Piperacillin and Tazobactam: Package Insert and Label Information (Page 2 of 5)

2.8 Compatibility with Aminoglycosides

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 [see Drug Interactions (7.1)].

In circumstances where co-administration via Y-site is necessary, piperacillin and tazobactam for injection is compatible for simultaneous co-administration via Y-site infusion only with the following aminoglycosides under the following conditions:

Table 5: Compatibility with Aminoglycosides

Aminoglycoside

Piperacillin andTazobactam forInjection Dose(grams)

Piperacillin andTazobactam forInjection DiluentVolume* (mL)

AminoglycosideConcentrationRange (mg/mL)

AcceptableDiluents

Amikacin

2.25

3.375

4.5

50

100

150

1.75 – 7.5

0.9% sodium chloride or 5% dextrose

Gentamicin

2.25

3.375

4.5

50

100

150

0.7 – 3.32

0.9% sodium chloride or 5% dextrose

* Diluent volumes apply only to single vials and bulk pharmacy containers.

† The concentration ranges in Table 5 are based on administration of the aminoglycoside in divided doses (10 to 15 mg/kg/day in two daily doses for amikacin and 3 to 5 mg/kg/day in three daily doses for gentamicin). Administration of amikacin or gentamicin in a single daily dose or in doses exceeding those stated above via Y-site with piperacillin and tazobactam for injection has not been evaluated. See package insert for each aminoglycoside for complete Dosage and Administration instructions.

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 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.

Piperacillin and tazobactam for injection is not compatible with tobramycin for simultaneous co-administration via Y-site infusion. Compatibility of piperacillin and tazobactam for injection 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.

3 DOSAGE FORMS AND STRENGTHS

Piperacillin and tazobactam for injection, USP pharmacy bulk package is supplied as a white to yellowish powder in a bottle of the following size:

Piperacillin and tazobactam for injection 13.5 g pharmacy bulk bottle contains piperacillin sodium equivalent to 12 grams of piperacillin and tazobactam sodium equivalent to 1.5 grams tazobactam.

4 CONTRAINDICATIONS

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.

5 WARNINGS AND PRECAUTIONS

5.1 Hypersensitivity Adverse 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 Severe Cutaneous Adverse Reactions

Piperacillin and tazobactam for injection 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 a skin rash they should be monitored closely and piperacillin and tazobactam for injection discontinued if lesions progress.

5.3 Hemophagocytic Lymphohistiocytosis

Cases of hemophagocytic lymphohistiocytosis (HLH) have been reported in pediatric and adult patients treated with piperacillin and tazobactam for injection. Signs and symptoms of HLH may include fever, rash, lymphadenopathy, hepatosplenomegaly and cytopenia. If HLH is suspected, discontinue piperacillin and tazobactam for injection immediately and institute appropriate management.

5.4 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 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, i.e., ≥ 21 days [see Adverse Reactions (6.1)].

5.5 Central Nervous System Adverse Reactions

As with other penicillins, piperacillin and tazobactam for injection 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) ].

5.6 Nephrotoxicity in Critically ill Patients

The use of piperacillin and tazobactam for injection 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 a 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 [see Dosage and Administration (2.4)].

Combined use of piperacillin/tazobactam and vancomycin may be associated with an increased incidence of acute kidney injury [see Drug Interactions (7.3)].

5.7 Electrolyte Effects

Piperacillin and tazobactam for injection contains a total of 2.35 mEq (54 mg) of Na+ (sodium) 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.

5.8 Clostridioides difficile – Associated Diarrhea

Clostridioides 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.

5.9 Development of Drug-Resistant Bacteria

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

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)]
Hematologic Adverse Reactions [see Warnings and Precautions (5.4)]
Central Nervous System Adverse Reactions [see Warnings and Precautions (5.5)]
Nephrotoxicity in Critically ill Patients [see Warnings and Precautions (5.6)]
Clostridioides difficile -Associated Diarrhea [see Warnings and Precautions (5.8)]

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.

