FDA label cf428d50-690d-4002-bf01-751bf8392d25

5. WARNINGS AND PRECAUTIONS 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 tazobactum for injection for progressive rashes. C lostridium 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.

6. ADVERSE REACTIONS The most common adverse reactions (incidence >5%) are diarrhea, constipation, nausea, headache and insomnia. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Mylan Pharmaceuticals Inc. at 1-877-446-3679 (1-877-4-INFO-RX) 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%) 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 Trails For adverse drug reactions that appeared in both studies the higher frequency is presented System Organ Class Adverse Reaction Blood and lymphatic system disorders Thrombocythemia (1.4%) Anemia (≤1%) Thrombocytopenia (≤1%) Eosinophilia (≤1%) Gastrointestinal disorders Diarrhea (20%) Constipation (8.4%) Nausea (5.8%) Vomiting (2.7%) Dyspepsia (1.9%) Abdominal pain (1.8%) Stomatitis (≤1%) General disorders and administration site conditions Fever (3.2%) Injection site reaction (≤1%) Infections and infestations Oral candidiasis (3.9%) Candidiasis (1.8%) Investigations BUN increased (1.8%) Blood creatinine increased (1.8%) Liver function test abnormal (1.4%) Alkaline phosphatase increased (≤1%) Aspartate aminotransferase increased (≤1%) Alanine aminotransferase increased (≤1%) Metabolism and nutrition disorders Hypoglycemia (≤1%) Hypokalemia (≤1%) Nervous system disorders Headache (4.5%) 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%) 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.

<table ID="ID208" width="100%"> <caption>Table 3: Adverse Reactions from Piperacillin and Tazobactam for Injection Monotherapy Clinical Trials</caption> <col width="100%"/> <tbody> <tr> <td align="left" valign="top" styleCode=" Toprule"> <content styleCode="bold">System </content> <content styleCode="bold">Organ </content> <content styleCode="bold">Class</content> </td> </tr> <tr> <td align="left" valign="top" styleCode=" Botrule">Adverse Reaction<content styleCode="bold"> </content> </td> </tr> <tr> <td align="left" valign="top" styleCode=" Toprule"> <content styleCode="bold">Gastrointestinal </content> <content styleCode="bold">disorders</content> <content styleCode="bold"> </content> Diarrhea (11.3%) Constipation (7.7%) Nausea (6.9%) Vomiting (3.3%) Dyspepsia (3.3%) Abdominal pain (1.3%) Pseudomembranous colitis (&#x2264;1%) </td> </tr> <tr> <td align="left" valign="top"> <content styleCode="bold">General </content> <content styleCode="bold">disorders </content> <content styleCode="bold">and </content> <content styleCode="bold">administration </content> <content styleCode="bold">site </content> <content styleCode="bold">conditions</content> Fever (2.4%) Injection site reaction (&#x2264;1%) Rigors (&#x2264;1%)<content styleCode="bold"> </content> </td> </tr> <tr> <td align="left" valign="top"> <content styleCode="bold">Immune </content> <content styleCode="bold">system </content> <content styleCode="bold">disorders</content> Anaphylaxis (&#x2264;1%) </td> </tr> <tr> <td align="left" valign="top"> <content styleCode="bold">Infections </content> <content styleCode="bold">and </content> <content styleCode="bold">infestations</content> Candidiasis (1.6%) </td> </tr> <tr> <td align="left" valign="top"> <content styleCode="bold">Metabolism </content> <content styleCode="bold">and </content> <content styleCode="bold">nutrition </content> <content styleCode="bold">disorders</content> Hypoglycemia (&#x2264;1%) </td> </tr> <tr> <td align="left" valign="top"> <content styleCode="bold">Musculoskeletal </content> <content styleCode="bold">and </content> <content styleCode="bold">connective </content> <content styleCode="bold">tissue </content> <content styleCode="bold">disorders</content> Myalgia(&#x2264;1%) Arthralgia (&#x2264;1%) </td> </tr> <tr> <td align="left" valign="top"> <content styleCode="bold">Nervous </content> <content styleCode="bold">system </content> <content styleCode="bold">disorders </content> <content styleCode="bold"> </content>Headache (7.7%) Insomnia (6.6%) </td> </tr> <tr> <td align="left" valign="top"> <content styleCode="bold">Skin </content> <content styleCode="bold">and </content> <content styleCode="bold">subcutaneous </content> <content styleCode="bold">tissue </content> <content styleCode="bold">disorders</content> Rash (4.2%, including maculopapular, bullous, and urticarial) Pruritus (3.1%) </td> </tr> <tr> <td align="left" valign="top" styleCode=" Botrule"> <content styleCode="bold">Vascular </content> <content styleCode="bold">disorders </content> <content styleCode="bold"> </content>Phlebitis (1.3%) Thrombophlebitis (&#x2264;1%) Hypotension (&#x2264;1%) Purpura (&#x2264;1%) Epistaxis (&#x2264;1%) Flushing (&#x2264;1%) </td> </tr> <tr> <td align="left" valign="top" styleCode=" Botrule Toprule">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%) patients in the piperacillin/tazobactam group and 14 (6.5%) in the imipenem/cilastatin group (p &gt; 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. </td> </tr> </tbody> </table>

<table ID="ID209" width="100%"> <caption>Table 4: Adverse Reactions From Piperacillin and Tazobactam for Injection Plus Aminoglycoside Clinical Trails<footnote ID="ID209_1">For adverse drug reactions that appeared in both studies the higher frequency is presented</footnote> </caption> <col width="100%"/> <tbody> <tr> <td align="left" valign="top" styleCode=" Botrule Toprule"> <content styleCode="bold">System </content> <content styleCode="bold">Organ </content> <content styleCode="bold">Class</content> <content styleCode="bold"> </content> <content styleCode="bold">Adverse </content> <content styleCode="bold">Reaction</content> <content styleCode="bold"> </content> </td> </tr> <tr> <td align="left" valign="top" styleCode=" Toprule"> <content styleCode="bold">Blood </content> <content styleCode="bold">and </content> <content styleCode="bold">lymphatic </content> <content styleCode="bold">system </content> <content styleCode="bold">disorders</content> Thrombocythemia (1.4%) Anemia (&#x2264;1%) Thrombocytopenia (&#x2264;1%) Eosinophilia (&#x2264;1%) </td> </tr> <tr> <td align="left" valign="top"> <content styleCode="bold">Gastrointestinal </content> <content styleCode="bold">disorders </content> <content styleCode="bold"> </content>Diarrhea (20%) Constipation (8.4%) Nausea (5.8%) Vomiting (2.7%) Dyspepsia (1.9%) Abdominal pain (1.8%) Stomatitis (&#x2264;1%) </td> </tr> <tr> <td align="left" valign="top"> <content styleCode="bold">General </content> <content styleCode="bold">disorders </content> <content styleCode="bold">and </content> <content styleCode="bold">administration </content> <content styleCode="bold">site </content> <content styleCode="bold">conditions</content> Fever (3.2%) Injection site reaction (&#x2264;1%) </td> </tr> <tr> <td align="justify" valign="top"> <content styleCode="bold">Infections </content> <content styleCode="bold">and </content> <content styleCode="bold">infestations </content> <content styleCode="bold"> </content>Oral candidiasis (3.9%) Candidiasis (1.8%) </td> </tr> <tr> <td align="left" valign="top"> <content styleCode="bold">Investigations</content> BUN increased (1.8%) Blood creatinine increased (1.8%) Liver function test abnormal (1.4%) Alkaline phosphatase increased (&#x2264;1%) Aspartate aminotransferase increased (&#x2264;1%) Alanine aminotransferase increased (&#x2264;1%) </td> </tr> <tr> <td align="left" valign="top"> <content styleCode="bold">Metabolism </content> <content styleCode="bold">and </content> <content styleCode="bold">nutrition </content> <content styleCode="bold">disorders </content> <content styleCode="bold"> </content>Hypoglycemia (&#x2264;1%) Hypokalemia (&#x2264;1%) </td> </tr> <tr> <td align="left" valign="top"> <content styleCode="bold">Nervous </content> <content styleCode="bold">system </content> <content styleCode="bold">disorders </content> <content styleCode="bold"> </content>Headache (4.5%) Insomnia (4.5%) </td> </tr> <tr> <td align="left" valign="top"> <content styleCode="bold">Renal </content> <content styleCode="bold">and </content> <content styleCode="bold">urinary </content> <content styleCode="bold">disorders</content> Renal failure (&#x2264;1%) </td> </tr> <tr> <td align="left" valign="top"> <content styleCode="bold">Skin </content> <content styleCode="bold">and </content> <content styleCode="bold">subcutaneous </content> <content styleCode="bold">tissue </content> <content styleCode="bold">disorders</content> Rash (3.9%) Pruritus (3.2%) </td> </tr> <tr> <td align="left" valign="top" styleCode=" Botrule"> <content styleCode="bold">Vascular </content> <content styleCode="bold">disorders </content> <content styleCode="bold"> </content>Thrombophlebitis (1.3%) Hypotension (1.3%) </td> </tr> </tbody> </table>