2 DOSAGE AND ADMINISTRATION Adult Patients With Indications Other Than Nosocomial Pneumonia; The usual daily dosage of piperacillin and tazobactam for injection, for intravenous use for adults is 3.375 g every six hours totaling 13.5 g (12 g piperacillin and 1.5 g tazobactam). ( 2.1 ) Adult Patients with Nosocomial Pneumonia: Initial presumptive treatment of patients with nosocomial pneumonia should start with piperacillin and tazobactam for injection, for intravenous use at a dosage of 4.5 g every six hours plus an aminoglycoside, totaling 18 g (16 g piperacillin and 2 g tazobactam). ( 2.2 ) Adult Patients with Renal Impairment: Dosage in patients with renal impairment (creatinine clearance ≤40 mL/min) and dialysis patients should be reduced, based on the degree of renal impairment. ( 2.3 ) Pediatric Patients by Indication and Age: See Table below ( 2.4 ) Recommended Dosage of piperacillin and tazobactam for injection, for intravenous use for Pediatric Patients 2 months of Age and Older, Weighing up to 40 Kg and With Normal Renal Function Age Appendicitis and /or Peritonitis Nosocomial Pneumonia 2 months to 9 months 90 mg/kg (80 mg piperacillin and 10 mg tazobactam) every 8 ( eight ) hours 90 mg/kg (80 mg piperacillin and 10 mg tazobactam) every 6 ( six ) hours Older than 9 months 112.5 mg/kg (100 mg piperacillin and 12.5 mg tazobactam) every 8 ( eight) hours 112.5 mg/kg (100 mg piperacillin and 12.5 mg tazobactam) every 6 ( six) hours Administer piperacillin and tazobactam for injection by intravenous infusion over 30 minutes to both adult and pediatric patients. ( 2.1 , 2.2 , 2.3 , 2.4 ) Piperacillin and tazobactam for injection and aminoglycosides should be reconstituted, diluted, and administered separately. Co-administration via Y-site can be done under certain conditions. ( 2.6 ) See the full prescribing information for the preparation and administration instructions for piperacillin and tazobactam for injection single-dose vials. 2.1 Dosage in Adult Patients with Indications Other Than Nosocomial Pneumonia The usual total daily dosage of piperacillin and tazobactam for injection for adult patients with indications other than nosocomial pneumonia is 3.375 g every six hours [totaling 13.5 g (12 g piperacillin and 1.5 g tazobactam)], to be administered by intravenous infusion over 30 minutes. The usual duration of piperacillin and tazobactam for injection treatment is from 7 to 10 days. 2.2 Dosage in Adult Patients with Nosocomial Pneumonia Initial presumptive treatment of adult patients with nosocomial pneumonia should start with piperacillin and tazobactam for injection at a dosage of 4.5 g every six hours plus an aminoglycoside, [totaling 18 g (16 g piperacillin and 2 g tazobactam)], administered by intravenous infusion over 30 minutes. The recommended duration of piperacillin and tazobactam for injection treatment for nosocomial pneumonia is 7 to 14 days. Treatment with the aminoglycoside should be continued in patients from whom P. aeruginosa is isolated. 2.3 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 piperacillin and tazobactam for injection should be reduced based on the degree of renal impairment. The recommended daily dosage of piperacillin and tazobactam for injection for patients with renal impairment administered by intravenous infusion over 30 minutes is described in Table 1. Table 1: Recommended Dosage of Piperacillin and Tazobactam for Injection in Patients with Normal Renal Function and Renal Impairment (As total grams piperacillin and tazobactam) # # Administer piperacillin and tazobactam for injection by intravenous infusion over 30 minutes. * Creatinine clearance for patients not receiving hemodialysis ** 0.75 g (0.67 g piperacillin and 0.08 g tazobactam) should be administered following each hemodialysis session on hemodialysis days Creatinine clearance, mL/min All Indications (except nosocomial pneumonia) Nosocomial Pneumonia Greater than 40 mL/min 3.375 every 6 hours 4.5 every 6 hours 20 to 40 mL/min* 2.25 every 6 hours 3.375 every 6 hours Less than 20 mL/min* 2.25 every 8 hours 2.25 every 6 hours Hemodialysis** 2.25 every 12 hours 2.25 every 8 hours CAPD 2.25 every 12 hours 2.25 every 8 hours For patients on hemodialysis, the maximum dose is 2.25 g every twelve hours for all indications other than nosocomial pneumonia and 2.25 g every eight hours for nosocomial pneumonia. Since hemodialysis removes 30% to 40% of the administered dose, an additional dose of 0.75 g piperacillin and tazobactam for injection (0.67 g piperacillin and 0.08 g tazobactam) should be administered following each dialysis period on hemodialysis days. No additional dosage of piperacillin and tazobactam for injection is necessary for CAPD patients. 