Frances T. Gipson, FACHE
Office of Executive Programs
Center for Drug Evaluation and Research
Department of Health and Human Services
Public Health Service
Food and Drug Administration
Rockville MD 20857
HFD 086

Frances T. Gipson,

You stated in your response to my concerns regarding the rampant devastation caused by the misuse of fluoroquinolones that since 1996 when the FDA allegedly first approval the use of fluoroquinolones that there have been several labeling supplements as well as new indications. Yet we fail to find within ANY of these changes any black box warnings regarding the NON ABATING nature of such reactions. In fact we find NO reference to the FACT that such events do no abate upon termination of therapy but continue for years as chronic, non-treatable, injuries. Yet in spite of a forty-year history of such events the FDA continues to approve new drugs within this class devoid of any such warnings. In fact, Nalidixic Acid (the "father: of fluoroquinolones), was added to the OEHHA Prop 65 list as a carcinogen May 15, 1998. [Nalidixic Acid, case number 389-08-02, listing mechanism AB, NTP (1989b]

Nalidixic Acid Belgium Patent Sterling Drugs [listed as a possible carcinogen 1998]
1967 Oxolinic Acid (quinoleine) German Patent Warner/Lambert
1973 Flumequine (benzo quinolizine) German Patent Rikker Labs [no longer in use due to ocular toxicity]
1974 Pipemidic Acid (pyrido-2-3-pyrimidine) German Patent Roger Bellon
1978 Norfloxacin (6-fluoro-7-pyrididino-quinoleine) Belgium Patent Kyorin
1979 Pefloxacin German Patent Roger Bellon/Dainippon
1982 Ofloxacin European Patent Daiichi [limited use due to CNS events]
1983 Ciprofloxacin German Patent Bayer AG [spontaneous tendon ruptures]
1985 Sparfloxacin Daiichippon [no longer in use due to significant phototoxicity and potential for serious cardiac dysrhythmias]
1987 Levofloxacin European Patent Daiichi
[Severe peripheral neuropathy, CNS and PNS events]
1987 Clinafloxacin Kyorin
1988 Temafloxacin Toyama [withdrawn due to , haemolytic–uraemic syndrome]
1988 Gatifloxacin Kyorin
1989 Grepafloxacin Otskuda [withdrawn due to torsades de pointes occurring with its use resulting in occurrence of seven cardiac deaths]
1993 Trovafloxacin Pfizer [restricted use due to liver toxicity, liver failure, hepatic dysfunction and pancreatitis]
1994 Moxifloxacin Bayer AG [severe CNS events]
1994 Gemifloxacin LG Chemicals LTD Korea

All of the drugs listed above were in use years before, as you state, the FDA approved the clinical use of such agents. Notice that the many of these drugs have been withdrawn due to SEVERE ADVERSE REACTIONS. Numerous drugs within this class have been either denied approval by the FDA, due to severe and toxic adverse reactions (i.e.: Factive/ Pfizer), or removed from clinical use (i.e.: Trovafloxacin/ Pfizer) for killing too many people. In June 1999, the U.S. Food and Drug Administration (FDA) issued a public health advisory warning about the risk of liver toxicity with Trovafloxacin after 14 cases of acute liver failure were associated with its use. The advisory recommended that Trovafloxacin therapy be reserved for infections judged to be life- or limb threatening, with treatment initiated only in the inpatient setting and when the benefits of Trovafloxacin outweigh the risks. Serious adverse reactions (liver failure, hepatic dysfunction and pancreatitis) have led to Trovafloxacin being either restricted for use in inpatients with life- or limb-threatening infections for which no suitable safe and effective alternatives are available (in the USA) or suspended from use (in Europe). In December 1999, Grepafloxacin was voluntarily withdrawn because of the possibility of torsades de pointes occurring with its use. The first fluoroquinolone, Flumequine, was used transiently until ocular toxicity was reported. However, Sparfloxacin has now largely been abandoned because of significant phototoxicity and potential for serious cardiac dysrhythmias, secondary to its effects on the QT interval. The 8-chloro compounds, such as Clinafloxacin and Sitafloxacin, were even more active, but also photo reactive. For example, haemolytic–uraemic syndrome was reported with Temafloxacin and resulted in its withdrawal, and prolongation of the electrocardiographic QT interval corrected for heart rate (QTc interval), possibly predisposing to ventricular arrhythmias, was seen with Sparfloxacin. The oral tolerance of Grepafloxacin is not optimal; it interacts significantly with Theophylline (via Cytochrome P450 1A2) and QTc prolongation may occur. The occurrence of seven cardiac deaths, possibly related to Grepafloxacin, led to the withdrawal of this drug by the manufacturer in October 1999. The manufacturer during the registration process voluntarily withdrew Clinafloxacin, at least in part because of the excess phototoxicity and reports of hypoglycaemia. In contrast, Lomefloxacin is associated with a significant photo toxic potential.
The following drugs within this class have either been removed from clinical use or severely restricted:

