INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. Serious Hypersensitivity ReactionsAdvise patients, their families, or caregivers that serious hypersensitivity reactions, including serious allergic cutaneous reactions, could occur with use of Piperacillin and Tazobactam for Injection and Sodium Chloride Injection that require immediate treatment. Ask them about any previous hypersensitivity reactions to Piperacillin and Tazobactam for Injection and Sodium Chloride Injection, other beta-lactams (including cephalosporins), or other allergens [see Warnings and Precautions (5.2)]. Hemophagocytic LymphohistiocytosisPrior to initiation of treatment with Piperacillin and Tazobactam for Injection and Sodium Chloride Injection, inform patients that excessive immune activation may occur with Piperacillin and Tazobactam for Injection and Sodium Chloride Injection and that they should report signs or symptoms such as fever, rash, or lymphadenopathy to healthcare provider immediately [see Warnings and Precautions (5.3)]. High Sodium Load Piperacillin and Tazobactam for Injection and Sodium Chloride Injection contains high sodium load. Instruct patients to inform their healthcare provider if they develop symptoms of difficulty breathing, swelling, or increased weight [see Warnings and Precautions (5.8)].DiarrheaAdvise patients, their families, or caregivers that diarrhea is common problem caused by antibacterial drugs, including Piperacillin and Tazobactam for Injection and Sodium Chloride Injection, 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 (5.9)]. Antibacterial ResistancePatients should be counseled that antibacterial drugs including Piperacillin and Tazobactam for Injection and Sodium Chloride Injection should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When Piperacillin and Tazobactam for Injection and Sodium Chloride Injection is prescribed to treat 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 Piperacillin and Tazobactam for Injection and Sodium Chloride Injection or other antibacterial drugs in the future.Pregnancy and LactationPatients should be counseled that Piperacillin and Tazobactam for Injection and Sodium Chloride Injection can cross the placenta in humans and is excreted in human milk [see Use in Specific Populations (8.1, 8.2)].

ADVERSE REACTIONS SECTION.

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)] 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.. 6.1Clinical Trials Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of 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 display of the adverse reactions of piperacillin and tazobactam in these adequate and well controlled studies.Clinical Trials in Adult PatientsDuring the initial clinical investigations, 2621 patients worldwide were treated with piperacillin and tazobactam in phase 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 TrialsSystem Organ Class Adverse ReactionGastrointestinal 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 TrialsTwo trials of nosocomial lower respiratory tract infections were conducted. In one study, 222 patients were treated with piperacillin and tazobactam in dosing regimen of 4.5 every hours in combination with an aminoglycoside and 215 patients were treated with imipenem/cilastatin (500 mg/500 mg every 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 dosing regimen of 3.375 given every hours with an aminoglycoside.Table 5: Adverse Reactions from Piperacillin and Tazobactam Plus Aminoglycoside Clinical TrialsFor adverse drug reactions that appeared in both studies the higher frequency is presented. System Organ Class Adverse ReactionBlood 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: NephrotoxicityIn randomized, multicenter, controlled trial in 1200 adult critically ill patients, piperacillin and tazobactam was found to be risk factor for renal failure (odds ratio 1.7, 95% CI 1.18 to 2.43), and associated with delayed recovery of renal function as compared to other beta-lactam antibacterial drugs1 [see Warnings and Precautions (5.7)]. Adverse Laboratory Changes (Seen During Clinical Trials)Of the trials reported, including that of nosocomial lower respiratory tract infections in which 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 timeHepatic--transient elevations of AST (SGOT), ALT (SGPT), alkaline phosphatase, bilirubinRenal--increases in serum creatinine, blood urea nitrogenAdditional 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 PatientsClinical studies of piperacillin and tazobactam in pediatric patients suggest similar safety profile to that seen in adults. In prospective, randomized, comparative, open-label clinical trial of pediatric patients, 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 hours and 269 patients were treated with cefotaxime (50 mg/kg) plus metronidazole (7.5 mg/kg) every 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 patients (1.9%) in the cefotaxime/metronidazole group discontinued due to an adverse event.In retrospective, cohort study, 140 pediatric patients 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 months to months treated with piperacillin and tazobactam 90 mg/kg intravenously every hours and patients older than months and less than 18 years of age treated with piperacillin and tazobactam 112.5 mg/kg intravenously every hours.. 6.2Postmarketing Experience. In addition to the adverse drug reactions identified in clinical trials in Table 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 population of uncertain size, it is not always possible to reliably estimate their frequency or establish causal relationship to drug exposure.Hepatobiliary--hepatitis, jaundiceHematologic--hemolytic anemia, agranulocytosis, pancytopeniaImmune--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 reactionRenal--interstitial nephritisNervous system disorders--seizuresPsychiatric disorders--deliriumRespiratory--eosinophilic pneumoniaSkin 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--rhabdomyolysisPostmarketing experience with piperacillin and tazobactam in pediatric patients suggests similar safety profile to that seen in adults.. 6.3Additional Experience with Piperacillin. The following adverse reaction has also been reported for piperacillin for injection:Skeletal--prolonged neuromuscular blockade [see Drug Interactions (7.5)].

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. CarcinogenesisLong-term carcinogenicity studies in animals have not been conducted with piperacillin and/or tazobactam.MutagenesisPiperacillin and tazobactam were negative in microbial mutagenicity assays, the unscheduled DNA synthesis (UDS) test, mammalian point mutation (Chinese hamster ovary cell HPRT) assay, and mammalian cell (BALB/c-3T3) transformation assay. In vivo, piperacillin and tazobactam did not induce chromosomal aberrations in rats.FertilityReproduction studies have been performed in rats and have revealed no evidence of impaired fertility when piperacillin and tazobactam is administered intravenously up to 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/m2).

