Zavicefta (ceftazidime–avibactam) | Spørsmål og svar om sikkerhet

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ZAVICEFTA (ceftazidime-avibactam) frequently asked questions

What AEs have been reported with ZAVICEFTA in adult patients? What might I expect?
What specific AEs led to discontinuation of ZAVICEFTA in adult patients?
What are the key potential AEs to consider when using ZAVICEFTA in paediatric populations? How do these compare with those for adults?
Do any concerns exist with Clostridium difficile–associated diarrhoea?
Are there any drug–drug interactions with ZAVICEFTA?
Have any other drug–drug interaction studies been conducted?
Does ZAVICEFTA have any impact on QTc prolongation?
Have cases of haemolysis as an AE been observed in studies of ZAVICEFTA, as with other β-lactamase inhibitors?
What are the contraindications to ZAVICEFTA?

1. What AEs have been reported with ZAVICEFTA in adult patients? What might I expect?

ZAVICEFTA has a safety and tolerability profile that is consistent with ceftazidime and comparable to carbapenems
The most common AEs reported in Phase II and III trials of 2,024 patients (occurring in ≥5% of patients) were positive Coombs direct test, nausea and diarrhoea
Other common AEs (very common ≥1/10 or common ≥1/100 and <1/10) that have been reported with ceftazidime alone or with ZAVICEFTA include candidiasis, eosinophilia, thrombocytosis, thrombocytopenia, headache, dizziness, abdominal pain, vomiting, increased alanine aminotransferase, increased aspartate aminotransferase, increased blood alkaline phosphatase, increased gamma-glutamyltransferase, increased blood lactate dehydrogenase, maculopapular rash, urticaria, pruritus, infusion site thrombosis, infusion site phlebitis and pyrexia

Abbreviation:

AE, adverse events.

Reference:

ZAVICEFTA SPC

2. What specific AEs led to discontinuation of ZAVICEFTA in adult patients?

Discontinuation rates in the Phase II and III trials were low and similar between treatment groups (<5%)^1–5
In the Phase II trials, three ZAVICEFTA subjects discontinued study drug due to rash; otherwise, no single TEAE leading to premature discontinuation of study drug occurred in more than one subject⁶
In the Phase III trials (RECLAIM 1 & 2 and 3, RECAPTURE 1 & 2, REPRISE and REPROVE), no single TEAE leading to premature discontinuation of study drug occurred in more than two subjects in any study⁶

Abbreviations:

AE, adverse events; TEAE, treatment-emergent adverse event.

References:

Lucasti C, et al. J Antimicrob Chemother 2013;68:1183–92.

Vazquez JA, et al. Curr Med Res Opin 2012;28:1921–31.

Mazuski JE, et al. Clin Infect Dis 2016;62:1380–9.

Carmeli Y, et al. Lancet Infect Dis 2016;16:661–73.

Wagenlehner FM, et al. Clin Infect Dis 2016;63:754−62.

Ceftazidime–avibactam for injection. FDA briefing document, 2014.

3. What are the key potential AEs to consider when using ZAVICEFTA in paediatric populations? How do these compare with those for adults?

In two paediatric trials, ZAVICEFTA had a similar safety and tolerability profile in paediatric patients (aged 3 months and older) to that observed in adults with cIAIs and cUTIs^1–3
The safety assessment in paediatric patients is based on data from two trials, in which 61 patients with cIAIs and 67 patients with cUTIs aged 3 months to <18 years received ZAVICEFTA¹
In the two paediatric trials, the AE profile of ZAVICEFTA was similar to that of comparator therapies^2,3
- The most common adverse reactions (>3%) for ZAVICEFTA were vomiting, diarrhoea, rash and infusion-site phlebitis
- Rates of discontinuation due to AEs were low, and no deaths were reported in either study

Abbreviations:

AE, adverse events; cIAI, complicated intra-abdominal infection; cUTI, complicated urinary tract infection.

References:

ZAVICEFTA SPC

Bradley JS, et al. Pediatr Infect Dis J 2019;38:920–8.

Bradley JS, et al. Pediatr Infect Dis J 2019;38:816–24.

