Zavicefta

Package leaflet: Information for the user

Zavicefta 2 g/0,5 g powder for concentrate for solution for infusion

ceftazidime/avibactam
Please read all of this leaflet carefully before you are given this medicine because it contains important information for you.

• Keep this leaflet. You may need to read it again.
• If you have any questions, ask your doctor or nurse.
• If you get any side effects, talk to your doctor or nurse. This includes any side effects not listed in this leaflet. See section 4.

Contents of this leaflet

1. What Zavicefta is and what it is used for
2. What you need to know before being given Zavicefta
3. How Zavicefta is given
4. Possible side effects
5. How to store Zavicefta
6. Contents of the pack and other information

1. What Zavicefta is and what it is used for

What Zavicefta is
Zavicefta is an antibiotic that contains two active substances, ceftazidime and avibactam.

• Ceftazidime belongs to a group of antibiotics called "cephalosporins". It can kill many types of bacteria.
• Avibactam is a "beta-lactamase inhibitor" that helps ceftazidime kill certain types of bacteria that it cannot eliminate on its own.

What Zavicefta is used for
Zavicefta is used in adults and paediatric patients from birth for the treatment of:

• infections of the stomach and intestine (abdomen)
• infections of the bladder or kidneys called "urinary tract infections"
• lung infection called "pneumonia"
• infections caused by bacteria that other antibiotics are unable to kill

Zavicefta is used in adults for the treatment of bloodstream infections associated with
abdominal, urinary tract, or lung infections (pneumonia).
How Zavicefta works
Zavicefta works by killing certain types of bacteria that can cause serious infections.

2. What you need to know before using Zavicefta

Do not use Zavicefta if:

• you are allergic to ceftazidime, avibactam, or to any of the other ingredients of this medicine (listed in section 6)
• you are allergic to other cephalosporin antibiotics
• you have ever had a severe allergic reaction to other antibiotics belonging to the penicillin or carbapenem groups

Do not use Zavicefta if any of the above apply to you. If you have any doubts, consult your doctor or nurse before using Zavicefta.
Warnings and precautions
Talk to your doctor or nurse before using Zavicefta if:

• you have ever had an allergic reaction (even just a skin rash) to other antibiotics belonging to the penicillin or carbapenem groups
• you have kidney problems; your doctor may prescribe a lower dose to ensure you do not receive too much medicine. This may help prevent symptoms such as seizures (see section If you use more Zavicefta than you should). If any of the above apply to you or if you have any doubts, consult your doctor or nurse before using Zavicefta.

Inform your doctor or nurse if you develop diarrhoea during treatment.
Other infections
There is a small possibility that you may develop a different infection caused by other bacteria during or after treatment with Zavicefta. These include oral or genital fungal infections (thrush).
Laboratory tests
Inform your doctor that you are taking Zavicefta if you are due to have any laboratory tests, as you may get an abnormal result in a test called “DAGT” or “Coombs”. This test detects the presence of antibodies directed against red blood cells.
Zavicefta may also affect the results of certain urine glucose tests. Inform the person collecting the sample that you have been administered Zavicefta.
Other medicines and Zavicefta
Inform your doctor or nurse if you are taking, have recently taken, or might take any other medicines.
Inform your doctor before using Zavicefta if you are taking any of the following medicines:

• an antibiotic called chloramphenicol
• a type of antibiotic called an aminoglycoside, such as gentamicin, tobramycin
• a diuretic called furosemide
• a medicine used to treat gout called probenecid

Before using Zavicefta, inform your doctor if any of the above situations apply to you.
Pregnancy and breastfeeding
If you are pregnant, think you may be pregnant, are planning to become pregnant, or are breastfeeding, ask your doctor for advice before using this medicine.
Driving and using machines
Zavicefta may cause dizziness, which may impair your ability to drive or operate machinery.
Zavicefta contains sodium
This medicine contains approximately 146 mg of sodium (a key component of table salt) per vial. This corresponds to 7.3% of the maximum daily dietary intake recommended for an adult.
Ask your doctor or pharmacist for advice if you need 3 or more vials per day for a prolonged period, especially if you have been advised to follow a low-salt (low-sodium) diet.

