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The Honorable Michael Bilirakis | See downloads for: Adobe Files |
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The Honorable Michael Bilirakis United States House of Representatives 2269 Rayburn House Office Building Washington, DC 20515-0909 Dear Mr. Michael Bilirakis, Having exhausted all possibility of the FDA responding favorably to my concerns regarding the severe, non-abating injuries that I have suffered as a direct result of fluoroquinolone toxicity, which has continued in excess of four years now, I am demanding, as my elected official, for you to take action. Not only on my behalf, as your constituent, but also on behalf of the hundreds of thousands of other victims whose lives this chemotherapeutic agent has destroyed. Severe and non-abating injury to the patient has been described within the medical community since the introduction of Nalidixic Acid in 1962. Such severe non-abating adverse reactions include, but not limited to:
In September of 1994 Dr. Kent A. Huston wrote a letter to the New England Journal of Medicine in which he stated: "Fluoroquinolone antibiotics have been associated with Achilles tendinitis and rupture in reports from Europe and New Zealand,. 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." Corinne Pierfitte et al responded: "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 dictionary 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. …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." Ana Szarfman et al of the FDA took the following action (January 19,1995): "On the basis of postmarketing reports and published articles, 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." August 1, 1996, Public Citizen filed a petition DEMANDING that the FDA take the action voluntarily noted above, that being the addition of a warning within the package inserts for ALL the drugs within the fluoroquinolone class. In spite of such assurances being made by the FDA in January of 1995, as of August 1996, no such action had taken place. Public Citizen requested within this petition that the prescribing physician be made aware of the very real and documented adverse reaction of spontaneous tendon ruptures (reported since 1982, Bailey et al and documented within this petition), via the addition of BLACK BOX warnings within the package inserts together with "Dear Doctor" letters being sent. The FDA did neither. In response to this petition the FDA issued a Medical Bulletin which stated in part: "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." Yet today, twenty two years after Bailey et al first described the association of these drugs with spontaneous tendon ruptures, ten years after this was first brought to the attention of the FDA, and eight years after the FDA issued it’s ONE AND ONLY warning regarding this, the physician refuses to recognize, treat and report such events. My life has been destroyed by the careless and willful manner in which physicians hand out these chemotherapeutic agents like Halloween candy. The drugs I am referring to are: Ciprofloxacin AKA Cipro Clinafloxacin Enofloxacin AKA Penetrex Enrofloxacin AKA Baytril Fleroxacin AKA Quinodis Floxin AKA Ocuflox Gatifloxacin AKA Tequin Gemifloxacin AKA Factive Grepafloxacin AKA Raxar Levofloxacin AKA Levaquin Lomefloxacin AKA Maxaquin Moxifloxacin AKA Avelox Nalidixic Acid AKA NegGram Pefloxacin AKA Peflacin Sparfloxacin AKA Zagam Temafloxacin AKA Omniflox Trovafloxacin AKA Trovan As a result of a misdiagnosis of a kidney stone, back in August 2000, I was prescribed Floxin, Ciprofloxacin and finally Levaquin within a three-month period. Which resulted in several trips to the emergency room for severe adverse reactions, which were neither recognized nor reported by the prescribing physician. Four years later I am a virtual cripple. I have damage to my liver, kidneys, heart, joints, tendons, vision, peripheral neuropathy as well as numerous other medical conditions directly attributed to these drugs. My life now consists of numerous medical specialists who have told me repeatedly that there is nothing that can be done to reverse this damage. My life as I knew it to exist has ended. I am in constant pain requiring the use of strong narcotic pain relievers and have nothing but misery to look forward to for the rest of my life. Yet we find no such warnings within the package inserts for these drugs regarding the permanent and non-abating nature of these injuries. EVERY single doctor who has attempted to treat these conditions denies ANY knowledge regarding these adverse events. Yet I have accumulated (and forwarded to the FDA) over 4000 medical journal entries, case reports, etc. which document the fact that these drugs can and will cause such damage. The FDA has shown NO interest in pursuing this further despite the fact that the Adverse Event Reporting System, maintained by the FDA has accumulated over 31,000 such reports from 1997-2001:
Table 1 Adverse drug reactions, MedWatch November 1997 – November 2001 (four years) Drug ADR rate Associated Fatality Cipro 12,444 328 Floxin 7,255 173 Levaquin 11,656 273
A total of 31,355 adverse drug reactions and 774 associated fatalities. Bayer, the manufacturer of Cipro states that "…30% of the patients treated with Cipro will experience an adverse drug reaction". Yet Mr. MacCarthy, vice president of U.S. Medical Science at Bayer’s West Haven facility states, "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". Those who have suffered these severe and non-abating side effects myself included dare to differ. The following is an alphabetical listing of the various adverse drug reactions listed within the monographs for these drugs: A Asthenia Abnormal Vision Anemia Angina Abnormal Coordination Arrhythmia Abnormal Dreaming Aggressive Reaction Agitation Anorexia Anxiety Atrial Fibrillation Abnormal Hepatic Function Aggravated Diabetes Arthralgia Arthritis Arthrosis Abnormal Platelets ARDS Asthma Abnormal Renal Function Acute Renal Failure Allergic Pneumonitis Anaphylactic Shock Anaphylactoid Reaction Abnormal EEG B Bradycardia C Cardiovascular Disorders Cardiac Failure Circulatory Failure Central and Peripheral Nervous System Disorders Coma Convulsions Cardiac Arrest Cholelithiasis Coronary Thrombosis Carcinoma Confusion Coughing Crystalluria Cylindruria Cerebrovascular Disorder Conjunctivitis Cornea Damage Cataracts D Dry Mouth Dysphagia Decreased Lymphocytes Decreased Glucose Decreased Magnesium Delirium Depression Dyspnea Diplopia Dysphonia Dehydration E Edema Ear Disorders