Zavicefta 2 G/0.5 G Solution

ZAVICEFTA is indicated in adults and paediatric patients 3 months of age and older for the treatment of infections caused by designated susceptible Gram-negative microorganisms (see section 4.4 and section 5.1). ZAVICEFTA should be reserved for the treatment of Gram-negative infections in adults and paediatric patients 3 months of age and older, caused by Gram-negative sensitive bacteria where other antimicrobials approved for similar infections and to which a causative bacteria are sensitive, were considered not to be an appropriate treatment option, have failed, are contraindicated or were not tolerated.

• Complicated intra-abdominal infections (cIAI), used in combination with metronidazole. ( Citrobacter freundii, Enterobacter cloacae, Escherichia coli, Klebsiella oxytoca, Klebsiella pneumoniae, Pseudomonas aeruginosa ).
• Complicated urinary tract infections (cUTI), including pyelonephritis. ( Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Enterobacter cloacae, Pseudomonas aeruginosa ).
• Hospital-acquired bacterial pneumonia (HABP). ( Enterobacter cloacae, Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Serratia marcescens, Pseudomonas aeruginosa ).
• Ventilator associated bacterial pneumonia (VABP). ( Enterobacter cloacae, Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Serratia marcescens, Pseudomonas aeruginosa ).

Treatment of adult patients with bacteraemia that occurs in association with, or is suspected to be associated with, any of the infections listed above.

Posology

Adults

The recommended dosage of ZAVICEFTA is 1 vial where each vial contains 2 g ceftazidime and 0,5 g avibactam administered by intravenous (IV) infusion in a volume of 100 mL at a constant rate over 120 minutes in patients aged 18 years or older. Treatment is repeated every 8 hours. For adults with renal impairment where CrCl u2264 50 mL/min, see dosing recommendations in Table 2.

Dosage in adults with creatinine clearance (CrCL) > 50 mL/min

Table 1 shows the recommended intravenous dose for adults with estimated creatinine clearance (CrCL) > 50 mL/min (see sections 4.4 and 5.1).

Table 1: Recommended dose for adults with estimated CrCL > 50 mL/min

1 CrCL estimated using the Cockcroft-Gault formula.

2 To be used in combination with metronidazole when anaerobic pathogens are known or suspected to be contributing to the infectious process.

3 To be used in combination with an antibacterial medicine active against Gram-positive pathogens when these are known or suspected to be contributing to the infectious process.

4 The total duration shown may include intravenous ZAVICEFTA followed by appropriate oral therapy. The time to switch from intravenous ZAVICEFTA to oral treatment with another antibiotic depends on the clinical situation but is normally after about 5 days (the minimum duration of treatment with ZAVICEFTA in clinical trials was 5 days). For complicated urinary tract infection (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 patientu2019s clinical and bacteriological progress.

Special populations

Elderly patients

No dosage adjustment is considered necessary in elderly patients (u2265 65 years). The dose regimen should be adjusted if renal impairment is present (see section 5.2).

Adults with renal impairment

The following dose adjustment is recommended in patients with renal impairment (see sections 4.4 and 5.2). Dose adjustments for ZAVICEFTA for patients with an estimated creatinine clearance (CrCl) u2264 50 mL/min are outlined in Table 2 below. The only information on dosing of ZAVICEFTA for patients requiring dialysis is in the setting of intermittent haemodialysis. For other types of dialysis, it is suggested that the dose/frequency of ZAVICEFTA should follow local label/local guidelines for dosing of ceftazidime. For example, for a dose of 500 mg ceftazidime the dose of ZAVICEFTA would be 500 mg ceftazidime/125 mg avibactam.

Table 2: Recommended dose for adults with estimated CrCL u2264 50 mL/min

1 CrCL estimated using the Cockcroft-Gault formula.

2 Dose recommendations are based on pharmacokinetic modelling (see section 5.2).

3 Ceftazidime and avibactam are removed by haemodialysis (see sections 4.9 and 5.2). Dosing of ZAVICEFTA on haemodialysis days should occur after completion of haemodialysis.

4 ZAVICEFTA is a combination medicine in a fixed 4:1 ratio and dosage recommendations are based on the ceftazidime component only (see section 6.6).

Haemodialysis

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

Haemofiltration

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

Peritoneal dialysis

There is insufficient data to make specific dosage adjustment recommendations for patients undergoing peritoneal dialysis.

Patients with hepatic impairment

No dosage adjustment is considered necessary in patients with hepatic impairment (see section 5.2). Close clinical monitoring for safety and efficacy is advised.

Paediatric patients

The safety and efficacy of ZAVICEFTA in paediatric patients < 3 months old have not been established. No data are available.

