21 May 2001

FDA approves levofloxacin antibiotic for pediatric patients exposed to aerosolized Bacillus anthracis (inhalational anthrax)

The US Food and Drug Administration (FDA) this month approved the antibiotic Levofloxacin (“Levaquin”) “for inhalational anthrax (post-exposure) to reduce the incidence or progression of disease following exposure to aerosolized Bacillus anthracis in pediatric patients (> 6 months of age or older)”.

The complete letter from the FDA with the “supplemental NDA approval”, dated May 5, 2008, can be found on the FDA website at: www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Search.Label_ApprovalHistory

Levofloxacin was approved in adults for this specific use, i.e., following exposure to aerosolized Bacillus anthracis on November 24, 2004.

In terms of the basis for approval, efficacy for post-exposure prevention of inhalational anthrax has not been tested in humans, for understandable ethical reasons. Instead, the FDA states that the effectiveness of levofloxacin “for this indication is based on plasma concentrations achieved in humans, a surrogate endpoint reasonably likely to predict clinical benefit”.

An animal efficacy study with levofloxacin was performed, however, and is briefly summarized in this FDA document. “A placebo-controlled animal study in rhesus monkeys exposed to an inhaled mean dose of 49 LD50 spores of B. anthracis (Ames strain) was conducted…Mortality due to anthrax for animals that received a 30 day regimen of oral LEVAQUIN beginning 24 hrs post exposure was significantly lower (1/10), compared to the placebo group (9/10)

[P=0.0011, 2-sided Fisher’s Exact Test]. The one levofloxacin treated animal that died of anthrax did so following the 30-day drug administration period.” Plasma concentrations of levofloxacin were measured during this animal study.

In terms of safety, this FDA document contains several cautions.

1. The FDA states that, except for this one indication of using levofloxacin “to prevent anthrax after possible exposure”, this antibiotic is “not recommended for children” due to “possible side effects.”

2. At the same time the FDA states that “Side effects that may occur during treatment to prevent anthrax might be acceptable due to the seriousness of the disease.”

3. Also of note, “the safety of Levaquin” in adults for durations of therapy beyond 28 days or in pediatric patients for durations of therapy beyond 14 days has not been studied.”

4. Under the section of this document titled “Adverse Events”

Table 1 compares the “Incidence of Musculoskeletal Disorders in Pediatric Clinical Trial”(s). A total of 1,340 children (6 months to 16 years of age) treated with oral and IV levofloxacin were compared with 893 children who were “non-fluoroquinolone treated” for “approximately 10 days”.

The two groups were compared after 60 days and after one year of follow-up. After 60 days, 2.1% of the levofloxacin- treated group and 0.9% of the control group (p=0.038) had musculoskeletal disorders; at one year, 3.4% of the levofloxacin- treated group and 1.8% in the control group did (p= 0.025). “Arthralgia was the most frequently occurring musculoskeletal disorder in both treatment groups.”

Importantly, “No child had a severe or serious disorder and all musculoskeletal disorders resolved without sequelae.” Again, the duration of levofloxacin was approximately 10 days in these clinical trials.

This 10-day time frame compares with the potentially much longer times of up to 60 days for post-exposure use to protect against inhalational anthrax. At the same time, however, this disease has a very high case fatality rate if not adequately treated before the third or “Late-Fulminant” clinical stage described in the current edition of Cecil’s Textbook of Medicine or the Principles and Practices of Infectious Diseases textbook edited by Mandell, Bennett, and Dolin.

Daniel R. Lucey, MD, MPH

Center for Biologic Counterrorism and Emerging Diseases

EROne Institutes, Department of Emergency Medicine

Washington Hospital Center

Adjunct Professor of Microbiology and Immunology

Georgetown University Medical Center, Washington, DC

Website for this posting: www.BePast.org

Email: Daniel.R.Lucey@Medstar.net