Embolism Epistaxis Ejaculation Failure Encephalopathy Eosinophilia Erythema Multiforme Erythema Nodosum Emotional Liability F Fever Facial Edema Fungal Infections G Gastrointestinal System Disorders Gastroenteritis G.I.Hemorrhage Genital Moniliasis Genital Pruritus Granulocytopenia H Hypertension Hyperkinesia Hypertonia Hypoaesthesia Hearing and Vestibular Disorders Heart Rate and Rhythm Disorders Heart Block Hepatic Coma Hematology Hyperglycemia Hyperkalemia Hypoglycemia Hypokalemia Hallucination Haemoptysis Hypoxia Hematuria Hemolytic Anemia I Increased LDH Impaired Concentration Impotence Increased International Normalized Ratio (INR) Prothrombin Time Involuntary Muscle Contractions Increased Calcium Increased Sweating J Jaundice K L Liver and Biliary System Disorders Leukocytosis Leukopenia Lymphadenopathy M Malaise Metabolic and Nutritional Disorders Mellitus Musculo-Skeletal System Disorders Muscle Weakness Myalgia Myo, Endo, Pericardial and Valve Disorders Myocardial Infarction Manic Reaction Mental Deficiency Multiple Punctate Lenticular Opacities Multi System Organ Failure (Death) N Neoplasms Nervousness O Osteromyelitis Ophthalmologic Abnormalities P Phlebitis Pleural Effusion Pectoris Parosmia Platelet, Bleeding and Clotting Disorders Purpura Psychiatric Disorders Paranoia Palpitation Paresthesia Paralysis Pancreatitis Pseudomembranous Colitis Q R Reproductive Disorders Resistance Mechanism Disorders Respiratory System Disorders Respiratory Insufficiency Respiratory Failure Rhabdomyolysis Rigors Red Blood Cell Disorders Retina Damage S Stevens-Johnson Syndrome Skin and Appendages Disorders Skin Disorders Skin Exfoliation Skin Ulceration Suicide Sleep Disorders Somnolence Substernal Chest Pain Syncope Seizures Speech Disorders Stupor Synovitis Supraventricular Tachycardia T Tremor Tongue Edema Tinnitus Tachycardia Tendinitis Thrombocytopenia Tendon Rupture Torsades de Pointes U Urticaria Urinary System Disorders V Vertigo Ventricular Fibrillation Vascular (Extracardiac) Disorders Vision Disorders Vasodilation W Weight Loss Withdrawal Syndrome White Cell and RES Disorders WBC Abnormal Count XYZ With over fourteen million prescriptions filled for Cipro alone we would expect a reported ADR rate of at least four million. We find a little over twelve thousand within the med watch database. These numbers found within the med watch database do NOT indicate a " safe and effective antibiotic with an excellent safety profiles… and to be remarkably free of clinically significant adverse effects", as claimed by the manufacturers, but the gross and complete failure of the med watch system. Such data accumulates year, after year, ignored by the FDA and never made available to the prescribing physician. In fact such data is not even allowed to be presented in civil suits for malpractice or product liability. The only one who reads this data are victims such as myself and even then it is easier to get a camel through the eye of a needle than it has been to gain such access. In 1982 spontaneous tendon ruptures were reported to have occurred long after such therapy had been terminated. In some cases well over a year later. Year after year numerous case studies, clinical trials and medical journal entries have documented this severe and crippling adverse drug reaction, often times citing the co-administration of steroids to be a contributory factor. The FDA has ignored this research and continued to approve additional agents and monographs devoid of this caveat for over twenty years. Only recently has the following warning been added to the monographs, twenty years later. "Achilles and other tendon ruptures that required surgical repair or resulted in prolonged disability have been reported with Ciprofloxacin and other quinolones. Ciprofloxacin should be discontinued if the patient experiences pain, inflammation, or rupture of a tendon."The patient being advised to: "To discontinue treatment; Yet when the patient presents with tendon pain and/or rupture he or she is told it cannot possibly be the drug by the attending physician. For more than fourteen years the FDA turned a blind eye to this until Public Citizen filed a petition demanding that they take action. They failed to do so. Despite the overwhelming evidence presented by Public Citizen, who demanded that at the very least a black box warning be added to the monographs and a "Dear Doctor" letter be sent, the FDA did nothing. No black box warning and no information provided to the prescribing physician, who to this day does not associate such spontaneous rupture to fluoroquinolone therapy. The clueless physician also prescribes STEROIDS to treat such events once they manifest in his or her patient. Which results in severe injury to the patient with the resulting tendon ruptures. . In fact the FDA has recently approved yet another fluoroquinolone with severe rash being a known adverse drug reaction together with the approval of the use of STEROIDS to treat such an event once it manifest in the patient. As stated before the physician has no clue as to what these drugs can and will do to a patient. There is no known treatment for a majority of the severe reactions. Such reactions DO NOT abate once therapy is discontinued in most patients and the current research indicates that such events are to be considered permanent in nature. A recent report published in the Annals of Pharmacotherapy, by Dr. Cohen emphasizes this. [The following text is from the article Peripheral Neuropathy Associated with Fluoroquinolones, Jay S Cohen:] "…Fluoroquinolones are important members of medicine’s arsenal of antibiotics. Serious ADEs involving the CNS and musculoskeletal systems have been reported but are considered infrequent. Mild ADEs involving the PNS have also been reported. This article, which presents a survey of a different population (with mainly serious, long-term symptoms) from a different source (the Internet), offers a new and different perspective on fluoroquinolone-related events involving the PNS. Further, better-controlled investigation is warranted. The FDA should also review and re-port on its cases relating to fluoroquinolone antibiotics. If the occurrence of fluoroquinolone-associated ADEs of this severity and duration is confirmed, physicians need to be informed and warnings might be considered for these drugs’ product information. In the meantime, healthcare providers may need to be vigilant regarding ADEs associated with fluoroquinolones, and even mild events involving the nervous or musculoskeletal systems should prompt immediate discontinuation."