Zosyn in an injectable antibacterial combination product consisting of the semisynthetic antibiotic piperacillin sodium and the (beta)-lactamase inhibitor tazobactam sodium for intravenous administration.

Piperacillin sodium is derived from D(-)-(alpha)-aminobenzylpenicillin. 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 ₂₃ H ₂₆ N ₅ NaO ₇ S and the molecular weight is 539.6.

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 ₁₀ H ₁₁ N ₄ NaO ₅ S and the molecular weight is 322.3.

Zosyn, piperacillin/tazobactam parenteral combination, 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 Zosyn 2.25 g single dose vial or ADD-Vantage® vial contains an amount of drug sufficient for withdrawal of piperacillin sodium equivalent to 2 grams of piperacillin and tazobactam sodium equivalent to 0.25 g of tazobactam.

Each Zosyn 3.375 g single dose vial or ADD-Vantage® vial contains an amount of drug sufficient for withdrawal of piperacillin sodium equivalent to 3 grams of piperacillin and tazobactam sodium equivalent to 0.375 g of tazobactam.

Each Zosyn 4.5 g single dose vial or ADD-Vantage® vial contains an amount of drug sufficient for withdrawal of piperacillin sodium equivalent to 4 grams of piperacillin and tazobactam sodium equivalent to 0.5 g of tazobactam.

Zosyn is a monosodium salt of piperacillin and a monosodium salt of tazobactam containing a total of 2.35 mEq (54 mg) of Na+ per gram of piperacillin in the combination product.

Peak plasma concentrations of piperacillin and tazobactam are attained immediately after completion of an intravenous infusion of Zosyn. Piperacillin plasma concentrations, following a 30-minute infusion of Zosyn, were similar to those attained when equivalent doses of piperacillin were administered alone, with mean peak plasma concentrations of approximately 134, 242 and 298 µg/mL for the 2.25 g, 3.375 g and 4.5 g Zosyn (piperacillin/tazobactam) doses, respectively. The corresponding mean peak plasma concentrations of tazobactam were 15, 24, and 34 µg/mL, respectively.

Following a 30-minute I.V. infusion of 3.375 g Zosyn every 6 hours, steady-state plasma concentrations of piperacillin and tazobactam were similar to those attained after the first dose. In like manner, steady-state plasma concentrations were not different from those attained after the first dose when 2.25 g or 4.5 g doses of Zosyn were administered via 30-minute infusions every 6 hours. Steady-state plasma concentrations after 30-minute infusions every 6 hours are provided in Table 1.

Following single or multiple Zosyn 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.

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 Zosyn are recommended when creatinine clearance is below 40 mL/min in patients receiving the usual recommended daily dose ofZosyn. (See DOSAGE AND ADMINISTRATION section 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 AND ADMINISTRATION section

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 Zosyn due to hepatic cirrhosis.

Microbiology

Piperacillin sodium exerts bactericidal activity by inhibiting septum formation and cell wall synthesis. In vitro , piperacillin is active against a variety of gram-positive and gram-negative aerobic and anaerobic bacteria. Tazobactam sodium has very little intrinsic microbiologic activity due to its very low level binding to penicillin-binding proteins; however, it is a (beta)-lactamase inhibitor of the 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 levels achieved with the recommended dosage regimen. Piperacillin/tazobactam has been shown to be active against most strains of the following piperacillin-resistant, (beta)-lactamase producing microorganisms both in vitro and in clinical infections as described in the section

Gram-positive aerobes:

Staphylococcus aureus (NOT methicillin/oxacillin-resistant strains)

Gram-negative aerobes:

Escherichia coli

Haemophilus influenzae (NOT (beta)-lactamase negative, ampicillin-resistant strains)

Gram-negative anaerobes:

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

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

Piperacillin/tazobactam exhibits in vitro minimum inhibitory concentrations (MICs) of 16.0 µg/mL or less against most (>/=90%) strains of Enterobacteriaceae , MICs of 1.0 µg/mL or less against most (>/=90%) strains of Haemophilus species, MICs of 8.0 µg/mL or less against most (>/=90%) strains of Staphylococcus species, and MICs of 16.0 µg/mL or less against most (>/=90%) strains of Bacteroides species. Beta-lactamase negative strains should be tested against piperacillin alone; piperacillin break points should be used in evaluation of these results. However, the safey and efficacy of piperacillin/tazobactam in treating clinical infections due to these microorganisms have not been established in adequate and well-controlled clinical trials.