Clinical Trials in Adult Patients

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 6: 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%)

General disorders and administration site conditions

Fever (2.4%)

Injection site reaction (≤1%)

Rigors (≤1%)

Immune system disorders

Anaphylaxis (≤1%)

Infections and infestations

Candidiasis (1.6%)

Pseudomembranous colitis (≤1%)

Metabolism and nutrition disorders

Hypoglycemia (≤1%)

Musculoskeletal and connective tissue disorders

Myalgia (≤1%)

Arthralgia (≤1%)

Nervous system disorders

Headache (7.7%)

Psychiatric disorders

Insomnia (6.6%)

Skin and subcutaneous tissue disorders

Rash (4.2%, including maculopapular, bullous, and urticarial)

Pruritus (3.1%)

Purpura (≤1%)

Vascular disorders

Phlebitis (1.3%)

Thrombophlebitis (≤1%)

Hypotension (≤1%)

Flushing (≤1%)

Respiratory, thoracic and mediastinal disorders

Epistaxis (≤1%)

Nosocomial Pneumonia Trials

Two trials of nosocomial lower respiratory tract infections were conducted. In one study, 222 patients were treated with piperacillin and tazobactam 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 every 6 hours) in combination with an aminoglycoside. In this trial, treatment-emergent adverse events were reported by 402 patients, 204 (91.9%) in the piperacillin/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 7: Adverse Reactions from Piperacillin and Tazobactam Injection plus Aminoglycoside Clinical Trials*

System Organ Class Adverse Reaction

Blood and lymphatic system disorders

Thrombocythemia (1.4%)

Anemia (≤1%)

Thrombocytopenia (≤1%)

Eosinophilia (≤1%)

Gastrointestinal disorders

Diarrhea (20%)

Constipation (8.4%)

Nausea (5.8%)

Vomiting (2.7%)

Dyspepsia (1.9%)

Abdominal pain (1.8%)

Stomatitis (≤1%)

General disorders and administration site conditions

Fever (3.2%)

Injection site reaction (≤1%)

Infections and infestations

Oral candidiasis (3.9%)

Candidiasis (1.8%)

Investigations

BUN increased (1.8%)

Blood creatinine increased (1.8%)

Liver function test abnormal (1.4%)

Alkaline phosphatase increased (≤1%)

Aspartate aminotransferase increased (≤1%)

Alanine aminotransferase increased (≤1%)

Metabolism and nutrition disorders

Hypoglycemia (≤1%)

Hypokalemia (≤1%)

Nervous system disorders

Headache (4.5%)

Psychiatric disorders

Insomnia (4.5%)

Renal and urinary disorders

Renal failure (≤1%)

Skin and subcutaneous tissue disorders

Rash (3.9%)

Pruritus (3.2%)

Vascular disorders

Thrombophlebitis (1.3%)

Hypotension (1.3%)

*For adverse drug reactions that appeared in both studies the higher frequency is presented.

Other Trials: Nephrotoxicity

In a randomized, multicenter, controlled trial in 1200 adult critically ill patients, piperacillin/tazobactam was found to be a risk factor for renal failure (odds ratio 1.7, 95% CI 1.18 to 2.43), and associated with delayed recovery of renal function as compared to other beta-lactam antibacterial drugs1 [see Warnings and Precautions (5.6)].

Adverse Laboratory Changes (Seen During Clinical Trials)

Of the trials reported, including that of nosocomial lower respiratory tract infections in which a higher dose of piperacillin and tazobactam 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.

Clinical Trials in Pediatric Patients

Clinical studies of piperacillin and tazobactam in pediatric patients suggest a similar safety profile to that seen in adults.

In a prospective, randomized, comparative, open-label clinical trial of pediatric patients, 2 to 12 years of age, with intra-abdominal infections (including appendicitis and/or peritonitis), 273 patients were treated with piperacillin and tazobactam 112.5 mg/kg given IV 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 group and 73 (27.1%) in the cefotaxime/metronidazole group. Six patients (2.2%) in the piperacillin and tazobactam group and 5 patients (1.9%) in the cefotaxime/metronidazole group discontinued due to an adverse event.

In a retrospective, cohort study, 140 pediatric patients 2 months to less than 18 years of age with nosocomial pneumonia were treated with piperacillin and tazobactam and 267 patients were treated with comparators (which included ticarcillin-clavulanate, carbapenems, ceftazidime, cefepime, or ciprofloxacin). The rates of serious adverse reactions were generally similar between the piperacillin and tazobactam and comparator groups, including patients aged 2 months to 9 months treated with piperacillin and tazobactam 90 mg/kg IV every 6 hours and patients older than 9 months and less than 18 years of age treated with piperacillin and tazobactam 112.5 mg/kg IV every 6 hours.

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