Prizma (ANTIBACTERIALS)

Prizma (ANTIBACTERIALS) is a combination product consisting of a penicillin-class antibacterial, piperacillin, and a β-lactamase inhibitor, tazobactam, indicated for the treatment of patients with moderate to severe infections caused by susceptible isolates of the designated bacteria in the conditions listed below.

Intra-abdominal Infections

Appendicitis (complicated by rupture or abscess) and peritonitis caused by β-lactamase producing isolates of Escherichia coli or the following members of the Bacteroides fragilis group: B. fragilis, B. ovatus, B. thetaiotaomicron, or B. vulgatus. The individual members of this group were studied in fewer than 10 cases.

Skin And Skin Structure Infections

Uncomplicated and complicated skin and skin structure infections, including cellulitis, cutaneous abscesses and ischemic/diabetic foot infections caused by β-lactamase producing isolates of Staphylococcus aureus.

Female Pelvic Infections

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

Community-acquired Pneumonia

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

Nosocomial Pneumonia

Nosocomial pneumonia (moderate to severe) caused by β-lactamase producing isolates of Staphylococcus aureus and by piperacillin/tazobactam-susceptible Acinetobacter baumannii, Haemophilus influenzae, Klebsiella pneumoniae, and Pseudomonas aeruginosa (Nosocomial pneumonia caused by P. aeruginosa should be treated in combination with an aminoglycoside).

Usage

To reduce the development of drug-resistant bacteria and maintain the effectiveness of Prizma (ANTIBACTERIALS) and other antibacterial drugs, Prizma (ANTIBACTERIALS) should be used only to treat or prevent infections that are proven or strongly suspected to be caused by bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy.

Prizma (ANTIBACTERIALS) should be administered by intravenous infusion over 30 minutes.

Adult Patients

The usual total daily dose of Prizma (ANTIBACTERIALS) for adults is 3.375 g every six hours totaling 13.5 g (12.0 g piperacillin/1.5 g tazobactam). The usual duration of Prizma (ANTIBACTERIALS) treatment is from 7 to 10 days.

Prizma (ANTIBACTERIALS) should be administered by intravenous infusion over 30 minutes.

Nosocomial Pneumonia

Initial presumptive treatment of patients with nosocomial pneumonia should start with Prizma (ANTIBACTERIALS) at a dosage of 4.5 g every six hours plus an aminoglycoside, totaling 18.0 g (16.0 g piperacillin/2.0 g tazobactam). The recommended duration of Prizma (ANTIBACTERIALS) treatment for nosocomial pneumonia is 7 to 14 days. Treatment with the aminoglycoside should be continued in patients from whom P. aeruginosa is isolated.

Renal Impairment

In patients with renal impairment (creatinine clearance ≤ 40 mL/min) and dialysis patients (hemodialysis and CAPD), the intravenous dose of Prizma (ANTIBACTERIALS) should be reduced to the degree of actual renal function impairment. The recommended daily doses of Prizma (ANTIBACTERIALS) for patients with renal impairment are as follows:

Table 1: Recommended Dosing of Prizma (ANTIBACTERIALS) in Patients with Normal Renal Function and Renal- Impairment (As total grams piperacillin/tazobactam)

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 Prizma (ANTIBACTERIALS) (0.67 g piperacillin/0.08 g tazobactam) should be administered following each dialysis period on hemodialysis days. No additional dosage of Prizma (ANTIBACTERIALS) 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 Prizma (ANTIBACTERIALS) dosage is 100 mg piperacillin/12.5 mg tazobactam per kilogram of body weight, every 8 hours. For pediatric patients between 2 months and 9 months of age, the recommended Prizma (ANTIBACTERIALS) dosage based on pharmacokinetic modeling, is 80 mg piperacillin/10 mg tazobactam per kilogram of body weight, every 8 hours. Pediatric patients weighing over 40 kg and with normal renal function should receive the adult dose.

It has not been determined how to adjust Prizma (ANTIBACTERIALS) dosage in pediatric patients with renal impairment.

Reconstitution And Dilution Of Powder Formulations

Pharmacy Bulk Vials

Reconstituted stock solution must be transferred and further diluted for intravenous infusion.

The pharmacy bulk vial is for use in a hospital pharmacy admixture service only under a laminar flow hood. After reconstitution, entry into the vial must be made with a sterile transfer set or other sterile dispensing device, and contents should be dispensed as aliquots into intravenous solution using aseptic technique. Use entire contents of pharmacy bulk vial promptly. Discard unused portion after 24 hours if stored at room temperature (20°C to 25°C [68°F to 77°F]), or after 48 hours if stored at refrigerated temperature (2°C to 8°C [36°F to 46°F]).

