Piperacillin And Tazobactam And Sodium Chloride

1 INDICATIONS AND USAGE Piperacillin and Tazobactam for Injection and Sodium Chloride Injection, 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 ) Usage to Reduce Development of Drug-Resistant Bacteria To reduce the development of drug-resistant bacteria and maintain the effectiveness of Piperacillin and Tazobactam for Injection and Sodium Chloride Injection and other antibacterial drugs, Piperacillin and Tazobactam for Injection and Sodium Chloride Injection 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 Piperacillin and Tazobactam for Injection and Sodium Chloride Injection 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 Piperacillin and Tazobactam for Injection and Sodium Chloride Injection 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 Piperacillin and Tazobactam for Injection and Sodium Chloride Injection 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 Piperacillin and Tazobactam for Injection and Sodium Chloride Injection 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 Piperacillin and Tazobactam for Injection and Sodium Chloride Injection 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 Development of Drug-Resistant Bacteria To reduce the development of drug-resistant bacteria and maintain the effectiveness of Piperacillin and Tazobactam for Injection and Sodium Chloride Injection and other antibacterial drugs, Piperacillin and Tazobactam for Injection and Sodium Chloride Injection 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.

2 DOSAGE AND ADMINISTRATION If a dose of Piperacillin and Tazobactam for Injection and Sodium Chloride injection is required that is not equal to 2.25 g, 3.375 g, or 4.5 g, this product is not recommended for use and an alternative formulation of piperacillin and tazobactam for injection should be considered ( 2.1 ). Adult Patients With Indications Other Than Nosocomial Pneumonia; The usual daily dosage of Piperacillin and Tazobactam for Injection and Sodium Chloride Injection, for intravenous use for adults is 3.375 g every 6 ( six ) hours. ( 2.2 ) Adult Patients with Nosocomial Pneumonia: Initial presumptive treatment of patients with nosocomial pneumonia should start with Piperacillin and Tazobactam for Injection and Sodium Chloride Injection, for intravenous use at a dosage of 4.5 g every 6 ( six ) hours plus an aminoglycoside. (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 Piperacillin and Tazobactam for Injection and Sodium Chloride Injection 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 Piperacillin and Tazobactam for Injection and Sodium Chloride Injection by intravenous infusion over 30 minutes to both adult and pediatric patients 2 months of age and older. ( 2.2 , 2.3 , 2.4 , 2.5 ) Piperacillin and Tazobactam for Injection and Sodium Chloride Injection and aminoglycosides should be reconstituted 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 Piperacillin and Tazobactam for Injection and Sodium Chloride Injection single-dose DUPLEX ® Container. 2.1 Important Administration Instructions If a dose of Piperacillin and Tazobactam for Injection and Sodium Chloride Injection is required that does not equal 2.25 g, 3.375 g, or 4.5 g, this product is not recommended for use and an alternative formulation of piperacillin and tazobactam for injection should be considered. 2.2 Recommended Dosage in Adult Patients With Indications Other Than Nosocomial Pneumonia The usual total daily dosage of Piperacillin and Tazobactam for Injection and Sodium Chloride Injection for adult patients with indications other than nosocomial pneumonia is 3.375 g every 6 ( six ) hours, to be administered by intravenous infusion over 30 minutes. The usual duration of Piperacillin and Tazobactam for Injection and Sodium Chloride Injection treatment is from 7 to 10 days. 2.3 Recommended Dosage in Adult Patients With Nosocomial Pneumonia Initial presumptive treatment of adult patients with nosocomial pneumonia should start with Piperacillin and Tazobactam for Injection and Sodium Chloride Injection at a dosage of 4.5 g every 6 ( six ) hours plus an aminoglycoside, administered by intravenous infusion over 30 minutes. The recommended duration of Piperacillin and Tazobactam for Injection and Sodium Chloride Injection 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 Recommended 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 Piperacillin and Tazobactam for Injection and Sodium Chloride Injection should be reduced based on the degree of renal impairment. The recommended daily dosage of Piperacillin and Tazobactam for Injection and Sodium Chloride Injection for patients with renal impairment administered by intravenous infusion over 30 minutes is described in Table 1. Table 1: Recommended Dosage of Piperacillin and Tazobactam in Patients with