Tazilsun

Piperacillin, tazobactam.

This drug is a white or off-white friable solid or powder, odorless; having a bitter taste and strong hygroscopicity.
Each 4.5 g single dose vial contains piperacillin sodium equivalent to 4 g of piperacillin and tazobactam sodium equivalent to 500 mg of tazobactam.
The ratio of piperacillin to tazobactam is 8:1.
Piperacillin and tazobactam for injection is an injectable antibacterial combination product consisting of piperacillin sodium (C₂₃H₂₆N₅NaO₇S; 539.5) and tazobactam sodium (C₁₀H₁₁N₄NaO₅S; 322.3).
Excipients/Inactive Ingredients: The excipient is sodium bicarbonate.

Pharmacology: Piperacillin, a broad spectrum, semisynthetic penicillin active against many gram-positive and gram-negative aerobic and anaerobic bacteria, exerts bactericidal activity by inhibition of both septum and cell wall synthesis. Tazobactam, a triazolylmethyl penicillanic acid sulphone, is a potent inhibitor of many β-lactamases, in particular the plasmid mediated enzymes which commonly cause resistance to penicillins and cephalosporins including third-generation cephalosporins. The presence of tazobactam in the piperacillin/tazobactam formulation enhances and extends the antibiotic spectrum of piperacillin to include many β-lactamase producing bacteria normally resistant to it and other β-lactam antibiotics. Thus, piperacillin/tazobactam combines the properties of a broad spectrum antibiotic and a β-lactamase inhibitor.
Pharmacokinetics: Adults: Peak plasma concentrations of piperacillin and tazobactam are attained immediately after completion of an intravenous infusion of this product (piperacillin and tazobactam for injection). Piperacillin plasma concentrations, following a 30-minute infusion of this product (piperacillin and tazobactam for injection), were similar to those attained when equivalent doses of piperacillin were administered alone, with mean peak plasma concentrations of approximately 134 μg/mL and 298 μg/mL for the 2.25 g and 4.5 g of this product (piperacillin and tazobactam for injection) doses, respectively. The corresponding mean peak plasma concentrations of tazobactam were 15 μg/mL and 34 μg/mL, respectively.
Following a 30-minute I.V. infusion of 2.25 g and 4.5 g of this product (piperacillin and tazobactam for injection) every 6 hours, steady-state plasma concentrations of piperacillin and tazobactam were similar to those attained after the first dose. Steady-state plasma concentrations after 30-minute infusions every 6 hours are provided in Table 1.
Following single or multiple doses of this product 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.
Piperacillin is metabolized to a minor microbiologically active desethyl metabolite. Tazobactam is metabolized to a single metabolite that lacks pharmacological and antibacterial activities. 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.
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.
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 this product are recommended when creatinine clearance is below 40 mL/min in patients receiving the usual recommended daily dose of this product. (See Dosage & Administration for specific recommendations for the treatment of patients with renal insufficiency.)
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 & Administration.
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 this product due to hepatic cirrhosis. (See Table 1.)

