This is the original article that appeared in the New Englang Journal of
Medicine, September of 1994:

"Achilles Tendinitis and Tendon Rupture Due to Fluoroquinolone Antibiotics
To the Editor: Tendinitis and tendon rupture are unusual and unexpected side effects of drugs1,2. An 85-year-old man had been treated for polymyalgia rheumatica with prednisone. His condition improved in the next three months, and the dose of prednisone was reduced to 15 mg per day. Two weeks later a urologist prescribed enoxacin (two 200-mg tablets twice a day) for a urinary tract infection. On the seventh day of enoxacin therapy, pain developed in both calves radiating to the heels. The patient noted mild swelling in the lower extremities. On examination a week later he had difficulty walking because of pain in his lower legs. There was marked tenderness to palpation in both Achilles tendons. The ankle reflexes were normal. Fluoroquinolone-induced bilateral Achilles
tendinitis was suspected, and nabumetone was prescribed. The patient continued to have difficulty walking, and twelve days later a defect was palpated in the right Achilles tendon. Magnetic resonance imaging showed a complete rupture of the right Achilles tendon approximately 3 cm above the calcaneus. The patient was treated with a brace on the right ankle, with improvement in pain. The pain in the left calf and Achilles tendon resolved. Fluoroquinolone antibiotics have been associated with Achilles tendinitis and rupture in reports from Europe and New Zealand1,2. As of 1992 more than 40 cases had been reported in France. This unusual side effect has not been widely recognized in the United States and is not mentioned in the Physicians' Desk Reference. Physicians should be aware of this potential complication.

Kent A. Huston, M.D.
4330 Wornall St.
Kansas City, MO 64111
References "

This is the French response to this letter:

"To the Editor: Huston's letter reporting a case of tendinitis followed by
tendon rupture induced by fluoroquinolone therapy points out that this side effect is little recognized in the United States. In France, this adverse reaction is reported in the Vidal pharmacologic dictionary1 and on the prescribing leaflets of fluoroquinolones.
We have described a series of 100 patients who had tendon disorders,
including 31 ruptures, between 1985 and July 1992.2 In our study, the patients (in a 3:1 ratio of men to women) were an average of 63 years old (range, 25 to 84), and many had received steroid therapy.2 The Achilles tendon was affected most often, and half the patients had bilateral tendinitis. However, other tendons can be damaged, such as the long head of the biceps and the long extensor muscle of the thumb. The average time between the start of treatment with the medication and the onset of the symptoms was 13 days, but in a few patients the tendinitis appeared within 1 or 2 days. The course was usually favorable, but a
third of patients had persistent symptoms over a period of more than two months.
Huston emphasizes the accuracy of magnetic resonance imaging (MRI) in detecting complete rupture of the Achilles tendon. Our preliminary results confirm that MRI is useful in patients with fluoroquinolone-induced tendinitis and that it allows the early detection and follow-up of any abnormal tendon signal. MRI readily detects thickening of the tendon or changes around the tendon. In addition, signs of degenerative changes or established rupture are also easy to see in T1 and T2 sequences.3 After the withdrawal of the fluoroquinolone, MRI
can help to guide treatment, which may include rest, the use of a cane in walking, and even a below-the-knee cast. Since 1992, practitioners and patients have been informed by the French authorities and pharmaceutical firms of the risk of fluoroquinolone-induced
tendinitis as well as of the guidelines to prevent rupture.

Corinne Pierfitte, M.D.
Pierre Gillet, M.D.
Rene J. Royer, M.D.
Centre Hospitalier Universitaire
54000 Nancy, France
References

1. Vidal 1994. 70th ed. Paris: OVP-Editions du Vidal, 1994.
2. Royer RJ, Pierfitte C, Netter P. Features of tendon disorders with
fluoroquinolones. Therapie 1994;49:75-76.[Medline]
3. Gillet P, Blum A, Pierfitte C, et al. Fluoroquinolone-associated Achille's
tendinitis: MRI findings. Arthritis Rheum 1993;36:Suppl:S163-S163.abstract "


This is the original FDA response to these issues, January 19,1995:

