Consumer medicine information

Zavicefta 2000/500

Ceftazidime; Avibactam

BRAND INFORMATION

Brand name

Zavicefta

Active ingredient

Ceftazidime; Avibactam

Schedule

SUMMARY CMI

Zavicefta^® 2000/500

Consumer Medicine Information (CMI) summary

The full CMI on the next page has more details. If you are worried about using this medicine, speak to your doctor or pharmacist.

▼ This medicine is new or being used differently. Please report side effects. See the full CMI for further details.

1. Why am I being treated with Zavicefta?

Zavicefta contains the active ingredients, ceftazidime and avibactam. It is used to treat serious infections of the tissues and organs within the stomach, urinary tract or kidney or certain serious lung infections.

For more information, see Section 1. Why am I being treated with Zavicefta? in the full CMI.

2. What should I know before treatment with Zavicefta?

Do not start treatment if you/your child have ever had an allergic reaction to Zavicefta/ceftazidime/avibactam, other antibiotics that are the same type, or any of the ingredients listed at the end of the CMI including sodium carbonate.

Tell the doctor if you/your child have had any allergic reaction to any antibiotic, have other medical conditions, are on a controlled sodium diet, take any other medicines or if you are pregnant, plan to become pregnant or are breastfeeding.

For more information, see Section 2. What should I know before treatment with Zavicefta? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with Zavicefta and affect how it works.

More instructions can be found in in Section 3. What if I am taking other medicines? in the full CMI.

4. How is Zavicefta given?

The doctor will decide how much Zavicefta is needed. It will depend on the type of infection, age and bodyweight (for children) and if you/your child have kidney problems.

More instructions can be found in Section 4. How is Zavicefta given? in the full CMI.

5. What should I know during treatment with Zavicefta?

Things you should do	Tell your doctor if you/your child have kidney problems, anaemia, are on a controlled sodium diet, had severe diarrhoea after taking any antibiotics or if you are pregnant, plan to become pregnant or are breastfeeding. For more information on "Things you should do" can be found in Section 6 in the full CMI.
Things you should not do	You/your child should not be treated with Zavicefta if you/your child have had a serious allergy to penicillin or the same type of antibiotics as Zavicefta.
Driving or using machines	Zavicefta may affect your ability to drive a car or operate machinery.
Looking after your medicine	Store in original carton at below 30°C until ready for use.

For more information, see Section 5. What should I know during treatment with Zavicefta? in the full CMI.

6. Are there any side effects?

Side effects may include swelling of the face, lips, mouth or throat, difficulty swallowing or breathing; shortness of breath or breathing difficulties; nausea or vomiting; changes in taste or a metallic taste; stomach or abdominal pain; severe diarrhoea or stools that contains blood or mucus; severe skin rash; weight gain; increased urine volume; night urination; numbness or a tingling sensation; redness, pain or swelling at the injection site or vein; headaches; dizziness; fever; itchy skin; hives/skin rash; white, furry layer on the tongue; unusual vaginal discharge; yellowing of skin and eyes (jaundice),.problems with your liver or kidneys, certain blood cells or the way your blood clots.

For more information, including what Zavicefta to do if you have any side effects, see Section 6. Are there any side effects? in the full CMI.

▼ This medicine is subject to additional monitoring in Australia. This will allow quick identification of new safety information. You can help by reporting any side effects you may get. You can report side effects to your doctor, or directly at www.tga.gov.au/reporting-problems.

FULL CMI

Zavicefta^® 2000/500

Active ingredient(s): ceftazidime/avibactam

Consumer Medicine Information (CMI)

This leaflet provides important information about Zavicefta. You should also speak to your doctor or pharmacist if you would like further information or if you have any concerns or questions about Zavicefta.

Where to find information in this leaflet:

1. Why am I being treated with Zavicefta?
2. What should I know before treatment with Zavicefta?
3. What if I am taking other medicines?
4. How is Zavicefta given to you?
5. What should I know while being treated with Zavicefta?
6. Are there any side effects?
7. Product details

1. Why am I being treated with Zavicefta?

Zavicefta contains the active ingredients ceftazidime and avibactam. Zavicefta is an antibiotic used in adults and children from 3 months to treat serious infections of the tissues and organs within the stomach, urinary tract or kidney infections and in adults to treat certain lung infections.

2. What should I know before treatment with Zavicefta?

Do not use Zavicefta if you/your child are:

allergic to Zavicefta/ceftazidime/avibactam or any of the ingredients listed at the end of this leaflet. Always check the ingredients to make sure you can use this medicine.
allergic to or have previously had a severe allergic reaction to penicillin or the same type of antibiotic as Zavicefta. Your doctor will know which antibiotics are the same type as Zavicefta.

Check with your doctor if you/your child:

have kidney problems
anaemia
are on a controlled sodium diet
have had severe diarrhoea after taking any antibiotics
are taking medicines for any other condition.

During treatment, you may be at risk of developing certain side effects. It is important you understand these risks and how to monitor for them. See additional information under Section 6. Are there any side effects?

Pregnancy and breastfeeding

Check with your doctor if you are pregnant or intend to become pregnant.

Talk to your doctor if you are breastfeeding or intend to breastfeed.

3. What if I am taking other medicines?

Tell your doctor or pharmacist if you/your child are taking any other medicines, including any medicines, vitamins or supplements that you buy without a prescription from your pharmacy, supermarket or health food shop.

Some medicines and Zavicefta may interfere with each other. These include:

probenecid, a medicine used to prevent gout and gouty arthritis
a type of antibiotic called aminoglycosides, such as gentamicin and tobramycin
a type of antibiotic called cephalosporins, such as cefazolin and ceftazidime
chloramphenicol, a medicine used to treat eye infections
medicines used to pass urine, such as frusemide

Check with your doctor or pharmacist if you are not sure about what medicines, vitamins or supplements you are taking and if these affect Zavicefta.

