The fixed combination of piperacillin sodium-tazobactam sodium is available as a lyophilized powder in preservative-free single-dose and ADD-Vantage vials containing 2.25 g (piperacillin 2 g plus tazobactam 250 mg), 3.375 g (piperacillin 3 g plus tazobactam 375 mg), or 4.5 g (piperacillin 4 g plus tazobactam 500 mg) as the sodium salts.2919; 2921 The drug is also available in a pharmacy bulk package containing 40.5 g (piperacillin 36 g plus tazobactam 4.5 g) as the sodium salts.2920
Generic piperacillin sodium-tazobactam sodium and Zosyn (Wyeth) products are not identical.2922; 2932 In 2006, all Zosyn products were reformulated to contain edetate disodium dihydrate (EDTA) as a metal chelator and sodium citrate as a buffering agent; these excipients were added to address issues with sporadic batch failures associated with excessive particulate matter related to commercially available diluents and solutions with acidic pH and the presence of trace amounts of zinc ions.2922; 2932 Other piperacillin sodium-tazobactam sodium products do not contain EDTA, sodium citrate, or any other excipients.2919; 2920; 2921 These formulation differences between Zosyn products and other piperacillin sodium-tazobactam sodium products have been demonstrated to result in some differing compatibilities with certain solutions (e.g., Ringer’s injection, lactated).2922; 2932; 2985 Therefore, results of compatibility tests for one formulation cannot be extrapolated to another.2922; 2932 (See Solution Compatibility.)
Each 2.25, 3.375, or 4.5 g (combined components) single-dose vial should be reconstituted with 10, 15, or 20 mL, respectively, of sterile water for injection, sodium chloride 0.9%, bacteriostatic water for injection or bacteriostatic sodium chloride 0.9% (preserved with benzyl alcohol or parabens), or dextrose 5% and should be swirled until dissolved.2921 The contents of each single-dose vial should then be diluted in 50 to 150 mL of a compatible infusion solution; however, if sterile water for injection is used as the solution, the maximum recommended volume per dose is 50 mL.2921
ADD-Vantage vials of piperacillin sodium-tazobactam sodium should be prepared with 50 or 100 mL of dextrose 5% or sodium chloride 0.9% in ADD-Vantage diluent bags.2919
The 40.5-g pharmacy bulk package should be reconstituted with 152 mL of sterile water for injection, sodium chloride 0.9%, bacteriostatic water for injection or bacteriostatic sodium chloride 0.9% (preserved with benzyl alcohol or parabens), or dextrose 5% and should be shaken until dissolved; the resulting solution contains piperacillin 200 mg/mL plus tazobactam 25 mg/mL.2920 The reconstituted pharmacy bulk package solution must be diluted further in a compatible infusion solution; the recommended volume per dose is 50 to 100 mL;2920 however, if sterile water for injection is used as the solution, the maximum recommended volume per dose is 50 mL.2920
Piperacillin sodium-tazobactam sodium (Zosyn, Wyeth) also is available as a frozen iso-osmotic premixed injection in single-dose Galaxy containers containing 2.25 g (piperacillin 2 g plus tazobactam 250 mg), 3.375 g (piperacillin 3 g plus tazobactam 375 mg), or 4.5 g (piperacillin 4 g plus tazobactam 500 mg) as the sodium salts in 50, 50, or 100 mL, respectively, with EDTA and sodium citrate dihydrate, in water for injection.2918; 2922 Dextrose hydrous is added to adjust the osmolality, and sodium bicarbonate and hydrochloric acid are used to adjust the pH.2918; 2922
pH
Zosyn (Wyeth) premixed infusion solution: From 5.5 to 6.8.2918; 2922
Sodium Content
Piperacillin sodium-tazobactam sodium products contain 2.35 to 2.84 mEq (54 to 65 mg) of sodium per gram of piperacillin in the combination product.2918; 2919; 2920; 2921
Trade Name(s)
Zosyn
