2-20-2004
Commissioner Food and Drug Administration

Dr. McClellan,
Please find attached the adverse drug reactions being reported on the quinolone adverse drug reaction forum and medications.com., for the month of January 2004. I would appreciate it if you would forward these to the appropriate party.
For more than ten years now the FDA has been fully aware of these adverse events and continues to do absolutely nothing about them. Public Citizen demanded that a black box warning be added to the package insert for these drugs back in 1996, together with a demand that the prescribing physician obtain adequate warning via "Dear Doctor" letters. Yet almost ten years later not a day goes by that we do not receive yet another report of the nonabating damage these drugs can and will do together with the adamant denial by the treating physicians that such damage is possible with the fluoroquinolones. How many more tragedies such as these must take place before the black box warnings are added and the "Dear Doctor" letters be sent? The carnage contained within these reports is totally avoidable and completely unnecessary.
Within the New Drug Approval package for Levaquin, yet another newer fluoroquinolone put into clinical practice in 1999 we find a total of 1265 patients taking part in five different clinical studies.(NDA 020634) 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. A forty-six percent adverse drug reaction rate with six associated fatalities is not less than the 5 percent rate claimed by the manufacturer within the package insert.
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. 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
It is criminal the manner in which the FDA sets idle and continues to ignore this clear and present danger, continuing to approve new drugs within this class, approving new indications for the existing drugs, and now allowing such proven neurotic drugs to be used in clinical trials for children as young as six months old for a common childhood ear infection acute otitis media. A disease state that normally resolves without medical intervention within three to four days. Yet we are subjecting these babies to the risk outlined within this letter. For years amoxacillin, a proven and safe antibiotic, has successfully treated this disease. What possible motivation do we have to risk the crippling of these children to find an alternative method of treatment other than pure financial gain? In a recent consensus meeting to update treatment for acute otitis media in children in the era of drug resistance it was recommended that amoxicillin should remain the first-line agent. Most appalling is the recent approval for Levaquin where we find within the NDA an adverse drug reaction rate of almost 46%, and six associated fatalities. Yet you approved this drug and the post marketing surveillance via Adverse Event Reports confirms the medical officers concerns as more than 5,276 individual reports have been filed within the past three years as well as 19,792 individual events and 473 associated deaths.
A review of the Adverse Event Reporting System (AERS) for Levaquin (1997 to Present) reveals over 2,898 adverse events reported (double of what we find for Ciprofloxacin) which were associated with bone, tendon, muscle and ligament damage. However the manner in which the FDA classifies such reports guarantees that significant "flags" such as these would be overlooked in the same manner as Ciprofloxacin.
Table 1
Adverse Event Reporting System Summary 11-1-1997 to present
Bone, Tendon, Muscle and Ligament Damage
Ciprofloxacin
Arthralgia 261 (within the top three reported events)
Pain in the Extremity 153
Myalgia 148
Tendinitis 122
Difficulty in walking 89
Tendon Rupture 89
Tendon Disorders 81
Rhabdomyolysis 66
Arthritis 42
Muscle Cramps 34
Arthropathy 34
Joint Swelling 32
Muscle Weakness 27
Neck Pain 19
Movement Disorders 19
Muscle Spasms 18
Limb Injury 18
Joint Stiffness 18
Muscle Twitching 17
Paralysis 16
Muscle Disorders 16
Osteoarthritis 15
Muscle Rupture 14
Musculoskeletal Stiffness 12
Polyarthritis 11
Tendon Injury 10
Tenosynovitis 9
Muscle Stiffness 8
Joint Effusion 8
Bone Pain 8
Rheumatoid Arthritis 7
Rotary Cuff Syndrome 6
Bone Disorders 6
Tongue Paralysis 5
Biopsy Bone Marrow Abnormal 5