Gram-positive aerobes:

Enterococcus faecalis (piperacillin susceptible)

Staphylococcus epidermidis (NOT methicillin/oxacillin-resistant strains)

Streptococcus agalactiae **

Streptococcus pneumoniae **

Streptococcus pyogenes **

Viridans group streptococci**

Gram-negative aerobes:

Klebsiella oxytoca

Klebsiella pneumoniae

Moraxella catarrhalis

Morganella morganii

Neisseria gonorrhoeae

Neisseria meningitidis**

Proteus mirabilis

Proteus vulgaris

Pseudomonas aeruginosa (piperacillin susceptible)

Serratia marcescens

Gram-positive anaerobes:

Clostridium perfringens

Gram-negative anaerobes:

Bacteroides distasonis

Fusobacterium nucleatum

Prevotella melaninogenica (formerly Bacteroides melaninogenicus)

** These are not (beta)-lactamase producing strains and, therefore, are susceptible to piperacillin alone.

Susceptibility Tests

Dilution Techniques

Quantitative methods are used to determine minimum inhibitory concentrations (MICs). These MICs provide estimates of the susceptibility of bacteria to antimicrobial compounds. The MICs should be determined using a standardized procedure. Standardized procedures are based on a dilution method (broth or agar) or equivalent with standardized inoculum concentrations and standardized concentrations of piperacillin and tazobactam powders. ¹ 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 the following criteria:

A report of "Susceptible" indicates that the pathogen is likely to be inhibited if the antimicrobial compound in the blood reaches the concentrations usually achievable. A report of "Intermediate" indicates that the result should be considered equivocal, and, if the microorganism is not fully susceptible to alternative, clinically feasible drugs, the test should be repeated. This category implies possible clinical applicability in body sites where the drug is physiologically concentrated or in situations where high dosage of drug can be used. This category also provides a buffer zone which prevents small uncontrolled technical factors from causing major discrepancies in interpretation. A report of "Resistant" indicates that the pathogen is not likely to be inhibited if the antimicrobial compound in the blood reaches the concentrations usually achievable; other therapy should be selected.

Standardized susceptibility test procedures require the use of laboratory control microorganisms to control the technical aspects of the laboratory procedures.

Laboratory control microorganisms are specific strains of microbiological assay organisms with intrinsic biological properties relating to resistance mechanisms and their genetic expression within bacteria; the specific strains are not clinically significant in their current microbiological status. Standard piperacillin and tazobactam powders should provide the following MIC values when tested against the designated quality control strains:

Anaerobic Techniques

For anaerobic bacteria, the susceptibility to piperacillin/tazobactam can be determined by the reference agar dilution method or by alternate standardized test methods. ²

For Bacteroides species, the dilution values should be interpreted as follows:

Serial dilutions of piperacillin combined with a fixed concentration of 4 µg/mL tazobactam should provide the following MIC values:

Diffusion Techniques

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. ³ 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. Interpretation is identical to that stated above for results using dilution techniques.

Reports from the laboratory providing results of the standard single-disk-susceptibility test with a 100/10-µg piperacillin/tazobactam disk should be interpreted according to the following criteria:

As with standardized dilution techniques, diffusion methods require the use of laboratory control microorganisms to control the technical aspects of the laboratory procedures. Laboratory control microorganisms are specific strains of microbiological assay organisms with intrinsic biological properties relating to resistance mechanisms and their genetic expression within bacteria; the specific strains are not clinically significant in their current microbiological status. For the diffusion technique, the 100/10-µg piperacillin/tazobactam disk should provide the following zone diameters in these laboratory test quality control strains:

Zosyn is indicated for the treatment of patients with moderate to severe infections caused by piperacillin-resistant, piperacillin/tazobactam-susceptible, (beta)-lactamase producing strains of the designated microorganisms in the specified conditions listed below:

Appendicitis (complicated by rupture or abscess) and peritonitis caused by piperacillin-resistant, (beta)-lactamase producing strains of Escherichia coli or the following members of the Bacteroides fragilis group B. fragilis , B. ovatus , B. thetaiotamicron , or B. vulgatus . The individual members of this group were studied in less than 10 cases.

