PIPERACILLIN AND TAZOBACTAM- piperacillin sodium and tazobactam sodium_injection, powder, for solution

Piperacillin and tazobactam for injection is an antibacterial drug [ see Microbiology ( 12. 4 The pharmacodynamic parameter for piperacillin/tazobactam that is most predictive of clinical and microbiological efficacy is time above MIC. The mean and coefficients of variation (CV%) for the pharmacokinetic parameters of piperacillin and tazobactam after multiple intravenous doses are summarized in Table 5. Table 5: Mean (CV%) Piperacillin and Tazobactam PK Parameters Piperacillin Piperacillin/Tazobactam C max AUC b CL V T 1/2 CL R Dose a mcg/mL mcgh/mL mL/min L h mL/min 2. 25 g 134 131 (14) 257 17. 375 g 242 242 (10) 207 15. 5 g 298 322 (16) 210 15. 84 - Tazobactam Piperacillin/Tazobactam C max AUC b CL V T 1/2 CL R Dose a mcg/mL mcgh/mL mL/min L h mL/min 2. 0 (21) 258 17. 375 g 24 25. 0 (8) 251 14. 8 (15) 206 14. 82 - a b Peak plasma concentrations of piperacillin and tazobactam are attained immediately after completion of an intravenous infusion of piperacillin and tazobactam for injection. Piperacillin plasma concentrations, following a 30-minute infusion of piperacillin and tazobactam for injection, were similar to those attained when equivalent doses of piperacillin were administered alone. Steady-state plasma concentrations of piperacillin and tazobactam were similar to those attained after the first dose due to the short half-lives of piperacillin and tazobactam. Distribution Both piperacillin and tazobactam are approximately 30% bound to plasma proteins. The protein binding of either piperacillin or tazobactam is unaffected by the presence of the other compound. Protein binding of the tazobactam metabolite is negligible. Piperacillin and tazobactam are widely distributed into tissues and body fluids including intestinal mucosa, gallbladder, lung, female reproductive tissues (uterus, ovary, and fallopian tube), interstitial fluid, and bile. Mean tissue concentrations are generally 50% to 100% of those in plasma. Distribution of piperacillin and tazobactam into cerebrospinal fluid is low in subjects with non-inflamed meninges, as with other penicillins (see Table 6). Table 6: Piperacillin/Tazobactam Concentrations in Selected Tissues and Fluids after Single 4 g/0. 5 g 30-min IV Infusion of Piperacillin and Tazobactam for Injection Tissue or Fluid N a Sampling period b Mean PIP Concentration Range Tissue:Plasma Range Tazo Concentration Range Tazo Tissue:Plasma Range Skin 35 0. 5 en dash 4. 8 en dash 94. 60 en dash 1. 0 en dash 7. 49 en dash 0. 93 Fatty Tissue 37 0. 0 en dash 10. 097 en dash 0. 7 en dash 1. 10 en dash 0. 13 Muscle 36 0. 4 en dash 23. 29 en dash 0. 4 en dash 2. 18 en dash 0. 30 Proximal Intestinal Mucosa 7 1. 5 en dash 2. 15 Distal Intestinal Mucosa 7 1. 1 Appendix 22 0. 5 en dash 64. 43 en dash 0. 1 en dash 18. 80 en dash 1. 35 a b Metabolism Piperacillin is metabolized to a minor microbiologically active desethyl metabolite. Tazobactam is metabolized to a single metabolite that lacks pharmacological and antibacterial activities. Excretion Following single or multiple piperacillin and tazobactam for injection doses to healthy subjects, the plasma half-life of piperacillin and of tazobactam ranged from 0. 