(sic) One cannot possibly agree with the statements being made by manufacturers with the full support of the FDA that "...the new fluoroquinolones have been in clinical use for 10 years and have an excellent record of safety and tolerance…" after reviewing the material presented so far. Yet when a patient presents with these adrs, they are told by the physician "it cannot be the drug." The recent study by Dr Cohen (noted above) highlights the fact that physicians are ignorant of the adrs associated with fluoroquinolone therapy and we have no one to blame but the FDA and the manufacturers for this sorry state of affairs. The most devastating ADR is peripheral neuropathy, first reported in 1992 (Peripheral neuropathy associated with fluoroquinolones. Lancet. 1992 Jul 11;340(8811):127.) Yet ten years later when Dr. Cohen brings this to the attention of the medical community, once again, the FDA ignores it. Eleven years after this was first reported in 1992, we find no such warnings regarding this PERMANENT DISABILITY of this injury within the monographs for these chemotherapeutic agents. Fluoroquinolones are not licensed for pediatric use (except the limited indication of Pseudomonas infection in cystic fibrosis on a compassionate basis) because of their potential to cause joint toxicity (observed in experiments using juvenile animal models). As recently as 2003 the FDA approves Vigamox antibiotic solution (Moxifloxacin 0.5%) in which this drug was tested on 336 pediatric patients, in spite of this ban. "...received approval from the U.S. Food and Drug Administration
(FDA) to market its Vigamox antibiotic solution (Moxifloxacin 0.5%)
for the treatment of bacterial conjunctivitis. In four studies, 336
pediatric patients and 392 adults had no safety concerns or adverse
events that were significantly different from placebo. I have been betrayed by the FDA, abandoned by the medical community and suffer endlessly as there are NO known treatment protocol when such events occur. Like a leper living outside the city gates my plight has been ignored by the FDA and those responsible for the manufacturing, sale and distribution of this toxic chemotherapeutic agent. In fact almost fifty percent of the fluoroquinolones introduced since 1980 have been removed from clinical practice or restricted in use due to toxicity issues. Yet physicians continue to hand them out like Halloween candy and the FDA continues to expand the approved uses and grants approval to the newer agents. Scripting abuse of these drugs have run rampant with no interference from the FDA. From January through November of 2001 we find over 3.4 million prescriptions for this class of chemotherapeutic agents commonly referred to as fluoroquinolones. With Cipro and Levaquin accounting for 80% of such prescriptions for the treatment of the following disease states: Bacterial Prostatitis Urinary Infections Pneumonia Acute Bronchitis Sore Throats Ear Infections Sinus Infections The utilization of the fluoroquinolones differs significantly by gender with 69% of such prescriptions prescribed for women. Perhaps this can be explained by the fact that among obstetricians/gynecologist 72% of the fluoroquinolone prescriptions were for Cipro, followed by Levaquin. Amongst Urologist, Cipro accounts for 52% of fluoroquinolone prescriptions. Despite the fact that in 95% of the case’s diagnosis as bacterial prostatitis we find no bacterial agent present. The patient is often times started on such therapy anyhow. Only about 5% of sinus infections are bacteria induced and in adults with upper respiratory infections we find about 2% of the cases complicated by bacterial sinusitis (sinus infection). In cases of bronchitis and pharyngitis (sore throat) we find 90% being the result of a viral infection. Rarely do we find bacteria to be the cause of episodes of sinusitis. Only about 10% of sore throats are true cases of strep throat. Taken as a whole one could arrive at the unmistakable conclusion that in 90% of the cases outlined above such therapy is useless. Research also indicates that in children with ear infections, whether viral or bacterial in nature, 80% will be better within a few days whether they receive such therapy or not. The fluoroquinolones have no effect whatsoever on viral infections. In acute bronchitis a viral infection is the cause 90% of the time. In the rare cases that a bacterial agent is actually the cause of the infection there are proven agents much safer that the fluoroquinolones. In November of 2000 Bristol-Myers proudly announced that their product, Tequin (a fluoroquinolone), reached the "ONE MILLION NEW PRESCRIPTION MARK" in the first ten months it was on the market. One million new prescriptions, for a drug that is indicated for community-acquired respiratory tract infections. The previous ten-month "new prescription" record was held by Levaquin, another fluoroquinolone manufactured by Ortho-McNeil. This of course does not include the "free samples" distributed by physicians, of which no such public record exist. Doctors prescribed the fluoroquinolones with the attitude that "they may not help, but they won’t hurt", believing that any really serious adverse drug events are well documented by the time the drug is marketed. Nothing could be further from the truth. Perhaps this scripting abuse, failure to provide adequate warnings, and the rubber stamp approval of the newer agents can be explained by the fact that more than 50% of the experts hired to advise the FDA on the safety and effectiveness issues have a financial relationship with the pharmaceutical companies that will be helped or hurt by their decisions. 54% of the time they have a direct financial interest in the drug topic they are asked to evaluate. Even though Federal Law generally prohibits such conflicts of interest the FDA has waved this restriction over 800 times within a two year span (1998 – 2000). Such conflicts take the form of stock options, consultation fees, or research grants. From January 1998 through June 2000 we find that: At 92% of the meetings at least ONE member had a financial conflict of interest. At 55% of these meetings 50% or more had a financial conflict of interest At 57 meetings, when broader issues were discussed we find 92% of the members had a financial conflict of interest The Media has ignored this tragic situation as well failing to report or investigate the horrendous damage being done day in and day out, since 1939 with the introduction of Chloroquine which has severe vision adverse reactions associated with it. 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. Clinafloxacin was voluntarily withdrawn by the manufacturer during the registration process, at least in part because of the excess phototoxicity and reports of hypoglycaemia. In contrast, Lomefloxacin is associated with a significant photo toxic potential. Table 2 Fluoroquinolones removed from clinical practice or use restricted 1962 Nalidixic Acid 1973 Flumequine 1985 Sparfloxacin 1988 Temafloxacin 1989 Grepafloxacin
