Consumer medicine information

Zavicefta 2000/500

Ceftazidime; Avibactam

BRAND INFORMATION

Brand name

Zavicefta

Active ingredient

Ceftazidime; Avibactam

Schedule

What is in this leaflet

This leaflet answers some common questions about Zavicefta. It does not contain all the available information. It does not take the place of talking to your doctor or pharmacist.

All medicines have risks and benefits. Your doctor has weighed the risks of you taking Zavicefta against the benefits they expect it will have for you.

If you have any concerns about taking this medicine, ask your doctor or pharmacist.

Keep this leaflet with the medicine. You may need to read it again.

What Zavicefta is used for

Zavicefta is an antibiotic used to treat serious infections caused by bacteria (germs), such as:

serious infections of the tissues and organs within the abdomen
serious infections of the urinary tract including kidney infections.
infections of the lungs that are caught in hospital including pneumonia caught from the ventilator (machine that helps a patient to breathe).

Zavicefta will not work against fungal or viral infections (such as colds or the flu).

Zavicefta is a combination of two medicines, ceftazidime and avibactam.

Ceftazidime belongs to a group of antibiotics called cephalosporins. It works by killing the bacteria that is causing the infection.

Avibactam belongs to a group of medicines called beta-lactamase inhibitors. It works by inhibiting the enzymes that break down ceftazidime in the body.

Zavicefta is given by injection and is usually given in hospital.

Ask your doctor if you have any questions about why this medicine has been prescribed for you. Your doctor may have prescribed it for another reason.

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

There is not enough information to recommend the use of this medicine for children under the age of 18 years.

Before treatment with Zavicefta

When Zavicefta must not be used

Zavicefta must not be given if you have an allergy to:

any medicine containing ceftazidime or avibactam, the active ingredients in Zavicefta
any of the ingredients listed at the end of this leaflet.
any other cephalosporin antibiotics
severe hypersensitivity to any other type of beta-lactam antibacterial agents such as penicillins, monobactams or carbapenems.

Some of the symptoms of an allergic reaction may include:

shortness of breath
wheezing or difficulty breathing
swelling of the face, lips, tongue or other parts of the body
rash, itching or hives on the skin.

Do not use Zavicefta if you have had a serious allergy to penicillins or beta-lactam antibiotics (e.g., carbapenems).

You may be more likely to have an allergic reaction to ceftazidime if you have had an allergic reaction to these other antibiotics.

The hospital staff will check that the expiry date printed on the pack has not passed and that the packaging is not torn or showing signs of tampering.

If you are not sure whether you should be given this medicine, talk to your doctor.

Before treatment with Zavicefta

Tell your doctor if you have allergies to any other medicines, foods, preservatives or dyes.

Tell your doctor if you have or have had any of the following medical conditions:

kidney problems
liver problems
severe diarrhoea after taking any antibiotics
anaemia
if you are on a controlled sodium diet.

Tell your doctor if you are pregnant or plan to become pregnant. Your doctor can discuss with you the risks and benefits involved.

Do not breast-feed if you are being given this medicine. The active ingredient, ceftazidime passes into breast milk and there is a possibility that your baby may be affected. The effect of the other active ingredient, avibactam, is unknown.

Tell your doctor if you are planning to have any urine tests conducted. Zavicefta may interfere with laboratory tests for the detection of glycosuria.

If you have not told your doctor about any of the above, tell him/ her before you start treatment with Zavicefta. Your doctor can discuss with you the risks and benefits involved.

Taking other medicines

Tell your doctor or pharmacist if you are taking any other medicines, including any that you get 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 antibiotic called cephalosporins, such as cefazolin and ceftazidime
chloramphenicol, a medicine used to treat eye infections.
medicines used to pass urine, such as frusemide.

These medicines may be affected by Zavicefta or may affect how well it works. You may need different amounts of your medicines, or you may need to take different medicines.

Your doctor and pharmacist have more information on medicines to be careful with or avoid while taking this medicine.

How Zavicefta is given

Zavicefta treatment is mostly given in hospital by your doctor or nurse.

The usual adult dose is 1 vial containing 2000 mg ceftazidime and 500 mg avibactam every 8 hours. It is given as a slow injection (infusion) directly into a vein, which usually takes 120 minutes.

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

Ask the doctor if you want more information about the dose of Zavicefta and how it is given.

Your doctor may lower the dose if you have kidney problems.

If too much has been given (overdose)

As Zavicefta is given under the close supervision of the doctor or nurse, it is unlikely that you will be given too much. If you are concerned that too much has been given, tell the doctor, nurse or pharmacist immediately.

Symptoms of an overdose may include confusion, difficulty remembering or focusing, drowsiness, muscle weakness, involuntary twitching, difficulty speaking or swallowing, seizures or coma.

While being treated with Zavicefta

Things you must do

If you are about to be started on any new medicine remind your doctor and pharmacist that you are taking Zavicefta.

Tell any other doctors, dentists, and pharmacists who treat you that you are taking this medicine.

If you are going to have surgery, tell the surgeon or anaesthetist that you are being treated with this medicine. It may affect other medicines used during surgery.

If you become pregnant while taking this medicine, tell your doctor immediately.

If you are about to have any blood tests tell your doctor that you are being treated with this medicine. It may interfere with the results of some tests.

If you get severe diarrhoea tell your doctor, pharmacist or nurse immediately. Do this even if it occurs several weeks after Zavicefta has been stopped.

Diarrhoea may mean that you have a serious condition affecting your bowel. You may need urgent medical care. Do not take any diarrhoea medicine without first checking with your doctor.

Things to be careful of

Be careful driving or operating machinery until you know how Zavicefta affects you. This medicine may cause dizziness in some people. If you have any of these symptoms, do not drive, operate machinery or do anything else that could be dangerous.

Side effects

Tell your doctor or pharmacist as soon as possible if you do not feel well while you are taking Zavicefta.

This medicine helps most people with certain serious infections but it may have unwanted side effects in a few people. All medicines can have side effects. Sometimes they are serious, most of the time they are not. You may need medical attention if you get some of the side effects.

Do not be alarmed by the following lists of side effects. You may not experience any of them.

Ask your doctor or pharmacist to answer any questions you may have.

Tell your doctor or pharmacist if you notice any of the following and they worry you:

diarrhoea, stomach pain
headache, dizziness
nausea, vomiting
rash, itchy skin
white, furry layer on the tongue
unusual vaginal discharge
changes in taste, or a metallic taste in the mouth
fever
redness, pain or swelling where Zavicefta was given into a vein.

The above list includes the more common side effects of your medicine.

If any of the following happen, tell your doctor immediately or go to Accident and Emergency at your nearest hospital:

abdominal pain
swelling of the limbs, face, lips, mouth or throat
shortness of breath or breathing difficulties
unusual weight gain
changes to urine volume
numbness or a tingling sensation
swelling of the face, lips, mouth or throat which may cause difficulty in swallowing or breathing
rash, itching, hives or severe skin reactions such as painful red areas, large blisters, peeling of your skin, and bleeding in the lips, eyes, mouth, nose and genitals
diarrhoea that keeps getting worse or does not go away, or stools that contains blood or mucus
yellowing of the skin and eyes (jaundice).

The above list includes very serious side effects. You may need urgent medical attention or hospitalisation. These side effects are very rare

Tell your doctor or pharmacist if you notice anything that is making you feel unwell.

Other side effects not listed above may also occur in some people.

Occasionally, Zavicefta may be associated with changes in your blood that may require your doctor or nurse to do certain blood tests.

After stopping your treatment

Tell your or your child's doctor or pharmacist if you notice any of the following side effects, particularly if they occur several weeks after stopping treatment with Zavicefta:

severe stomach cramps
watery and severe diarrhoea (which may be bloody), fever, in combination with one or both of the above.

Zavicefta can cause some bacteria, which are normally present in the bowel and normally harmless, to multiply and therefore cause the above symptoms. You may need urgent medical attention.

Tell your doctor if you notice any other side effects.

Other side effects not listed above may also occur in some people.

After stopping treatment

Storage

The hospital and/or pharmacy staff will store Zavicefta vials in a safe place at a temperature below 25°C and away from light. They will also prepare and store the infusion bags/ bottles ready for the injection.

Hospital staff will make sure the medicine is not used after the expiry date printed on the bag.

Product description

What it looks like

Zavicefta is a white to yellow powder supplied in a glass vial.

This product is supplied in packs of 10 vials.

Ingredients

Zavicefta contains 2000 mg of ceftazidime (as pentahydrate) and 500 mg of avibactam (as sodium) as the active ingredients.

The inactive ingredient is anhydrous sodium carbonate.

This medicine does not contain lactose, sucrose, gluten, tartrazine or any other azo dyes.

Supplier

Zavicefta is supplied in Australia by:

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

Australian Registration Number

AUST R 301205.

This leaflet was prepared in May 2019.

® Registered trademark.

Published by MIMS December 2019

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 listed in 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 information on the management of overdose, contact the Poisons Information Centre on 131126 (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).