Muscle Contractions Involuntary 4
Joint Sprain 4
Cartilage Injury 3
Musculoskeletal Discomfort 3
Muscle Necrosis 3
Joint Range of Motion Decreased 3
Joint Crepitation 3
Facial Bone Fracture 3
Connective Tissue Disorders 3
Buttock Pain 3
Cartilage Disorders 2
Ligament Disorders 2
Fibromyalgia 2
Musculoskeletal Disorders 2
Muscle Tightness 2
Muscle Strain 2
Muscle Spasticity 2
Muscle Rigidity 2
Muscle Injury 2
Muscle Fatique 2
Mobility Decreased 2
Foot Fracture 1
Synovial Cyst 1
Skull Fractured Base 1
Rheumatoid Factor Positive 1
Posture Abnormal 1
Neuromusculuar Disorders 1
Musculoskeletal Pain 1
Muscle Haemorrhage 1
Limb Discomforts 1
Joint Dislocation 1
Joint Arthroplasty 1
Burning Sensation Mucosal 1
Finger Deformity 1
Bone Lesions 1
Bone Erosion 1
Arthritis Reactive 1
Arthritis Allergic 1
Ankle Fracture 1
TOTAL EVENTS REPORTED 1,558
Table 2
Adverse Event Reporting System Summary 11-1-1997 to present
Bone, Tendon, Muscle and Ligament Damage
Levaquin
Arthralgia 368 (The number one event reported)
Tendon Disorders 318 (The number two event reported)
Tendonitis 232
Pain 204
Myalgia 193
Pain in the extremity 190
Asthenia 166
Difficulty walking 151
Paraesthesia 127
Tendon Rupture 97
Rhabdomyolysis 66
Back pain 59
Swelling 50
Muscle Weakness 42
Joint Swelling 37
Muscle Twitching 30
Arthritis 30
Joint Stiffness 27
Muscle Cramp 25
Muscle Spasms 23
Movement Disorders 23
Myositis 20
Paralysis 18
Neck Pain 18
Muscle Rupture 16
Bone Pain 15
Contusions 15
Muscle Contractions Involuntary 14
Joint Effusion 12
Osteroarthritis 11
Muscle Injury 11
Muscle Atrophy 11
Cartilage Injury 11
Rotary Cuff Syndrome 10
Joint Ligament Rupture 10
Tendon Injury 9
Muscle Tightness 9
Muscle Stiffness 9
Musculoskeletal Stiffness 8
Muscle Disorders 8
Muscle Rigidity 6
Synovitis 6
Nuclear MRI Abnormal 5
Paresis 5
Joint Sprain 5
Joint Dislocation 5
Tenosynovitis 5
Cartilage Disorder 5
Carpal Tunnel Syndrome 5
Polyarthritis 4
Monoparesis 4
Fibromyalgia 4
Rheumatoid Factor Positive 3
Ligament Injury 3
Juvenile Arthritis 3
Jaw Disorders 3
Bone Disorders 3
Ligament Disorders 2
Joint Range of Motion Decreased 2
Fibromyalgia Syndrome 2
Polymyositis 2
Polymyalgia Rheumatica 2
Polymalgia 2
Osteopenia 2
Osteochondrosis 2
Orthopnoea 2
Muscle Hemmorage 2
Arthritis Reactive 2
Atherosclerosis 2
Tendon Repair 1
Synovial cyst 1
Smooth Muscle Antibody Positive 1
Quadriplegia 1
Limb Discomfort 1
Joint Contracture 1
Humerus Fracture 1
Ganglion Cyst 1
Exercise Tolerance Decreased 1
Exercise Capacity Decreased 1
Musculoskeletal Pain 1
Musculoskeletal Disorders 1
Musculoskeletal Discomfort 1
Muscle Necrosis 1
Muscle Abscess 1
Menigus Lesion 1
Physical Disability 1 (Despite over hundreds of such reports filed by the members of the adverse drug reaction forum)
Connective Tissue Disorders 1
TOTAL EVENTS REPORTED 2,898
A review of yet another online adverse drug reaction reporting forum: www.Medications.com (October 2002 to present) reveals that Levaquin is associated with approximately17% of ALL adverse drug reactions being reported to this site, regardless of the drug being reported upon. Medications.com is an Internet community that allows people interested in commonly prescribed drugs to interact so that they can discuss the implications -- both positive and negative of using these important tools in modern medicine. Medications.com list over 4,500 drugs in common use to date, users have posted thousands of side effects and messages about many of these drugs. The total number of adverse reactions, regardless of the drug mentioned, as of 2-11-2004, totals approximately 4,469. Levaquin, by far, received more such post than ANY other fluoroquinolone drug listed on this site. Of the 774 adverse reactions reported for all of the fluoroquinolones listed, 752 were for Levaquin. The only fatality listed for a fluoroquinolone was for Levaquin. 97.5% of all adverse reactions to the fluoroquinolones were reported for Levaquin. As such reports are received anonymously the verification of such reports is not feasible nor did the authors attempt this. But one can assume that receiving this many reports over the past sixteen months that the majority of such reports are indeed valid. This study also lacks the necessary controls required to present the above as fact and as such should be viewed in this context.
A review of the side effects posted on Medications.com for the fluoroquinolone used in clinical practice in the United States reveals the following:
Table 4
Adverse Events Reported VIA Medications.com
Inclusive of all fluoroquinolones listed
Avelox 8 post
Ciprofloxacin 7 post
Floxin 5 post
Levaquin 752 post w/(1) fatality
Tequin 2 post
The predominate adverse reactions reported for Levaquin are as follows:
Nuerotoxicity
Tendon Damage and or rupture
Insomnia
Non abating injury (multiskeletical)
Peripheral Neuropathy
Gastrointestinal
Anxiety and Panic attacks
Vision Problems
Rash, sweats, taste perversions, hearing loss
Table 6
Citations and references found with the literature
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
Table 7
Foreign post marketing reports
Tendon, Muscle and Ligament Associated Events
France 921 reported tendon disorders 1996
100 reported tendinopathies 1985-1992
WHO 340 reported tendonitis, 81 tendon ruptures 1996
Australia 25 reports of tendinitis
60 reports of tendinitis, and/or tendon rupture 1997
UK 704 Achilles tendinitis 1992-1998
38 Achilles tendon rupture 1992-1998
Finland 42 reported tendinopathies 2000
England 216 Tendon inflammation of rupture 1987-1997

Table 8
Domestic Post Marketing Reports
United States of America
As Reported by the FDA
Tendon Rupture Domestic 48
Tendon Rupture Foreign 45
Tendinopathy Domestic 68
Tendinopathy Foreign 35
Tenosynovitis Domestic 13
Tenosynovitis Foreign 7
We find the same problems when it comes to peripheral neuropathy, which again has been associated with these drugs since the introduction of Nalidixic Acid, which has recently been deemed by the EPA to be a cancer causing agent. In spite of the numerous reports found within the medical journals starting in 1991 and most recently reported by Dr. Jay S. Cohen in 2001, who states that he has brought his findings to your attention numerous times yet no warnings exist within the package inserts.