3. How to use Zavicefta

Zavicefta will be administered to you by a doctor or a nurse.
What dose to use
The recommended dose for adults is one vial (2 g of ceftazidime and 0.5 g of avibactam) every 8 hours. The dose for pediatric patients from birth will be calculated by the doctor based on the child's weight and age.
It is administered by intravenous infusion, usually over a period of approximately 2 hours.
A course of treatment typically lasts from 5 to 14 days, depending on the type of infection you have and how you respond to treatment.
Patients with kidney problems
If you have kidney problems, your doctor may reduce your dose, as Zavicefta is eliminated from the body through the kidneys.
If you use more Zavicefta than you should
Zavicefta will be administered by a doctor or nurse; therefore, it is unlikely that you will receive an incorrect dose.
However, if you experience adverse effects or think you have received too high a dose of Zavicefta, inform your doctor or nurse immediately. If you are given too much Zavicefta, it may affect the brain and cause seizures or coma.
If you forget to use a dose of Zavicefta
If you think you have missed a dose, inform your doctor or nurse immediately.
If you have any doubts about how to use this medicine, consult your doctor or nurse.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them. The following side effects may occur with this medicine:

Serious side effects
Contact your doctor immediately if you notice any of the following serious side effects – you may need urgent medical treatment:

• severe allergic reactions – signs include sudden swelling of the lips, face, throat or tongue, a severe skin rash or other serious skin reactions, difficulty swallowing, breathing problems or sudden chest pain (which may be a sign of Kounis syndrome). These reactions may be life-threatening.
• diarrhoea that continues to worsen or does not go away, or stools containing blood or mucus – this may occur during or after treatment with Zavicefta. If this happens, do not take medicines that block or slow down intestinal movements. Contact your doctor immediately if you notice any of the serious side effects listed above.

Other side effects
Tell your doctor or nurse if you notice any of the following side effects:

Very common: (may affect more than 1 in 10 people)

• abnormal result in a test called “DAT” or “Coombs test”. This test looks for antibodies directed against red blood cells. This may lead to anaemia (which may make you feel tired) and jaundice (yellowing of the skin and eyes).

Common: (may affect up to 1 in 10 people)

• fungal infections, including those of the mouth and vagina
• changes in the number of certain types of blood cells (called “eosinophils” and “platelets”), detected by blood tests
• headache
• dizziness
• feeling unwell (nausea) or sickness (vomiting)
• stomach pain
• diarrhoea
• increased levels of certain liver enzymes, detected by blood tests
• raised, itchy skin rash (“urticaria”)
• itching
• redness, pain or swelling at the site where Zavicefta was given intravenously
• fever

Uncommon: (may affect up to 1 in 100 people)

• increased number of a type of blood cell (called “lymphocytes”), detected by blood tests
• decreased number of certain types of blood cells (called “leukocytes”), detected by blood tests
• tingling or numbness
• unpleasant taste in the mouth
• increased levels of certain substances in the blood (called “creatinine” and “urea”). These substances indicate how well your kidneys are functioning

Very rare: (may affect up to 1 in 10,000 people)

• swelling of part of the kidney leading to reduced normal kidney function

Not known: (frequency cannot be estimated from the available data)

• marked decrease in the type of white blood cells used to fight infection, detected by blood tests
• decrease in the number of red blood cells (haemolytic anaemia), detected by blood tests
• severe allergic reaction (see above Serious side effects)
• yellowing of the whites of the eyes or skin
• sudden onset of a severe skin rash or blisters or skin peeling, possibly accompanied by high fever or joint pain (these may be signs of more serious conditions such as toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema multiforme or a condition called DRESS, drug reaction with eosinophilia and systemic symptoms)
• swelling under the skin, particularly of the lips and around the eyes

Tell your doctor or nurse if you notice any of the side effects listed above.

Reporting of side effects
If you get any side effects, including those not listed in this leaflet, talk to your doctor or nurse. You can also report side effects directly via the national reporting system listed in Annex V. Reporting side effects can help provide more information on the safety of this medicine.

