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Piperacillin and Tazobactam

Pronunciation

Generic Name: piperacillin sodium and tazobactam sodium
Dosage Form: injection, powder, for solution

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.

Indications and Usage for Piperacillin and Tazobactam

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.

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.

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.

Female Pelvic Infections

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

Community-acquired Pneumonia

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

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)].

Usage

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. 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 Dosage and Administration

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

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.

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.

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:

Table 1: Recommended Dosing of Piperacillin and Tazobactam for Injection in Patients with Normal Renal Function and Renal ‑ Impairment (As total grams piperacillin/tazobactam)
Renal Function
(creatinine clearance,
mL/min)
All Indications
(except nosocomial
pneumonia)

Nosocomial
Pneumonia
*
Creatinine clearance for patients not receiving hemodialysis
0.75 g (0.67 g piperacillin/0.08 g tazobactam) should be administered following each hemodialysis session on hemodialysis days

>40 mL/min

3.375 q 6 h

4.5 q 6 h

20-40 mL/min*

2.25 q 6 h

3.375 q 6 h

<20 mL/min*

2.25 q 8 h

2.25 q 6 h

Hemodialysis

2.25 q 12 h

2.25 q 8 h

CAPD

2.25 q 12 h

2.25 q 8 h

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.

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.

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.

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.

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:

Table 2: Compatibility with Aminoglycosides
*
The concentration ranges in Table 2 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.




Aminoglycoside

Piperacillin and
Tazobactam for
Injection Dose
(grams)

Piperacillin and
Tazobactam for
Injection Diluent
Volume (mL)

Aminoglycoside
Concentration
Range
*
(mg/mL)



Acceptable
Diluents

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

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.

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.

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.

Warnings and Precautions

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.

Hematologic Adverse Reactions

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)].

Central Nervous System Adverse Reactions

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).

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.

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.

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.

Adverse Reactions

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%)

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 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 Trials*
System Organ Class
  Adverse Reaction
*
For adverse drug reactions that appeared in both studies the higher frequency is presented.

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%)

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.

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.

Hepatobiliary–hepatitis, jaundice

Hematologic–hemolytic anemia, agranulocytosis, pancytopenia

Immune–hypersensitivity reactions, anaphylactic/anaphylactoid reactions (including shock)

Renal–interstitial nephritis

Respiratory–eosinophilic pneumonia

Skin and Appendages–erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, drug reaction with eosinophilia and systemic symptoms, (DRESS), acute generalized exanthematous pustulosis (AGEP), dermatitis exfoliative

Additional Experience with Piperacillin

The following adverse reaction has also been reported for piperacillin for injection:

Skeletal–prolonged muscle relaxation [see Drug Interactions (7.5)].

Post-marketing experience with Piperacillin and Tazobactam for injection in pediatric patients suggests a similar safety profile to that seen in adults.

Drug Interactions

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)].

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.

Vancomycin

A limited number of retrospective studies have detected an increased incidence of acute kidney injury in patients concomitantly administered piperacillin/tazobactam and vancomycin as compared to vancomycin alone. Monitor kidney function in patients concomitantly administered with piperacillin/tazobactam and vancomycin.

No pharmacokinetic interactions have been noted between piperacillin/tazobactam and vancomycin.

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 (5.3)]

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).

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.

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.

USE IN SPECIFIC POPULATIONS

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.

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.

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.

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.

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)].

Hepatic Impairment

Dosage adjustment of Piperacillin and Tazobactam for injection is not warranted in patients with hepatic cirrhosis [See Clinical Pharmacology (12.3)].

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.

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 (5.4)].

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)].

Piperacillin and Tazobactam 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 - piperazine‑carboxamido) - 2 - phenylacetamido] - 3,3 - dimethyl - 7 - oxo - 4 - thia - 1 - azabicyclo[3.2.0]heptane - 2‑carboxylate. The chemical formula is C23H26N5NaO7S and the molecular weight is 539.5. The chemical structure of piperacillin sodium is:

Tazobactam sodium, a derivative of the penicillin nucleus, is a penicillanic acid sulfone. Its chemical name is sodium (2S,3S,5R)-3-methyl-7-oxo-3-(1H - 1,2,3 - triazol - 1 - ylmethyl) - 4 - thia - 1‑azabicyclo[3.2.0]heptane - 2 - carboxylate - 4,4 - dioxide. The chemical formula is C10H11N4NaO5S and the molecular weight is 322.3. The chemical structure of tazobactam sodium is:

Piperacillin and Tazobactam for injection, USP, is a white to yellowish sterile, cryodesiccated powder consisting of Piperacillin and Tazobactam as their sodium salts packaged in glass vials. The product does not contain excipients or preservatives. Dilute solutions are colorless to yellowish.