Normal Renal Function and Renal Impairment (As total grams piperacillin and tazobactam) Administer Piperacillin and Tazobactam for Injection and Sodium Chloride Injection by intravenous infusion over 30 minutes. Creatinine clearance, mL/min All Indications (except nosocomial pneumonia) Nosocomial Pneumonia Greater than 40 mL/min 3.375 g every 6 hours 4.5 g every 6 hours 20 to 40 mL/min Creatinine clearance for patients not receiving hemodialysis 2.25 g every 6 hours 3.375 g every 6 hours Less than 20 mL/min 2.25 g every 8 hours 2.25 g 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 g every 12 hours 2.25 g every 8 hours CAPD 2.25 g every 12 hours 2.25 g every 8 hours For patients on hemodialysis, the maximum dose is 2.25 g every 12 hours for all indications other than nosocomial pneumonia and 2.25 g every 8 hours for nosocomial pneumonia. Since hemodialysis removes 30% to 40% of the administered dose, an additional dose of 0.75 g piperacillin and tazobactam for injection should be administered following each dialysis period on hemodialysis days. No additional dosage of Piperacillin and Tazobactam for Injection and Sodium Chloride Injection is necessary for CAPD patients. 2.5 Dosage in Pediatric Patients 2 months of Age and Older With Appendicitis (complicated by rupture or abscess) and/or Peritonitis or Nosocomial Pneumonia with normal renal function If a dose of Piperacillin and Tazobactam for Injection and Sodium Chloride injection is required that is not equal to 2.25 g, 3.375 g, or 4.5 g, this product is not recommended for use and an alternative formulation of piperacillin and tazobactam for injection should be considered [see Use in Specific Populations (8.4) ]. The recommended dosage for pediatric patients with appendicitis (complicated by rupture or abscess) 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 Piperacillin and Tazobactam in Pediatric Patients 2 Months of Age and Older, Weighing Up to 40 kg, and With Normal Renal Function Administer Piperacillin and Tazobactam for Injection and Sodium Chloride Injection by intravenous infusion over 30 minutes 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 Piperacillin and Tazobactam for Injection and Sodium Chloride Injection in pediatric patients with renal impairment has not been determined. 2.6 Preparation and Administration of Piperacillin and Tazobactam for Injection and Sodium Chloride Injection in the DUPLEX ® Container Important Administration Instructions Do not use in series connections. Such use would 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. If administration is controlled by a pumping device, care must be taken to discontinue pumping action before the container runs dry or air embolism may result. Do not introduce additives into the DUPLEX ® Container. Piperacillin and Tazobactam for Injection and Sodium Chloride Injection is not chemically stable in solutions that contain only sodium bicarbonate and solutions that significantly alter the pH. Piperacillin and Tazobactam for Injection and Sodium Chloride Injection should not be added to blood products or albumin hydrolysates. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Use only if solution is clear and container and seals are intact. Administer Piperacillin and Tazobactam for Injection and Sodium Chloride Injection intravenously over 30 minutes. This reconstituted solution is for intravenous use only. DUPLEX ® Container Storage To avoid inadvertent activation, the DUPLEX ® Container should remain in the folded position until activation is intended. Patient Labeling and Drug Powder/Diluent Inspection Apply patient-specific label on foil side of container. Use care to avoid activation. Do not cover any portion of foil strip with patient label. Peel sticker halfway off and unfold DUPLEX ® Container (see Diagram 1 ). Visually inspect diluent chamber for particulate matter. Use only if container and seals are intact. To inspect the drug powder for foreign matter or discoloration, peel foil strip from drug chamber (see Diagram 2 ). Protect from light after removal of foil strip. Note: If foil strip is removed, the container should be re-folded and the sticker reapplied until ready to activate. The product must then be used within 7 days at room temperature at 20°C to 25°C (68°F to 77°F), but not beyond the labeled expiration date. Reconstitution (Activation) Do not use directly after storage by refrigeration, allow the product to equilibrate to room temperature before patient use. Unfold the DUPLEX ® Container and point the set port in a downward direction. Starting at the hanger tab end, fold the DUPLEX ® Container just below the diluent meniscus trapping all air above the fold. To activate, squeeze the folded diluent chamber until the seal between the diluent and powder opens, releasing diluent into the drug powder chamber (see