5. How to store Zavicefta

Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date stated on the carton. The expiry date refers to the last day of that month.
Store in the original packaging to protect the medicine from light.
Do not dispose of medicines via wastewater or household waste. Ask your pharmacist how to dispose of medicines no longer required. This will help protect the environment.

6. Package contents and other information

What Zavicefta contains

• The active substances are ceftazidime and avibactam. Each vial contains ceftazidime pentahydrate equivalent to 2 g of ceftazidime and sodium avibactam equivalent to 0.5 g of avibactam.
• The other component is sodium carbonate (anhydrous) (see section 2, “Zavicefta contains sodium”).

Description of the appearance of Zavicefta and contents of the pack
Zavicefta is a white to yellow powder for concentrate for solution for infusion, contained in a vial. It is available in packs containing 10 vials.

Marketing Authorisation Holder
Pfizer Ireland Pharmaceuticals
Operations Support Group
Ringaskiddy, County Cork
Ireland

Manufacturer
ACS Dobfar S.p.A.
Via Alessandro Fleming 2
37135 Verona
Italy

For further information about this medicinal product, please contact the local representative of the Marketing Authorisation Holder:

België/Belgique/Belgien Lietuva
Luxembourg/Luxemburg Pfizer Luxembourg SARL filialas Lietuvoje
Pfizer NV/SA Tel. +370 5 251 4000
Tél/Tel: +32 (0)2 554 62 11

България Magyarország
Пфайзер Люксембург САРЛ, Клон България Pfizer Kft.
Тел: +359 2 970 4333 Tel.: + 36 1 488 37 00

Česká republika Malta
Pfizer, spol. s r.o. Vivian Corporation Ltd.
Tel: +420 283 004 111 Tel.: +356 21344610

Danmark Nederland
Pfizer ApS Pfizer bv
Tlf: +45 44 20 11 00 Tel: +31 (0)800 63 34 636

Deutschland Norge
PFIZER PHARMA GmbH Pfizer AS
Tel: +49 (0)30 550055-51000 Tlf: +47 67 52 61 00

Eesti Österreich
Pfizer Luxembourg SARL Eesti filiaal Pfizer Corporation Austria Ges.m.b.H.
Tel: +372 666 7500 Tel: +43 (0)1 521 15-0

Ελλάδα Polska
Pfizer Ελλάς Α.Ε. Pfizer Polska Sp. z o.o.
Τηλ.: +30 210 6785800 Tel.: +48 22 335 61 00

España Portugal
Pfizer, S.L. Laboratórios Pfizer, Lda.
Tel: +34 91 490 99 00 Tel: +351 21 423 5500

France România
Pfizer Pfizer Romania S.R.L.
Tél: +33 (0)1 58 07 34 40 Tel: +40 (0) 21 207 28 00

Hrvatska Slovenija
Pfizer Croatia d.o.o. Pfizer Luxembourg SARL
Tel: +385 1 3908 777 Pfizer, podružnica za svetovanje s področja
farmacevtske dejavnosti, Ljubljana
Tel.: +386 (0)1 52 11 400

Ireland Slovenská republika
Pfizer Healthcare Ireland Pfizer Luxembourg SARL, organizačná zložka
Tel: +1800 633 363 (toll free) Tel: + 421 2 3355 5500
Tel: +44 (0)1304 616161

Ísland Suomi/Finland
Icepharma hf. Pfizer Oy
Sími: +354 540 8000 Puh/Tel: +358 (0)9 430 040

Italia Sverige
Pfizer S.r.l. Pfizer AB
Tel: +39 06 33 18 21 Tel: +46 (0)8 550 520 00

Κύπρος United Kingdom (Northern Ireland)
Pfizer Ελλάς Α.Ε. (Cyprus Branch) Pfizer Limited
Τηλ.: +357 22817690 Tel: +44 (0) 1304 616161

Latvija
Pfizer Luxembourg SARL filiāle Latvijā
Tel: + 371 670 35 775

Other sources of information
More detailed information on this medicinal product is available on the website of the European Medicines Agency: https://www.ema.europa.eu.