Each Piperacillin and Tazobactam for injection, USP 2.25 g ADD-Vantage® vial contains an amount of drug sufficient for withdrawal of piperacillin sodium equivalent to 2 grams of Piperacillin and Tazobactam sodium equivalent to 0.25 g of tazobactam. Each vial contains 4.69 mEq (108 mg) of sodium.

Each Piperacillin and Tazobactam for injection, USP 3.375 g ADD-Vantage® vial contains an amount of drug sufficient for withdrawal of piperacillin sodium equivalent to 3 grams of Piperacillin and Tazobactam sodium equivalent to 0.375 g of tazobactam. Each vial contains 7.04 mEq (162 mg) of sodium.

Each Piperacillin and Tazobactam for injection, USP 4.5 g ADD-Vantage® vial contains an amount of drug sufficient for withdrawal of piperacillin sodium equivalent to 4 grams of Piperacillin and Tazobactam sodium equivalent to 0.5 g of tazobactam. Each vial contains 9.39 mEq (216 mg) of sodium.

Piperacillin and Tazobactam for injection, USP contains a total of 2.35 mEq (54 mg) of sodium (Na+) per gram of piperacillin in the combination product.

Meets USP Organic Impurities Procedure 3.

Piperacillin and Tazobactam - Clinical Pharmacology

Mechanism of Action

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

Pharmacodynamics

The pharmacodynamic parameter for piperacillin/tazobactam that is most predictive of clinical and microbiological efficacy is time above MIC.

Pharmacokinetics

The mean and coefficients of variation (CV%) for the pharmacokinetic parameters of Piperacillin and Tazobactam after multiple intravenous doses are summarized in Table 6.

Table 6: Mean (CV%) Piperacillin and Tazobactam PK Parameters
*
Piperacillin and Tazobactam were given in combination, infused over 30 minutes.
Numbers in parentheses are coefficients of variation (CV%).

Piperacillin

Piperacillin/
Tazobactam
Dose
*


Cmax
mcg/mL


AUC

mcg•h/mL


CL
mL/min


V
L



T1/2 h


CLR
mL/min

2.25 g

134

131 (14)

257

17.4

0.79

-‑

3.375 g

242

242 (10)

207

15.1

0.84

140

4.5 g

298

322 (16)

210

15.4

0.84

--

Tazobactam

Piperacillin/
Tazobactam
Dose
*


Cmax
mcg/mL


AUC

mcg•h/mL


CL
mL/min


V
L



T1/2 h


CLR
mL/min

2.25 g

15

16 (21)

258

17

0.77

-‑

3.375 g

24

25 (8)

251

14.8

0.68

166

4.5 g

34

39.8 (15)

206

14.7

0.82

-‑

Peak plasma concentrations of Piperacillin and Tazobactam are attained immediately after completion of an intravenous infusion of Piperacillin and Tazobactam for injection. Piperacillin plasma concentrations, following a 30-minute infusion of Piperacillin and Tazobactam for injection, were similar to those attained when equivalent doses of piperacillin were administered alone. Steady-state plasma concentrations of Piperacillin and Tazobactam were similar to those attained after the first dose due to the short half-lives of Piperacillin and Tazobactam.

Distribution

Both Piperacillin and Tazobactam are approximately 30% bound to plasma proteins. The protein binding of either piperacillin or tazobactam is unaffected by the presence of the other compound. Protein binding of the tazobactam metabolite is negligible.

Piperacillin and Tazobactam are widely distributed into tissues and body fluids including intestinal mucosa, gallbladder, lung, female reproductive tissues (uterus, ovary, and fallopian tube), interstitial fluid, and bile. Mean tissue concentrations are generally 50% to 100% of those in plasma. Distribution of Piperacillin and Tazobactam into cerebrospinal fluid is low in subjects with non-inflamed meninges, as with other penicillins (see Table 7).

Table 7: Piperacillin/Tazobactam Concentrations in Selected Tissues and Fluids after Single 4 g/0.5 g 30-min IV Infusion of Piperacillin and Tazobactam for Injection
*
Each subject provided a single sample.
Time from the start of the infusion.



Tissue
or Fluid




N
*


Sampling
period

(h)

Mean PIP
Concentration
Range
(mg/L)


Tissue:
Plasma
Range

Tazo
Concentration
Range
(mg/L)

Tazo
Tissue:
Plasma
Range

Skin

35

0.5 – 4.5

34.8 – 94.2

0.6 – 1.1

4 – 7.7

0.49 – 0.93

Fatty Tissue

37

0.5 – 4.5

4 – 10.1

0.097 – 0.115

0.7 – 1.5

0.1 – 0.13

Muscle

36

0.5 – 4.5

9.4 – 23.3

0.29 – 0.18

1.4 – 2.7

0.18 – 0.3

Proximal Intestinal Mucosa

7

1.5 – 2.5

31.4

0.55

10.3

1.15

Distal Intestinal Mucosa

7

1.5 – 2.5

31.2

0.59

14.5

2.1

Appendix

22

0.5 – 2.5

26.5 – 64.1

0.43 – 0.53

9.1 – 18.6

0.8 – 1.35

Metabolism

Piperacillin is metabolized to a minor microbiologically active desethyl metabolite. Tazobactam is metabolized to a single metabolite that lacks pharmacological and antibacterial activities.

Excretion

Following single or multiple Piperacillin and Tazobactam for injection doses to healthy subjects, the plasma half-life of piperacillin and of tazobactam ranged from 0.7 to 1.2 hours and was unaffected by dose or duration of infusion.

Both Piperacillin and Tazobactam are eliminated via the kidney by glomerular filtration and tubular secretion. Piperacillin is excreted rapidly as unchanged drug with 68% of the administered dose excreted in the urine. Tazobactam and its metabolite are eliminated primarily by renal excretion with 80% of the administered dose excreted as unchanged drug and the remainder as the single metabolite. Piperacillin, tazobactam and desethyl piperacillin are also secreted into the bile.

Specific Populations

Renal Impairment

After the administration of single doses of piperacillin/tazobactam to subjects with renal impairment, the half-life of piperacillin and of tazobactam increases with decreasing creatinine clearance. At creatinine clearance below 20 mL/min, the increase in half-life is twofold for piperacillin and fourfold for tazobactam compared to subjects with normal renal function. Dosage adjustments for Piperacillin and Tazobactam for injection are recommended when creatinine clearance is below 40 mL/min in patients receiving the usual recommended daily dose of Piperacillin and Tazobactam for injection. See Dosage and Administration (2) for specific recommendations for the treatment of patients with renal impairment.

Hemodialysis removes 30% to 40% of a piperacillin/tazobactam dose with an additional 5% of the tazobactam dose removed as the tazobactam metabolite. Peritoneal dialysis removes approximately 6% and 21% of the Piperacillin and Tazobactam doses, respectively, with up to 16% of the tazobactam dose removed as the tazobactam metabolite. For dosage recommendations for patients undergoing hemodialysis [see Dosage and Administration (2)].

Hepatic Impairment

The half-life of piperacillin and of tazobactam increases by approximately 25% and 18%, respectively, in patients with hepatic cirrhosis compared to healthy subjects. However, this difference does not warrant dosage adjustment of Piperacillin and Tazobactam for injection due to hepatic cirrhosis.

Pediatrics

Piperacillin and Tazobactam pharmacokinetics were studied in pediatric patients 2 months of age and older. The clearance of both compounds is slower in the younger patients compared to older children and adults.

In a population PK analysis, estimated clearance for 9 month-old to 12 year-old patients was comparable to adults, with a population mean (SE) value of 5.64 (0.34) mL/min/kg. The piperacillin clearance estimate is 80% of this value for pediatric patients 2 to 9 months old. In patients younger than 2 months of age, clearance of piperacillin is slower compared to older children; however, it is not adequately characterized for dosing recommendations. The population mean (SE) for piperacillin distribution volume is 0.243 (0.011) L/kg and is independent of age.