2000 Factive (originally denied but recently received approval) Table 3 Severe adverse drug reactions associated with fluoroquinolone currently in use
[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]
The allegations being made are self-evident and the research so compelling that a Congressional Hearing is mandated into the class of chemotherapeutic agents we refer to as Fluoroquinolones. Yet Congress refuses to act. Specifically this research supports an investigation into how it is possible for such a dangerous and toxic drug continue to receive the blessings of the FDA. I believe these adverse drug reactions to be of such a grievous nature that this class of drugs should be removed from clinical practice immediately. Failing in that I would request that Congress mandate that the FDA require the various manufacturers to include a black box warning for the more severe adrs (Peripheral Neuropathy, spontaneous tendon rupture, CNS and PNS events) together with the issuing of a "Dear Doctor" letter (as requested over seven years ago) to both the physician who prescribes these drugs together with the pharmacist who fills such prescriptions. The issuing of "free samples" should no longer be allowed as such warnings are rarely if ever included with such dispersion. Congress should also mandate that the manufacturers of fluoroquinolones formulate a treatment protocol for addressing these issues once they manifest during such therapy. In addition steps need to be taken immediately to prevent "off label" usage and these drugs need to be restricted to FDA approved use only. Physicians need to be deprived of their discretion when prescribing fluoroquinolones as their total lack of knowledge regarding the damage this class of drugs can and will do is appalling. The saddest part of all is the fact that this can so easily be prevented if the FDA would simply follow it’s mandate and Congress investigate why the have failed so miserably regarding fluoroquinolones. Yet in spite of numerous request that this be done, by Public Citizen, the victims of fluoroquinolone toxicity and the loved ones of those so affected, Congress and the FDA have done absolutely nothing to prevent such injury from occurring. I bring all of the above to your attention, not only on my behalf as well as the other victims of this scripting abuse but also on behalf of the pediatric population. In spite of the fact that I have been providing such documentation to the FDA for almost four years now, the FDA has chosen to ignore all of this research and is currently allowing clinical trials involving children as young as six months of age: Levofloxacin In The Treatment Of Children With Recurrent And/or Persistent Acute Otitis Media This study is currently recruiting patients. Sponsored by Johnson & Johnson Pharmaceutical Research and Development, L.L.C. Purpose The purpose of this study is to demonstrate non-inferiority of levofloxacin compared with amoxicillin/clavulanate on the clinical response at the end of therapy in infants and children who have recurrent and/or persistent acute otitis media. Drug: Levofloxacin Drug: Augmentin ES-600 Expected Total Enrollment: 1650 Location and Contact Information Alabama Edward Goldblatt, M.D., Alabaster, Alabama, 35007, United States; Terminated Clinical Research Consultants, Inc., Hoover, Alabama, 35216, United States; Terminated University of Alabama at Birmingham, Birmingham, Alabama, 35233, United States; Terminated Arizona Kevin Concannon, MD, Tucson, Arizona, 85741, United States; Recruiting California Center for Clinical Trials, LLC, Paramount, California, 90723, United States; Recruiting Madera Family Medical Group, Madera, California, 93637, United States; Recruiting Peninsula Research Assoc., Inc., Rolling Hills Est, California, 90274, United States; Recruiting Wignes Warren, MD, West Covina, California, 91790, United States; Recruiting Delaware J. Jordan Storlazzi, Jr., Wilmington, Delaware, 19810, United States; Recruiting J. Jordan Storlazzi, Jr., MD 302-478-1975 Dana Miller, RN 302-478-8337 Florida Mobeen Rathore, MD, Jacksonville, Florida, 32209, United States; Recruiting Mobeen Rathore, MD 904-244-3051 Michelle Eagle, PA-C 904-244-5331 HYPERLINK Georgia Columbus Regional Healthcare System, Columbus, Georgia, 31902, United States; Terminated River Birch Research Alliance, Blue Ridge, Georgia, 30513, United States; Recruiting Willis Memorial Hospital, Augusta, Georgia, 30909, United States; Terminated Hawaii Hawaii Pacific Health Research Institute, Honolulu, Hawaii, 96813, United States; Recruiting Illinois Kristi Lundblad, MD, Park Ridge, Illinois, 60068, United States; Recruiting Kristi Lundblad, MD 847-723-8409 Mount Sinai Hospital, Chicago, Illinois, 60608, United States; Recruiting Iowa John Sutherland, MD, Waterloo, Iowa, 50702, United States; Terminated Kentucky Commonwealth Ear, Nose & Throat, Louisville, Kentucky, 40207, United States; Recruiting Christopher Harrison, MD, Louisville, Kentucky, 40202, United States; Recruiting Kentucky Pediatric/Adult Research, Bardstown, Kentucky, 40004, United States; Recruiting Louisiana LSU Medical Center, Shreveport, Louisiana, 71130, United States; Recruiting Eduardo Hernandez, MD, Slidell, Louisiana, 70461, United States; Recruiting Eduardo Hernandez, MD 985-781-7337 Amy Adama, LPN Michigan Children's Hospital of Michigan, Detroit, Michigan, 48201, United States; Recruiting Nebraska Creighton University, Omaha, Nebraska, 68131, United States; Recruiting Sondra Spaulding 402-280-4583 New York Regional Clinical Research, Johnson City, New York, 13790, United States; Recruiting Winthrop Pediatric Infectious Diseases, Mineola, New York, 11501, United States; Recruiting New York Weill Cornell Center, New York, New York, 10022, United States; Recruiting North Carolina Emmanuel Walter, MD, Durham, North Carolina, 27704, United States; Recruiting Ohio Rainbow Babies & Children's Hospital, Cleveland, Ohio, 44106, United States; Recruiting Children's Hospital Medical Center of Akron, Akron, Ohio, 44308-1062, United States; Recruiting Phillip