Uncomplicated and complicated skin and skin structure infections, including cellulitis, cutaneous abscesses and ischemic/diabetic foot infections caused by piperacillin-resistant, (beta)-lactamase producing strains of Staphylococcus aureus.

Postpartum endometritis or pelvic inflammatory disease caused by piperacillin-resistant, (beta)-lactamase producing strains of Escherichia coli.

Community-acquired pneumonia (moderate severity only) caused by piperacillin-resistant, (beta)-lactamase producing strains of Haemophilius influenzae.

Nosocomial pneumonia (moderate to severe) caused by piperacillin-resistant, (beta)-lactamase producing strains of Staphylococcus aureus. (See DOSAGE AND ADMINISTRATION .)

As a combination product, Zosyn is indicated only for the specified conditions listed above. Infections caused by piperacillin-susceptible organisms, for which piperacillin has been shown to be effective, are also amenable to Zosyn treatment due to its piperacillin content. The tazobactam component of this combination product does not decrease the activity of the piperacillin component against piperacillin-susceptible organisms. Therefore, the treatment of mixed infections caused by piperacillin-susceptible organisms and piperacillin-resistant, (beta)-lactamase producing organisms susceptible to Zosyn should not require the addition of another antibiotic. (See DOSAGE AND ADMINISTRATION .)

Zosyn is useful as presumptive therapy in the indicated conditions prior to the identification of causative organisms because of its broad spectrum of bactericidal activity against gram-positive and gram-negative aerobic and anaerobic organisms.

Appropriate cultures should usually be performed before initiating antimicrobial treatment in order to isolate and identify the organisms causing infection and to determine their susceptibility to Zosyn. Antimicrobial therapy should be adjusted, if appropriate, once the results of culture(s) and antimicrobial testing are known.

CONTRAINDICATIONS

Zosyn is contraindicated in patients with a history of allergic reactions to any of the penicillins, cephalosporins, or (beta)-lactamase inhibitors.

SERIOUS AND OCCASIONALLY FATAL HYPERSENSITIVITY (ANAPHYLACTIC) REACTIONS HAVE BEEN REPORTED IN PATIENTS ON PENICILLIN THERAPY. THESE REACTIONS ARE MORE LIKELY TO OCCUR IN INDIVIDUALS WITH A HISTORY OF PENICILLIN HYPERSENSITIVITY OR A HISTORY OF SENSITIVITY TO MULTIPLE ALLERGENS. THERE HAVE BEEN REPORTS OF INDIVIDUALS WITH A HISTORY OF PENICILLIN HYPERSENSITIVITY WHO HAVE EXPERIENCED SEVERE REACTIONS WHEN TREATED WITH CEPHALOSPORINS. BEFORE INITIATING THERAPY WITH ZOSYN, CAREFUL INQUIRY SHOULD BE MADE CONCERNING PREVIOUS HYPERSENSITIVITY REACTIONS TO PENICILLINS, CEPHALOSPORINS, OR OTHER ALLERGENS. IF AN ALLERGIC REACTION OCCURS, ZOSYN SHOULD BE DISCONTINUED AND APPROPRIATE THERAPY INSTITUTED. SERIOUS ANAPHYLACTIC REACTIONS REQUIRE IMMEDIATE EMERGENCY TREATMENT WITH EPINEPHRINE. 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 in severity from mild to life-threatening. Therefore, it is important to consider this diagnosis in patients who present with diarrhea subsequent to the administration of antibacterial agents.

Treatment with antibacterial agents alters the 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, 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 clinically effective against Clostridium difficile colitis

PRECAUTIONS

General

Bleeding manifestations have occurred in some patients receiving (beta)-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, Zosyn 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).

Zosyn is a monosodium salt of piperacillin and a monosodium salt of tazobactam and contains a total of 2.35 mEq (54 mg) of Na ⁺ per gram of piperacillin in the combination product. This should be considered when treating patients requiring restricted salt intake. Periodic electrolyte determinations should be performed in patients with low potassium reserves, and the possibility of hypokalemia should be kept in mind with patients who have potentially low potassium reserves and who are receiving cytotoxic therapy or diuretics.

As with other semisynthetic penicillins, piperacillin therapy has been associated with an increased incidence of fever and rash in cystic fibrosis patients.