The following information is intended exclusively for healthcare professionals:

Important: Refer to the Summary of Product Characteristics before prescribing this
medicinal product.
The compatibility of Zavicefta with other medicinal products has not been established. Zavicefta must not be mixed or physically combined with solutions containing other medicinal products.
The powder must be reconstituted with water for injections and the resulting concentrate must then be diluted immediately prior to use. The reconstituted solution is pale yellow in colour and free from particles.
Gently swirl to reconstitute the medicinal product and ensure that the contents are completely dissolved. Parenteral medicinal products should be inspected visually for particulate matter prior to administration.

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

Infusion syringes
If the intravenous solution is prepared with the diluents listed in section 6.6 (ceftazidime concentration from ≥8 mg/mL to 40 mg/mL), chemical and physical "in-use" stability (from initial vial puncture) has been demonstrated for up to 6 hours at a temperature not exceeding 25 °C.
From a microbiological standpoint, the medicinal product should be used immediately unless reconstitution and dilution have taken place under validated aseptic and controlled conditions. If not used immediately, 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.

Zavicefta (ceftazidime/avibactam) is a fixed 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 solely on the ceftazidime component.
Standard aseptic techniques must be used for preparation and administration of the solution.
Doses may be prepared in an infusion bag or in an appropriately sized infusion syringe.
The resulting solution must be administered over 120 minutes.
Each vial is for single use only.
Unused medicinal product and waste material must be disposed of in accordance with local requirements.
The total time interval from initial reconstitution to completion of intravenous infusion preparation must not exceed 30 minutes.

Instructions for preparation of doses for adult and paediatric patients in INFUSION BAG or INFUSION SYRINGE:
NOTE: The following procedure describes steps to prepare an infusion solution with a final concentration of 8–40 mg/mL of ceftazidime. All calculations must be completed before beginning these steps.

• For paediatric patients aged 3 to 12 months, the detailed steps below describe preparation of a 20 mg/mL concentration (sufficient in most cases).
• For paediatric patients from birth (including preterm neonates) to <3 months of age, the detailed steps below describe preparation of a 10 mg/mL concentration (sufficient in most cases).

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 obtain a clear solution.
   c) Insert a venting needle through the vial closure after the product has dissolved to reduce internal pressure (this step is important to maintain product sterility).

2. Prepare the final infusion solution (final concentration must be 8–40 mg/mL of ceftazidime):
   a) Infusion bag: Further dilute the reconstituted solution by transferring a calculated volume of the reconstituted solution into an infusion bag containing one of the following solutions: 9 mg/mL (0.9%) sodium chloride injection, 50 mg/mL (5%) dextrose injection, or Ringer's lactate solution.
   b) Infusion syringe: Further dilute the reconstituted solution by transferring a calculated volume of the reconstituted solution combined with a sufficient volume of diluent (9 mg/mL (0.9%) sodium chloride injection or 50 mg/mL (5%) dextrose injection) into an infusion syringe.

Refer to the following Table.
Preparation of Zavicefta doses for adult and paediatric patients in INFUSION BAG or INFUSION SYRINGE.

| Zavicefta dose (ceftazidime) | Final volume after dilution in infusion bag | Final volume in infusion syringe | Volume to withdraw from reconstituted vial | |-------------------------------|-----------------------------------------------|--------------------------------------|---------------------------------------------| | 2 g | Entire contents (approx. 12 mL) | 50 mL | 50 mL | | 1 g | 6 mL | 25–125 mL | 25–50 mL | | 0.75 g | 4.5 mL | 19–93 mL | 19–50 mL | | All other doses | Volume (mL) calculated based on required dose: Dose (mg of ceftazidime) ÷ 167.3 mg/mL of ceftazidime (must be 8–40 mg/mL of ceftazidime) | Volume (mL) varies depending on availability of infusion bag sizes | Volume (mL) varies depending on availability of infusion syringe sizes |

Based solely on the ceftazidime component.
Dilute to a final ceftazidime concentration of 8 mg/mL for "in-use" stability of up to 12 hours at 2–8 °C, followed by up to 4 hours at not more than 25 °C (e.g., dilute a 2 g ceftazidime dose in 250 mL, a 1 g ceftazidime dose in 125 mL, a 0.75 g ceftazidime dose in 93 mL, etc.). All other ceftazidime concentrations (from >8 mg/mL to 40 mg/mL) have in-use stability of up to 4 hours at not more than 25 °C.
Dilute to a final ceftazidime concentration from ≥8 mg/mL to 40 mg/mL for in-use stability of up to 6 hours at a temperature not exceeding 25 °C.