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. Piperacillin and Tazobactam for Injection and Sodium Chloride Injection 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 6.Cmax maximum observed concentration, AUC: Area under the curve, CL=clearance, CLR= Renal clearance V=volume of distribution, T1/2 elimination half-lifeTable 6: Mean (CV%) Piperacillin and Tazobactam PK Parameters PiperacillinPiperacillin and Tazobactam DosePiperacillin and tazobactam were given in combination, infused over 30 minutes. Cmax (mcg/mL)AUCNumbers in []parentheses are coefficients of variation [CV%]. (mcgh/mL)CL (mL/min)V (L)T1/2 (h)CLR (mL/min)2.25 g134131 [14]25717.40.79--3.375 g242242 [10]20715.10.841404.5 g298322 [16]21015.40.84--TazobactamPiperacillin and Tazobactam Dose Cmax (mcg/mL)AUC (mcgh/mL)CL (mL/min)V (L)T1/2 (h)CLR (mL/min)2.25 g1516.0 [21]25817.00.77--3.375 g2425.0 [8]25114.80.681664.5 g3439.8 [15]20614.70.82--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 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.DistributionBoth 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 g/0.5 30-min Intravenous Infusion of Piperacillin and Tazobactam Tissue or FluidNEach subject provided single sample. Sampling periodTime from the start of the infusion (h)Mean PIP Concentration Range (mg/L)Tissue:Plasma RangeTazo Concentration Range (mg/L)Tazo Tissue:Plasma RangeSkin350.5 4.534.8 94.20.60 1.14.0 7.70.49 0.93Fatty Tissue370.5 4.54.0 10.10.097 0.1150.7 1.50.10 0.13Muscle360.5 4.59.4 23.30.29 0.181.4 2.70.18 0.30Proximal Intestinal Mucosa71.5 2.531.40.5510.31.15Distal Intestinal Mucosa71.5 2.531.20.5914.52.1Appendix220.5 2.526.5 64.10.43 0.539.1 18.60.80 1.35EliminationMetabolismPiperacillin is metabolized to minor microbiologically active desethyl metabolite. Tazobactam is metabolized to single metabolite that lacks pharmacological and antibacterial activities.ExcretionFollowing 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 PopulationsPatients with Renal ImpairmentAfter 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 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 ImpairmentThe 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 months of age and older. The clearance of both compounds is slower in the younger patients compared to older pediatric patients and adults.In population PK analysis, estimated clearance for month-old to 12 year-old patients was comparable to adults, with population mean (SE) value of 5.64 (0.34) mL/min/kg. The piperacillin clearance estimate is 80% of this value for pediatric patients to months old. In patients younger than 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.RaceThe 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 doses.Drug InteractionsThe 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)]. 12.4Microbiology. Mechanism of ActionPiperacillin sodium exerts bactericidal activity by inhibiting septum formation and cell wall synthesis of susceptible bacteria. In vitro, piperacillin is active against 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, beta-lactamase inhibitor of the Molecular class 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 ActivityPiperacillin and Tazobactam for Injection and Sodium Chloride Injection 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 Piperacillin and Tazobactam for Injection and Sodium Chloride Injection 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 TestingFor 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.

CONTRAINDICATIONS SECTION.

4 CONTRAINDICATIONS. Piperacillin and Tazobactam for Injection and Sodium Chloride Injection is contraindicated in patients with history of allergic reactions to any of the penicillins, cephalosporins, or betalactamase inhibitors.. Patients with history of allergic reactions to any of the penicillins, cephalosporins, or beta-lactamase inhibitors. (4).

DESCRIPTION SECTION.