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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 2-9 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.
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 at concentrations up to 14.84/1.86 μg/plate. Piperacillin/tazobactam was negative in the unscheduled DNA synthesis (UDS) test at concentrations up to 5689/711 μg/mL. Piperacillin/tazobactam was negative in a mammalian point mutation (Chinese hamster ovary cell HPRT) assay at concentrations up to 8000/1000 μg/mL. Piperacillin/tazobactam was negative in a mammalian cell (BALB/c-3T3) transformation assay at concentrations up to 8/1 μg/mL. In vivo, piperacillin/tazobactam did not induce chromosomal aberrations in rats dosed I.V. with 1500/187.5 mg/kg; this dose is similar to the maximum recommended human daily dose on a body-surface-area basis (mg/m²).
Piperacillin: Piperacillin was negative in microbial mutagenicity assays at concentrations up to 50 μg/plate. There was no DNA damage in bacteria (Rec assay) exposed to piperacillin at concentrations up to 200 μg/disk. Piperacillin was negative in the UDS test at concentrations up to 10,000 μg/mL. In a mammalian point mutation (mouse lymphoma cells) assay, piperacillin was positive at concentrations ≥2500 μg/mL. Piperacillin was negative in a cell (BALB/c-3T3) transformation assay at concentrations up to 3000 μg/mL. In vivo, piperacillin did not induce chromosomal aberrations in mice at I.V. doses up to 2000 mg/kg/day or rats at I.V. doses up to 1500 mg/kg/day. These doses are half (mice) or similar (rats) to the maximum recommended human daily dose based on body surface area (mg/m²). In another in vivo test, there was no dominant lethal effect when piperacillin was administered to rats at I.V. doses up to 2000 mg/kg/day, which is similar to the maximum recommended human daily dose based on body surface area (mg/m²). When mice were administered piperacillin at I.V. doses up to 2000 mg/kg/day, which is half the maximum recommended human daily dose based on body surface area (mg/m²), urine from these animals was not mutagenic when tested in a microbial mutagenicity assay. Bacteria injected into the peritoneal cavity of mice administered piperacillin at I.V. doses up to 2000 mg/kg/day did not show increased mutation frequencies.
Tazobactam: Tazobactam was negative in microbial mutagenicity assays at concentrations up to 333 μg/plate. Tazobactam was negative in the UDS test at concentrations up to 2000 μg/mL. Tazobactam was negative in a mammalian point mutation (Chinese hamster ovary cell HPRT) assay at concentrations up to 5000 μg/mL. In another mammalian point mutation (mouse lymphoma cells) assay, tazobactam was positive at concentrations ≥3000 μg/mL. Tazobactam was negative in a cell (BALB/c-3T3) transformation assay at concentrations up to 900 μg/mL. In an in vitro cytogenetics (Chinese hamster lung cells) assay, tazobactam was negative at concentrations up to 3000 μg/mL. In vivo, tazobactam did not induce chromosomal aberrations in rats at I.V. doses up to 5000 mg/kg, which is 23 times the maximum recommended human daily dose based on body surface area (mg/m²).
Microbiology: Piperacillin/tazobactam is highly active against piperacillin-susceptible microorganisms as well as many β-lactamase producing, piperacillin-resistant microorganisms.
Gram-negative bacteria: β-lactamase producing and non-β-lactamase producing strains of Escherichia coli, Citrobacter spp. (including C. farmeri, C. braakii), Klebsiella spp. (including K. oxytoca, K. pneumoniae), Enterobacter spp. (including E. cloacae, E. aerogenes), Proteus vulgaris, Proteus mirabilis, Providencia rettgeri, Providencia stuartii, Plesiomonas shigelloides, Morganella morganii, Serratia spp. (including S. marcescens, S. liquefaciens), Salmonella spp., Shigella spp., Pseudomonas aeruginosa and other Pseudomonas spp. (including P. cepacia, P. fluorescens), Xanthomonas maltophilia, Neisseria gonorrhoeae, Neisseria meningitidis, Moraxella spp. (including M. catarrhalis), Acinetobacter spp., Haemophilus influenzae, Haemophilus parainfluenzae, Pasteurella multocida, Yersinia spp., Campylobacter spp., Gardnerella vaginalis. The in vitro studies have shown that piperacillin/tazobactam acts synergistically with aminoglycosides against multiple-resistant Pseudomonas aeruginosa.
Gram-positive bacteria: β-lactamase producing and non-β-lactamase producing strains of Streptococci (S. pneumoniae, S. pyogenes, S. bovis, S. agalactiae, Group C, Group G, S. viridans), Enterococci (E. faecalis, E. faecium), Staphylococcus aureus (not methicillin-resistant S. aureus), S. saprophyticus, S. epidermidis (coagulase-negative staphylococci), Corynebacteria, Listeria monocytogenes, Nocardia spp.
Anaerobic bacteria: β-lactamase producing and non-β-lactamase producing anaerobes such as Bacteroides spp. (including B. bivius, B. disiens, B. capillosus, B. melaninogenicus, B. oralis), Bacteroides fragilis group (including B. fragilis, B. vulgatus, B. distasonis, B. ovatus, B. thetaiotaomicron, B. uniformis, B. asaccharolyticus), as well as Peptostreptococcus spp., Fusobacterium spp., Eubacterium group, Clostridium spp. (including C. difficile, C. perfringens), Veillonella spp., and Actinomyces spp.
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. 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 2.
Diffusion Technique: Quantitative methods that require measurement of zone diameters also provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. One such standardized procedure, requires the use of standardized inoculum concentrations. This procedure uses paper disks impregnated with 100 μg of piperacillin and 10 μg of tazobactam to test the susceptibility of microorganisms to piperacillin/tazobactam. The disk diffusion interpreted criteria are provided in Table 3.
Anaerobic Techniques: For anaerobic bacteria, the susceptibility to piperacillin/tazobactam can be determined by the reference agar dilution method. (See Table 2.)