Table 9
Adverse Event Reporting System Summary 11-1-1997 to present
Peripheral Neuropathy / Nuerotoxicity
Ciprofloxacin
Pain 191
Paresthesia 99
Peripheral Neuropathy 58
Burning Sensations 43
Neurological Disorders 41
Polyneuropathy 30
Gamma-Glutamyltransferase Increased 29
Guillain Barre Syndrome 13
Neuralgia 12
Peripheral Sensory Neuropathy 7
Nerve Root Lesions 6
Neuropathy 5
Third Nerve Paralysis 4
Neurotoxicity 3
Neuropathic pain 3
Demyelination 2
Demyelinating Polyneuropathy 2
Skin burning sensation 2
Sjogren's Syndrome 2
Perineal Nerve Palsy 2
Peripheral Sensor Motor Neuropathy 2
Peripheral Coldness 2
Nerve Injury 2
Diabetic Neuropathy 1
Peripheral nerve injury 1
Peripheral Motor Neuropathy 1
Nerve Conduction Studies Abnormal 1
Nerve Compression 1
Neuromuscular Disorders 1
Burning sensation mucosal 1
TOTAL REPORTED EVENTS 567
Table 10
Adverse Event Reporting System Summary 11-1-1997 to present
Peripheral Neuropathy / Nuerotoxicity
Nalidixic Acid
(Total number of reports contained within the summary 12, regardless of events)
Burning Sensation 1
TOTAL REPORTED EVENTS 1

Table 11
Adverse Event Reporting System Summary 11-1-1997 to present
Peripheral Neuropathy / Nuerotoxicity
Levaquin
Burning sensations 55
Disseminated Intravascular Coagulation 43
Peripheral Neuropathy 34
Neurological Disorders 34
Polyneuropathy 23
Feeling hot 22
Epilepsy 9
Sensory Disturbances 9
Neuropathy 9
Feeling cold 9
Peripheral Ischaemia 8
Nerve Injury 6
Peripheral coldness 6
Sensory loss 5
Peripheral nerve injury 4
Neurotoxicity 4
Central Nervous System Stimulation 4
Temperature intolerance 3
Myopathy toxic 3
Feeling hot and cold 3
Vith Nerve Paralysis 2
Perineal Nerve Injury 2
Peripheral Sensory Neuropathy 2
Demylelinating Polyneuropathy 2
Trigeminal Nerve Disorders 1
Sciatic Nerve Lesions 1
Diabetic Neuropathy 1
Nerve Root Injury Sacral 1
Nerve Conductive Studies Abnormal 1
Optic Nerve Injury 1
Neuropathic pain 1
Demyelination 1
TOTAL NUMBER OF REPORTS 309
As stated within Dr. Cohen's study, such injuries are nonabating and there is no known treatment protocol. Such reports date all the way back to when Nalidixic Acid was first put into clinical practice in 1963. For more than forty years such injuries have been occurring and not recognized, treated or reported by the physician, nor addressed by the FDA. Nalidixic Acid is now listed as a carcinogen (1998).
Upon receiving notice that a class action lawsuit had been filed on behalf of the Capital Hill Staff, the Postal Workers and others who had suffered severe and non-abating injury as a result of the prophylactic use of Ciprofloxacin during the Anthrax Scare, Mr. MacCarthy, vice president of U.S. Medical Science at Bayer's West Haven facility, adding insult to injury stated "If you are telling me that someone had these effects and they were persisting, long term, months to years after treatment I would be surprised." The observed side effects, according to Dr. MacCarthy, "were typically gastrointestinal, nausea, vomiting, diarrhea…were talking side effects less than 5 percent". This is not what we find within the literature or the studies submitted with this drug application or for any of the fluoroquinolones, Ciprofloxacin included, for that matter.