Laboratory Tests

Periodic assessment of hematopoietic function should be performed, especially with prolonged therapy, i.e., >/=21 days. (See ADVERSE REACTIONS , Adverse Laboratory Events .)

Drug Interactions

Aminoglycosides

The mixing of Zosyn with an aminoglycoside in vitro can result in substantial inactivation of the aminoglycoside. (See DOSAGE AND ADMINISTRATION -- Compatible Intravenous Diluent Solutions .)

When Zosyn was co-administered with tobramycin, the area under the curve, renal clearance and urinary recovery of tobramycin were decreased by 11%, 32% and 38%, respectively. The alterations in the pharmacokinetics of tobramycin when administered in combination with piperacillin/tazobactam may be due to in vivo and in vitro inactivation of tobramycin in the presence of piperacillin/tazobactam. 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. In patients with severe renal dysfunction (i.e., chronic hemodialysis patients), the pharmacokinetics of tobramycin are significantly altered when tobramycin is administered in combination with piperacillin. ⁴ The alteration of tobramycin pharmacokinetics and the potential toxicity of the penicillin-aminoglycoside complexes in patients with mild to moderate renal dysfunction who are administered an aminoglycoside in combination with piperacillin/tazobactam are unknown.

Probenecid

Probenecid administered concomitantly with Zosyn prolongs the half-life of piperacillin by 21% and that of tazobactam by 71%.

Vancomycin

No pharmacokinetic interactions have been noted between Zosyn 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. Zosyn (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.)

Drug/Laboratory Test Interactions

As with other penicillins, the administration of Zosyn 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.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Long term carcinogenicity studies in animals have not been conducted with piperacillin/tazobactam, piperacillin, or 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/m ² ).

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/m ² ). 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/m ² ). 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/m ² ), 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 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/m ² ).

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/m ² ).

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/m ² ).

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/m ² ).

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/m ² ).

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/m ² ). 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 Zosyn is administered to a nursing woman.

Pediatric Use

Safety and efficacy in pediatric patients have not been established.

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 insufficiency. (See DOSAGE AND ADMINISTRATION .)

ADVERSE REACTIONS

During the initial clinical investigations, 2621 patients worldwide were treated with Zosyn in phase 3 trials. In the key North American 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, Zosyn was discontinued because of adverse events primarily involving the skin (1.3%), including rash and pruritis; the gastrointestinal system (0.9%), including diarrhea, nausea, and vomiting; and allergic reactions (0.5%).

Adverse local reactions that were reported, irrespective of relationship to therapy with Zosyn, were phlebitis (1.3%), injection site reaction (0.5%), pain (0.2%), inflammation (0.2%), thrombophlebitis (0.2%), and edema (0.1%).

In the completed study of nosocomial lower respiratory tract infections, 155 patients were treated with Zosyn in a dosing regimen of 3.375 g every 4 hours in combination with an aminoglycoside. In this trial, 88.5% of the adverse experiences reported were mild to moderate in severity and transient in nature. However, in this trial, therapy with Zosyn was discontinued in four patients (2.6%) due to adverse experiences.

Irrespective of drug relationship or degree of severity, the adverse experiences which led to the discontinuation ofZosyn in these four patients were: thrombocytopenia and pancreatitis in one patient; fever in one patient; fever and eosinophilia in another patient; and diarrhea and elevated liver enzymes in the fourth patient.

Adverse Clinical Events

Based on patients from the North American trials (n=1063), the events with the highest incidence in patients, irrespective of relationship to Zosyn therapy, were diarrhea (11.3%); headache (7.7%); constipation (7.7%); nausea (6.9%); insomnia (6.6%); rash (4.2%), including maculopapular, bullous, urticarial, and eczematoid; vomiting (3.3%); dyspepsia (3.3%); pruritis (3.1%); stool changes (2.4%); fever (2.4%); agitation (2.1%); pain (1.7%); moniliasis (1.6%); hypertension (1.6%); dizziness (1.4%); abdominal pain (1.3%); chest pain (1.3%); edema (1.2%); anxiety (1.2%); rhinitis (1.2%); and dyspnea (1.1%).