2.4 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 [see Use in Specific Populations (8.4) and Clinical Pharmacology (12.3) ] . Table 2: Recommended Dosage of Piperacillin and Tazobactam for Injection in Pediatric Patients 2 Months of Age and Older, Weighing Up to 40 kg, and With Normal Renal Function # # Administer piperacillin and tazobactam for injection by intravenous infusion over 30 minutes Age Appendicitis and/or Peritonitis Nosocomial Pneumonia 2 months to 9 months 90 mg/kg (80 mg piperacillin and 10 mg tazobactam) every 8 ( eight ) hours 90 mg/kg (80 mg piperacillin and 10 mg tazobactam) every 6 ( six ) hours Older than 9 months of age 112.5 mg/kg (100 mg piperacillin and 12.5 mg tazobactam) every 8 ( eight ) hours 112.5 mg/kg (100 mg piperacillin and 12.5 mg tazobactam) every 6 ( six ) hours Pediatric patients weighing over 40 kg and with normal renal function should receive the adult dose [see Dosage and Administration (2.1 , 2.2) ] . Dosage of piperacillin and tazobactam for injection in pediatric patients with renal impairment has not been determined. 2.5 Reconstitution and Dilution of Piperacillin and Tazobactam for Injection Reconstitution of Piperacillin and Tazobactam for Injection for Adult Patients and Pediatric Patients Weighing Over 40 kg Single-Dose Vials Reconstitute piperacillin and tazobactam for injection single-dose vials with a compatible reconstitution diluent from the list provided below. 2.25 g, 3.375 g, and 4.5 g piperacillin and tazobactam for injection should be reconstituted with 10 mL, 15 mL, and 20 mL, respectively. Swirl until dissolved. After reconstitution, the single-dose vials will have a concentration of 202.5 mg/mL (180 mg/mL of piperacillin and 22.5 mg/mL of tazobactam). Compatible Reconstitution Diluents for 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 Dilution of the Reconstituted Piperacillin and Tazobactam for Injection Solution for Adult Patients and Pediatric Patients Weighing Over 40 kg Reconstituted piperacillin and tazobactam for injection solutions for 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 Single-Dose Vials 0.9% sodium chloride for injection Sterile water for injection (Maximum recommended volume per dose of sterile water for injection is 50 mL) Dextran 6% in saline Dextrose 5% LACTATED RINGER'S SOLUTION IS NOT COMPATIBLE WITH PIPERACILLIN AND TAZOBACTAM FOR INJECTION. Piperacillin and tazobactam should not be mixed with other drugs in a syringe or infusion bottle since compatibility has not been established. Piperacillin and tazobactam is not chemically stable in solutions that contain only sodium bicarbonate and solutions that significantly alter the pH. Piperacillin and tazobactam 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. Dilution of the Reconstituted Piperacillin and Tazobactam Solution for Pediatric Patients Weighing up to 40 kg The volume of reconstituted solution required to deliver the dose of piperacillin and tazobactam is dependent on the weight of the child [see Dosage and Administration (2.4) ] . Reconstituted piperacillin and tazobactam solutions for single-dose vials should be further diluted in a compatible intravenous solution listed above. Calculate patient dose as described in Table 2 above [see Dosage and Administration (2.4) ] . Reconstitute vial with a compatible reconstitution diluent, as listed above under the subheading "Compatible Reconstitution Diluents for Single-Dose Vials," using the appropriate volume of diluent, as listed in table 3 below. Following the addition of the diluent, swirl the single-dose vial until the powder is completely dissolved. Table 3: Reconstitution of Single-Dose Vials and Resulting Concentration Strength per Single-Dose Vial Volume of Diluent to be Added to the Vial Concentration of the Reconstituted Product 2.25 g (2 g piperacillin and 0.25 g tazobactam) 10 