4. How is Zavicefta given?

How much will be given

The doctor will decide what dose of Zavicefta is needed depending on certain factors such as the type of infection, age and bodyweight (for children) and if you/your child have kidney problems.

How long will Zavicefta need to be given?

Treatment is usually given every day for 5 days to up to 14 days. The doctor will decide how many days you will need treatment with Zavicefta.

If too much Zavicefta is given

If you think that you/your child have been given too much Zavicefta, you may need urgent medical attention.

You should immediately:

phone the Poisons Information Centre
(by calling 13 11 26), or
contact your doctor, or
go to the Emergency Department at your nearest hospital.

You should do this even if there are no signs of discomfort or poisoning.

5. What should I know during treatment with Zavicefta?

Things you should do

If you/your child are about to have any blood tests, tell the doctor or nurse that you/your child were recently treated with Zavicefta.

Call your doctor straight away if you/your child:

get severe diarrhoea. Do this even if it occurs several weeks after Zavicefta has been stopped.

Remind any doctor, nurse, dentist or pharmacist you see that you are using Zavicefta.

Driving or using machines

Be careful before you drive or use any machines or tools until you know how Zavicefta affects you.

Zavicefta may affect your ability to drive a car or operate machinery.

Drinking alcohol

No information available.

Looking after your medicine

Zavicefta should be stored in the original carton below 30°C.

If you are keeping this medicine at home, store it in a cool dry place away from moisture, heat or sunlight. For example, do not store it in the bathroom, near a sink or in the car or on windowsills.

Keep it where young children cannot reach it.

When to discard your medicine

Discard any medicine that has passed the expiry date.

This medicine should only be used on one patient and any unused medicine should be discarded.

Getting rid of any unwanted medicine

If you no longer need to use this medicine or it is out of date, take it to any pharmacy for safe disposal.

6. Are there any side effects?

All medicines can have side effects. If you do experience any side effects, most of them will be minor and temporary. However, some side effects may need medical attention.

See the information below and, if you need to, ask your doctor, nurse or pharmacist if you have any further questions about side effects.

Side effects

What to do

Stomach pain
Diarrhoea
Nausea or vomiting
Changes in taste or a metallic taste in the mouth
Itchy skin
Skin rash or hives.
Dizziness
Headache
Fever
White, furry layer on the tongue
Unusual vaginal discharge
Redness, pain or swelling where injection was given into a vein
Problems with your liver or kidneys*
Problems with certain blood cells or the way your blood clots.*

*These side effects may show up when you have a blood test.

Speak to your doctor if you have any of these side effects and they worry you.

Side effects

What to do

Swelling of the face, lips, mouth or throat which may cause difficulty in swallowing or breathing
Shortness of breath or breathing difficulties
Abdominal pain
Diarrhoea that keeps getting worse or does not go away, or stools that contains blood or mucus. This may occur even after treatment
Rash or hives with unusual weight gain, increased urine volume and night urination
Changes to urine volume.
Numbness or a tingling sensation
Severe skin reactions such as painful red areas, large blisters, peeling of your skin, and bleeding in the lips, eyes, mouth, nose and genitals
Swelling of the limbs, face, lips, mouth or throat
Yellowing of the skin and eyes (jaundice).

Call your doctor straight away, or go straight to the Emergency Department at your nearest hospital if you notice any of these serious side effects.

Tell your doctor or pharmacist if you notice anything else that may be making you feel unwell.

Other side effects not listed here may occur in some people.

Reporting side effects

After you have received medical advice for any side effects you experience, you can report side effects to the Therapeutic Goods Administration online at www.tga.gov.au/reporting-problems. By reporting side effects, you can help provide more information on the safety of this medicine.

Always make sure you speak to your doctor or pharmacist before you decide to stop taking any of your medicines.

7. Product details

This medicine is only available with a doctor's prescription.

What Zavicefta contains

Active ingredients	Ceftazidime and avibactam
Other ingredients (inactive ingredients)	Sodium bicarbonate

Do not take this medicine if you are allergic to any of these ingredients.

What Zavicefta looks like

Zavicefta is a white to yellow powder, which will be dissolved to a clear and colourless to yellow solution before it is given to you.

Australian Registration Number: AUST R 301205.

Who distributes Zavicefta

Pfizer Australia Pty Ltd
Sydney NSW.
Toll Free Number: 1800 675 229.
www.pfizer.com.au.

This leaflet was prepared in May 2021.

® Registered trademark.

Published by MIMS July 2021

BRAND INFORMATION

Brand name

Zavicefta

Active ingredient

Ceftazidime; Avibactam

Schedule

1 Name of Medicine

Ceftazidime (as pentahydrate)/avibactam (as sodium).

2 Qualitative and Quantitative Composition

Each vial contains ceftazidime (as pentahydrate) equivalent to 2000 mg ceftazidime and avibactam (as sodium) equivalent to 500 mg avibactam.
After reconstitution, 1 mL of solution contains 167.3 mg of ceftazidime (CAZ) and 41.8 mg of avibactam (AVI).
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Powder for Injection.
Zavicefta is white to light yellow powder.
The reconstituted solution is a clear and colourless to yellow solution free from visible particulate matter.