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Quality Control: Standardized susceptibility test procedures require the use of laboratory control microorganisms to control the technical aspects of the test procedures. Standard piperacillin/tazobactam powder should provide the following ranges of values noted in Table 3. Quality control microorganisms are specific strains of microorganisms 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. (See Table 3.)

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Piperacillin/tazobactam is indicated for the treatment of the following systemic and/or local bacterial infections in which susceptible organisms have been detected or are suspected: Lower respiratory tract infections; Urinary tract infections (complicated and uncomplicated); Intra-abdominal infections; Skin and skin structure infections; Bacterial septicaemia; Gynaecological infections; Bacterial infections in neutropenic patients in combination with an aminoglycoside; Bone and joint infections.
Polymicrobic infections: Piperacillin/tazobactam is indicated for polymicrobic infections including those where aerobic and anaerobic organisms are suspected (intra-abdominal, skin and skin structure, upper and lower respiratory tract, gynaecological).
While piperacillin/tazobactam is indicated only for the conditions listed previously, infections caused by piperacillin susceptible organisms are also amenable to piperacillin/tazobactam treatment due to its piperacillin content. Therefore, the treatment of mixed infections caused by piperacillin susceptible organisms and β-lactamase producing organisms susceptible to piperacillin/tazobactam should not require the addition of another antibiotic.
Appropriate culture and susceptibility tests should be performed before treatment in order to identify organisms causing infections and to determine their susceptibilities to piperacillin/tazobactam. Because of its broad-spectrum of activity against Gram-positive and Gram-negative aerobic and anaerobic organisms as listed previously, piperacillin/tazobactam is particularly useful in the treatment of mixed infections and in presumptive therapy prior to the availability of the results of susceptibility tests. Therapy with piperacillin/tazobactam may, however, be initiated before results of such tests are known. Modification of the treatment may be required once these results become available or if there is no clinical response.
In serious infections, presumptive therapy with piperacillin/tazobactam may be initiated before susceptibility test results are available.
Piperacillin/tazobactam acts synergistically with aminoglycosides against certain strains of Pseudomonas aeruginosa. Combined therapy has been successful, especially in patients with impaired host defences. Both drugs should be used in full therapeutic doses. As soon as results of culture and susceptibility tests become available, antimicrobial therapy should be adjusted.
In the treatment of bacterial infections in neutropenic patients, full therapeutic doses of piperacillin/tazobactam plus an aminoglycoside should be used. Periodical electrolyte determinations should be made in patients with low potassium reserves and the possibility of hypokalaemia should be kept in mind with patients who have potentially low potassium reserves.

