Cases of tendinopathy reported to the FDA from 1987 to June 1997 (this is a graphic file, press the "Back" button on your browser to return to this page once you have viewed this file)

42 reported tendinopathies 2000
Finland:
Register of adverse drug reactions in 2000

The majority of ADR reports received among antibacterials concerned levofloxacin, which is a fluoroquinolone antibiotic. Fourteen of the reports were on tendinitis or rupture of the Achilles tendon. Tendinitis caused by fluoroquinolones was discussed in TABU for the first time in 1996. Since then the ADR register has received a total of 42 reports on tendinopathies caused by
fluoroquinolones, over a third of which were ruptures of the tendon.
The use of fluoroquinolones has in-creased by about 75% since 1996. Levofloxacin is responsible for the major part of this increase. It has been marketed in Finland since mid 1998.
source: www.nam.fi/uploads/english/Publications/Tabu/tabu22001_eng.pdf
 

ENGLAND

130 reported tendon inflammation or rupture (England, France and Belgium, 1996)
The group cited 130 reports of tendon inflammation or rupture in people who used the prescription drug in England, France and Belgium. The FDA has received at least 52 reports of patients in the U.S. who have suffered tendon damage
(from public citizens 1996 petition)
 

FRANCE

921 reported tendon disorders France
340 reported tendonitis, 81 tendon ruptures 1996, WHO
Adverse drug reactions with fluoroquinolones The French system of drug surveillance has analyzed the reports of adverse drug reactions (ADRs) to fluoroquinolones since they were launched. The frequency of reactions ranges from 1/15000 to 1/208000 case per days of treatment. Cutaneous disorders and tendon disorders dominate in France, whereas cutaneous effects and neuropsychiatric disorders are predominant in the UK; tendon disorders take up only the 5th position. Among the most unexpected ADRs are the following: 1- Shock 2- Acure renal failure Tendon ruptures represent 81 cases for 921 reports of tendon disorders which are related in decreasing order to pefloxacin 1/23130 case per days of treatment, ofloxin, norfloxacin and ciprofloxacin 1/779600 case per days of treatment. Age and corticosteroids increase the risk of tendon rupture. Therapie 1996; 51; 419-420 Tendon disorders with fluoroquinolones 421 cases have been collected by the Centre de Pharmacovigilance: 340 of tendinitis and 81 of tendon rupture. These cases were attributed to Peflacine, Oflocet, Noroxine, Ciflox. Tendinitis was characterized by a bilateral malleolar oedema associated with a sudden pain. Sometimes this oedema evoked phlebitis. The tendon rupture was generally preceded by a tendinitis but in half of the cases it occurred without warning.
Source: http://www.who-umc.org/newsletter/newsltr97_1.html (sic)

100 reported tendinopathies 1985-1992 France
In France, between 1985 and 1992, 100 patients who were being managed with fluoroquinolones had tendon disorders, which included thirty-one ruptures (Royer, R. J.; Pierfitte, C.; and Netter, P.: Features of tendon disorders with fluoroquinolones. Therapie, 49: 75-76, 1994.)
http://www.studiomedico.it/allegati/achille.pdf

Szarfman et al. recommended that the labeling on packaging for fluoroquinolone be up-dated to include a warning about the possibility of tendon rupture. In its recommendations on the use of
this class of antibiotics, the British National Formulary
suggested that "at the first sign of pain or inflammation, patients should discontinue the treatment and rest the affected limb until the tendon symptoms have resolved."
British National Formulary. No. 32, p. 259. London, British Medical Association, Royal Pharmaceutical Society of Great Britain, 1996.
{Notice how this labeling change has not be altered since 1996 and appears to have been copied word for word in every monograph.}

93 ruptures, 103 tendinopathies, 20 tenasynovitis, 1987-1997
Source: http://www.sma.org/smj1999/junesmj99/harrell.pdf

421 reported tendon disorders and 81 tendon ruptures 1999
Therapie 1996; 51: 419-420 Tendon disorders with fluoroquinolones 421 cases have been collected by the Centre de Pharmacovigilance, 340 of tendinitis and 81 cases of tendon rupture.
 