4 Clinical Particulars

4.1 Therapeutic Indications

Zavicefta is indicated for the treatment of the following infections in adults (see Section 4.4 Special Warnings and Precautions for Use; Section 5.1 Pharmacodynamic Properties):
Complicated intra-abdominal infection (cIAI) in combination with metronidazole.
Complicated urinary tract infection (cUTI) including pyelonephritis.
Hospital-acquired pneumonia (HAP) including ventilator associated pneumonia (VAP).
Zavicefta is indicated for the treatment of the following infections in infants and paediatric patients (≥ 3 months to < 18 years) (see Section 4.4 Special Warnings and Precautions for Use; Section 5.1 Pharmacodynamic Properties):
Complicated intra-abdominal infection (cIAI) in combination with metronidazole.
Complicated urinary tract infection (cUTI) including pyelonephritis.
Consideration should be given to official guidance on the appropriate use of antibacterial agents.
To reduce the development of drug-resistant bacteria and maintain the effectiveness of Zavicefta and other antibiotics, Zavicefta should be used in combination with an antibacterial agent(s) active against Gram-positive and/or anaerobic pathogens when these are known or suspected to be contributing to the infectious process.

4.2 Dose and Method of Administration

Dosage.

Adult. The recommended dosage is one vial where each vial contains 2000 mg ceftazidime and 500 mg avibactam. Treatment is repeated every 8 hours. See Table 1. For patients with renal impairment, see Dosage adjustments, Renal impairment later in this section.

For cUTI including pyelonephritis, the total duration of treatment could be increased to 14 days for patients with bacteraemia.
The duration of treatment should be guided by the severity of the infection, the pathogen(s) and the patient's clinical and bacteriological progress.

Dosage adjustments.

Adults.

Renal impairment.

No dosage adjustment is required in patients with mild renal impairment (estimated creatinine clearance (CrCl) ≥ 51 ≤ 80 mL/min).
Dosage adjustment of Zavicefta is recommended in patients with moderate and severe renal impairment and end-stage renal disease. Table 2 shows the recommended dose adjustments for patients with estimated CrCl ≤ 50 mL/min. For patients with changing renal function, CrCl should be monitored at least daily and the dosage of Zavicefta adjusted accordingly. (See Section 4.4 Special Warnings and Precautions for Use, Use in renal impairment; Section 5.1, Clinical trials; Section 5.2 Pharmacokinetic Properties, Renal impairment.)

Haemodialysis.

Both ceftazidime and avibactam are haemodialysable; thus, Zavicefta should be administered after haemodialysis on haemodialysis day.

Haemofiltration or peritoneal dialysis.

There is insufficient data to make specific dosage adjustment recommendations for patients undergoing continuous veno-venous haemofiltration or peritoneal dialysis.

Hepatic impairment.

No dosage adjustment is required in patients with hepatic impairment (see Section 5.2 Pharmacokinetic Properties). Close clinical monitoring for safety and efficacy is advised.

Elderly.

No dosage adjustment is required in elderly patients (see Section 5.2 Pharmacokinetic Properties).
Paediatric population. Safety and efficacy in infants < 3 months old have not been established. The recommended dosage and duration of treatment for infants and paediatric patients (≥ 3 months to < 18 years old) is summarised in Table 3. Dosage adjustment of Zavicefta in paediatric patients with renal impairment (2 years to < 18 years) are shown in Table 4.

Paediatric patients with renal impairment.

See Table 4.

There is insufficient information to recommend a dosage regimen for paediatric patients less than 2 years of age with a creatinine clearance of < 50 mL/min/1.73 m².
There is insufficient clinical data to make specific dosage adjustment recommendations for children < 18 years undergoing haemofiltration or peritoneal dialysis.

Method of administration.

Zavicefta is administered by intravenous infusion over 120 minutes For instructions on reconstitution, dilution and preparation of infusion volume of the product before administration see information under the subsection heading, Reconstitution and Preparation of infusion volume later in this section.

Reconstitution.

The powder must be reconstituted with water for injections and the resulting solution must then be immediately diluted prior to use.
Standard aseptic techniques should be used for solution preparation and administration.
The reconstitution time can be up to 4 minutes.
Parenteral medicinal products should be inspected visually for particulate matter prior to administration.
Doses may be prepared in an appropriately sized infusion bags or infusion syringes.
The total time interval between starting reconstitution and completing preparation of the intravenous infusion should not exceed 30 minutes.
See Section 6.3 Shelf Life for shelf life of the dry powder, reconstituted solution and the diluted solutions stored in infusion bags and infusion syringes.
Each vial is for single use only. Discard any residues.

Preparation of infusion volume.

Zavicefta (ceftazidime/avibactam) is a combination product; each vial contains 2000 mg of ceftazidime and 500 mg of avibactam in a fixed 4:1 ratio. Dosage recommendations are based on the ceftazidime component only.
Instructions for preparing adult and paediatric doses for patients older than 12 months in infusion bags or in infusion syringes.

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 solution are provided later in this section (see Table 6).
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 (must contain 8-40 mg/mL 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.
See Table 5.

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 a 20 mg/mL ceftazidime infusion solution. Alternative doses may be prepared, but the final solution must contain 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 of 20 mg/mL 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. See Table 6 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.

4.3 Contraindications

Hypersensitivity to the active substances or to any of the excipients, see Section 6.1 List of Excipients.
Hypersensitivity to any cephalosporin antibacterial agent.
Severe hypersensitivity (e.g. anaphylactic reaction, severe skin reaction) to any other type of β-lactam antibacterial agent (e.g. penicillins, monobactams or carbapenems).

4.4 Special Warnings and Precautions for Use

Hypersensitivity reactions.

Serious and occasionally fatal hypersensitivity reactions are possible (see Section 4.3 Contraindications; Section 4.8 Adverse Effects (Undesirable Effects)). In case of hypersensitivity reactions, treatment with Zavicefta must be discontinued immediately and adequate emergency measures must be initiated.
Before beginning treatment, it should be established whether the patient has a history of hypersensitivity reactions to ceftazidime, to other cephalosporins or to any other type of β-lactam antibacterial agent. Caution should be used if ceftazidime/avibactam is given to patients with a history of non-severe hypersensitivity to penicillins, monobactams or carbapenems.

Clostridium difficile-associated diarrhoea.

Clostridium difficile-associated diarrhoea has been reported with ceftazidime/avibactam, and can range in severity from mild to life-threatening. This diagnosis should be considered in patients who present with diarrhoea during or subsequent to the administration of Zavicefta (see Section 4.8 Adverse Effects (Undesirable Effects)). Discontinuation of therapy with Zavicefta and the administration of specific treatment for Clostridium difficile should be considered. Medicinal products that inhibit peristalsis should not be given.

Nephrotoxicity.

Concurrent treatment with high doses of cephalosporins and nephrotoxic medicinal products such as aminoglycosides or potent diuretics (e.g. furosemide) may adversely affect renal function.

Direct antiglobulin test (DAGT or Coombs test) seroconversion and potential risk of haemolytic anaemia.

Ceftazidime/avibactam use may cause development of a positive direct antiglobulin test (DAGT, or Coombs test), which may interfere with the cross-matching of blood and/or may cause drug induced immune haemolytic anaemia (see Section 4.8 Adverse Effects (Undesirable Effects)). While DAGT seroconversion in patients receiving Zavicefta was very common in clinical studies (the estimated range of seroconversion across Phase 3 studies was 3.2% to 20.8% in patients with a negative Coombs test at baseline and at least one follow-up test), there was no evidence of haemolysis in patients who developed a positive DAGT on treatment. However, the possibility that haemolytic anaemia could occur in association with Zavicefta treatment cannot be ruled out. Patients experiencing anaemia during or after treatment with Zavicefta should be investigated for this possibility.

Dermatological adverse events.

Severe cutaneous adverse reactions (SCARs), such as Stevens-Johnson syndrome, toxic epidermal necrolysis (TEN) and drug reaction with eosinophilia and systemic symptoms (DRESS) and acute generalised exanthematous pustulosis (AGEP), which can be life threatening or fatal, have been reported in patients taking beta-lactam antibiotics (see Section 4.8 Adverse Effects (Undesirable Effects)). When SCAR is suspected, Zavicefta should be discontinued immediately and an alternative treatment should be considered. See Section 4.8 Adverse Effects (Undesirable Effects).

Spectrum of activity of ceftazidime/avibactam.

Ceftazidime has little or no activity against the majority of Gram-positive organisms and anaerobes (see Section 4.2 Dose and Method of Administration; Section 5.1 Pharmacodynamic Properties). Additional antibacterial agents should be used when these pathogens are known or suspected to be contributing to the infectious process.
The inhibitory spectrum of avibactam includes many of the enzymes that inactivate ceftazidime, including Ambler class A β-lactamases and class C β-lactamases. Avibactam does not inhibit class B enzymes (metallo-β-lactamases) and is not able to inhibit many of the class D enzymes (see Section 5.1 Pharmacodynamic Properties).

Non-susceptible organisms.

Prolonged use may result in the overgrowth of non-susceptible organisms (e.g. Enterococci, fungi), which may require interruption of treatment or other appropriate measures.

Development of drug-resistant bacteria.

Prescribing Zavicefta in the absence of a proven or strongly suspected bacterial infection is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria (see Section 4.1 Therapeutic Indications).

Controlled sodium diet.

Each vial contains approximately 6.37 mmol of sodium per vial. This total is the combined sodium from avibactam sodium and the excipient sodium carbonate. This should be considered when administering Zavicefta to patients who are on a controlled sodium diet.

Neurotoxicity.

There have been reports of neurotoxicity associated with cephalosporin treatment. Symptoms of neurotoxicity include encephalopathy, seizures and/or myoclonus. Risk factors for developing neurotoxicity with cephalosporin treatment include being elderly, renal impairment, central nervous system disorders and intravenous administration. Withdrawal of the medicine should be considered if there are signs of neurotoxicity.

Use in renal impairment.

Ceftazidime and avibactam are eliminated via the kidneys, therefore, the dose should be reduced according to the degree of renal impairment (see Section 4.2 Dose and Method of Administration). Neurological sequelae, including tremor, myoclonus, non-convulsive status epilepticus, convulsion, encephalopathy and coma, have occasionally been reported with ceftazidime when the dose has not been reduced in patients with renal impairment.
In patients with renal impairment, close monitoring of estimated creatinine clearance is advised. In some patients, the creatinine clearance estimated from serum creatinine can change quickly, especially early in the course of treatment for the infection (see Section 5.1, Clinical trials; Section 5.2 Pharmacokinetic Properties, Renal impairment).

Use in the elderly.

No dosage adjustment is required in elderly patients (see Section 4.2 Dose and Method of Administration; Section 5.2 Pharmacokinetic Properties).

Paediatric use.

The safety and efficacy of Zavicefta in paediatric patients (< 3 months) have not been established.
There is a potential risk of overdosing, particularly for paediatric patients aged from 3 to less than 12 months of age. Care should be taken when calculating the volume of administration of the dose (see Section 4.2 Dose and Method of Administration; Section 4.9 Overdose).

Effects on laboratory tests.

Ceftazidime may interfere with copper reduction methods (Benedict's, Fehling's, Clinitest) for detection of glycosuria leading to false positive results. Ceftazidime does not interfere with enzyme-based tests for glycosuria.

4.5 Interactions with Other Medicines and Other Forms of Interactions

In vitro, avibactam is a substrate of OAT1 and OAT3 transporters which might contribute to the active uptake of avibactam from the blood compartment and therefore affect its excretion. Probenecid (a potent OAT inhibitor) inhibits this uptake by 56% to 70% in vitro and therefore, has the potential to alter the elimination of avibactam. Since a clinical interaction study of avibactam and probenecid has not been conducted, co-administration of avibactam with probenecid is not recommended.
Avibactam showed no significant inhibition of cytochrome P450 enzymes in vitro. Avibactam and ceftazidime showed no in vitro cytochrome P450 induction at clinically relevant concentrations. Avibactam and ceftazidime do not inhibit the major renal or hepatic transporters in the clinically relevant exposure range, therefore the interaction potential via these mechanisms is considered to be low.
Clinical data have demonstrated that there is no interaction between ceftazidime and avibactam, and between ceftazidime/avibactam and metronidazole.

Other types of interaction.

Concurrent treatment with high doses of cephalosporins and nephrotoxic medicinal products such as aminoglycosides or potent diuretics (e.g. furosemide) may adversely affect renal function (see Section 4.4 Special Warnings and Precautions for Use).
Chloramphenicol is antagonistic in vitro with ceftazidime and other cephalosporins. The clinical relevance of this finding is unknown, but due to the possibility of antagonism in vivo this drug combination should be avoided.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

The effects of ceftazidime/avibactam on fertility in humans have not been studied. No data are available on animal studies with ceftazidime. Animal studies with avibactam do not indicate harmful effects with respect to male fertility. Studies in female rats showed a dose-related increase in pre- and post-implantation losses and smaller live litter size at ≥ 500 mg/kg/day (≥ 3 times the human therapeutic exposure at 500 mg three times a day, based on AUC).
(Category B3)

Ceftazidime.

The safety of ceftazidime in pregnancy has not been established, although animal studies have not produced evidence of embryopathic or teratogenic effects attributable to ceftazidime.

Avibactam (pregnancy category B3).

Animal studies with avibactam have shown reproductive toxicity without evidence of teratogenic effects.
In pregnant rabbits administered avibactam at 300 and 1000 mg/kg/day (5-21 times the human therapeutic exposure based on AUC), there was a dose-related lower mean fetal weight and delayed ossification, associated with maternal toxicity (decreased food consumption and body weight gain). Plasma exposure levels at maternal and fetal NOAEL (100 mg/kg/day) indicate low margins of safety (1.5 times the human therapeutic exposure based on AUC).
In the rat, no adverse effects were observed on embryofetal development at up to 1000 mg/kg/day (6 times the human therapeutic exposure based on AUC). Following administration of avibactam throughout pregnancy and lactation in the rat, there was no effect on pup survival, growth or development, however there was an increase in incidence of dilation of the renal pelvis and ureters in less than 10% of the rat pups at maternal exposures ≥ 450 mg/kg/day (greater than or equal to approximately 3 times the human therapeutic exposures based on AUC). Ceftazidime/avibactam should only be used during pregnancy if the potential benefit outweighs the possible risk.
Ceftazidime is excreted in human milk in small quantities.
It is unknown whether avibactam is excreted in human milk. Avibactam was excreted in rat milk (~20% of plasma C_max), and very low levels were detected in pup plasma (< 0.03% of nonclinical maternal plasma C_max) as a result of exposure from milk.
A risk to newborns/infants cannot be excluded. A decision must be made whether to discontinue breastfeeding or to discontinue/abstain from ceftazidime/avibactam therapy taking into account the benefit of breastfeeding for the child and the benefit of therapy for the woman.

4.7 Effects on Ability to Drive and Use Machines

Undesirable effects may occur (e.g. dizziness), which may influence the ability to drive and use machines following administration of Zavicefta (see Section 4.8 Adverse Effects (Undesirable Effects)).

4.8 Adverse Effects (Undesirable Effects)

In seven Phase 2 and Phase 3 clinical trials, 2024 adult patients were treated with Zavicefta. Table 7 lists the adverse events (regardless of causality) occurring in ≥ 1% of patients treated with Zavicefta with or without metronidazole or comparator from Phase 2 and Phase 3 clinical trials.
The most common adverse reactions occurring in ≥ 5% of patients treated with Zavicefta were Coombs direct test positive, nausea, and diarrhoea. Nausea and diarrhoea were usually mild or moderate in intensity. No clinically significant differences were observed in the safety profile across indications.
The following adverse reactions have been reported with ceftazidime alone and/or identified during the Phase 2 and Phase 3 trials with Zavicefta. Adverse reactions are classified according to frequency as defined in Table 8 and System Organ Class. Frequency categories are derived from adverse reactions and/or potentially clinically significant laboratory abnormalities.

Use in paediatrics.

The safety assessment in paediatric patients is based on the safety data from two clinical trials in which 61 paediatric patients (aged from 3 years to less than 18 years) with cIAI and 67 patients with cUTI (aged from 3 months to less than 18 years) received Zavicefta. Hence, no adverse drug reactions were seen which are expected to be observed in less than 1 in 100 patients (i.e. frequency categories of uncommon, rare, very rare, and frequency unknown). The safety profile in children appears to mirror the safety profile in adults and uncommon, rare, and very rare adverse events seen in adults are likely to occur in children as paediatric usage of the drug increases.

Post-marketing experience.

Nervous system disorders.

Seizures, encephalopathy, myoclonus - frequency unknown.

Reporting of suspected adverse effects.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions at http://www.tga.gov.au/reporting-problems.

