On July 8, 2008, the FDA requested that the different manufacturers of fluoroquinolone antibiotics strengthen the warnings section in their prescribing information (PI) by adding a black box warning. This black box warning includes information about the increased risk of developing tendonitis and tendon rupture in patients taking fluoroquinolones.1
A black box warning is issued by the FDA during the postapproval monitoring phase. It is developed based on adverse effects that were not seen during the initial drug investigation as a result of preclinical testing of animals and data collected during phase 1-3 clinical testing. (see Black box warning guidelines.)
Background
Fluoroquinolone antibiotics, introduced in the U.S. market in the 1980s, have grown in momentum as one of the antimicrobial classes extensively used to treat a number of infections. In a sense, fluoroquinolones are a modified version of the quinolones that were discovered in the 1960s.3
Nalidixic acid (NegGram) was first discovered in 1962 and is considered a first-generation drug because it is the first compound of its kind and because of its limited activity. This agent was used to treat Gram-negative urinary tract infections.4 The second-generation fluoroquinolones have gained more Gram-negative coverage, as well as some Gram-positive and atypical pathogen coverage. These include ciprofloxacin (Cipro), norfloxacin (Noroxin), and ofloxacin (Floxin).4 The third-generation agents, including levofloxacin (Levaquin), and moxifloxacin (Avelox), gained a larger coverage including Gram-positive organisms, especially penicillin-resistant Streptococcus pneumoniae, and atypical pathogens.4 Lastly, the fourth-generation drugs keep the Gram-positive and Gram-negative coverage, but is also active against anaerobes. Gemifloxacin (Factive) is the drug most commonly used in this category.
Mechanism of action
All fluoroquinolones act in the same manner. The activity of all of these agents involves inhibition of bacterial topoisomerase IV and DNA gyrase. These are both enzymes that are required for DNA replication, transcription, repair, and recombination.5-7 All fluoroquinolones are bactericidal and have a postbiotic effect.
Indications and uses of fluoroquinolones
As a class, the fluoroquinolones have a number of therapeutic uses associated with them. These uses include the treatment of urinary tract infections, lower respiratory tract infections, skin and skin-structure infections, urethral and cervical gonococcal infections, prostatitis, acute sinusitis, exacerbations of chronic bronchitis, and community-acquired pneumonia.5-7
Adverse reactions
Overall, fluoroquinolone antibiotics are well tolerated. Most of the adverse reactions noted are mild in severity, as well as self-limiting. However, fluoroquinolones are associated with serious adverse reactions. The most common adverse reactions of this class of antibiotics include gastrointestinal distress such as nausea, vomiting, diarrhea, constipation, and abdominal pain.8 Another adverse reaction is central nervous system disturbances including headache, dizziness, drowsiness, and insomnia.8 Other adverse reactions of the fluoroquinolone antibiotics include phototoxicity, hepatotoxicity, cardiovascular effects, hypoglycemia or hyperglycemia, hypersensitivity reactions, and tendonitis and tendon damage.8 These last two led to the FDA's issuance of a black box warning for fluoroquinolones as a whole.1
Tendinopathy
Fluoroquinolones can cause the development of tendonitis or tendon rupture in 0.14% to 0.4% of patients using these agents.9 Quinolone-induced tendinopathy was first noted in 1983 with tendon rupture reported in 1987.10 The development of tendinopathy occurs more in patients with the following risk factors: 50 years of age or older, hemodialysis, renal transplantation, renal failure, corticosteroid use, diabetes mellitus, gout, peripheral vascular disease, strength training and aerobic exercise, and rheumatic disease.9 Tendinopathy associated with fluoroquinolone use occurs more in patients who are over the age of 60, use corticosteroids concomitantly, or are heart, lung, or kidney transplant recipients.9
There are many proposed mechanisms by which patients who are receiving fluoroquinolone therapy develop tendonitis or tendon rupture. These mechanisms of action include an ischemic vascular process (due to narrowed vasculature of the tendon leading to changes in blood flow), direct toxicity to the collagen (these agents cause tendon necrosis), or reduced clearance of the drug (due to decreased renal function).3
In patients presenting with tendonitis or tendon rupture, symptoms occurred on average 2 weeks after the start of the fluoroquinolone, but they can start as early as a few hours after the initial dose or up to 6 months after stopping drug therapy.10 These symptoms may not subside for at least 2 months after therapy is discontinued.8
Special instructions
Besides including the black box warning on all PIs for fluoroquinolones, the FDA is requiring all of the manufacturers to develop a medication guide for patients. This warning applies only to fluoroquinolones that are used for systemic administration, not ophthalmic or otic use.1
It is important to remember that there is an increased risk of developing tendonitis and tendon rupture (especially the Achilles tendon, shoulder, hand, or other tendons) in patients taking fluoroquinolones who are also over the age of 60, are heart, lung, or kidney transplant recipients, or are taking concomitant corticosteroids.1 Other risks of tendon rupture include rigorous physical activity or exercise, kidney failure, or tendon problems in the past, such as rheumatoid arthritis.1
At the first sign of tendon pain, swelling, or inflammation, the patient should be advised to:
* stop taking the fluoroquinolone drug
* avoid exercise and use of the affected area
* promptly contact the prescriber about changing to another antibiotic.1
Some signs and symptoms associated with tendon rupture include:
* a snap or pop in a tendon area
* bruising right after an injury in a tendon area
* inability to move the affected area or bear weight.1
In the past, the PI for all fluoroquinolones included a warning concerning the risk of developing tendonitis or tendon rupture. After many years of adverse reactions reported to the Adverse Events Reporting System, along with reassessment of the medical literature, the FDA made the decision to add a black box warning on all fluoroquinolones.1 As with any medication, the risk of developing an adverse reaction can be decreased and possibly prevented with proper education, monitoring, and patient selection.1
All healthcare providers must be aware of the possibility of tendonitis and tendon rupture in patients taking fluoroquinolones in order to make well-informed decisions regarding patient care.11
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