Piperacillin Sodium,tazobactam Sodium

Piperacillin and tazobactam for injection is a combination product consisting of a penicillin-class antibacterial, piperacillin, and a β-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 β-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 )

1.1 Intra-abdominal Infections Appendicitis (complicated by rupture or abscess) and peritonitis caused by β-lactamase producing isolates of Escherichia coli or the following members of the Bacteroides fragilis group: B. fragilis , B. ovatus , B. thetaiotaomicron , or B. vulgatus . The individual members of this group were studied in fewer than 10 cases.

1.2 Skin and Skin Structure Infections Uncomplicated and complicated skin and skin structure infections, including cellulitis, cutaneous abscesses and ischemic/diabetic foot infections caused by β-lactamase producing isolates of Staphylococcus aureus .

1.3 Female Pelvic Infections Postpartum endometritis or pelvic inflammatory disease caused by β-lactamase producing isolates of Escherichia coli .

1.4 Community-acquired Pneumonia Community-acquired pneumonia (moderate severity only) caused by β-lactamase producing isolates of Haemophilus influenzae .

1.5 Nosocomial Pneumonia Nosocomial pneumonia (moderate to severe) caused by β-lactamase producing isolates of Staphylococcus aureus and by piperacillin/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 ) ]. 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 is supplied as a white to off-white powder in vials of the following sizes: Each Piperacillin and Tazobactam for Injection 2.25 g vial provides piperacillin sodium equivalent to 2 grams of piperacillin and tazobactam sodium equivalent to 0.25 g of tazobactam. Each Piperacillin and Tazobactam for Injection 3.375 g vial provides piperacillin sodium equivalent to 3 grams of piperacillin and tazobactam sodium equivalent to 0.375 g of tazobactam. Each Piperacillin and Tazobactam for Injection 4.5 g vial provides piperacillin sodium equivalent to 4 grams of piperacillin and tazobactam sodium equivalent to 0.5 g of tazobactam. Piperacillin and Tazobactam for Injection: 2.25 g, 3.375 g, and 4.5 g lyophilized powder for reconstitution in single-dose vials ( 3 )

Piperacillin and tazobactam for injection is contraindicated in patients with a history of allergic reactions to any of the penicillins, cephalosporins, or β-lactamase inhibitors. Patients with a history of allergic reactions to any of the penicillins, cephalosporins, or β-lactamase inhibitors. ( 4 )

Serious hypersensitivity reactions (anaphylactic/anaphylactoid) reactions have been reported in patients receiving Piperacillin and Tazobactam for Injection. Discontinue Piperacillin and Tazobactam for Injection if a reaction occurs. ( 5.1 ) Serious skin reactions, such as Stevens-Johnson syndrome and toxic epidermal necrolysis, have been reported ( 5.2 ). Discontinue Piperacillin and Tazobactam for Injection for progressive rashes. Clostridium difficile associated diarrhea: evaluate patients if diarrhea occurs. ( 5.3 ) Hematological effects (including bleeding, leukopenia and neutropenia) have occurred. Monitor hematologic tests during prolonged therapy. ( 5.4 )

5.1 Hypersensitivity Reactions Serious and occasionally fatal hypersensitivity (anaphylactic/anaphylactoid) reactions (including shock) have been reported in patients receiving therapy with piperacillin and tazobactam for injection. These reactions are more likely to occur in individuals with a history of penicillin, cephalosporin, or carbapenem hypersensitivity or a history of sensitivity to multiple allergens. Before initiating therapy with piperacillin and tazobactam for injection, careful inquiry should be made concerning previous hypersensitivity reactions. If an allergic reaction occurs, piperacillin and tazobactam for injection should be discontinued and appropriate therapy instituted.

5.2 Serious Skin Reactions Serious skin reactions, such as Stevens-Johnson syndrome and toxic epidermal necrolysis, have been reported in patients receiving piperacillin and tazobactam for injection. If patients develop a skin rash they should be monitored closely and piperacillin and tazobactam for injection discontinued if lesions progress.