mL 202.5 mg/mL (180 mg/mL piperacillin and 22.5 mg/mL tazobactam) 3.375 g (3 g piperacillin and 0.375 g tazobactam) 15 mL 4.5 g (4 g piperacillin and 0.5 g tazobactam) 20 mL Calculate the required volume (mL) of reconstituted piperacillin and tazobactam solution based on the required dose. Aseptically withdraw the required volume of reconstituted piperacillin and tazobactam solution from the single-dose vial. It should be further diluted to a final piperacillin concentration of between 20 mg/mL to 80 mg/mL (tazobactam between 2.5 mg/mL to 10 mg/mL) in a compatible intravenous solution (as listed above) in an appropriately sized syringe or IV bag. Administer the diluted piperacillin and tazobactam solution by infusion over a period of at least 30 minutes (a programmable syringe or infusion pump is recommended). During the infusion it is desirable to discontinue the primary infusion solution. Stability of Piperacillin and Tazobactam for Injection Following Reconstitution and Dilution Piperacillin and tazobactam for injection reconstituted from single-dose vials is stable in glass and plastic containers (plastic syringes, IV bags and tubing) when used with compatible diluents. The single-dose vials should NOT be frozen after reconstitution. Single-dose vials should be used immediately after reconstitution. Discard any unused portion after storage for 24 hours at room temperature (20° to 25°C [68° to 77°F]), or after storage for 48 hours at refrigerated temperature (2° to 8°C [36° to 46°F]). Stability studies in the IV 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. Piperacillin and tazobactam for injection contains no preservatives. Appropriate consideration of aseptic technique should be used. Piperacillin and tazobactam for injection reconstituted from single-dose vials can be used in ambulatory intravenous infusion pumps. Stability of piperacillin and tazobactam for injection 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 supply of dosing solution were aseptically transferred into the medication reservoir (IV bags or cartridge). The reservoir was fitted to a preprogrammed ambulatory intravenous infusion pump per the manufacturer’s instructions. Stability of piperacillin and tazobactam for injection is not affected when administered using an ambulatory intravenous infusion pump. 2.6 Compatibility with Aminoglycosides Due to the in vitro inactivation of aminoglycosides by piperacillin, piperacillin and tazobactam and aminoglycosides are recommended for separate administration. Piperacillin and tazobactam and aminoglycosides should be reconstituted, diluted, and administered separately when concomitant therapy with aminoglycosides is indicated [see Drug Interactions (7.1) ] . In circumstances where co-administration via Y-site is necessary, piperacillin and tazobactam is compatible for simultaneous co-administration via Y-site infusion only with the following aminoglycosides under the following conditions: Table 5: Compatibility with Aminoglycosides Aminoglycoside Piperacillin and Tazobactam Dose (grams) Piperacillin and Tazobactam Diluent Volume a (mL) Aminoglycoside Concentration Range b (mg/mL) Acceptable Diluents a Diluent volumes apply only to single-dose vials b The concentration ranges in Table 5 are based on administration of the aminoglycoside in divided doses (10 to 15 mg/kg/day in two daily doses for amikacin and 3 to 5 mg/kg/day in three daily doses for gentamicin). Administration of amikacin or gentamicin in a single daily dose or in doses exceeding those stated above via Y-site with piperacillin and tazobactam has not been evaluated. See package insert for each aminoglycoside for complete Dosage and Administration instructions. Amikacin 2.25 3.375 4.5 50 100 150 1.75 to 7.5 0.9% sodium chloride or 5% dextrose Gentamicin 2.25 3.375 4.5 50 100 150 0.7 to 3.32 0.9% sodium chloride or 5% dextrose Only the concentration and diluents for amikacin or gentamicin with the dosages of piperacillin and tazobactam 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 piperacillin and tazobactam. Piperacillin and tazobactam is not compatible with tobramycin for simultaneous co-administration via Y-site infusion. Compatibility of piperacillin and tazobactam for injection 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.