Piperacillin and Tazobactam

Hospira, Inc

HIGHLIGHTS OF PRESCRIBING INFORMATIONThese highlights do not include all the information needed to use PIPERACILLIN and TAZOBACTAM FOR INJECTION USP safely and effectively. See full prescribing information for PIPERACILLIN and TAZOBACTAM FOR INJECTION USP. PIPERACILLIN and TAZOBACTAM FOR INJECTION USP, ADD-Vantage vialsInitial U.S. Approval: 1993MicrobiologyTo 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.INDICATIONS AND USAGEPiperacillin and tazobactam for injection USP 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) DOSAGE AND ADMINISTRATION •The usual daily dose of piperacillin and tazobactam for injection for adults is 3.375 g every six hours totaling 13.5 g (12 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 g (16 g piperacillin/2 g tazobactam). (2.2) •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. (2.3) •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.(2.4) •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. (2.7) DOSAGE FORMS AND STRENGTHSPiperacillin and tazobactam for injection: 2.25 g, 3.375 g, and 4.5 g lyophilized powder for reconstitution in ADD-Vantage® vials (3)CONTRAINDICATIONSPatients with a history of allergic reactions to any of the penicillins, cephalosporins, or β-lactamase inhibitors. (4)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 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) Side EffectsThe most common adverse reactions (incidence >5%) are diarrhea, constipation, nausea, headache and insomnia. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Hospira Inc. at 1-800-441-4100 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. DRUG INTERACTIONS •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) USE IN SPECIFIC POPULATIONS •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)

FULL PRESCRIBING INFORMATION: CONTENTS*

• 1 PIPERACILLIN AND TAZOBACTAM INDICATIONS AND USAGE
  • 1.1 Intra-abdominal Infections
  • 1.2 Skin and Skin Structure Infections
  • 1.3 Female Pelvic Infections
  • 1.4 Community-acquired Pneumonia
  • 1.5 Nosocomial Pneumonia
• 2 PIPERACILLIN AND TAZOBACTAM DOSAGE AND ADMINISTRATION
  • 2.1 Adult Patients
  • 2.2 Nosocomial Pneumonia
  • 2.3 Renal Impairment
  • 2.4 Pediatric Patients
  • 2.5 Directions for Reconstitution and Dilution for Use
  • 2.6 Instructions for Use of the ADD-Vantage System
  • 2.7 Compatibility with Aminoglycosides
• 3 DOSAGE FORMS AND STRENGTHS
• 4 PIPERACILLIN AND TAZOBACTAM CONTRAINDICATIONS
• 5 WARNINGS AND PRECAUTIONS
  • 5.1 Hypersensitivity Reactions
  • 5.2 Serious Skin Reactions
  • 5.3 Associated Diarrhea
  • 5.4 Hematologic Effects
  • 5.5 Central Nervous System Effects
  • 5.6 Electrolyte Effects
  • 5.7 Development of Drug-Resistant Bacteria
• 6 PIPERACILLIN AND TAZOBACTAM ADVERSE REACTIONS
  • 6.1 Clinical Trials Experience
  • 6.2 Post-Marketing Experience
  • 6.3 Additional Experience with Piperacillin
• 7 DRUG INTERACTIONS
  • 7.1 Aminoglycosides
  • 7.2 Probenecid
  • 7.3 Anticoagulants
  • 7.4 Vecuronium
  • 7.5 Methotrexate
  • 7.6 Effects on Laboratory Tests
• 8 USE IN SPECIFIC POPULATIONS
  • 8.1 Pregnancy
  • 8.3 Nursing Mothers
  • 8.4 Pediatric Use
  • 8.5 Geriatric Use
  • 8.6 Renal Impairment
  • 8.7 Hepatic Impairment
  • 8.8 Patients with Cystic Fibrosis
• 10 OVERDOSAGE
• 11 PIPERACILLIN AND TAZOBACTAM DESCRIPTION
• 12 CLINICAL PHARMACOLOGY
  • 12.1 Mechanism of Action
  • 12.2 Pharmacodynamics
  • 12.3 Pharmacokinetics
  • 12.4 Microbiology
• 13 NONCLINICAL TOXICOLOGY
  • 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
• 15 REFERENCES
• 16 HOW SUPPLIED/STORAGE AND HANDLING
• 17 PATIENT COUNSELING INFORMATION
• 2.25 grams Label
• 3.375 grams Label
• 4.5 grams Label

FULL PRESCRIBING INFORMATION

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 or prevent infections that are proven or strongly suspected to be caused by bacteria.

1 INDICATIONS AND USAGE

Piperacillin and tazobactam for injection USP 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.

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 Ac inetobacter 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 USP and other antibacterial drugs, piperacillin and tazobactam for injection USP 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.

2 DOSAGE AND ADMINISTRATION

Piperacillin and tazobactam for injection should be administered by intravenous infusion over 30 minutes.

2.1 Adult Patients

The usual total daily dose of piperacillin and tazobactam for injection for adults is 3.375 g every six hours totaling 13.5 g (12 g piperacillin/1.5 g tazobactam). The usual duration of piperacillin and tazobactam for injection treatment is from 7 to 10 days.

Piperacillin and tazobactam for injection should be administered by intravenous infusion over 30 minutes.

2.2 Nosocomial Pneumonia

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 g (16 g piperacillin/2 g tazobactam). 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 is isolated.

2.3 Renal Impairment

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:

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.

2.4 Pediatric 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 (8.4) and Clinical Pharmacology (12.3)]. Pediatric patients weighing over 40 kg and with normal renal function should receive the adult dose.

It has not been determined how to adjust piperacillin and tazobactam for injection dosage in pediatric patients with renal impairment.