5.3 Clostridium difficile Associated Diarrhea Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including piperacillin and tazobactam for injection, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile . C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibacterial drug use. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents. If CDAD is suspected or confirmed, ongoing antibacterial drug use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibacterial treatment of C. difficile , and surgical evaluation should be instituted as clinically indicated.

5.4 Hematologic Effects Bleeding manifestations have occurred in some patients receiving β-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 should be discontinued and appropriate therapy instituted. The leukopenia/neutropenia associated with piperacillin and tazobactam for injection administration appears to be reversible and most frequently associated with prolonged administration. Periodic assessment of hematopoietic function should be performed, especially with prolonged therapy, ie, ≥ 21 days [ see Adverse Reactions ( 6.1 ) ].

5.5 Central Nervous System Effects As with other penicillins, patients may experience neuromuscular excitability or convulsions if higher than recommended doses are given intravenously (particularly in the presence of renal failure).

5.6 Electrolyte Effects Piperacillin and tazobactam for injection contains a total of 2.35 mEq (54 mg) of Na + per gram of piperacillin in the combination product. This should be considered 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.

5.7 Development of Drug-Resistant Bacteria Prescribing piperacillin and tazobactam for injection in the absence of a proven or strongly suspected bacterial infection is unlikely to provide benefit to the patient and increases the risk of development of drug-resistant bacteria.

The most common adverse reactions (incidence >5%) are diarrhea, constipation, nausea, headache and insomnia. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Fresenius Kabi USA, LLC Vigilance and Medical Affairs at 1-800-551-7176 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. 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 (0.5%). Table 3: Adverse Reactions from Piperacillin and Tazobactam for Injection Monotherapy Clinical Trials System Organ Class Adverse Reaction Gastrointestinal disorders Diarrhea (11.3%) Constipation (7.7%) Nausea (6.9%) Vomiting (3.3%) Dyspepsia (3.3%) Abdominal pain (1.3%) Pseudomembranous colitis (≤1%) 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%) Metabolism and nutrition disorders Hypoglycemia (≤1%) Musculoskeletal and connective tissue disorders Myalgia(≤1%) Arthralgia (≤1%) Nervous system disorders Headache (7.7%) Insomnia (6.6%) Skin and subcutaneous tissue disorders Rash (4.2%, including maculopapular, bullous, and urticarial) Pruritus (3.1%) Vascular disorders Phlebitis (1.3%) Thrombophlebitis (≤1%) Hypotension (≤1%) Purpura (≤1%) Epistaxis (≤1%) Flushing (≤1%) Nosocomial Pneumonia Trials Two trials of nosocomial lower respiratory tract infections were conducted. In one study, 222 patients were treated with piperacillin and tazobactam 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 Adverse Reaction Blood and lymphatic system disorders Thrombocythemia (1.4%) Anemia (≤1%) Thrombocytopenia (≤1%) Eosinophilia (≤1%) Gastrointestinal disorders Diarrhea (20%) Constipation (8.4%) Nausea (5.8%) Vomiting (2.7%) Dyspepsia (1.9%) Abdominal pain (1.8%) Stomatitis (≤1%) General disorders and administration site conditions Fever (3.2%) Injection site reaction (≤1%) Infections and infestations Oral candidiasis (3.9%) Candidiasis (1.8%) Investigations BUN increased (1.8%) Blood creatinine increased (1.8%) Liver function test abnormal (1.4%) Alkaline phosphatase increased (≤1%) Aspartate aminotransferase increased (≤1%) Alanine aminotransferase increased (≤1%) Metabolism and nutrition disorders Hypoglycemia (≤1%) Hypokalemia (≤1%) Nervous system disorders Headache (4.5%) 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%) a For adverse drug reactions that appeared in both studies the higher frequency is presented. 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 —decreases in hemoglobin and hematocrit, thrombocytopenia, increases in platelet count, eosinophilia, leukopenia, neutropenia. These patients were withdrawn from therapy; some had accompanying systemic symptoms (e.g., fever, rigors, chills). Coagulation —positive direct Coombs' test, prolonged prothrombin time, prolonged partial thromboplastin time Hepatic —transient elevations of AST (SGOT), ALT (SGPT), alkaline phosphatase, bilirubin Renal —increases in serum creatinine, blood urea nitrogen Additional laboratory events include abnormalities in electrolytes (i.e., increases and decreases in sodium, potassium, and calcium), hyperglycemia, decreases in total protein or albumin, blood glucose decreased, gamma-glutamyltransferase increased, hypokalemia, and bleeding time prolonged.