Based on patients in the completed study of nosocomial lower respiratory tract infections (n=155), using every 4 hour dosing and aminoglycoside therapy, the events with the highest incidence in patients, irrespective of relationship to Zosyn and aminoglycoside therapy were: diarrhea (20%); constipation (8.4%); agitation (7.1%); nausea (5.8%); headache (4.5%); insomnia (4.5%); oral thrush (3.9%); erythematous rash (3.9%); anxiety (3.2%); fever (3.2%); pain (3.2%); pruritis (3.2%); hiccough (2.6%); vomiting (2.6%); dyspepsia (1.9%); edema (1.9%); fluid overload (1.9%); stool changes (1.9%); anorexia (1.3%); cardiac arrest (1.3%); confusion (1.3%); diaphoresis (1.3%); duodenal ulcer (1.3%); flatulence (1.3%); hypertension (1.3%); hypotension (1.3%); inflammation at injection site (1.3%); pleural effusion (1.3%); pneumothorax (1.3%); rash, not otherwise specified (1.3%); supraventricular tachycardia (1.3%); thrombophlebitis (1.3%); and urinary incontinence (1.3%).

Additional adverse systemic clinical events reported in 1.0% or less of the patients in the initial North American trials and/or in the patients administered Zosyn 3.375 g every 4 hours plus an aminoglycoside in the study of nosocomial lower respiratory tract are listed below within each body system (bracketed events occurred only in the nosocomial pneumonia trial);

Autonomic nervous system-- hypotension, ileus, syncope

Body as a whole-- rigors, back pain, malaise, [asthenia, chest pain]

Cardiovascular tachycardia, including supraventricular and ventricular; bradycardia; arrhythmia, including atrial fibrillation, ventricular fibrillation, cardiac arrest, cardiac failure, circulatory failure, myocardial infarction, [angina]

Central nervous system-- tremor, convulsions, vertigo, [aggressive reaction (combative)]

Gastrointestinal melena, flatulence, hemorrhage, gastritis, hiccough, ulcerative stomatitis, [fecal incontinence, gastric ulcer, pancreatitis]

Pseudomembranous colitis was reported in one patient during the clinical trials. The onset of pseudomembranous colitis symptoms may occur during or after antibacterial treatment. (See .)

Hearing and Vestibular System-- tinnitus, [deafness, earache]

Hypersensitivity anaphylaxis

Metabolic and Nutritional-- symptomatic hypoglycemia, thirst, [gout, vitamin B ₁₂ deficiency anemia]

Musculoskeletal myalgia, arthralgia

Platelet, Bleeding, Clotting-- mesenteric embolism, purpura, epistaxis, pulmonary embolism, [ecchymosis, hemoptysis] (See PRECAUTIONS , General .)

Psychiatric confusion, hallucination, depression

Reproductive, Female-- leukorrhea, vaginitis, [perineal irritation/pain]

Reproductive, Male-- balanoposthitis

Respiratory pharyngitis, pulmonary edema, bronchospasm, coughing, [atelectasis, dyspnea, hypoxia]

Skin and Appendages-- genital pruritus, diaphoresis, [conjunctivitis, xerosis]

Special senses-- taste perversion

Urinary-- retention, dysuria, oliguria, hematuria, incontinence, [urinary tract infection with trichomonas, yeast in urine]

Vision photophobia

Vascular (extracardiac)-- flushing, [cerebrovascular accident]

Additional adverse events reported from worldwide marketing experience with Zosyn, occurring under circumstances where causal relationship to Zosyn is uncertain:

Gastrointestinal hepatitis, cholestatic jaundice

Hematologic-- hemolytic anemia

Renal-- rarely, interstitial nephritis

Skin and Appendages-- erythema multiforme and Stevens-Johnson syndrome, rarely reported

Adverse Laboratory Events (Seen During Clinical Trials)

Of the studies reported, including that of nosocomial lower respiratory tract infections in which a higher dose of Zosyn was used in combination with an aminoglycoside, changes in laboratory parameters, without regard to drug relationship include:

Hematologic-- decreases in hemoglobin and hematocrit, thrombocytopenia, increases in platelet count, eosinophilia, leukopenia, neutropenia. The leukopenia/neutropenia associated with Zosyn administration appears to be reversible and most frequently associated with prolonged administration, i.e., >/=21 days of therapy. 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

Urinalysis-- proteinuria, hematuria, pyuria

Additional laboratory events include abnormalities in electrolytes (i.e., increases and decreases in sodium, potassium, and calcium), hyperglycemia, decreases in total protein or albumin.

