NDC 68001-507 Piperacillin And Tazobactam

Piperacillin And Tazobactam

NDC Product Code 68001-507

NDC 68001-507-82

Package Description: 10 VIAL, SINGLE-DOSE in 1 CARTON > 15 mL in 1 VIAL, SINGLE-DOSE (68001-507-53)

NDC Product Information

Piperacillin And Tazobactam with NDC 68001-507 is a a human prescription drug product labeled by Bluepoint Laboratories. The generic name of Piperacillin And Tazobactam is piperacillin and tazobactam. The product's dosage form is injection, powder, for solution and is administered via intravenous form. The RxNorm Crosswalk for this NDC code indicates multiple RxCUI concepts are associated to this product: 1659131, 1659137 and 1659149.

Dosage Form: Injection, Powder, For Solution - A sterile preparation intended for reconstitution to form a solution for parenteral use.

Product Type: Human Prescription Drug What kind of product is this?
Indicates the type of product, such as Human Prescription Drug or Human Over the Counter Drug. This data element matches the “Document Type” field of the Structured Product Listing.

Piperacillin And Tazobactam Active Ingredient(s)

What is the Active Ingredient(s) List?
This is the active ingredient list. Each ingredient name is the preferred term of the UNII code submitted.


Administration Route(s)

What are the Administration Route(s)?
The translation of the route code submitted by the firm, indicating route of administration.

  • Intravenous - Administration within or into a vein or veins.

Pharmacological Class(es)

What is a Pharmacological Class?
These are the reported pharmacological class categories corresponding to the SubstanceNames listed above.

  • Penicillin-class Antibacterial - [EPC] (Established Pharmacologic Class)
  • Penicillins - [CS]
  • beta Lactamase Inhibitors - [MoA] (Mechanism of Action)
  • beta Lactamase Inhibitor - [EPC] (Established Pharmacologic Class)

Product Labeler Information

What is the Labeler Name?
Name of Company corresponding to the labeler code segment of the Product NDC.

Labeler Name: Bluepoint Laboratories
Labeler Code: 68001
FDA Application Number: ANDA204959 What is the FDA Application Number?
This corresponds to the NDA, ANDA, or BLA number reported by the labeler for products which have the corresponding Marketing Category designated. If the designated Marketing Category is OTC Monograph Final or OTC Monograph Not Final, then the Application number will be the CFR citation corresponding to the appropriate Monograph (e.g. “part 341”). For unapproved drugs, this field will be null.

Marketing Category: ANDA - A product marketed under an approved Abbreviated New Drug Application. What is the Marketing Category?
Product types are broken down into several potential Marketing Categories, such as NDA/ANDA/BLA, OTC Monograph, or Unapproved Drug. One and only one Marketing Category may be chosen for a product, not all marketing categories are available to all product types. Currently, only final marketed product categories are included. The complete list of codes and translations can be found at www.fda.gov/edrls under Structured Product Labeling Resources.

Start Marketing Date: 08-11-2021 What is the Start Marketing Date?
This is the date that the labeler indicates was the start of its marketing of the drug product.

Listing Expiration Date: 12-31-2022 What is the Listing Expiration Date?
This is the date when the listing record will expire if not updated or certified by the product labeler.

Exclude Flag: N - NO What is the NDC Exclude Flag?
This field indicates whether the product has been removed/excluded from the NDC Directory for failure to respond to FDA"s requests for correction to deficient or non-compliant submissions ("Y"), or because the listing certification is expired ("E"), or because the listing data was inactivated by FDA ("I"). Values = "Y", "N", "E", or "I".

* Please review the disclaimer below.

Piperacillin And Tazobactam Product Labeling Information

The product labeling information includes all published material associated to a drug. Product labeling documents include information like generic names, active ingredients, ingredient strength dosage, routes of administration, appearance, usage, warnings, inactive ingredients, etc.

Product Labeling Index

1.1 Intra-Abdominal Infections

Piperacillin and tazobactam for injection, USP is indicated in adults and pediatric patients (2 months of age and older) for the treatment of appendicitis (complicated by rupture or abscess) and peritonitis caused by beta-lactamase producing isolates of


Escherichia coli or the following members of the


Bacteroides fragilis group:


B. fragilis,


B. ovatus,


B. thetaiotaomicron, or


B. vulgatus.

1.2 Nosocomial Pneumonia

Piperacillin and tazobactam for injection, USP is indicated in adults and pediatric patients (2 months of age and older) for the treatment of nosocomial pneumonia (moderate to severe) caused by beta-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)]

.

1.3 Skin And Skin Structure Infections

Piperacillin and tazobactam for injection, USP is indicated in adults for the treatment of uncomplicated and complicated skin and skin structure infections, including cellulitis, cutaneous abscesses and ischemic/diabetic foot infections caused by beta-lactamase producing isolates of


Staphylococcus aureus.

1.4 Female Pelvic Infections

Piperacillin and tazobactam for injection, USP is indicated in adults for the treatment of postpartum endometritis or pelvic inflammatory disease caused by beta-lactamase producing isolates of


Escherichia coli.

1.5 Community-Acquired Pneumonia

Piperacillin and tazobactam for injection, USP is indicated in adults for the treatment of community-acquired pneumonia (moderate severity only) caused by beta-lactamase producing isolates of


Haemophilus influenzae.

1.6 Usage

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 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.

2.1 Dosage In Adult Patients With Indications Other Than Nosocomial Pneumonia

The usual total daily dosage of piperacillin and tazobactam for injection, USP for adult patients with indications other than nosocomial pneumonia is 3.375 g every six hours [totaling 13.5 g (12 g piperacillin/1.5 g tazobactam)], to be administered by intravenous infusion over 30 minutes. The usual duration of piperacillin and tazobactam for injection, USP treatment is from 7 to 10 days.

2.2 Dosage In Adult Patients With Nosocomial Pneumonia

Initial presumptive treatment of adult patients with nosocomial pneumonia should start with piperacillin and tazobactam for injection, USP at a dosage of 4.5 g every six hours plus an aminoglycoside, [totaling 18 g (16 g piperacillin/2 g tazobactam)], administered by intravenous infusion over 30 minutes. The recommended duration of piperacillin and tazobactam for injection, USP 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 Dosage In Adult Patients With Renal Impairment

In adult patients with renal impairment (creatinine clearance ≤ 40 mL/min) and dialysis patients (hemodialysis and CAPD), the intravenous dose of piperacillin and tazobactam for injection, USP should be reduced based on the degree of renal impairment. The recommended daily dosage of piperacillin and tazobactam for injection, USP for patients with renal impairment administered by intravenous infusion over 30 minutes is described in Table 1Table 1: Recommended Dosage of Piperacillin and Tazobactam for Injection in Patients with Normal Renal Function and Renal Impairment (As total grams piperacillin/tazobactam)


Administer piperacillin and tazobactam for injection by intravenous infusion over 30 minutes.Creatinine clearance, mL/minAll Indications (except nosocomial pneumonia)Nosocomial PneumoniaGreat than 40 mL/min3.375 every 6 hours4.5 every 6 hours20 to 40 mL/min


Creatinine clearance for patients not receiving hemodialysis2.25 every 6 hours3.375 every 6 hoursLess than 20 mL/min


2.25 every 8 hours2.25 every 6 hoursHemodialysis


0.75 g (0.67 g piperacillin/0.08 g tazobactam) should be administered following each hemodialysis session on hemodialysis days2.25 every 12 hours2.25 every 8 hoursCAPD2.25 every 12 hours2.25 every 8 hoursFor 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, USP (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, USP is necessary for CAPD patients.

2.4 Dosage In Pediatric Patients With Appendicitis/Peritonitis Or Nosocomial Pneumonia

The recommended dosage for pediatric patients with appendicitis and/or peritonitis or nosocomial pneumonia aged 2 months of age and older, weighing up to 40 kg, and with normal renal function, is described in Table 2


[see Use in Specific Populations (8.4) and

Clinical Pharmacology (12.3)]

.

Table 2: Recommended Dosage of Piperacillin and Tazobactam for Injection in Pediatric Patients 2 Months of Age and Older, Weighing Up to 40 kg, and With Normal Renal Function


Administer piperacillin and tazobactam for injection by intravenous infusion over 30 minutesAgeAppendicitis and/or PeritonitisNosocomial Pneumonia2 months to 9 months90 mg/kg


(80 mg piperacillin/10 mg tazobactam)


every 8 (


eight) hours


90 mg/kg


(80 mg piperacillin/10 mg tazobactam)


every 6 (


six) hours


Older than 9 months of age112.5 mg/kg


(100 mg piperacillin/12.5 mg tazobactam)


every 8 (


eight) hours


112.5 mg/kg


(100 mg piperacillin/12.5 mg tazobactam)


every 6 (


six) hours


Pediatric patients weighing over 40 kg and with normal renal function should receive the adult dose


[see


Dosage and Administration (2.1,


2.2)]


.


Dosage of piperacillin and tazobactam for injection in pediatric patients with renal impairment has not been determined.

Other

Single dose vialsReconstitute piperacillin and tazobactam for injection, USP vials with a compatible reconstitution diluent from the list provided below.


2.25 g, 3.375 g, and 4.5 g piperacillin and tazobactam for injection, USP should be reconstituted with 10 mL, 15 mL, and 20 mL, respectively. Swirl until dissolved.


Compatible Reconstitution Diluents for Single Dose Vials0.9% sodium chloride for injection


Sterile water for injection


Dextrose 5%


Bacteriostatic saline/parabens


Bacteriostatic water/parabens


Bacteriostatic saline/benzyl alcohol


Bacteriostatic water/benzyl alcohol


Reconstituted piperacillin and tazobactam for injection, USP solutions for single dose vials should be further diluted (recommended volume per dose of 50 mL to 150 mL) in a compatible intravenous solution listed below. Administer by infusion over a period of at least 30 minutes. During the infusion it is desirable to discontinue the primary infusion solution.Compatible Intravenous Solutions for Single Dose Vials0.9% sodium chloride for injection


sterile water for injection


‡Dextran 6% in saline


Dextrose 5%


LACTATED RINGER'S SOLUTION IS NOT COMPATIBLE WITH PIPERACILLIN AND TAZOBACTAM FOR INJECTION, USP‡ Maximum recommended volume per dose of sterile water for injection is 50 mL.


Piperacillin and tazobactam for injection, USP should not be mixed with other drugs in a syringe or infusion bottle since compatibility has not been established.


Piperacillin and tazobactam for injection, USP is not chemically stable in solutions that contain only sodium bicarbonate and solutions that significantly alter the pH.


Piperacillin and tazobactam for injection, USP 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, USP Powder Formulations Following ReconstitutionPiperacillin and tazobactam for injection, USP reconstituted from single vials is stable in glass and plastic containers (plastic syringes, I.V. bags and tubing) when used with compatible diluents.Single dose vial should be used immediately after reconstitution. Discard any unused portion after 24 hours if stored at room temperature (20°C to 25°C [68°F to 77°F]), or after 48 hours if stored at refrigerated temperature (2°C to 8°C [36°F to 46°F]). Vials should not be frozen after reconstitution.Stability studies in the I.V. bags have demonstrated chemical stability (potency, pH of reconstituted solution and clarity of solution) for up to 24 hours at room temperature and up to one week at refrigerated temperature. Piperacillin and tazobactam for injection, USP contains no preservatives. Appropriate consideration of aseptic technique should be used.Piperacillin and tazobactam for injection, USP reconstituted from single vials can be used in ambulatory intravenous infusion pumps. Stability of piperacillin and tazobactam for injection, USP in an ambulatory intravenous infusion pump has been demonstrated for a period of 12 hours at room temperature. Each dose was reconstituted and diluted to a volume of 37.5 mL or 25 mL. One-day supplies of dosing solution were aseptically transferred into the medication reservoir (I.V. bags or cartridge). The reservoir was fitted to a preprogrammed ambulatory intravenous infusion pump per the manufacturer's instructions. Stability of piperacillin and tazobactam for injection, USP is not affected when administered using an ambulatory intravenous infusion pump.

Nosocomial Pneumonia Trials Two trials of nosocomial lower respiratory tract infections were conducted. In one study, 222 patients were treated with piperacillin and tazobactam for injection in a dosing regimen of 4.5 g every 6 hours in combination with an aminoglycoside and 215 patients were treated with imipenem/cilastatin (500 mg/500 mg every 6 hours) in combination with an aminoglycoside. In this trial, treatment-emergent adverse events were reported by 402 patients, 204 (91.9%) in the piperacillin/tazobactam group and 198 (92.1%) in the imipenem/cilastatin group. Twenty-five (11.0 %) patients in the piperacillin/tazobactam group and 14 (6.5%) in the imipenem/cilastatin group (p > 0.05) discontinued treatment due to an adverse event.The second trial used a dosing regimen of 3.375 g given every 4 hours with an aminoglycoside.Table 5: Adverse Reactions from Piperacillin and Tazobactam for Injection Plus Aminoglycoside Clinical Trials


For adverse drug reactions that appeared in both studies the higher frequency is presented.System Organ Class  Adverse ReactionBlood 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%)

Other Trials: NephrotoxicityIn a randomized, multicenter, controlled trial in 1200 adult critically ill patients, piperacillin/tazobactam was found to be a risk factor for renal failure (odds ratio 1.7, 95% CI 1.18 to 2.43), and associated with delayed recovery of renal function as compared to other beta-lactam antibacterial drugs.


1[see


Warnings and Precautions (5.5)]


.


Adverse Laboratory Changes (Seen During Clinical Trials)Of the trials reported, including that of nosocomial lower respiratory tract infections in which a higher dose of piperacillin and tazobactam for injection was used in combination with an aminoglycoside, changes in laboratory parameters include:Hematologic—decreases in hemoglobin and hematocrit, thrombocytopenia, increases in platelet count, eosinophilia, leukopenia, neutropenia. These patients were withdrawn from therapy; some had accompanying systemic symptoms (e.g., fever, rigors, chills)


Coagulation—positive direct Coombs' test, prolonged prothrombin time, prolonged partial thromboplastin time


Hepatic—transient elevations of AST (SGOT), ALT (SGPT), alkaline phosphatase, bilirubin


Renal—increases in serum creatinine, blood urea nitrogen


Additional laboratory events include abnormalities in electrolytes (i.e., increases and decreases in sodium, potassium, and calcium), hyperglycemia, decreases in total protein or albumin, blood glucose decreased, gamma-glutamyltransferase increased, hypokalemia, and bleeding time prolonged.

Clinical Trials in Pediatric PatientsClinical 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, 2 to 12 years of age, with intra-abdominal infections (including appendicitis and/or peritonitis), 273 patients were treated with piperacillin and tazobactam for injection 112.5 mg/kg given IV every 8 hours and 269 patients were treated with cefotaxime (50 mg/kg) plus metronidazole (7.5 mg/kg) every 8 hours. In this trial, treatment-emergent adverse events were reported by 146 patients, 73 (26.7%) in the piperacillin and tazobactam 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.In a retrospective, cohort study, 140 pediatric patients 2 months to less than 18 years of age with nosocomial pneumonia were treated with piperacillin and tazobactam for injection and 267 patients were treated with comparators (which included ticarcillin-clavulanate, carbapenems, ceftazidime, cefepime, or ciprofloxacin). The rates of serious adverse reactions were generally similar between the piperacillin and tazobactam for injection and comparator groups, including patients aged 2 months to 9 months treated with piperacillin and tazobactam for injection 90 mg/kg IV every 6 hours and patients older than 9 months and less than 18 years of age treated with piperacillin and tazobactam for injection 112.5 mg/kg IV every 6 hours.

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)]


.

Risk SummaryPiperacillin and tazobactam cross the placenta in humans. However, there are insufficient data with piperacillin and/or tazobactam in pregnant women to inform a drug-associated risk for major birth defects and miscarriage. No fetal structural abnormalities were observed in rats or mice when piperacillin/tazobactam was administered intravenously during organogenesis at doses 1 to 2 times and 2 to 3 times the human dose of piperacillin and tazobactam, respectively, based on body-surface area (mg/m


2). However, fetotoxicity in the presence of maternal toxicity was observed in developmental toxicity and peri/postnatal studies conducted in rats (intraperitoneal administration prior to mating and throughout gestation or from gestation day 17 through lactation day 21) at doses less than the maximum recommended human daily dose based on body-surface area (mg/m


2) [


see


Data].


The background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2–4% and 15–20%, respectively.

Data

Animal DataIn embryo-fetal development studies in mice and rats, pregnant animals received intravenous doses of piperacillin/tazobactam up to 3000/750 mg/kg/day during the period of organogenesis. There was no evidence of teratogenicity up to the highest dose evaluated, which is 1 to 2 times and 2 to 3 times the human dose of piperacillin and tazobactam, in mice and rats respectively, based on body-surface area (mg/m


2). Fetal body weights were reduced in rats at maternally toxic doses at or above 500/62.5 mg/kg/day, minimally representing 0.4 times the human dose of both piperacillin and tazobactam based on body-surface area (mg/m


2).


A fertility and general reproduction study in rats using intraperitoneal administration of tazobactam or the combination piperacillin/tazobactam prior to mating and through the end of gestation, reported a decrease in litter size in the presence of maternal toxicity at 640 mg/kg/day tazobactam (4 times the human dose of tazobactam based on body-surface area), and decreased litter size and an increase in fetuses with ossification delays and variations of ribs, concurrent with maternal toxicity at ≥640/160 mg/kg/day piperacillin/tazobactam (0.5 times and 1 times the human dose of piperacillin and tazobactam, respectively, based on body-surface area).Peri/postnatal development in rats was impaired with reduced pup weights, increased stillbirths, and increased pup mortality concurrent with maternal toxicity after intraperitoneal administration of tazobactam alone at doses ≥320 mg/kg/day (2 times the human dose based on body surface area) or of the combination piperacillin/tazobactam at doses ≥640/160 mg/kg/day (0.5 times and 1 times the human dose of piperacillin and tazobactam, respectively, based on body-surface area) from gestation day 17 through lactation day 21.

Risk SummaryPiperacillin is excreted in human milk; tazobactam concentrations in human milk have not been studied. No information is available on the effects of piperacillin and tazobactam on the breast-fed child or on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for piperacillin and tazobactam for injection and any potential adverse effects on the breastfed child from piperacillin and tazobactam for injection or from the underlying maternal condition.

DistributionBoth 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 8).


Table 8: 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 a Each subject provided a single sample.


b Time from the start of the infusion


Tissue orFluidN


aSamplingperiod


b(h)Mean PIPConcentrationRange(mg/L)Tissue:Plasma RangeTazoConcentrationRange(mg/L)Tazo Tissue:Plasma RangeSkin 35 0.5 - 4.5 34.8 - 94.2 0.60 - 1.1 4.0 - 7.7 0.49 - 0.93 Fatty Tissue 37 0.5 - 4.5 4.0 - 10.1 0.097 - 0.115 0.7 - 1.5 0.10 - 0.13 Muscle 36 0.5 - 4.5 9.4 - 23.3 0.29 - 0.18 1.4 - 2.7 0.18 - 0.30 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 0.80 - 1.35

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

ExcretionFollowing 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 ImpairmentAfter 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 ImpairmentThe 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.

PediatricsPiperacillin 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 volume of distribution is 0.243 (0.011) L/kg and is independent of age.

GeriatricsThe 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 piperacillin 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.

RaceThe 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.

Antimicrobial ActivityPiperacillin and tazobactam for injection 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)]:


Aerobic bacteriaGram-positive bacteriaStaphylococcus aureus (methicillin susceptible isolates only)


Gram-negative bacteriaAcinetobacter baumanniiEscherichia coliHaemophilus influenzae (excluding beta-lactamase negative, ampicillin-resistant isolates)


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


Anaerobic bacteriaBacteroides 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 percent of the following bacteria exhibit an


in vitro minimum inhibitory concentration (MIC) less than or equal to the susceptible breakpoint for piperacillin/tazobactam against isolates of similar genus or organism group.


However, the efficacy of piperacillin and tazobactam for injection in treating clinical infections caused by these bacteria has not been established in adequate and well-controlled clinical trials.Aerobic bacteriaGram-positive bacteriaEnterococcus 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 bacteriaCitrobacter koseriMoraxella catarrhalisMorganella morganiiNeisseria gonorrhoeaeProteus mirabilisProteus vulgarisSerratia marcescensProvidencia stuartiiProvidencia rettgeriSalmonella entericaAnaerobic bacteriaClostridium perfringensBacteroides distasonisPrevotella melaninogenica†These are not beta-lactamase producing bacteria and, therefore, are susceptible to piperacillin alone.

Susceptibility TestingFor specific information regarding susceptibility test interpretive criteria and associated test methods and quality control standards recognized by FDA for this drug, please see: https://www.fda.gov/STIC.

MutagenesisPiperacillin/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.

FertilityReproduction 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/m


2).

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)] .

DiarrheaAdvise 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 ResistanceCounsel 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.Counsel patients that piperacillin and tazobactam for injection can cross the placenta in humans and is excreted in human milk.

Manufactured by:Shandong Anxin Pharmaceutical Co., Ltd.


Dongjia Town, Licheng District, Jinan, Shandong, 250105, ChinaFor BluePoint LaboratoriesCLINITEST


® is a registered trademark of Siemens Healthcare Diagnostics Inc.


Code number: 34050020511ARevised: 07/2021

2.7 Compatibility With Aminoglycosides

Due to the


in vitro inactivation of aminoglycosides by piperacillin, piperacillin and tazobactam for injection, USP and aminoglycosides are recommended for separate administration. Piperacillin and tazobactam for injection, USP and aminoglycosides should be reconstituted, diluted, and administered separately when concomitant therapy with aminoglycosides is indicated


[see


Drug Interactions (7.1)].


In circumstances where co-administration via Y-site is necessary, piperacillin and tazobactam for injection is compatible for simultaneous co-administration via Y-site infusion only with the following aminoglycosides under the following conditions:Table 3: Compatibility with AminoglycosidesAminoglycosidePiperacillin and Tazobactam for Injection Dose (grams)Piperacillin and Tazobactam for Injection Diluent VolumeDiluent volumes apply only to single vials(mL)Aminoglycoside Concentration RangeThe concentration ranges in Table 3 are based on administration of the aminoglycoside in divided doses (10-15 mg/kg/day in two daily doses for amikacin and 3-5 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.(mg/mL)Acceptable DiluentsAmikacin2.25


3.375


4.5


50


100


150


1.75 - 7.50.9% sodium chloride or 5% dextroseGentamicin2.25


3.375


4.5


50


100


150


0.7 - 3.320.9% sodium chloride or 5% dextroseOnly the concentration and diluents for amikacin or gentamicin with the dosages of piperacillin and tazobactam for injection, USP listed above have been established as compatible for co-administration via Y-site infusion. Simultaneous co-administration via Y-site infusion in any manner other than listed above may result in inactivation of the aminoglycoside by piperacillin and tazobactam for injection, USP.Piperacillin and tazobactam for injection, USP is not compatible with tobramycin for simultaneous co-administration via Y-site infusion. Compatibility of piperacillin and tazobactam for injection, USP 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 a white to off-white powder in vials:2.25 g single-dose vial (piperacillin sodium equivalent to 2 grams of piperacillin and tazobactam sodium equivalent to 0.25 g of tazobactam).
  • 3.375 g single-dose vial (piperacillin sodium equivalent to 3 grams of piperacillin and tazobactam sodium equivalent to 0.375 g of tazobactam).
  • 4.5 g single-dose vial (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 beta-lactamase inhibitors.

5.1 Hypersensitivity Adverse Reactions

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

5.2 Severe Cutaneous Adverse Reactions

Piperacillin and tazobactam for injection may cause severe cutaneous adverse reactions, such as Stevens-Johnson syndrome, toxic epidermal necrolysis, drug reaction with eosinophilia and systemic symptoms, and acute generalized exanthematous pustulosis. If patients develop a skin rash they should be monitored closely and piperacillin and tazobactam for injection discontinued if lesions progress.

5.3 Hematologic Adverse Reactions

Bleeding manifestations have occurred in some patients receiving beta-lactam drugs, including piperacillin. These reactions have sometimes been associated with abnormalities of coagulation tests such as clotting time, platelet aggregation and prothrombin time, and are more likely to occur in patients with renal failure. If bleeding manifestations occur, piperacillin and tazobactam for injection should be discontinued and appropriate therapy instituted.The leukopenia/neutropenia associated with piperacillin and tazobactam for injection administration appears to be reversible and most frequently associated with prolonged administration.Periodic assessment of hematopoietic function should be performed, especially with prolonged therapy, i.e., ≥ 21 days


[see


Adverse Reactions (6.1)]


.

5.4 Central Nervous System Adverse Reactions

As with other penicillins, piperacillin and tazobactam for injection may cause neuromuscular excitability or seizures. Patients receiving higher doses, especially patients with renal impairment may be at greater risk for central nervous system adverse reactions. Closely monitor patients with renal impairment or seizure disorders for signs and symptoms of neuromuscular excitability or seizures


[see Adverse Reactions (6.2)]

.

5.5 Nephrotoxicity In Critically Ill Patients

The use of piperacillin and tazobactam for injection was found to be an independent risk factor for renal failure and was associated with delayed recovery of renal function as compared to other beta-lactam antibacterial drugs in a randomized, multicenter, controlled trial in critically ill patients


[see


Adverse Reactions (6.1)]. Based on this study, alternative treatment options should be considered in the critically ill population. If alternative treatment options are inadequate or unavailable, monitor renal function during treatment with piperacillin and tazobactam for injection


[see


Dosage and Administration (2.3)].


Combined use of piperacillin/tazobactam and vancomycin may be associated with an increased incidence of acute kidney injury


[see


Drug Interactions (7.3)].

5.6 Electrolyte Effects

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


+ (sodium) per gram of piperacillin in the combination product. This should be considered when treating patients requiring restricted salt intake. Periodic electrolyte determinations should be performed in patients with low potassium reserves, and the possibility of hypokalemia should be kept in mind with patients who have potentially low potassium reserves and who are receiving cytotoxic therapy or diuretics.

5.7 Clostridioides Difficile-Associated Diarrhea

Clostridioides difficile-associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including piperacillin and tazobactam for injection, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of


C. difficile.


C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin producing strains of


C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibacterial drug use. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents.


If CDAD is suspected or confirmed, ongoing antibacterial drug use not directed against


C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibacterial treatment of


C. difficile, and surgical evaluation should be instituted as clinically indicated.

5.8 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.

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.Clinical Trials in Adult PatientsDuring 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 4: Adverse Reactions from Piperacillin and Tazobactam for Injection Monotherapy Clinical TrialsSystem Organ Class  Adverse Reaction


Gastrointestinal disorders  Diarrhea (11.3%)


  Constipation (7.7%)


  Nausea (6.9%)


  Vomiting (3.3%)


  Dyspepsia (3.3%)


  Abdominal pain (1.3%)


General disorders and administration site conditions  Fever (2.4%)


  Injection site reaction (≤1%)


  Rigors (≤1%)


Immune system disorders  Anaphylaxis (≤1%)


Infections and infestations  Candidiasis (1.6%)


  Pseudomembranous colitis (≤1%)


Metabolism and nutrition disorders  Hypoglycemia (≤1%)


Musculoskeletal and connective tissue disorders  Myalgia(≤1%)


  Arthralgia (≤1%)


Nervous system disorders  Headache (7.7%)


Psychiatric disorders  Insomnia (6.6%)


Skin and subcutaneous tissue disorders  Rash (4.2%, including maculopapular, bullous, and urticarial)


  Pruritus (3.1%)


  Purpura (≤1%)


Vascular disorders  Phlebitis (1.3%)


  Thrombophlebitis (≤1%)


  Hypotension (≤1%)


  Flushing (≤1%)


Respiratory, thoracic and mediastinal disorders  Epistaxis (≤1%)

6.2 Postmarketing Experience

In addition to the adverse drug reactions identified in clinical trials in Table 4 and Table 5, the following adverse reactions have been identified during post-approval 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 a causal relationship to drug exposure.Hepatobiliary—hepatitis, jaundice


Hematologic—hemolytic anemia, agranulocytosis, pancytopenia


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


Renal—interstitial nephritis


Nervous system disorders—seizures


Psychiatric disorders-delirium


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


Postmarketing experience with piperacillin and tazobactam for injection in pediatric patients suggests a similar safety profile to that seen in adults.

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 (7.5)]


.

7.1 Aminoglycosides

Piperacillin may inactivate aminoglycosides by converting them to microbiologically inert amides.

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 Vancomycin

Studies have detected an increased incidence of acute kidney injury in patients concomitantly administered piperacillin/tazobactam and vancomycin as compared to vancomycin alone


[see


Warnings and Precautions (5.5)]


.


Monitor kidney function in patients concomitantly administered with piperacillin/tazobactam and vancomycin.No pharmacokinetic interactions have been noted between piperacillin/tazobactam and vancomycin.

7.4 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)]


.

7.5 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).

7.6 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.

7.7 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.

8.4 Pediatric Use

The safety and effectiveness of piperacillin and tazobactam for injection for intra-abdominal infections, and nosocomial pneumonia have been established in pediatric patients 2 months of age and older.Use of piperacillin and tazobactam for injection in pediatric patients 2 months of age and older with intra-abdominal infections including 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 intra-abdominal infections (including appendicitis and/or peritonitis), in which 273 pediatric patients received piperacillin/tazobactam.


[see


Adverse Reactions (6.1) and


Clinical Pharmacology (12.3)]


.


Use of piperacillin and tazobactam for injection in pediatric patients 2 months of age and older with nosocomial pneumonia is supported by evidence from well-controlled studies in adults with nosocomial pneumonia, a simulation study performed with a population pharmacokinetic model, and a retrospective, cohort study of pediatric patients with nosocomial pneumonia in which 140 pediatric patients were treated with piperacillin and tazobactam for injection and 267 patients treated with comparators (which included ticarcillin-clavulanate, carbapenems, ceftazidime, cefepime, or ciprofloxacin)


[see


Adverse Reactions (6.1) and


Clinical Pharmacology (12.3)].


The safety and effectiveness of piperacillin and tazobactam for injection have not been established in pediatric patients less than 2 months of age


[see


Clinical Pharmacology (12) and


Dosage and Administration (2)]


.


Dosage of piperacillin and tazobactam for injection in pediatric patients with renal impairment has not been determined.

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 seizures 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)]


.

11 Description

  • Piperacillin and tazobactam for injection, USP are injectable antibacterial combination products consisting of the semisynthetic antibacterial piperacillin sodium and the beta-lactamase inhibitor tazobactam sodium for intravenous administration.Piperacillin sodium is derived from D(-)-α-aminobenzyl-penicillin. The chemical name of piperacillin sodium is sodium (2
  • S,5
  • R,6
  • R)-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 C
  • 23H
  • 26N
  • 5NaO
  • 7S 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 (2
  • S,3
  • S,5
  • R)-3-methyl-7-oxo-3-(1
  • H-1,2,3-triazol-1-ylmethyl)-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate-4,4-dioxide. The chemical formula is C
  • 10H
  • 11N
  • 4NaO
  • 5S and the molecular weight is 322.3. The chemical structure of tazobactam sodium is:
  • Piperacillin and tazobactam for injection, USP is a white to off-white sterile, cryodesiccated powder consisting of piperacillin and tazobactam as their sodium salts packaged in glass vials. The product does not contain excipients or preservatives.Each piperacillin and tazobactam for injection, USP 2.25 g single dose 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 single dose 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 single dose 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.

12.1 Mechanism Of Action

Piperacillin and tazobactam for injection, USP is an antibacterial drug


[see


Microbiology (12.4)]


.

12.2 Pharmacodynamics

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

12.3 Pharmacokinetics

The mean and coefficients of variation (CV%) for the pharmacokinetic parameters of piperacillin and tazobactam after multiple intravenous doses are summarized in Table 7.Table 7: Mean (CV%) Piperacillin and Tazobactam PK ParametersC


max : maximum observed concentration, AUC: Area under the curve, CL=clearance, CL


R= Renal clearance


V=volume of distribution, T


1/2 = elimination half-life


PiperacillinPiperacillin/Tazobactam Dose


Piperacillin and tazobactam were given in combination, infused over 30 minutes.C


max(mcg/mL)


AUC


Numbers in [] parentheses are coefficients of variation [CV%].(mcg∙h/mL)


CL


(mL/min)


V


(L)


T


1/2 (h)


CL


R(mL/min)


2.25 g134131 [14]25717.40.79--3.375 g242242 [10]20715.10.841404.5 g298322 [16]21015.40.84--TazobactamPiperacillin/Tazobactam Dose


C


max(mcg/mL)


AUC


(mcg∙h/mL)


CL


(mL/min)


V


(L)


T


1/2 (h)


CL


R(mL/min)


2.25 g1516.0 [21]25817.00.77--3.375 g2425.0 [8]25114.80.681664.5 g3439.8 [15]20614.70.82--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.

Drug Interactions

Drug InteractionsThe 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)]


.

Mechanism Of Action

Mechanism of ActionPiperacillin 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 beta-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 beta-lactamases at tazobactam concentrations achieved with the recommended dosage regimen.

13.1 Carcinogenesis, Mutagenesis, Impairment Of Fertility

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

15 References

  • Jensen J-US, Hein L, Lundgren B, et al. BMJ Open 2012; 2:e000635. doi:10.1136.

16 How Supplied/Storage And Handling

  • Piperacillin and tazobactam for injection, USP are supplied as single-dose vials in the following sizes:Each piperacillin and tazobactam for injection, USP 2.25 g vial provides 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. Single dose vial – NDC 68001-506-28, supplied 10 per box - NDC 68001-506-30
  • Each piperacillin and tazobactam for injection, USP 3.375 g vial provides 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. Single dose vial – NDC 68001-507-53, supplied 10 per box - NDC 68001-507-82
  • Each piperacillin and tazobactam for injection, USP 4.5 g vial provides 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. Single dose vial – NDC 68001-508-29, supplied 10 per box - NDC 68001-508-31
  • Piperacillin and tazobactam for injection, USP vials should be stored at controlled room temperature (20°C to 25°C [68°F to 77°F]) prior to reconstitution.

* Please review the disclaimer below.