2 hours and was unaffected by dose or duration of infusion. Both piperacillin and tazobactam are eliminated via the kidney by glomerular filtration and tubular secretion. Piperacillin is excreted rapidly as unchanged drug with 68% of the administered dose excreted in the urine. Tazobactam and its metabolite are eliminated primarily by renal excretion with 80% of the administered dose excreted as unchanged drug and the remainder as the single metabolite. Piperacillin, tazobactam and desethyl piperacillin are also secreted into the bile. Specific Populations Renal impairment After the administration of single doses of piperacillin/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 are recommended when creatinine clearance is below 40 mL/min in patients receiving the usual recommended daily dose of piperacillin and tazobactam for injection. See Dosage and Administration (2) Hemodialysis removes 30% to 40% of a piperacillin/tazobactam dose with an additional 5% of the tazobactam dose removed as the tazobactam metabolite. Peritoneal dialysis removes approximately 6% and 21% of the piperacillin and tazobactam doses, respectively, with up to 16% of the tazobactam dose removed as the tazobactam metabolite. For dosage recommendations for patients undergoing hemodialysis [ see Dosage and Administration (2) Hepatic Impairment The half-life of piperacillin and of tazobactam increases by approximately 25% and 18%, respectively, in patients with hepatic cirrhosis compared to healthy subjects. However, this difference does not warrant dosage adjustment of piperacillin and tazobactam for injection due to hepatic cirrhosis. Pediatrics Piperacillin and tazobactam pharmacokinetics were studied in pediatric patients 2 months of age and older. The clearance of both compounds is slower in the younger patients compared to older children and adults. In a population PK analysis, estimated clearance for 9 month-old to 12 year-old patients was comparable to adults, with a population mean (SE) value of 5. 34) mL/min/kg. The piperacillin clearance estimate is 80% of this value for pediatric patients 2-9 months old. In patients younger than 2 months of age, clearance of piperacillin is slower compared to older children; however, it is not adequately characterized for dosing recommendations. The population mean (SE) for piperacillin distribution volume is 0. 011) L/kg and is independent of age. Geriatrics The impact of age on the pharmacokinetics of piperacillin and tazobactam was evaluated in healthy male subjects, aged 18-35 years (n=6) and aged 65 to 80 years (n=12). Mean half-life for piperacilln and tazobactam was 32% and 55% higher, respectively, in the elderly compared to the younger subjects. This difference may be due to age-related changes in creatinine clearance. Race The effect of race on piperacillin and tazobactam was evaluated in healthy male volunteers. No difference in piperacillin or tazobactam pharmacokinetics was observed between Asian (n=9) and Caucasian (n=9) healthy volunteers who received single 4/0. Drug Interactions The potential for pharmacokinetic drug interactions between piperacillin and tazobactam for injection and aminoglycosides, probenecid, vancomycin, heparin, vecuronium, and methotrexate has been evaluated [ see Drug Interactions ( 7 Mechanism of Action Piperacillin sodium exerts bactericidal activity by inhibiting septum formation and cell wall synthesis of susceptible bacteria. In vitro in vitro Spectrum of Activity Piperacillin/tazobactam has been shown to be active against most isolates of the following microorganisms both in vitro see Indications and Usage ( 1 Gram-positive bacteria: Staphylococcus aureus Gram-negative bacteria: Acinetobacter baumannii Escherichia coli Haemophilus influenzae Klebsiella pneumoniae Pseudomonas aeruginosa Anaerobic bacteria: Bacteroides fragilis B. fragilis, B. thetaiotaomicron, B. vulgatus The following in vitro but their clinical significance is unknown At least 90% of the following microorganisms exhibit an in vitro Gram-positive bacteria: Enterococcus faecalis Staphylococcus epidermidis Streptococcus agalactiae dagger Streptococcus pneumoniae dagger Streptococcus pyogenes dagger dagger 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 