Geriatrics

The impact of age on the pharmacokinetics of Piperacillin and Tazobactam was evaluated in healthy male subjects, aged 18 to 35 years (n=6) and aged 65 to 80 years (n=12). Mean half-life for piperacilln and tazobactam was 32% and 55% higher, respectively, in the elderly compared to the younger subjects. This difference may be due to age-related changes in creatinine clearance.

Race

The effect of race on Piperacillin and Tazobactam was evaluated in healthy male volunteers. No difference in piperacillin or tazobactam pharmacokinetics was observed between Asian (n=9) and Caucasian (n=9) healthy volunteers who received single 4/0.5 g doses.

Drug Interactions

The potential for pharmacokinetic drug interactions between Piperacillin and Tazobactam for injection and aminoglycosides, probenecid, vancomycin, heparin, vecuronium, and methotrexate has been evaluated [see Drug Interactions (7)].

Microbiology

Mechanism of Action

Piperacillin sodium exerts bactericidal activity by inhibiting septum formation and cell wall synthesis of susceptible bacteria. In vitro, piperacillin is active against a variety of Gram-positive and Gram-negative aerobic and anaerobic bacteria. Tazobactam sodium has little clinically relevant in vitro activity against bacteria due to its reduced affinity to penicillin-binding proteins. It is, however, a β-lactamase inhibitor of the Molecular class A enzymes, including Richmond- Sykes class III (Bush class 2b & 2b') penicillinases and cephalosporinases. It varies in its ability to inhibit class II and IV (2a & 4) penicillinases. Tazobactam does not induce chromosomally‑ mediated β-lactamases at tazobactam concentrations achieved with the recommended dosage regimen.

Spectrum of Activity

Piperacillin/tazobactam has been shown to be active against most isolates of the following microorganisms both in vitro and in clinical infections [see Indications and Usage (1)].

Gram-positive bacteria:

Staphylococcus aureus (methicillin susceptible isolates only)

Gram-negative bacteria:

Acinetobacter baumannii

Escherichia coli

Haemophilus influenzae (excluding β-lactamase negative, ampicillin-resistant isolates)

Klebsiella pneumoniae

Pseudomonas aeruginosa (given in combination with an aminoglycoside to which the isolate is susceptible)

Anaerobic bacteria:

Bacteroides fragilis group (B. fragilis, B. ovatus, B. thetaiotaomicron, and B. vulgatus)

The following in vitro data are available, but their clinical significance is unknown.

At least 90% of the following microorganisms exhibit an in vitro minimum inhibitory concentration (MIC) less than or equal to the susceptible breakpoint for piperacillin/tazobactam. However, the safety and effectiveness of piperacillin/tazobactam in treating clinical infections due to these bacteria have not been established in adequate and well-controlled clinical trials.

Gram-positive bacteria:

Enterococcus faecalis (ampicillin or penicillin-susceptible isolates only)

Staphylococcus epidermidis (methicillin susceptible isolates only)

Streptococcus agalactiae

Streptococcus pneumoniae (penicillin-susceptible isolates only)

Streptococcus pyogenes

Viridans group streptococci

Gram-negative bacteria:

Citrobacter koseri

Moraxella catarrhalis

Morganella morganii

Neisseria gonorrhoeae

Proteus mirabilis

Proteus vulgaris

Serratia marcescens

Providencia stuartii

Providencia rettgeri

Salmonella enterica

Anaerobic bacteria:

Clostridium perfringens

Bacteroides distasonis

Prevotella melaninogenica

These are not β-lactamase producing bacteria and, therefore, are susceptible to piperacillin alone.

Susceptibility Testing Methods

As is recommended with all antimicrobials, the results of in vitro susceptibility tests, when available, should be provided to the physician as periodic reports, which describe the susceptibility profile of nosocomial and community-acquired pathogens. These reports should aid the physician in selecting the most effective antimicrobial.

Dilution Techniques:

Quantitative methods are used to determine antimicrobial minimum inhibitory concentrations (MICs). These MICs provide estimates of the susceptibility of bacteria to antimicrobial compounds. The MICs should be determined using a standardized procedure. Standardized procedures are based on a dilution method (broth or agar) or equivalent with standardized inoculum concentrations and standardized concentrations of Piperacillin and Tazobactam powders.1,2 MIC values should be determined using serial dilutions of piperacillin combined with a fixed concentration of 4 μg/mL tazobactam. The MIC values obtained should be interpreted according to criteria provided in Table 8.

