 2.4 , 8.6 ) 8.1 Pregnancy Risk Summary Piperacillin and tazobactam cross the placenta in humans. However, there are insufficient data with piperacillin and/or tazobactam in pregnant women to inform a drug-associated risk for major birth defects and miscarriage. No fetal structural abnormalities were observed in rats or mice when piperacillin and tazobactam was administered intravenously during organogenesis at doses 1 to 2 times and 2 to 3 times the human dose of piperacillin and tazobactam, respectively, based on body-surface area (mg/m 2 ). However, fetotoxicity in the presence of maternal toxicity was observed in developmental toxicity and peri/postnatal studies conducted in rats (intraperitoneal administration prior to mating and throughout gestation or from gestation day 17 through lactation day 21) at doses less than the maximum recommended human daily dose based on body-surface area (mg/m 2 ) (see Data ) . The background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2–4% and 15–20%, respectively. Data Animal Data In embryo-fetal development studies in mice and rats, pregnant animals received intravenous doses of piperacillin and tazobactam up to 3000/750 mg/kg/day during the period of organogenesis. There was no evidence of teratogenicity up to the highest dose evaluated, which is 1 to 2 times and 2 to 3 times the human dose of piperacillin and tazobactam, in mice and rats respectively, based on body-surface area (mg/m 2 ). Fetal body weights were reduced in rats at maternally toxic doses at or above 500/62.5 mg/kg/day, minimally representing 0.4 times the human dose of both piperacillin and tazobactam based on body-surface area (mg/m 2 ). A fertility and general reproduction study in rats using intraperitoneal administration of tazobactam or the combination piperacillin and tazobactam prior to mating and through the end of gestation, reported a decrease in litter size in the presence of maternal toxicity at 640 mg/kg/day tazobactam (4 times the human dose of tazobactam based on body-surface area), and decreased litter size and an increase in fetuses with ossification delays and variations of ribs, concurrent with maternal toxicity at ≥640/160 mg/kg/day piperacillin and tazobactam (0.5 times and 1 times the human dose of piperacillin and tazobactam, respectively, based on body-surface area). Peri/postnatal development in rats was impaired with reduced pup weights, increased stillbirths, and increased pup mortality concurrent with maternal toxicity after intraperitoneal administration of tazobactam alone at doses ≥320 mg/kg/day (2 times the human dose based on body surface area) or of the combination piperacillin and tazobactam at doses ≥640/160 mg/kg/day (0.5 times and 1 times the human dose of piperacillin and tazobactam, respectively, based on body-surface area) from gestation day 17 through lactation day 21. 8.2 Lactation 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. 8.4 Pediatric Use 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 and 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) ]. 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 2.6) ] . 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. 8.5 Geriatric Use Patients over 65 years are not at an increased risk of developing adverse effects solely because of age. However, dosage should be adjusted in the presence of renal impairment [see Dosage and Administration (2) ] . In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. 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. The geriatric population may respond with a blunted natriuresis to salt loading. This may be clinically important with regard to such diseases as congestive heart failure. This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. 8.6 Renal Impairment In patients with creatinine clearance ≤ 40 mL/min and dialysis patients (hemodialysis and CAPD), the intravenous dose of ZOSYN should be reduced to the degree of renal function impairment [see Dosage and Administration (2) ] . 8.7 Hepatic Impairment Dosage adjustment of ZOSYN is not warranted in patients with hepatic cirrhosis [see Clinical Pharmacology (12.3) ] . 8.8 Patients with Cystic Fibrosis As with other semisynthetic penicillins, piperacillin therapy has been associated with an increased incidence of fever and rash in cystic fibrosis patients.

16 HOW SUPPLIED/STORAGE AND HANDLING ZOSYN ® (piperacillin and tazobactam) Injection in GALAXY Containers are supplied as a frozen, iso-osmotic, sterile, nonpyrogenic solution in single-dose plastic containers as follows: • 2.25 g (piperacillin sodium equivalent to 2 g piperacillin and tazobactam sodium equivalent to 0.25 g tazobactam) in 50 mL. Each container has 5.58 mEq (128 mg) of sodium. Supplied 24/box—NDC 0206-8860-02 • 3.375 g (piperacillin sodium equivalent to 3 g piperacillin and tazobactam sodium equivalent to 0.375 g tazobactam) in 50 mL. Each container has 8.38 mEq (192 mg) of sodium. Supplied 24/box—NDC 0206-8861-02 • 4.5 g (piperacillin sodium equivalent to 4 g piperacillin and tazobactam sodium equivalent to 0.5 g tazobactam) in 100 mL. Each container has 11.17 mEq (256 mg) of sodium. Supplied 12/box—NDC 0206-8862-02 ZOSYN ® Injection in GALAXY Containers should be stored at or below -20°C (-4°F) [see Dosage and Administration (2.6) ]. Handle frozen product containers with care. Product containers may be fragile in the frozen state.