6.2 Post-Marketing Experience 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 —hepatitis, jaundice Hematologic —hemolytic anemia, agranulocytosis, pancytopenia Immune —hypersensitivity reactions, anaphylactic/anaphylactoid reactions (including shock) Renal —interstitial nephritis Skin and Appendages —erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis

6.3 Additional Experience with piperacillin The following adverse reaction has also been reported for piperacillin for injection: Skeletal —prolonged muscle relaxation [ 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 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 unless the benefit outweighs the risk. ( 7.2 ) Monitor coagulation parameters in patients receiving Piperacillin and Tazobactam for Injection and heparin or oral anticoagulants. ( 7.3 ) 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 )

7.1 Aminoglycosides Piperacillin may inactivate aminoglycosides by converting them to microbiologically inert amides. In vivo inactivation : When aminoglycosides are administered in conjunction with piperacillin to patients with end-stage renal disease requiring hemodialysis, the concentrations of the aminoglycosides (especially tobramycin) may be significantly reduced and should be monitored. Sequential administration of 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 inactivation: Due to the in vitro inactivation of aminoglycosides by piperacillin, piperacillin and tazobactam for injection and aminoglycosides are recommended for separate administration. Piperacillin and tazobactam for injection and aminoglycosides should be reconstituted, diluted, and administered separately when concomitant therapy with aminoglycosides is indicated. Piperacillin and tazobactam for injection is compatible with amikacin and gentamicin for simultaneous Y-site infusion in certain diluents and at specific concentrations. Piperacillin and tazobactam for injection is not compatible with tobramycin for simultaneous Y-site infusion [ see Dosage and Administration ( 2.6 ) ].

7.2 Probenecid 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.

7.3 Anticoagulants Coagulation parameters should be tested more frequently and monitored regularly during simultaneous administration of high doses of heparin, oral anticoagulants, or other drugs that may affect the blood coagulation system or the thrombocyte function [ see Warnings and Precautions ( 5.4 ) ].

7.4 Vecuronium 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).

7.5 Methotrexate Limited data suggests that co-administration of methotrexate and piperacillin may reduce the clearance of methotrexate due to competition for renal secretion. The impact of tazobactam on the elimination of methotrexate has not been evaluated. If concurrent therapy is necessary, serum concentrations of methotrexate as well as the signs and symptoms of methotrexate toxicity should be frequently monitored.

7.6 Effects on Laboratory Tests There have been reports of positive test results using the Bio-Rad Laboratories Platelia Aspergillus EIA test in patients receiving piperacillin/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/tazobactam should be interpreted cautiously and confirmed by other diagnostic methods. 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 ® ). It is recommended that glucose tests based on enzymatic glucose oxidase reactions be used.

Dosage in patients with renal impairment (≤40 mL/min of CRCL) should be reduced to the degree of actual renal function impairment. ( 2.3 , 8.6 )

8.1 Pregnancy Teratogenic effects—Pregnancy 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.

8.3 Nursing Mothers 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.

8.4 Pediatric Use 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 ) and Dosage and Administration ( 2 ) ]. It has not been determined how to adjust piperacillin and tazobactam for injection dosage in pediatric patients with renal impairment.

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 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 (28.2 and 37.6 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.

8.6 Renal Impairment 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 ) ].

8.7 Hepatic Impairment Dosage adjustment of piperacillin and tazobactam for injection is not warranted in patients with hepatic cirrhosis [See Clinical Pharmacology ( 12.3 )].

8.8 Patients with Cystic Fibrosis As with other semisynthetic penicillins, piperacillin therapy has been associated with an increased incidence of fever and rash in cystic fibrosis patients.

Piperacillin and tazobactam for injection is an antibacterial drug [ see Microbiology ( 12.4 ) ].