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ZOSYN®Dosage and Administration (piperacillin, tazobactam)

2 DOSAGE AND ADMINISTRATION

2.1 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.

2.2 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/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.

2.3 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/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.

2.4 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/tazobactam)*
Creatinine clearance, mL/minAll Indications (except nosocomial pneumonia)Nosocomial Pneumonia
*
Administer ZOSYN by intravenous infusion over 30 minutes.
Creatinine clearance for patients not receiving hemodialysis
0.75 g (0.67 g piperacillin/0.08 g tazobactam) should be administered following each hemodialysis session on hemodialysis days
Greater than 40 mL/min3.375 every 6 hours4.5 every 6 hours
20 to 40 mL/min2.25 every 6 hours3.375 every 6 hours
Less than 20 mL/min2.25 every 8 hours2.25 every 6 hours
Hemodialysis2.25 every 12 hours2.25 every 8 hours
CAPD2.25 every 12 hours2.25 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/0.08 g tazobactam) should be administered following each dialysis period on hemodialysis days. No additional dosage of ZOSYN is necessary for CAPD patients.

2.5 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 ZOSYN in Pediatric Patients 2 Months of Age and Older, Weighing Up to 40 kg, and With Normal Renal Function*,
AgeAppendicitis and/or PeritonitisNosocomial Pneumonia
*
Administer ZOSYN by intravenous infusion over 30 minutes
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 [see Use in Specific Populations (8.4)].
2 months to 9 months90 mg/kg
(80 mg piperacillin/10 mg tazobactam) every 8 (eight) hours
90 mg/kg
(80 mg piperacillin/10 mg tazobactam) every 6 (six) hours
Older than 9 months of age112.5 mg/kg
(100 mg piperacillin/12.5 mg tazobactam) every 8 (eight) hours
112.5 mg/kg
(100 mg piperacillin/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 (2.2, 2.3)].

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

2.6 Reconstitution and Dilution of ZOSYN for Injection

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 (2.5)]. 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 (2.5)].
  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.
    Table 3: Reconstitution of Single-Dose Vials and Resulting Concentration
    Strength per Single-Dose VialVolume of Diluent to be Added to the VialConcentration of the Reconstituted Product
    2.25 g (2 g piperacillin /0.25 g tazobactam)10 mL202.5 mg/mL
    (180 mg/mL piperacillin/22.5 mg/mL tazobactam)
    3.375 g (3 g piperacillin /0.375 g tazobactam)15 mL
    4.5 g (4 g piperacillin /0.5 g tazobactam)20 mL
    Table 4: Reconstitution of Pharmacy Bulk Vial and Resulting Concentration
    Strength per Pharmacy Bulk VialVolume of Diluent to be Added to the VialConcentration of the Reconstituted Product
    40.5 g (36 g piperacillin /4.5 g tazobactam)152 mL225 mg/mL
    (200 mg/mL piperacillin/25 mg/mL tazobactam)
  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.

2.7 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 [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.

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.

Administration Instruction for ZOSYN Injection in GALAXY Containers to Pediatric Patients Weighing up to 40 kg

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.

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 [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 ZOSYN Injection.

2.8 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:

Table 5: Compatibility with Aminoglycosides
AminoglycosideZOSYN
Dose
(grams)
ZOSYN
Diluent Volume *
(mL)
Aminoglycoside Concentration Range
(mg/mL)
Acceptable Diluents
*
Diluent volumes apply only to single vials and bulk pharmacy containers
The concentration ranges in Table 5 are based on administration of the aminoglycoside in divided doses (10–15 mg/kg/day in two daily doses for amikacin and 3–5 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 ZOSYN containing EDTA has not been evaluated. See package insert for each aminoglycoside for complete Dosage and Administration instructions.
ZOSYN 3.375 g per 50 mL GALAXY Containers are NOT compatible with gentamicin for co-administration via a Y-site due to the higher concentrations of piperacillin and tazobactam.
Amikacin2.25
3.375
4.5
50
100
150
1.75 – 7.50.9% sodium chloride or 5% dextrose
Gentamicin2.25
3.375
4.5
50
100
150
0.7 – 3.320.9% 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.

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