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POSTED: OCTOBER 04, 2013
Tygacil Gets Black Box Warning on Increased Risk for Death
by Ben Guarino
The FDA has issued a black box warning label for the IV antibiotic tigecycline because patients receiving the drug have an increased risk for dying.
In 2010, the FDA had issued a safety alert stating that administration of tigecycline (Tygacil, Pfizer) was associated with an increased risk for death, but the agency did not add a warning label until now.
The new warning may affect institutions that have been using tigecycline, according to Dorothy McCoy, PharmD, BCPS-ID, a clinical assistant professor at the Ernest Mario School of Pharmacy at Rutgers University, in Piscataway, N.J. But, she said, the antibiotic’s risks are well known to many infectious disease pharmacists. “This is not surprising.”
For the watchdog organization Public Citizen, the label change is not only unsurprising, but it comes a few years too late. “The requirement for a black box warning was a step in the right direction,” said Michael Carome, MD, the director of Public Citizen’s Health Research Group, “but it was not timely, in our view.”
In October 2011, the Health Research Group petitioned the FDA to add a warning label to the antibiotic, stating that tigecycline “should be used only as a last-resort antibiotic in the treatment of serious infections, and then only in combination with one or more bactericidal antibiotics.”
Dr. Carome said Public Citizen isn’t seeking the removal of the drug by the FDA, but wants the agency to make sure providers are aware of its risks.
The FDA based its latest decision on a meta-analysis of 10 studies that showed increased mortality among patients receiving tigecycline. According to the FDA review, of 2,640 patients who received tigecycline, 2.5% died, compared with 1.8% of 2,628 patients who were given other antibacterial drugs. The adjusted risk difference for death was 0.6% (95% confidence interval [CI], 0.0-1.2%). The FDA attributed the majority of deaths to infection complications, worsening infections and other underlying medical conditions (FDA Drug Safety Communication, 2013).
“This information is the same information the FDA had three years ago,” Dr. Carome said. “The trend has been a consistent signal since 2010.” The FDA made no comment on this point.
A previous meta-analysis of 13 Phase III and IV trials, cited by the FDA in its 2010 statement, also demonstrated an increased risk for death. Among 3,788 patients who received tigecycline, 148 deaths occurred (4% mortality), compared with 106 deaths among 3,646 patients (3% mortality) who were administered other antimicrobials, resulting in an adjusted risk difference of 0.6% (95% CI, 0.1%-1.2%) (FDA Drug Safety Communication, 2010).
“The higher death rate in some populations of patients with severe illness has been known with Tygacil monotherapy,” wrote Gary Stein, PharmD, a professor of medicine and pharmacology in the Division of Infectious Diseases at Michigan State University, East Lansing, in an email.
When the FDA approved tigecycline in 2005, the drug was the first glycylcycline, a tetracycline derivative, available for use in a clinical setting. Tigecycline binds to the 30S subunit of microbial ribosomes and disrupts protein translation inside bacteria. The antibiotic is indicated for complicated skin and skin structure infections, complicated intraabdominal infections and community-acquired bacterial pneumonia. The FDA has not approved tigecycline for diabetic foot infection or hospital-acquired pneumonia, including ventilator-associated pneumonia.
Although Public Citizen welcomed the FDA’s addition of a black box warning label to tigecycline, Dr. Carome said he would like to see Pfizer release a Dear Doctor letter. “It’s most important that the physician prescribers understand this risk,” he said.
At Hackensack University Medical Center, in New Jersey, where Dr. McCoy practices, tigecycline is listed as a restricted antibiotic under the institution’s antibiotic stewardship program. Infectious disease clinicians prescribe other agents first, reserving tigecycline for cases of allergic reactions or multidrug resistance.
“If you have a resistant gram-negative organism, when you can’t use the first-, second- or third-line choices,” Dr. McCoy said, “you might [still] look to use this agent. That’s probably how most people have used it, and that’s why the warning might not change [practice] much.”
Drs. Carome and McCoy reported no conflicts of interest. Dr. Stein has received research grants from Pfizer, Inc.