Dosage in paediatric patients with creatinine clearance (CrCL) > 50 mL/min/1,73 m2

Table 3 shows the recommended intravenous doses for paediatric patients with estimated creatinine clearance (CrCL) > 50 mL/min/1,73 m2 (see sections 4.4 and 5.1).

Table 3: Recommended dose for paediatric patients with estimated CrCL > 50 mL/min/1,73 m2

1 CrCL estimated using the Schwartz bedside formula.

2 To be used in combination with metronidazole when anaerobic pathogens are known or suspected to be contributing to the infectious process.

3 To be used in combination with an antibacterial medicine active against Gram-positive pathogens when these are known or suspected to be contributing to the infectious process.

4 The total treatment duration shown may include intravenous ZAVICEFTA followed by appropriate oral therapy.

5 There is limited experience with the use of ZAVICEFTA in paediatric patients 3 months to < 6 months (see section 5.2).

6 ZAVICEFTA is a combination medicine in a fixed 4:1 ratio and dosage recommendations are based on the ceftazidime component only (see section 6.6).

Method of administration

For intravenous use. ZAVICEFTA is administered by intravenous infusion over 120 minutes in an appropriate infusion volume of 100 mL. For instructions on reconstitution and dilution before administration of ZAVICEFTA, see section 6.6.

• Hypersensitivity to ceftazidime, avibactam or to any of the excipients contained in ZAVICEFTA (listed in section 6.1).
• Hypersensitivity to the cephalosporin class of antibacterials.
• Immediate and severe hypersensitivity (e.g. anaphylactic reaction) to any other type of u03b2-lactam antibacterial medicine (e.g. penicillins, monobactams or carbapenems).

Antibiotic stewardship

Prescribers should adhere to the principles of antimicrobial stewardship. To reduce the development of drug-resistant bacteria and maintain the effectiveness of ZAVICEFTA, ZAVICEFTA should be used to treat only indicated infections that are proven or strongly suspected to be caused by susceptible bacteria. It is recommended that ZAVICEFTA be used only after consultation with a medical practitioner with appropriate experience in the management of infectious diseases.

Hypersensitivity reactions

Serious and occasionally fatal hypersensitivity reactions have been reported (see sections 4.3 and 4.8). In severe 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 severe hypersensitivity reactions to ceftazidime, to other cephalosporins or to any other type of u03b2-lactam medicine. Caution should be used if ZAVICEFTA is given to patients with a history of non-severe hypersensitivity to other u03b2-lactam medicines.

Clostridium difficile-associated diarrhoea

Antibacterial medicine-associated colitis and pseudo-membranous colitis have been reported with ZAVICEFTA and may range in severity from mild to life-threatening. Therefore, it is important to consider this diagnosis in patients who present with diarrhoea during or subsequent to the administration of ZAVICEFTA (see section 4.8). Discontinuation of therapy with ZAVICEFTA and the administration of specific treatment for Clostridium difficile should be considered. Medicines that inhibit peristalsis should not be given.

Patients with renal impairment

Ceftazidime and avibactam are eliminated via the kidneys; therefore, the dose of ZAVICEFTA should be reduced according to the degree of renal impairment. Patients with renal impairment should be closely monitored for both safety and efficacy. Neurological sequelae, including tremor, myoclonus, non-convulsive status epilepticus, convulsion, encephalopathy and coma, have been reported with ceftazidime when the dose has not been reduced in patients with renal impairment (see section 4.2). In patients with impaired renal function, regular monitoring of estimated creatinine clearance is advised as in some patients, especially early in the course of their infection, the creatinine clearance estimated from serum creatinine can change quickly.

Nephrotoxicity

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

Non-susceptible organisms

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

Non-medicine interference

Ceftazidime does not interfere with enzyme-based tests for glycosuria, but slight interference (false-positive) may occur with copper reduction methods (Benedict's, Fehling's, Clinitest). Ceftazidime does not interfere in the alkaline picrate assay for creatinine.

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

ZAVICEFTA 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 medicine induced immune haemolytic anaemia. While DAGT seroconversion in patients receiving ZAVICEFTA was frequent in clinical studies, there was no evidence of haemolysis in patients who developed a positive DAGT on treatment (see section 4.8). 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.

Controlled sodium diet

For patients who are on a controlled sodium diet, the following important information about the ingredients of ceftazidime and avibactam should be considered:

• 2 g powder for solution for infusion - ceftazidime 2 g contains 4,52 mmol of sodium per vial; and
• 500 mg powder for solution for infusion - avibactam 500 mg contains 1,92 mmol of sodium per vial.