Piperacillin-tazobactam solution for infusion prepared from single-dose vials or the pharmacy bulk package should be administered by intravenous infusion over at least 30 minutes after dilution in a compatible diluent to provide a recommended volume per dose of 50 to 150 mL.2920; 2921 Such solutions for infusion prepared using single-dose vials or the pharmacy bulk package also can be infused using ambulatory infusion pumps.2920; 2921
Piperacillin sodium-tazobactam sodium (Zosyn, Wyeth) frozen iso-osmotic premixed injection in single-dose Galaxy containers should be thawed (see Stability: Freezing Solutions), and the solution should be administered by intravenous infusion over at least 30 minutes.2918
Use of extended infusion strategies (e.g., infusion over 4 hours) for piperacillin-tazobactam has been described in the literature.2934 In such circumstances, however, careful attention must be paid to the possibility of incomplete dose administration resulting from drug loss through tubing residuals.2934 Such loss is a function of both the concentration of the solution being infused and the residual volume of the specific tubing used for administration.2934
The white to off-white2920; 2921 or yellowish2919 piperacillin sodium-tazobactam sodium lyophilized powder in intact vials should be stored at controlled room temperature.2919; 2920; 2921
Single-dose vials and pharmacy bulk packages of the solution should be used immediately after reconstitution2920.2921 Any remaining unused portion should be discarded after 24 hours at room temperature (20 to 25°C) or 48 hours under refrigeration (2 to 8°C).2920; 2921 Vials should NOT be frozen after reconstitution.2920; 2921
After dilution in compatible infusion solutions, the drug is stable for up to 24 hours at room temperature or 1 week under refrigeration.2920; 2921 Glass and plastic (including syringes, intravenous solution bags, and tubing) do not affect stability.2918; 2919; 2920; 2921
Solutions prepared using the ADD-Vantage vials are stable for up to 24 hours at room temperature.2919 These solutions should not be refrigerated nor frozen following reconstitution.2919
Concentration Effects
In one study, piperacillin plus tazobactam dissolved in sterile water for injection to concentrations greater than 128 plus 16 g/L, respectively, resulted in unacceptably viscous solutions that impeded flow from elastomeric pumps to less than 75% of the nominal flow rate.3105
Freezing Solutions
The commercially available, premixed frozen injection in single-dose Galaxy containers should be stored at or below -20°C.2918 Solutions should be thawed at room temperature or under refrigeration; the manufacturer states that solutions should not be force thawed by immersion in water baths or by microwave radiation.2918 Thawed solutions should not be refrozen.2918 After the thawed solution has reached room temperature, the solution should be agitated.2918 Thawed solutions are stable for 24 hours at room temperature or 14 days refrigerated.2918 The manufacturer states that precipitation may occur in the frozen solution which will dissolve with little or no agitation upon reaching room temperature.2918 The container should be agitated after reaching room temperature.2918 Discard the solution if it is cloudy or precipitate is present or if any seals or ports are not intact.2918
Piperacillin 80 mg/mL plus tazobactam 10 mg/mL in polyvinyl chloride (PVC) bags of dextrose 5% and sodium chloride 0.9% was frozen at -15°C for 30 days and thawed by microwave radiation for 45 seconds with no loss of either component.1768
Piperacillin 150 mg/mL plus tazobactam 18.75 mg/mL and piperacillin 200 mg/mL plus tazobactam 25 mg/mL in dextrose 5% and sodium chloride 0.9% were drawn as 20-mL aliquots into polypropylene syringes (Becton Dickinson). The syringes were frozen at -15°C for 30 days and then stored at 4°C for 7 days with no loss of either component.1768
Piperacillin 40 mg/mL plus tazobactam 5 mg/mL in dextrose 5% lost less than 3% after 3 months stored at -20°C. After microwave thawing, refrigerated storage resulted in 10% loss in 35 days.2614
