Pharmaceutical particulars : מידע רוקחי

6.    PHARMACEUTICAL PARTICULARS

6.1   List of excipients

Sodium carbonate (anhydrous)
6.2 Incompatibilities
The compatibility of Zavicefta with other medicines has not been established. Zavicefta should not be mixed with or physically added to solutions containing other medicinal products.
This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.

6.3   Shelf life

Dry powder
The expiry date of the product is indicated on the packaging materials.

After reconstitution

The reconstituted vial should be used immediately.
After dilution

Infusion bags
If the intravenous solution is prepared with diluents listed in section 6.6 (ceftazidime concentration 8 mg/mL), the chemical and physical in-use stability has been demonstrated (from initial vial puncture) for up to 12 hours at 2 -8°C, followed by up to 4 hours at not more than 25°C.
If the intravenous solution is prepared with diluents listed in section 6.6 (ceftazidime concentration > 8 mg/mL to 40 mg/mL), the chemical and physical in-use stability has been demonstrated (from initial vial puncture) for up to 4 hours at not more than 25°C. From a microbiological point of view, the medicinal product should be used immediately, unless reconstitution and dilution have taken place in controlled and validated aseptic conditions. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and must not exceed those stated above.

Infusion syringes

The chemical and physical in-use stability has been demonstrated (from initial vial puncture) for up to 6 hours at not more than 25°C.

From a microbiological point of view, the medicinal product should be used immediately unless reconstitution and dilution have taken place in controlled and validated aseptic conditions. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and must not exceed 6 hours at not more than 25°C.

6.4   Special precautions for storage

Do not store above 30°C
Store in the original package in order to protect from light.

For storage conditions of the reconstituted and diluted medicinal product, see section 6.3.

6.5   Nature and contents of container

20 mL glass vial (Type 1) closed with a rubber (halobutyl) stopper and aluminium seal with flip-off cap.

The medicinal product is supplied in packs of 10 vials.
6.6   Special precautions for disposal and other handling

The powder must be reconstituted with water for injections and the resulting concentrate must then be immediately diluted prior to use. The reconstituted solution is pale yellow solution and free of particles.

Zavicefta (ceftazidime/avibactam) is a combination product; each vial contains 2 g of ceftazidime and 0.5 g of avibactam in a fixed 4:1 ratio. Dosage recommendations are based on the ceftazidime component only.

Standard aseptic techniques should be used for solution preparation and administration.
Doses may be prepared in an appropriately sized infusion bag or infusion syringe.

Parenteral medicinal products should be inspected visually for particulate matter prior to administration.
Each vial is for single use only.

Any unused product or waste material should be disposed of in accordance with local requirements.

The total time interval between starting reconstitution and completing preparation of the intravenous infusion should not exceed 30 minutes.

Instructions for preparing adult and paediatric doses in INFUSION BAG or in INFUSION SYRINGE: 
NOTE: The following procedure describes the steps to prepare an infusion solution with a final concentration of 8-40 mg/mL of ceftazidime. All calculations should be completed prior to initiating these steps. For paediatric patients aged 3 to 12 months, detailed steps to prepare a 20 mg/mL concentration (sufficient for most scenarios) are also provided.

1. Prepare the reconstituted solution (167.3 mg/mL of ceftazidime): a) Insert the syringe needle through the vial closure and inject 10 mL of sterile water for injections.
b) Withdraw the needle and shake the vial to give a clear solution.
c) Insert a gas relief needle through the vial closure after the product has dissolved to relieve the internal pressure (this is important to preserve product sterility).
2. Prepare the final solution for infusion (final concentration must be 8-40 mg/mL of ceftazidime): a) Infusion bag: Further dilute the reconstituted solution by transferring an appropriately calculated volume of the reconstituted solution to an infusion bag containing any of the following: sodium chloride 9 mg/mL (0.9%) solution for injection, dextrose 50 mg/mL (5%) solution for injection, or Lactated Ringer’s solution.
b) Infusion syringe: Further dilute the reconstituted solution by transferring an appropriately calculated volume of the reconstituted solution combined with a sufficient volume of diluent (sodium chloride 9 mg/mL (0.9%) solution for injection or dextrose 50 mg/mL (5%) solution for injection) to an infusion syringe.

Refer to Table 7 below.

Table 7: Preparation of Zavicefta for adult and paediatric doses in INFUSION BAG or in INFUSION SYRINGE.
Zavicefta             Volume to                Final volume             Final volume in infusion Dose                  withdraw from            after dilution in        syringe (ceftazidime)1        reconstituted vial       infusion bag2
2g                    Entire contents
(approximately 12        50 mL to 250 mL          50 mL mL)
Zavicefta            Volume to                 Final volume                Final volume in infusion Dose                 withdraw from             after dilution in           syringe (ceftazidime)1       reconstituted vial        infusion bag2
1g                   6 mL                      25 mL to 125 mL            25 mL to 50 mL 0.75 g               4.5 mL                    19 mL to 93 mL             19 mL to 50 mL All other            Volume (mL)               Volume (mL) will        Volume (mL) will vary based doses                calculated based          vary based on             on infusion syringe size on dose required:         infusion bag size        availability and preferred availability and             final concentration
Dose (mg                  preferred final            (must be 8-40 mg/mL of ceftazidime) ÷            concentration              ceftazidime)
167.3 mg/mL               (must be 8-40 ceftazidime               mg/mL of ceftazidime)
1
Based on ceftazidime component only.
2
Dilute to final ceftazidime concentration of 8 mg/mL for in-use stability up to 12 hours at 2 - 8°C, followed by up to 4 hours at not more than 25°C (i.e. dilute 2 g dose of ceftazidime in 250 mL, 1 g dose of ceftazidime in 125 mL, 0.75 g dose of ceftazidime in 93 mL, etc.). All other ceftazidime concentrations (> 8 mg/mL to 40 mg/mL) have in-use stability up to 4 hours at not more than 25°C.