Reconstitute the pharmacy bulk vial with exactly 152 mL of a compatible reconstitution diluent, listed below, to a concentration of 200 mg/mL of piperacillin and 25 mg/mL of tazobactam. Shake well until dissolved. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to and during administration whenever solution and container permit.

Single Dose Vials

Reconstitute Prizma (ANTIBACTERIALS) vials with a compatible reconstitution diluent from the list provided below. 2.25 g, 3.375 g, and 4.5 g Prizma (ANTIBACTERIALS) should be reconstituted with 10 mL, 15 mL, and 20 mL, respectively. Swirl until dissolved.

Compatible Reconstitution Diluents for Pharmacy and Single Dose Vials

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 Prizma (ANTIBACTERIALS) solutions for both bulk and single dose vials should be further diluted (recommended volume per dose of 50 mL to 150 mL) in a compatible intravenous solution listed below. Administer by infusion over a period of at least 30 minutes. During the infusion it is desirable to discontinue the primary infusion solution.

Compatible Intravenous Solutions for Pharmacy and Single Dose Vials

0.9% sodium chloride for injection
sterile water for injection‡
Dextran 6% in saline
Dextrose 5%
Lactated Ringer's Solution (compatible only with reformulated Prizma (ANTIBACTERIALS) containing EDTA and is compatible for co-administration via a Y-site)

‡ Maximum recommended volume per dose of sterile water for injection is 50 mL.

Prizma (ANTIBACTERIALS) should not be mixed with other drugs in a syringe or infusion bottle since compatibility has not been established.

Prizma (ANTIBACTERIALS) is not chemically stable in solutions that contain only sodium bicarbonate and solutions that significantly alter the pH.

Prizma (ANTIBACTERIALS) should not be added to blood products or albumin hydrolysates. Parenteral drug products should be inspected visually for particulate matter or discoloration prior to administration, whenever solution and container permit.

Stability of Prizma (ANTIBACTERIALS) Powder Formulations Following Reconstitution

Prizma (ANTIBACTERIALS) reconstituted from bulk and single vials is stable in glass and plastic containers (plastic syringes, I.V. bags and tubing) when used with compatible diluents. The pharmacy bulk vial should NOT be frozen after reconstitution. Discard unused portions after storage for 24 hours at room temperature or after storage for 48 hours at refrigerated temperature (2°C to 8°C [36°F to 46°F]).

Single dose or pharmacy vials should be used immediately after reconstitution. Discard any unused portion after 24 hours if stored at room temperature (20°C to 25°C [68°F to 77°F]), or after 48 hours if stored at refrigerated temperature (2°C to 8°C [36°F to 46°F]). Vials should not be frozen after reconstitution.

Stability studies in the I.V. bags have demonstrated chemical stability (potency, pH of reconstituted solution and clarity of solution) for up to 24 hours at room temperature and up to one week at refrigerated temperature. Prizma (ANTIBACTERIALS) contains no preservatives. Appropriate consideration of aseptic technique should be used.

Prizma (ANTIBACTERIALS) reconstituted from bulk and single vials can be used in ambulatory intravenous infusion pumps. Stability of Prizma (ANTIBACTERIALS) 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 Prizma (ANTIBACTERIALS) is not affected when administered using an ambulatory intravenous infusion pump.

Directions For Use Of Prizma (ANTIBACTERIALS) In GALAXY Containers

Prizma (ANTIBACTERIALS) Injection is to be administered using sterile equipment, after thawing to room temperature.

Prizma (ANTIBACTERIALS) 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 Prizma (ANTIBACTERIALS) should be discarded.

CAUTION: 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.

Thawing Of Plastic Container

Thaw frozen container at room temperature 20°C to 25°C [68°F to 77°F] or under refrigeration (2°C to 8°C [36°F to 46°F]). 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.

Administer by infusion over a period of at least 30 minutes. During the infusion it is desirable to discontinue the primary infusion solution.

Storage

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 [36°F to 46°F]) or 24 hours at room temperature 20°C to 25°C [68°F to 77°F]. Do not refreeze thawed Prizma (ANTIBACTERIALS).

Compatibility With Aminoglycosides

Due to the in vitro inactivation of aminoglycosides by piperacillin, Prizma (ANTIBACTERIALS) and aminoglycosides are recommended for separate administration. Prizma (ANTIBACTERIALS) 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, Prizma (ANTIBACTERIALS) formulations containing EDTA are compatible for simultaneous co-administration via Y-site infusion only with the following aminoglycosides under the following conditions:

Table 2: Compatibility with Aminoglycosides

Only the concentration and diluents for amikacin or gentamicin with the dosages of Prizma (ANTIBACTERIALS) 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 Prizma (ANTIBACTERIALS).

Prizma (ANTIBACTERIALS) is not compatible with tobramycin for simultaneous co-administration via Y-site infusion. Compatibility of Prizma (ANTIBACTERIALS) 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.