2.5 Directions for Reconstitution and Dilution for Use

ADD-Vantage^® System Admixtures

Dextrose 5% in Water (50 or 100 mL)

0.9% Sodium Chloride (50 or 100 mL)

For ADD-Vantage^® vials reconstitution directions see Instructions for Use of the ADD-Vantage^® System

LACTATED RINGER’S SOLUTION IS NOT COMPATIBLE WITH PIPERACILLIN AND TAZOBACTAM FOR INJECTION.

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 is stable in glass and plastic containers (plastic syringes, I.V. bags and tubing) when used with compatible diluents.

Stability studies with the admixed ADD-Vantage^® system have demonstrated chemical stability (potency, pH of reconstituted solution and clarity of solution) for up to 24 hours at room temperature. (Note: The admixed ADD-Vantage^® should not be refrigerated or frozen after reconstitution.). Piperacillin and tazobactam for injection contains no preservatives. Appropriate consideration of aseptic technique should be used.

2.6 Instructions for Use of the ADD-Vantage System

To Open Diluent Container:

Peel overwrap from the corner and remove container. Some opacity of the plastic due to moisture absorption during the sterilization process may be observed. This is normal and does not affect the solution quality or safety. The opacity will diminish gradually.

To Assemble Vial and Flexible Diluent Container (Use Aseptic Technique):

• 1.Remove the protective covers from the top of the vial and the vial port on the diluent container as follows:
  • A.To remove the breakaway vial cap, swing the pull ring over the top of the vial and pull down far enough to start the opening (SEE FIGURE 1.), then pull straight up to remove the cap. (SEE FIGURE 2.) NOTE: Do not access vial with syringe.
    
  • B.To remove the vial port cover, grasp the tab on the pull ring, pull up to break the three tie strings, then pull back to remove the cover. (SEE FIGURE 3.)
• 2.Screw the vial into the vial port until it will go no further. THE VIAL MUST BE SCREWED IN TIGHTLY TO ASSURE A SEAL. This occurs approximately 1/2 turn (180°) after the first audible click. (SEE FIGURE 4.) The clicking sound does not assure a seal; the vial must be turned as far as it will go. NOTE: Once vial is seated, do not attempt to remove. (SEE FIGURE 4.)
• 3.Recheck the vial to assure that it is tight by trying to turn it further in the direction of assembly.
• 4.Label appropriately.
  

To Prepare Admixture:

• 1.Squeeze the bottom of the diluent container gently to inflate the portion of the container surrounding the end of the drug vial.
• 5.With the other hand, push the drug vial down into the container telescoping the walls of the container. Grasp the inner cap of the vial through the walls of the container. (SEE FIGURE 5.)
• 6.Pull the inner cap from the drug vial. (SEE FIGURE 6.) Verify that the rubber stopper has been pulled out, allowing the drug and diluent to mix.
• 7.Mix container contents thoroughly and use within the specified time.
  

Preparation for Administration (Use Aseptic Technique):

• 1.Confirm the activation and admixture of vial contents.
• 2.Check for leaks by squeezing container firmly. If leaks are found, discard unit as sterility may be impaired.
• 3.Close flow control clamp of administration set.
• 4.Remove cover from outlet port at bottom of container.
• 5.Insert piercing pin of administration set into port with a twisting motion until the pin is firmly seated. NOTE: See full directions on administration set carton.
• 6.Lift the free end of the hanger loop on the bottom of the vial, breaking the two tie strings. Bend the loop outward to lock it in the upright position, then suspend container from hanger.
• 7.Squeeze and release drip chamber to establish proper fluid level in chamber.
• 8.Open flow control clamp and clear air from set. Close clamp.
• 9.Attach set to venipuncture device. If device is not indwelling, prime and make venipuncture.
• 10.Regulate rate of administration with flow control clamp.

WARNING: Do not use flexible container in series connections.

2.7 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, Y-site infusion only with the following aminoglycosides under the following conditions:

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 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 is supplied as a white to yellowish powder in vials of the following sizes:

Each piperacillin and tazobactam for injection USP 2.25 g ADD-Vantage^® 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 USP 3.375 g ADD-Vantage^® 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 USP 4.5 g ADD-Vantage^® vial provides piperacillin sodium equivalent to 4 grams of piperacillin and tazobactam sodium equivalent to 0.5 g of 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 β-lactamase inhibitors.

5 WARNINGS AND PRECAUTIONS

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 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

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%).

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 Injection Plus Aminoglycoside Clinical TrialsFor 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

7 DRUG INTERACTIONS

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 (2.7)].

7.2 Probenecid

Probenecid administered concomitantly with piperacillin and tazobactam for injection prolongs the half-life of piperacillin by 21% and that of tazobactam by 71% because probenecid inhibits tubular renal secretion of both piperacillin and tazobactam. Probenecid should not be co-administered with piperacillin and tazobactam for injection 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

8 USE IN SPECIFIC POPULATIONS

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/m²).

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 to 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

10 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)].

11 DESCRIPTION

Piperacillin and tazobactam for injection USP is an injectable antibacterial combination product consisting of the semisynthetic antibacterial piperacillin sodium and the β-lactamase inhibitor tazobactam sodium for intravenous administration.

Piperacillin sodium is derived from D(-)-α-aminobenzyl-penicillin. The chemical name of piperacillin sodium is sodium (2S,5R,6R)-6-[(R)-2-(4-ethyl-2,3-dioxo-1-piperazine­carboxamido)-2-phenylacetamido]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2­carboxylate. The chemical formula is C₂₃H₂₆N₅NaO₇S and the molecular weight is 539.5. The chemical structure of piperacillin sodium is: