Fluoroquinolone Toxicity Research Foundation 09-28-2003

Director

fqresearch@aol.com

The following letter had been sent to

Patrick Rucker c/o Fairfield Weekly One Dock Street, 5th floor Stamford, CT 06902 (203) 406-2406
fax (203) 406-1099

Washington Post 1150 15^th St. NW Washington DC 20071

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RE: Cipro side effects

For more than forty years the victims of fluoroquinolone toxicity have been shouting from the rooftops regarding the non abating nature of such injuries. No one listened then but perhaps they will listen now. As you have noted within your recent article the law firm of Sheller, Ludwig and Badey has made known their intentions of holding the manufacturer of Cipro, Bayer AG, responsible for such injuries. This Philadelphia law firm, one of the biggest product liability and class-action firms on the East Coast, is preparing a class action suit against Bayer Pharmaceuticals. This suit is being filed on behalf of the Capitol Hill staff, the Washington postal workers, and the employees of the American Media who were exposed to this drug during the recent anthrax scare. They claim to have suffered the non-abating adverse drug reactions to Cipro. This suit also includes those who have suffered a similar fate due to the prescribing of this drug for various disease states.

The severe and non-abating nature of the adverse drug reactions to fluoroquinolones, to which Cipro is one such drug, has been reported within medical journals for more than forty years. Since the introduction of the first quinolone, Nalidixic Acid, the FDA has allowed the manufacturers of the class of chemotherapeutic agents, commonly referred to as fluoroquinolones to be aggressively marketed as a " safe and effective antibiotic with an excellent safety profiles… and to be remarkably free of clinically significant adverse effects." This has been done in spite of compelling evidence to the contrary. Evidence that the FDA has ignored since 1962. For almost forty years the FDA has turned a blind eye to the severe, crippling and at times fatal adverse drug reactions associated with this chemotherapeutic agent. Even going so far as to allow these drugs to be marketed to physicians as a safe antibiotic with minimum side effects. First and foremost one must understand that fluoroquinolones are NOT an antibiotic but a man made chemotherapeutic agent, concocted in a laboratory, genetically engineered to destroy the DNA of the bacterial agent. They are not and cannot be put in the same class as antibiotics, which are substances produced as metabolic products of one microorganism, which inhibit or kill other microorganisms. Antibiotics may exhibit adverse drug reactions but such reactions resolve upon cessation of therapy or modification of the therapeutic dose. The toxic adverse drug reactions associated with fluoroquinolones do not appear to be not dose dependant and do NOT resolve upon cessation of therapy in some cases. In most cases such adverse drug reactions do not even manifest until weeks, months and even years after such therapy has been terminated. These latent reactions also do NOT appear to resolve and become chronic conditions to which there is no known treatment protocol. Tens of thousands (literally) of patients may have died as a result of such therapy and hundreds of thousands more have had their lives destroyed by these drugs. Yet the FDA does nothing to prevent this ongoing carnage and continues to approve additional agents within this class without a moment’s hesitation. In fact, Nalidixic Acid (the "father: of fluoroquinolones), was added to the OEHHA Prop 65 list as a carcinogen May 15, 1998. [Nalidixic Acid, case number 389-08-02, listing mechanism AB, NTP (1989b]

A review of the med watch database (November 1997- November 2001) indicates that the FDA has received no less than 32,000 adverse drug reaction reports with 774 associated fatalities involving Cipro, Floxin and Levaquin. One must keep in mind that the data found within the med watch database consist of LESS than 4% of such events. 96% of the adverse events are NEVER reported to the FDA. A majority of the physicians are not even aware such a program even exists. Less than 5% even bother to make such reports to the FDA. Often times citing that they find it to be a nuisance and an inconvenience. Physicians routinely fail to recognize, treat and report such events. The threat of litigation, should they document an adverse drug reaction, appears to be the primary motivator for failure to take such action. Reviewing the data that was received from the FDA we find the following:

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 in your article, "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 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

As one member of the Quinolone Adverse Drug Reaction Forum so eloquently stated…" Mr. MacCarthy is a damned liar". 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 allowed to be presented in civil suits for malpractice or product liability. The only one who reads this data are researchers 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.

The patient being advised to:

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.
Silver LH, Burkey R, Montgomery D, Gower L, Dickerson J, Crenshaw K, Potts S, Gross R, Schlech B. Safety of ophthalmic Moxifloxacin in the treatment of newborns, infants and toddlers, children and adolescents with bacterial conjunctivitis. ARVO 2003; Abstract 804"

The patient has been betrayed by the FDA, abandoned by the medical community and suffers endlessly as there are NO known treatment protocol when such events occur. Like lepers living outside the city gates their plight has been ignored by the FDA and those responsible for the manufacture, 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.

1962 Nalidixic Acid

1973 Flumequine

1985 Sparfloxacin

1988 Temafloxacin

1989 Grepafloxacin

1993. Trovafloxacin

2000 Factive (originally denied but recently received approval)

1982. Ofloxacin

[Severe peripheral neuropathy, spontaneous tendon rupture, CNS and PNS events, vision damage]

1983 Ciprofloxacin

[Severe peripheral neuropathy, spontaneous tendon rupture, CNS and PNS events, vision damage]

1987 Levofloxacin

[Severe peripheral neuropathy, spontaneous tendon rupture, CNS and PNS events, vision damage]

1994 Moxifloxacin

[Severe peripheral neuropathy, spontaneous tendon rupture, CNS and PNS events, vision damage]

You will find within the attached research CD over 4000 medical articles, etc. that support all that is being stated here. 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.

The members of the various forums found on the Internet, which deals with these issues, wishes Steven Sheller success in his firm’s litigation. Perhaps when these proofs are offered up in open court the media and the FDA will take action. Such events are not rare, the victims noted in your article are not "amongst the first" to suffer such events, their name is legions. Should Mr. Sheller prove to be successful they will then become the "media’s darlings". Should he fail they shall continue to suffer in silence for no one is listening. They have not listened for more than forty years. Perhaps you will be one of the firsts to pay attention to this clear and present danger. Together with the enclosed research CD I have included a number of the articles reference to within this letter for your review.

Sincerely yours

Director

Fluoroquinolone Toxicity Research Foundation

[as of 2-3-2004 I have yet to receive ANY response from the above enumerated media outlets to this letter]