Diagram 3 ). Agitate the liquid-powder mixture until the drug powder is completely dissolved. Note: Following reconstitution (activation), the reconstituted product must be used within 24 hours if stored at room temperature at 20°C to 25°C (68°F to 77°F) or within 7 days if stored under refrigeration at 2°C to 8°C (36°F to 46°F). Administration Visually inspect the reconstituted solution for particulate matter. Point the set port in a downwards direction. Starting at the hanger tab end, fold the DUPLEX ® Container just below the solution meniscus trapping all air above the fold. Squeeze the folded DUPLEX ® Container until the seal between reconstituted drug solution and set port opens, releasing liquid to set port (see Diagram 4 ). Prior to attaching the intravenous set, check for minute leaks by squeezing container firmly. If leaks are found, discard container and solution as sterility may be compromised. Using aseptic technique, peel foil cover from the set port and attach sterile administration set (see Diagram 5 ). Refer to directions for use accompanying the administration set. Discard unused portion. Compatible Intravenous Solutions for Co-administration via a Y-site 0.9% sodium chloride for injection Sterile water for injection (Maximum recommended volume per dose of sterile water for injection is 50 mL) Dextrose 5% Lactated Ringer's Solution Piperacillin and Tazobactam for Injection and Sodium Chloride Injection should not be mixed with other drugs in a syringe or infusion bottle since compatibility has not been established. Piperacillin and Tazobactam for Injection and Sodium Chloride Injection for Pediatric Patients Weighing up to 40 kg The volume of reconstituted solution required to deliver the dose of Piperacillin and Tazobactam is dependent on the weight of the pediatric patient [see Dosage and Administration (2.5) ]. 1. Calculate patient dose as described in Table 2 above [see Dosage and Administration (2.5) ]. 2. Piperacillin and Tazobactam for Injection and Sodium Chloride Injection in the DUPLEX ® Container should be used only in patients who require the entire 2.25 g, 3.375 g, or 4.5 g dose and not any fraction thereof. Stability of Piperacillin and Tazobactam for Injection and Sodium Chloride Injection Following Reconstitution Stability studies after reconstitution in the DUPLEX ® Containers, have demonstrated chemical stability (potency, pH of reconstituted solution and clarity of solution) for up to 24 hours at room temperature at 20°C to 25°C (68°F to 77°F) and up to 7 days at refrigerated temperature at 2°C to 8°C (36°F to 46°F). Piperacillin and Tazobactam for Injection and Sodium Chloride Injection contains no preservatives. Appropriate consideration of aseptic technique should be used. Diagram 1 Diagram 2 Diagram 3 Diagram 4 Diagram 5 2.7 Compatibility With Aminoglycosides Due to the in vitro inactivation of aminoglycosides by piperacillin, Piperacillin and Tazobactam for Injection and Sodium Chloride Injection and aminoglycosides are recommended for separate administration. Piperacillin and Tazobactam for Injection and Sodium Chloride Injection and aminoglycosides should be reconstituted 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, Piperacillin and Tazobactam for Injection and Sodium Chloride Injection is compatible for simultaneous co-administration via Y-site infusion only with the following aminoglycosides under the following conditions: Table 3: Compatibility with Aminoglycosides Aminoglycoside Piperacillin and Tazobactam Dose Piperacillin and Tazobactam Diluent Volume Aminoglycoside Concentration Range The concentration ranges in Table 3 are based on administration of the aminoglycoside in divided doses (10 to 15 mg/kg/day in two daily doses for amikacin and 3 to 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 Piperacillin and Tazobactam for Injection and Sodium Chloride Injection has not been evaluated. See package insert for each aminoglycoside for complete Dosage and Administration instructions. Acceptable Diluents for Aminoglycosides Amikacin 2.25 g 3.375 g 4.5 g 50 mL 50 mL 100 mL 1.75 mg/mL to 7.5 mg/mL 0.9% sodium chloride or 5% dextrose Gentamicin 2.25 g 3.375 g 4.5 g 50 mL 50 mL 100 mL 0.7 mg/mL to 3.32 mg/mL 0.9% sodium chloride or 5% dextrose Only the concentration and diluents for amikacin or gentamicin with the dosages of Piperacillin and Tazobactam for Injection and Sodium Chloride Injection 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 Piperacillin and Tazobactam for Injection and Sodium Chloride Injection. Piperacillin and Tazobactam for Injection and Sodium Chloride Injection is not compatible with tobramycin for simultaneous co-administration via Y-site infusion. Compatibility of Piperacillin and Tazobactam for Injection and Sodium Chloride Injection with other aminoglycosides has not been established.

