Hypersensitivity reactions: Serious and occasionally fatal hypersensitivity reactions are possible (see Contraindications and Adverse Reactions). In case of hypersensitivity reactions, treatment with Zavicefta must be discontinued immediately and adequate emergency measures must be initiated.
Serious and occasionally fatal hypersensitivity reactions (including anaphylactoid and severe cutaneous adverse reactions) have been reported in patients receiving therapy with beta-lactams. Before initiating therapy with Zavicefta, careful inquiry should be made concerning previous hypersensitivity reactions to penicillins, cephalosporins, carbapenems or other beta-lactam agents. If an allergic reaction occurs, Zavicefta must be discontinued immediately and appropriate alternative therapy instituted.
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 Adverse Reactions). 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 Adverse Reactions). 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) have been reported in patients taking beta-lactam antibiotics. When SCAR is suspected, Zavicefta should be discontinued immediately and an alternative treatment should be considered. See Adverse Reactions.
Spectrum of activity of ceftazidime/avibactam: Ceftazidime has little or no activity against the majority of Gram-positive organisms and anaerobes (see Dosage & Administration and Pharmacology: Pharmacodynamics under Actions). 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 Pharmacology: Pharmacodynamics under Actions).
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.
Controlled sodium diet: Each vial contains a total of approximately 6.3744 mmol of sodium (approximately 146 mg). This should be considered when administering Zavicefta to patients who are on a controlled sodium diet.
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 Dosage & 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 Pharmacology: Pharmacodynamics: Clinical trials and Pharmacokinetics: Renal impairment under Actions).
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.
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 Adverse Reactions).
Use in the elderly: No dosage adjustment is required in elderly patients (see Dosage & Administration and Pharmacology: Pharmacokinetics under Actions).
Use in children: The safety and efficacy of Zavicefta in paediatric patients (< 18 years of age) have not been established.