Special Warning : אזהרת שימוש

4.4      Special warnings and precautions for use

Hypersensitivity reactions


Serious and occasionally fatal hypersensitivity reactions are possible (see sections 4.3 and 4.8). In case of hypersensitivity reactions, treatment with Zavicefta® must be discontinued immediately and adequate emergency measures must be initiated.

There have been reports of hypersensitivity reactions which progressed to Kounis syndrome (acute allergic coronary arteriospasm that can result in myocardial infarction, see section 4.8).

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.

Clostridioides difficile -associated diarrhoea

Clostridioides 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).
Discontinuation of therapy with Zavicefta® and the administration of specific treatment for Clostridioides difficile should be considered. Medicinal products that inhibit peristalsis should not be given.

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). 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.

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). 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.

Limitations of the clinical data

Clinical efficacy and safety studies of Zavicefta® have been conducted in cIAI, cUTI and HAP (including VAP).

Complicated intra-abdominal infections in adults
In two studies in patients with cIAI, the most common diagnosis (approximately 42%) was appendiceal perforation or peri-appendiceal abscess. Approximately 87% of patients had APACHE II scores of ≤ 10 and 4% had bacteraemia at baseline. 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.

Complicated urinary tract infections in adults
In two studies in patients with cUTI, 381/1091 (34.9%) patients were enrolled with cUTI without pyelonephritis while 710 (65.1%) were enrolled with acute pyelonephritis (mMITT population). A total of 81 cUTI patients (7.4%) had bacteraemia at baseline.

Hospital-acquired pneumonia, including ventilator-associated pneumonia in adults In a single study in patients with nosocomial pneumonia 280/808 (34.7%) had VAP and 40/808 (5%) were bacteraemic at baseline.

Patients with limited treatment options
The use of ceftazidime/avibactam to treat patients with infections due to Gram-negative aerobic pathogens who have limited treatment options is based on experience with ceftazidime alone and on analyses of the pharmacokinetic-pharmacodynamic relationship for ceftazidime/avibactam (see section 5.1).

Spectrum of activity of ceftazidime/avibactam

Ceftazidime has little or no activity against the majority of Gram-positive organisms and anaerobes (see sections 4.2 and 5.1). 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).

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.

Interference with 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.


Controlled sodium diet

This medicinal product 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 product 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 aged from 3 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).

Effects on Driving

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).