11 DESCRIPTION. Piperacillin and Tazobactam for Injection and Sodium Chloride 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(-)--aminobenzyl-penicillin. The chemical name of piperacillin sodium is sodium (2S,5R,6R)-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 C23H26N5NaO7S and the molecular weight is 539.5. The chemical structure of piperacillin sodium is:Tazobactam sodium, derivative of the penicillin nucleus, is penicillanic acid sulfone. Its chemical name is sodium (2S,3S,5R)-3-methyl-7-oxo-3-(1H-1,2,3-triazol-1-ylmethyl)-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate-4,4-dioxide. The chemical formula is C10H11N4NaO5S and the molecular weight is 322.3. The chemical structure of tazobactam sodium is:Piperacillin and Tazobactam for Injection and Sodium Chloride Injection is supplied as sterile powder for injection and sterile solution in single-dose DUPLEX(R) Container with strength of 2.25 g, 3.375 g, or 4.5 in the following presentations:2.25 g: contains grams of piperacillin (equivalent to 2.085 of piperacillin sodium), 0.25 of tazobactam (equivalent to 0.269 of tazobactam sodium), 0.5 mg of edetate sodium dihydrate (EDTA), and 100 mg of sodium citrate dihydrate in the powder chamber. The diluent chamber contains 225 mg of sodium chloride and 50 mL of water for injection.3.375 g: contains grams of piperacillin (equivalent to 3.127 of piperacillin sodium) and 0.375 of tazobactam (equivalent to 0.402 of tazobactam sodium), 0.75 mg of EDTA, and 150 mg of sodium citrate dihydrate in the powder chamber. The diluent chamber contains 150 mg of sodium chloride and 50 mL of water for injection.4.5 g: contains grams of piperacillin (equivalent to 4.170 of piperacillin sodium), 0.5 of tazobactam (equivalent to 0.538 of tazobactam sodium), mg of EDTA, and 200 mg of sodium citrate dihydrate. The diluent chamber contains 450 mg of sodium chloride and 100 mL of water for injection.Piperacillin and Tazobactam for Injection and Sodium Chloride Injection contains total of 9.6 mEq (220 mg), 11.1 mEq (256 mg), and 19.1 mEq (440 mg) of sodium (Na+) per 2.25 g, 3.375 g, and 4.5 product, respectively [see Warnings and Precautions (5.8) and Use in Specific Populations (8.5)].The reconstituted solution has pH between 5.0 and 7.0. The osmolality of the reconstituted solution of Piperacillin and Tazobactam for Injection and Sodium Chloride Injection is approximately 318 mOsmol/kg for the 2.25 strength, approximately 348 mOsmol/kg for the 3.375 strength, and approximately 318 mOsmol/kg for the 4.5 strength.Piperacillin and Tazobactam for Injection and Sodium Chloride Injection Meets USP Monograph Organic Impurities Procedure 3.The DUPLEX(R) Container is flexible dual chamber container. After removing the peelable foil strip, activating the seals, and thoroughly mixing, the reconstituted drug product is hyperosmotic and is intended for single intravenous use. The product (diluent and drug) contact layer is mixture of thermoplastic rubber and polypropylene copolymer that contains no plasticizers.Not made with natural rubber latex, PVC or Di(2-ethylhexyl)phthalate (DEHP).. 2.25 g: contains grams of piperacillin (equivalent to 2.085 of piperacillin sodium), 0.25 of tazobactam (equivalent to 0.269 of tazobactam sodium), 0.5 mg of edetate sodium dihydrate (EDTA), and 100 mg of sodium citrate dihydrate in the powder chamber. The diluent chamber contains 225 mg of sodium chloride and 50 mL of water for injection.. 3.375 g: contains grams of piperacillin (equivalent to 3.127 of piperacillin sodium) and 0.375 of tazobactam (equivalent to 0.402 of tazobactam sodium), 0.75 mg of EDTA, and 150 mg of sodium citrate dihydrate in the powder chamber. The diluent chamber contains 150 mg of sodium chloride and 50 mL of water for injection.. 4.5 g: contains grams of piperacillin (equivalent to 4.170 of piperacillin sodium), 0.5 of tazobactam (equivalent to 0.538 of tazobactam sodium), mg of EDTA, and 200 mg of sodium citrate dihydrate. The diluent chamber contains 450 mg of sodium chloride and 100 mL of water for injection.. Chemical Structure illustration of piperacillin sodium. Chemical structure illustration of tazobactam sodium.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. If 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 every (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 dosage of 4.5 every (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 months of Age and Older, Weighing up to 40 Kg and With Normal Renal FunctionAgeAppendicitis and /or PeritonitisNosocomial Pneumonia2 months to months90 mg/kg (80 mg piperacillin and 10 mg tazobactam) every (eight) hours 90 mg/kg (80 mg piperacillin and 10 mg tazobactam) every (six) hours Older than months112.5 mg/kg (100 mg piperacillin and 12.5 mg tazobactam) every (eight) hours 112.5 mg/kg (100 mg piperacillin and 12.5 mg tazobactam) every (six) hours Administer Piperacillin and Tazobactam for Injection and Sodium Chloride Injection by intravenous infusion over 30 minutes to both adult and pediatric patients 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(R) Container.. If 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 every (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 dosage of 4.5 every (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). Administer Piperacillin and Tazobactam for Injection and Sodium Chloride Injection by intravenous infusion over 30 minutes to both adult and pediatric patients 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(R) Container.. 2.1 Important Administration Instructions. If 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 every (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 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 dosage of 4.5 every (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 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/minAll Indications (except nosocomial pneumonia)Nosocomial Pneumonia Greater than 40 mL/min 3.375 every hours 4.5 every hours 20 to 40 mL/minCreatinine clearance for patients not receiving hemodialysis 2.25 every hours 3.375 every hours Less than 20 mL/min 2.25 every hours 2.25 every hours Hemodialysis0.75 (0.67 piperacillin and 0.08 tazobactam) should be administered following each hemodialysis session on hemodialysis days 2.25 every 12 hours 2.25 every hours CAPD 2.25 every 12 hours 2.25 every hoursFor patients on hemodialysis, the maximum dose is 2.25 every 12 hours for all indications other than nosocomial pneumonia and 2.25 every hours for nosocomial pneumonia. Since hemodialysis removes 30% to 40% of the administered dose, an additional dose of 0.75 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 months of Age and Older With Appendicitis (complicated by rupture or abscess) and/or Peritonitis or Nosocomial Pneumonia with normal renal function. If 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 months of age and older, weighing up to 40 kg, and with normal renal function, is described in Table [see Use in Specific Populations (8.4) and Clinical Pharmacology (12.3)]. Table 2: Recommended Dosage of Piperacillin and Tazobactam in Pediatric Patients Months of Age and Older, Weighing Up to 40 kg, and With Normal Renal FunctionAdminister Piperacillin and Tazobactam for Injection and Sodium Chloride Injection by intravenous infusion over 30 minutes Age Appendicitis and/or Peritonitis Nosocomial Pneumonia months to months90 mg/kg (80 mg piperacillin and 10 mg tazobactam) every (eight) hours 90 mg/kg (80 mg piperacillin and 10 mg tazobactam) every (six) hours Older than months of age112.5 mg/kg (100 mg piperacillin and 12.5 mg tazobactam) every (eight) hours 112.5 mg/kg (100 mg piperacillin and 12.5 mg tazobactam) every (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(R) Container. Important Administration InstructionsDo 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 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(R) 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(R) Container StorageTo avoid inadvertent activation, the DUPLEX(R) Container should remain in the folded position until activation is intended.Patient Labeling and Drug Powder/Diluent InspectionApply 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(R) 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 days at room temperature at 20C to 25C (68F to 77F), 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(R) Container and point the set port in downward direction. Starting at the hanger tab end, fold the DUPLEX(R) 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 20C to 25C (68F to 77F) or within days if stored under refrigeration at 2C to 8C (36F to 46F).AdministrationVisually inspect the reconstituted solution for particulate matter.Point the set port in downwards direction. Starting at the hanger tab end, fold the DUPLEX(R) Container just below the solution meniscus trapping all air above the fold. Squeeze the folded DUPLEX(R) 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 Y-site0.9% sodium chloride for injectionSterile water for injection (Maximum recommended volume per dose of sterile water for injection is 50 mL)Dextrose 5%Lactated Ringers SolutionPiperacillin and Tazobactam for Injection and Sodium Chloride Injection should not be mixed with other drugs in 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 kgThe 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 above [see Dosage and Administration (2.5)]. 2. Piperacillin and Tazobactam for Injection and Sodium Chloride Injection in the DUPLEX(R) Container should be used only in patients who require the entire 2.25 g, 3.375 g, or 4.5 dose and not any fraction thereof.Stability of Piperacillin and Tazobactam for Injection and Sodium Chloride Injection Following ReconstitutionStability studies after reconstitution in the DUPLEX(R) Containers, have demonstrated chemical stability (potency, pH of reconstituted solution and clarity of solution) for up to 24 hours at room temperature at 20C to 25C (68F to 77F) and up to days at refrigerated temperature at 2C to 8C (36F to 46F). Piperacillin and Tazobactam for Injection and Sodium Chloride Injection contains no preservatives. Appropriate consideration of aseptic technique should be used.. 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 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(R) 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.. To avoid inadvertent activation, the DUPLEX(R) Container should remain in the folded position until activation is intended.. 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(R) 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 days at room temperature at 20C to 25C (68F to 77F), but not beyond the labeled expiration date. Do not use directly after storage by refrigeration, allow the product to equilibrate to room temperature before patient use.. Unfold the DUPLEX(R) Container and point the set port in downward direction. Starting at the hanger tab end, fold the DUPLEX(R) 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 20C to 25C (68F to 77F) or within days if stored under refrigeration at 2C to 8C (36F to 46F).. Visually inspect the reconstituted solution for particulate matter.. Point the set port in downwards direction. Starting at the hanger tab end, fold the DUPLEX(R) Container just below the solution meniscus trapping all air above the fold. Squeeze the folded DUPLEX(R) 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.. 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 RangeThe concentration ranges in Table are based on administration of the aminoglycoside in divided doses (10 to 15 mg/kg/day in two daily doses for amikacin and to mg/kg/day in three daily doses for gentamicin). Administration of amikacin or gentamicin in 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 Amikacin2.25 g3.375 g4.5 g50 mL50 mL100 mL 1.75 mg/mL to 7.5 mg/mL0.9% sodium chloride or 5% dextrose Gentamicin2.25 g3.375 g4.5 g50 mL 50 mL 100 mL 0.7 mg/mL to 3.32 mg/mL0.9% sodium chloride or 5% dextroseOnly 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.