Walson, MD, Cincinnati, Ohio, 45229-30339, United States; Recruiting Pennsylvania Keystone Clinical Solutions, Altoona, Pennsylvania, 16602, United States; Recruiting Primary Physician's Research, Inc., Pittsburgh, Pennsylvania, 15241, United States; Recruiting Peter Lane, MD, Philadelphia, Pennsylvania, 19141, United States; Recruiting Primary Physicians Research, Inc., Pittsburgh, Pennsylvania, 15241, United States; Recruiting South Carolina Medical University of South Carolina, Charleston, South Carolina, 29425, United States; Recruiting Tennessee Integrity Clinical Research (Attn: Kristi Johnson), Milan, Tennessee, 38358, United States; Terminated Texas South Texas Applied Research, Corpus Christi, Texas, 78411, United States; Recruiting Texas Children's Hospital, Houston, Texas, 77030, United States; Recruiting Utah American Fork Hospital, American Fork, Utah, 84003, United States; Recruiting Kelly E. Stoker, MD, Salt Lake City, Utah, 84102, United States; Recruiting Virginia Inova Fairfax Hospital, Burke, Virginia, 22015, United States; Recruiting Advanced Pediatrics, Vienna, Virginia, 22124, United States; Recruiting Argentina, Buenos Aires Victor Israele, MD, San Isidro, Buenos Aires, 1642, Argentina; Recruiting Abel Jasovich, MD, Capital Federal, Buenos Aires, 1425, Argentina; Recruiting PAIDEIA, Salguero, Buenos Aires, 1425DEM, Argentina; Recruiting Juan B. Justo 4332, Capital Federal, Buenos Aires, 1416, Argentina; Recruiting Carota Russ, MD, Gaona, Buenos Aires, 1416, Argentina; Recruiting Brazil, Curitiba-PR-CEP Hospital Nossa Sra das Gracas, Setor Estar Medico, Curitiba-PR-CEP, 80810-050, Brazil; Recruiting Hospital de Clinicas do Parana, Otarrino - 5 andar anexo B, Curitiba-PR-CEP, 80060-900, Brazil; Recruiting Hospital de Clinicas - UFPR, Infectologia - 3 andar, Curitiba-PR-CEP, 80060-900, Brazil; Recruiting Brazil, Jacana-Sao Paulo-SP-CEP Hospital Sao Luiz Gonzaga, Depto de Pediatria, Jacana-Sao Paulo-SP-CEP, 02276-140, Brazil; Recruiting Brazil, Porto Alegre-RS-CEP Hospital de Clinicas de Porto Alegre, Depto de Otorrinolaringologia, Porto Alegre-RS-CEP, 90035-003, Brazil; Terminated Brazil, Ribeirao Preto-Sao Paulo-SP-CEP Hospital Santa Lidia, Servico de Otorrino, Ribeirao Preto-Sao Paulo-SP-CEP, 14085070, Brazil; Recruiting Marcelo Toledo Piza, MD 011-55-16-610-6515 Brazil, Sao Paulo-SP-CDP Hospital Israelita Albert Einstein, Paraisopolis, Sao Paulo-SP-CDP, 05663-020, Brazil; Recruiting Brazil, Sao Paulo-SP-CEP Hospital de Clinicas FMUSP, Pronto Socorro, Sao Paulo-SP-CEP, 05409-003, Brazil; Recruiting Costa Rica, San Jose Neeman-Instituto Costarricense de Investigaciones Clinicas, Los Arboles, San Jose, Costa Rica; Completed Mexico, Jalisco Hospital Universitario Angel Leano, Zapopan, Jalisco, 45200, Mexico; Terminated Mexico, Puebla Alejandro Flores-Nunez, MD, Atlixa, Puebla, 72190, Mexico; Terminated Mexico, Towca Felipe Oliveros Lozano, MD, Vialidad A. del majo Esqv., Towca, 50010, Mexico; Terminated In spite of the overwhelming evidence presented at that 62 Meeting of the Anti-Infective Drugs Advisory Committee that the fluoroquinolones cause irreversible joint damage in the pediatric population the FDA has recently added the use of Ciprofloxacin in the pediatric population. Treating children as young as one years of age. We are currently faced with a clear and present danger regarding these drugs as the FDA, ignoring the tragic results of such careless scripting, has now authorized this use knowing full well that the physician will continue to abuse their discretion. I challenge you to explain to me how the FDA expect a child who cannot even walk or talk yet to register a complaint of joint and tendon pain. Numerous studies have indicated that such use in a pediatric patient runs the risk of crippling the child for life. One such patient has undergone numerous surgeries to repair this damage and remains crippled to this day. Another has suffered severe brain damage and is paralyzed fighting for her life even as I prepare this plea for your intervention. Yet additional clinical trials continue aided and abetted by the FDA, for other drugs in this class other than Ciprofloxacin. A disaster that is detailed within the 62nd meeting of the Anti-Infective Drugs Advisory Committee where it was so eloquently stated: "…when we talk about the issue of arthropathy that potentially includes a number of things, ranging from simple effusion, for instance, of a knee joint, which might rapidly resolve after the conclusion of therapy, to a more permanent disability. .." (sic) "…in September of 1997 there is now a ciprofloxacin suspension which is available, and although it continues to have the same warning statements about arthropathy in juvenile animals and the potential concern in pediatric populations, obviously, the issue of off label use will extend over to pediatric populations in this formulation…."(sic) "…An important safety question is, what adverse events should be monitored, and Doctor Goldberger alluded to this earlier. This is some of the examples I present. One is permanent lameness, reversible lameness, joint effusion, joint pain, and even latent articular disease or damage that may occur months or years following drug exposure, and there may be others…."(sic) "…And, data submitted to the Agency, as well as data from the scientific literature, indicate that these lesions don't appear to be reversible…"(sic) "…Doctor Stahlmann in Berlin is working on an idea that it may be an effect between the endocrines, the magnesium and the matrix and the quinolone. And that data is just coming out now. But as to the exact mechanism, I think you're right. I don't think we have a handle, as far as I know, on the exact mechanism. If there's anybody else that does, I'd sure like to hear it…"(sic) "… Relating your personal experience, I was wondering about the potential for a delayed effect that in fact one might have a patient who had some histologic changes that would not be manifest clinically for many years. Is that a potential?" (sic) "… I think it is a potential…"(sic) "… In trying to assess toxicity with a very sensitive assay, obviously you've got tissue that you can look at in your animal models. There is some human data that were collected by Doctor Urs Schaad using MRI scanning in children and I'm wondering if you can correlate some of your histopathologic findings with MR in the animal model to give us an idea of how sensitive it would be sort of as a follow-up to Doctor Klein's question is the MR something that will be able to predict long-term outcomes, even if there are no clinical symptoms during therapy…."