Diffusion Technique:

Quantitative methods that require measurement of zone diameters also provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. The zone size provides an estimate of the susceptibility of bacteria to antimicrobial compounds. The zone size should be determined using a standardized test method1,3 and requires the use of standardized inoculum concentrations. This procedure uses paper disks impregnated with 100 mcg of piperacillin and 10 mcg of tazobactam to test the susceptibility of microorganisms to piperacillin/tazobactam. The disk diffusion interpreted criteria are provided in Table 8.

Anaerobic Techniques

For anaerobic bacteria, the susceptibility to piperacillin/tazobactam can be determined by the reference agar dilution method.4

Table 8: Susceptibility Interpretive Criteria for Piperacillin/Tazobactam
Susceptibility Test Result Interpretive Criteria
Minimal Inhibitory
Concentration
(MIC in mcg/mL)
Disk Diffusion
(Zone Diameter
in mm)
Pathogen S I R S I R
*
These interpretive criteria for Haemophilus influenzae are applicable only to tests performed using Haemophilus Test Medium inoculated with a direct colony suspension and incubated at 35°C in ambient air for 20 to 24 hours. Note: Susceptibility of staphylococci to piperacillin/tazobactam may be deduced from testing only penicillin and either cefoxitin or oxacillin.

Enterobacteriaceae

≤ 16

32 – 64

≥ 128

≥ 21

18 – 20

≤ 17

Acinetobacter baumannii

≤ 16

32 – 64

≥ 128

≥ 21

18 – 20

≤ 17

Haemophilus influenzae*

≤ 1

-

≥ 2

≥ 21

-

-

Pseudomonas aeruginosa

≤ 16

32 – 64

≥ 128

≥ 21

15 – 20

≤ 14

Bacteroides fragilis group

≤ 32

64

≥ 128

-

-

-

A report of S (“Susceptible”) indicates that the pathogen is likely to be inhibited if the antimicrobial compound in the blood reaches the concentration at the infection site necessary to inhibit growth of the pathogen. A report of I (“Intermediate”) indicates that the results should be considered equivocal, and if the microorganism is not fully susceptible to alternative, clinically feasible drugs, the test should be repeated. This category implies possible clinical applicability in body sites where the drug is physiologically concentrated or in situations where high dosage of drug can be used. This category also provides a buffer zone, which prevents small, uncontrolled technical factors from causing major discrepancies in interpretation. A report of R (“Resistant”) indicates that the pathogen is not likely to be inhibited even if the antimicrobial compound in the blood reaches the concentration usually achievable at the infection site; other therapy should be considered.

Quality Control

Standardized susceptibility test procedures require the use of quality controls to monitor and ensure the accuracy and precision of supplies and reagents used in the assay, and the techniques of the individuals performing the test procedures.1,2,3,4 Standard piperacillin/tazobactam powder should provide the following ranges of values noted in Table 9. Quality control bacteria are specific strains of bacteria with intrinsic biological properties relating to resistance mechanisms and their genetic expression within the microorganism; the specific strains used for microbiological quality control are not clinically significant.

Table 9: Acceptable Quality Control Ranges for Piperacillin/Tazobactam to Be Used in Validation of Susceptibility Test
Acceptable Quality Control Ranges


QC Strain
Minimum Inhibitory
Concentration
Range (MIC in mcg/mL)
Disk Diffusion
Zone Diameter
Ranges in mm
*
This quality control range for Haemophilus influenzae is applicable only to tests performed using Haemophilus Test Medium inoculated with a direct colony suspension and incubated at 35°C in ambient air for 20 to 24 hours.
The quality control ranges for Bacteroides fragilis and Bacteroides thetaiotaomicron are applicable only to tests performed using the agar dilution method.

Escherichia coli
ATCC 25922

1 – 4

24 – 30

Escherichia coli
ATCC 35218

0.5 – 2

24 – 30

Pseudomonas aeruginosa
ATCC 27853

1 – 8

25 – 33

Haemophilus influenzae*
ATCC 49247

0.06 – 0.5

33 – 38

Staphylococcus aureus
ATCC 29213

0.25 – 2

-

Staphylococcus aureus
ATCC 25923

-

27 – 36

Bacteroides fragilis
ATCC 25285

0.12 – 0.5

-

Bacteroides thetaiotaomicron
ATCC 29741

4 – 16

-

Clostridium difficile
ATCC 700057

4 – 16

-

Eubacterium lentum
ATCC 43055

4 – 16

-

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment of Fertility

Long-term carcinogenicity studies in animals have not been conducted with piperacillin/tazobactam, piperacillin, or tazobactam.

