2 DOSAGE AND ADMINISTRATION
2.1 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 [totaling 13.5 g (12.0 g piperacillin and 1.5 g tazobactam)], to be administered by intravenous infusion over 30 minutes. The usual duration of ZOSYN 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 ZOSYN at a dosage of 4.5 g every six hours plus an aminoglycoside, [totaling 18.0 g (16.0 g piperacillin and 2.0 g tazobactam)], 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.
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 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.
| 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 ZOSYN (0.67 g piperacillin and 0.08 g tazobactam) should be administered following each dialysis period on hemodialysis days. No additional dosage of ZOSYN 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)].
| Age | Appendicitis and/or Peritonitis | Nosocomial Pneumonia |
|---|---|---|
| ||
2 months to 9 months | 90 mg/kg | 90 mg/kg |
Older than 9 months of age | 112.5 mg/kg | 112.5 mg/kg |
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 ZOSYN in pediatric patients with renal impairment has not been determined.
2.5 Reconstitution and Dilution of ZOSYN for Injection
ZOSYN (piperacillin and tazobactam) for Injection is not currently being marketed.
Reconstitution of ZOSYN For Injection for Adult Patients and Pediatric Patients Weighing Over 40 kg
Pharmacy Bulk Vials
Reconstituted pharmacy bulk vial 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 ZOSYN single-dose vials with a compatible reconstitution diluent from the list provided below.
2.25 g, 3.375 g, and 4.5 g ZOSYN 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 Pharmacy Bulk Vials 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
Dilution of the Reconstituted ZOSYN Solution for Adult Patients and Pediatric Patients Weighing Over 40 kg
Reconstituted ZOSYN solutions for both pharmacy bulk vials 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 Bulk Vials and 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 (compatible only with reformulated ZOSYN containing EDTA and is compatible for co-administration via a Y-site)
ZOSYN should not be mixed with other drugs in a syringe or infusion bottle since compatibility has not been established.
ZOSYN is not chemically stable in solutions that contain only sodium bicarbonate and solutions that significantly alter the pH.
ZOSYN 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 ZOSYN Solution for Pediatric Patients Weighing up to 40 kg
The volume of reconstituted solution required to deliver the dose of ZOSYN is dependent on the weight of the child [see Dosage and Administration (2.4)]. Reconstituted ZOSYN solutions for both bulk and single-dose vials should be further diluted in a compatible intravenous solution listed above.
- 1.
- Calculate patient dose as described in Table 2 above [see Dosage and Administration (2.4)].
- 2.
- Reconstitute vial with a compatible reconstitution diluent, as listed above under the subheading "Compatible Reconstitution Diluents for Pharmacy Bulk Vials and Single-Dose Vials," using the appropriate volume of diluent, as listed in tables 3 and 4 below. Following the addition of the diluent, swirl the single-dose vial or shake the pharmacy bulk vial until the powder is completely dissolved.
| 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 |
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 |
| Strength per Pharmacy Bulk Vial | Volume of Diluent to be Added to the Vial | Concentration of the Reconstituted Product |
|---|---|---|
40.5 g (36 g piperacillin and 4.5 g tazobactam) | 152 mL | 225 mg/mL |
- 3.
- Calculate the required volume (mL) of reconstituted ZOSYN solution based on the required dose.
- 4.
- Aseptically withdraw the required volume of reconstituted ZOSYN solution from either the pharmacy bulk vial or 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.
- 5.
- Administer the diluted ZOSYN 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 ZOSYN for Injection Following Reconstitution and Dilution
ZOSYN for Injection reconstituted from pharmacy bulk vials and single-dose vials is stable in glass and plastic containers (plastic syringes, IV bags and tubing) when used with compatible diluents. The pharmacy bulk vials and single-dose vials should NOT be frozen after reconstitution.
Single-dose or pharmacy bulk vials should be used immediately after reconstitution. Discard any unused portion after storage for 24 hours at room temperature (20°C to 25°C [68°F to 77°F]), or after storage for 48 hours at refrigerated temperature (2°C to 8°C [36°F 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. ZOSYN for Injection contains no preservatives. Appropriate consideration of aseptic technique should be used.
ZOSYN for Injection reconstituted from bulk and single-dose vials can be used in ambulatory intravenous infusion pumps. Stability of ZOSYN 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 ZOSYN 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, 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 [see Drug Interactions (7.1)].
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:
| Aminoglycoside | ZOSYN Dose (grams) | ZOSYN Diluent Volume * (mL) | Aminoglycoside Concentration Range † (mg/mL) | Acceptable Diluents |
|---|---|---|---|---|
| ||||
Amikacin | 2.25 | 50 | 1.75 – 7.5 | 0.9% sodium chloride or 5% dextrose |
Gentamicin | 2.25 | 50 | 0.7 – 3.32 | 0.9% sodium chloride or 5% dextrose |
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.