AUSTRALIA

THE ACHILLES HEEL OF FLUOROQUINOLONES
One of the more unusual adverse reactions known to be associated with the fluoroquinolone antibiotics is the occurrence of tendinitis. This is a serious effect since it may progress to tendon rupture with many weeks of disability as a result. Over 200 cases have been reported in the literature with the majority from France. Most members of the class including ciprofloxacin, enoxacin, ofloxacin, and norfloxacin have been implicated. The Achilles tendon is most often involved.
In Australia, there have been 25 reports of tendinitis in association with fluoroquinolones. Most (22) have been with ciprofloxacin and the other three with norfloxacin. The majority of the patients involved were elderly, ranging in age from 46 to 91 (median 69) years and the sex distribution was equal. For ciprofloxacin, daily dosages ranged from 750 mg to 2250 mg although most (13) patients were taking 1000 mg daily. For norfloxacin, all three patients were taking the usual dose of 800 mg daily. Time to onset ranged from the same day that the drug was commenced (in two patients) to two months although in 13 of the 24 reports which provided the information, the reaction occurred within the first week. Almost all (23) of the reports specified the Achilles tendon as the site of the tendinitis. Tendinitis was described as bilateral in 11 cases. Only 8 patients had recovered at the time the report was submitted and the other patients were being treated with rest and/or physiotherapy. There have been no reports of tendon rupture in Australia although in one severe case, the patient required a plaster cast up to the mid thigh.
A number of risk factors have been identified with regard to this adverse reaction. These include old age, renal dysfunction, and concomitant corticosteroid therapy. Of the patients reported to ADRAC, 72% were older than 60 years. Nine of these patients were taking corticosteroids as were three of the younger patients.
Prescribers are reminded that tendinitis, especially involving the Achilles tendon, is a rare adverse effect of the fluoroquinolones. It is more likely to occur in association with the risk factors referred to above. The antibiotic should be withdrawn immediately to reduce the risk of tendon rupture.

Australia. The Adverse Drug Reactions Advisory Committee first reported tendinitis in association with fluoroquinolone antibiotics in 1997. The Committee has continued to monitor this adverse reaction, and has now received 60 reports of tendinitis, tensosynovitis and/or tendon rupture in association with these drugs. Ciprofloxacin was most frequently cited (55 reports), as well as norfloxacin (4) and enoxacin (1).
Forty-five reports described tendinitis alone, one report described tensosynovitis, and 14 reports documented tendon tear or rupture. Fifty-five of the 60 reports specified the Achilles tendon, including 20 which described bilateral Achilles tendon damage. All 14 reports of tendon rupture involved the Achilles tendon. The 58 patients ranged in age from 38 to 91 years (median: 69), with no significant difference between those with tendinitis and those with tendon rupture.
The daily doses of ciprofloxacin ranged from 500 mg to 2250 mg, with 46% of patients taking 1500 mg and 46% of patients taking 1000 mg daily. For those who developed tendon rupture, 57% were taking 1500 mg daily. Time to onset varied from within 24 hours after the drug was commenced to 3 months after starting, but the majority of cases of tendinitis occurred within the first week. Time to rupture was longer with a median time of 2-3 weeks. Known risk factors for these reactions include old age, renal dysfunction and concomitant corticosteroid therapy. In the cases reported to the ADRAC, 29 reports documented concomitant corticosteroid use, and in 21 of the other 31 reports the patients were aged 69 years or older. In the reports of tendon rupture, 12 of the 14 described either concomitant steroid use (9) or old age (9).
Prescribers are reminded to be alert for this reaction and to withdraw the fluoroquinolone immediately when symptoms of tendinitis appear in order to reduce the risk of tendon rupture.
[See also Pharmaceuticals Newsletter Nos. 7&8, July&August 1997.]

60 reported tendonitis August 1999
Fluoroquinolones tendinitis update Australia
Tendinitis associated with Fluoroquinolone therapy
(Pharmaceuticals Newsletters Nos 7&8 July & August 1997)
Australia
ADRAC Bulletin, vol 18, No 3, August 1999
Tendinitis and tendon rupture with
fluoroquinolones
The Adverse Drug Reactions Advisory Committee (ADRAC) first reported tendinitis in association with the fluoroquinolone antibiotics in 1997. The Committee has continued to monitor this adverse
reaction, and has now received 60 reports of tendinitis, tenosynovitis and/or tendon rupture in association with these drugs. Most involved was ciprofloxacin (55), but there were also reports with norfloxacin (4) and enoxacin (1). Fortyfive reports described tendinitis alone, one report described tenosynovitis, and 14 reports documented tendon tear or rupture. Fifty five of the 60 reports specified the Achilles tendon, including 20 which described bilateral
Achilles tendon damage. All 14 reports of tendon rupture
involved the Achilles tendon.
Source: http://www.who.int/medicines/library/pnewslet/pndec99.html
 