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) ] Rhabdomyolysis [see Warnings and Precautions (5.4) ] Hematologic Adverse Reactions [see Warnings and Precautions (5.5) ] Central Nervous System Adverse Reactions [see Warnings and Precautions (5.6) ] Nephrotoxicity in Critically Ill Patients [see Warnings and Precautions (5.7) ] High Sodium Load and Electrolyte Effects [see Warnings and Precautions (5.8) ] Clostridioides difficile -Associated Diarrhea [see Warnings and Precautions (5.9) ] The most common adverse reactions (incidence >5%) are diarrhea, constipation, nausea, headache, and insomnia. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact B. Braun Medical Inc. at 1-833-425-1464 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. The safety of Piperacillin and Tazobactam for Injection and Sodium Chloride Injection has been established from adequate and well-controlled studies of piperacillin and tazobactam. Below is a display of the adverse reactions of piperacillin and tazobactam in these adequate and well controlled studies. Clinical Trials in Adult Patients During the initial clinical investigations, 2621 patients worldwide were treated with piperacillin and tazobactam 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, piperacillin and tazobactam 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 Piperacillin and Tazobactam 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 piperacillin and tazobactam 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 Piperacillin and Tazobactam 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 (5.7) ]. 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 piperacillin and tazobactam 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 piperacillin and tazobactam 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 piperacillin and tazobactam 112.5 mg/kg given intravenously 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, adverse reactions were reported by 146 patients, 73 (26.7%) in the piperacillin and tazobactam group and 73 (27.1%) in the cefotaxime/metronidazole group. Six patients (2.2%) in the piperacillin and tazobactam 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 piperacillin and tazobactam 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 piperacillin and tazobactam and comparator groups, including patients aged 2 months to 9 months treated with piperacillin and tazobactam 90 mg/kg intravenously every 6 hours and patients older than 9 months and less than 18 years of age treated with piperacillin and tazobactam 112.5 mg/kg intravenously 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 piperacillin and tazobactam. 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), acute myocardial ischemia with or without myocardial infarction may occur as part of an allergic reaction 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, and linear IgA bullous dermatosis Musculoskeletal —rhabdomyolysis Postmarketing experience with piperacillin and tazobactam 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) ].

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 6. 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 Table 6: Mean (CV%) Piperacillin and Tazobactam PK Parameters 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 Piperacillin and Tazobactam for Injection and Sodium Chloride Injection. Piperacillin plasma concentrations, following a 30-minute infusion of Piperacillin and Tazobactam for Injection and Sodium Chloride Injection, 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 7). Table 7: Piperacillin and Tazobactam Concentrations in Selected Tissues and Fluids after Single 4 g/0.5 g 30-min Intravenous Infusion of Piperacillin and Tazobactam 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 Elimination 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 Piperacillin and Tazobactam for Injection and Sodium Chloride Injection 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 Patients with 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 Piperacillin and Tazobactam for Injection and Sodium Chloride Injection are recommended when creatinine clearance is below 40 mL/min in patients receiving the usual recommended daily dose of Piperacillin and Tazobactam for Injection and Sodium Chloride Injection. Specific recommendations for the treatment of adult patients with renal impairment are presented in another section of the prescribing information [see Dosage and Administration (2) ] . 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. Dosage recommendations for patients undergoing hemodialysis are presented in another section of the prescribing information [see Dosage and Administration (2) ] . Patients with 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 Piperacillin and Tazobactam for Injection and Sodium Chloride Injection due to hepatic cirrhosis. Pediatric Patients 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 pediatric patients 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 to 9 months old. In patients younger than 2 months of age, clearance of piperacillin is slower compared to older pediatric patients; 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. Geriatric Patients The impact of age on the pharmacokinetics of piperacillin and tazobactam was evaluated in healthy male subjects, aged 18 to 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 White (n=9) healthy volunteers who received single 4/0.5 g doses. Drug Interactions The potential for pharmacokinetic drug interactions between Piperacillin and Tazobactam for Injection and Sodium Chloride Injection and aminoglycosides, probenecid, vancomycin, heparin, vecuronium, and methotrexate has been evaluated [see Drug Interactions (7) ].