ZAVICEFTA contains approximately 146 mg sodium per vial, equivalent to 7,3 % of the WHO recommended maximum daily intake (RDI) of 2 g sodium for an adult. The maximum daily dose of this medicine is equivalent to 22 % of the WHO recommended maximum daily intake for sodium. ZAVICEFTA is considered high in sodium. This should be considered when administering ZAVICEFTA to patients who are on a controlled sodium diet. ZAVICEFTA may be diluted with sodium-containing solutions (see section 6.6) and this should be considered in relation to the total sodium from all sources that will be administered to the patient.

Paediatric population

There is a potential risk of overdosing, particularly for paediatric patients from 3 of age to less than 12 months of age. Care should be taken when calculating the volume of administration of the dose (see sections 4.9 and 6.6).

Concurrent treatment with high doses of cephalosporins and nephrotoxic medicines such as aminoglycosides or potent diuretics (e.g. furosemide) may adversely affect renal function (see section 4.4). Chloramphenicol is antagonistic in vitro with ceftazidime and other cephalosporins. The clinical relevance of this finding is unknown, but if concurrent administration of ZAVICEFTA with chloramphenicol is proposed, the possibility of antagonism should be considered. Avibactam showed no significant inhibition of cytochrome P450 enzymes. Avibactam and ceftazidime showed no in vitro cytochrome P450 induction in the clinically relevant exposure range. Avibactam and ceftazidime do not inhibit the major renal or hepatic transporters in the clinically relevant exposure range, therefore the drug-drug interaction potential via these mechanisms is considered low. In vitro, avibactam is a substrate of OAT1 (organic anion transporter) and OAT3 transporters which might contribute to the active uptake from the blood compartment and, thereby 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 when co-dosed. Since a clinical interaction study of avibactam and probenecid has not been conducted, co-dosing of avibactam with probenecid is not recommended.

Pregnancy

Safe use during pregnancy has not been established. Following administration of avibactam throughout pregnancy and lactation in the rat at maternal exposures greater than or equal to approximately 1,5 times human therapeutic exposures, there were minor changes in the morphology of the kidney and ureters in the rat pups. ZAVICEFTA should not be used during pregnancy unless clearly necessary.

Breastfeeding

Ceftazidime is excreted in human milk. Avibactam is excreted in rodent milk; it is unknown whether avibactam is excreted in human milk. Women receiving ZAVICEFTA should not breastfeed their infants.

Fertility

The effects of ZAVICEFTA on fertility in humans have not been studied. Animal studies with ceftazidime or avibactam do not indicate harmful effects with respect to fertility.

Undesirable effects may occur (e.g. dizziness), which may influence the ability to drive and use machines (see section 4.8).

Summary of the safety profile

In seven phase 2 and phase 3 clinical trials, 2 024 adult patients were treated with ZAVICEFTA. The most common adverse reactions occurring in u2265 5 % of patients treated with ZAVICEFTA were a positive direct antiglobulin test (DAGT), nausea, and diarrhoea. These were usually mild or moderate in intensity. No clinically significant differences were observed in the safety profile across indications.

Tabulated list of adverse reactions

The following adverse reactions have been reported with ceftazidime alone and/or identified during all Phase 2 and Phase 3 clinical trials with ZAVICEFTA (n=2 024). Adverse reactions are classified according to frequency and system organ class. Frequency categories are derived from adverse reactions and/or potentially clinically significant laboratory abnormalities, and are defined according to the following conventions: Very common (u2265 1/10); common (u2265 1/100 and < 1/10); uncommon (u2265 1/1 000 and <1/100); rare (u2265 1/10 000 and < 1/1 000); very rare (< 1/10 000); unknown (cannot be estimated from the available data). If an event was not seen in the overall Phase 2 and Phase 3 pool but was a known adverse reaction for ceftazidime alone, the frequency category for ceftazidime alone was used (including the category unknown).

Table 6: Frequency of adverse reactions by system organ class

Paediatric population

The safety assessment in paediatric patients is based on the safety data from two trials in which 61 patients (from 3 to less than 18 years of age) with cIAI and 67 patients with cUTI (from 3 months to less than 18 years of age) received ZAVICEFTA. Overall, the safety profile in these 128 paediatric patients was similar to that observed in the adult population with cIAI and cUTI.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicine is important. It allows continued monitoring of the benefit/risk balance of the medicine. Health care providers are asked to report any suspected adverse reactions to SAHPRA via the u201c6.04 Adverse Drug Reactions Reporting Formu201d, found online under SAHPRAu2019s publications: https://www.sahpra.org.za/Publications/Index/8

Overdosing with ZAVICEFTA can lead to neurological sequelae including encephalopathy, convulsions and coma, due to the ceftazidime component. Symptomatic and supportive treatment for overdose should follow local standard medical practice. Both ceftazidime and avibactam can be partially removed by haemodialysis.