dagger Susceptibility Testing Methods As is recommended with all antimicrobials, the results of in vitro Dilution Techniques: Quantitative methods are used to determine antimicrobial minimum inhibitory concentrations (MICs). These MICs provide estimates of the susceptibility of bacteria to antimicrobial compounds. The MICs should be determined using a standardized procedure. Standardized procedures are based on a dilution method (broth or agar) or equivalent with standardized inoculum concentrations and standardized concentrations of piperacillin and tazobactam powders. 1,2 Diffusion Technique: Quantitative methods that require measurement of zone diameters also provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. The zone size provides an estimate of the susceptibility of bacteria to antimicrobial compounds. The zone size should be determined using a standardized test method 1,3 Anaerobic Techniques For anaerobic bacteria, the susceptibility to piperacillin/tazobactam can be determined by the reference agar dilution method. 4 Table 7: Susceptibility Interpretive Criteria for Piperacillin/Tazobactam Susceptibility Test Result Interpretive Criteria Minimal Inhibitory Concentration Disk Diffusion (MIC in mcg/mL) (Zone Diameter in mm) Pathogen S I R S I R Enterobacteriaceae <= 16 32 en dash 64 >= 128 >= 21 18 en dash 20 <= 17 Acinetobacter baumannii <= 16 32 en dash 64 >= 128 >= 21 18 en dash 20 <= 17 Haemophilus influenzae a <= 1 - >= 2 >= 21 - - Pseudomonas aeruginosa <= 16 32 en dash 64 >= 128 >= 21 15 en dash 20 <= 14 Bacteroides fragilis group <= 32 64 >= 128 - - - a Haemophilus influenzae A report of S (“Susceptible”) indicates that the pathogen is likely to be inhibited if the antimicrobial compound in the blood reaches the concentration at the infection site necessary to inhibit growth of the pathogen. A report of I (“Intermediate”) indicates that the results should be considered equivocal, and if the microorganism is not fully susceptible to alternative, clinically feasible drugs, the test should be repeated. This category implies possible clinical applicability in body sites where the drug is physiologically concentrated or in situations where high dosage of drug can be used. This category also provides a buffer zone, which prevents small, uncontrolled technical factors from causing major discrepancies in interpretation. A report of R (“Resistant”) indicates that the pathogen is not likely to be inhibited even if the antimicrobial compound in the blood reaches the concentration usually achievable at the infection site; other therapy should be considered. Quality Control Standardized susceptibility test procedures require the use of quality controls to monitor and ensure the accuracy and precision of supplies and reagents used in the assay, and the techniques of the individuals performing the test procedures. Table 8: Acceptable Quality Control Ranges for Piperacillin/Tazobactam to Be Used in Validation of Susceptibility Test Acceptable Quality Control Ranges Minimum Inhibitory Concentration Disk Diffusion QC Strain Range (MIC in mcg/mL) Zone Diameter Ranges in mm Escherichia coli 1 en dash 4 24 en dash 30 Escherichia coli ATCC 35218 0. 5 en dash 2 24 en dash 30 Pseudomonas aeruginosa ATCC 27853 1 en dash 8 25 en dash 33 Haemophilus influenzae a ATCC 49247 0. 06 en dash 0. 5 33 en dash 38 Staphylococcus aureus ATCC 29213 0. 25 en dash 2 - Staphylococcus aureus ATCC 25923 - 27 en dash 36 Bacteroides fragilis b ATCC 25285 0. 12 en dash 0. 5 - Bacteroides thetaiotaomicron b ATCC 29741 4 en dash 16 - Clostridium difficile b ATCC 700057 4 en dash 16 - Eubacterium lentum b ATCC 43055 4 en dash 16 - a Haemophilus influenzae b Bacteroides fragilis Bacteroides thetaiotaomicron.

