Zosyn Drug Information

Important Administration Instructions If a dose of ZOSYN is required that does not equal 2.25 g, 3.375 g, or 4.5 g, ZOSYN injection in GALAXY Containers is not recommended for use and an alternative formulation of ZOSYN should be considered.

Dosage in Adult Patients With Indications Other Than Nosocomial Pneumonia The usual total daily dosage of ZOSYN for adult patients with indications other than nosocomial pneumonia is 3.375 g every six hours, to be administered by intravenous infusion over 30 minutes. The usual duration of ZOSYN treatment is from 7 to 10 days.

Dosage in Adult Patients With Nosocomial Pneumonia

Initial presumptive treatment of adult patients with nosocomial pneumonia should start with ZOSYN at a dosage of 4.5 g every six hours plus an aminoglycoside,, administered by intravenous infusion over 30 minutes. The recommended duration of ZOSYN treatment for nosocomial pneumonia is 7 to 14 days. Treatment with the aminoglycoside should be continued in patients from whom P. aeruginosa is isolated.

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 ZOSYN should be reduced based on the degree of renal impairment. The recommended daily dosage of ZOSYN for patients with renal impairment administered by intravenous infusion over 30 minutes is described in Table 1. Table 1: Recommended Dosage of ZOSYN in Patients with Normal Renal Function and Renal Impairment (As total grams piperacillin and tazobactam) Administer ZOSYN by intravenous infusion over 30 minutes.

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. No additional dosage of ZOSYN is necessary for CAPD patients.

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. Pediatric patients weighing over 40 kg and with normal renal function should receive the adult dose. Dosage of ZOSYN in pediatric patients with renal impairment has not been determined.

Directions for Use of ZOSYN Injection Important Administration Instructions for ZOSYN Injection in GALAXY Containers Administer ZOSYN Injection in GALAXY Containers using sterile equipment, after thawing to room temperature. ZOSYN containing EDTA is compatible for co-administration via a Y-site intravenous tube with Lactated Ringer's injection, USP. Do NOT add supplementary medication.

Unused portions of ZOSYN Injection should be discarded. Do NOT use plastic containers in series connections. Such use could result in air embolism due to residual air being drawn from the primary container before administration of the fluid from the secondary container is complete.

Handle frozen product containers with care. Product containers may be fragile in the frozen state. Thawing of Plastic Container Thaw frozen container at room temperature 20°C to 25°C or under refrigeration (2°C to 8°C ).

Do not force thaw by immersion in water baths or by microwave irradiation. Check for minute leaks by squeezing container firmly. If leaks are detected, discard solution as sterility may be impaired.

The container should be visually inspected. Components of the solution may precipitate in the frozen state and will dissolve upon reaching room temperature with little or no agitation. Potency is not affected.

Agitate after solution has reached room temperature. If after visual inspection, the solution remains cloudy or if an insoluble precipitate is noted or if any seals or outlet ports are not intact, the container should be discarded. Administration Instructions for ZOSYN Injection in GALAXY Containers to Adult Patients Administer by infusion over a period of at least 30 minutes.

During the infusion it is desirable to discontinue the primary infusion solution. Storage of ZOSYN Injection Store in a freezer capable of maintaining a temperature of -20°C (-4°F). For GALAXY Containers, the thawed solution is stable for 14 days under refrigeration (2°C to 8°C ) or 24 hours at room temperature 20°C to 25°C.

Do not refreeze thawed ZOSYN Injection.

Compatibility With Aminoglycosides Due to the in vitro inactivation of aminoglycosides by piperacillin, ZOSYN and aminoglycosides are recommended for separate administration. ZOSYN and aminoglycosides should be reconstituted, diluted, and administered separately when concomitant therapy with aminoglycosides is indicated. In circumstances where co-administration via Y-site is necessary, ZOSYN formulations containing EDTA are compatible for simultaneous co-administration via Y-site infusion only with the following aminoglycosides under the following conditions: Table 3: Compatibility with Only the concentration and diluents for amikacin or gentamicin with the dosages of ZOSYN 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 ZOSYN. ZOSYN is not compatible with tobramycin for simultaneous co-administration via Y-site infusion. Compatibility of ZOSYN 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.

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 Patients During the initial clinical investigations, 2621 patients worldwide were treated with ZOSYN 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, ZOSYN 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 ZOSYN Monotherapy Clinical Trials Nosocomial Pneumonia Trials Two trials of nosocomial lower respiratory tract infections were conducted. The second trial used a dosing regimen of 3.375 g given every 4 hours with an aminoglycoside.

Table 5: Adverse Reactions from ZOSYN Plus Aminoglycoside Clinical Trials For adverse drug reactions that appeared in both studies the higher frequency is presented. Other Trials: Nephrotoxicity In a randomized, multicenter, controlled trial in 1200 adult critically ill patients, piperacillin and tazobactam was found to be a risk factor for renal failure odds ratio and associated with delayed recovery of renal function as compared to other beta-lactam antibacterial drugs 1. 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 ZOSYN 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 Patients Clinical studies of ZOSYN in pediatric patients suggest a similar safety profile to that seen in adults. Six patients (2.2%) in the ZOSYN 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 ZOSYN and 267 patients were treated with comparators (which included ticarcillin-clavulanate, carbapenems, ceftazidime, cefepime, or ciprofloxacin). 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), hemophagocytic lymphohistiocytosis (HLH) 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 ZOSYN in pediatric patients suggests a similar safety profile to that seen in adults.

Additional Experience with Piperacillin

The following adverse reaction has also been reported for piperacillin for injection: Skeletal —prolonged neuromuscular blockade.

Aminoglycosides Piperacillin may inactivate aminoglycosides by converting them to microbiologically inert amides. In vivo inactivation: When aminoglycosides are administered in conjunction with piperacillin to patients with end-stage renal disease requiring hemodialysis, the concentrations of the aminoglycosides (especially tobramycin) may be significantly reduced and should be monitored. Sequential administration of ZOSYN 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, ZOSYN and aminoglycosides are recommended for separate administration. ZOSYN and aminoglycosides should be reconstituted, diluted, and administered separately when concomitant therapy with aminoglycosides is indicated. ZOSYN, which contains EDTA, is compatible with amikacin and gentamicin for simultaneous Y-site infusion in certain diluents and at specific concentrations.

ZOSYN is not compatible with tobramycin for simultaneous Y-site infusion.

Probenecid

Probenecid administered concomitantly with ZOSYN 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 ZOSYN unless the benefit outweighs the risk.

Vancomycin Studies have detected an increased incidence of acute kidney injury in patients concomitantly administered piperacillin and tazobactam and vancomycin as compared to vancomycin alone. Monitor kidney function in patients concomitantly administered with piperacillin and tazobactam and vancomycin. No pharmacokinetic interactions have been noted between piperacillin and tazobactam and vancomycin.

Anticoagulants

Coagulation parameters should be tested more frequently and monitored regularly during simultaneous administration of high doses of heparin, oral anticoagulants, or other drugs that may affect the blood coagulation system or the thrombocyte function.

Vecuronium Piperacillin when used concomitantly with vecuronium has been implicated in the prolongation of the neuromuscular blockade of vecuronium. ZOSYN 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 neuromuscular blockers could be prolonged in the presence of piperacillin.

Monitor for adverse reactions related to neuromuscular blockade (see package insert for vecuronium bromide).

Methotrexate

Limited data suggests that co-administration of methotrexate and piperacillin may reduce the clearance of methotrexate due to competition for renal secretion. The impact of tazobactam on the elimination of methotrexate has not been evaluated. If concurrent therapy is necessary, serum concentrations of methotrexate as well as the signs and symptoms of methotrexate toxicity should be frequently monitored.

Effects on Laboratory Tests There have been reports of positive test results using the Bio-Rad Laboratories Platelia Aspergillus EIA test in patients receiving piperacillin and 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 and tazobactam should be interpreted cautiously and confirmed by other diagnostic methods.

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 be used.

Pregnancy Risk Summary Piperacillin 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 and 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 Data In embryo-fetal development studies in mice and rats, pregnant animals received intravenous doses of piperacillin and 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 and 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 and 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 and 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.

Pediatric Use The safety and effectiveness of ZOSYN for intra-abdominal infections, and nosocomial pneumonia have been established in pediatric patients 2 months of age and older. Use of ZOSYN 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 and tazobactam.

Use of ZOSYN 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 ZOSYN and 267 patients treated with comparators (which included ticarcillin-clavulanate, carbapenems, ceftazidime, cefepime, or ciprofloxacin). Because of the limitations of the available strengths and administration requirements (i.e., administration of fractional doses is not recommended) of ZOSYN Injection supplied in GALAXY Containers, and to avoid unintentional overdose, this product is not recommended for use if a dose of ZOSYN Injection in GALAXY Containers that does not equal 2.25 g, 3.375 g, or 4.5 g is required and an alternative formulation of ZOSYN should be considered. The safety and effectiveness of ZOSYN have not been established in pediatric patients less than 2 months of age.

Dosage of ZOSYN in pediatric patients with renal impairment has not been determined.

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

There have been postmarketing reports of overdose with piperacillin and 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).

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 and tazobactam, the percentage of the piperacillin and tazobactam dose removed by hemodialysis was approximately 31% and 39%, respectively.