LACTATION SECTION.

8.2 Lactation. Risk SummaryPiperacillin 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 mothers clinical need for Piperacillin and Tazobactam for Injection and Sodium Chloride Injection and any potential adverse effects on the breast-fed child from Piperacillin and Tazobactam for Injection and Sodium Chloride Injection or from the underlying maternal condition.

MECHANISM OF ACTION SECTION.

12.1 Mechanism of Action. Piperacillin and Tazobactam for Injection and Sodium Chloride Injection is an antibacterial drug [see Microbiology (12.4)].

DOSAGE FORMS & STRENGTHS SECTION.

3 DOSAGE FORMS AND STRENGTHS. Piperacillin and Tazobactam for Injection USP and Sodium Chloride Injection USP is supplied as white to off-white powder and clear, colorless solution in single-dose DUPLEX(R) Container consisting of:2.25 Piperacillin and Tazobactam for Injection USP (2 of piperacillin and 0.25 of tazobactam) and 50 mL of 0.45% Sodium Chloride Injection USP.3.375 Piperacillin and Tazobactam for Injection USP (3 of piperacillin and 0.375 of tazobactam) and 50 mL of 0.3% Sodium Chloride Injection USP.4.5 Piperacillin and Tazobactam for Injection USP (4 of piperacillin and 0.5 of tazobactam) and 100 mL of 0.45% Sodium Chloride Injection USP.. 2.25 Piperacillin and Tazobactam for Injection USP (2 of piperacillin and 0.25 of tazobactam) and 50 mL of 0.45% Sodium Chloride Injection USP.. 3.375 Piperacillin and Tazobactam for Injection USP (3 of piperacillin and 0.375 of tazobactam) and 50 mL of 0.3% Sodium Chloride Injection USP.. 4.5 Piperacillin and Tazobactam for Injection USP (4 of piperacillin and 0.5 of tazobactam) and 100 mL of 0.45% Sodium Chloride Injection USP.. Piperacillin and Tazobactam for Injection and Sodium Chloride Injection in single-dose DUPLEX(R) Container consisting of:2.25 Piperacillin and Tazobactam for Injection USP and 50 mL of 0.45% Sodium Chloride Injection USP (3)3.375 Piperacillin and Tazobactam for Injection USP and 50 mL of 0.3% Sodium Chloride Injection USP (3)4.5 Piperacillin and Tazobactam for Injection USP and 100 mL of 0.45% Sodium Chloride Injection USP (3). 2.25 Piperacillin and Tazobactam for Injection USP and 50 mL of 0.45% Sodium Chloride Injection USP (3). 3.375 Piperacillin and Tazobactam for Injection USP and 50 mL of 0.3% Sodium Chloride Injection USP (3). 4.5 Piperacillin and Tazobactam for Injection USP and 100 mL of 0.45% Sodium Chloride Injection USP (3).

DRUG INTERACTIONS SECTION.

7 DRUG INTERACTIONS. Piperacillin and Tazobactam for Injection and Sodium Chloride Injection 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 Piperacillin and Tazobactam for Injection and Sodium Chloride Injection unless the benefit outweighs the risk. (7.2)Co-administration of Piperacillin and Tazobactam for Injection and Sodium Chloride Injection with vancomycin may increase the incidence of acute kidney injury. Monitor kidney function in patients receiving Piperacillin and Tazobactam for Injection and Sodium Chloride Injection and vancomycin. (7.3)Monitor coagulation parameters in patients receiving Piperacillin and Tazobactam for Injection and Sodium Chloride Injection and heparin or oral anticoagulants. (7.4)Piperacillin and Tazobactam for Injection and Sodium Chloride Injection may prolong the neuromuscular blockade of vecuronium and other non-depolarizing neuromuscular blockers. Monitor for adverse reactions related to neuromuscular blockade. (7.5). Piperacillin and Tazobactam for Injection and Sodium Chloride Injection 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 Piperacillin and Tazobactam for Injection and Sodium Chloride Injection unless the benefit outweighs the risk. (7.2). Co-administration of Piperacillin and Tazobactam for Injection and Sodium Chloride Injection with vancomycin may increase the incidence of acute kidney injury. Monitor kidney function in patients receiving Piperacillin and Tazobactam for Injection and Sodium Chloride Injection and vancomycin. (7.3). Monitor coagulation parameters in patients receiving Piperacillin and Tazobactam for Injection and Sodium Chloride Injection and heparin or oral anticoagulants. (7.4). Piperacillin and Tazobactam for Injection and Sodium Chloride Injection may prolong the neuromuscular blockade of vecuronium and other non-depolarizing neuromuscular blockers. Monitor for adverse reactions related to neuromuscular blockade. (7.5). 7.1Aminoglycosides. 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 piperacillin and tazobactam 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, piperacillin and tazobactam 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. Piperacillin and Tazobactam for Injection and Sodium Chloride Injection, which contains EDTA, is compatible with amikacin and gentamicin for simultaneous Y-site infusion in certain diluents and at specific concentrations. Piperacillin and Tazobactam for Injection and Sodium Chloride Injection is not compatible with tobramycin for simultaneous Y-site infusion [see Dosage and Administration (2.7)]. 7.2Probenecid. Probenecid administered concomitantly with Piperacillin and Tazobactam for Injection and Sodium Chloride Injection 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 Piperacillin and Tazobactam for Injection and Sodium Chloride Injection unless the benefit outweighs the risk.. 7.3Vancomycin. 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 (5.7)]. Monitor kidney function in patients concomitantly administered with Piperacillin and Tazobactam for Injection and Sodium Chloride Injection and vancomycin.No pharmacokinetic interactions have been noted between piperacillin and tazobactam and vancomycin.. 7.4Anticoagulants. 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 (5.5)]. 7.5Vecuronium. Piperacillin when used concomitantly with vecuronium has been implicated in the prolongation of the neuromuscular blockade of vecuronium. Piperacillin and Tazobactam for Injection and Sodium Chloride Injection 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).. 7.6Methotrexate. 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.. 7.7Effects 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 piperacillin and tazobactam may result in false-positive reaction for glucose in the urine using copper-reduction method (CLINITEST(R)). It is recommended that glucose tests based on enzymatic glucose oxidase reactions be used.

GERIATRIC USE SECTION.