Piperacillin and tazobactam for injection is a combination product consisting of a penicillin-class antibacterial, piperacillin, and a beta-lactamase inhibitor, tazobactam, indicated for the treatment of patients with moderate to severe infections caused by susceptible isolates of the designated bacteria in the conditions listed below. Piperacillin and Tazobactam for Injection is a combination penicillin-class antibacterial and beta-lactamase inhibitor indicated for treatment of: Intra-abdominal infections ( 1. 1 Skin and skin structure infections ( 1. 2 Female pelvic infections ( 1. 3 Community-acquired pneumonia ( 1. 4 Nosocomial pneumonia ( 1. 5 Appendicitis (complicated by rupture or abscess) and peritonitis caused by beta-lactamase producing isolates of Escherichia coli Bacteroides fragilis B. thetaiotaomicron B. vulgatus 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 Postpartum endometritis or pelvic inflammatory disease caused by beta-lactamase producing isolates of Escherichia coli Community-acquired pneumonia (moderate severity only) caused by beta-lactamase producing isolates of Haemophilus influenzae Nosocomial pneumonia (moderate to severe) caused by beta-lactamase producing isolates of Staphylococcus aureus Acinetobacter baumannii Haemophilus influenzae Klebsiella pneumoniae Pseudomonas aeruginosa P. aeruginosa see Dosage and Administration ( 2 To reduce the development of drug-resistant bacteria and maintain the effectiveness of piperacillin and tazobactam for injection and other antibacterial drugs, piperacillin and tazobactam for injection should be used only to treat 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.

Piperacillin and tazobactam for injection should be administered by intravenous infusion over 30 minutes. The usual daily dose of Piperacillin and Tazobactam for Injection for adults is 3. 375 g every six hours totaling 13. 0 g piperacillin/1. 5 g tazobactam) ( 2. 1 Initial presumptive treatment of patients with nosocomial pneumonia should start with Piperacillin and Tazobactam for Injection at a dosage of 4. 5 g every six hours plus an aminoglycoside, totaling 18. 0 g piperacillin/2. 0 g tazobactam). 2 Dosage in patients with renal impairment (<=40 mL/min of CRCL) and dialysis patients should be reduced, based on the degree of actual renal function impairment. 3 For children with appendicitis and/or peritonitis the recommended Piperacillin and Tazobactam for Injection dosage is 100 mg piperacillin/12. 5 mg tazobactam per kilogram of body weight, every 8 hours in pediatric patients 9 months of age and older. For pediatric patients 2 to 9 months of age, the recommended dosage is 80 mg piperacillin/10 mg tazobactam per kilogram of body weight, every 8 hours. 4 Piperacillin and Tazobactam for Injection and aminoglycosides should be reconstituted, diluted, and administered separately. Co-administration via Y-site can be done under certain conditions. 6 The usual total daily dose of piperacillin and tazobactam for injection for adults is 3. 5 g tazobactam). The usual duration of piperacillin and tazobactam for injection treatment is from 7 to 10 days. Initial presumptive treatment of patients with nosocomial pneumonia should start with piperacillin and tazobactam for injection at a dosage of 4. The recommended duration of piperacillin and tazobactam for injection treatment for nosocomial pneumonia is 7 to 14 days. Treatment with the aminoglycoside should be continued in patients from whom P. aeruginosa In patients with renal impairment (creatinine clearance <= 40 mL/min) and dialysis patients (hemodialysis and CAPD), the intravenous dose of piperacillin and tazobactam for injection should be reduced to the degree of actual renal function impairment. The recommended daily doses of piperacillin and tazobactam for injection for patients with renal impairment are as follows: Table 1: Recommended Dosing of Piperacillin and Tazobactam for Injection in Patients with Normal Renal Function and Renal Impairment (As total grams piperacillin/tazobactam) Renal Function (creatinine clearance, All Indications Nosocomial mL/min) (except nosocomial pneumonia) Pneumonia >40 mL/min 3. 5 q6h 20-40 mL/min* 2. 375 q6h <20 mL/min* 2. 25 q6h Hemodialysis** 2. 25 q8h CAPD 2. 25 q8h *Creatinine clearance for patients not receiving hemodialysis For patients on hemodialysis, the maximum dose is 2. 25 g every twelve hours for all indications other than nosocomial pneumonia and 2. 25 g every eight hours for nosocomial pneumonia. Since hemodialysis removes 30% to 40% of the administered dose, an additional dose of 0. 75 g piperacillin and tazobactam for injection (0. 67 g piperacillin/0. 