Piperacillin/Tazobactam

Piperacillin/tazobactam was negative in microbial mutagenicity assays, the unscheduled DNA synthesis (UDS) test, a mammalian point mutation (Chinese hamster ovary cell HPRT) assay, and a mammalian cell (BALB/c-3T3) transformation assay. In vivo, piperacillin/tazobactam did not induce chromosomal aberrations in rats.

Piperacillin/Tazobactam

Reproduction studies have been performed in rats and have revealed no evidence of impaired fertility when piperacillin/tazobactam is administered intravenously up to a dose of 1280/320 mg/kg piperacillin/tazobactam, which is similar to the maximum recommended human daily dose based on body-surface area (mg/m2).

REFERENCES

1.
Clinical and Laboratory Standards Institute (CLSI). Performance Standards for Antimicrobial Susceptibility Testing; Twenty-third Informational Supplement. CLSI document M100-S23, Clinical and Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne, Pennsylvania 19087, USA, 2013.
2.
Clinical and Laboratory Standards Institute (CLSI). Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria that Grow Aerobically; Approved Standard – Ninth Edition. CLSI document M07-A9, Clinical and Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne, Pennsylvania 19087, USA, 2012.
3.
Clinical and Laboratory Standards Institute (CLSI). Performance Standards for Antimicrobial Disk Diffusion Susceptibility Tests; Approved Standard – Eleventh Edition. CLSI document M02-A11, Clinical and Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne, Pennsylvania 19087, USA, 2012.
4.
Clinical and Laboratory Standards Institute (CLSI). Methods for Antimicrobial Susceptibility Testing of Anaerobic Bacteria; Approved Standard – Eight Edition. CLSI document M11-A8. Clinical and Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne, PA 19087 USA, 2012.

CLINITEST® is a registered trademark of Siemens Healthcare Diagnostics Inc.

ADD-Vantage® is a registered trademark of Hospira, Inc.

How Supplied/Storage and Handling

Piperacillin and Tazobactam for injection, USP is supplied as ADD-Vantage® vials in 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 ADD-Vantage® vial contains 4.69 mEq (108 mg) of sodium.

Supplied 10 per box – NDC 0409-3374-02

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 ADD-Vantage® vial contains 7.04 mEq (162 mg) of sodium.

Supplied 10 per box – NDC 0409-3378-13

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. Each ADD-Vantage® vial contains 9.39 mEq (216 mg) of sodium.

Supplied 10 per box – NDC 0409-3379-04

Piperacillin and Tazobactam for injection, USP ADD-Vantage® vials should be stored at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature] prior to reconstitution.

Patient Counseling Information

Serious Hypersensitivity Reactions

Advise patients, their families, or caregivers that serious hypersensitivity reactions, including serious allergic cutaneous reactions, could occur that require immediate treatment. Ask them about any previous hypersensitivity reactions to Piperacillin and Tazobactam for injection, other beta-lactams (including cephalosporins), or other allergens [see Warnings and Precautions (5.2)].

Diarrhea

Advise patients, their families, or caregivers that diarrhea is a common problem caused by antibacterial drugs which usually ends when the drug is discontinued. Sometimes after starting treatment with antibacterial drugs, patients can develop watery and bloody stools (with or without stomach cramps and fever) even as late as two or more months after having taken the last dose of the drug. If this occurs, patients should contact their physician as soon as possible.

Antibacterial Resistance

Counsel patients that antibacterial drugs including Piperacillin and Tazobactam for injection should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When Piperacillin and Tazobactam for injection is prescribed to treat a bacterial infection, patients should be told that although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed. Skipping doses or not completing the full course of therapy may (1) decrease the effectiveness of the immediate treatment and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by Piperacillin and Tazobactam for injection or other antibacterial drugs in the future.

06-2016M

EN-4386

46189099

Manufactured by Sandoz GmbH for Hospira Worldwide, Inc.,

Lake Forest, IL 60045, USA. Made in Kundl, Austria.