1962 Nalidixic Acid
1973 Flumequine
1985 Sparfloxacin
1988 Temafloxacin
1989 Grepafloxacin
1993 Trovafloxacin
2000 Factive (originally denied but recently received approval)

Severe adverse drug reactions associated with fluoroquinolone currently in use:

1982 Ofloxacin
[Severe peripheral neuropathy, spontaneous tendon rupture, CNS and PNS events, vision damage]
1983 Ciprofloxacin
[Severe peripheral neuropathy, spontaneous tendon rupture, CNS and PNS events, vision damage]
1987 Levofloxacin
[Severe peripheral neuropathy, spontaneous tendon rupture, CNS and PNS events, vision damage]
1994 Moxifloxacin
[Severe peripheral neuropathy, spontaneous tendon rupture, CNS and PNS events, vision damage]

A review of the med watch database (November 1997- November 2001) indicates that the FDA has received no less than 32,000 adverse drug reaction reports with 774 associated fatalities involving Cipro, Floxin and Levaquin. It has been over two years since I had requested the data associated with the other fluoroquinolones under the Freedom of Information Act, and I have yet to receive this information. One must keep in mind that the data found within the med watch database consist of LESS than 4% of such events. 96% of the adverse events are NEVER reported to the FDA. A majority of the physicians are not even aware such a program even exists. Less than 5% even bother to make such reports to the FDA. Often times citing that they find it to be a nuisance and an inconvenience. Physicians routinely fail to recognize, treat and report such events. The threat of litigation, should they document an adverse drug reaction, appears to be the primary motivator for failure to take such action. As such the FDA cannot point to the complete and utter failure of the med watch program and state that these drugs are safe.

You are correct when you state that the majority of the post marketing surveillance reports that I have forward on to the FDA are indeed well-known side effects to this class of drugs. The problem is that the patient and the physician HAVE NO KNOWLEDGE regarding this fact. The number one complaint that I have received for years is that the physician continues to deny ANY SUCH ASSOCIATION. Even though spontaneous tendon rupture has been reported each and every year since 1982 (Bailey et al) we still find the overwhelming majority of the physicians when faced with such an adverse reaction adamantly denies any involvement of the drug. This sir is the problem. Rampant and total ignorance of how dangerous and toxic these drugs are.