The following adverse reaction has also been reported for PIPRACIL® (sterile piperacillin sodium):

Skeletal prolonged muscle relaxation (See PRECAUTIONS , Drug Interactions .)

OVERDOSAGE

Information on overdosage of Zosyn in humans is not available.

Excessive serum levels of either piperacillin or tazobactam may be reduced by hemodialysis. (See .) No specific antidote is known. As with other penicillins, neuromuscular excitability or convulsions have occurred following large intravenous doses, primarily in patients with impaired renal function.

In the case of motor excitability or convulsions, general supportive measures, including administration of anticonvulsive agents (e.g., diazepam or barbiturates), may be considered.

DOSAGE AND ADMINISTRATION

Zosyn should be administered by intravenous infusion over 30 minutes

Normal Renal Function (Creatinine Clearance >/=90 mL/min)

The usual total dose of Zosyn for adults is 3.375 g every six hours totalling 13.5 g (12 g piperacillin sodium/1.5 g tazobactam sodium).

Initial presumptive treatment of patients with nosocomial pneumonia should start with Zosyn at a dosage of 3.375 g every four hours plus an aminoglycoside . Treatment with the aminoglycoside should be continued in patients from whom Pseudomonas aeruginosa is isolated. If Pseudomonas aeruginosa is not isolated, the aminoglycoside may be discontinued at the discretion of the treating physician. (See DOSAGE AND ADMINISTRATION .)

Renal Insufficiency

In patients with renal insufficiency (Creatinine Clearance <90 mL/min), the intravenous dose of Zosyn 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 Zosyn® for patients with renal insufficiency are as follows:

For patients on hemodialysis, irrespective of the condition under treatment, the maximum dose is 2.25 g Zosyn every eight hours. In addition, because hemodialysis removes 30% to 40% of a Zosyn dose in four hours, one additional dose of 0.75 g Zosyn should be administered following each dialysis period. For patients with renal failure, measurement of serum levels of piperacillin and tazobactam will provide additional guidance for adjusting dosage.

Duration of Therapy

The usual duration of Zosyn treatment is from seven to ten days. However, the recommended duration of Zosyn treatment of nosocomial pneumonia is seven to fourteen days. In all conditions, the duration of therapy should be guided by the severity of the infection and the patient' clinical and bacteriological progress.

Intravenous Administration

For conventional vials, reconstitute Zosyn per gram of piperacillin with 5 mL of a compatible reconstitution diluent from the list provided below. Shake well until dissolved. Single dose vials should be used immediately after reconstitution. Discard any unused portion after 24 hours if stored at room temperature (20° to 25° C [68° to 77° F]), or after 48 hours if stored at refrigerated temperature (2° to 8° C [36° to 46° F]).

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 Zosyn solution should be further diluted (recommended volume per dose of 50 mL to 150 mL) in a compatible intravenous diluent 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 Diluent 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 RINGERS SOLUTION IS NOT COMPATIBLE WITH ZOSYN .

When concomitant therapy with aminoglycosides is indicated, Zosyn and the aminoglycoside should be reconstituted and administered separately, due to the in vitro inactivation of the aminoglycoside by the penicillin. (See PRECAUTIONS , Drug Interactions.)

Zosyn can be used in ambulatory intravenous infusion pumps.

Stability of Zosyn Following Reconstitution

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

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. Zosyn contains no preservatives. Appropriate consideration of aseptic technique should be used.

Stability of Zosyn 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 Zosyn 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 ad-mixed 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.

HOW SUPPLIED

Zosyn® (sterile piperacillin sodium and tazobactam sodium) is supplied in the following sizes:

Each Zosyn 2.25 g vial provides piperacillin sodium equivalent to 2 grams of piperacillin and tazobactam sodium equivalent to 0.25 gram of tazobactam. Each vial contains 4.69 mEq (108 mg) of sodium.

Supplied 10 per box-NDC 0206-8452-16

Each Zosyn 3.375 g vial provides piperacillin sodium equivalent to 3 grams of piperacillin and tazobactam sodium equivalent to 0.375 gram of tazobactam. Each vial contains 7.04 mEq (162 mg) of sodium.