2.25 grams Label

NDC 0409-3374-02 Rx only

Piperacillin and Tazobactam

for Injection, USP

2.25 grams*/ADD-Vantage® vial

10 x 2.25 gram Single Dose ADD-Vantage® Vials

ADD-Vantage® Vial For IV Use

*Each vial provides piperacillin and

tazobactam for injection equivalent to

2 g piperacillin, 0.25 g tazobactam and

4.69 mEq (108 mg) of sodium.

Hospira

3.375 grams Label

NDC 0409-3378-13 Rx only

Piperacillin and Tazobactam

for Injection, USP

3.375 grams*/ADD-Vantage® vial

10 x 3.375 gram Single Dose ADD-Vantage® Vials

ADD-Vantage® Vial For IV Use

*Each vial provides piperacillin and

tazobactam for injection equivalent to

3 g piperacillin, 0.375 g tazobactam and

7.04 mEq (162 mg) of sodium.

Hospira

4.5 grams Label

NDC 0409-3379-04 Rx only

Piperacillin and Tazobactam

for Injection, USP

4.5 grams*/ADD-Vantage® vial

10 x 4.5 gram Single Dose ADD-Vantage® Vials

ADD-Vantage® Vial For IV Use

*Each vial provides piperacillin and

tazobactam for injection equivalent to

4 g piperacillin, 0.5 g tazobactam and

9.39 mEq (216 mg) of sodium.

Hospira

Piperacillin and Tazobactam 
Piperacillin and Tazobactam injection, powder, lyophilized, for solution
Product Information
Product Type HUMAN PRESCRIPTION DRUG LABEL Item Code (Source) NDC:0409-3374
Route of Administration INTRAVENOUS, PARENTERAL DEA Schedule     
Active Ingredient/Active Moiety
Ingredient Name Basis of Strength Strength
PIPERACILLIN SODIUM (PIPERACILLIN ANHYDROUS) PIPERACILLIN ANHYDROUS 2 g
TAZOBACTAM SODIUM (TAZOBACTAM) TAZOBACTAM 0.25 g
Packaging
# Item Code Package Description
1 NDC:0409-3374-02 10 VIAL, SINGLE-USE in 1 CARTON
1 1 INJECTION, POWDER, LYOPHILIZED, FOR SOLUTION in 1 VIAL, SINGLE-USE
Marketing Information
Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
ANDA ANDA065363 10/21/2010
Piperacillin and Tazobactam 
Piperacillin and Tazobactam injection, powder, lyophilized, for solution
Product Information
Product Type HUMAN PRESCRIPTION DRUG LABEL Item Code (Source) NDC:0409-3378
Route of Administration INTRAVENOUS, PARENTERAL DEA Schedule     
Active Ingredient/Active Moiety
Ingredient Name Basis of Strength Strength
PIPERACILLIN SODIUM (PIPERACILLIN ANHYDROUS) PIPERACILLIN ANHYDROUS 3 g
TAZOBACTAM SODIUM (TAZOBACTAM) TAZOBACTAM 0.375 g
Packaging
# Item Code Package Description
1 NDC:0409-3378-13 10 VIAL, SINGLE-USE in 1 CARTON
1 1 INJECTION, POWDER, LYOPHILIZED, FOR SOLUTION in 1 VIAL, SINGLE-USE
Marketing Information
Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
ANDA ANDA065363 10/21/2010
Piperacillin and Tazobactam 
Piperacillin and Tazobactam injection, powder, lyophilized, for solution
Product Information
Product Type HUMAN PRESCRIPTION DRUG LABEL Item Code (Source) NDC:0409-3379
Route of Administration INTRAVENOUS, PARENTERAL DEA Schedule     
Active Ingredient/Active Moiety
Ingredient Name Basis of Strength Strength
PIPERACILLIN SODIUM (PIPERACILLIN ANHYDROUS) PIPERACILLIN ANHYDROUS 4 g
TAZOBACTAM SODIUM (TAZOBACTAM) TAZOBACTAM 0.5 g
Packaging
# Item Code Package Description
1 NDC:0409-3379-04 10 VIAL, SINGLE-USE in 1 CARTON
1 1 INJECTION, POWDER, LYOPHILIZED, FOR SOLUTION in 1 VIAL, SINGLE-USE
Marketing Information
Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
ANDA ANDA065363 10/21/2010
Labeler - Hospira, Inc (141588017)
Revised: 07/2016
 
Hospira, Inc
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