1983-2003

1983 Peddie BA: Norfloxacin induced rhuematic disease RR, JA

1986 JG, Sports Med: tendon lesions

1987 Goodchild MC: Arthropathy in a patient with Cystic Fibrosis …(context)

1987 Schluter G: Ciprofloxacin review of potential toxicological effects

1988 Davey PG: Ciprofloxacin and tenosynovisits (context)

1991 Wolfson JS: Fluoroquinolone antimicrobial agents (context)

1991 Jorgenson, Anya: Arthropathy wich Achilles tendon involvement induce by perflosacin (context)

1991 Weinstabl, Stiskal et al : Classifying calcaneal tendon injury according to MRI findings (context)

1991 Ribard, Audisis: Seven Achilles tendinitis including three complicated by rupture

1991 Chaslerie, Bannwarth: Rupture tendisneuse et fluoroquinolones: Un effet undesirable

1992 Ribard P, Audisio F, Kahn MF, et al: Seven Achilles tendinits including 3 complicated by rupture

1992 Lee WT, Collins JF: Ciprofloxacin associated bilateral Achilles tendon rupture

1993 Collins JF: Ciprofloxacin associated bilateral Achilles' tendon rupture

1993 Lafon M: Tendonopathies et fluoroquinolones

1993 Gillet P, Blum A, Pierfitte C et al: Fluoroquinolone associated Achilles tendinitis

1993 Falt-Rolachon, Pireyre et al: Rupture bilaterale de coiffe des rotateurs lors d'un tratitem…

1993 Borderie, Marcelli et al: Spontaneous rotator cuff tear during fluoroquinolone therapy

1994 Hestin, Mainard et al: Spontaneous bilateral rupture of the Achilles Tendon…

1994 R J Netter: Features of tendon disorders with fluoroquinolones…

1995 Gillette, Hestin et al: Fluoroquinolone induced tenosynovisitis of the wrist

1995 FDA, Blum M.D. : More on fluoroquinolone antibiotics and tendon rupture…

1995 J C Chauveaux: Epidondylitis after treatment with fluoroquinolone antibiotics

1996 Zabraniecki, Negrier et al: Fluoroquinolone induced tendinopathy report of 6 cases

1996 HRG Publication #1399: Petition to require a warning of all fluoroquinolones antibiotics

1996 Szarfman et al: Labeling changes British National Formulary

1996 FDA Medical Bulletin October 1996 Volume 26 Number 3; Reports of adverse events with fluoroquinolones

1997 Movin, Gad et al: Pathology of the achilles tendon in association with Ciprofloxacin

1997 Andujar et al: Tendinitis associated with ciprofloxacin

1998 Levadouxe M, Carli P, Gadea J F: Repeated rupture of the extensor tendons of the hand…

1999 Van der Linden PD: Achilles tendinitis associated with fluoroquinolones

1999 Harrell R M: Fluoroquinolone induced tendinopathy: What do we know?

2000 Stahlmann: Arthropathies

2000 Williams R: Ciprofloxacin associated with destructive enzymes

2001 Van Der Linden et al: Tendon disorders attributed to fluoroquinolones a study of 42 cases

2001 Malaguti et al: Ciprofloxacin associated Achilles tendon rupture in a hemodialyis patient

2002 Rudzinski: Toctoc Response, since 1983 fluoroquinolones have been associated with tendon pathology…

2003 Gold et al: Levofloxacin-Induced Tendon Rupture: A Case Report and Review of the Literature

Your continuing to monitor these events does absolutely NOTHING to prevent these tragedies from occurring. Day after day, week after week, month after month, year after year, not a day goes by that I do not hear from yet another victim(s) the damage these drugs have inflicted, together with the total and complete denial of any such association within the medical community. I have viewed the FDA reports regarding Floxin, Cipro, Levaquin and Nalidixic Acid. The numbers continue to climb each and every year yet you have failed to provide adequate warning to the prescribing physician and the clueless victim. No black box warning has been added even though the documentation found within the literature together with these post-marketing reports justifies such a warning. Even though requested by Public Citizen years ago no such warning exist.

You have requested that I encourage those reporting such events to file a med watch report. I assure you that they have done exactly that, yet when viewing these reports we find NO MENTION of the non-abating nature of such injuries that they have reported. Even my own reports, which I had filed personally numerous times indicating that I have been severely disabled for over three and one half years, cannot be found within these reports.

You had also stated that the FDA would weigh all risks and benefits associated with the fluoroquinolones prior to taking action. It has been over eight years now that spontaneous tendon rupture was first brought to your attention. You have yet to add a black box warning regarding this. For more than eight years patients have suffered severe and debilitating injury do to your failure to do so. What more possible documentation could you possibly need to add this warning? Peripheral neuropathy was first reported in 1992, again in 1996 and as of late, in 2001 by Dr. Cohen et al. Yet we still, twelve years later, fail to find any such warnings within the package inserts let alone a black box warning regarding this severe and non abating injury. As recently as January of 2004 Dr. Cohen again brought this to the attention of Congressman Rush Holt:


Jay S, Cohen, M.D.
13622 Nogales Drive
Del Mar, CA 92014
Tel: 858-481-3758
Fax: 858-509-8944
Email: jacohen@ucsd.edu


January 21, 2004

The Honorable Rush Holt
Member, U.S. House of Representatives
1630 Longworth Building
Washington DC 20515

Dear Congressman Holt.