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.Piperacillin and Tazobactam for Injection and Sodium Chloride Injection contains total of 220 mg, 256 mg, 440 mg of sodium per 2.25 g, 3.375 g, and 4.5 product, respectively. At the usual recommended doses, patients would receive between 1,320 and 1,760 mg/day of sodium. The geriatric population may respond with blunted natriuresis to salt loading. This may be clinically important with regard to such diseases as congestive heart failure [see Warnings and Precautions (5.8)]. 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 [see Warnings and Precautions (5.7)].

HEPATIC IMPAIRMENT SUBSECTION.

8.7Hepatic Impairment. Dosage adjustment of Piperacillin and Tazobactam for Injection and Sodium Chloride Injection is not warranted in patients with hepatic cirrhosis [see Clinical Pharmacology (12.3)].

HOW SUPPLIED SECTION.

16 HOW SUPPLIED/STORAGE AND HANDLING. Piperacillin and Tazobactam for Injection USP and Sodium Chloride Injection USP is white to off-white powder and clear, colorless solution supplied in single-dose DUPLEX(R) Container (packaged 24 single-dose units per case) in the following strengths described in Table below:Table 8: Strengths, Volume of Diluent, National Drug Code (NDC), Total Sodium for Piperacillin and Tazobactam for Injection and Sodium Chloride InjectionStrength (piperacillin and tazobactam) Piperacillin Tazobactam Volume of Diluent NDC Total Sodium REF 2.25 2 0.25 g50 mL of 0.45% Sodium Chloride0264- 3446-119.6 mEq (220 mg) 3446-11 3.375 3 0.375 g50 mL of 0.3% Sodium Chloride0264- 3448-1111.1 mEq (256 mg) 3448-11 4.5 4 0.5 g100 mL of 0.45% Sodium Chloride0264- 3450-2219.1 mEq (440 mg) 3450-22 Prior to reconstitution, store Piperacillin and Tazobactam for Injection USP and Sodium Chloride Injection USP at 20C to 25C (68F to 77F); excursions permitted to 15C to 30C (59F to 86F). [See USP Controlled Room Temperature.]Do not remove the foil strip until ready to use to protect from light. After removal of the foil strip, product must be used within days, but not beyond the labeled expiration date. Protect from light after removal of foil strip.Storage conditions for reconstituted Piperacillin and Tazobactam for Injection are described in another section of labeling [see Dosage and Administration (2.5)]. Do not freeze.

INDICATIONS & USAGE SECTION.

1 INDICATIONS AND USAGE. Piperacillin and Tazobactam for Injection and Sodium Chloride Injection, is combination of piperacillin, penicillin-class antibacterial and tazobactam, beta-lactamase inhibitor, indicated for the treatment of:Intra-abdominal infections in adult and pediatric patients months of age and older (1.1)Nosocomial pneumonia in adult and pediatric patients 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 BacteriaTo 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). Intra-abdominal infections in adult and pediatric patients months of age and older (1.1). Nosocomial pneumonia in adult and pediatric patients 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). 1.1Intra-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.. 1.2Nosocomial 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)]. 1.3Skin 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.. 1.4Female 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.. 1.5Community-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.. 1.6Usage 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.

MICROBIOLOGY SECTION.

12.4Microbiology. Mechanism of ActionPiperacillin sodium exerts bactericidal activity by inhibiting septum formation and cell wall synthesis of susceptible bacteria. In vitro, piperacillin is active against 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, beta-lactamase inhibitor of the Molecular class 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 ActivityPiperacillin and Tazobactam for Injection and Sodium Chloride Injection 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 Piperacillin and Tazobactam for Injection and Sodium Chloride Injection 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 TestingFor 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.

NONCLINICAL TOXICOLOGY SECTION.

13 NONCLINICAL TOXICOLOGY. 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. CarcinogenesisLong-term carcinogenicity studies in animals have not been conducted with piperacillin and/or tazobactam.MutagenesisPiperacillin and tazobactam were negative in microbial mutagenicity assays, the unscheduled DNA synthesis (UDS) test, mammalian point mutation (Chinese hamster ovary cell HPRT) assay, and mammalian cell (BALB/c-3T3) transformation assay. In vivo, piperacillin and tazobactam did not induce chromosomal aberrations in rats.FertilityReproduction studies have been performed in rats and have revealed no evidence of impaired fertility when piperacillin and tazobactam is administered intravenously up to 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/m2).

OVERDOSAGE SECTION.

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 (5.6)]. Treatment should be supportive and symptomatic according to the patients clinical presentation. Excessive serum concentrations of either piperacillin or tazobactam may be reduced by hemodialysis. Following single 3.375 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)].

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

PRINCIPAL DISPLAY PANEL 2.25 Container. Piperacillin and Tazobactamfor Injection USP andSodium Chloride Injection USP2.25 g50 mLNDC 0264-3446-11DUPLEX(R) CONTAINERUSE ONLY AFTER MIXING CONTENTS OF BOTH CHAMBERS.FOR INTRAVENOUS INFUSION.SINGLE-DOSE Each dry powder chamber provides g piperacillin (equivalent to 2.085 ofpiperacillin sodium), 0.25 tazobactam (equivalent to 0.268 of tazobactamsodium), 0.5 mg of edetate disodium dihydrate, and 100 mg of sodium citratedihydrate. Contains no preservative.After reconstitution each 50 mL single-dose DUPLEX(R) unit contains Piperacillin andTazobactam for Injection (equivalent to g of piperacillin and 0.25 of tazobactam)and 50 mL of 0.45% sodium chloride injection. Total sodium content of 220 mg (9.6mEq). Approximate osmolality: 318 mOsmol/kg. Dosage: see Prescribing Information.Prior to Reconstitution: Store at 20C to 25C (68F to 77F); excursions permittedto 15C to 30C (59F to 86F). [See USP Controlled Room Temperature.] Use only ifcontainer and seals are intact. Do not peel foil strip until ready for use in order toprotect from light. After foil strip removal, product must be used within days, butnot beyond the labeled expiration date. Protect from light after removal of foil strip.Reconstitute Prior to Administration: Hold container with set port in downwarddirection and fold the diluent chamber just below the solution meniscus. To activateseal, squeeze folded diluent chamber until seal between diluent and drug chamberopens, releasing diluent into drug chamber. Agitate the reconstituted solution untilthe drug powder is completely dissolved. Fold the container second time andsqueeze until seal between drug chamber and set port opens.After Reconstitution: Use only if prepared solution is clear and free from particulatematter. Use within 24 hours if stored at room temperature or within days if storedunder refrigeration. Do not use in series connection. Do not introduce additives intothis container. Prior to administration check for minute leaks by squeezing containerfirmly. If leaks are found, discard container and solution as sterility may be impaired.Do not freeze. Discard unused portion. Not made with natural rubber latex, PVCor DEHP. REF 3446-11Rx onlyManufactured for:B. Braun Medical Inc. Exp :Lot No:NDC No. (01)10302643446113Prepared in Italy. API from Italy.Y37-002-612 LD-804-2F50000403335PEEL HEREDrug ChamberDiscard unit if foil strip is damaged. Peel foil strip only whenready for use. Visually inspect drug prior to reconstitution.See package insert for complete directions for reconstitutionand administration.LD-617-1 X27-001-488. 3446-11 Container Label. 50 mL Drug Chamber Label.