Preparation of Zavicefta for use in paediatric patients aged 3 to 12 months of age in INFUSION SYRINGE:

NOTE: The following procedure describes the steps to prepare an infusion solution with a final concentration of 20 mg/mL of ceftazidime (sufficient for most scenarios). Alternative concentrations may be prepared, but must have a final concentration range of 8-40 mg/mL of ceftazidime.

1. Prepare the reconstituted solution (167.3 mg/mL of ceftazidime): a) Insert the syringe needle through the vial closure and inject 10 mL of sterile water for injections.
b) Withdraw the needle and shake the vial to give a clear solution.
c) Insert a gas relief needle through the vial closure after the product has dissolved to relieve the internal pressure (this is important to preserve product sterility).
2. Prepare the final solution for infusion to a final concentration of 20 mg/mL of ceftazidime: a) Further dilute the reconstituted solution by transferring an appropriately calculated volume of the reconstituted solution combined with a sufficient volume of diluent (sodium chloride 9 mg/mL (0.9%) solution for injection or dextrose 50 mg/mL (5%) solution for injection) to an infusion syringe.
b) Refer to Table 8, 9, or 10 below to confirm the calculations. Values shown are approximate as it may be necessary to round to the nearest graduation mark of an appropriately sized syringe. Note that the tables are NOT inclusive of all possible calculated doses but may be utilized to estimate the approximate volume to verify the calculation.


Table 8: Preparation of Zavicefta (final concentration of 20 mg/mL of ceftazidime) in paediatric patients 3 to 12 months of age with creatinine clearance (CrCL) > 50 mL/min/1.73 m 2 Volume of
Volume of reconstituted
Age and Zavicefta                            Dose                                    diluent to add Weight (kg)                              solution to be
Dose (mg/kg)1                         (mg ceftazidime)                               for mixing withdrawn from vial
(mL)
(mL)
5                 250                    1.5                    11
6                 300                    1.8                    13
6 months to              7                 350                    2.1                    15 12 months
8                 400                    2.4                    18
9                 450                    2.7                    20
50 mg/kg of ceftazidime           10                 500                     3                     22 11                 550                    3.3                    24
12                 600                    3.6                    27
4                 160                     1                    7.4
3 months to              5                 200                    1.2                   8.8 < 6 months               6                 240                    1.4                    10 7                 280                    1.7                    13
40 mg/kg               8                 320                    1.9                    14 of ceftazidime            9                 360                    2.2                    16 10                 400                    2.4                    18
1
Based on ceftazidime component only.

Table 9: Preparation of Zavicefta (final concentration of 20 mg/mL of ceftazidime) in paediatric patients 3 to 12 months of age with CrCL 31 to 50 mL/min/1.73 m 2
Volume of
Volume of reconstituted solution
Age and Zavicefta                            Dose                                    diluent to add Weight (kg)                          to be withdrawn from
Dose (mg/kg)1                         (mg ceftazidime)                               for mixing vial
(mL)
(mL)
5                 125                    0.75                   5.5
6                 150                     0.9                   6.6
6 months to              7                 175                      1                    7.4 12 months               8                 200                     1.2                   8.8 25 mg/kg               9                 225                     1.3                   9.6 of ceftazidime           10                 250                     1.5                   11 11                 275                     1.6                   12
12                 300                     1.8                   13
4                  80                    0.48                   3.5
3 months to              5                 100                     0.6                   4.4 < 6 months               6                 120                    0.72                   5.3 7                 140                    0.84                   6.2
20 mg/kg               8                 160                      1                    7.4 of ceftazidime            9                 180                     1.1                   8.1 10                 200                     1.2                   8.8
1
Based on ceftazidime component only.


Table 10: Preparation of Zavicefta (final concentration of 20 mg/mL of ceftazidime) in paediatric patients 3 to 12 months of age with CrCL 16 to 30 mL/min/1.73 m 2
Volume of
Dose          reconstituted solution      Volume of
Age and Zavicefta
Weight  (kg)            (mg          to be withdrawn  from     diluent  to add Dose (mg/kg) 1 ceftazidime)                vial           for mixing (mL)
(mL)
5                93.75                   0.56                  4.1
6                112.5                   0.67                  4.9
6 months to              7               131.25                   0.78                  5.7 12 months               8                 150                    0.9                   6.6 18.75 mg/kg              9               168.75                    1                    7.4 of ceftazidime           10                187.5                   1.1                   8.1 11               206.25                   1.2                   8.8
12                 225                    1.3                   9.6
4                  60                    0.36                  2.7
3 months to              5                  75                    0.45                  3.3 < 6 months               6                  90                    0.54                   4 7                 105                    0.63                  4.6
15 mg/kg               8                 120                    0.72                  5.3 of ceftazidime            9                 135                    0.81                   6 10                 150                    0.9                   6.6
1
Based on ceftazidime component only.