I would like this letter to be entered into the record in your hearings on fluoroquinolone antibiotics (e.g. Levaquin, Cipro, Floxin, Tequin). I am the author of a study about severe, long-term fluoroquinolone reactions published in the December 2001 issue of the Annals of Pharmacotherapy. Actually, the publisher and I pre-released this article in October 2001, during the anthrax scare when Cipro was being prescribed indiscriminately and without warnings to patients. Within days of publication of my paper, the U.S. Centers for Disease Control changed their guidelines, placing the antibiotics doxycycline and penicillin above Cipro as the preferred treatments for anthrax exposure. Doxycycline and penicillin have fewer severe side effects than fluoroquinolones, and they are not associated with the devastating, disabling, long-term reactions that my study identified.

These severe reactions are occurring in patients who are usually healthy, active, and young. Most often, the antibiotics are prescribed for mild infections such as sinusitis, urinary or prostate infections. Most reactions occur very quickly, sometimes with just a few doses of the fluoroquinolone antibiotic. Reactions are acute, severe, frightening, and often disabling. In most cases, side effects are multiple, involving many systems of the body. In my study, nervous system symptoms occurred in 91% of patients, musculoskeletal 73%, sensory system 42%, cardiovascular 36%. skin 29%, gastrointestinal 18%.

These numbers do not adequately capture the severity and permanence of these reactions. Here are some examples:

Male, age 36, previously in good health, received Cipro for possible urinary infection:
Chronic, debilitating multi-focal neuropathy, fibromyalgia, chronic fatigue, gastrointestinal problems, heart arrhythmia requiring pacemaker, carpal tunnel syndrome, chronic multiple joint pains, chronic pain. Functional ability: disabled. Duration: 5 years (patient now age 41).

Female, age 32, previously in good health, received Cipro for urinary infection: After 5
days. developed pain in wrists, neck, back, knees, hips, elbows, shoulders, and Achilles tendons. Having difficulty writing. Medical workup normal. Functional ability: greatly limited.

Female: age 47, previously in good health. received Levaquin for sinusitis: Within 2 days developed joint pain (severe in hands). insomnia, severe agitation, weakness, dizziness. severe fatigue, mental infusion, abnormal dreams, gastrointestinal symptoms. Duration:
Still severe after 7 months.

Female, age 49. previously in good health, received Floxin for a pelvic infection: Burning pain. memory loss, joint pains. palpitations. nerve pain, insomnia, abnormal sense of smell, tinnitus, panic attacks. Duration: more than 3 years.

Male, age 34, previously in good health, received l.evaquin for prostate infection: Muscle spasms and twitching. numbness, impaired coordination, weakness, increased sensitivity to temperatures, ftigue, multiple joint, muscle pain, palpitations, blurred vision. Duration: more than 1 year.

Male, age 35. in good health, received Levaquin for prostate infection: I dose led to a ranch, ringing in the ears, and peripheral nerve symptoms lasting 2 weeks. Then tendinitis began in shoulders, elbows. wrists, hands, and Achilles tendons, with burning pain and tightness in calves. After 2 months. still unable to walk more than a short distance. This man told me. ‘Prior to taking the medication I asked about side effects and was told there were none for adults except an upset stomach. Afterwards I was told that what I was experiencing could not be related to the drug. Obviously the doctor had never read the documentation that states otherwise.”

These are not isolated cases. Since the publication of my article with its 45 cases two and a half years ago, I have received e-mails from more than 100 people seeking help for their reactions. In most eases, their doctors have dismissed their complaints or outright deny that the reactions could occur with fluoroquinolones. Yet extensive medical workups do not find any other cause. Worse, there are no known effective treatments. [hus. these people suffer pain and disability for weeks, months. years.

Overall, my sense is that these reactions are not rare. I have spoken to the U.S. Food and Drug Administration about this. I am shocked that the agency stilt hasn’t acted. Other major reactions such as Stevens-Johnson syndrome or Churg Strauss syndrome from medications are posted prominently on drug labels. These reactions are much rarer than the ones occurring with fluoroquinolone antibiotics.. .At the very least,.black boxes should he placed in fluoroquinolone package inserts about severe, multi- system reactions.

I readily agree that fluoroquinolone antibiotics play an important role in treating infections diseases, hut we must alert doctors and patients about the potential devastating effects of these drugs. We must educate them that if any signs of reactions occur, such signs should be reported immediately and the drugs should be discontinued. Most of all, we must educate doctors to avoid prescribing fluoroquinoloncs for minor infections, instead saving them for serious infections, just as we do with other groups of antibiotics with serious toxicities.

I hope you will serious look at this problem and respond accordingly. These people need your help. This is largely a preventable problem.. Thank you..