PEDIATRIC USE SECTION.

8.4 Pediatric Use. The safety and effectiveness of Piperacillin and Tazobactam for Injection and Sodium Chloride Injection for intra-abdominal infections, and nosocomial pneumonia have been established in pediatric patients months of age and older.Use of Piperacillin and Tazobactam for Injection and Sodium Chloride Injection in pediatric patients 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 prospective, randomized, comparative, open-label clinical trial with 542 pediatric patients to 12 years of age with intra-abdominal infections (including appendicitis (complicated by rupture or abscess) and/or peritonitis), in which 273 pediatric patients received piperacillin and tazobactam [see Adverse Reactions (6.1) and Clinical Pharmacology (12.3)]. Use of Piperacillin and Tazobactam for Injection and Sodium Chloride Injection in pediatric patients months of age and older with nosocomial pneumonia is supported by evidence from well-controlled studies in adults with nosocomial pneumonia, simulation study performed with population pharmacokinetic model, and retrospective, cohort study of pediatric patients with nosocomial pneumonia in which 140 pediatric patients were treated with Piperacillin and Tazobactam for Injection and 267 patients treated with comparators (which included ticarcillinclavulanate, 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 Piperacillin and Tazobactam for Injection and Sodium Chloride Injection, and to avoid unintentional overdose, this product is not recommended for use if dose of Piperacillin and Tazobactam for Injection and Sodium Chloride Injection, that does not equal 2.25 g, 3.375 g, or 4.5 is required, and an alternative formulation of piperacillin and tazobactam for injection should be considered [see Dosage and Administration (2.5)]. The safety and effectiveness of Piperacillin and Tazobactam for Injection and Sodium Chloride Injection have not been established in pediatric patients less than months of age [see Clinical Pharmacology (12) and Dosage and Administration (2)]. Dosage of Piperacillin and Tazobactam for Injection and Sodium Chloride Injection in pediatric patients with renal impairment has not been determined.

PHARMACODYNAMICS SECTION.

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

PHARMACOKINETICS SECTION.

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.Cmax maximum observed concentration, AUC: Area under the curve, CL=clearance, CLR= Renal clearance V=volume of distribution, T1/2 elimination half-lifeTable 6: Mean (CV%) Piperacillin and Tazobactam PK Parameters PiperacillinPiperacillin and Tazobactam DosePiperacillin and tazobactam were given in combination, infused over 30 minutes. Cmax (mcg/mL)AUCNumbers in []parentheses are coefficients of variation [CV%]. (mcgh/mL)CL (mL/min)V (L)T1/2 (h)CLR (mL/min)2.25 g134131 [14]25717.40.79--3.375 g242242 [10]20715.10.841404.5 g298322 [16]21015.40.84--TazobactamPiperacillin and Tazobactam Dose Cmax (mcg/mL)AUC (mcgh/mL)CL (mL/min)V (L)T1/2 (h)CLR (mL/min)2.25 g1516.0 [21]25817.00.77--3.375 g2425.0 [8]25114.80.681664.5 g3439.8 [15]20614.70.82--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 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.DistributionBoth 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 g/0.5 30-min Intravenous Infusion of Piperacillin and Tazobactam Tissue or FluidNEach subject provided single sample. Sampling periodTime from the start of the infusion (h)Mean PIP Concentration Range (mg/L)Tissue:Plasma RangeTazo Concentration Range (mg/L)Tazo Tissue:Plasma RangeSkin350.5 4.534.8 94.20.60 1.14.0 7.70.49 0.93Fatty Tissue370.5 4.54.0 10.10.097 0.1150.7 1.50.10 0.13Muscle360.5 4.59.4 23.30.29 0.181.4 2.70.18 0.30Proximal Intestinal Mucosa71.5 2.531.40.5510.31.15Distal Intestinal Mucosa71.5 2.531.20.5914.52.1Appendix220.5 2.526.5 64.10.43 0.539.1 18.60.80 1.35EliminationMetabolismPiperacillin is metabolized to minor microbiologically active desethyl metabolite. Tazobactam is metabolized to single metabolite that lacks pharmacological and antibacterial activities.ExcretionFollowing 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 PopulationsPatients with Renal ImpairmentAfter 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 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 ImpairmentThe 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 months of age and older. The clearance of both compounds is slower in the younger patients compared to older pediatric patients and adults.In population PK analysis, estimated clearance for month-old to 12 year-old patients was comparable to adults, with population mean (SE) value of 5.64 (0.34) mL/min/kg. The piperacillin clearance estimate is 80% of this value for pediatric patients to months old. In patients younger than 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.RaceThe 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 doses.Drug InteractionsThe 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)].

PREGNANCY SECTION.

8.1 Pregnancy. Risk SummaryPiperacillin and tazobactam cross the placenta in humans. However, there are insufficient data with piperacillin and/or tazobactam in pregnant women to inform 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 to times and to times the human dose of piperacillin and tazobactam, respectively, based on body-surface area (mg/m2). 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/m2) (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 to 4% and 15 to 20%, respectively.DataAnimal DataIn 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 to times and to times the human dose of piperacillin and tazobactam, in mice and rats respectively, based on body-surface area (mg/m2). 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/m2).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 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 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 times the human dose of piperacillin and tazobactam, respectively, based on body-surface area) from gestation day 17 through lactation day 21.

REFERENCES SECTION.

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

RENAL IMPAIRMENT SUBSECTION.

8.6Renal Impairment. In adult patients with 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 to the degree of renal function impairment [see Dosage and Administration (2)].

SPL UNCLASSIFIED SECTION.

1.1Intra-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.

USE IN SPECIFIC POPULATIONS SECTION.