4.9 Overdose

Overdose with ceftazidime/avibactam can lead to neurological sequelae including encephalopathy, convulsions and coma, due to the ceftazidime component.
Serum levels of ceftazidime can be reduced by haemodialysis or peritoneal dialysis. During a 4-hour haemodialysis period, 55% of the avibactam dose was removed.
For advice on the management of overdose please contact the Poisons Information Centre on 13 11 26 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Antibacterials for systemic use, ceftazidime, combinations, ATC code: J01DD52.

Mechanism of action.

Ceftazidime inhibits bacterial peptidoglycan cell wall synthesis following binding to penicillin binding proteins (PBPs), which leads to bacterial cell lysis and death. Avibactam is a non β-lactam, β-lactamase inhibitor that acts by forming a covalent adduct with the enzyme that is stable to hydrolysis. It inhibits both Ambler class A and class C β-lactamases and some class D enzymes, including extended-spectrum β-lactamases (ESBLs), KPC and OXA-48 carbapenemases, and AmpC enzymes. Avibactam does not inhibit class B enzymes (metallo-β-lactamases) and is not able to inhibit many class D enzymes.
Resistance. Bacterial resistance mechanisms that could potentially affect ceftazidime/avibactam include mutant or acquired PBPs, decreased outer membrane permeability to either compound, active efflux of either compound, and β-lactamase enzymes refractory to inhibition by avibactam and able to hydrolyse ceftazidime.
Antibacterial activity in combination with other antibacterial agents. No synergy or antagonism was demonstrated in in vitro drug combination studies with ceftazidime/avibactam and metronidazole, tobramycin, levofloxacin, vancomycin, linezolid, colistin and tigecycline.
Susceptibility testing breakpoints. Susceptibility testing interpretation according to the European Committee on Antimicrobial Susceptibility Testing (EUCAST) is recommended (https://www.eucast.org/). Minimum Inhibitory Concentration (MIC) breakpoints established by the European Committee on Antimicrobial Susceptibility Testing (EUCAST) for ceftazidime/avibactam are as follows. See Table 9.

Clinical efficacy against specific pathogens. As detailed in the clinical studies discussed below, efficacy has been demonstrated against the following pathogens that were susceptible to ceftazidime/avibactam in vitro.

Complicated intra-abdominal infections. Gram-negative micro-organisms.

Citrobacter freundii (C. freundii), Enterobacter cloacae (E. cloacae), Escherichia coli (E.coli), Klebsiella oxytoca (K. oxytoca), Klebsiella pneumoniae (K. pneumoniae), Pseudomonas aeruginosa (P. aeruginosa).

Complicated urinary-tract infections. Gram-negative micro-organisms.

E. coli, K. pneumoniae, Proteus mirabilis (P. mirabilis), E. cloacae, P. aeruginosa.

Hospital-acquired pneumonia including ventilator-associated pneumonia. Gram-negative micro-organisms.

E. cloacae, E. coli, K. pneumoniae, P. mirabilis, Serratia marcescens (S. marcescens), P. aeruginosa.
Clinical efficacy has not been established against the following pathogens that are relevant to the approved indications although in vitro studies suggest that they would be susceptible to ceftazidime/avibactam in the absence of acquired mechanisms of resistance.

Gram-negative micro-organisms.

Citrobacter koseri (C. koseri), Enterobacter aerogenes (E. aerogenes), Morganella morganii (M. morganii), Proteus vulgaris (P. vulgaris), Providencia rettgeri (P. rettgeri).
In-vitro data indicate that the following species are not susceptible to ceftazidime/avibactam.
Staphylococcus aureus (methicillin-susceptible and methicillin-resistant), Anaerobes, Enterococcus spp., Stenotrophomonas maltophilia, Acinetobacter spp.
Australian antibiotic resistance prevalence data. A surveillance study conducted in 2016 examined the susceptibility of ceftazidime/avibactam against clinical isolates collected from hospitalised patients. The in vitro data for clinical isolates are summarised in Table 10. All isolates were obtained from specimens collected from patients with documented IAI, UTI, skin and skin structure infections (SSTI), blood cultures, or lower respiratory tract infections (LRTI). Only one strain per patient infection episode was included in the surveillance programme. Susceptibility testing methods according to Clinical Laboratory Standards Institute (CLSI) (M2-09) were used and where applicable, susceptibility interpretive criteria applied were CLSI M100-S27 (2017).

Clinical trials.

Complicated intra-abdominal infections (cIAI). In two identical randomised, multi-centre, multinational, double-blind studies (RECLAIM 1 and RECLAIM 2), a total of 1058 adults with cIAI were randomised to receive treatment comparing Zavicefta (2000 mg of CAZ and 500 mg of AVI) administered intravenously over 120 minutes every 8 hours plus metronidazole (500 mg) to meropenem (1000 mg) administered intravenously over 30 minutes. Treatment duration was 5 to 14 days. cIAI (defined as infections that require surgical intervention and extend beyond the hollow viscus into the intraperitoneal space) included appendicitis, cholecystitis, diverticulitis, gastric/duodenal perforation, perforation of the intestine, and other causes of intra-abdominal abscesses and peritonitis.
The modified intent-to-treat (MITT) population included all patients who met the disease definition of cIAI and received at least 1 dose of the study drug. The clinically evaluable (CE) population included patients who had an appropriate diagnosis of cIAI and excluded patients with a bacterial species typically not expected to respond to both study drugs (i.e. Acinetobacter baumannii or Stenotrophomonas spp) and/or who had an important protocol deviation impacting the assessment of efficacy.
The primary efficacy endpoint was the clinical response at the Test of Cure (TOC) visit in the co-primary populations of the CE and MITT patients in Table 11.

Clinical cure rates at TOC by pathogen in the microbiologically modified intent-to-treat (mMITT) population for Gram-negative aerobes are shown in Table 12.