08 g tazobactam) should be administered following each dialysis period on hemodialysis days. No additional dosage of piperacillin and tazobactam for injection is necessary for CAPD patients. For children with appendicitis and/or peritonitis 9 months of age or older, weighing up to 40 kg, and with normal renal function, the recommended piperacillin and tazobactam for injection dosage is 100 mg piperacillin/12. 5 mg tazobactam per kilogram of body weight, every 8 hours. For pediatric patients between 2 months and 9 months of age, the recommended piperacillin and tazobactam for injection dosage based on pharmacokinetic modeling, is 80 mg piperacillin/10 mg tazobactam per kilogram of body weight, every 8 hours [ see Use in Specific Populations ( 8. 3 Single Dose Vials Reconstitute piperacillin and tazobactam for injection vials with a compatible reconstitution diluent from the list provided below. 375 g, and 4. 5 g piperacillin and tazobactam for injection should be reconstituted with 10 mL, 15 mL, and 20 mL, respectively. Swirl until dissolved. Compatible Reconstitution Diluents for Single Dose Vials double dagger Reconstituted piperacillin and tazobactam for injection solution should be further diluted (recommended volume per dose of 50 mL to 150 mL) in a compatible intravenous solution listed below. Administer by infusion over a period of at least 30 minutes. During the infusion it is desirable to discontinue the primary infusion solution. Compatible Intravenous Solutions for Pharmacy Bulk Package Bottles and Single Dose Vials double dagger LACTATED RINGER’S SOLUTION IS NOT COMPATIBILE WITH PIPERACILLIN AND TAZOBACTAM FOR INJECTION double dagger Piperacillin and tazobactam for injection should not be mixed with other drugs in a syringe or infusion bottle since compatibility has not been established. Piperacillin and tazobactam for injection is not chemically stable in solutions that contain only sodium bicarbonate and solutions that significantly alter the pH. Piperacillin and tazobactam for injection should not be added to blood products or albumin hydrolysates. Parenteral drug products should be inspected visually for particulate matter or discoloration prior to administration, whenever solution and container permit. Stability of Piperacillin and Tazobactam for Injection Powder Formulations Following Reconstitution Piperacillin and tazobactam for injection reconstituted from single vials is stable in glass and plastic containers (plastic syringes, I. bags and tubing) when used with compatible diluents. Discard unused portions after storage for 24 hours at room temperature or after storage for 48 hours at refrigerated temperature 2°C to 8°C (36°F to 46°F). Single dose vials should be used immediately after reconstitution. Discard any unused portion after 24 hours if stored at room temperature 20°C to 25°C (68°F to 77°F), or after 48 hours if stored at refrigerated temperature 2°C to 8°C (36°F to 46°F). Vials should not be frozen after reconstitution. Stability studies in the I. bags have demonstrated chemical stability (potency, pH of reconstituted solution and clarity of solution) for up to 24 hours at room temperature and up to one week at refrigerated temperature. Piperacillin and tazobactam for injection contains no preservatives. Appropriate consideration of aseptic technique should be used. Piperacillin and tazobactam for injection reconstituted from single vials can be used in ambulatory intravenous infusion pumps. Stability of piperacillin and tazobactam for injection in an ambulatory intravenous infusion pump has been demonstrated for a period of 12 hours at room temperature. Each dose was reconstituted and diluted to a volume of 37. 5 mL or 25 mL. One-day supplies of dosing solution were aseptically transferred into the medication reservoir (I. bags or cartridge). The reservoir was fitted to a preprogrammed ambulatory intravenous infusion pump per the manufacturer's instructions. Stability of piperacillin and tazobactam for injection is not affected when administered using an ambulatory intravenous infusion pump. Due to the in vitro see Drug Interactions ( 7. 1 In circumstances where co-administration via Y-site is necessary, piperacillin and tazobactam for injection, is compatible for simultaneous coadministration via Y-site infusion only with the following aminoglycosides under the following conditions: Table 2: Compatibility with Aminoglycosides Aminoglycoside Piperacillin and Tazobactam Dose (grams) Piperacillin and Tazobactam Diluent Volume (mL) Aminoglycoside Concentration Range a (mg/mL) Acceptable Diluents Amikacin 2. 5 50, 100, 150 1. 75 en dash 7. 9% sodium chloride or 5% dextrose Gentamicin 2. 5 50, 100, 150 0. 7 en dash 3. 9% sodium chloride or 5% dextrose a Only the concentration and diluents for amikacin or gentamicin with the dosages of piperacillin and tazobactam for injection listed above have been established as compatible for coadministration via Y-site infusion. Simultaneous coadministration via Y-site infusion in any manner other than listed above may result in inactivation of the aminoglycoside by piperacillin and tazobactam for injection. Piperacillin and tazobactam for injection is not compatible with tobramycin for simultaneous coadministration via Y-site infusion. Compatibility of piperacillin and tazobactam with other aminoglycosides has not been established. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