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 SummaryPiperacillin and tazobactam cross the placenta in humans. However, there are insufficient data with piperacillin and/or tazobactam in pregnant women to inform 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 to times and to times the human dose of piperacillin and tazobactam, respectively, based on body-surface area (mg/m2). 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/m2) (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 to 4% and 15 to 20%, respectively.DataAnimal DataIn 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 to times and to times the human dose of piperacillin and tazobactam, in mice and rats respectively, based on body-surface area (mg/m2). 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/m2).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 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 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 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 SummaryPiperacillin 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 mothers clinical need for Piperacillin and Tazobactam for Injection and Sodium Chloride Injection and any potential adverse effects on the breast-fed child from Piperacillin and Tazobactam for Injection and Sodium Chloride Injection or from the underlying maternal condition.. 8.4 Pediatric Use. The safety and effectiveness of Piperacillin and Tazobactam for Injection and Sodium Chloride Injection for intra-abdominal infections, and nosocomial pneumonia have been established in pediatric patients months of age and older.Use of Piperacillin and Tazobactam for Injection and Sodium Chloride Injection in pediatric patients 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 prospective, randomized, comparative, open-label clinical trial with 542 pediatric patients to 12 years of age with intra-abdominal infections (including appendicitis (complicated by rupture or abscess) and/or peritonitis), in which 273 pediatric patients received piperacillin and tazobactam [see Adverse Reactions (6.1) and Clinical Pharmacology (12.3)]. Use of Piperacillin and Tazobactam for Injection and Sodium Chloride Injection in pediatric patients months of age and older with nosocomial pneumonia is supported by evidence from well-controlled studies in adults with nosocomial pneumonia, simulation study performed with population pharmacokinetic model, and retrospective, cohort study of pediatric patients with nosocomial pneumonia in which 140 pediatric patients were treated with Piperacillin and Tazobactam for Injection and 267 patients treated with comparators (which included ticarcillinclavulanate, 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 Piperacillin and Tazobactam for Injection and Sodium Chloride Injection, and to avoid unintentional overdose, this product is not recommended for use if dose of Piperacillin and Tazobactam for Injection and Sodium Chloride Injection, that does not equal 2.25 g, 3.375 g, or 4.5 is required, and an alternative formulation of piperacillin and tazobactam for injection should be considered [see Dosage and Administration (2.5)]. The safety and effectiveness of Piperacillin and Tazobactam for Injection and Sodium Chloride Injection have not been established in pediatric patients less than months of age [see Clinical Pharmacology (12) and Dosage and Administration (2)]. Dosage of Piperacillin and Tazobactam for Injection and Sodium Chloride Injection 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.Piperacillin and Tazobactam for Injection and Sodium Chloride Injection contains total of 220 mg, 256 mg, 440 mg of sodium per 2.25 g, 3.375 g, and 4.5 product, respectively. At the usual recommended doses, patients would receive between 1,320 and 1,760 mg/day of sodium. The geriatric population may respond with blunted natriuresis to salt loading. This may be clinically important with regard to such diseases as congestive heart failure [see Warnings and Precautions (5.8)]. 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 [see Warnings and Precautions (5.7)]. 8.6Renal Impairment. In adult patients with 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 to the degree of renal function impairment [see Dosage and Administration (2)]. 8.7Hepatic Impairment. Dosage adjustment of Piperacillin and Tazobactam for Injection and Sodium Chloride Injection is not warranted in patients with hepatic cirrhosis [see Clinical Pharmacology (12.3)]. 8.8Patients 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.