NETHERLANDS

704 achilles tendinitis, 38 ruptures 1992-1998 Netherlands
Fluoroquinolone use and the change in incidence of tendon rupture in the Netherlands
Van der Linden et al (Pharmacy World and Science vol 23 no 3 2001 pg 89-92)
The cohort included 46 776 users of fluoroquinolones between 1 July 1992 and 30 June 30 1998, of whom 704 had Achilles tendinitis and 38 had Achilles tendon rupture
source: http://bmj.com/cgi/content/full/324/7349/1306


42 spontaneous reports 1988-1998
Tendon disorders attributed to fluoroquinolones; a study on 42 spontaneous reports in the period 1988-1998
Van Der Linden et al (American College of Rheumatology; Arthritis Care and Research 45; 2001 pages 235-239) June 2001
http://www.rheumatology.org/arhp/acnr/2001/0106.html
 

DUTCH

Fluoroquinolones have been associated with tendon disorders, usually during the first month of treatment,1-5 but the epidemiological evidence is scanty. We did a nested case-control study among users of fluoroquinolones in a large UK general practice database to study the association with Achilles tendon disorders.

Participants, methods, and results

We obtained data from the IMS Health database (UK MediPlus), which contains data from general practice on consultations, morbidity, prescriptions, and other interventions in a source population of 1-2 million inhabitants. The base cohort consisted of all patients aged 18 years or over who had received a fluoroquinolone. We excluded people with a history of Achilles tendon disorders, cancer, AIDS, illicit drug use, or alcohol misuse. We identified potential cases by reviewing patient profiles and clinical data and excluded tendon disorders due to direct trauma. We randomly sampled a group of 10 000 control patients from the study cohort.

We defined four categories of exposure to fluoroquinolones: current use, recent use, past use, and no use. We defined current use as when the tendon disorder occurred in the period between the start of the fluoroquinolone treatment and the calculated end date plus 30 days, recent use as when the calculated end date was between 30 and 90 days before the occurrence of the disorder, and past use as when the calculated end date was more than 90 days before the occurrence of the disorder. We used unconditional logistic regression analysis to calculate adjusted relative risks and 95% confidence intervals for Achilles tendon disorders, using the no use group as the reference. We adjusted for age, sex, number of visits to the general practitioner, use of corticosteroid, calendar year, obesity, and history of musculoskeletal disorders.

The cohort included 46 776 users of fluoroquinolones between 1 July 1992 and 30 June 30 1998, of whom 704 had Achilles tendinitis and 38 had Achilles tendon rupture. Four hundred and fifty three (61%) of the cases were women, and the mean age was 56 years. Cases visited the general practitioner significantly more often than did controls (mean 20 v 17). Cases and controls were similar with respect to indications for use of fluoroquinolone. Age, number of visits to the general practitioner in the previous 18 months, gout, obesity, and use of corticosteroid were determinants of Achilles tendon disorders. The adjusted relative risk of Achilles tendon disorders with current use of fluoroquinolones was 1.9 (95% confidence interval 1.3 to 2.6). The risk for recent and past use was similar to that for no use. The relative risk with current use was 3.2 (2.1 to 4.9) among patients aged 60 and over and 0.9 (0.5 to 1.6) among patients aged under 60 (table). In patients aged 60 or over, concurrent use of corticosteroids and fluoroquinolones increased the risk to 6.2 (3.0 to 12.8).

Relative risk of Achilles tendon disorders associated with use of fluoroquinolones according to age
Current exposure to fluoroquinolones increases the risk of Achilles tendon disorders. This finding is in agreement with a smaller study, in which we found an association between tendinitis and fluoroquinolones.5 Our results indicate that this adverse effect is relatively rare, with an overall excess risk of 3.2 cases per 1000 patient years. The effect seems to be restricted to people aged 60 or over, and within this group concomitant use of corticosteroids increased the risk substantially. The proportion of Achilles tendon disorders among patients with both risk factors that is attributable to their interaction was 87%. Although the mechanism is unknown, the sudden onset of some tendinopathies, occasionally after a single dose of a fluoroquinolone, suggests a direct toxic effect on collagen fibres. Prescribers should be aware of this risk, especially in elderly people taking corticosteroids.