Paediatric patients aged 3 to 12 months
NOTE: The following procedure describes 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 fall within 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 obtain a clear solution.
   c) Insert a venting needle through the vial closure after the product has dissolved to reduce internal pressure (this step is important to maintain product sterility).

2. Prepare the final infusion solution at a final concentration of 20 mg/mL of ceftazidime:
   a) Further dilute the reconstituted solution by transferring a calculated volume of the reconstituted solution combined with a sufficient volume of diluent (9 mg/mL (0.9%) sodium chloride injection or 50 mg/mL (5%) dextrose injection) into an infusion syringe.
   b) Refer to the tables below to confirm calculations. Values provided are approximate, as rounding to the nearest graduation mark on an appropriately sized syringe may be necessary. Note that the tables do not include all possible calculated doses but can be used to estimate approximate volume to verify the calculation.

Preparation of Zavicefta (final concentration of 20 mg/mL of ceftazidime) in paediatric patients aged 3 to 12 months with creatinine clearance (CrCL) > 50 mL/min/1.73 m²

Based solely on the ceftazidime component.
Preparation of Zavicefta (final concentration of 20 mg/mL of ceftazidime) in pediatric patients aged
3 to 12 months with CrCL from 31 to 50 mL/min/1.73 m²

Based exclusively on the ceftazidime component.
Preparation of Zavicefta (final concentration of 20 mg/mL of ceftazidime) in pediatric patients from
3 to 12 months of age with CrCL from 16 to 30 mL/min/1.73 m²

Exclusively based on the ceftazidime component.
Pediatric patients from birth (including preterm infants) to < 3 months of age:
NOTE: The following procedure describes the steps to prepare a stock solution for infusion with a final concentration of 10 mg/mL of ceftazidime, suitable for administering doses below 250 mg to pediatric patients from birth (including preterm infants) up to < 3 months of age. Alternative concentrations may be prepared, but the final concentration range must be between 8–40 mg/mL of ceftazidime.

1. Prepare the reconstituted solution (167.3 mg/mL of ceftazidime):
   a) Insert the needle of a syringe through the closure of the vial and inject 10 mL of sterile water for injections.
   b) Remove the needle and shake the vial until the solution becomes clear.
   c) Insert a venting needle through the closure of the vial after the product has dissolved to reduce internal pressure (this step is important to maintain product sterility).

2. Prepare the final stock solution for infusion at a final concentration of 10 mg/mL of ceftazidime:
   a) Further dilute the reconstituted solution by transferring 3 mL into an infusion bag or syringe containing 47 mL of diluent (sodium chloride 9 mg/mL (0.9%) solution for injection or glucose 50 mg/mL (5%) solution for injection) to obtain a final volume of 50 mL.
   b) Mix thoroughly (e.g., gently invert the infusion bag or, using a syringe connector, gently pass the solution back and forth between two syringes at least five times).
   c) Transfer an appropriate volume of the 10 mg/mL ceftazidime stock solution into an infusion syringe. For the volume of stock solution to transfer into the infusion syringe for administration, refer to the table below. The values indicated are approximate, as rounding to the nearest graduation mark on an appropriately sized syringe may be required. The tables do not include all possible calculated doses but can be used to estimate the approximate volume for verification of calculations.

Dosage of Zavicefta in pediatric patients from birth (including preterm infants) up to < 3 months of age using a 50 mL Zavicefta stock solution (final concentration of 10 mg/mL of ceftazidime) prepared with 3 mL of reconstituted solution drawn from the vial and added to 47 mL of diluent.