Zavicefta

/ Pfizer

It is recommended that this drug should be used to treat infections due to aerobic Gram-negative organisms in adults and paediatric patients aged 3 months and older, with limited treatment options only after consultation with a physician with appropriate experience in the management of infectious diseases.
For recommended intravenous dose for adult and paediatric patients with estimated creatinine clearance (CrCL) > 50 mL/min, see prescribing information.
Elderly: No dosage adjustment is required in elderly patients.
Renal impairment: No dosage adjustment is required in patients with mild renal impairment (estimated CrCL > 50 – ≤ 80 mL/min). See prescribing information for dose adjustments in adults and pediatrics with CrCL ≤ 50 mL/min.
There is insufficient information to recommend a dosage regimen for paediatric patients < 2 years of age that have a CrCL < 16 mL/min/1.73 m2.
Hepatic impairment: No dosage adjustment is required in patients with hepatic impairment.
Paediatric population: The safety and efficacy of this medical product in paediatric patients < 3 months old have not been established. No data are available.

This medicinal product is indicated in adults and paediatric patients aged 3 months and older for the treatment of the following infections:
* Complicated intra-abdominal infection (cIAI), used in combination with Metronidazole
* Complicated urinary tract infection (cUTI), including pyelonephritis
* Hospital-acquired pneumonia (HAP), including ventilator associated pneumonia (VAP)
Treatment of adult patients with bacteraemia that occurs in association with, or is suspected to be associated with, any of the infections listed above.
This medicinal product is also indicated for the treatment of infections due to aerobic Gram-negative organisms in adults and paediatric patients aged 3 months and older with limited treatment options.
Consideration should be given to official guidance on the appropriate use of antibacterial agents.

Hypersensitivity to the active substances or to any of the 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).

Hypersensitivity reactions: Serious and occasionally fatal hypersensitivity reactions are possible. In case of hypersensitivity reactions, treatment with this agent 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.
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.
Clostridioidesdifficile-associated diarrhoea:
Clostridioidesdifficile-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. Discontinuation of therapy 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 . 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 this agent 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 this agent treatment cannot be ruled out. Patients experiencing anaemia during or after treatment with this agent should be investigated for this possibility.
Limitations of the clinical data: Clinical efficacy and safety studies of this agent have been conducted in cIAI, cUTI and HAP (including VAP).
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 prescribing information for full details.

Candidiasis (including vulvovaginal candidiasis and oral candidiasis), eosinophilia, thrombocytosis, thrombocytopenia, headache, dizziness, diarrhea, abdominal pain, nausea , vomiting, alanine aminotransferase increased, aspartate aminotransferase increased, blood alkaline phosphatase increased, gamma-glutamyltransferase increased, blood lactate dehydrogenase, rash maculo-papular, urticaria, pruritus, infusion site thrombosis, infusion site phlebitis, pyrexia.
See prescribing information for full details.

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.
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.

Pregnancy: Ceftazidime/avibactam should only be used during pregnancy if the potential benefit outweighs the possible risk.
Lactation: Ceftazidime is excreted in human milk in small quantities.
See prescribing information for full details.

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.

Storage: Store below 30°C.
After dilution: The chemical and physical in-use stability has been demonstrated for up to 24 hours at 2 – 8°C, followed by up to 12 hours at not more than 25°C.
From a microbiological point of view, the medicinal product should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 24 hours at 2 – 8ºC, unless reconstitution/dilution has taken place in controlled and validated aseptic conditions.