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Cefepime (marketed as Maxipime) Update of Ongoing Safety Review

Audience: Infectious disease healthcare professionals

ROCKVILLE, Md., June 17, 2009--FDA notified healthcare professionals that it has finished its analysis of a possible risk of higher death with cefepime, an antibiotic, following publication of a study that suggested a higher rate of death in patients treated with this drug, as compared to patients treated with similar drugs. FDA reviewed this study data and conducted additional analyses based on additional data, including data submitted by Bristol Myers Squibb. FDA has determined that the data do not indicate a higher rate of death in cefepime-treated patients. Cefepime remains an appropriate therapy for its approved indications.

FDA will continue to review the safety of cefepime. As part of this ongoing review, both FDA and Bristol Meyers Squib are conducting separate analyses of death potentially associated with cefepime, using hospital drug use data. The results of these analyses likely will be reported in approximately one year.

[06/17/2009 - Information for Healthcare Professionals - FDA]

Previous MedWatch safety alert:

November 2007, updated May 2008 - Cefepime (marketed as Maxipime)

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Information for Healthcare Professionals: Cefepime (marketed as Maxipime)

FDA ALERT [06/17/2009]:  

 

The purpose of this communication is to share information about the FDA’s continuing safety review about the potential increased mortality in patients treated with cefepime. Cefepime is a cephalosporin antibacterial and is a member of the β–lactam class of antibacterial drugs. Cefepime is currently approved for the treatment of a variety of infections due to susceptible strains of microorganisms.

FDA performed meta-analyses based on additional data beyond those included in the Yahav et al. publication. In the FDA analyses, no statistically significant increase in mortality was seen in cefepime-treated patients compared to comparator-treated patients.

Based on the results of FDA's meta-analyses, the FDA has determined that cefepime remains an appropriate therapy for its approved indications.

 

This information reflects FDA’s current analysis of data available to FDA concerning cefepime.  Posting this information does not mean that FDA has concluded there is a causal relationship between the drug product and the emerging safety issue.  Nor does it mean that FDA is advising health care professionals to discontinue prescribing this product. FDA intends to update this document when additional information or analyses become available.


Background Information

 

On November 14, 2007, FDA announced that it was reviewing safety data about the potential increased mortality in patients treated with cefepime compared to other β–lactam antibacterials (comparator drugs).  Early Communication About an Ongoing Safety Review of Cefepime (marketed as Maxipime) 

The potential for increased mortality was noted in a meta-analysis published by Yahav et al.

To evaluate the finding from this meta-analysis, FDA requested data from the Sponsor, Bristol-Meyers Squibb (BMS) to perform additional analyses.  On May 14, 2008, FDA provided an update of its progress in reviewing the safety data submitted. Follow-up to the November 14, 2007, Communication about the Ongoing Safety Review of Cefepime 

 

Yahav et al. meta-analysis:  The Yahav et al. meta-analysis was based on 57 publications, mortality data were only available from 41 publications. Only 38 clinical trials were included in these 41 publications. Yahav et al. reported that in their trial-level meta-analysis using the Mantel-Haenszel fixed-effects model, 30 day all-cause mortality was higher with cefepime compared to other β -lactams (Risk Ratio [RR] 1.26 [95% CI 1.08-1.49]); adjusted risk difference as estimated by FDA= 17.02 per 1000 population (95% CI: 5.54, 28.5). In the subset of febrile neutropenia (19 publications), the authors reported a statistically significant increase in risk of 30-day all-cause mortality associated with cefepime [RR = 1.42 (95% CI: 1.09-1.84); adjusted risk difference as estimated by FDA= 18.99 per 1000 population (95% CI: 4.96-33.02)]. The Yahav et al. meta-analysis evaluated trial-level data but did not include patient-level data.

FDA Analyses:  The FDA performed meta-analyses based on both trial-1 and patient-level 2 data.   Data were derived from all available cefepime comparative clinical trials with evaluable data available to the FDA. In order to include trials in which there were no deaths in both treatment groups, the FDA used the Mantel-Haenszel risk difference method stratified by trial to estimate the risk of mortality in the trials—this is different from the risk ratio method used by Yahav et al. 