Piperacillin/tazobactam may be given by slow intravenous infusion (over 20-30 minutes) or by slow intravenous injection (over at least 3-5 minutes). Piperacillin/tazobactam should be administered separately from any other antibiotic such as an aminoglycoside. The mixing of piperacillin/tazobactam with aminoglycosides in vitro can result in substantial inactivation of the aminoglycoside. Piperacillin/tazobactam and the aminoglycoside should be reconstituted, diluted, and administered separately when concomitant therapy with aminoglycosides is indicated (see Interactions).
Adults and children 12 years and older: The usual intravenous dosage for adults and children with normal renal function is 4 g piperacillin/0.5 g tazobactam given every eight hours. The total daily dose depends on the severity and localization of the infection and can vary from 2 g piperacillin/0.25 g tazobactam to 4 g piperacillin/0.5 g tazobactam administered every six, eight or twelve hours.
Duration of Therapy: The usual duration of piperacillin/tazobactam treatment is from seven to ten days. However, the recommended duration of piperacillin/tazobactam treatment of nosocomial pneumonia is 7 to 14 days. In all conditions, the duration of therapy should be guided by the severity of the infection and the patient's clinical and bacteriological progress.
Renal Insufficiency: In patients with renal insufficiency (Creatinine Clearance ≤40 mL/min), or patients on hemodialysis, the intravenous dose and dosing interval of this product (piperacillin and tazobactam for injection) should be adjusted to the degree of actual renal function impairment. In patients with nosocomial pneumonia receiving concomitant aminoglycoside therapy, the aminoglycoside dosage should be adjusted according to the recommendations of the manufacturer. The recommended daily doses of this product for patients with renal insufficiency are as follows: See Table 4.

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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/tazobactam should be administered following each dialysis period on hemodialysis days. No additional dosage of this product 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 dosage of this product 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 dosage of this product based on pharmacokinetic modeling, is 80 mg piperacillin/10 mg tazobactam per kilogram of body weight, every 8 hours (see Use in Children under Precautions and Pharmacology: Pharmacokinetics under Actions). Pediatric patients weighing over 40 kg and with normal renal function should receive the adult dose. There are no dosage recommendations for this product in pediatric patients with impaired renal function.

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).
Treatment should be supportive and symptomatic according to 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 piperacillin and tazobactam dose removed by hemodialysis was approximately 31% and 39%, respectively. (See Pharmacology under Actions.)

Hypersensitivity to any of the β-lactams (including penicillins and cephalosporins) or to β-lactamase inhibitors.

Before initiating therapy with piperacillin/tazobactam, careful inquiry should be made concerning previous hypersensitivity reactions to penicillins, cephalosporins, and other allergens. Serious and occasionally fatal hypersensitivity (anaphylactic/anaphylactoid [including shock]) reactions have been reported in patients receiving therapy with penicillins including piperacillin/tazobactam. These reactions are more likely to occur in persons with a history of sensitivity to multiple allergens. If an allergic reaction occurs, this drug should be discontinued and the appropriate therapy instituted. Serious anaphylactic/anaphylactoid reactions require immediate emergency treatment with adrenaline. Oxygen, intravenous steroids and airway management, including intubation, should also be administered as indicated.
Pseudomembranous colitis has been reported with nearly all antibacterial agents, including piperacillin/tazobactam, and may range from mild to life-threatening severe, persistent diarrhea. The onset of pseudomembranous colitis symptoms may occur during or after antibacterial treatment. Therefore, it it important to consider this diagnosis in patients who present with diarrhea subsequent to the administration of antibacterial agents.
Treatment with antibacterial agents alters normal flora of the colon and may permit overgrowth of Clostridia. Studies indicate that a toxin produced by Clostridium difficile is one primary cause of antibiotic-associated colitis.
After the diagnosis of pseudomembranous colitis has been established, appropriate therapeutic measures should be initiated. Mild cases of pseudomembranous colitis usually respond to drug discontinuation alone. In moderate to severe cases, consideration should be given to management with fluids and electrolytes, protein supplementation, and treatment with an antibacterial drug effective against Clostridium difficile.