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

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

Hypersensitivity Adverse Reactions

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

Severe Cutaneous Adverse Reactions

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

Hematologic Adverse Reactions

Bleeding manifestations have occurred in some patients receiving β-lactam drugs, including piperacillin. These reactions have sometimes been associated with abnormalities of coagulation tests such as clotting time, platelet aggregation and prothrombin time, and are more likely to occur in patients with renal failure. If bleeding manifestations occur, Prizma (ANTIBACTERIALS) should be discontinued and appropriate therapy instituted.

The leukopenia/neutropenia associated with Prizma (ANTIBACTERIALS) administration appears to be reversible and most frequently associated with prolonged administration.

Periodic assessment of hematopoietic function should be performed, especially with prolonged therapy, ie, ≥ 21 days.

Central Nervous System Adverse Reactions

As with other penicillins, patients may experience neuromuscular excitability or convulsions if higher than recommended doses are given intravenously (particularly in the presence of renal failure).

Nephrotoxicity In Critically Ill Patients

The use of Prizma (ANTIBACTERIALS) was found to be an independent risk factor for renal failure and was associated with delayed recovery of renal function as compared to other beta-lactam antibacterial drugs in a randomized, multicenter, controlled trial in critically ill patients. Based on this study, alternative treatment options should be considered in the critically ill population. If alternative treatment options are inadequate or unavailable, monitor renal function during treatment with Prizma (ANTIBACTERIALS).

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

Electrolyte Effects

Prizma (ANTIBACTERIALS) contains a total of 2.84 mEq (65 mg) of Na+ (sodium) per gram of piperacillin in the combination product. This should be considered when treating patients requiring restricted salt intake. Periodic electrolyte determinations should be performed in patients with low potassium reserves, and the possibility of hypokalemia should be kept in mind with patients who have potentially low potassium reserves and who are receiving cytotoxic therapy or diuretics.

Clostridium Difficile Associated Diarrhea

Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including Prizma (ANTIBACTERIALS), and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile.

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

If CDAD is suspected or confirmed, ongoing antibacterial drug use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibacterial treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated.

Development Of Drug-Resistant Bacteria

Prescribing Prizma (ANTIBACTERIALS) in the absence of a proven or strongly suspected bacterial infection is unlikely to provide benefit to the patient and increases the risk of development of drug-resistant bacteria.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment Of Fertility

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

Piperacillin/Tazobactam

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

Piperacillin/tazobactam

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

Use In Specific Populations

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/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/m²). 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/m²).

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/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/m²). 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/m²).

A fertility and general reproduction study in rats using intraperitoneal administration of tazobactam or the combination piperacillin/tazobactam prior to mating and through the end of gestation, reported a decrease in litter size in the presence of maternal toxicity at 640 mg/kg/day tazobactam (4 times the human dose of tazobactam based on body-surface area), and decreased litter size and an increase in fetuses with ossification delays and variations of ribs, concurrent with maternal toxicity at ≥ 640/160 mg/kg/day piperacillin/tazobactam (0.5 times and 1 times the human dose of piperacillin and tazobactam, respectively, based on body-surface area).

Peri/postnatal development in rats was impaired with reduced pup weights, increased stillbirths, and increased pup mortality concurrent with maternal toxicity after intraperitoneal administration of tazobactam alone at doses ≥ 320 mg/kg/day (2 times the human dose based on body surface area) or of the combination piperacillin/tazobactam at doses ≥ 640/160 mg/kg/day (0.5 times and 1 times the human dose of piperacillin and tazobactam, respectively, based on body-surface area) from gestation day 17 through lactation day 21.

Lactation

Risk Summary

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

Pediatric Use

Use of Prizma (ANTIBACTERIALS) 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.

It has not been determined how to adjust Prizma (ANTIBACTERIALS) dosage in pediatric patients with renal impairment.

Geriatric Use

Patients over 65 years are not at an increased risk of developing adverse effects solely because of age. However, dosage should be adjusted in the presence of renal impairment.

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.

Prizma (ANTIBACTERIALS) contains 65 mg (2.84 mEq) of sodium per gram of piperacillin in the combination product. At the usual recommended doses, patients would receive between 780 and 1040 mg/day (34.1 and 45.5 mEq) of sodium. The geriatric population may respond with a blunted natriuresis to salt loading. This may be clinically important with regard to such diseases as congestive heart failure.

This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.

Renal Impairment

In patients with creatinine clearance ≤ 40 mL/min and dialysis patients (hemodialysis and CAPD), the intravenous dose of Prizma (ANTIBACTERIALS) should be reduced to the degree of renal function impairment.

Hepatic Impairment

Dosage adjustment of Prizma (ANTIBACTERIALS) is not warranted in patients with hepatic cirrhosis.