"To the Editor: In his letter (Sept. 15 issue),1 Huston described bilateral
rupture of the Achilles tendon in a patient treated with enoxacin and
prednisone. Although no cases of tendon rupture were reported to the Food and Drug
Administration (FDA) during premarketing clinical trials of fluoroquinolones currently on the market, the following information from the FDA's Postmarketing Spontaneous Reporting System does support the need for increased awareness of this adverse event.
As of October 1994, 25 cases of tendon rupture were reported, 22 of them occurring outside the United States. The patients whose ages were reported ranged from 33 to 85 years old; 12 were men and 7 were women. Most of the patients received recommended dosages of fluoroquinolones. However, in seven cases, fluoroquinolone levels could have exceeded the therapeutic ranges because of renal insufficiency, age, or the use of diuretic agents. Seventeen ruptures occurred
unilaterally or bilaterally in the Achilles tendon, with the remainder
occurring in the shoulder joint or hand. Eleven patients were hospitalized, had surgical repairs, or were disabled for prolonged periods. The ruptures occurred 2 to 42 days after the start of fluoroquinolone therapy. Nine patients had no relevant risk factors for tendon rupture. In the remaining 16, the relevant risk factors included concomitant corticosteroid use in 14, advanced age in 4, and long-term dialysis in 2. One patient, a physician, repeatedly ruptured tendons while playing football. Currently, the approved product labeling for corticosteroids and ofloxacin lists tendon rupture as a possible adverse event. In addition, there is a warning applicable to this class of drugs that precludes the use of fluoroquinolones in children, adolescents, and pregnant or lactating women. This warning is based on the occurrence of arthropathy in immature animals of various species when fluoroquinolones were administered at doses close to the therapeutic dose in humans. The disruption of the extracellular matrix of cartilage and the depletion of collagen seen in animals suggest that similar degradation may occur in humans with tendon rupture. Further studies are needed to understand the pathogenesis of these lesions.
On the basis of postmarketing reports and published articles,1,2 the FDA will update the labeling for all marketed fluoroquinolones to include a warning about the possibility of tendon rupture. Until further information is available, this will include a recommendation to discontinue treatment with these drugs at the first sign of tendon pain or inflammation and to refrain from exercise until the diagnosis of tendinitis can be confidently excluded. Any serious adverse events suspected to be associated with drug use should be reported to the FDA's MedWatch system (telephone 1-800-FDA-1088).

Ana Szarfman, M.D., Ph.D.
Min Chen, R.Ph., M.S.
Michael D. Blum, M.D.
Food and Drug Administration
Rockville, MD 20857
References

1. Huston KA. Achilles tendinitis and tendon rupture due to fluoroquinolone antibiotics. N Engl J Med 1994;331:748-748.[Full Text]
2. Chaslerie A, Bannwarth B, Landreau JM, Yver L, Begaud B. Ruptures
tendineuses et fluoro-quinolones: un effet indesirable de classe. Rev Rhum Mal Osteoartic 1992;59:297-298.[Medline] "

All of the above were published in the New England Journal of Medicine back in 1994/1995.(full text available at fqresearch.org)

In August,1996, Public Citizen filed a petition demanding that warnings be given both to the prescribing physician and the patient, the following is an abreviated version of this petition:

"Petition to Require a Warning on All Fluoroquinolone Antibiotics (HRG
Publication #1399)
August 1, 1996
David A. Kessler, M.D., J.D.
Commissioner, Food and Drug Administration
5600 Fishers Lane
Rockville, MD 20857
Petition To Require A Warning On All Fluoroquinolone Antibiotics

Dear Dr. Kessler:

