Tigecycline Graduates to a Black Box

Tigecycline Graduates to a Black Box

By Stan Deresinski, MD, FACP, FIDSA, Clinical Professor of Medicine, Stanford University, Hospital Epidemiologist, Sequoia Hospital, Redwood City, CA, Editor of Infectious Disease Alert.

In the U.S., tigecycline has received indications for use in the treatment of complicated skin and skin structure infections (cSSSI), complicated intra-abdominal infections (cIAI), and community-acquired bacterial pneumonia (CABP) caused by susceptible strains of designated bacteria. Several years ago, however, analysis of 13 randomized trials found evidence of numerically excess mortality in those assigned tigecycline in 12. This finding was obviously of concern and a bolded statement was added to product prescribing information. At the time, the explanation was unclear and it was felt that further analysis was warranted.

Further analysis of the trials has led to alterations of the product label that include:

"Addition of a boxed warning to highlight the increased all-cause mortality risk in adults that has been observed in a meta-analysis of all Phase 3 and 4 clinical trials and stating that TYGACIL should be reserved for use in situations when alternative treatments are not suitable. The previous TYGACIL label included a bolded warning which provided data from this analysis, which showed an increase in all-cause mortality in TYGACIL-treated adult patients compared to controls with a risk difference of 0.6% (95% CI 0.1, 1.2).

"Addition of information to the Warnings and Precautions section (5.1) that an increase in all-cause mortality was also seen in a meta-analysis limited to the approved indications with a risk difference of 0.6% (95% CI 0.0, 1.2).

"Addition of Limitations of Use to the Indications and Usage section. Based on data from clinical trials, TYGACIL is not indicated for treatment of diabetic foot infection or hospital-acquired or ventilator-associated pneumonia.

"TYGACIL should be reserved for use in situations when alternative treatments are not suitable."

This change was based on evidence of an increase in all-cause mortality observed in a meta-analysis of the 13 Phase 3 and 4 clinical trials in tigecycline-treated patients versus comparator-treated patients. In these trials, death occurred in 150/3788 (4.0%) of patients receiving tigecycline and 110/3646 (3.0%) of patients receiving comparator antibiotics. Using a random effects model by trial weight in a pooled analysis of all 13 trials, the adjusted difference in risk of all-cause mortality was 0.6% (95% CI, 0.1 to 1.2), with tigecycline having the higher mortality risk.

Further analysis of mortality observed in all the trials, including post-marketing trials, that were conducted for the 3 approved indications, found an adjusted mortality rate of 2.5% (66/2640) for tigecycline and 1.8% (48/2628) for comparator agents, respectively. When stratified by trial weight, the adjusted risk difference was 0.6% (95% CI, 0.0 to 1.2).

The cause of this mortality difference has not been unequivocally established. Generally, deaths were the result of worsening infection, complications of infection or underlying co-morbidities. The most dramatic difference in the individual trials was in a randomized, double-blind Phase 3 study comparing tigecycline to imipenem/cilastatin in the treatment of 945 patients with hospital-acquired pneumonia (HAP), including patients with ventilator-associated pneumonia and it is suspected that dosing was inadequate for this infection.

As a consequence of these findings, tigecycline administration should be reserved for use in situations when alternative treatments are not available.

Reference

1. FDA Drug Safety Communication: FDA warns of increased risk of death with IV antibacterial Tygacil (tigecycline) and approves new Boxed Warning: http://www.fda.gov/Drugs/DrugSafety/ucm369580.htm TYGACIL Full Prescribing Information: www.tygacil.com