Patients With Cystic Fibrosis

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

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

During the initial clinical investigations, 2621 patients worldwide were treated with Prizma (ANTIBACTERIALS) 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, Prizma (ANTIBACTERIALS) was discontinued because of adverse events primarily involving the skin (1.3%), including rash and pruritus; the gastrointestinal system (0.9%), including diarrhea, nausea, and vomiting; and allergic reactions (0.5%).

Table 3: Adverse Reactions from Prizma (ANTIBACTERIALS) Monotherapy Clinical Trials

Nosocomial Pneumonia Trials

Two trials of nosocomial lower respiratory tract infections were conducted. In one study, 222 patients were treated with Prizma (ANTIBACTERIALS) in a dosing regimen of 4.5 g every 6 hours in combination with an aminoglycoside and 215 patients were treated with imipenem/cilastatin (500 mg/500 mg q6h) in combination with an aminoglycoside. In this trial, treatment-emergent adverse events were reported by 402 patients, 204 (91.9%) in the piperacillin/tazobactam group and 198 (92.1%) in the imipenem/cilastatin group. Twenty-five (11.0%) patients in the piperacillin/tazobactam group and 14 (6.5%) in the imipenem/cilastatin group (p > 0.05) discontinued treatment due to an adverse event.

The second trial used a dosing regimen of 3.375 g given every 4 hours with an aminoglycoside.

Table 4: Adverse Reactions from Prizma (ANTIBACTERIALS) Plus Aminoglycoside Clinical Trials^a

Other Trials: Nephrotoxicity

In a randomized, multicenter, controlled trial in 1200 adult critically ill patients, piperacillin/tazobactam was found to be a risk factor for renal failure (odds ratio 1.7, 95% CI 1.18 to 2.43), and associated with delayed recovery of renal function as compared to other betalactam antibacterial drugs.1.

Pediatrics

Studies of Prizma (ANTIBACTERIALS) in pediatric patients suggest a similar safety profile to that seen in adults. In a prospective, randomized, comparative, open-label clinical trial of pediatric patients with severe intra-abdominal infections (including appendicitis and/or peritonitis), 273 patients were treated with Prizma (ANTIBACTERIALS) (112.5 mg/kg every 8 hours) and 269 patients were treated with cefotaxime (50 mg/kg) plus metronidazole (7.5 mg/kg) every 8 hours. In this trial, treatment-emergent adverse events were reported by 146 patients, 73 (26.7%) in the Prizma (ANTIBACTERIALS) group and 73 (27.1%) in the cefotaxime/metronidazole group. Six patients (2.2%) in the Prizma (ANTIBACTERIALS) group and 5 patients (1.9%) in the cefotaxime/metronidazole group discontinued due to an adverse event.

Adverse Laboratory Events (Seen During Clinical Trials)

Of the trials reported, including that of nosocomial lower respiratory tract infections in which a higher dose of Prizma (ANTIBACTERIALS) was used in combination with an aminoglycoside, changes in laboratory parameters include:

Hematologic - decreases in hemoglobin and hematocrit, thrombocytopenia, increases in platelet count, eosinophilia, leukopenia, neutropenia. These patients were withdrawn from therapy; some had accompanying systemic symptoms (e.g., fever, rigors, chills)

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

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

Renal - increases in serum creatinine, blood urea nitrogen

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

Post-Marketing Experience

In addition to the adverse drug reactions identified in clinical trials in Table 3 and Table 4, the following adverse reactions have been identified during post-approval use of Prizma (ANTIBACTERIALS). Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Hepatobiliary - hepatitis, jaundice

Hematologic - hemolytic anemia, agranulocytosis, pancytopenia

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

Renal - interstitial nephritis

Respiratory - eosinophilic pneumonia

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

Additional Experience With piperacillin

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

Skeletal - prolonged muscle relaxation.

Post-marketing experience with Prizma (ANTIBACTERIALS) in pediatric patients suggests a similar safety profile to that seen in adults.

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 the patient's clinical presentation. Excessive serum concentrations of either piperacillin or tazobactam may be reduced by hemodialysis. Following a single 3.375 g dose of piperacillin/tazobactam, the percentage of the piperacillin and tazobactam dose removed by hemodialysis was approximately 31% and 39%, respectively.

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

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

Table 6: Mean (CV%) Piperacillin and Tazobactam PK Parameters

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

Distribution

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

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

Table 7: Piperacillin/Tazobactam Concentrations in Selected Tissues and Fluids after Single 4 g/0.5 g 30-min IV Infusion of Prizma (ANTIBACTERIALS)

Metabolism

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

Excretion

Following single or multiple Prizma (ANTIBACTERIALS) doses to healthy subjects, the plasma half-life of piperacillin and of tazobactam ranged from 0.7 to 1.2 hours and was unaffected by dose or duration of infusion.

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