Bleeding manifestations have occurred in some patients receiving β-lactam antibiotics, 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, antibiotic (piperacillin and tazobactam for injection) therapy should be discontinued and appropriate therapy instituted.
The possibility of the emergence of resistant organisms that might cause superinfections should be kept in mind. If this occurs, appropriate measures should be taken.
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).
This product contains a total of 64 mg (2.79 mEq) of Na⁺ per gram of piperacillin which may increase a patient's overall sodium intake. 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 or who are receiving concomitant medications that may lower potassium levels (cytotoxic therapy or diuretics).
As with other semisynthetic penicillins, piperacillin therapy has been associated with an increased incidence of fever and rash in cystic fibrosis patients.
In patients with creatinine clearance ≤40 mL/min and dialysis patients (hemodialysis and CAPD), the intravenous dose should be adjusted to the degree of renal function impairment. (See Dosage & Administration.)
Prescribing piperacillin and tazobactam in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of development of drug-resistant bacteria.
Leukopenia and neutropenia may occur, especially during prolonged therapy. Therefore, periodic assessment of hematopoietic function should be performed.
In patients with renal insufficiency and hemodialysis patients, the intravenous dose should be adjusted to the degree of renal function impairment.
Information for Patient: Patients should be counseled that antibacterial drugs including this drug should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When this drug 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 decrease the effectiveness of the immediate treatment and increase the likelihood that bacteria will develop resistance and will not be treatable by this drug or other antibacterial drugs in the future.
Laboratory Tests: Periodic assessment of hematopoietic function should be performed, especially with prolonged therapy, ie, ≥21 days. (See Adverse Reactions.)
Use in Children: Use of this product 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 2-12 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 Pharmacology: Pharmacokinetics under Actions and Dosage & Administration). There are no dosage recommendations for this product in pediatric patients with impaired renal function.
Use in the Elderly: 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 insufficiency. (See Dosage & Administration.)
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.
This drug contains 64 mg (2.79 mEq) of sodium per gram of piperacillin in the combination product. At the usual recommended doses, patients would receive between 768 and 1024 mg/day (33.5 and 44.6 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.

Pregnancy: Teratogenic effects: Pregnancy Category B.
Piperacillin/tazobactam: Reproduction studies have been performed in rats and have revealed no evidence of impaired fertility due to piperacillin/tazobactam administered up to a dose which is similar to the maximum recommended human daily dose based on body surface area (mg/m²). Studies in mice and rats have not demonstrated any embryotoxic or teratogenic effects of the piperacillin-tazobactam combination.
Teratology studies have been performed in mice and rats and have revealed no evidence of harm to the fetus due to piperacillin/tazobactam administered up to a dose 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. Pregnant women should be treated only if the expected benefit outweighs the possible risks to the pregnant woman and fetus.
Piperacillin: Reproduction and teratology studies have been performed in mice and rats and have revealed no evidence of impaired fertility or harm to the fetus due to piperacillin administered up to a dose which is half (mice) or similar (rats) to the maximum recommended human daily dose based on body surface area (mg/m²).
Tazobactam: Reproduction studies have been performed in rats and have revealed no evidence of impaired fertility due to tazobactam administered at doses up to 3 times the maximum recommended human daily dose based on body surface area (mg/m²).
Teratology studies have been performed in mice and rats and have revealed no evidence of harm to the fetus due to tazobactam administered at doses up to 6 and 14 times, respectively, the human dose based on body surface area (mg/m²).
In rats, tazobactam crosses the placenta. Concentrations in the fetus are less than or equal to 10% of those found in maternal plasma.
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 this drug (piperacillin and tazobactam for injection) is administered to a nursing woman. Women who are breast-feeding should be treated only if the expected benefit outweighs the possible risks to the nursing woman and child.

A classification of adverse reactions is based on CIOMS frequencies. (See Tables 5 and 6.)

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Piperacillin therapy has been associated with an increased incidence of fever and rash in cystic fibrosis patients.