(sic) "… That I don't know. I'll just be perfectly frank. I don't know. But on the slides I've seen from the animals from the chronic study, the repaired articular cartilage that is there is principally fibrocartilage yet it will provide the same joint margin and it has a calcified base and when we stain it with safrain O screen there's no proteoglycans there so it's going to make it an extremely chondromalaistic area and beyond the one year I can't tell you what the results will be…"(sic) "…Anyway, it was by a group in Vienna where they looked at the articular cartilage of postmortem specimens of articular cartilage from kids with cystic fibrosis that had been on quinolones for a period of time and they found that there was damage in the chondrocytes…."(sic) "…There were no deaths reported in U.S. pediatric zero to 18 year old cases where a flouroquinolone was reported as the suspect drug. However, there are eight deaths in the whole cohort of suspect and concomitant flouroquinolone drug reports in the system. Five of these deaths reported ciprofloxacin as a concomitant drug and not the suspect drug. These five were U.S. cases with ages ranging from seven months to six years. The remaining three deaths were all foreign, all 18 year old patients with either ofloxacin or norfloxacin reported as the suspect drug…."(sic) "…There are 14 reports of arthropathy or arthralgia in the pediatric zero to 18 year old flouroquinolone reports. One report of a 14 year old girl had both ofloxacin and lomefloxacin as the suspect drug so there is an extra count because of the two flouroquinolones on this one report. This particular report indicates that a pediatric orthopedic surgeon diagnosed femoral anteversion as the cause for the girl's arthralgia, therefore you see it listed twice, and not the flouroquinolones. Most of the reports indicated that either an involved knee or elbow with or without other joints was involved…."(sic) "…One interesting case which is not included on this slide for arthralgias was a 15 year old boy who received ofloxacin IV for an emergency appendectomy and had not grown more than his 70 inches in height over the last year. The 15th percentile for height for a 15 year old boy however is 66.5 inches and the expected growth rate is about two inches per year…"(sic) "…Three patients had their seizure after the first dose of flouroquinolone, one on ciprofloxacin and the other two on ofloxacin, one of which had received ofloxacin several months earlier…"(sic) "…The 15 psychiatric reports are a loose grouping of reports which include events ranging from euphoria to psychosis. The ages range from five to 18 years with the median at 15 years. There were two suicide attempts, one on ofloxacin and the other on norfloxacin, three reports of hallucination, one each on ciprofloxacin, ofloxacin and norfloxacin, and one report of aggressive behavior with confusion in a patient who had a psychiatric history and was on norfloxacin. The seven cases of photosensitivity were reported with lomefloxacin with one case on ciprofloxacin and two cases on ofloxacin. …"(sic) "…I will mention that there were 152 U.S. cases aged zero to 18 years in the U.S. AERS system suspect flouroquinolones in the WHO line listing. The country with the most pediatric reports in the WHO foreign reports is the United Kingdom with 177 reports followed by Germany with 72 and France with 71. The rest of the countries had 20 or fewer reports…."(sic) "…And with regards to muscular-skeletal events, 21 percent of the patients had an event in ciprofloxacin…"(sic) "…We have focused our analysis on joint disorders and pefloxacin. 79 cases were reported and consist mainly of arthralgia. I don't know the pronunciation of hydrarthrosis -- 49 persons. It involved the knee in 52 cases, the wrist in 20 cases, the elbow in 20 cases, the shoulder in 6 cases, the ankle in 5 cases, and the hip once. It is associated with a functional discomfort in all cases, and when the duration of this discomfort is known, it can persist more than one month in 61 percent of these cases. But the outcome was favorable in 58 cases without discontinuation in two cases. …"(sic) "…There have been sequelae in three cases with knee effusions persisting one year later in one case with discomfort following 8 months later in the second case. The third case is articular. It is a 17-year-old patient who experienced arthropathy and the drug was not suspected and the treatment was continued two following months. It leads to destructive arthropathy of the knees and the hip and prothesis was performed three years later. He was treated for a cerebral abscess. The outcome was unknown in 18 cases. In 9 cases, there was no follow-up. In the 9 last cases, we had a follow-up three months later and patients were not -- were still with disabilities and after we have no evolution…." (sic) "… It is my understanding that one of the children had a joint replacement, is that correct?" " Pardon me?" " One of the children with the complications had an artificial joint replacement?" "Yes." "…If an irreversible cartilaginous lesion can occur, it is very likely that is going to cause problems down the line and we can't even anticipate what they are like…" (sic) In spite of the following horrendous side effects: Permanent disability Permanent lameness Joint effusion Joint pain Latent articular disease or damage that may occur months or years following drug exposure Lesions that don't appear to be reversible Potential for a delayed effect that would not be manifest clinically for many years Damage in the chondrocytes Eight deaths (five of which involved Ciprofloxacin) 14 reports of arthropathy Seizures Stunted growth Suicide attempts Hallucinations Photosensitivity Knee effusions persisting one year later with destructive arthropathy of the knees and the hip (And with regards to muscular-skeletal events, 21 percent of the patients had an event in Ciprofloxacin) As one member of this advisory committee stated "…If an irreversible cartilaginous lesion can occur, it is very likely that is going to cause problems down the line and we can't even anticipate what they are like…" As such the FDA has no idea what risk these children face nor how to treat such events once they occur. Yet in conclusion this committee stated "…We clearly want to encourage development of these drug for use in pediatrics…". Within the newest package insert for Ciprofloxacin we find peripheral neuropathy being added as a severe, non-abating adverse drug reaction. A