ZAVICEFTA SmPC and API

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Zavicefta®(ceftazidime and avibactam) 2g/0.5g powder for concentrate for solution for infusion. Prescribing Information:

Please refer to the Summary of Product Characteristics (SmPC) before prescribing Zavicefta. Indications: Zavicefta is indicated in adults for treatment of complicated intra-abdominal infection (cIAI), complicated urinary tract infection (cUTI), including pyelonephritis and hospital-acquired pneumonia (HAP), including ventilator associated pneumonia (VAP).  Also indicated for the treatment of infections due to aerobic Gram-negative organisms in adult patients with limited treatment options. Consideration should be given to official guidance on the appropriate use of antibacterial agents. Presentation: 2g ceftazidime (as ceftazidime pentahydrate) and 0.5g avibactam (as avibactam sodium) powder for concentrate for solution for infusion.  After reconstitution, 1mL of solution contains 167.3mg of ceftazidime and 41.8mg of avibactam. Dosage and administration: Zavicefta is administered by intravenous infusion over 120 minutes in an infusion volume of 100mL.  The recommended intravenous dose for patients with estimated creatinine clearance (CrCL) ≥ 51mL/min is 2g ceftazidime and 0.5g avibactam every 8 hours, for a duration of 5 to 14 days for complicated IAI, 5-10 days for complicated UTI including pyelonephritis and 7-14 days for Hospital-acquired pneumonia, including VAP. For infections due to aerobic Gram-negative organisms in patients with limited treatment options, duration of treatment should be guided by the  severity of infection, pathogen and patient’s clinical and bacteriological progress.  Special populationsElderly:  No dose adjustment required.  Renal impairment:  Mild (estimated CrCL ≥ 51 - ≤ 80mL/min):  No dose adjustment.  CrCL 31‑50mL/ min (estimated):  1g ceftazidime and 0.25g avibactam, every 8 hours.  CrCL 16‑30mL/ min (estimated):  0.75g ceftazidime and 0.1875g avibactam, every 12 hours.  CrCL 6‑15mL/ min (estimated):  0.75g ceftazidime and 0.1875g avibactam, every 24 hours.  ESRD including on haemodialysis:  0.75g ceftazidime and 0.1875g avibactam, every 48 hours.  Hepatic impairment:  No dose adjustment required.  Paediatric population: <18 years old: Safety and efficacy not established.

Contraindications:  Hypersensitivity to the active substances, any of the excipients or 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). Warnings and precautions:  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: Discontinuation of Zavicefta and the administration of specific treatment for Clostridium difficile should be considered in patients who present with diarrhoea during or subsequent to the administration of Zavicefta.  Medicinal products that inhibit peristalsis should not be given.  Renal impairment:  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.  Close monitoring of estimated creatinine clearance is advised. 

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, which may interfere with the cross-matching of blood and/or may cause drug induced immune haemolytic anaemia. Patients experiencing anaemia during or after treatment with Zavicefta should be investigated for this possibility.  Spectrum of activity:  Ceftazidime has little or no activity against the majority of Gram-positive organisms and anaerobes.  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.  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:  Consideration should be given to patients who are on a controlled sodium diet. 

Drug interactions: Co‑administration with probenecid may affect elimination of avibactam and is therefore not recommended.  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.  No interaction between ceftazidime and avibactam, or between ceftazidime/avibactam and metronidazole have been demonstrated.  Concurrent treatment with high doses cephalosporins and aminoglycosides or potent diuretics (e.g. furosemide) may adversely affect renal function.  Chloramphenicol should be avoided, due to the possibility of antagonism in vivo. Pregnancy and lactation:  Zavicefta should only be used during pregnancy if the potential benefit outweighs the possible risk.  Ceftazidime is excreted in human milk in small quantities.  A risk to newborns/infants cannot be excluded. A decision must be made whether to discontinue breast feeding Ability to drive and use machines:  Undesirable effects may occur (e.g. dizziness).  Undesirable events: Very commonCoombs direct test positive.  CommonCandidiasis (including vulvovaginal candidiasis and oral candidiasis), eosinophilia, thrombocytosis, thrombocytopenia, headache, dizziness, diarrhoea, abdominal pain, nausea, vomiting, alanine aminotransferase increased, aspartate aminotransferase increased, blood alkaline phosphatase increased, gamma-glutamyltransferase increased, blood lactate dehydrogenase increased, rash maculo-papular, urticaria, pruritus, infusion site thrombosis, infusion site phlebitis, pyrexia. Uncommon: Clostridium difficile colitis, pseudomembranous colitis, neutropenia, leukopenia, lymphocytosis, paraesthesia, dysgeusia, blood creatinine and urea increased, acute kidney injury.  Very rareTubulointerstitial nephritis.  Unknown:  Agranulocytosis, haemolytic anaemia, anaphylactic reaction, jaundice,  toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema multiforme, angioedema, jaundice, drug reaction with eosinophilia and systemic symptoms (DRESS). Refer to SmPC for further information on side effects. Overdose: Overdose with ceftazidime/avibactam can lead to neurological sequelae including encephalopathy,convulsions and coma.

Legal Category: S1A. Marketing Authorisation Number: EU/1/16/1109/001 - 2g/0.5g powder for concentrate for solution for infusion, 20 mL vial. Marketing Authorisation Holder: Pfizer Ireland Pharmaceuticals, Operations Support Group, Ringaskiddy, County Cork, Ireland. For full prescribing information see Summary of Product Characteristics. For further information on this medicine please contact: Pfizer Medical Information on 1800 633 363 or at [email protected]. For queries regarding product availability please contact: Pfizer Healthcare Ireland, Pfizer Building 9, Riverwalk, National Digital Park, Citywest Business Campus, Dublin 24 + 353 1 4676500.

This medicinal product is subject to additional monitoring.  This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions. Refer to section 4.8 of the SPC for how to report adverse reactions.

 

Last revised: January 2018

 

Ref: ZV 2_0