A further 432 adults with complicated intra-abdominal infections were randomised and received treatment in a multi-centre, double-blind study (RECLAIM 3) conducted in 3 Asian countries (China, Republic of Korea and Vietnam). The patient population and key aspects of the study design were identical to RECLAIM apart from the primary efficacy endpoint of clinical response at the TOC visit being solely in the CE population (see Table 13).

Clinical cure rates at TOC by pathogen in the microbiologically modified intent-to-treat (mMITT) population for Gram-negative aerobes are shown in Table 14.

In Phase 3 cIAI clinical trials, death occurred in 2.1% (18/857) of patients who received Zavicefta and metronidazole and in 1.4% (12/863) of patients who received meropenem. Among a subgroup with baseline CrCl 30 to 50 mL/min, death occurred in 16.7% (9/54) of patients who received Zavicefta and metronidazole and 6.8% (4/59) of patients who received meropenem. Patients with CrCl 30 to 50 mL/min received a lower dose of Zavicefta than is currently recommended for patients in this sub-group.
In a phase 3 cIAI clinical trial, clinical cure rates were lower in a subgroup of patients with baseline CrCl of 30 to 50 mL/min compared to those with CrCl > 50 mL/min. The reduction in clinical cure rates was more marked in patients treated with Zavicefta plus metronidazole compared to meropenem-treated patients. The decreased clinical response was not observed for patients with moderate renal impairment at baseline (CrCl of 30 to 50 mL/min) in the Phase 3 cUTI trials or the Phase 3 HAP/VAP trial. See Section 4.2 Dose and Method of Administration; Section 4.4 Special Warnings and Precautions for Use, Use in renal impairment; Section 5.2 Pharmacokinetic Properties, Renal impairment.
Complicated urinary tract infections (cUTI). A total of 1020 adults with documented cUTI (737 with acute pyelonephritis and 283 with cUTI without acute pyelonephritis) were randomised and received treatment in a phase III multicentre, double-blind, comparative study. cUTI included acute pyelonephritis and complicated lower urinary tract infections. Treatment was with either ceftazidime/avibactam (2000 mg/500 mg) IV over 120 mins every 8 hours or doripenem 500 mg IV over 60 mins every 8 hours. There was an optional switch to oral therapy for patients who had clinical improvement as defined in the study protocol after a minimum of 5 days IV treatment. Total duration of antibiotic therapy (IV plus oral) was 10 days (optionally up to 14 if bacteraemic). The mMITT population included all patients with a confirmed cUTI diagnosis, received at least 1 dose of study treatment and had a study-qualifying pre-treatment urine culture containing 105 CFU/mL of a Gram-negative pathogen and no more than 2 species of microorganisms. Any patient with a Gram-positive pathogen, or a bacterial species not expected to respond to both study drugs was excluded. Patients with CrCl < 30 mL/min were excluded.
The primary efficacy endpoint was per-patient microbiological response at the TOC visit in the mMITT analysis set. See Table 15.

Favourable microbiological response rates at TOC by pathogen in the mMITT population are shown in Table 16.

Hospital-acquired pneumonia (HAP). In a phase III double-blind, comparative study, a total of 808 adults with nosocomial pneumonia (280/808, 34.7% with VAP and 40/808 (5.0%) were bacteraemic at baseline) were randomised to receive treatment of ceftazidime/avibactam (2000 mg/500 mg) IV over 120 mins every 8 hours or meropenem 1 g IV over 30 mins every 8 hours. Treatment duration was 7 to 14 days. Nosocomial pneumonia was defined as an onset of relevant signs and symptoms ≥ 48 hours after admission or < 7 days after discharge from an inpatient acute or chronic care facility, and a new or worsening infiltrate on chest X-ray obtained within 48 hours prior to randomisation. Patients with infections only due to Gram-positive organisms were excluded from the trial, when this could be determined before enrollment. Following randomisation, patients in both treatment groups could receive empiric open-label linezolid or vancomycin to cover for Gram-positive pathogens while awaiting culture results. Treatment with Gram-positive coverage continued in patients with Gram-positive pathogens.
The clinically modified intent-to-treat (cMITT) population included patients who met the minimum disease criteria, received at least 1 dose of study treatment and who had properly obtained baseline respiratory or blood cultures demonstrating Gram-negative pathogens excluding patients with monomicrobial Gram-negative infections with species not expected to respond to both study drugs (e.g. Acinetobacter species or Stenotrophomonas species). The cMITT also included patients in whom no aetiologic pathogens were identified from respiratory or blood cultures at baseline. The CE at TOC analyses set was the clinically evaluable subset of the cMITT.
The primary efficacy endpoint was the clinical response at the TOC visit in the co-primary populations of the cMITT and CE at TOC. See Table 17.

All-cause mortality rates at Day 28 (cMITT) was 8.4% (30/356) and 7.3% (27/370) ceftazidime/avibactam and meropenem treated patients, respectively.
Clinical cure rate and favourable microbiological response rate at TOC by pathogen in mMITT for Gram-negative aerobes are shown in Tables 18 and 19.

Paediatric patients. Ceftazidime/avibactam has been evaluated in paediatric patients in two Phase 2 single-blind, randomised, comparative clinical studies, one in patients with cIAI and one in patients with cUTI. Patients aged 3 months to < 18 years were eligible for both studies, but in the cIAI study, the youngest patient was 3 years of age (median age: 11 years). Patients aged ≥ 3 months to < 1 year must have been born at term (defined as gestational age ≥ 37 weeks). Patients treated with ceftazidime/avibactam in the cIAI trial also received metronidazole (administered per local label; suggested dose: 10 mg/kg every 8 hours, administered IV over 20 to 30 minutes). The primary objective in each study was to assess safety and tolerability of ceftazidime/avibactam or ceftazidime/avibactam plus metronidazole. Secondary objectives included assessment of PK and efficacy; efficacy was a descriptive endpoint in both studies.

cIAI.