disease state in which the peripheral nerves are so badly damaged the patient will spend the rest of their natural life in severe, non-abating pain for there is no treatment protocol available for such a disease state that offers any relief. For more than forty years since the introduction of Nalidixic Acid in 1962, severe and permanent injury to the patient has been documented. Not one year in the past twenty has gone by without additional articles being published in the leading medical journals documenting the horrendous damage these drugs can and will do since the introduction of Nadilixac Acid. Now the FDA has given they’re blessing on the use of chemotherapeutic agents within the pediatric population. The use of these drugs will NOT be restricted to the approved indications either. The FDA has stated "…obviously, the issue of off label use will extend over to pediatric populations …" So now a child with a minor ear ache or sore throat will risk being crippled for the rest of their lives and the FDA will continue to turn a blind eye to such abuse for it is NOT within the legal rights of the FDA to control how such drugs are used once they have been approved. The FDA has no say in the manner in which a physician chooses to utilized a drug once it has been approved. As such we now look forward to a whole generation of pediatric patients being destroyed by the careless manner in which such drugs are utilized and the treating physician will continue to fail to recognize, treat and report such events. Just as they have been doing for the past forty years. Numerous forums now exist on the Internet in which the adult patients have been reporting such severe reactions since 1999. We can all now look forward to the distraught parents of these children joining such forums as a direct result of this total and complete failure of the FDA to protect the health and welfare of the pediatric population. Ignoring their own research and the findings of their advisory committee, they have approved a proven dangerous and toxic drug for the use in children. We find the same thing being repeated regarding vision loss, which is permanent, heart failure, kidney failure, liver failure, thousands of documented deaths, all of which the FDA has chosen to ignore. I, as well as other victims continue to collect post-marketing reports regarding the non-abating nature of the severe and crippling adverse drug reactions associated with fluoroquinolone therapy via the Internet. Since the research forum went on line in August of 2003, the Fluoroquinolone Toxicity Research Forum hosted by Yahoo has received hundreds of reports, including numerous associated fatalities. The homepage for the Fluoroquinolone Toxicity Research Foundation, www.fqresearch.org has accumulated over 4000 medical journal entries, newspaper articles, post marketing reports, lawsuits and other such supporting data the clearly shows the rampant ignorance and denial within the medical community regarding the non-abating nature of such events.For more than forty years, since the introduction of Nalidixic Acid in 1962, the victims of fluoroquinolone toxicity have been denied the medical care they so desperately need as their physicians have routinely failed to recognize, treat and report such events. Peripheral Neuropathy, spontaneous tendon rupture, severe and non abating joint and tendon damage, resulting from such toxicity, are all known, listed and published adverse drug reactions to these chemotherapeutic agents, commonly referred to as fluoroquinolones or quinolones. Yet the victims continue to be told by their physicians "it cannot be the drug". Numerous news stories since the anthrax scare have documented such injuries with the most recent being the death of the daughter of one member of the research forum, whose death was the direct result of such careless scripting of these toxic and dangerous drugs. Another forum, the quinolone adverse drug reaction forum, hosted by Yahoo since February 14, 1999, has accumulated over 17,000 such post regarding the damage this class of chemotherapeutic agents can and will do. In spite of the overwhelming evidence of the non-abating nature of such injuries, the FDA continues to approve new drugs within this class together with new indications for those already on the market. Ignoring the 5,276 reports that include 473 associated deaths and 19,792 total reactions found within the AERS reports for Levofloxacin. Together with the 4,995 reports which include 480 associated deaths and 20,890 total reactions for Ciprofloxacin found within the AERS reports as well. Almost fifty percent of such chemotherapeutic agents have been removed from clinical practice or their use severely curtailed, due to toxicity issues. Yet, Mr. MacCarthy, Vice President of U.S. Medical Science at Bayer’s West Haven facility states "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 victims of these adverse drug reactions have been telling Mr. MacCarthy’s employer exactly that for years. I state unequivocally that Mr. MacCarthy is being less than forthright in the statements he has made. Such documentation has been made available to the firm he works for year after year. The adverse reactions experienced by the victims have shown to be both persistent and non-abating, "year after year", contrary to what Mr. MacCarthy has stated publicly. The following two letters had been sent to the head of the FDA, detailing the devastation and ignorance surrounding these drugs: Commissioner of the FDA: My name is Gary Pettijohn, residing in Batesville, Indiana. Although I have not personally taken or suffered any adverse reaction to a chemotherapeutic agent, commonly referred to as a fluoroquinolone type drug, I make this statement on behalf of a loved one who cannot be with us today to tell of her plight. My daughter, Kristen Pettijohn, passed away from complications resulting from multiple simultaneous severe adverse reactions to the fluoroquinolone, Avelox. These reactions are documented by the extensive autopsy and toxicology tests performed after her death by the Indiana University Medical hospital in Indianapolis. Within 8 days I watched in horror as a vibrant, energetic, healthy
young lady went from a mild respiratory illness to suffering from
severe abdominal pain, hallucinating, incoherent, a skin rash to
comatose, liver failure, kidneys failing, skin peeling off in sheets
(toxic epidermal necrolysis), and on life support and then ultimately
death, a direct result of taking but 3 doses of Avelox for a minor
respiratory infection.