Based on more than 130 reports of tendon inflammation (many involving
rupture), most frequently involving the Achilles tendon, in persons using the widely-prescribed class of antibiotics known as fluoroquinolones, Public Citizen, representing consumers nationwide, hereby petitions the F.D.A., pursuant to the Federal Food, Drug and Cosmetic Act 21, U.S.C. Section 355(e)(3), and C.F.R. 10.30, to add a warning about this serous problem to the label of all fluoroquinolone antibiotics marketed in the United States. These include: ciprofloxacin (Cipro, Bayer Corporation), enoxacin (Penetrex, Rhone-Poulenc Rorer),
lomefloxacin (Maxaquin, G.D. Searle), norfloxacin (Noroxin, Merck & Company), and ofloxacin (Floxin, McNeil Pharmaceutical). (In 1995, there were 14.4 million prescriptions filled for these antibiotics in U.S. retail pharmacies according to data from IMS.) In addition, consumers must be warned through F.D.A. approved MedGuides (patient package inserts) how to recognize and react to this potentially serious adverse effect of fluoroquinolone antibiotics.Only one fluoroquinolone antibiotic sold in the U.S., ofloxacin (Floxin) (which accounts for less than one-fifth of fluoroquinolone prescriptions), now carries any statement that tendinitis or rupture have been reported with its use, but even this statement is in a part of the label which misleadingly implies that tendon damage may have no relationship to using the drug.(1) Doctors and the public must be warned to immediately discontinue use of fluoroquinolone antibiotics at the onset of tendon pain. The frequency of tendon damage from fluoroquinolones is unknown, but Achilles tendon rupture is a
serious condition, often requiring surgical repair. Prompt cessation of use of these antibiotics if patients get tendinitis may avoid the progression to frank rupture of the Achilles or other tendons....

...In a January 19, 1995 letter to the New England Journal of Medicine F.D.A. staff wrote that the agency knew of 25 cases of tendon rupture, 22 of them occurring outside the U.S. In this letter it was stated on the basis of postmarketing reports and published articles, the F.D.A."will update the labeling [package insert] for all marketed fluoroquinolones to include a warning about the possibility of tendon rupture." The updated product labeling would also include a recommendation to discontinue treatment with these drugs at the first sign of tendon pain or inflammation and to refrain from exercise until the diagnosis of tendinitis can be confidently excluded.6

 

Conclusion
It is 18 months since F.D.A. staff published their letter and the agency now has at least 38 reports of tendon rupture. This includes 12 reported
hospitalizations from fluoroquinolone antibiotics. Yet, nothing has been done to warn doctors, pharmacists or the public about this potentially serious adverse effect. This is irresponsible.British and French package inserts for the very same drugs warn doctors and pharmacists about the risk of tendon damage. In the rest of Europe, consumers are warned of possible tendon damage from fluoroquinolone antibiotics. European
Community regulations now require that prescription drug consumers receive drug information written specifically for them that accurately reflects the same information given to doctors and pharmacists with each new and refill prescription. Sadly, this simple solution--routine patient package inserts for all prescription drugs--to preventing drug induced injury has been denied to U.S. consumers by organized pharmacy and medicine and the drug industry since the early 1980s. Very recently, attempts have been made in Congress to pass l legislation which would stop the FDA from implementing programs to increase the number of patient package inserts and thereby allow U.S. consumers to receive objective useful information about prescription drugs...."(full text available at fqresearch.org)


A year later the following bulletin was put out by the FDA.  No 'DEAR DOCTOR" letters were ever sent:

"FDA Medical Bulletin * October 1996 * Volume 26 Number 3
REPORTS OF ADVERSE EVENTS
WITH FLUOROQUINOLONES

FDA is asking prescribers and pharmacists to alert patients and other
caregivers to the potential for tendinitis and tendon rupture while taking or after taking antimicrobial fluoroquinolones. The Agency has taken steps to have the package insert revised for the following antimicrobial agents:ciprofloxacin, enoxacin, lomefloxacin, norfloxacin, and ofloxacin. Letters have been issued to the manufacturers requesting that they revise their package inserts to include the following information: The WARNINGS section will have a new paragraph that should read: "Ruptures of the shoulder, hand, and Achilles tendons that required surgical repair or resulted in prolonged disability have been reported with [the specific drug name]. [The specific drug name] should be discontinued if the patient experiences pain, inflammation, or rupture of a tendon. Patients should rest and refrain from exercise until the diagnosis of tendinitis or tendon rupture has been confidently excluded. Tendon rupture can occur at any time during or after therapy with [the specific drug name]." As an added precaution, the following statement will be added to the Information for Patients subsection of the RECAUTIONS section: "Patients should be advised to discontinue treatment and inform their physician if they experience pain, inflammation, or rupture of a tendon, and to rest and refrain from exercise." The revisions have been made to the ciprofloxacin, enoxacin, and norfloxacin package inserts. The lomefloxacin and ofloxacin revisions should be completed shortly. REPORT SERIOUS ADVERSE EVENTS AND PRODUCT PROBLEMS TO MEDWATCH

1-800-FDA-1088"