The most common adverse reactions (incidence >5%) are diarrhea, constipation, nausea, headache and insomnia. 1 To report SUSPECTED ADVERSE REACTIONS, contact Sandoz Inc. , at 1-800-525-8747 or FDA at 1-800-FDA-1088 or www. gov/medwatch. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. During the initial clinical investigations, 2621 patients worldwide were treated with piperacillin and tazobactam for injection in phase 3 trials. In the key North American monotherapy clinical trials (n=830 patients), 90% of the adverse events reported were mild to moderate in severity and transient in nature. However, in 3. 2% of the patients treated worldwide, piperacillin and tazobactam for injection 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. Table 3: Adverse Reactions from Piperacillin and Tazobactam for Injection Monotherapy Clinical Trials System Organ Class Gastrointestinal disorders General disorders and administration site conditions Immune system disorders Infections and infestations Metabolism and nutrition disorders Musculoskeletal and connective tissue disorders Nervous system disorders Skin and subcutaneous tissue disorders Vascular disorders Nosocomial Pneumonia Trials Two trials of nosocomial lower respiratory tract infections were conducted. In one study, 222 patients were treated with piperacillin and tazobactam for injection in a dosing regimen of 4. 5 g every 6 hours in combination with an aminoglycoside and 215 patients were treated with imipenem/cilastatin (500 mg/500 mg q6h) in combination with an aminoglycoside. In this trial, treatment-emergent adverse events were reported by 402 patients, 204 (91. 9%) in the piperacillin/tazobactam group and 198 (92. 1%) in the imipenem/cilastatin group. Twenty-five (11. 0%) patients in the piperacillin/tazobactam group and 14 (6. 5%) in the imipenem/cilastatin group (p > 0. 05) discontinued treatment due to an adverse event. The second trial used a dosing regimen of 3. 375 g given every 4 hours with an aminoglycoside. Table 4: Adverse Reactions from Piperacillin and Tazobactam for Injection Plus Aminoglycoside Clinical Trials a System Organ Class Blood and lymphatic system disorders Gastrointestinal disorders General disorders and administration site conditions Infections and infestations Investigations Metabolism and nutrition disorders Nervous system disorders Renal and urinary disorders Skin and subcutaneous tissue disorders Vascular disorders a Pediatrics Studies of piperacillin and tazobactam for injection in pediatric patients suggest a similar safety profile to that seen in adults. In a prospective, randomized, comparative, open-label clinical trial of pediatric patients with severe intra-abdominal infections (including appendicitis and/or peritonitis), 273 patients were treated with piperacillin and tazobactam for injection (112. 5 mg/kg every 8 hours) and 269 patients were treated with cefotaxime (50 mg/kg) plus metronidazole (7. 5 mg/kg) every 8 hours. In this trial, treatment-emergent adverse events were reported by 146 patients, 73 (26. 7%) in the piperacillin and tazobactam for injection group and 73 (27. 1%) in the cefotaxime/metronidazole group. Six patients (2. 2%) in the piperacillin and tazobactam for injection group and 5 patients (1. 9%) in the cefotaxime/metronidazole group discontinued due to an adverse event. Adverse Laboratory Events (Seen During Clinical Trials) Of the trials reported, including that of nosocomial lower respiratory tract infections in which a higher dose of piperacillin and tazobactam for injection was used in combination with an aminoglycoside, changes in laboratory parameters include: Hematologic Coagulation Hepatic Renal Additional laboratory events include abnormalities in electrolytes (i. , 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. In addition to the adverse drug reactions identified in clinical trials in Table 3 and Table 4, the following adverse reactions have been identified during postapproval use of piperacillin and tazobactam for injection. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish causal relationship to drug exposure. Gastrointestinal Hematologic Immune Renal Skin and Appendages The following adverse reaction has also been reported for piperacillin for injection: Skeletal see Drug Interactions ( 7. 4 Post-marketing experience with piperacillin and tazobactam for injection in pediatric patients suggests a similar safety profile to that seen in adults.