4. Do any concerns exist with Clostridium difficile–associated diarrhoea?

Nearly all systemic antibacterial drugs, including ZAVICEFTA, have been associated with C. difficile–associated diarrhoea, which can range in severity from mild to life-threatening. Antibacterial drugs can alter the normal flora of the colon, which may lead to overgrowth of C. difficile¹
If C. difficile–associated diarrhoea is suspected or confirmed, discontinuation of any antibacterial agents that are not directed against C. difficile should be considered¹
In a study assessing the effect of ZAVICEFTA on the human intestinal microbiota, there was a significant decrease in the presence of clostridia, although the ecological pattern differed among the volunteers²
Toxigenic C. difficile strains were detected in 5 of 12 subjects’ faecal samples submitted for culture and susceptibility testing. Three out of these five subjects reported loose stools, and one subject reported flatulence; however, no colitis was reported. Three out of four of these gastrointestinal AEs occurred and resolved by the day the subjects’ prospectively planned faecal samples were identified as positive for C. difficile; all four resolved without treatment²
Across the ZAVICEFTA programme, the incidence of C. difficile–associated diarrhoea has been very low and similar to that of the comparators studied³
In the Phase III clinical trial programme, the incidence of C. difficile infections was similar for ZAVICEFTA and carbapenems^4–6
In RECLAIM 1 & 2, there was one local laboratory-confirmed toxin-positive case of C. difficile enterocolitis in each treatment group, with both cases considered non-serious and moderate in intensity⁴
In RECAPTURE 1 & 2, three AEs of C. difficile colitis were reported in 2 (0.4%) patients receiving ZAVICEFTA. None were reported in the doripenem treatment group⁵
In REPROVE, there were two confirmed AEs of C. difficile colitis reported in patients receiving treatment with ZAVICEFTA. Both events were non-serious and reported to be mild in intensity; both resolved. The investigator considered these AEs to be related to treatment with ZAVICEFTA in both patients. There was also one unconfirmed event of C. difficile infection reported in one patient treated with ZAVICEFTA. This event was non-serious and moderate in intensity and was not considered related to treatment by the investigator^6,7
Diarrhoea and C. difficile–associated diarrhoea are expected events for ZAVICEFTA and meropenem. In addition to study treatment, most patients in REPROVE also received concomitant antibiotics that may lead to antibiotic-associated diarrhoea⁶
There were three post-treatment events of pseudomembranous colitis in REPROVE: one in the ZAVICEFTA group and two in the meropenem group. These events were all non-serious and mild in intensity⁶

Abbreviation:

AE, adverse events.

References:

ZAVICEFTA SPC

Rashid MU, et al. Int J Antimicrob Agents 2015;46:60–5.

Ceftazidime-avibactam for injection. FDA briefing document, 2014.

Mazuski JE, et al. Clin Infect Dis 2016;62:1380–9.

Wagenlehner FM, et al. Clin Infect Dis 2016;63:754−62

Torres A, et al. Lancet Infect Dis 2018;18: (Suppl)285–95.

Torres A, et al. Lancet Infect Dis 2018;18:285–95.

5. Are there any drug–drug interactions with ZAVICEFTA?

There are no known, clinically significant interactions, except for probenecid
Probenecid inhibits OAT uptake of avibactam by 56% to 70% in vitro and has the potential to decrease the elimination of avibactam when co-administered
A clinical interaction study of avibactam with probenecid has not been conducted; therefore, co-administration of avibactam and probenecid is not recommended
In vitro, avibactam is a substrate of OAT1 and OAT3 transporters, which may contribute to the active uptake from the blood compartment and its excretion
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

Reference:

ZAVICEFTA SPC

6. Have any other drug–drug interaction studies been conducted?

No drug–drug interaction studies have been conducted
Clinical data have demonstrated that there is no interaction between ceftazidime and avibactam and between ZAVICEFTA and metronidazole

Reference:

ZAVICEFTA SPC

7. Does ZAVICEFTA have any impact on QTc prolongation?

In a comprehensive QT study, a supratherapeutic dose of ceftazidime (3000 mg) in combination with a supratherapeutic dose of avibactam (2000 mg) given as a 30-minute single infusion was investigated for QT effects. At peak plasma concentrations, or at any other time, no significant effect on QTcF interval was detected

Abbreviations:

QT, QT interval; QTc, corrected QT interval; QTcF Fridericia’s corrected QT interval.

Reference:

Das S, et al. J Clin Pharmacol 2013;54:331–40.

8. Have cases of haemolysis as an AE been observed in studies of ZAVICEFTA, as with other β-lactamase inhibitors?

ZAVICEFTA use may cause development of a positive direct antiglobulin test (DAGT, or Coombs test), which may interfere with the crossmatching of blood and/or may cause drug-induced immune haemolytic anaemia. There was no evidence of haemolysis in patients who developed a positive DAGT on treatment in the clinical trials of ZAVICEFTA

Abbreviations:

AE, adverse events; DAGT, direct antiglobulin test.

Reference:

ZAVICEFTA SPC

9. What are the contraindications to ZAVICEFTA?

Sodium carbonate is an active substance causing hypersensitivity
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, carbapenems)

Reference:

ZAVICEFTA SPC

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