Jay S. Cohen, M.D.
Associate Professor (voluntary)
Departments of amity and Preventive Medicine and of Psychiatry
University of California, San Diego

President and Executive Director
The Center for the Prevention of Medication Side Effects
A Nonprofit, Tax-Exempt [501 (C)(3)} Corporation


With all due respect Frances, it is far past the time that the FDA “continues to monitor future adverse events” and take the initiative require to prevent them. Try as I might I cannot possibly find even one justification for the FDA’s continuing failure to address these severe adverse events by providing “Dear Doctor” letters and adding a black box warning regarding the non-abating nature of such adverse reactions.
In fact we find the exact opposite as Levaquin eye drops has recently received the blessing of the FDA again devoid of any warnings regarding all that I have stated here. Even with the initial approval of Levaquin back in 1996 we find one or more adverse drug reaction reported by almost 46% of the patients studied. (A total of the 1265 patients taking part in five different clinical studies. 578 of these patients had one or more adverse drug reactions, almost 46% of the patients being studied). Sixty-one patient’s adverse reactions were so severe they were dropped from the study. We also find 6 associated fatalities. (NDA 020634) A forty six percent adverse drug reaction rate with six associated fatalities is not to be considered in my mind an “acceptable risk”. This data was taken DIRECTLY from this drugs new drug approval.
The medical review officer also stated that she had found “significant flaws” with the studies being submitted including but not limited to the protocol’s designs and implementations, clinical assessments, categories that were inappropriate, the use of a quinolone antimicrobial for infections involving Streptococcus pneumonia. (NDA 020634) Despite these issues raised by the medical review officer and the extremely high level of adverse events, not to mention the number of possible associated deaths, this drug was approved. Since that time almost 20,000 serious adverse events have been reported together with 473 associated fatalities and the drug continues to be heavily promoted as a “safe and effective antibiotic with minimum side effects” with the full blessing of the FDA. Nor do we find any reference to the post marketing reports for this drug which had been on the market in Asia for a great number of years before this application was made to market it in the United States.

With this new approval for Levaquin eye drops we also find an adverse drug reaction rate of 10% or more, and this was only within the 280 patients being studied who had a documented bacterial infection. You know as well as I do that this drug will be heavily promoted and in the majority of the cases such use would not be justified. You also know that the physician will receive NO WARNINGS regarding such non-abating adverse reactions as I have been reporting to the FDA for years. This is what I take issue with. Not whether or not the drug is effective. But the fact that the FDA has withheld pertinent data from both the physician and the patient regarding the serious and non abating nature of such injury. I truly believe that such data was also withheld from the panel that approved the recent indication of Levaquin eye drops. This is what I am concerned the most about. Failure to provide informed consent. The data supports the FDA taking immediate action, yet you have failed to do so for over forty years. Nothing has been done to warn doctors, pharmacists or the public about these potentially serious and non-abating adverse effects. This is what I take issue with the FDA.

Having received what appeared to me to be a bureaucratic form letter from you which fails to address these issues, though I do appreciate you taking the time to send even that acknowledgement, I will attempt once again to present my case. (Improperly addressed to ‘Mrs.’ rather than “Mr.” I might add) Perhaps now that I have made my position absolutely clear you can explain to me why there are no black box warnings and why the physicians responsible for handing out these drugs like Halloween candy continue to deny any such association. These two actions taken by the FDA would prevent hundreds of thousands of such tragedies from being repeated. Completely avoidable tragedies that I have reported to the FDA for years now that you continue to fail to act upon.

Perhaps I am mistaken but I thought that the mandate of the FDA was to prevent needless injury to the patient, not to protect the profits of the drug manufacturer. You apparently are allowing the various manufacturers to continue to promote a neuro-toxic and dangerous chemotherapeutic agent (as I believe the literature supports such reactions as being a class effect) as a “safe and effective antibiotic with a minimum of side effects” and to continue to profit from such frivolous and misleading statements. In fact they are not even to be considered true antibiotics but a toxic form of chemotherapeutic agents and as such, misbranded. You are also allowing them to withhold the non-abating nature of such injury when it occurs from both the physician and the patient by your continuing failure to take immediate action. This I find to be totally irresponsible and unforgivable.


Sincerely


Director
Fluoroquinolone Toxicity Research Foundation.