Piperacillin and tazobactam for injection is contraindicated in patients with a history of allergic reactions to any of the penicillins, cephalosporins, or beta-lactamase inhibitors. Patients with a history of allergic reactions to any of the penicillins, cephalosporins, or beta-lactamase inhibitors.

Dosage in patients with renal impairment (<=40 mL/min of CRCL) should be reduced to the degree of actual renal function impairment. 6 Teratogenic effectsem dashPregnancy Category B Piperacillin/Tazobactam Teratology studies have been performed in mice and rats and have revealed no evidence of harm to the fetus when piperacillin/tazobactam is administered intravenously up to a dose of 3000/750 mg/kg piperacillin/tazobactam which is 1 to 2 times and 2 to 3 times the human dose of piperacillin and tazobactam, respectively, based on body-surface area (mg/m 2 Piperacillin and tazobactam cross the placenta in humans. There are, however, no adequate and well-controlled studies with the piperacillin/tazobactam combination or with piperacillin or tazobactam alone in pregnant women. Because animal reproduction studies are not always predictive of the human response, this drug should be used during pregnancy only if clearly needed. Piperacillin is excreted in low concentrations in human milk; tazobactam concentrations in human milk have not been studied. Caution should be exercised when piperacillin and tazobactam for injection is administered to a nursing woman. Use of piperacillin and tazobactam for injection in pediatric patients 2 months of age or older with appendicitis and/or peritonitis is supported by evidence from well-controlled studies and pharmacokinetic studies in adults and in pediatric patients. This includes a prospective, randomized, comparative, open-label clinical trial with 542 pediatric patients 2-12 years of age with complicated intra-abdominal infections, in which 273 pediatric patients received piperacillin/tazobactam. Safety and efficacy in pediatric patients less than 2 months of age have not been established [ see Clinical Pharmacology ( 12 2 It has not been determined how to adjust piperacillin and tazobactam for injection dosage in pediatric patients with renal impairment. 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 contains 54 mg (2. 35 mEq) of sodium per gram of piperacillin in the combination product. At the usual recommended doses, patients would receive between 648 and 864 mg/day (28. 6 mEq) of sodium. The geriatric population may respond with a blunted natriuresis to salt loading. This may be clinically important with regard to such diseases as congestive heart failure. This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. In patients with creatinine clearance <= 40 mL/min and dialysis patients (hemodialysis and CAPD), the intravenous dose of piperacillin and tazobactam for injection should be reduced to the degree of renal function impairment [ see Dosage and Administration ( 2 Dosage adjustment of piperacillin and tazobactam for injection is not warranted in patients with hepatic cirrhosis [See Clinical Pharmacology ( 12. 3 As with other semisynthetic penicillins, piperacillin therapy has been associated with an increased incidence of fever and rash in cystic fibrosis patients.