Piperacillin sodium-tazobactam sodium (Pfizer) in sterile water for injection in syringes (Becton Dickinson) was stored frozen at -22 to -18°C for 60 days in the dark followed by thawing at room temperature (20 to 24°C) and additional storage at room temperature for 24 hours with approximately 10 hours exposure to light.3895; 3896 At a concentration of piperacillin 2 g plus tazobactam 0.25 g in 10 mL, 1.5% piperacillin and 6.4% tazobactam losses were noted in samples assayed immediately after thawing and 1% piperacillin and 6% tazobactam losses in samples that were stored for an additional 24 hours at room temperature.3895 At a concentration of piperacillin 3 g plus tazobactam 0.375 g in 10 mL, no losses of either component were noted immediately after thawing or after an additional 24 hours at room temperature.3895
Syringes
Piperacillin 150 mg/mL plus tazobactam 18.75 mg/mL and piperacillin 200 mg/mL plus tazobactam 25 mg/mL in dextrose 5% and sodium chloride 0.9% were drawn as 20-mL aliquots into polypropylene syringes (Becton Dickinson). The syringes were stored at 25°C for 1 day and at 4°C for 7 days with no loss of either drug in the dextrose 5% samples. Similarly, no tazobactam loss occurred in the sodium chloride 0.9% solutions. However, piperacillin losses of 7% in 1 day at 25°C and 4% in 7 days at 4°C were found in the sodium chloride 0.9% solutions.1768
Piperacillin sodium-tazobactam sodium (Pfizer) prepared at concentrations of piperacillin 2 g plus tazobactam 0.25 g in 10 mL and piperacillin 3 g plus tazobactam 0.375 g in 10 mL in sterile water for injection in syringes (Becton Dickinson) exhibited no losses of either component in 9 days refrigerated at 4 to 5°C in dark followed by 24 hours at 20 to 24°C with approximately 10 hours exposure to light.3895
Ambulatory Pumps
Infusion solutions prepared from single-dose vials and the bulk product have been shown to be stable for up to 12 hours at room temperature in an ambulatory infusion pump.2918; 2920; 2921; 2922 Each dose was diluted to 25 or 37.5 mL, and stability was not affected.2918; 2920; 2921
Central Venous Catheter
Piperacillin 10 mg/mL plus tazobactam 1.25 mg/mL (Lederle) in dextrose 5% was found to be compatible with the ARROWg+ard Blue Plus (Arrow International) chlorhexidine-bearing triple-lumen central catheter. Essentially complete delivery of the drug was found with little or no drug loss occurring. Furthermore, chlorhexidine delivered from the catheter remained at trace amounts with no substantial increase due to the delivery of the drug through the catheter.2335
Drugs in Syringe Compatibility
Y-Site Injection Compatibility (1:1 Mixture)
Additional Compatibility Information
Infusion Solutions
Piperacillin-tazobactam (Zosyn, Wyeth) containing EDTA is compatible with Ringer’s injection, lactated solution only for Y-site administration.2918 Formulations of the drug that do not contain EDTA are incompatible with Ringer’s injection, lactated solution.2919; 2920; 2921
In a simulated Y-site administration study, piperacillin 40 mg/mL plus tazobactam 5 mg/mL without EDTA (Premier Pro Rx) in dextrose 5% was physically compatible with Normosol R for up to 4 hours at 21°C protected from light.3719
Peritoneal Dialysis Solutions
The physical and chemical stability of piperacillin plus tazobactam (without EDTA) at concentrations of 200 plus 25 mcg/mL, respectively, were evaluated in Dianeal PD-2 with dextrose 1.5% and Dianeal PD-2 with dextrose 4.25%. Samples were stored at 4°C for 14 days, 23°C for 7 days, and 37°C for 1 day. The samples were physically and chemically stable. Little or no loss of either component occurred in the 4°C samples throughout the 14-day period. At 23°C, losses of each component were in the range of 3 to 6% in 7 days. The 1-day losses at 37°C were similarly small.2018
For a list of references cited in the text of this monograph, search the monograph titled References.