Supplied 10 per box-NDC 0206-8454-55

Each Zosyn 4.5 g vial provides piperacillin sodium equivalent to 4 grams of piperacillin and tazobactam sodium equivalent to 0.5 gram of tazobactam. Each vial contains 9.39 mEq (216 mg) of sodium.

Supplied 10 per box-NDC 0206-8455-25

Each Zosyn 2.25 g ADD-Vantage® vial provides piperacillin sodium equivalent to 2 grams of piperacillin and tazobactam sodium equivalent to 0.25 grams of tazobactam. Each ADD-Vantage® vial contains 4.69 mEq (108 mg) of sodium.

Supplied 10 per box--NDC 0206-8452-17.

Each Zosyn 3.375 g ADD-Vantage® vial provides piperacillin sodium equivalent to 3 grams of piperacillin and tazobactam sodium equivalent to 0.375 grams of tazobactam. Each ADD-Vantage® vial contains 7.04 mEq (162 mg) of sodium.

Supplied 10 per box--NDC 0206-8454-17.

Each Zosyn 4.5 g ADD-Vantage® vial provides piperacillin sodium equivalent to 4 grams of piperacillin and tazobactam sodium equivalent to 0.5 grams of tazobactam. Each ADD-Vantage® vial contains 9.39 mEq (216 mg) of sodium.

Supplied 10 per box--NDC 0206-8455-17.

Zosyn conventional and ADD-Vantage® vials should be stored at controlled room temperature (20° to 25°C [68° to 77°F]) prior to reconstitution.

Also Available

Zosyn is also supplied as follows:

Zosyn® (piperacillin sodium and tazobactam sodium injection) in Galaxy® Container (PL 2040 Plastic) is supplied as a frozen, iso-osmotic, sterile, nonpyrogenic solution in single-dose plastic containers as follows:

2.25 g (2 g piperacillin/0.25 g tazobactam) in 50 mL. Each container has 5.7 mEq (131 mg) of sodium.

Supplied 24/box--NDC 0206-8820-02

3.375 g (3 g piperacillin/0.375 g tazobactam) in 50 mL. Each container has 8.6 mEq (197 mg) of sodium.

Supplied 24/box--NDC 0206-8821-02

4.5 g (4 g piperacillin/0.5 g tazobactam) in 100 mL. Each container has 11.4 mEq (263 mg) of sodium.

Supplied 12/box--NDC 0206-8822-02

ALSO AVAILABLE

Zosyn is also supplied as follows:

40.5 g pharmacy bulk vial containing 36 grams of piperacillin and 4.5 grams of tazobactam. Each pharmacy bulk vial contains 84.5 mEq (1,944 mg) of sodium.

NDC 0206-8620-11

REFERENCES

1. National Committee for Clinical Laboratory Standards, Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria that Grow Aerobically -Fourth Edition. Approved Standard NCCLS Document M7-A4, Vol. 17, No. 2, NCCLS, Wayne, PA, January, 1997.
2. National Committee for Clinical Laboratory Standards, Methods for Antimicrobial Susceptibility Testing for Anaerobic Bacteria -Third Edition. Approved Standard NCCLS Document M11-A3, Vol. 13, No. 26, NCCLS, Villanova, PA, December, 1993.
3. National Committee for Clinical Laboratory Standards. Performance Standard for Antimicrobial Disk Susceptibility Tests -Sixth Edition. Approved Standard NCCLS Document M2-A6, Vol. 17, No. 1, NCCLS, Wayne, PA, January, 1997.
4. Halstenson CE, Hirata CAI, Heim-Duthoy KL, Abraham PA, and Matzke GR. Effect of concomitant administraton of piperacillin on the dispositions of netilmicin and tobramycin in patients with end-stage renal disease. Antimicrob Agents Chemother 34(1):128-133, 1990.

CLINITEST® and DIASTIX® are registered trademarks of Ames Division, Miles Laboratories, Inc.

TES-TAPE® is a registered trademark of Eli Lilly and Company.

Galaxy® is a registered trademark of Baxter International, Inc.

ADD-VANTAGE is a registered trademark of Abbott Laboratories

Manufactured by:

LEDERLE PIPERACILLIN, INC.

Carolina, Puerto Rico 00987

CI 4630-2  Revised March 25, 1999

PRODUCT PHOTO(S):