Piperacillin and Tazobactam for Injection administration can significantly reduce tobramycin concentrations in hemodialysis patients. Monitor tobramycin concentrations in these patients. 1 Probenecid prolongs the half-lives of piperacillin and tazobactam and should not be co-administered with Piperacillin and Tazobactam for Injection unless the benefit outweighs the risk. 2 Monitor coagulation parameters in patients receiving Piperacillin and Tazobactam for Injection and heparin or oral anticoagulants. 3 Piperacillin and Tazobactam for Injection may prolong the neuromuscular blockade of vecuronium and other non-depolarizing muscle relaxants. Monitor for adverse reactions related to neuromuscular blockade ( 7. 4 Piperacillin may inactivate aminoglycosides by converting them to microbiologically inert amides. In vivo : 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 for injection 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 Due to the in vitro see Dosage and Administration ( 2. 6 Probenecid administered concomitantly with piperacillin and tazobactam 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 unless the benefit outweighs the risk. Coagulation parameters should be tested more frequently and monitored regularly during simultaneous administration of high doses of heparin, oral anticoagulants, or other drugs that may affect the blood coagulation system or the thrombocyte function [ see Warnings and Precautions ( 5. 4 Piperacillin when used concomitantly with vecuronium has been implicated in the prolongation of the neuromuscular blockade of vecuronium. Piperacillin and tazobactam for 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 muscle relaxants could be prolonged in the presence of piperacillin. Monitor for adverse reactions related to neuromuscular blockade (See package insert for vecuronium bromide). 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. There have been reports of positive test results using the Bio-Rad Laboratories Platelia Aspergillus Aspergillus Aspergillus Aspergillus As with other penicillins, the administration of piperacillin and tazobactam for injection may result in a false-positive reaction for glucose in the urine using a copper-reduction method (CLINITEST registered.

OVERDOSAGE
There have been postmarketing reports of overdose with piperacillin/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 convulsions if higher than recommended doses are given intravenously (particularly in the presence of renal failure) [ see Warnings and Precautions ( 5.5 Treatment should be supportive and symptomatic according the patient''s clinical presentation. Excessive serum concentrations of either piperacillin or tazobactam may be reduced by hemodialysis. Following a single 3.375 g dose of piperacillin/tazobactam, the percentage of the piperacillin and tazobactam dose removed by hemodialysis was approximately 31% and 39%, respectively [ see Clinical Pharmacology ( 12
NONCLINICAL TOXICOLOGY
Long-term carcinogenicity studies in animals have not been conducted with piperacillin/tazobactam, piperacillin, or tazobactam. Piperacillin/Tazobactam Piperacillin/tazobactam was negative in microbial mutagenicity assays, the unscheduled DNA synthesis (UDS) test, a mammalian point mutation (Chinese hamster ovary cell HPRT) assay, and a mammalian cell (BALB/c-3T3) transformation assay. In vivo Piperacillin/Tazobactam Reproduction studies have been performed in rats and have revealed no evidence of impaired fertility when piperacillin/tazobactam is administered intravenously up to a dose of 1280/320 mg/kg piperacillin/tazobactam, which is similar to the maximum recommended human daily dose based on body-surface area (mg/m 2
REFERENCES
1. Clinical and Laboratory Standards Institute (CLSI). Performance Standards for Antimicrobial Susceptibility Testing; Twenty-third Informational Supplement 2. Clinical and Laboratory Standards Institute (CLSI). Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria that Grow Aerobically; Approved Standard en dash Ninth Edition 3. Clinical and Laboratory Standards Institute (CLSI). Performance Standards for Antimicrobial Disk Diffusion Susceptibility Tests; Approved Standard en dash Eleventh Edition. 4. Clinical and Laboratory Standards Institute (CLSI). Methods for Antimicrobial Susceptibility Testing of Anaerobic Bacteria; Approved Standard en dash Eight Edition CLINITEST registered

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PIPERACILLIN AND TAZOBACTAM- piperacillin sodium and tazobactam sodium_injection, powder, for solution Product manual source documgent