Aminoglycosides: The mixing of β-lactam antibiotics with aminoglycosides in vitro can result in substantial inactivation of the aminoglycoside. However, amikacin and gentamicin have been shown to be compatible in vitro with reformulated piperacillin/tazobactam containing EDTA supplied in vials or bulk pharmacy containers in certain diluents at specific concentrations for a simultaneous Y-site infusion. Reformulated piperacillin/tazobactam containing EDTA is not compatible with tobramycin for simultaneous co-administration via Y-site infusion.
The inactivation of aminoglycosides in the presence of penicillin-class drugs has been recognized. It has been postulated that penicillin-aminoglycoside complexes form; these complexes are microbiologically inactive and of unknown toxicity. Sequential administration of this drug with tobramycin to patients with normal renal function and mild to moderate renal impairment has been shown to modestly decrease serum concentrations of tobramycin but does not significantly affect tobramycin pharmacokinetics. When aminoglycosides are administered in combination with piperacillin to patients with end-stage renal disease requiring hemodialysis, the concentrations of the aminoglycosides (especially tobramycin) may be significantly altered and should be monitored. Since aminoglycosides are not equally susceptible to inactivation by piperacillin, consideration should be given to the choice of the aminoglycoside when administered in combination with piperacillin to these patients.
Probenecid: Similar with other penicillins, concurrent administration of probenecid and piperacillin/tazobactam produced a longer half-life (piperacillin by 21%, tazobactam by 71%) and lower renal clearance for both piperacillin and tazobactam. However, peak plasma concentrations of either drug are unaffected.
Vancomycin: No pharmacokinetic interactions have been noted between this drug and vancomycin.
Heparin: 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.
Vecuronium: Piperacillin when used concomitantly with vecuronium has been implicated in the prolongation of the neuromuscular blockade of vecuronium. This product (piperacillin/tazobactam) 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. (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.
Drug/Laboratory Test Interactions: As with other penicillins, the administration of this product (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 (such as DIASTIX or TES-TAPE) be used.
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.

Directions for Reconstitution and Dilution for Use: Intravenous Administration: For conventional vials, reconstitute this drug per gram of piperacillin with 5 mL of a compatible reconstitution diluent from the list provided as follows. Reconstitute each vial with the volume of diluent shown in the following table, using one of the compatible diluents. Swirl until dissolved. (See Table 7.)

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The reconstituted solution should be used immediately. Discard any unused portion after 24 hours if stored at room temperature (20°C to 25°C), or after 48 hours if stored at refrigerated temperature (2°C to 8°C).
Compatible Reconstitution Diluents: 0.9% 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 solution should be further diluted (recommended volume per dose of 50 mL to 150 mL) in a compatible intravenous solution listed as follows. 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: 0.9% Sodium Chloride for Injection; Sterile Water for Injection**; Dextrose 5%; Dextran 6% in Saline.
** Maximum recommended volume per dose of Sterile Water for Injection is 50 mL.
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 sheet provided in the box. Lactated Ringer's Solution is compatible only with reformulated piperacillin/tazobactam containing EDTA.
Piperacillin/tazobactam should not be added to blood products or albumin hydrolysates.
Piperacillin/tazobactam should not be mixed with other drugs in a syringe or infusion bottle since compatibility has not been established.
Piperacillin/tazobactam is not chemically stable in solutions that contain only sodium bicarbonate.
Piperacillin/tazobactam can be used in ambulatory intravenous infusion pumps.
Stability of This Product Following Reconstitution: This product is stable in glass and plastic containers (plastic syringes, I.V. bags and tubing) when used with compatible diluents.
The reconstituted solution should be used immediately. Discard any unused portion after 24 hours if stored at room temperature (20°C to 25°C), or after 48 hours if stored at refrigerated temperature (2°C to 8°C). The vial 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. This product contains no preservatives. Appropriate consideration of aseptic technique should be used and 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 this product is not affected when administered using an ambulatory intravenous infusion pump. Stability studies with the admixed ADD-Vantage system have demonstrated chemical stability (potency, pH and clarity) through 24 hours at room temperature. (Note: The admixed ADD-Vantage should not be refrigerated or frozen after reconstitution.) Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

Store airtight in a dry place at room temperature (≤ 25°C) and protect from light.
Shelf-Life: 24 months.

Penicillins

J01CR05 - piperacillin and beta-lactamase inhibitor ; Belongs to the class of penicillin combinations, including beta-lactamase inhibitors. Used in the systemic treatment of infections.

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