Acknowledgments
We acknowledge the cooperation of IMS Health United Kingdom.
Contributors: PDvdL, MCJMS, and BHChS formulated the design of the study. PDvdL carried out the analyses. PDvdL, MCJMS, and BHChS wrote the paper, and RMCH and HGML edited it. BHChS and HGML are guarantors for the paper.

Footnotes

Funding: Dutch Inspectorate for Health Care.
Competing interests: MCJMS is a consultant for Lundbeck (France) and Beaufour (UK) and has previously been a consultant for Pfizer (USA), Roche (Switzerland), and Novartis Consumerhealth (Switzerland). None of these consultancies related to quinolones. MCJMS is responsible for research conducted with the integrated primary care information database in the Netherlands, which is supported by project specific grants from GlaxoSmithKline, AstraZeneca, Merck Sharp & Dohme, Pharmacia & Upjohn, Bristol-Myers Squibb, Eli Lilly, Wyeth, and Yamanouchi. MCJMS has conducted research projects on use of antibiotics for Merck & Co (USA) and Bayer (Italy), but none was related to the adverse effects of quinolones.

References

1. McEwan SR, Davey PG. Ciprofloxacin and tenosynovitis. Lancet 1988; 2: 900.
2. Huston KA. Achilles tendinitis and tendon rupture due to fluoroquinolone antibiotics. N Engl J Med 1994; 331: 748[Free Full Text].
3. McGarvey WC, Singh D, Trevino SG. Partial Achilles tendon ruptures associated with fluoroquinolone antibiotics: a case report and literature review. Foot Ankle Int 1996; 17: 496-498[ISI][Medline].
4. Szarfman A, Chen M, Blum MD. More on fluoroquinolone antibiotics and tendon rupture. N Engl J Med 1995; 332: 193[Free Full Text].
5. Van der Linden PD, van de Lei J, Nab HW, Knol A, Stricker BHCh. Achilles tendinitis associated with fluoroquinolones. Br J Clin Pharmacol 1999; 48: 433-437[CrossRef][ISI][Medline].

(Accepted 9 January 2002)
© BMJ 2002 (sic)

 

MISC

1847 reported tendinopathies December 2001
Tabelle 7
Pharmacovigilance: Meldungen von Tendinopathien im Vergleich zu allen gemeldeten unerwünschten Arzneimittelwirkungen (UAW), Stand 17. Dezember 2001.

Meldungen Schweiz (IKS-Datenbank) Welt (WHO-Datenbank)
Tendinopathie alle UAW Tendinopathie alle UAW
Ciprofloxacin    8   (5%) 155 649(2,2%) 29 090
Fleroxacin        9   (1,2 %) 754
Norfloxacin       1 (1%) 91 163 (2,1%) 7536
Ofloxacin          2 (6%) 34 432 (1,8%) 23 990
Levofloxacin    32 (41%) 79 576 (7,8%) 7432
Moxifloxacin    18 (4,5 %) 4030
Source: http://www.saez.ch/pdf/2003/2003-02/2003-02-694.PDF
http://www.saez.ch/pdf/2003/2003-02/2003-02-694.PDF
 

U.S. ARMED FORCES

Spontaneous Ruptures of the Achilles Tendon, US Armed Forces, 1998-2001
Methods. The Defense Medical Surveillance System was searched to identify all incident ambulatory visits of active duty servicemembers with a primary diagnosis of non-traumatic rupture of the achilles tendon (ICD-9- CM code 727.67) and other tendon ruptures (ICD-9- CM codes 727.60-727.66, 727.68-727.69) between January 1998 and May 2001.
The most striking finding of this analysis is the sudden and significant increase in rates of achilles tendon ruptures beginning in calendar year 2000. The increase was manifested across all Services and in most demographic subgroups (table 1). Rates
of non-traumatic ruptures of several other tendons also increased during the period; and increases in ruptures of the rotator cuff were comparable to those of the achilles tendon.
Source: http://amsa.army.mil/1Msmr/2002/v08_n01.pdf