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. Serious hypersensitivity reactions (anaphylactic/anaphylactoid) reactions have been reported in patients receiving piperacillin and tazobactam. Discontinue Piperacillin and Tazobactam for Injection and Sodium Chloride Injection if reaction occurs. (5.1)Piperacillin and tazobactam may cause severe cutaneous adverse reactions, such as Stevens-Johnson syndrome, toxic epidermal necrolysis, drug reaction with eosinophilia and systemic symptoms, and acute generalized exanthematous pustulosis. Discontinue Piperacillin and Tazobactam for Injection and Sodium Chloride Injection for progressive rashes. (5.2)Hemophagocytic lymphohistiocytosis (HLH) has been reported with the use of piperacillin and tazobactam. If HLH is suspected, discontinue Piperacillin and Tazobactam for Injection and Sodium Chloride Injection immediately. (5.3)Rhabdomyolysis: If signs or symptoms of rhabdomyolysis are observed, discontinue Piperacillin and Tazobactam for Injection and Sodium Chloride Injection and initiate appropriate therapy. (5.4)Hematological effects (including bleeding, leukopenia and neutropenia) have occurred. Monitor hematologic tests during prolonged therapy. (5.5)As with other penicillins, piperacillin and tazobactam may cause neuromuscular excitability or seizures. Patients receiving higher doses, especially in the presence of renal impairment may be at greater risk. Closely monitor patients with renal impairment or seizure disorders for signs and symptoms of neuromuscular excitability or seizures. (5.6)Nephrotoxicity in critically ill patients has been observed; the use of piperacillin and tazobactam was found to be an independent risk factor for renal failure and was associated with delayed recovery of renal function as compared to other beta-lactam antibacterial drugs in randomized, multicenter, controlled trial in critically ill patients. Based on this study, alternative treatment options should be considered in the critically ill population. If alternative treatment options are inadequate or unavailable, monitor renal function during treatment with Piperacillin and Tazobactam for Injection and Sodium Chloride Injection. (5.7)High Sodium Load and Electrolyte Effects: Piperacillin and Tazobactam for Injection and Sodium Chloride Injection contains total of 220 mg, 256 mg, 440 mg of sodium per 2.25 g, 3.375 g, and 4.5 product, respectively. Consider an alternative formulation of piperacillin-tazobactam in patients requiring restricted sodium intake. Periodic electrolyte determinations should be performed in patients with low potassium reserves. (5.8)Clostridioides difficile-Associated Diarrhea: Evaluate patients if diarrhea occurs. (5.9). Serious hypersensitivity reactions (anaphylactic/anaphylactoid) reactions have been reported in patients receiving piperacillin and tazobactam. Discontinue Piperacillin and Tazobactam for Injection and Sodium Chloride Injection if reaction occurs. (5.1). Piperacillin and tazobactam may cause severe cutaneous adverse reactions, such as Stevens-Johnson syndrome, toxic epidermal necrolysis, drug reaction with eosinophilia and systemic symptoms, and acute generalized exanthematous pustulosis. Discontinue Piperacillin and Tazobactam for Injection and Sodium Chloride Injection for progressive rashes. (5.2). Hemophagocytic lymphohistiocytosis (HLH) has been reported with the use of piperacillin and tazobactam. If HLH is suspected, discontinue Piperacillin and Tazobactam for Injection and Sodium Chloride Injection immediately. (5.3). Rhabdomyolysis: If signs or symptoms of rhabdomyolysis are observed, discontinue Piperacillin and Tazobactam for Injection and Sodium Chloride Injection and initiate appropriate therapy. (5.4). Hematological effects (including bleeding, leukopenia and neutropenia) have occurred. Monitor hematologic tests during prolonged therapy. (5.5). As with other penicillins, piperacillin and tazobactam may cause neuromuscular excitability or seizures. Patients receiving higher doses, especially in the presence of renal impairment may be at greater risk. Closely monitor patients with renal impairment or seizure disorders for signs and symptoms of neuromuscular excitability or seizures. (5.6). Nephrotoxicity in critically ill patients has been observed; the use of piperacillin and tazobactam was found to be an independent risk factor for renal failure and was associated with delayed recovery of renal function as compared to other beta-lactam antibacterial drugs in randomized, multicenter, controlled trial in critically ill patients. Based on this study, alternative treatment options should be considered in the critically ill population. If alternative treatment options are inadequate or unavailable, monitor renal function during treatment with Piperacillin and Tazobactam for Injection and Sodium Chloride Injection. (5.7). High Sodium Load and Electrolyte Effects: Piperacillin and Tazobactam for Injection and Sodium Chloride Injection contains total of 220 mg, 256 mg, 440 mg of sodium per 2.25 g, 3.375 g, and 4.5 product, respectively. Consider an alternative formulation of piperacillin-tazobactam in patients requiring restricted sodium intake. Periodic electrolyte determinations should be performed in patients with low potassium reserves. (5.8). Clostridioides difficile-Associated Diarrhea: Evaluate patients if diarrhea occurs. (5.9). 5.1Hypersensitivity Adverse Reactions. Serious and occasionally fatal hypersensitivity (anaphylactic/anaphylactoid) reactions (including shock) have been reported in patients receiving therapy with piperacillin and tazobactam. These reactions are more likely to occur in individuals with history of penicillin, cephalosporin, or carbapenem hypersensitivity or history of sensitivity to multiple allergens. Before initiating therapy with Piperacillin and Tazobactam for Injection and Sodium Chloride Injection, careful inquiry should be made concerning previous hypersensitivity reactions. If an allergic reaction occurs, Piperacillin and Tazobactam for Injection and Sodium Chloride Injection should be discontinued and appropriate therapy instituted.. 5.2Severe Cutaneous Adverse Reactions. Piperacillin and tazobactam may cause severe cutaneous adverse reactions, such as Stevens-Johnson syndrome, toxic epidermal necrolysis, drug reaction with eosinophilia and systemic symptoms, and acute generalized exanthematous pustulosis. If patients develop skin rash they should be monitored closely and Piperacillin and Tazobactam for Injection and Sodium Chloride Injection discontinued if lesions progress.. 5.3Hemophagocytic Lymphohistiocytosis. Cases of hemophagocytic lymphohistiocytosis (HLH) have been reported in pediatric and adult patients treated with piperacillin and tazobactam. Signs and symptoms of HLH may include fever, rash, lymphadenopathy, hepatosplenomegaly and cytopenia. If HLH is suspected, discontinue Piperacillin and Tazobactam for Injection and Sodium Chloride Injection immediately and institute appropriate management.. 5.4 Rhabdomyolysis. Rhabdomyolysis has been reported with the use of piperacillin and tazobactam [see Adverse Reactions (6.2)]. If signs or symptoms of rhabdomyolysis such as muscle pain, tenderness or weakness, dark urine, or elevated creatine phosphokinase are observed, discontinue Piperacillin and Tazobactam for Injection and Sodium Chloride Injection and initiate appropriate therapy.. 5.5 Hematologic Adverse Reactions. Bleeding manifestations have occurred in some patients receiving beta-lactam drugs, including piperacillin. These reactions have sometimes been associated with abnormalities of coagulation tests such as clotting time, platelet aggregation and prothrombin time, and are more likely to occur in patients with renal failure. If bleeding manifestations occur, Piperacillin and Tazobactam for Injection and Sodium Chloride Injection should be discontinued, and appropriate therapy instituted.The leukopenia/neutropenia associated with piperacillin and tazobactam administration appears to be reversible and most frequently associated with prolonged administration. Periodic assessment of hematopoietic function should be performed, especially with prolonged therapy, i.e., >= 21 days [see Adverse Reactions (6.1)]. 5.6 Central Nervous System Adverse Reactions. As with other penicillins, piperacillin and tazobactam may cause neuromuscular excitability or seizures. Patients receiving higher doses, especially patients with renal impairment may be at greater risk for central nervous system adverse reactions. Closely monitor patients with renal impairment or seizure disorders for signs and symptoms of neuromuscular excitability or seizures [see Adverse Reactions (6.2)]. 5.7 Nephrotoxicity in Critically Ill Patients. The use of piperacillin and tazobactam was found to be an independent risk factor for renal failure and was associated with delayed recovery of renal function as compared to other beta-lactam antibacterial drugs in randomized, multicenter, controlled trial in critically ill patients [see Adverse Reactions (6.1)]. Based on this study, alternative treatment options should be considered in the critically ill population. If alternative treatment options are inadequate or unavailable, monitor renal function during treatment with Piperacillin and Tazobactam for Injection and Sodium Chloride Injection [see Dosage and Administration (2.4)] Combined use of piperacillin and tazobactam and vancomycin may be associated with an increased incidence of acute kidney injury [see Drug Interactions (7.3)]. 5.8 High Sodium Load and Electrolyte Effects. Piperacillin and Tazobactam for Injection and Sodium Chloride Injection contains total of 220 mg, 256 mg, and 440 mg of sodium per 2.25 g, 3.375 g, and 4.5 product, respectively. Consider using an alternative formulation of piperacillin and tazobactam when treating patients requiring restricted salt intake. Periodic electrolyte determinations should be performed in patients with low potassium reserves, and the possibility of hypokalemia should be kept in mind with patients who have potentially low potassium reserves and who are receiving cytotoxic therapy or diuretics.. 5.9 Clostridioides difficile-Associated Diarrhea. Clostridioides difficile-associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including piperacillin and tazobactam, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile.C. difficile produces toxins and which contribute to the development of CDAD. Hypertoxin producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibacterial drug use. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents.If CDAD is suspected or confirmed, ongoing antibacterial drug use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibacterial treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated.. 5.10 Development of Drug-Resistant Bacteria. Prescribing Piperacillin and Tazobactam for Injection and Sodium Chloride Injection in the absence of proven or strongly suspected bacterial infection or prophylactic indication is unlikely to provide benefit to the patient and increases the risk of development of drug-resistant bacteria.