It is absolutely inconceivable that Mr. MacCarthy would have no prior knowledge regarding the non-abating nature of the severe adverse drug reactions associated with his company's products. As noted above in December of 2001 Dr. Jay Cohen published his findings regarding this in the Annals of Pharmacotherapy in which Dr. Cohen documented the non abating nature of such injury, reporting on the very same events that have been described in the literature since 1991:
"In contrast to previous reports suggesting that fluoroquinolone-associated PNS events are mild and short-term, 36 of the 45 cases reported severe events that typically involved multiple organ systems. Although many newer cases are still evolving, symptoms had lasted more than three months in 71% of cases and more than one year in 58%." (The Annals of Pharmacotherapy 2001 December, Volume 35 1; Peripheral Neuropathy Associated with Fluoroquinolones, Jay S Cohen, www.theannals.com)
A spokeswoman for Bayer, manufacturer of Ciprofloxacin, stated in December of 2001 that the study was lacking in detail. She pointed out that it did not address the fact that peripheral tingling, one of the suspected adverse reactions mentioned in the study, was known to be a symptom in some urinary tract infections. Of the forty-five patients studied by Dr. Cohen only six were being treated for a urinary tract infection and of these six only three had complaints of "peripheral tingling". Only ONE of these patients was taking Cipro for a urinary tract infection and this patient did not experience long term effects. In fact this patient stated that such effects ceased upon termination of therapy. The patient who did suffer long-term disability was a 44-year-old female who took Cipro for bronchitis NOT a urinary tract infection. This patient suffered numbness, allodynia, esthesia, tremors, "electrical" sensations, diffuse burning, confirmed nonspecific nerve damage symptoms, tremors, twitching, disorientation, visual impairment, nausea, temperature intolerance, rash and palpitations and remains disabled after 29 months. I rather doubt that this severe non-abating adverse reactions compare to the "peripheral tingling" alluded to by this spokeswoman from Bayer. Yet Mr. MacCarthy continues denies any knowledge of this even though Bayer addressed these issues over three years ago. Not to mention the vast number of Med Watch reports filed by Bayer as required by the Adverse Event Reporting System.
Public Citizen filed a petition in August of 1996 in which it was requested that the FDA immediately inform all U.S. physicians through a "Dear Doctor Letter" by registered mail about the risk of tendon rupture with fluoroquinolone antibiotics. Eight years later the physician continues to fail to recognize, treat and report such events, stating to the patient "…It cannot be the drug…" in spite of the fact that such injury has been reported each and every year since Bailey et al in 1983. We continue to see reports within the medical journals stating this to be a rather new and rare event. I believe this to be a direct result of FDA inaction. Yet nothing has been done to warn the physician, the pharmacist, or the patient about this crippling adverse event other than the addition of a irrelevant and frivolous warning buried within the package insert, which in most cases is not even read by the physician or provided to the patient. This warning found within the Final Draft Package Insert of Moxifloxacin (Avelox, 1999) states:
"Although NOT observed in Moxifloxacin clinical trials, Achilles and other tendon ruptures that required surgical repair or resulted in prolonged disability have been reported with quinolones. Moxifloxacin should be discontinued if the patient experiences pain, inflammation, or rupture of a tendon."
This warning is absolutely useless as first it gives the impression that such events are NOT associated with Avelox. Secondly it states that such events are associated with quinolones yet Avelox is NOT a quinolone but a fluoroquinolone. Thirdly once a patient experiences "pain, inflammation, or rupture of a tendon" the damage has already been done and discontinuing the drug will do nothing to prevent it. Post marketing reports, animal studies, and case histories clearly indicate that spontaneous tendon rupture is a known, listed and published adverse drug reaction to any drug within the fluoroquinolone class. There is no question what so ever that this class of drugs has a direct toxic effect on tendon resulting in such injury. At a minimum these drugs should contain a black box warning stating exactly that. Together with a warning that such injury to the tendons, muscles, ligaments, and bones may result in non-abating and severely crippling disease state to which there is no known treatment protocol. It should also be mandated that the physician may not prescribe any drug within this class without first presenting the patient with a full and complete package insert and engaging in a risk/benefit discussion regarding the very real risk of such events occurring. Yet even this is not sufficient to warn the physician as they rarely if ever review the package insert even after a patient presents with a known adverse reaction.
Nevertheless I once again bring this to your attention and have included the monthly adverse reports from the forums. Which I have continued to do on a monthly basis for years now in the vain hope that someone, somewhere will put an end to this carnage. I have also included two statements from members who have lost their children due to the adverse reactions from these drugs. Avoidable deaths to which I hold the inaction of the FDA directly responsible. Had the FDA acted responsibly ten years ago these deaths would have never had occurred. How many more children must we bury before you take heed?

 
Respectfully submitted,
Fluoroquinolone Toxicity Research Foundation
fqresearch@asol.com
.