Unfortunately, this information was not known at the time that she
took the first of 3 doses Mr. and Mrs. Gary Pettijohn (sic) To the Commissioner of the FDA: Dear Sir: I feel it is extremely urgent that an investigation be conducted by
the FDA to ascertain whether these drugs should be taken off the
market, or at least, their use limited to cases where they are the
"drug of last resort". As well as the following which was sent to 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 Profes r (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 (sic)
A review of the online adverse drug reaction reporting forum: www.Medications.com (online October 2002) reveals that Levaquin is associated with approximately17% of ALL adverse drug reactions being reported to this site, irregardless of the drug being reported upon. Medications.com started receiving such reports as of October of 2002. 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. A review of the side effects posted on Medications.com for the fluoroquinolone used in clinical practice in the United States reveals the following: 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 This trend is repeated on a number of adverse drug reaction forums dealing with the adverse drug reactions as they relate to the Fluoroquinolones. As the above data has not been verified other than visiting this site and doing a physical count the absolute accuracy has not been determined. However this presents a survey of a specific population with mainly non-abating long-term symptoms from a different source than is commonly used to research such events. The conclusions reached raises serious concerns regarding the safety profile of Levaquin. The Internet offers a new perspective on fluoroquinolone-related adverse drug reactions, which with better-controlled investigations may warrant additional warnings within the package inserts regarding such events. The FDA should also review and reassess the cases relating to the Adverse Event Reporting System for Levaquin as well as the other fluoroquinolone antibiotics. If the occurrence of fluoroquinolone-associated adverse drug reactions of this severity and duration is confirmed, physicians need to be informed and warnings must be added to these drugs’ product information. In the meantime, physicians and other healthcare providers need to pay additional attention to the adverse drug reactions being reported to them by their patients and even mild adverse reactions involving the nervous or musculoskeletal systems should prompt immediate discontinuation. The number one complaint received from those who have suffered such an event is the fact that their physician failed to recognize, treat and report the adverse drug reaction they experienced while undergoing fluoroquinolone therapy. I sent the following letter to Dr. McClellan, Commissioner Food and Drug Administration in February 2004:
CC: To Dr. Galson 2-23-04 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 non-abating 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 Arthralgia 261 (within the top three reported events) Table 2 Arthralgia 368 (The number one event reported) 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 3 Avelox 8 post The predominate adverse reactions reported for Levaquin are as follows: Nuerotoxicity Table 4 1983 Peddie BA: Norfloxacin induced rhuematic disease RR, JA Table 5 France 921 reported tendon disorders 1996 WHO 340 reported tendonitis, 81 tendon ruptures 1996 Australia 25 reports of tendinitis UK 704 Achilles tendinitis 1992-1998 Finland 42 reported tendinopathies 2000 England 216 Tendon inflammation of rupture 1987-1997
Tendon Rupture Domestic 48 Tendinopathy Domestic 68 Tenosynovitis Domestic 13 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.
Pain 191 Table 8 Burning Sensation 1
Burning sensations 55 As stated within Dr. Cohen's study, such injuries are non-abating, 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, 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,
To which I received the following "form letter" response a month and one half later: DEPARTMENT OF HEALTH & HUMAN SERVICES Food and Drug Administration Rockville MD 20857 March 12, 2004
This is in response to your emails to Dr. McClellan, Dr. Sherman, and Dr. Galson of February and March 2004 regarding Quinolone post marketing reports. They have forwarded your emails to the Center for Drug Evaluation and Research's Office of Executive Programs to respond. We would like to thank you for your post marketing surveillance reports of January and February, 2004. However, CDER's Office of Pharmaceutical Science reviewed your initial submission for January and the numbers are not consistent with the reported numbers within our office. It was also noted that the majority of those adverse events reported are well-known side effects of the Fluoroquinolone class of drugs. Since approving the first Class of Fluoroquinolones in 1996 for treatment of acute maxillary sinusitis, acute bacterial exacerbations, of chronic bronchitis, community-acquired pneumonia, uncomplicated skin and skin structure infections, complicated urinary tract infections and acute pyelonephritis, there have been several labeling supplements added as well as adding new indications since the original approval in 1996. As you know, we will weigh all risks and benefits associated with Fluoroquinolone Class Drugs prior to taking any additional action. We will continue to monitor future adverse events reported to us. We recommend that your organization encourage those individuals contacting you regarding adverse events experienced when taking Quinolone submit a MedWatch report at http://www. fda. gov/medwatch. If you would like to view FDA's reports on adverse events associated with Fluoroquinolones, please submit a Freedom of Information request. The following web address will provide instructions on how to submit your request: http://www.fda.gov/opacom/backgrounders/foiahand.htmlAdditionally, you can contact the Office of Training and Communications, Division of Drug ~nformation at 88 8-INFO FDA (463-6332) for additional assistance. Again, thank you for submissions and interest in this issue. Sincerely, Frances T. Gipson, FACHE Office of Executive Programs Center for Drug Evaluation and Research Regarding this response I have the following comments to make: "…reviewed your initial submissi |