  • Trial-level meta-analysis:  The FDA’s trial-level meta-analysis included data from 88 clinical trials – the 38 trials that were included in the Yahav et al. meta-analysis, plus data from an additional 50 trials.  These 88 trials included 9,467 cefepime-treated patients and 8,288 comparator-treated patients.  No statistically significant difference in mortality was observed between cefepime and the comparators in the FDA trial-level meta-analysis.

All-cause mortality rates at 30-days post-therapy were 6.21% (588/9467) for cefepime-treated patients and 6.00% (497/8288) for comparator-treated patients with adjusted risk difference = 5.38 per 1000 population (95% C.I.: -1.53, 12.28). 

For the subset of 50 trials that were not included in the Yahav et al. meta-analysis, the all-cause mortality rates at 30-days post-therapy were 5.26% (290/5517) for cefepime-treated patients and 5.98% (290/4848) for comparator-treated patients with adjusted risk difference = -2.83 per 1000 population (95% C.I.: -11.47, 5.80).  

As the 95% confidence intervals for these two risk difference analyses include “0,” the difference in mortality rates between the cefepime-treated patients and the comparator-treated patients is not considered statistically significant.

 

A comparison of the Yahav et al. meta-analysis and the FDA trial-level meta-analysisa is provided in the following table:

 

 

Yahav et al. meta-analysis

FDA meta-analysis

 Trials not included in Yahav et al. meta-analysis

Combined (Yahav et al. + additional trials)

   

Number of Trials Included

38

trials

(41 publications)

50 trials

88 trials

Risk of all-cause mortality cefepime against comparator at 30-days post-therapy   

Risk Ratiob = 1.26

(95% CI: 1.08,1.49)

Adjusted risk difference= 17.02 per 1000 population (95% CI: 5.54, 28.5)

Adjusted risk difference = -2.83 per 1000 population (95% CI: -11.47, 5.80)

Adjusted risk difference = 5.38 per 1000 population (95% C.I.: -1.53, 12.28)

aTrial-level data refers to summary information from all patients in the trial without specifying details on any one patient.

b Note that different analyses methods were used in the Yahav et al. meta-analysis and in the FDA analysis. The Adjusted risk difference for the Yahav et al. meta-analysis was estimated by FDA.

 

  • Patient-level meta-analysis:  The FDA’s patient-level meta-analysis included 35 comparative clinical trials. The all-cause mortality rates at 30-days post-therapy were 5.63% (285/5058) for cefepime-treated patients and 5.68% (226/3976) for comparator-treated patients [adjusted risk difference = 4.83 per 1000 population (95% C.I.: -4.72, 14.38)].  No statistically significant difference in mortality was observed between cefepime and the comparators in the FDA patient-level meta-analysis.
  • Febrile Neutropenia Trials: The FDA’s trial-level meta-analysis of 24 febrile neutropenia trials did not show a statistically significant increased mortality in cefepime treated patients compared to those treated with comparators [adjusted risk difference = 9.67 per 1000 population (95% CI: -2.87, 22.21)].

Additional analyses of cefepime comparative febrile neutropenia trials with patient-level data were performed to further understand the causes of death and to identify potential risk factors for mortality such as co-morbid conditions, demographics, and concomitant drugs. In the meta-analysis of 7 comparative trials, all-cause mortality rates at 30-days post-therapy were 7.86% (61/776) for cefepime-treated patients and 6.55% (41/626) for comparator-treated patients [adjusted risk difference = 18.1 per 1000 population (95% C.I.: -9.22, 45.42)]. A review of all deaths in these febrile neutropenia trials revealed that most patients appeared to have died from their underlying malignancies and/or co-morbid conditions.

 

Conclusions:  At this time, the FDA has determined that cefepime remains an appropriate therapy for its approved indications.  This determination was based on the findings of both FDA's trial-level and patient-level meta-analyses, neither of which showed a statistically significant difference in mortality with cefepime.

FDA is continuing to review the safety of cefepime.  As part of the ongoing review, both the FDA and BMS are conducting separate analyses of mortality associated with cefepime using hospital drug utilization data.  The results of these analyses will likely not be reported for at least one year.

Adverse reactions or quality problems experienced with the use of this Product may be reported to the FDA's MedWatch Adverse Event Reporting program either online, by regular mail or by fax, using the contact information at the bottom of this sheet.

 

1 Trial-level data refers to summary information from all patients in the trials without specifying details of the patients.

2Patient-level data refers to detailed information about each patient in the trials.

    

 
 

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Posted: June 2009


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