A total of 83 paediatric patients with cIAI were randomised (3:1) and received treatment with either CAZ/AVI plus metronidazole (n=61) (doses provided in Table 3), or meropenem (n=22), 20 mg/kg IV every 8 hours. After a minimum of 72 hours of IV treatment, there was an optional switch to oral therapy for patients who had clinical improvement, as defined in the study protocol. The total duration of antibiotic therapy (IV plus oral) was between 7 and 15 days. TOC assessments were performed 8 to 15 days after the last dose of study drug (IV or oral).
The majority of patients (87%) had appendiceal perforation or peri-appendiceal abscess (52/61, 85.2% CAZ/AVI plus metronidazole; 20/22, 90.9% meropenem). The CE population included patients who had a confirmed diagnosis of cIAI and received a minimum duration of IV study drug, and excluded patients who had a clinical response of indeterminate and/or an important protocol deviation impacting the assessment of efficacy. The microbiological intent-to treat (micro-ITT) population included 69 patients (50 CAZ/AVI plus metronidazole, 19 meropenem) who had at least one baseline intra-abdominal pathogen. Favourable clinical response rates at TOC are presented in Table 20.

The predominant pathogens isolated at baseline were E. coli (55/69, 79.7%) and P. aeruginosa 23/69 (33.3%). Favourable clinical response rates at TOC by baseline pathogen in the micro-ITT population are presented in Table 21.

cUTI.

A total of 95 paediatric patients with cUTI were randomised (3:1) and received treatment with either CAZ/AVI (n=67) (doses provided in Table 3), or cefepime (n=28), dosed per local prescribing information (maximum dose 2000 mg). After a minimum of 72 hours of IV treatment, there was an optional switch to oral therapy for patients who had clinical improvement, as defined in the study protocol. The total duration of antibiotic therapy (IV plus oral) was between 7 and 14 days. TOC assessments were performed 8 to 15 days after the last dose of study drug (IV or oral).
The majority of patients (83.2%) had acute pyelonephritis (55/67, 82.1% ceftazidime-avibactam; 24/28, 85.7% cefepime). The micro-ITT population included 77 randomised patients (54 ceftazidime-avibactam, 54 cefepime) who had at least 1 Gram negative typical pathogen known to cause cUTI and no Gram-positive pathogen in the urine at baseline. Favourable clinical, microbiological and combined clinical and microbiological response rates at TOC in the micro-ITT population are presented in Table 22.

The predominant baseline pathogen was E. coli (71/77, 92.2%). Favourable microbiological response rates by baseline pathogen at TOC in the micro-ITT population are presented in Table 23.

Limitations of clinical trial data. Patients with evidence of significant immunocompromise were excluded from the Phase 2 and 3 clinical trials.

5.2 Pharmacokinetic Properties

Distribution.

The human protein binding of both ceftazidime and avibactam is approximately 10% and 8%, respectively. The steady-state volumes of distribution of ceftazidime and avibactam were about 17 L and 22 L, respectively in healthy adults following multiple doses of 2000 mg/500 mg ceftazidime/avibactam infused over 2 hours every 8 hours. Both ceftazidime and avibactam penetrate into human bronchial epithelial lining fluid (ELF) to the same extent with concentrations around 30% of those in plasma. The concentration time profiles are similar for ELF and plasma.
Penetration of ceftazidime into the intact blood-brain barrier is poor. Ceftazidime concentrations of 4 to 20 mg/L or more are achieved in the CSF when the meninges are inflamed. Avibactam penetration of the blood brain barrier has not been studied clinically; however, in rabbits with inflamed meninges, CSF exposures of ceftazidime and avibactam were 43% and 38% of plasma AUC, respectively. Ceftazidime crosses the placenta readily, and is excreted in the breast milk.

Metabolism.

Ceftazidime is not metabolised. No metabolism of avibactam was observed in human liver preparations (microsomes and hepatocytes). Unchanged avibactam was the major drug-related component in human plasma and urine following dosing with [¹⁴C]-avibactam.

Excretion.

The terminal half-life (t_1/2) of both ceftazidime and avibactam is about 2 h after intravenous administration. Ceftazidime is excreted unchanged into the urine by glomerular filtration; approximately 80-90% of the dose is recovered in the urine within 24 h. Avibactam is excreted unchanged into the urine with a renal clearance of approximately 158 mL/min, suggesting active tubular secretion in addition to glomerular filtration. Approximately 97% of the avibactam dose is recovered in the urine, 95% within 12 h. Less than 1% of ceftazidime is excreted via the bile and less than 0.25% of avibactam is excreted into faeces.

Linearity/non-linearity.

The pharmacokinetics of both ceftazidime and avibactam are approximately linear across the dose range studied (50 mg to 2000 mg) for a single intravenous administration. No appreciable accumulation of ceftazidime or avibactam was observed following multiple intravenous infusions of 2000 mg/500 mg of ceftazidime/avibactam administered every 8 hours for up to 11 days in healthy adults with normal renal function.

Pharmacokinetic/pharmacodynamic relationship(s).

The antimicrobial activity of ceftazidime against specific pathogens has been shown to best correlate with the percent time of free-drug concentration above the ceftazidime/avibactam minimum inhibitory concentration over the dose interval (% fT > MIC of ceftazidime/avibactam). For avibactam the PK-PD index is the percent time of the free drug concentration above a threshold concentration over the dose interval (% fT > C_T).